SYNTHESIS METHOD FOR HALOFUGINONE AND HALOFUGINONE INTERMEDIATES
20220371995 · 2022-11-24
Assignee
Inventors
Cpc classification
C07C69/76
CHEMISTRY; METALLURGY
B01J31/0239
PERFORMING OPERATIONS; TRANSPORTING
International classification
B01J31/02
PERFORMING OPERATIONS; TRANSPORTING
Abstract
The present disclosure relates to a synthesis method for halofuginone and its intermediates, with the reaction formulas as shown below, wherein, R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert-butyl:, R.sub.2 is selected from: methyl, ethyl:, R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl. The synthesis method in the present disclosure has many advantages, such as simple process, low cost, few by-products in the synthesis process, simple purification process, no need for column chromatography purification, high product yield, few impurities, high purity, controllable product quality, easy to meet the requirements of ICH declaration, and it can be used for industrial production of halofuginone.
##STR00001##
Claims
1. A synthesis method for the halofuginone intermediate with the structure shown in Formula 9, comprising the following steps: ##STR00053## (a) alkylation reacting diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2; (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3; (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4; (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, and then nitrogen protection reacting with amino protection reagent to produce the compound of Formula 5; (e) Dieckmann condensation reacting the compound of Formula 5 under the action of the base to produce the compound of Formula 6; (f) decarboxylation reacting the compound of Formula 6 in the presence of inorganic salt to produce the compound of Formula 7; (g) reduction reacting the compound of Formula 7 under the action of a reducing agent to produce the compound of Formula 8; (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9; the reaction formulas are as follows: ##STR00054## wherein, R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert -butyl; R.sub.2 is selected from: methyl, ethyl; R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl.
2. The synthesis method for the halofuginone intermediate according to claim 1, wherein the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride and potassium hydride; the catalyst in step (a) is the combination of quaternary ammonium salt and iodide; wherein the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyl triethyl ammonium chloride; and the iodide is any one selected from sodium iodide, potassium iodide and lithium iodide; the solvent used in the alkylation in step (a) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation in step (a) is 20° C.-120° C.; the molar ratio of diethyl acetaminomalonate, 2,3-dichloropropene, catalyst and base in step (a) is 1:(1-2):(0.1-0.5):(1-3); the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5 mol/L-12 mol/L; the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30); the acid in step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid; the solvent for the esterification reaction in step (c) is selected from at least one of ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol and benzyl alcohol; the reaction temperature of the esterification reaction in step (c) is 0° C.-120° C.; the base in step (d) is selected from any one of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene; the 4-halobutyrate in step (d) is selected from any one of 4-bromobutyrate, 4-chlorobutyrate and 4-iodobutyrate; the catalyst in step (d) is a quaternary ammonium salt or a combination of quaternary ammonium salt and iodide, wherein the quaternary ammonium salt is selected from any one of tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide and benzyltriethylammonium chloride; and the iodide is selected from any one of sodium iodide and potassium iodide; the solvent for the alkylation of nitrogen in step (d) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation of nitrogen in step (d) is 20° C.-100° C.; the molar ratio of the compound of Formula 4 in step (d), 4-halobutyrate, base and catalyst is 1:(1-1.5):(1-3):(0.01-0.2); the amine protection reagent in step (d) is selected from any one of benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide and benzyl chloride; the molar ratio of the amine protection reagent in step (d) to the compound of Formula 4 is (0.8-2):1; the reaction temperature of the nitrogen protection reaction in step (d) is 0° C.-100° C.; the base in step (e) is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide and potassium bis-(trimethylsilyl) amide; the solvent for the Dieckmann condensation reaction in step (e) is selected from any one or a combination of two of tetrahydrofuran, toluene, xylene, methyl tert butyl ether, methanol and ethanol; the molar ratio of the base in step (e) to the compound of Formula 5 is (1-3):1; the reaction temperature of the Dieckmann condensation reaction in step (e) is −20° C. to 80° C.; the inorganic salt in step (f) is selected from any one of sodium chloride, lithium chloride, sodium bromide and lithium bromide; the reaction solvent of the decarboxylation in step (f) is a combination of organic solvent and water, and the organic solvent in step (f) is selected from any one of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide; the molar ratio of the inorganic salt in step (f) to the compound of Formula 6 is (1-3):1; the reaction temperature of the decarboxylation reaction in step (f) is 100° C. to 150° C.; the reducing agent in step (g) is selected from any one of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminumhydride, borane, sodium amalgam and lithium tri-tert-butoxyaluminum hydride; the solvent of the reduction reaction in step (g) is ethanol; the molar ratio of the reducing agent in step (g) to the compound of Formula 7 is (1-2):1; and/or the temperature of the reduction reaction in step (g) is 0° C.-10° C.
3. The synthesis method for the halofuginone intermediate according to claim 2, wherein the molar ratio of the quaternary ammonium salt to iodide is 1:(2-6); the volume mass ratio of the organic solvent, water and the compound of Formula 6 in step (f) is (3-5) L:(0.1-1) L:1 kg.
4. The synthesis method for the halofuginone intermediate according to claim 1, wherein R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction under the action of acid to produce the compound of Formula 9; wherein the acid is selected from at least one of hydrochloric acid, hydrobromic acid and sulfuric acid; the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol, and the alcohol is any one of methanol, ethanol and isopropanol.
5. The synthesis method for the halofuginone intermediate according to claim 1, wherein R.sub.1 is ethyl; R.sub.2 is ethyl; and R.sub.3 is benzyloxyformyl.
6. A preparation method of cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity, comprising the following steps: (1) in the first organic solvent, salt formation reacting the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with dibenzoyl tartaric acid or its derivatives to produce a precipitate, and the precipitate is recrystallized to obtain a chiral double salt; (2) in the second organic solvent, the chiral double salt is neutralized to alkalinity with an alkaline aqueous solution to obtain a cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity; the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure as shown in Formula (±)-9; the optically active cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure as shown in Formula (+)-9 or Formula (−)-9; the dibenzoyl tartaric acid or its derivative has the structure as shown in Formula 15 or Formula 16; the chiral double salt has the structure as shown in Formula 14 or Formula 17; the reaction formulas are as follows: ##STR00055## wherein each R is independently selected from: hydrogen or C.sub.1-C.sub.4 alkoxy.
7. The preparation method according to claim 6, wherein the dibenzoyl tartaric acid of Formula 15 or its derivative in step (1) is L-(−)-dibenzoyl tartaric acid or L-(−)-di-p-methoxybenzoyl tartaric acid; and the dibenzoyl tartaric acid of Formula 16 or its derivative is D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-methoxybenzoyl tartaric acid; the molar ratio of the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine to dibenzoyl tartaric acid or its derivatives in step (1) is 1:(1-2); the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (1-10):1; wherein the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1,4-dioxane and acetone; the first organic solvent in step (1) is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, acetone and ethyl acetate; the second organic solvent described in step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane; the temperature of the salt formation reaction is 0° C.-100° C.; and/or the temperature of recrystallization is 0° C.-30° C.; and/or the alkaline aqueous solution in step (2) is any one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, potassium carbonate aqueous solution and sodium carbonate aqueous solution, and neutralization to pH 8-14.
8. The preparation method according to claim 6, wherein the synthesis method of racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine comprises the following steps: (a) alkylation reacting diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2; (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3; (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4; (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, and then nitrogen protection reacting with an amino protection reagent to produce the compound of Formula 5; (e) Dieckmann condensation reacting the compound of Formula 5 under the action of a base to produce the compound of Formula 6; (f) decarboxylation reacting the compound of Formula 6 in the presence of an inorganic salt to produce the compound of Formula 7; (g) reduction reacting the compound of Formula 7 under the action of a reducing agent to produce the compound of Formula 8; (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of the reaction formulas are as follows: ##STR00056## wherein, R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert -butyl; preferably, methyl and ethyl; R.sub.2 is selected from: methyl and ethyl; R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl.
9. The preparation method according to claim 8, wherein the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride and potassium hydride; the catalyst in step (a) is a combination of a quaternary ammonium salt and an iodide; the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyl triethyl ammonium chloride; and the iodide is any one selected from sodium iodide, potassium iodide and lithium iodide; the solvent for the alkylation in step (a) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation in step (a) is 20° C.-120° C.; the molar ratio of diethyl acetaminomalonate, 2,3-dichloropropene, catalyst and base in step (a) is 1:(1-2):(0.1-0.5):(1-3); the acid in step (b) is a hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5 mol/L-12 mol/L; the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30); the acid in step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid; the solvent for the esterification reaction in step (c) is selected from at least one of ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol and benzyl alcohol; the reaction temperature of the esterification reaction in step (c) is 0° C.-120° C.; the base in step (d) is selected from any one of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undeca-7-ene; the 4-halobutyrate in step (d) is selected from any one of 4-bromobutyrate, 4-chlorobutyrate and 4-iodobutyrate; the catalyst in step (d) is a quaternary ammonium salt or a combination of a quaternary ammonium salt and an iodide, wherein the quaternary ammonium salt is selected from any one of tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide and benzyltriethylammonium chloride; and the iodide is selected from any one of sodium iodide and potassium iodide; the solvent for the alkylation of nitrogen in step (d) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation of nitrogen in step (d) is 20° C.-100° C.; the molar ratio of compound of Formula 4, 4-halobutyrate, base and catalyst in step (d) is 1:(1-1.5):(1-3):(0.01-0.2); the amine protection reagent in step (d) is selected from any one of benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide and benzyl chloride; the molar ratio of the amine protection reagent to the compound of Formula 4 in step (d) is (0.8-2):1; the reaction temperature of the nitrogen protection reaction in step (d) is 0° C.-100° C.; the base in step (e) is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide and potassium bis-(trimethylsilyl) amide; the solvent of the Dieckmann condensation reaction in step(e) is selected from any one or a combination of two of tetrahydrofuran, toluene, xylene, methyl tert butyl ether, methanol and ethanol; the molar ratio of the base in step (e) to the compound of Formula 5 is (1-3):1; the reaction temperature of the Dieckmann condensation in step (e) is −20° C. to 80° C.; the inorganic salt in step (f) is selected from any one of sodium chloride, lithium chloride, sodium bromide and lithium bromide; the reaction solvent of decarboxylation is a combination of organic solvent and water, and the organic solvent in step (f) is selected from any one of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide; the molar ratio of the inorganic salt in step (f) to the compound of formula 6 is (1-3):1; the reaction temperature of the decarboxylation reaction in step (f) is 100° C. to 150° C; the reducing agent in step (g) is selected from any one of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminumhydride, borane, sodium amalgam and lithium tri-tert-butoxyaluminum hydride; the solvent of the reduction reaction in step (g) is ethanol; and/or the molar ratio of the reducing agent to the compound of formula 7 in step (g) is (1-2):1; the reduction reaction temperature in step (g) is 0° C.-10° C.
10. The preparation method according to claim 8, wherein R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction under the action of acid to produce the compound of Formula 9, wherein the acid is selected from at least one of hydrochloric acid, hydrobromic acid and sulfuric acid; the solvent for the deprotection reaction in step (h) is acetic acid, water or a combination of water and alcohol, wherein the alcohol is any one of methanol, ethanol and isopropanol.
11. The preparation method according to claim 8, wherein R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
12. A synthesis method of racemic or optically active halofuginone, comprising the following steps: (i) reacting the compound of Formula 9, Formula (+)-9 or Formula (−)-9 with the amino protection reagent under the action of alkali to produce a compound of Formula 10, Formula (+)-10 or Formula (−)-10; (j) reacting the compound of Formula 10, Formula (+)-10 or Formula (−)-10 with olefin halogenation reagent and water, to produce a compound of Formula 11, Formula (+)-11 or Formula (−)-11; (k) reacting the compound of Formula 11, Formula (+)-11 or Formula (−)-11 with the compound of Formula 12 under the action of a base; and then removing the 9-fluorenylmethoxyformyl protecting group on piperidine ring nitrogen, to produce a compound of Formula 13, Formula (+)-13 or Formula (−)-13; (1) isomerization reacting the compound of Formula 13, Formula (+)-13 or Formula (−)-13 to produce a compound of Formula 1, Formula (+)-1 or Formula (−)-1, wherein the compound of Formula 1 is halofuginone, Formula (+)-1 or Formula (−)-1 is halofuginone with optical activity; the reaction formulas are as follows: ##STR00057## ##STR00058## wherein, X is chlorine, bromine or iodine.
13. The synthesis method for the halofuginone according to claim 12, wherein the alkali in step (i) and step (3) is selected from any one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate; the amino protection reagent in step (i) and step (3) is selected from any one of 9-fluorenylmethyl chloroformate, 9-fluorenylmethyl-l-benzotriazolyl carbonate and 9-fluorenylmethyl-n-succinimide carbonate; the solvent in step (i) and step (3) is a combination of organic solvent and water, wherein the organic solvent is any one of 1,4-dioxane and tetrahydrofuran; the molar ratio of the base, the amino protection reagent and the compound of Formula 9, Formula (+)-9 or Formula(−)-9 in step (i) and step (3) is (1-5):(1-2):1; the reaction temperature in step (i) and step (3) is 0° C.-20° C.; the olefin halogenation reagent in step (j) and step (4) is selected from any one of N-bromosuccinimide, N-chlorosuccinimide, n-iodobutanimide, trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dibromo-5,5-dimethylhydantoin; the solvent in step (j) and step (4) is selected from any one of acetonitrile, tetrahydrofuran and 1,4-dioxane; the molar ratio of the olefin halogenation reagent to the compound of Formula 10, Formula (+)-10 or Formula (−)-10 in step (j) and step (4) is 0.9-1.2:1; the reaction temperature in step (j) and step (4) is −10° C. to 35° C.; the bases used in step (k) and step (5) is selected from any one of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide, potassium bis-(trimethylsilyl) amide; the solvent in step (k) and step (5) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the molar ratio of the compound of Formula 12, the base and the compound of Formula 11, Formula (+)-11 or Formula (−)-11 in step (k) and step (5) is 1:(1-2):(0.8-1.2); the reaction temperature in step (k) and step (5) is −10° C. to 25° C.; the reaction for removing the 9-fluorenylmethoxyformyl protecting group from piperidine ring in step (k) and step (5), is carried out under the action of a secondary organic amine or a tertiary organic amine; the reaction temperature for removing the 9-fluorenylmethoxyformyl protecting group from the piperidine ring in step (k) and step (5) is −10° C. to 25° C.; the solvent for the isomerization reaction in steps (1) and step (6) is selected from any one or a combination of water, ethanol, methanol, n-butanol, n-propanol, tert-butanol, N,N-dimethylformamide, tetrahydrofuran and 1,4-dioxane; and/or the reaction temperature of the isomerization reaction in step (1) and step (6) is 50° C.-80° C.
14. The synthesis method for the halofuginone according to claim 13, wherein the secondary organic amine or the tertiary organic amine is diethylamine.
15. The synthesis method for the halofuginone according to claim 12, wherein the preparation method of the compound of Formula (+)-9 or Formula (−)-9 comprises the following steps: (1) in the first organic solvent, salt formation reacting the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with dibenzoyl tartaric acid or its derivatives to produce a precipitate, and the precipitate is recrystallized to obtain a chiral double salt; (2) in the second organic solvent, the chiral double salt is neutralized to alkalinity with an alkaline aqueous solution to obtain a cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity; wherein the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure shown in formula (±)-9; the compound having the structure shown in formula (+)-9 or formula (−)-9 is optically active cis-2-(2-chloropropenyl)-3-hydroxypiperidine; the dibenzoyl tartaric acid or its derivative has the structure shown in Formula 15 or Formula 16; the chiral double salt has the structure shown in Formula 14 or Formula 17; the reaction formulas are as follows: ##STR00059## wherein each R is independently selected from: hydrogen or C.sub.1-C.sub.4 alkoxy.
16. The synthesis method for the halofuginone according to claim 15 wherein the dibenzoyl tartaric acid of Formula 15 or its derivative in step (1) is L-(−)-dibenzoyl tartaric acid or L-(−)-di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of Formula 16 or its derivative is D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-methoxybenzoyl tartaric acid; the molar ratio of racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine to dibenzoyl tartaric acid or its derivatives in step (1) is 1:(1-2); the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (1-10):1; wherein the third organic solvent is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, 1,4-dioxane and acetone; the first organic solvent in step (1) is selected from any one or more of ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, acetone and ethyl acetate; the second organic solvent in step (2) is selected from any one or more of ethyl acetate, dichloromethane and trichloromethane; the temperature of the salt formation reaction is 0° C.-100° C.; the temperature of recrystallization is 0° C.-30° C.; and/or the alkaline aqueous solution in step (2) is any one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, potassium carbonate aqueous solution and sodium carbonate aqueous solution, and neutralization to alkalinity of pH 8-14.
17. The synthesis method for the halofuginone according to claim 12, further comprising the following steps of: (a) alkylation reacting diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2; (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3; (e) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4; (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, and then nitrogen protection reacting with amino protection reagent to produce the compound of Formula 5; (e) Dieckmann condensation reacting the compound of Formula 5 under the action of a base to produce the compound of Formula 6; (f) decarboxylation reacting the compound of Formula 6 in the presence of an inorganic salt to produce the compound of Formula 7; (g) reduction reacting the compound of Formula 7 through the action of a reducing agentto produce the compound of Formula 8; (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9; the reaction formulas are as follows: ##STR00060## wherein, R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert-butyl; R.sub.2 is selected from: methyl, ethyl; R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl.
18. The synthesis method for the halofuginone according to claim 17, wherein the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride and potassium hydride; the catalyst in step (a) is a combination of quaternary ammonium salt and an iodide; wherein the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyl triethyl ammonium chloride, and the iodide is any one selected from sodium iodide, potassium iodide and lithium iodide; the solvent for the alkylation in step (a) is selected from any one of acetonitrile, methanol, ethanol, N N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation in step (a) is 20° C.˜120° C.; the molar ratio of diethyl acetaminomalonate, 2,3-dichloropropene, catalyst and base in step (a) is 1:(1-2):(0.1-0.5):(1-3); the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5 mol/L-12 mol/L; the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30); the acid in step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid; the solvent for the esterification reaction in step (c) is selected from at least one of ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol and benzyl alcohol; the reaction temperature of the esterification reaction in step (c) is 0° C.-120° C.; the base used in step (d) is selected from any one of potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine,1,8-diazabicyclo [5.4.0]undeca-7-ene; the 4-halobutyrate in step (d) is selected from any one of 4-bromobutyrate, 4-chlorobutyrate and 4-iodobutyrate; the catalyst in step (d) is a quaternary ammonium salt or a combination of quaternary ammonium salt and an iodide, wherein the quaternary ammonium salt is selected from any one of tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide and benzyltriethylammonium chloride; and the iodide is selected from any one of sodium iodide and potassium iodide; the solvent in the alkylation of nitrogen in step (d) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane; the reaction temperature of the alkylation of nitrogen in step (d) is 20-100° C.; the molar ratio of the compound of Formula 4 in step (d), 4-halobutyrate, base and catalyst is 1:(1-1.5):(1-3):(0.01-0.2); the amine protection reagent in step (d) is selected from any one of benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide and benzyl chloride; the molar ratio of the amine protection reagent to the compound of Formula 4 in step (d) is (0.8-2):1; the reaction temperature of the nitrogen protection reaction in step (d) is 0° C.-100° C.; the base is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide and potassium bis-(trimethylsilyl) amide; the solvent of the Dieckmann condensation reaction in step (e) is selected from any one or a combination of two of tetrahydrofuran, toluene, xylene, methyl tert butyl ether, methanol and ethanol; the molar ratio of the base to the compound of Formula 5 in step (e) is (1-3):1; the reaction temperature of the Dieckmann condensation in step (e) is −20° C. to 80° C.; the inorganic salt in step (f) is selected from any one of sodium chloride, lithium chloride, sodium bromide and lithium bromide; the reaction solvent of the decarboxylation reaction in step (f) is a combination of organic solvent and water, wherein the organic solvent is selected from any one of dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide; the molar ratio of the inorganic salt to the compound of formula 6 in step (f) is (1-3):1; the reaction temperature of the decarboxylation reaction in step (f) is 100° C. to 150° C.; the reducing agent in step (g) is selected from any one of sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminumhydride, borane, sodium amalgam and lithium tri-tert-butoxyaluminum hydride; the solvent of the reduction reaction in step (g) is ethanol; the molar ratio of the reducing agent to the compound of formula 7 in step (g) is (1-2):1; and/or the temperature of the reduction reaction in step (g) is 0° C.-10° C.
19. The synthesis method for the halofuginone according to claim 17 wherein R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes a nitrogen deprotection reaction under the action of acid to produce a compound of Formula 9, wherein the acid is selected from at least one of hydrochloric acid, hydrobromic acid and sulfuric acid; and the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol; wherein the alcohol is any one of methanol, ethanol and isopropanol.
20. The synthesis method for the halofuginone according to claim 17, wherein R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
Description
DETAILED DESCRIPTION
[0070] The synthesis method for halofuginone and halofuginone intermediate according to the present disclosure is further described below through specific embodiments.
[0071] In the present disclosure, the compounds shown in Formula 8, Formula 9, Formula 10, Formula 11, Formula 13 and Formula 1 are referred as racemic compound when they are not marked with (+) or (−), or marked with (±). The stereoscopic structure in the Formula is relative configuration, not absolute configuration; the compounds in Formula 8, Formula 9, Formula 10, Formula 11, Formula 13 and Formula 1 are referred as chiral compounds with optical activity when marked with (+) or (−), and the stereostructure in the Formula is absolute configuration.
[0072] In one aspect, the present disclosure provides a synthesis method for the halofuginone intermediate having the structure as shown in Formula 9, comprises the following steps:
##STR00019##
[0073] (a) alkylation reacting diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2;
[0074] (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3;
[0075] (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4;
[0076] (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, and then nitrogen protection reacting with amino protection reagent to produce the compound of Formula 5;
[0077] (e) Dieckmann condensation reacting the compound of Formula 5 under the action of the base to produce the compound of Formula 6;
[0078] (f) decarboxylation reacting the compound of Formula 6 in the presence of inorganic salt to produce the compound of Formula 7;
[0079] (g) reduction reacting reacting the compound of Formula 7 to produce the compound of Formula 8;
[0080] (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9;
[0081] the reaction Formulas are as following:
##STR00020##
[0082] wherein,
[0083] R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert-butyl, preferably methyl and ethyl;
[0084] R.sub.2 is selected from: methyl, ethyl;
[0085] R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl, preferably benzyloxyformyl.
[0086] In some embodiments, the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride and potassium hydride.
[0087] In some embodiments, the catalyst in step (a) is the combination of quaternary ammonium salt and iodide; wherein the quaternary ammonium salt was any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyl triethyl ammonium chloride; and the iodide is any one selected from sodium iodide, potassium iodide, and lithium iodide.
[0088] In some embodiments, the molar ratio of the quaternary ammonium salt to the iodide is 1:(2-6).
[0089] In some embodiments, the solvent used in the alkylation in step (a) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.
[0090] In some embodiments, the reaction temperature of the alkylation in step (a) is 20-120° C.
[0091] In some embodiments, the molar ratio of Diethyl acetaminomalonate, 2,3-dichloropropene, catalyst, and base in step (a) is 1:(1-2):(0.1-0.5):(1-3).
[0092] In some embodiments, the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5-12 mol/L.
[0093] In some embodiments, the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30).
[0094] In some embodiments, the acid in step (c) is any one selected from sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid.
[0095] In some embodiments, the solvent for the esterification reaction in step (c) is at least one selected from ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol and benzyl alcohol.
[0096] In some embodiments, the reaction temperature of the esterification reaction in step (c) is 0-120° C.
[0097] In some embodiments, the base used in step (d) is any one selected from potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecan-7-ene.
[0098] In some embodiments, the 4-halobutyrate in step (d) is any one selected from 4-bromobutyrate, 4-chlorobutyrate, and 4-iodobutyrate.
[0099] In some embodiments, the catalyst in step (d) is quaternary ammonium salt or a combination of quaternary ammonium salt and iodide, wherein the quaternary ammonium salt is any one selected from tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide and benzyltriethylammonium chloride, and the iodide is any one selected from sodium iodide and potassium iodide.
[0100] In some embodiments, the solvent in the alkylation of nitrogen in step (d) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.
[0101] In some embodiments, the reaction temperature of the alkylation of nitrogen in step (d) is 20-120° C.
[0102] In some embodiments, in step (d), the molar ratio of compound of Formula 4, 4-halobutyrate, base, and catalyst is 1:(1-1.5):(1-3):(0.01-0.2).
[0103] In some embodiments, the amine protection reagent in step (d) is any one selected from benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide, and benzyl chloride.
[0104] In some embodiments, in step (d), the molar ratio of the amine protection reagent to the compound of Formula 4 is (0.8-2):1.
[0105] In some embodiments, the reaction temperature of the nitrogen protection reaction in step (d) is 0-100° C.
[0106] In some embodiments, the 4-halobutyrate in step (d) is Ethyl 4-bromobutyrate.
[0107] In some embodiments, the amine protection reagent in step (d) is benzyl chloroformate, and the molar ratio of benzyl chloroformate to the compound of Formula 4 is (0.8-1.2):1, and the reaction temperature is 0˜50° C.
[0108] In some embodiments, the base in step (e) is any one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide and potassium bis-(trimethylsilyl) amide.
[0109] In some embodiments, the solvent of Dieckmann condensation reaction in step (e) is any one or combination of two selected from tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol, and ethanol.
[0110] In some embodiments, in step (e), the molar ratio of base to the compound of Formula 5 is (1-3):1.
[0111] In some embodiments, the reaction temperature of the Dieckmann condensation in step (e) is −20 to 80° C.
[0112] In some embodiments, the inorganic salt in step (f) is any one selected from sodium chloride, lithium chloride, sodium bromide, and lithium bromide.
[0113] In some embodiments, the molar ratio of the inorganic salt to the compound of Formula 6 in step (f) is (1-3):1.
[0114] In some embodiments, the reaction solvent of decarboxylation in step (f) is a combination of organic solvent and water, wherein the organic solvent is any one selected from dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylacetamide, and N,N-dimethylformamide.
[0115] In some embodiments, the volume mass ratio of the organic solvent, water and the compound of Formula 6 in step (f) is (3-5):(0.1-1):1.
[0116] In some embodiments, the reaction temperature of decarboxylation reaction in step (f) is 100 to 150° C.
[0117] In some embodiments, the inorganic salt in step (f) is lithium chloride, and the reaction solvent for decarboxylation is the combination of N,N-dimethylformamide and water.
[0118] In some embodiments, the reducing agent in step (g) is any one selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminumhydride, borane, sodium amalgam and lithium tri-tert-butoxyaluminum hydride; preferably sodium borohydride.
[0119] In some embodiments, the solvent of the reduction reaction in step (g) is ethanol.
[0120] In some embodiments, the molar ratio of the reducing agent to the compound of Formula 7 in step (g) is (1-2):1.
[0121] In some embodiments, the reduction reaction temperature in step (g) is 0-10° C.
[0122] In some embodiments, R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction in the presence of acid to produce the compound of Formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid and sulfuric acid; and the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol, and the alcohol is any one from methanol, ethanol and isopropanol.
[0123] In some embodiments, R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
[0124] On the other hand, the present disclosure provides a synthesis method for optically active halofuginone, which is a synthesis method for cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity, comprising the following steps of:
[0125] (1) In the first organic solvent, salt formation reacting the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with dibenzoyl tartaric acid or its derivatives to produce a precipitate, which is recrystallized to obtain a chiral complex salt;
[0126] (2) In the second organic solvent, the chiral complex salt is neutralized to alkalinity with an alkaline aqueous solution to obtain cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity;
[0127] The racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure shown in Formula (±)-9; the optically active cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure shown in Formula (+)-9 or Formula (−)-9; the dibenzoyl tartaric acid or its derivative has the structure shown in Formula 15 or Formula 16; the chiral complex salt has the structure shown in Formula 14 or Formula 17; the reaction equation is as follows:
##STR00021##
wherein each R is independently selected from: hydrogen or C.sub.1-C.sub.4 alkoxy.
[0128] In some embodiments, the dibenzoyl tartaric acid of Formula 15 or its derivative in step (1) is L-(−)-dibenzoyl tartaric acid or L-(−)-di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of Formula 16 or its derivative is D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-methoxybenzoyl tartaric acid.
[0129] In some embodiments, the molar ratio of racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine to dibenzoyl tartaric acid or its derivatives in step (1) is 1:(1-2).
[0130] In some embodiments, the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (1-10):1; the third organic solvent is any one or more selected from ethanol, methanol, isopropanol, acetonitrile, 1,4-dioxane, and acetone.
[0131] In some embodiments, the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (3-5):1, wherein the third organic solvent is acetonitrile.
[0132] In some embodiments, the first organic solvent in step (1) is any one or more selected from ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, acetone, and ethyl acetate.
[0133] In some embodiments, the second organic solvent described in step (2) is any one or more selected from ethyl acetate, dichloromethane, and trichloromethane.
[0134] In some embodiments, the temperature of the salt formation reaction is 0-100° C.
[0135] In some embodiments, the temperature of the salt formation reaction is 20-40° C.
[0136] In some embodiments, the temperature of recrystallization is 0-30° C.
[0137] In some embodiments, the temperature of recrystallization is 15-28° C.
[0138] In some embodiments, the alkaline aqueous solution in step (2) is any one selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, potassium carbonate aqueous solution, and sodium carbonate aqueous solution, and the neutralization to alkalinity is to pH 8-14.
[0139] In some embodiments, the synthesis method for racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity comprises the following steps:
[0140] (a) alkylation reacting Diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2;
[0141] (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3;
[0142] (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4;
[0143] (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, then nitrogen protection reacting with an amino protection reagent to produce the compound of Formula 5;
[0144] (e) Dieckmann condensation reacting the compound of Formula 5 under the action of a base to produce the compound of Formula 6;
[0145] (f) decarboxylation reacting the compound of Formula 6 in the presence of the inorganic salt to produce the compound of Formula 7;
[0146] (g) reduction reacting the compound of Formula 7 to produce the compound of Formula 8;
[0147] (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9; the reaction formulas are as follows:
##STR00022##
[0148] R.sub.1 is selected from: methyL ethyl, propyl, isopropyl or tort-butyl: preferably, methyl and ethyl;
[0149] R.sub.2 is selected from: methyl, ethyl;
[0150] R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl, preferably, benzyloxyformyl.
[0151] In some embodiments, the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, and potassium hydride.
[0152] In some embodiments, the catalyst in step (a) is the combination of a quaternary ammonium salt and an iodide; wherein the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide, and Benzyl triethyl ammonium chloride, and the iodide is any one selected from sodium iodide, potassium iodide, and lithium iodide.
[0153] In some embodiments, the molar ratio of the quaternary ammonium salt to iodide is 1:(2-6).
[0154] In some embodiments, the solvent used in the alkylation in step (a) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.
[0155] In some embodiments, the reaction temperature of the alkylation in step (a) is 20-120° C. .
[0156] In some embodiments, the molar ratio of Diethyl acetaminomalonate, 2,3-dichloropropene, catalyst and base in step (a) is 1:(1-2):0.1-0.5):(1-3).
[0157] In some embodiments, the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5 mol/L-12 mol/L.
[0158] In some embodiments, the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30).
[0159] In some embodiments, the acid in step (c) is any one selected from sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid.
[0160] In some embodiments, the solvent for the esterification reaction in step (c) is at least one selected from ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol, and benzyl alcohol.
[0161] In some embodiments, the reaction temperature of the esterification reaction in step (c) is 0-120° C.
[0162] In some embodiments, the base in step (d) is any one selected from potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, and 1,8-diazabicyclo[5.4.0]undecan-7-ene.
[0163] In some embodiments, the 4-halobutyrate in step (d) is any one selected from 4-bromobutyrate, 4-chlorobutyrate, and 4-iodobutyrate.
[0164] In some embodiments, the catalyst in step (d) is a quaternary ammonium salt or a combination of quaternary ammonium salt and iodide, wherein the quaternary ammonium salt is any one selected from tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide, and Benzyltriethylammonium chloride, and the iodide is any one selected from sodium iodide and potassium iodide.
[0165] In some embodiments, the solvent in the alkylation of nitrogen in step (d) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.
[0166] In some embodiments, the reaction temperature of the alkylation of nitrogen in step (d) is 20-120° C.
[0167] In some embodiments, the molar ratio of compound of Formula 4, 4-halobutyrate, base and catalyst in step (d) is 1:(1-1.5):(1-3):(0.01-0.2).
[0168] In some embodiments, the amine protection reagent in step (d) is any one selected from benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide, and benzyl chloride.
[0169] In some embodiments, the molar ratio of the amine protection reagent in step (d) to the compound of Formula 4 is (0.8-2):1.
[0170] In some embodiments, the reaction temperature of the nitrogen protection reaction in step (d) is 0-100° C.
[0171] In some embodiments, the 4-halobutyrate used in step (d) is 4-bromobutyrate.
[0172] In some embodiments, the amine protection reagent in step (d) is benzyl chloroformate, and the molar ratio of benzyl chloroformate to the compound of Formula 4 is (0.8˜1.2):1, and the reaction temperature is 0˜50° C.
[0173] In some embodiments, the base in step (e) is selected from any one of sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide, and potassium bis-(trimethylsilyl) amide.
[0174] In some embodiments, the solvent of Dieckmann condensation reaction in step (e) is any one or a combination of two selected from tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol, and ethanol.
[0175] In some embodiments, the molar ratio of the base to the compound of Formula 5 in step (e) is (1-3):1.
[0176] In some embodiments, the reaction temperature of the Dieckmann condensation in step (e) is −20 to 80° C.
[0177] In some embodiments, the inorganic salt in step (f) is any one selected from sodium chloride, lithium chloride, sodium bromide, and lithium bromide.
[0178] In some embodiments, the molar ratio of the inorganic salt to the compound of Formula 6 in step (f) is (1-3):1.
[0179] In some embodiments, the reaction solvent of decarboxylation in step (f) is a combination of organic solvent and water, wherein the organic solvent is any one selected from dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-Dimethylacetamide, N,N-dimethylformamide.
[0180] In some embodiments, the volume mass ratio of the organic solvent, water and the compound of Formula 6 in step (f) is (3-5):(0.1-1):1.
[0181] In some embodiments, the reaction temperature of decarboxylation reaction in step (f) is 100 to 150° C.
[0182] In some embodiments, the inorganic salt in step (f) is lithium chloride, and the reaction solvent for decarboxylation is the combination of N,N-dimethylformamide and water.
[0183] In some embodiments, the reducing agent in step (g) is any one selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminumhydride, borane, sodium amalgam, and lithium tri-tert-butoxyaluminum hydride, preferably sodium borohydride.
[0184] In some embodiments, the solvent of the reduction reaction in step (g) is ethanol.
[0185] In some embodiments, the molar ratio of the reducing agent to the compound of Formula 7 in step (g) is (1-2):1.
[0186] In some embodiments, the reduction reaction temperature in step (g) is 0° C.-10° C. .
[0187] In some embodiments, R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction under the action of acid to produce the compound of Formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid, and sulfuric acid; the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol, and the alcohol is any one selected from methanol, ethanol, and isopropanol.
[0188] In some embodiments, R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
[0189] In the third aspect, the present disclosure also provides a synthesis method for racemic halofuginone with the structure shown in Formula 1, comprising the following steps:
##STR00023##
[0190] (i) reacting the compound of Formula 9 with the amino protection reagent under the action of alkali to produce a compound of Formula 10;
[0191] (j) reacting the compound of Formula 10 with olefin halogenation reagent and water, to produce a compound of Formula 11;
[0192] (k) reacting the compound of Formula 11 with the compound of Formula 12 under the action of base, then removing the 9-fluorenylmethoxyformyl protecting group on piperidine ring nitrogen, to produce a compound of Formula 13;
[0193] (l) isomerization reacting the compound of Formula 13 to produce a compound of Formula 1.
##STR00024##
[0194] wherein, X is chlorine, bromine or iodine, preferably bromine.
[0195] In some embodiments, the base in step (i) is any one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
[0196] In some embodiments, the amino protection reagent described in step (i) is any one selected from 9-fluorenylmethyl chloroformate, 9-fluorenylmethyl-1-benzotriazolyl carbonate, and 9-fluorenylmethyl-n-succinimide carbonate.
[0197] In some embodiments, the solvent in step (i) is a combination of organic solvent and water, wherein the organic solvent is any one selected from 1,4-dioxane and tetrahydrofuran.
[0198] In some embodiments, the molar ratio of the base, the amino protection reagent and the compound of Formula 9 in step (i) is (1-5):(1-2):1.
[0199] In some embodiments, the reaction temperature in step (i) is 0-20° C.
[0200] In some embodiments, the olefin halogenation reagent in step (j) is any one selected from N-bromosuccinimide, N-chlorosuccinimide, n-iodobutanimide, trichloroisocyanuric acid, 1,3-dichloro-5,5-dimethylhydantoin, and 1,3-dibromo-5,5-dimethylhydantoin.
[0201] In some embodiments, the solvent in step (j) is any one selected from acetonitrile, tetrahydrofuran, and 1,4-dioxane.
[0202] In some embodiments, the molar ratio of the alkene halogenation reagent in step (j) to the compound of Formula 10 is (0.9-1.2):1.
[0203] In some embodiments, the reaction temperature in step (j) is −10 to 35° C.
[0204] In some embodiments, the olefin halogenation reagent in step (j) is N-bromosuccinimide; wherein the molar ratio of the olefin halogenation reagent to the compound of formula 10 is (0.9-1):1; and the reaction solvent is acetonitrile; and the reaction temperature is −10° C. to 10° C.
[0205] In some embodiments, the base in step (k) is any one selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide, and potassium bis-(trimethylsilyl) amide.
[0206] In some embodiments, the solvent in step (k) is any one selected from acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.
[0207] In some embodiments, the molar ratio of the compound of Formula 12 in step (k) and the compound of Formula 11, and the base is 1:(1-2):(0.8-1.2).
[0208] In some embodiments, the reaction temperature in step (k) is −10° C. to 25° C.
[0209] In some embodiments, the base used in step (k) is potassium hydroxide. The reaction solvent is N,N-dimethylacetamide. The molar ratio of the compound of Formula 12 and the base, the compound of Formula 11 is 1:(1˜1.1):(0.8˜1.2), and the reaction temperature in step (k) is ˜10 to 25° C.
[0210] In some embodiments, the reaction for removing the 9-fluorenylmethoxyformyl protecting group from piperidine ring in step (k), is carried out under the action of secondary organic amine or tertiary organic amine, preferably diethylamine.
[0211] In some embodiments, the reaction temperature for removing the 9-fluorenylmethoxyformyl protecting group from the piperidine ring in step (k) is ˜10° C. to 25° C. .
[0212] In some embodiments, the solvent for the isomerization reaction in steps (1) is any one or a combination selected from water, ethanol, methanol, n-butanol, n-propanol, tert- butanol, N,N-dimethylformamide, tetrahydrofuran and 1,4-dioxane.
[0213] In some embodiments, the reaction temperature of the isomerization reaction in step (1) is 50-80° C.
[0214] In some embodiments, the synthesis method of the said halofuginone comprises the following steps:
[0215] (a) alkylation reacting diethyl acetaminomalonate with 2,3-dichloropropene under the action of a base and a catalyst to form the compound of Formula 2;
[0216] (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3;
[0217] (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4;
[0218] (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of a base and a catalyst, and then nitrogen protection reacting with amino protection reagent to produce the compound of Formula 5;
[0219] (e) Dieckmann condensation reacting the compound of Formula 5 under the action of the base to produce the compound of Formula 6;
[0220] (f) decarboxylation reacting the compound of Formula 6 in the presence of inorganic salt to produce the compound of Formula 7;
[0221] (g) reduction reacting the compound of Formula 7 under the action of a reducing agent to produce the compound of Formula 8;
[0222] (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9;
[0223] the reaction formulas are as follows:
##STR00025##
[0224] wherein,
[0225] R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert-butyl; preferably, methyl and ethyl;
[0226] R.sub.2 is selected from: methyl, ethyl;
[0227] R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert-butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl, preferably, benzyloxyformyl.
[0228] In some embodiments, the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride and potassium hydride.
[0229] In some embodiments, the catalyst in step (a) is the combination of quaternary ammonium salt and iodide; wherein the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide and benzyl triethyl ammonium chloride; and the iodide is any one selected from sodium iodide, potassium iodide and lithium iodide.
[0230] In some embodiments, the molar ratio of the quaternary ammonium salt to the iodide is 1:(2-6).
[0231] In some embodiments, the solvent used in the alkylation in step (a) is selected from any one of acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.
[0232] In some embodiments, the reaction temperature of the alkylation in step (a) is 20-120° C. .
[0233] In some embodiments, the molar ratio of diethyl acetaminomalonate, 2,3-dichloropropene, catalyst and base in step (a) is 1:(1-2):(0.1-0.5):(1-3).
[0234] In some embodiments, the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5 mol/L-12 mol/L.
[0235] In some embodiments, the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30).
[0236] In some embodiments, the acid in step (c) is selected from any one of sulfuric acid, phosphoric acid, hydrochloric acid and p-toluenesulfonic acid.
[0237] In some embodiments, the solvent for the esterification reaction in step (c) is at least one selected from ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol and benzyl alcohol.
[0238] In some embodiments, the reaction temperature of the esterification reaction in step (c) is 0-120° C.
[0239] In some embodiments, the base used in step (d) is any one selected from potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0]undeca-7-ene.
[0240] In some embodiments, the 4-halobutyrate used in step (d) is any one selected from 4-bromobutyrate, 4-chlorobutyrate and 4-iodobutyrate.
[0241] In some embodiments, the catalyst used in step (d) is a quaternary ammonium salt or a combination of quaternary ammonium salt and iodide, wherein the quaternary ammonium salt is any one selected from tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide and benzyltriethylammonium chloride, and the iodide is selected any one from sodium iodide and potassium iodide.
[0242] In some embodiments, the solvent used in the alkylation of nitrogen in step (d) is selected any one from acetonitrile, methanol, ethanol, N,N-dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane and 1,2-dichloroethane.
[0243] In some embodiments, the reaction temperature of the alkylation of nitrogen in step (d) is 20-120° C.
[0244] In some embodiments, the molar ratio of compound of Formula 4, 4-halobutyrate, base and catalyst in step (d) is 1:(1-1.5):(1-3):(0.01-0.2).
[0245] In some embodiments, the amine protection reagent in step (d) is any one selected from benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide and benzyl chloride.
[0246] In some embodiments, the molar ratio of the amine protection reagent in step (d) to the compound of Formula 4 is (0.8-2):1.
[0247] In some embodiments, the reaction temperature of the nitrogen protection reaction in step (d) is 0-100° C.
[0248] In some embodiments, the 4-halobutyrate in step (d) is Ethyl 4-bromobutyrate.
[0249] In some embodiments, the amine protection reagent in step (d) is benzyl chloroformate, and the molar ratio of benzyl chloroformate to the compound of Formula 4 is (0.8˜1.2):1, and the reaction temperature is 0˜50° C.
[0250] In some embodiments, the base in step (e) is any one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide and potassium bis-(trimethylsilyl) amide.
[0251] In some embodiments, the solvent of Dieckmann condensation reaction in step (e) is any one or combination of two selected from tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol and ethanol.
[0252] In some embodiments, the molar ratio of the base to the compound of Formula 5 in step (e) is (1-3):1.
[0253] In some embodiments, the reaction temperature of the Dieckmann condensation in step (e) is −20° C. to 80° C.
[0254] In some embodiments, the inorganic salt in step (f) is any one selected from sodium chloride, lithium chloride, sodium bromide and lithium bromide.
[0255] In some embodiments, the molar ratio of the inorganic salt to the compound of formula 6 in step (f) is (1-3):1.
[0256] In some embodiments, the reaction solvent of decarboxylation in step (f) is a combination of organic solvent and water, wherein the organic solvent is any one selected from dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-dimethylacetamide, N,N-dimethylformamide.
[0257] In some embodiments, the volume mass ratio of the organic solvent, water and the compound of Formula 6 in step (f) is (3-5) L:(0.1-1) L:1 kg.
[0258] In some embodiments, the reaction temperature of decarboxylation reaction in step (f) is 100° C. to 150° C.
[0259] In some embodiments, the inorganic salt in step (f) is lithium chloride, the reaction solvent for decarboxylation is a combination of N,N-dimethylformamide and water.
[0260] In some embodiments, the reducing agent in step (g) is any one selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy) aluminumhydride, borane, sodium amalgam and lithium tri-tert-butoxy aluminum hydride.
[0261] In some embodiments, the solvent of the reduction reaction in step (g) is ethanol.
[0262] In some embodiments, the molar ratio of the reducing agent to the compound of formula 7 in step (g) is (1-2):1.
[0263] In some embodiments, the reduction reaction temperature in step (g) is 0° C.-10° C.
[0264] In some embodiments, R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction under the action of acid to produce the compound of Formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid and sulfuric acid; the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol, and the alcohol is any one selected from methanol, ethanol and isopropanol.
[0265] In some embodiments, R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
[0266] In the fourth aspect, the present disclosure also provides a synthesis method for halofuginone salt, included the following steps: synthesizing halofuginone by the synthesis method of halofuginone descried above, then reacting the halofuginone with acid to obtain the halofuginone salt.
[0267] In some embodiments, the acid is hydrobromic acid, hydrochloric acid or lactic acid.
[0268] Understandably, in the above method for synthesizing halofuginone and halofuginone salt, the reaction products obtained from any step through step (a) to (g) and (1) to (6) can be used as raw materials to directly carry out subsequent reactions to synthesize halofuginone salt. For example, a compound of Formula 9 can be used as a raw material to synthesize halofuginone and halofuginone salts through steps (i) to (l) as described above, or a compound of Formula 3 can be used as a raw material to synthesize halofuginone and halofuginone salt through steps (c) to (l) as described above.
[0269] In the fifth aspect, the present disclosure also provides a synthesis method for halofuginone with optical activity, comprising the following steps:
[0270] (3) reacting the optically active cis-2-(2-chloropropenyl)-3-hydroxypiperidin with an amino protecting agent in the presence of a base to form optically active compounds of Formula (+)-10 or Formula (−)-10;
[0271] (4) reacting the optically active compound of Formula (+)-10 or Formula (−)-10 with olefin bromination reagent and water to form optically active compound of Formula (+)-11 or Formula (−)-11;
[0272] (5) reacting the optically active compound of Formula (+)-11 or Formula (−)-11 with the compound of Formula F2 under the action of a base, and then the 9-fluorenylmethoxyformyl protecting group on the piperidine ring nitrogen is removed to form the optically active compound of Formula (+)-13 or Formula (−)-13;
[0273] (6) The optically active compound of Formula (+)-13 or Formula (−)-13 is isomerized to produce the optically active halofuginone.
[0274] the optically active halofuginone has the structure shown in Formula (+)-1 or Formula (−)-1, and the reaction equation is as follows:
##STR00026## ##STR00027##
[0275] In some embodiments, the alkali in step (3) is any one selected from sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate.
[0276] In some embodiments, the amino protection reagent described in step (3) is any one selected from 9-fluorenylmethyl chloroformate, 9-fluorenylmethyl-1-benzotriazolyl carbonate, and 9-fluorenylmethyl-n-succinimide carbonate.
[0277] In some embodiments, the solvent in step (3) is a combination of organic solvent and water, and the organic solvent is either 1,4-dioxane or tetrahydrofuran.
[0278] In some embodiments, the molar ratio of the base, the amino protection reagent and cis-2-(2-chloropropenyl)-3-hydroxypiperidin in step (3) is (1-5):(1-2):1.
[0279] In some embodiments, the reaction temperature in step (3) is 0-20° C.
[0280] In some embodiments, the olefin halogenation reagent in step (4) is any one selected from N-bromosuccinimide and 1,3-dibromo-5,5-dimethylhydantoin.
[0281] In some embodiments, the solvent in step (4) is any one selected from acetonitrile, tetrahydrofuran and 1,4-dioxane.
[0282] In some embodiments, the molar ratio of the alkene halogenation reagent in step (4) to the compound of Formula (+)-10 or Formula (−)-10 is (0.9-1.2):1.
[0283] In some embodiments, the reaction temperature in step (4) is −10° C. to 35° C. .
[0284] In some embodiments, the reaction temperature is −10° C. to 10° C. .
[0285] In some embodiments, the base in step (5) is any one selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, cesium carbonate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, diisopropyl amino lithium, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide, and potassium. bis-(trimethylsilyl) amide
[0286] In some embodiments, the solvent in step (5) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.
[0287] In some embodiments, the molar ratio of the compound of Formula (+)-11 or Formula (−)-11 in step (5), the compound of Formula 12, and the base is (0.8-1.2):1:(1-2).
[0288] In some embodiments, the reaction temperature in step (5) is −10° C. to 25° C.
[0289] In some embodiments, the reaction for removing the 9-fluorenylmethoxyformyl protecting group from piperidine ring in step (5) is carried out under the action of secondary organic amine or tert-iary organic amine.
[0290] In some embodiments, the reaction temperature for removing the 9-fluorenylmethoxyformyl protecting group from the piperidine ring in step (5) is −10° C. to 25° C.
[0291] In some embodiments, the secondary organic amine or the tertiary organic amine is diethylamine.
[0292] In some embodiments, the solvent for the isomerization reaction in steps (6) is any one or a combination of two selected from water, ethanol, methanol, n-butanol, n-propanol, tert-butanol, N,N-dimethylformamide, tetrahydrofuran, and 1,4-dioxane.
[0293] In some embodiments, the reaction temperature of the isomerization reaction in step (6) is 50-80° C.
[0294] In some embodiments, the synthesis method for the optically active halofuginone also includes the step of preparing cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity, comprising the following steps:
[0295] (1) In the first organic solvent, salt formation reacting the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with dibenzoyl tartaric acid or its derivatives to produce a precipitate, which is recrystallized to obtain a chiral complex salt;
[0296] (2) In the second organic solvent, the chiral complex salt is neutralized to alkalinity with an alkaline aqueous solution to obtain cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity;
[0297] The racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure shown in Formula (±)-9; the optically active cis-2-(2-chloropropenyl)-3-hydroxypiperidine has the structure shown in Formula (+)-9 or Formula (−)-9; the dibenzoyl tartaric acid or its derivative has the structure shown in Formula 15 or Formula 16; the chiral complex salt has the structure shown in Formula 14 or Formula 17; the reaction equation is as follows:
##STR00028##
[0298] wherein each R is independently selected from: hydrogen or C.sub.1-C.sub.4 alkoxy.
[0299] In some embodiments, the dibenzoyl tartaric acid of Formula 15 or its derivative in step (1) is L-(−)-dibenzoyl tartaric acid or L-(−)-di-p-methoxybenzoyl tartaric acid, and the dibenzoyl tartaric acid of Formula 16 or its derivative is D-(+)-dibenzoyl tartaric acid or D-(+)-di-p-methoxybenzoyl tartaric acid.
[0300] In some embodiments, the molar ratio of racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine to dibenzoyl tartaric acid or its derivatives in step (1) is 1:(1-2).
[0301] In some embodiments, the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (1-10):1; the third organic solvent is any one or more selected from ethanol, methanol, isopropanol, acetonitrile, 1,4-dioxane, and acetone.
[0302] In some embodiments, the recrystallization is carried out in a mixed solvent of a third organic solvent and water with a volume ratio of (3-5):1, wherein the third organic solvent is acetonitrile.
[0303] In some embodiments, the first organic solvent in step (1) is any one or more selected from ethanol, methanol, isopropanol, acetonitrile, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, acetone, and ethyl acetate.
[0304] In some embodiments, the second organic solvent described in step (2) is any one or more selected from ethyl acetate, dichloromethane, and trichloromethane.
[0305] In some embodiments, the temperature of the salt formation reaction is 0-100° C.
[0306] In some embodiments, the temperature of the salt formation reaction is 20-40° C.
[0307] In some embodiments, the temperature of recrystallization is 0-30° C.
[0308] In some embodiments, the temperature of recrystallization is 15-28° C.
[0309] In some embodiments, the alkaline aqueous solution in step (2) is any one selected from sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, lithium hydroxide aqueous solution, potassium carbonate aqueous solution, and sodium carbonate aqueous solution, and the neutralization to alkalinity is pH 8-14.
[0310] In some embodiments, the synthesis method for racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine with optical activity comprises the following steps:
[0311] (a) alkylation reacting Diethyl acetaminomalonate with 2,3-dichloropropene under the action of base and catalyst to form the compound of Formula 2;
[0312] (b) decarboxylation reacting the compound of Formula 2 in the presence of an acid catalyst to produce the compound of Formula 3;
[0313] (c) esterification reacting the compound of Formula 3 in the presence of an acid catalyst to produce the compound of Formula 4;
[0314] (d) nitrogen alkylation reacting the compound of Formula 4 with 4-halogenated butyrate under the action of abase and a catalyst, then nitrogen protection reacting with an amino protection reagent to produce the compound of Formula 5;
[0315] (e) Dieckmann condensation reacting the compound of Formula 5 under the action of a base to produce the compound of Formula 6.
[0316] (f) decarboxylation reacting the compound of Formula 6 in the presence of the inorganic salt to produce the compound of Formula 7.
[0317] (g) reduction reacting the compound of Formula 7 to produce the compound of Formula 8;
[0318] (h) nitrogen deprotection reacting the compound of Formula 8 to produce the compound of Formula 9.
[0319] the reaction formulas are as follows:
##STR00029##
[0320] wherein,
[0321] R.sub.1 is selected from: methyl, ethyl, propyl, isopropyl or tert-butyl; preferably, methyl and ethyl;
[0322] R.sub.2 is selected from: methyl, ethyl;
[0323] R.sub.3 is selected from: methoxyformyl, ethoxyformyl, tert--butoxyformyl, benzyloxyformyl, trichloroethoxyformyl or benzyl, preferably, benzyloxyformyl.
[0324] In some embodiments, the base in step (a) is at least one selected from potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, and potassium hydride.
[0325] In some embodiments, the catalyst in step (a) is the combination of a quaternary ammonium salt and an iodide; wherein the quaternary ammonium salt is any one selected from tetrabutylammonium bromide, tetraethylammonium bromide, tetrabutylammonium iodide, and Benzyl triethyl ammonium chloride, and the iodide is any one selected from sodium iodide, potassium iodide, and lithium iodide.
[0326] In some embodiments, the molar ratio of the quaternary ammonium salt to iodide is 1:(2-6).
[0327] In some embodiments, the solvent used in the alkylation in step (a) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.
[0328] In some embodiments, he reaction temperature of the alkylation in step (a) is 20˜120° C.
[0329] In some embodiments, the molar ratio of Diethyl acetaminomalonate, 2,3-dichloropropene, catalyst, and base in step (a) is 1:(1-2):(0.1-0.5):(1-3).
[0330] In some embodiments, the acid in step (b) is hydrogen chloride aqueous solution, and the concentration of the hydrogen chloride aqueous solution is 5-12 mol/L.
[0331] In some embodiments, the molar ratio of the compound of Formula 2 to hydrogen chloride is 1:(5-30).
[0332] In some embodiments, the acid in step (c) is any one selected from sulfuric acid, phosphoric acid, hydrochloric acid, and p-toluenesulfonic acid.
[0333] In some embodiments, the solvent for the esterification reaction in step (c) is at least one selected from ethanol, diethyl carbonate, dimethyl carbonate, methanol, propanol, and benzyl alcohol.
[0334] In some embodiments, the reaction temperature of the esterification reaction in step (c) is 0-120° C.
[0335] In some embodiments, the base in step(d) is any one selected from potassium carbonate, potassium bicarbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undecan-7-ene.
[0336] In some embodiments, the 4-halobutyrate in step (d) is any one selected from 4-bromobutyrate, 4-chlorobutyrate, and 4-iodobutyrate.
[0337] In some embodiments, the catalyst in step (d) is quaternary ammonium salt or a combination of quaternary ammonium salt and iodide, wherein the quaternary ammonium salt is any one selected from tetrabutyl ammonium bromide, tetraethyl ammonium bromide, tetrabutyl ammonium iodide, and Benzyltriethylammonium chloride, and the iodide is any one selected from sodium iodide and potassium iodide.
[0338] In some embodiments, the solvent in the alkylation of nitrogen in step (d) is any one selected from acetonitrile, methanol, ethanol, N,N-Dimethylacetamide, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,4-dioxane, toluene, dichloromethane, and 1,2-dichloroethane.
[0339] In some embodiments, the reaction temperature of the alkylation of nitrogen in step (d) is 20-100° C.
[0340] In some embodiments, the molar ratio of compound of Formula 4, 4-halobutyrate, base, and catalyst in step (d) is 1:(1-1.5):(1-3):(0.01-0.2).
[0341] In some embodiments, the amine protection reagent in step (d) is any one selected from benzyl chloroformate, di-tert-butyl dicarbonate, methyl chloroformate, ethyl chloroformate, trichloroethyl chloroformate, benzyl bromide, and benzyl chloride.
[0342] In some embodiments, the molar ratio of the amine protection reagent to the compound of Formula 4 in step (d) is (0.8-2):1.
[0343] In some embodiments, the reaction temperature of the nitrogen protection reaction in step (d) is 0-100° C.
[0344] In some embodiments, the 4-halobutyrate in step (d) is ethyl 4-bromobutyrate.
[0345] In some embodiments, the amine protection reagent in step (d) is benzyl chloroformate, and the molar ratio of benzyl chloroformate to the compound of Formula 4 is (0.8-1.2):1, and the reaction temperature is 0-50° C.
[0346] In some embodiments, the base in step (e) is any one selected from sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, lithium hydride, lithium diisopropylamide, sodium bis-(trimethylsilyl) amide, lithium bis-(trimethylsilyl) amide, and potassium bis-(trimethylsilyl) amide.
[0347] In some embodiments, the solvent of Dieckmann condensation reaction in step (e) is any one or a combination of two selected from tetrahydrofuran, toluene, xylene, methyl tert-butyl ether, methanol, and ethanol.
[0348] In some embodiments, the molar ratio of the base in step (e) to the compound of Formula 5 is (1-3):1.
[0349] In some embodiments, the reaction temperature of the Dieckmann condensation in step (e) is −20 to 80° C.
[0350] In some embodiments, the inorganic salt in step (f) is any one selected from sodium chloride, lithium chloride, sodium bromide, and lithium bromide.
[0351] In some embodiments, the molar ratio of the inorganic salt to the compound of Formula 6 in step (f) is (1-3):1.
[0352] In some embodiments, the reaction solvent of decarboxylation in step (f) is a combination of organic solvent and water, wherein the organic solvent is any one selected from dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, N,N-Dimethylacetamide, and N,N-dimethylformamide.
[0353] In some embodiments, wherein the volume mass ratio of the organic solvent, water and the compound of Formula 6 in step (f) is (3-5):(0.1-1):1.
[0354] In some embodiments, the reaction temperature of decarboxylation reaction in step (0 is 100 to 150° C.
[0355] In some embodiments, the inorganic salt in step (f) is lithium chloride, the reaction solvent for decarboxylation is a combination of N,N-dimethylformamide and water.
[0356] In some embodiments, the reducing agent in step (g) is any one selected from sodium borohydride, potassium borohydride, lithium borohydride, lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminumhydride, borane, sodium amalgam, and lithium tri-tert-butoxyaluminum hydride.
[0357] In some embodiments, the solvent of the reduction reaction in step (g) is ethanol.
[0358] In some embodiments, the molar ratio of the reducing agent to the compound of Formula 7 in step (g) is (1-2):1.
[0359] In some embodiments, the reduction reaction temperature in step (g) is 0-10° C.
[0360] In some embodiments, R.sub.3 is benzyloxyformyl, and the compound of Formula 8 undergoes nitrogen deprotection reaction under the action of acid to produce the compound of Formula 9, wherein the acid is at least one selected from hydrochloric acid, hydrobromic acid, and sulfuric acid; the solvent for the deprotection reaction in step (h) is acetic acid, water or the combination of water and alcohol, and the alcohol is any one selected from methanol, ethanol, and isopropanol.
[0361] In some embodiments, R.sub.1 is ethyl; R.sub.2 is ethyl; R.sub.3 is benzyloxyformyl.
[0362] In the sixth aspect, the present disclosure also provides a synthesis method for optically active halofuginone salt, comprising the following steps: synthesizing optically active halofuginone by the synthesis method for halofuginone descried above, then reacting the halofuginone with acid to obtain the optically active halofuginone salt.
[0363] In some embodiments, the acid is hydrobromic acid, hydrochloric acid or lactic acid.
[0364] Understandably, in the above method for synthesizing optically active halofuginone and its salt, the reaction products obtained from any step through step (a) to (g) and (1) to (6) can be used as raw materials to directly carry out subsequent reactions to synthesize optically active halofuginone. For example, the racemic cis-2-(2-chloropropenyl)-3-hydroxypiperidine can be used as the raw material to synthesize the optically active halofuginone through step (1) to (6) as described above, or the compound of Formula 3 can be used as the raw material to synthesize the optically active halofuginone through step (c) to (g) and (1) to (6) as described above.
EMBODIMENTS
Embodiment 1 Synthesis of Racemic Halofuginone
Preparation of Intermediate Compound of Formula 4 (R.SUB.1.=Et)
[0365] ##STR00030##
[0366] Step (a): At room temperature, diethyl acetylaminomalonic acid (5.00 kg, 23.02 mol), anhydrous potassium carbonate (6.35 kg, 46.04 mol), potassium iodide (0.76 kg, 4.6 mol), tetrabutylammonium bromide (0.37 kg, 1.15 mol) and acetonitrile (25 L) were added into a 50 L reaction kettle. After being stirred for 20 minutes, 2,3-dichloropropene (3.07 kg, 27.62 mol) was added. The reaction was carried out at 85-90° C. and monitored by HPLC. After the end of the reaction, the reaction mixture was cooled to a temperature within 25° C., then added dropwise with diluted hydrochloric acid to neutralize the reaction mixture to pH 7-7.5. The reaction solution was left to separation, then the organic layer was concentrated under reduced pressure at 50° C. The concentrated residue was added with ethanol-water (1:10, 20 L) and stirred for 1 hour for crystallization. After vacuum filtration, the filter cake was washed with water to obtain compound of Formula 2, which was a yellow solid (wet weight 10.50 kg), which was not dried and directly put into the next reaction.
[0367] .sup.1H NMR (500 MHz, Chloroform-d) δ 5.28 (d, J=1.2 Hz, 1H), 5.17 (d, J=1.1 Hz, 1H), 4.26 (qd, J=7.1, 2.4 Hz, 4H), 3.47 (s, 2H), 2.03 (s, 3H), 1.55-1.51 (m, 1H), 1.27 (t, J=7.1 Hz, 6H).
[0368] .sup.13C NMR (126 MHz, Chloroform-d) δ 169.3, 167.3, 136.5, 117.8, 65.2, 63.0, 41.6, 23.0, 14.0.
[0369] HRMS (m/z): calc. for C.sub.12H.sub.19ClNO.sub.5 [M+H].sup.+=292.0952; found, 292.0954
[0370] Step (b): At room temperature, the compound of Formula 2 (wet weight 10.5 kg, 23.02 mol) and hydrochloric acid solution (6 mol/L, 57.5 l, 345.27 mol) were added into a 100 L reaction kettle, stirred and heated to 100° C. for reflux reaction, and the reaction was monitored by TLC. After the end of the reaction, activated carbon (650 g) was added to the reaction kettle and cooled to not to exceed 50° C. After vacuum filtration, the filter cake was washed with water, then the filtrate was combined and concentrated under reduced pressure at 80-85° C. to remove the solvent to obtain compound of Formula 3, which was a light-yellow solid (4.05 kg). The product was directly put into the next reaction without further purification.
[0371] Step (c): At room temperature, compound of Formula 3 (4.05 kg, 21.77 mol), diethyl carbonate (12 L) and anhydrous ethanol (4 L) were added into a 50 L reaction kettle and stirred. Concentrated sulfuric acid (1.13 kg, 11.51 mol) was added dropwise and completed within 20-30 minutes. Then, heated to 85-95° C. for reflux reaction, and the reaction was monitored by HPLC. After the end of the reaction, the reaction solution was cooled to 50-60° C. and concentrated under reduced pressure, and the remaining liquid was diluted with water and cooled to not to exceed 10° C. 30% sodium hydroxide was added dropwise to adjust the solution to pH 8-9, then moved to room temperature for extraction using dichloromethane (10 L×3). After extraction, the organic layers were combined, added with anhydrous sodium sulfate and dried. After vacuum filtration, the filtrate was concentrated at 40° C. to obtain compound of Formula 4 which is a light brown oil (3.07 kg, The total yield of 3 steps is 75%).
[0372] .sup.1H NMR (500 MHz, Chloroform-d) δ 5.30 (d, J=1.3 Hz, 1H), 5.26 (q, J=1.1 Hz, 1H), 4.20 (q, J=7.1 Hz, 2H), 3.78 (dd, J=8.6, 4.8 Hz, 1H), 2.81 (ddd, J=14.2, 4.8, 1.1 Hz, 1H), 2.56 (dd, J=14.2, 8.6 Hz, 1H), 1.28 (t, J=7.1 Hz, 3H).
[0373] .sup.13C NMR (126 MHz, Chloroform-d) δ 174.5, 138.5, 115.9, 61.4, 52.3, 44.6, 14.3.
[0374] HRMS (m/z): calc. for C.sub.7H.sub.13ClNO.sub.2 [M+H].sup.+=178.0635; found, 178.0628.
[0375] Note: in step (a), the product was wet without being dried, so the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 2 was 23.02 mol.
Preparation of Intermediate Compound of Formula 6 (R.sub.1=Et; R.sub.2=Et; R.sub.3=Cbz)
##STR00031##
[0376] Step (d): At room temperature, compound of Formula 4 (3.07 kg, 17.26 mol), anhydrous sodium carbonate (5.49 kg, 51.79 mol), tetrabutylammonium iodide (0.64 kg, 1.73 mol) and toluene (9 L) were added into a 50 L reaction kettle, and toluene (6 L) solution of ethyl 4-bromobutyrate (3.37 kg, 17.26 mol) was added after stirring for 20 minutes. The reaction was stirred at 75-80° C. and monitored by HPLC. After the end of the reaction, the temperature was cooled to 20-25° C. Water (9 L) was added and stirred for 10-15 minutes, then benzyl chloroformate (2.94 kg, 17.26 mol) was added dropwise and completed within about 2-3 hours. The reaction was continuously stirred at 20-25° C. and monitored by TLC. After the reaction, water (10 L) and toluene (10 L) were added and stirred for 0.5 h to separate the solution. The organic layer was successively washed with 5% NaOH (15 L), water (20 L), 5% hydrochloric acid (15 L) and water (20 L). The organic layer was added with activated carbon (250.0 g) and stirred at room temperature for 1 hour. After vacuum filtration, the filtrate was concentrated under reduced pressure at 60° C. to obtain compound 5 which was a brown oil (8.10 kg). The product was directly put into the next reaction without further purification.
[0377] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.39-7.27 (m, 5H), 5.19 (d, J=1.3 Hz, 1H), 5.17-5.07 (m, 2.6H), 5.02 (s, 0.4H), 4.27-3.89 (m, 5H), 3.68-3.56 (m, 1H), 3.23-3.10 (m, 1.6H), 3.02-2.90 (m, 1.4H), 2.47-2.26 (m, 2H), 1.99-1.90 (m, 2H), 1.27-1.17 (m, 4.8H), 1.13 (t, J=7.2 Hz, 1.2H).
[0378] .sup.13C NMR (126 MHz, Chloroform-d) δ 173.3, 173.2, 170.3, 170.2, 155.6, 138.8, 138.4, 136.7, 136.2, 128.7, 128.6, 128.4, 128.2, 127.9, 116.3, 116.0, 67.6, 67.4, 61.7, 60.5, 59.6, 58.7, 49.2, 48.9, 40.5, 39.4, 31.6, 31.4, 24.2, 23.7, 14.4, 14.14, 14.07.
[0379] HRMS (m/z): calc. for C.sub.21H.sub.29ClNO.sub.6 [M+H].sup.+=426.1683; found, 426.1678
##STR00032##
[0380] Step (e): At room temperature and under the protection of nitrogen, sodium tert-butoxide (3.31 kg, 34.53 mol) and anhydrous tetrahydrofuran (38L) were added into a 100 L reaction kettle and stirred, then cooled to below −5° C. The compound of Formula 5 (8.10 kg, 17.26 mol) was dissolved in tetrahydrofuran (15 L) and then added dropwise into the reaction kettle. The temperature during the dripping process was controlled not to exceed 0° C. and complete dripping within 4-5 hours. Continued stirring at 0° C.-5° C. after the dripping process and the reaction was monitored by HPLC. After the end of the reaction, dilute hydrochloric acid was added to the kettle to adjust the solution to pH5-6, then ethyl acetate (10 L) was added, and stirred at room temperature to divide the solution. The organic layer was washed with saturated sodium chloride (20 L×2), and the aqueous layer is extracted once with ethyl acetate (10 L). Then the organic layer was combined, and activated carbon (500 g) was added and stirred for 1 hour at room temperature. After vacuum filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula 6 which is a light brown oil (5.44 kg, yield of two steps is 83%).
[0381] .sup.1H NMR (500 MHz, Chloroform-d) δ 12.23 (s, 1H), 7.41-7.28 (m, 5H), 5.27-5.05 (m, 4H), 5.01 (s, 0.4H), 4.94-4.82 (m, 0.6H), 4.30 (dd, J=13.6, 5.7 Hz, 0.6H), 4.23 (q, J=7.1 Hz, 2H), 4.19-4.12 (m, 0.4H), 3.09-2.66 (m, 3H), 2.46-2.23 (m, 2H), 1.30 (t, J=7.1 Hz, 3H).
[0382] .sup.13C NMR (126 MHz, Chloroform-d) δ 172.0, 171.9, 168.8, 168.2, 155.2, 155.1, 138.4, 138.3, 136.7, 136.3, 128.5, 128.2, 128.0, 115.8, 115.6, 97.7, 97.4, 67.7, 67.5, 61.0, 52.7, 52.5, 41.5, 40.7, 38.2, 37.3, 22.8, 22.3, 14.3.
[0383] HRMS (m/z): calc. for C.sub.19H.sub.23ClNO.sub.5 [M+H].sup.+=380.1265; found, 380.1266
[0384] Note: in step (d), the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 5 was 17.26 mol.
Preparation of Intermediate Compound of Formula 7 (R.SUB.3.=Cbz)
[0385] ##STR00033##
[0386] Step (f): Compound of Formula 6 (5.44 kg, 14.33 mol), DMF (16.3 L), water (2.7 L) and lithium chloride (0.61 kg, 14.33 mol) were added into a 50 L reaction kettle at room temperature and stirred. The reaction mixture was stirred and heated to 120° C., and the reaction was monitored by HPLC. After the end of the reaction, the reaction mixture was cooled to 20-25° C. Water (25 L) and methyl tert-butyl ether (30 L) were added, stirred and separated. The organic layer was washed with water (25 L×2) and separated, then the generated aqueous layer was extracted with methyl tert-butyl ether (25 L). By combining the organic layers and concentrating under reduced pressure at 45° C., compound of Formula 7 (4.19 kg, yield 95%) was obtained, which was a brown oil.
[0387] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.40-7.29 (m, 5H), 5.32-5.03 (m, 4H), 4.86 (s, 1H), 4.34-3.98 (m, 1H), 3.23 (s, 1H), 2.94-2.59 (m, 2H), 2.59-2.39 (m, 2H), 2.05 (s, 1H), 2.01-1.92 (m, 1H).
[0388] .sup.13C NMR (126 MHz, Chloroform-d) δ 206.7, 155.5, 128.6, 128.3, 116.1, 67.8, 61.8, 37.1, 22.5.
[0389] HRMS (m/z): calc. for C.sub.16H.sub.19ClNO.sub.3 [M+H].sup.+=308.1053; found, 308.1057
[0390] Preparation of Intermediate Compound of Formula 8 (R.sub.3=Cbz)
##STR00034##
[0391] Step (g): Anhydrous ethanol (18 L) and sodium borohydride (0.51 kg, 13.61 mol) were added into a 50 L reaction kettle at room temperature and stirred, then cooled to 5-10° C. Compound of Formula 7 (4.19 kg, 13.61 mol) was dissolved in anhydrous ethanol (9 L) and added dropwise into the reactor under the temperature controlled not to exceed 10° C. Keep stirring at 5-10° C. The reaction was monitored by HPLC. After the end of the reaction, water (20 L) was added dropwise into the kettle. After the dripping process, methyl tert-butyl ether (25 L) was added, stirred and separated. The organic layer was washed sequentially with 10% NaOH (10 L), 5% hydrochloric acid (10 L×2) and Water (10 L). The generated aqueous layer was extracted with methyl tert-butyl ether (25 L). The organic layers were combined, and added with activated carbon (500 g) and stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure at 45° C. to obtain the compound of Formula 8 (3.50 kg, yield 83%), which was a brown oil.
[0392] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.42 — 7.27 (m, 5H), 5.21-5.06 (m, 4H), 4.76 (s, 1H), 4.05 (d, J=14.0 Hz, 1H), 3.92-3.79 (m, 1H), 2.84-2.60 (m, 3H), 1.87-1.76 (m, 1H), 1.76-1.65 (m, 1H), 1.58-1.42 (m, 2H).
[0393] .sup.13C NMR (126 MHz, Chloroform-d) δ 155.8, 139.8, 136.7, 128.5, 128.2, 128.1, 114.5, 68.7, 67.5, 54.2, 37.9, 33.5, 27.9, 24.3.
[0394] HRMS (m/z): calc. for C.sub.16H.sub.21ClNO.sub.3 [M+H].sup.+=310.1210; found, 310.1208
Preparation of Intermediate Compound of Formula 9
[0395] ##STR00035##
[0396] Step (h): Compound of Formula 8 (3.55 kg, 12.36 mol), hydrochloric acid (6 mol/L, 18.83 l, 112.98 mol) and ethanol (20 L) were added into a 50 L reaction kettle at room temperature, stirred and heated for reflux reaction and the reaction was monitored by HPLC. After the reaction was completed, the reaction solution was cooled to 50-55° C. and concentrated under reduced pressure to remove ethanol. The remaining liquid was added with methyl tert-butyl ether (20 L×2), stirred and separated. The aqueous layer was adjusted to pH>11 with 40% sodium hydroxide, and then added ethyl acetate (20 L×2) for extraction. The organic layers were combined, and added with anhydrous magnesium sulfate and dried. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. Acetonitrile (5 L) was added to the crude product, stirred to dissolve at 70° C., and then the product was crystallized at room temperature. After filtration and vacuum drying, compound of Formula 9 (1.01 kg, yield 50.7%) was obtained, which was a nearly white solid.
[0397] .sup.1H NMR (500 MHz, Chloroform-d) δ 5.25 (d, J=1.1 Hz, 1H), 5.23 (t, J=1.0 Hz, 1H), 3.65 (S, 1H), 3.03 (ddt, J=11.5, 4.3, 2.0 Hz, 1H), 2.88 (ddd, J=7.5, 6.3, 1.4 Hz, 1H), 2.65 (td, J=11.9, 2.9 Hz, 1H), 2.49 (d, J=6.8 Hz, 2H), 1.91 (dtt, J=13.4, 4.0, 2.0 Hz, 1H), 1.73 (qt, J=13.1, 4.3 Hz, 1H), 1.54 (tdd, J=13.3, 4.7, 2.5 Hz, 1H), 1.45 (ddq, J=12.9, 4.9, 2.6 Hz, 1H).
[0398] .sup.13C NMR (126 MHz, Chloroform-d) δ 139.8, 115.2, 67.1, 57.7, 47.2, 43.0, 32.2, 20.4.
[0399] HRMS (m/z): calc. for C.sub.8H.sub.15ClNO [M+H].sup.+=176.0842; found, 176.0837
Preparation of Intermediate Compound of Formula 13
[0400] ##STR00036##
[0401] Step (i): Compound of Formula 9 (1 kg, 5.69 mol), 1,4-dioxane (5 L), water (5 L), sodium carbonate (0.91 kg, 8.54 mol) were added into a 50 L reaction kettle at room temperature, stirred and cooled to 5-10° C. 9-fluorenylmethyl chloroformate (1.47 kg, 5.69 mol) was dissolved in 1,4-dioxane (2 L) and then added dropwise into the reaction kettle, with the temperature controlled not to exceed 20° C. After the dripping process, stirred to continue the reaction at room temperature, monitored by TLC. After the end of the reaction, ethyl acetate (20 L) and water (20 L) were added and stirred, then the solution was separated. The organic layer was washed with saturated sodium chloride (5 L×2) and separated. The aqueous layer was extracted once with ethyl acetate (10 L). The organic layers were combined, added with activated carbon (500 g) at room temperature and stirred for 1 hour. After filtration, the filtrate was concentrated to produce compound of Formula 10, which was a yellowish thick substance (2.81 kg). The product did not need for further purification and was directly put into the next reaction.
[0402] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.81-7.71 (m, 2H), 7.65-7.53 (m, 2H), 7.40 (td, J=7.5, 2.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 5.17 (s, 1H), 5.14 (s, 1H), 4.93-4.51 (m, 1H), 4.49 (dd, J=10.7, 6.7 Hz, 1H), 4.41 (dd, J=10.7, 6.5 Hz, 1H), 4.25 (t, J=6.5 Hz, 1H), 3.92 (s, 1H), 3.76 (s, 1H), 2.85-2.54 (m, 3H), 1.87-1.74 (m, 1H), 1.73-1.58 (m, 1H), 1.57-1.33 (m, 2H).
[0403] .sup.13C NMR (126 MHz, Chloroform-d) δ 155.8, 144.1, 141.5, 141.4, 139.8, 127.73, 127.70, 127.15, 127.10, 125.09, 125.06, 120.02, 119.99, 114.4, 68.4, 67.5, 54.3, 47.5, 37.9, 33.3, 27.7, 24.2.
[0404] HRMS (m/z): calc. for C.sub.23H.sub.25ClNO.sub.3 [M+H].sup.+=398.1523; found, 398.1530
##STR00037##
[0405] Step (j): Compound of Formula 10 (2.81 kg, 5.69 mol), acetonitrile (10 L) and water (5 L) were added into a 50 L reaction kettle at room temperature, stirred and cooled to 0-5° C. N-bromosuccinimide (1.01 kg, 5.69 mol) was added into the kettle in batches, and the temperature was controlled not to exceed 5° C. After it was completed, stirred to continue the reaction at 0-5° C. and the reaction was monitored by HPLC. After the end of the reaction, 10% sodium sulfite solution (10 L) was added and stirred for 0.5 h. Ethyl acetate (10 L×2) was added for extraction and separation. The organic layer is washed with saturated sodium bicarbonate (5 L) and saturated sodium chloride (5 L×2) and separated. The organic layer was added with activated carbon (320 g) and stirred at room temperature for 1 hour, then anhydrous magnesium sulfate was added and stirred for 0.5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula 11, which was a dense substance (2.85 kg). The product was directly put into the next reaction without further purification.
[0406] Note: in step (i), the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 10 was 5.69 mol.
##STR00038##
[0407] Step (k): Compound of Formula 12 (1.40 kg, 5.41 mol), lithium hydroxide (0.15 kg, 6.26 mol) and N,N-dimethylformamide (28 L) were added into a 100 L reactor at room temperature, and then the mixture was stirred at room temperature for 1 hour, then cooled to 0-5° C. Compound of Formula 11 (2.85 kg, 5.69 mol) was dissolved in N,N-dimethylformamide (2.8 L) and then added dropwise into the reactor with temperature controlled not to exceed 5° C. the dripping process completed within 4-5 hours. The reaction was monitored by HPLC. After the reaction was completed, diethylamine (1 L) was added into the reactor and stirred at 0° C.-5° C.
[0408] The reaction was monitored by HPLC. After the reaction was completed, water (25 L) and ethyl acetate (30 L) were added into the reactor, then the liquid was separated by stirring. The aqueous layer was extracted by ethyl acetate (20 L×3). The organic layers were combined and concentrated at 50° C. under reduced pressure. The concentrated residue was added with 85% lactic acid solution (1.5 kg), stirred at room temperature for 1 hour, and then added with methyl tert- butyl ether (10 L×2) for extraction The aqueous layer was added with potassium carbonate to adjust to pH 8-9. Then ethyl acetate (15 L×3) was added and the organic layer was combined and concentrated at 45-50° C. under reduced pressure to produce the crude product, which was added with ethyl acetate (8 L) and stirred at room temperature for 0.5 h. After filtration, the filter cake was vacuum dried to obtain Compound of Formula 13 (1.84 kg, 3-step yield 78%), which was a white solid.
[0409] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 4.34 (d, J=13.9 Hz, 1H), 4.16 (d, J=13.9 Hz, 1H), 3.88 (t, J=3.1 Hz, 1H), 3.29 (t, J=3.4 Hz, 1H), 2.97 (d, J=10.9 Hz, 1H), 2.52 (t, J=11.8 Hz, 1H), 2.10 (d, J=15.1 Hz, 1H), 2.03 (dd, J=13.1, 3.7 Hz, 2H), 1.83 (d, J=13.2 Hz, 1H), 1.81-1.72 (m, 1H), 1.54 (ddt, J=15.0, 12.0, 3.4 Hz, 2H).
[0410] .sup.13C NMR (126 MHz, Chloroform-d) δ 160.1, 149.5, 147.2, 133.4, 132.7, 129.4, 127.9, 122.1, 105.3, 78.0, 55.8, 50.3, 44.67, 43.7, 26.9, 20.2.
[0411] HRMS (m/z): calc. for C.sub.16H.sub.18BrClN.sub.3O.sub.3 [M+H].sup.+=414.0220/416.0200; found, 414.0216/416.0197
[0412] Note: in step (i) and (j), the calculated yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of compound of Formula 11 was 5.69 mol.
Synthesis of Halofuginone (Compound of Formula 1)
[0413] ##STR00039##
[0414] Step (1): Compound of Formula 13 (1.84 kg, 4.43 mol) and anhydrous ethanol (20 L) were added into a 50 L reaction kettle at room temperature, stirred and heated to reflux reaction, and the reaction was monitored by HPLC. After the reaction, the reaction liquid was cooled to 55-60° C. After vacuum filtration, the filter cake was washed with ethanol and vacuum dried to obtain Compound of Formula 1, which was a white solid (1.31 kg, yield 71.2%, HPLC purity 98.6%).
[0415] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 4.99 (d, J=2.8 Hz, 2H), 4.79 (d, J=5.8 Hz, 1H), 2.98 (dt, J=15.3, 4.7 Hz, 2H), 2.78 (d, J=12.3 Hz, 1H), 2.64 (td, J=8.9, 3.8 Hz, 1H), 2.44 (dd, J=15.5, 8.7 Hz, 1H), 2.36 (td, J=12.1, 2.7 Hz, 1H), 1.95-1.83 (m, 1H), 1.56 (dt, J=13.3, 3.2 Hz, 1H), 1.34 (qt, J=12.4, 3.7 Hz, 1H), 1.28-1.13 (m, 1H).
[0416] .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 200.7, 158.6, 149.5, 147.2, 132.4, 131.8, 128.4, 126.8, 121.7, 66.7, 56.2, 54.4, 43.0, 30.5, 20.1.
[0417] HRMS (m/z): calc. for C.sub.16H.sub.18BrClN.sub.3O.sub.3 [M+H].sup.+=414.0220/416.0200; found, 414.0214/416.0195
Embodiment 2 Synthesis of Racemic Halofuginone
Preparation of Intermediate Compound of Formula 13
[0418] ##STR00040##
[0419] Step (i): Compound of Formula 9 (0.7 kg, 3.98 mol), 1,4-dioxane (3.5 L), water (3.5 L), sodium carbonate (0.63 kg, 5.98 mol) were added into a 50 L reaction kettle at room temperature, stirred and cooled to 5-10° C. Chloroformate-9-fluorene methyl ester (1.03 kg, 3.98 mol) was dissolved in 1,4-dioxane (1.4 L) and then added dropwise into the reaction kettle, with the temperature controlled not to exceed 20° C. After the dripping process, stirred to continue the reaction at room temperature, monitored by TLC. After the end of the reaction, ethyl acetate (15 L) and water (15 L) were added and stirred, then the solution was separated. The organic layer was washed with saturated sodium chloride (3 L×2) and separated. The aqueous layer was extracted once with ethyl acetate (8 L). The organic layers were combined, added with activated carbon (300 g) at room temperature and stirred for 1 hour. After filtration, the filtrate was concentrated to produce compound of Formula 10, which was a yellowish thick substance (1.81 kg). The product did not need further purification and was directly put into the next reaction.
##STR00041##
[0420] Step (j): Compound of Formula 10 (1.81 kg, 3.98 mol), acetonitrile (7 L) and water (3.5 L) were added into a 50 L reaction kettle at room temperature, stirred and cooled to 0-5° C. N-bromosuccinimide (0.71 kg, 3.98 mol) was added into the kettle in batches, and the temperature was controlled not to exceed 5° C. After it was completed, stirred to continue the reaction at 0-5° C. and monitored by HPLC. After the reaction, 10% sodium sulfite solution (7 L) was added and stirred for 0.5 h. Ethyl acetate (7 L×2) was added to extraction and separation. The organic layer is washed with saturated sodium bicarbonate (3 L) and saturated sodium chloride (3 L×2) and separated. The organic layer was added with activated carbon (200 g) and stirred at room temperature for 1 hour, then anhydrous magnesium sulfate was added and stirred for 0.5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula 11, which was a dense substance (1.85 kg). The product was directly put into the next reaction without further purification.
[0421] Note: in step (i), the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 10 was 3.98 mol.
##STR00042##
[0422] Step (k): Compound of Formula 12 (0.98 kg, 3.79 mol), lithium hydroxide (100 g, 4.38 mol) and N,N-dimethylformamide (20 L) were added into a 100 L reactor at room temperature, and then the mixture was stirred at room temperature for 1 hour, then cooled to 0-5° C. Compound of Formula 11 (1.85 kg, 3.98 mol) was dissolved in N,N-dimethylformamide (2 L) and then added dropwise into the reactor with temperature controlled not to exceed 5° C., the dripping process completed within 4-5 hours. The reaction was monitored by HPLC. After the reaction was completed, diethylamine (0.7 L) was added into the reactor and stirred at 0-5° C. . The reaction was monitored by HPLC. After the reaction was completed, water (16 L) and ethyl acetate (20 L) were added into the reactor, then the liquid was separated by stirring. The aqueous layer was extracted by ethyl acetate (15 L×3). The organic layers were combined and concentrated at 50° C. The concentrated residue was added with 85% lactic acid solution (1.05 kg), stirred at room temperature for 1 hour, and then added with methyl tert-butyl ether (8 L×2) for extraction. The aqueous layer was added with potassium carbonate to adjust to pH 8-9. Then ethyl acetate (10 L×3) was added and the organic layer was combined and concentrated at 45-50° C. under reduced pressure to produce the crude product, which was added with ethyl acetate (5 L) and stirred at room temperature for 0.5 h. After filtration, the filter cake was vacuum dried to obtain Compound of Formula 13 (1.31 kg, 3-step yield 79%), which was a white solid.
[0423] Note: in step (i) and (j), the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 11 was 3.98 mol.
Synthesis of Halofuginone (Compound of Formula 1)
[0424] ##STR00043##
[0425] Step (1): Compound of Formula 13 (1.31 kg, 3.16 mol) and anhydrous ethanol (16 L) were added into a 50 L reaction kettle at room temperature, stirred and heated to reflux reaction, and the reaction was monitored by HPLC. After the end of the reaction, the reaction liquid was cooled to 55-60° C. After vacuum filtration, the filter cake was washed with ethanol and vacuum dried to obrain Compound of Formula 1, which was a white solid (0.91 kg, yield 70%, HPLC purity 98.4%).
Embodiment 3 Synthesis of Racemic Halofuginone
Preparation of Intermediate Compound of Formula 4 (R.SUB.1.=Et)
[0426] ##STR00044##
[0427] Step (a): At room temperature, diethyl acetylaminomalonic acid (2.50 kg, 11.51 mol), anhydrous potassium carbonate (3.18 kg, 23.02 mol), potassium iodide (0.38 kg, 2.3 mol), tetrabutylammonium bromide (0.19 kg, 0.58 mol) and acetonitrile (13 L) were added into a 50 L reaction kettle. After being stirred for 20 minutes, 2,3-dichloropropene (1.53 kg,13.81 mol) was added. The reaction was carried out at 85-90° C. and monitored by HPLC. After the end of the reaction, the reaction mixture was cooled to a temperature within 25° C., and diluted hydrochloric acid was added dropwise into the reactor to neutralize the reaction mixture to pH 7-7.5. The reaction solution was left to separation, then the organic layer was concentrated under reduced pressure at 50° C. The concentrated residue was added with ethanol water (1:10, 10 L) and stirred for 1 hour for crystallization. After vacuum filtration, the filter cake was washed with water to obtain compound of Formula 2, which was a yellow solid (wet weight 5.82 kg), which was not dried and directly put into the next reaction.
[0428] Step (b): At room temperature, the compound of Formula 2 (wet weight 5.82 kg, 11.5 lmol) and hydrochloric acid solution (6 mol/L, 30 L, 180 mol) were added into a 100 L reaction kettle, stirred and heated to 100° C. for reflux reaction, and the reaction was monitored by TLC. After the end of the reaction, the reaction kettle was added with activated carbon (250 g) and cooled to not to exceed 50° C. After vacuum filtration, the filter cake was washed with water, then the filtrate was combined and concentrated under reduced pressure at 80-85° C. to remove the solvent to obtain compound of Formula 3, which was a light-yellow solid (2.05 kg). The product was directly put into the next reaction without further purification.
[0429] Step (c): At room temperature, compound of Formula 3 (2.05 kg, 11.02 mol), diethyl carbonate (6 L) and anhydrous ethanol (2 L) were added into a 50 L reaction kettle and stirred.
[0430] Concentrated sulfuric acid (0.56 kg, 5.75 mol) was added dropwise and completed within 20-30 minutes. Then, heated to 85-95° C. for reflux reaction, and the reaction was monitored by HPLC. After the end of the reaction, the reaction solution was cooled to 50-60° C. and concentrated under reduced pressure, and the remaining liquid was diluted with water and cooled to not to exceed 10° C. 30% sodium hydroxide was added dropwise to adjust the solution to pH 8-9, then moved to room temperature for extraction using dichloromethane (5 L×3). After extraction, the organic layers were combined, added with anhydrous sodium sulfate and dried. After vacuum filtration, the filtrate was concentrated at 40° C. to obtain compound of Formula 4, which was a light brown oil (1.59 kg, The total yield of 3 steps is 78%).
[0431] Note: in step (a), the product was wet without being dried, so the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 2 was 11.51 mol.
Preparation of Intermediate Compound of Formula 6 (R.sub.1=Et; R.sub.2=Et; R.sub.3=Cbz)
##STR00045##
[0432] Step (d): At room temperature, compound of Formula 4 (1.50 kg, 8.44 mol), anhydrous sodium carbonate (2.69 kg, 25.33 mol), tetrabutylammonium iodide (0.31 kg, 0.84 mol) and toluene (4.5 L) were added into a 50 L reaction kettle, and toluene (3 L) solution of ethyl 4-bromobutyrate (1.65 kg, 8.44 mol) was added after stirring for 20 minutes. The reaction was stirred at 75-80° C. and monitored by HPLC. After the end of the reaction, the temperature was cooled to 20-25° C. Water (5 L) was added and stirred for 10-15 minutes, then benzyl chloroformate (1.44 kg, 8.44 mol) was added dropwise and completed within about 2-3 hours. The reaction was continuously stirred at 20-25° C. and monitored by TLC. After the reaction, water (5 L) and toluene (5 L) were added and stirred for 0.5 h to separate the solution. The organic layer was successively washed with 5% NaOH (10 L), water (10 L), 5% hydrochloric acid (15 L) and water (10 L). The organic layer was added with activated carbon (100.0 g) and stirred at room temperature for 1 hour. After vacuum filtration, the filtrate was concentrated under reduced pressure at 60° C. to obtain compound of Formula 5 which was a brown oil (4.18 kg). The product was directly put into the next reaction without further purification.
##STR00046##
[0433] Step (e): At room temperature and under the protection of nitrogen, sodium tert-butoxide (1.62 kg, 16.89 mol) and anhydrous tetrahydrofuran (19 L) were added into a 100 L reaction kettle and stirred, then cooled to below −5° C. The compound of Formula 5 (4.18 kg, 8.44 mol) was dissolved in tetrahydrofuran (8 L) and then added dropwise into the reaction kettle. The temperature during the dripping process was controlled not to exceed 0° C. and completed dripping within 4-5 hours. Continued stirring at 0-5° C. after the dripping process and the reaction was monitored by HPLC. After the end of the reaction, dilute hydrochloric acid was added to the kettle to adjust the solution to pH5-6. Ethyl acetate (5 L) was added, and stirred at room temperature to divide the solution. The organic layer was washed with saturated sodium chloride (10 L×2), and the aqueous layer was extracted once with ethyl acetate (5 L). The organic layer was combined and added with activated carbon (200 g) and stirred for 1 hour at room temperature. After vacuum filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula 6, which was a light brown oil (2.73 kg, The total yield of two steps is 85%).
[0434] Note: in step (d), the yield exceeded the theoretical value. Therefore, according to the 100% yield, the mole number of the compound of Formula 5 was 8.44 mol.
Preparation of Intermediate Compound of Formula 7 (R.SUB.3.=Cbz)
[0435] ##STR00047##
[0436] Step (f): Compound of Formula 6 (2.00 kg, 5.27 mol), DMF (6 l), water (1 L) and lithium chloride (0.22 kg, 2.27 mol) were added into a 50 L reaction kettle at room temperature and stirred. The reaction mixture was stirred and heated to 120° C. and the reaction was monitored by HPLC. After the end of the reaction, the reaction mixture was cooled to 20-25° C. Water (12 L) and methyl tert-butyl ether (15 L) were added, stirred and separated. The organic layer was washed with water (15 L×2) and separated, then the generated aqueous layer was extracted with methyl tert-butyl ether (15 L). By combining the organic layers and concentrating under reduced pressure at 45° C., compound of Formula 7 (1.52 kg, yield 94%) was obtained, which was a brown oil.
Preparation of Intermediate Compound of Formula 8 (R.SUB.3.=Cbz)
[0437] ##STR00048##
[0438] Step (g): Anhydrous ethanol (7 L) and sodium borohydride (0.19 kg, 4.95 mol) were added into a 50 L reaction kettle at room temperature and stirred, then cooled to 5-10° C. Compound of Formula 7 (1.52 kg, 4.95 mol) was dissolved in anhydrous ethanol (3 L) and added dropwise into the reactor under the temperature controlled not to exceed 10° C. Keep stirring at 5-10° C. The reaction was monitored by HPLC. After the end of the reaction, water (10 L) was added dropwise into the kettle. After the dripping process, methyl tert-butyl ether (10 L) was added, stirred and separated. The organic layer was washed sequentially with 10% NaOH (5 L), 5% hydrochloric acid (5 L×2) and Water (5 L). The generated aqueous layer was extracted with methyl tert-butyl ether (15 L). The organic layers were combined, and added with activated carbon (200 g) and stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure at 45° C. to obtain the compound of Formula 8 (1.30 kg, yield 85%), which was a brown oil.
Preparation of Intermediate Compound of Formula 9
[0439] ##STR00049##
[0440] Step (h): Compound of Formula 8 (1.30 kg, 4.21 mol), hydrochloric acid (6 mol/L, 5.61 L, 33.68 mol) and ethanol (6 L) were added into a 50 L reaction kettle at room temperature, stirred and heated for reflux reaction and the reaction was monitored by HPLC. After the reaction was completed, the reaction solution was cooled to 50-55° C. and concentrated under reduced pressure to remove ethanol. The remaining liquid was added with methyl tert-butyl ether (7 L×2), stirred and separated. The aqueous layer was adjusted to pH>11 with 40% sodium hydroxide, and then added with ethyl acetate (10 L)×2) for extraction. The organic layers were combined, added with anhydrous magnesium sulfate and dried. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. Acetonitrile (2 L) was added to the crude product, stirred to dissolve at 70° C., and then the product was crystallized at room temperature. After filtration and vacuum drying, compound of Formula 9 (0.35 kg, yield 48%) was obtained, which was a nearly white solid.
Embodiment 4 Synthesis of Halofuginone Hydrobromate
[0441] Synthesis of Halofuginone Hydrobromate (Compound of Formula 1)
[0442] Hydrobromate (100 g, 0.24 mol) and hydrobromic acid solution (4.8%, 700 ml) were added into a 1 L glass reaction flask at room temperature, and stirred for 2 hours. After decompression filtration, the filter cake was washed with pure water and dried in vacuum to obtain halofuginone hydrobromate, which was a white solid (118 g, yield 99%, HPLC purity 98.6%).
Embodiment 5 Synthesis of Lactate of Halofuginone
Synthesis of Lactate of Halofuginone (Compound of Formula 1)
[0443] Halofuginone (100 g, 0.24 mol), pure water (400 ml) and DL-lactic acid (85% aqueous solution, 25.6 g, 0.24 mol) were added into a 500 mL glass reaction flask at room temperature. After being stirred and dissolved, the reaction solution was concentrated to remove water at 60° C. under reduced pressure. After concentration, the remaining liquid was added with ethanol (500 mL) and stirred at 0° C. for crystallization. After filtration under reduced pressure, the filter cake was dried in vacuum to obtain the lactate of halofuginone, which was a white solid (84 g, yield 70%, HPLC purity 99.2%).
Embodiment 6
[0444] Synthesis of Compound of Formula (+)-9(dextro optically active [(+)-(2S, 3S)-2-(2-chloropropenyl)-3-hydroxypiperidine])
##STR00050##
[0445] Step (1): Racemic compound of Formula 9 (140 g, 0.797 mol, prepared according to the method of embodiment 1) and acetonitrile (1400 mL) were added into a 5 L three-mouth bottle at room temperature, heated to 60° C. and stirred to dissolve. L-(−)-dibenzoyl tartaric acid (300 g, 0.837 mol) of Formula 15 was dissolved in acetonitrile (800 mL), and then added dropwise to the reaction flask. The dripping process was completed within about 10 min, continued stirring for 20-30 minutes. Then the bottle was moved to room temperature and stirred for 2 hours. After filtration, the filter was washed with acetonitrile (300 mL) and drain to obtain crude compound salt, which was added with pure water and acetonitrile (1:4, 2000 mL), stirred and heated to 80° C. to dissolve, filtered while hot, and the filtrate was stirred at room temperature for 2 hours for crystallization. The compound of Formula 14 (136 g, yield 32%) was obtained by filtration, acetonitrile leaching and drying.
[0446] Step (2): At room temperature, compound of Formula 14 (136 g), pure water (700 mL) and ethyl acetate (700 mL) were added into a 5 L three-mouth flask, stirred, and 1 mol/L NaOH was added dropwise to adjust to pH 12-14. The aqueous layer was separated with ethyl acetate (700 mL×2). After extraction, organic layers were combined, added anhydrous MgSO.sub.4 to dry. After filtration, and the filtrate was concentrated at 50° C. under reduced pressure to obtain compound (+)-9, which wasa white solid (44 g, yield 98%).
[0447] [α].sub.D=+8.43° (c=0.46, MeOH)
[0448] .sup.1H NMR (500 MHz, Chloroform-d) δ 5.25 (d, J=1.1 Hz, 1H), 5.23 (t, J=1.0 Hz, 1H), 3.65 (S, 1H), 3.03 (ddt, J=11.5, 4.3, 2.0 Hz, 1H), 2.88 (ddd, J=7.5, 6.3, 1.4 Hz, 1H), 2.65 (td, J=11.9, 2.9 Hz, 1H), 2.49 (d, J=6.8 Hz, 2H), 1.91 (dtt, J=13.4, 4.0, 2.0 Hz, 1H), 1.73 (qt, J=13.1, 4.3 Hz, 1H), 1.54 (tdd, J=13.3, 4.7, 2.5 Hz, 1H), 1.45 (ddq, J=12.9, 4.9, 2.6 Hz, 1H).
[0449] .sup.13C NMR (126 MHz, Chloroform-d) δ 139.8, 115.2, 67.1, 57.7, 47.2, 43.0, 32.2, 20.4.
[0450] HRMS (m/z): calc. for C.sub.8H.sub.15ClNO [M+H].sup.+=176.0842; found, 176.0837
Embodiment 7
[0451] Synthesis of Compound of Formula (−)-9(I-optically active [(−)-(2R,3R)-2-(2-chloropropenyl)-3-hydroxypiperidine)]
##STR00051##
[0452] Step (1): Racemic compound of Formula 9 (14 g, 79.7 mmol, prepared according to the method of embodiment 1) and acetonitrile (140 ml) were added into a 5 L three-mouth bottle at room temperature, heated to 60° C. and stirred to dissolve. L-(−)-dibenzoyl tartaric acid (30 g, 83.7 mmol) of Formula 16 is dissolved in acetonitrile (80 mL), and then added dropwise into the reaction flask. The dripping process was completed within about 10 min, continued stirring for 20-30 minutes. Then the bottle was moved to room temperature and stirred for 2 hours. After filtration, the filter was washed with acetonitrile (30 mL) and drain to obtain crude compound salt, which was added with pure water and acetonitrile (1:4, 200 mL), stirred and heated to 80° C. to dissolve, filtered while hot, and the filtrate was stirred at room temperature for 2 hours for crystallization. The compound of Formula 17 (12.1 g, yield 28.4%) was obtained by filtration, acetonitrile leaching and drying.
[0453] Step (2): At room temperature, compound of Formula 17 (12.1 g), pure water (70 mL) and ethyl acetate (100 mL) were added into a 5 L three-mouth flask, stirred, and 1 mol/L NaOH was added dropwise to adjust to pH 12-14. The aqueous layer was separated with ethyl acetate (100 ml×2). After extraction, organic layers were combined, added anhydrous MgSO4 to dry. After filtration, the filtrate was concentrated at 50° C. under reduced pressure to obtain compound (−)-9, which was a white solid (3.7 g, yield 93.1%).
[0454] [α].sub.D=−8.43° (c=0.46, MeOH)
[0455] .sup.1H NMR (500 MHz, Chloroform-d) δ 5.25 (d, J=1.1 Hz, 1H), 5.23 (t, J=1.0 Hz, 1H), 3.65 (S, 1H), 3.03 (ddt, J=11.5, 4.3, 2.0 Hz, 1H), 2.88 (ddd, J=7.5, 6.3, 1.4 Hz, 1H), 2.65 (td, J=11.9, 2.9 Hz, 1H), 2.49 (d, J=6.8 Hz, 2H)., 1.91 (dtt, J=13.4, 4.0, 2.0 Hz, 1H), 1.73 (qt, J=13.1, 4.3 Hz, 1H), 1.54 (tdd, J=13.3, 4.7, 2.5 Hz, 1H), 1.45 (ddq, J=12.9, 4.9, 2.6 Hz, 1H).
[0456] .sup.13C NMR (126 MHz, Chloroform-d) δ 139.8, 115.2, 67.1, 57.7, 47.2, 43.0, 32.2, 20.4.
[0457] HRMS (m/z): calc. for C.sub.8H.sub.15ClNO [M+H].sup.+=176.0842; found, 176.0837
Embodiment 8
[0458] Synthesis of Compound of Formula (+)-1, namely (+)-halofuginone (d-halofuginone)
##STR00052##
[0459] Step (3): Compound (+)-9 (10 g, 56.9 mmol), 1,4-dioxane (50 mL), water (50 mL) and sodium carbonate (9.1 g, 85.4 mmol) were added into a 500 mL reaction flask at room temperature, stirred and cooled to 5-10° C. 9-fluorenylmethyl chloroformate (14.7 g, 56.9 mmol) was dissolved in 1,4-dioxane (20 mL) and then added dropwise to the reaction flask with the temperature controlled not to exceed 20° C. The reaction was continued at room temperature and monitored by TLC. After the reaction, ethyl acetate (200 mL) and water (200 mL) were added. The reaction solution was stirred and separated. The organic layer was washed with Saturated sodium chloride (50 mL×2) and separated. The aqueous layer was extracted once with ethyl acetate (100 mL). The organic layers were combined, added with activated carbon (5 g) and stirred at room temperature for 1 hour. After filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula (+)-10, which was a light yellow consistency (25.1 g, EE=96%). The product was directly put into the next reaction without further purification.
[0460] [α].sub.D=+25.42° (c=0.35, CHCl.sub.3)
[0461] .sup.1H NMR (500 MHz, Chloroform-d) δ 7.81-7.71 (m, 2H), 7.65-7.53 (m, 2H), 7.40 (td, J=7.5, 2.4 Hz, 2H), 7.31 (t, J=7.4 Hz, 2H), 5.17 (s, 1H), 5.14 (s, 1H), 4.93-4.51 (m, 1H), 4.49 (dd, J=10.7, 6.7 Hz, 1H), 4.41 (dd, J=10.7, 6.5 Hz, 1H), 4.25 (t, J=6.5 Hz, 1H), 3.92 (s, 1H), 3.76 (s, 1H), 2.85-2.54 (m, 3H), 1.87-1.74 (m, 1H), 1.73-1.58 (m, 1H), 1.57-1.33 (m, 2H).
[0462] .sup.13C NMR (126 MHz, Chloroform-d) δ 155.8, 144.1, 141.5, 141.4, 139.8, 127.73, 127.70, 127.15, 127.10, 125.09, 125.06, 120.02, 119.99, 114.4, 68.4, 67.5, 54.3, 47.5, 37.9, 33.3, 27.7, 24.2.
[0463] HRMS (m/z): calc. for C.sub.23H.sub.25ClNO.sub.3 [M+H].sup.+=398.1523; found, 398.1530
[0464] Step (4): Compound of Formula (+)-10 (28 g, 56.9 mol), acetonitrile (100 mL) and water (50 mL) were added into a 500 ml reaction flask at room temperature, stirred and cooled to 0° C.-5° C. N-bromosuccinimide (10.1 g, 56.9 mol) was added into the reaction flask in batches with the temperature controlled not to exceed 5° C. After the dripping process, stirred to continue the reaction at 0-5° C. and monitored by HPLC. After the reaction, 10% sodium sulfite solution (100 mL) was added and stirred for 0.5 h. Then ethyl acetate (100 mL×2) was added for extraction and separation. The organic layer was washed with saturated sodium bicarbonate (50 mL) and saturated sodium chloride (50 mL×2) and separated. After the organic layer was added with activated carbon (5 g) and stirred at room temperature for 1 hour, anhydrous magnesium sulfate was added and stirred for 0.5 hours. After filtration, the filtrate was concentrated under reduced pressure to obtain compound of Formula (+)-11 [27.5 g, [α].sub.D=+36.66° (c=0.30, CHCl.sub.3)], which was a thick substance. The product was directly put into the next step without further purification.
[0465] Step (5): Compound of Formula 12 (14 g, 54.1 mol), lithium hydroxide (1.5 g, 62.6 mol) and N,N-dimethylformamide (280 mL) were added into a 1000 mL reaction flask at room temperature, stirred at room temperature for 1 hour, and then cooled down to 0-5° C. Compound of Formula (+)-11 (27.5 g, 56.9 mol) was dissolved in N,N-dimethylformamide (30 mL) and then added dropwise into the reactor with the temperature controlled not to excess 5° C., the dripping process was completed within 4-5 hours. Then stirred to continue the reaction at 0-5° C. and the reaction was monitored by HPLC. After the reaction was completed, diethylamine (10 mL) was added to the reactor and stirred at 0-5° C. The reaction was monitored by HPLC. At the end of the reaction, water (250 mL) and ethyl acetate (300 mL) were added into the reactor, and the solution was separated by stirring. The aqueous layer was extracted with Ethyl acetate (200 mL×3). After extraction, the organic layers were combined and concentrated at 50° C. The concentrated residue was added with 85% lactic acid solution (15 g), stirred at room temperature for 1 hour, and then methyl tert-butyl ether (100 mL×2) was added for extraction. The aqueous layer was added with potassium carbonate to adjust to pH 8-9, then added with ethyl acetate (150 mL×3) for extraction. The organic layers were combined and concentrated at 45-50° C. under reduced pressure to obtain a crude product, which then was added with ethyl acetate (80 mL) and stirred at room temperature for 0.5 h. After filtration, the filter cake was dried in vacuum to obtain compound of Formula (+)-13 (16.8 g, 3-step yield 71%), which was a white solid.
[0466] [α].sub.D=+81.21° (c=0.52, CHCl.sub.3)
[0467] .sup.1H NMR (400 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.26 (s, 1H), 7.98 (s, 1H), 4.34 (d, J=13.9 Hz, 1H), 4.16 (d, J=13.9 Hz, 1H), 3.88 (t, J=3.1 Hz, 1H), 3.29 (t, J=3.4 Hz, 1H), 2.97 (d, J=10.9 Hz, 1H), 2.52 (t, J=11.8 Hz, 1H), 2.10 (d, J=15.1 Hz, 1H), 2.03 (dd, J=13.1, 3.7 Hz, 2H), 1.83 (d, J=13.2 Hz, 1H), 1.81-1.72 (m, 1H), 1.54 (ddt, J=15.0, 12.0, 3.4 Hz, 2H).
[0468] .sup.13C NMR (126 MHz, Chloroform-d) δ 160.1, 149.5, 147.2, 133.4, 132.7, 129.4, 127.9, 122.1, 105.3, 78.0, 55.8, 50.3, 44.67, 43.7, 26.9, 20.2.
[0469] HRMS (m/z): calc. for C.sub.16H.sub.18BrClN.sub.3O.sub.3 [M+H].sup.+=414.0220/416.0200; found, 414.0216/416.0197
[0470] Step (6): Compound of Formula (+)-13 (15 g, 36.17 mmol) and anhydrous ethanol (150 mL) were added into a 500 mL reaction flask at room temperature, stirred and heated to reflux reaction which was monitored by HPLC. After the reaction, the reaction liquid was cooled to 55-60° C. After filtration under reduced pressure, the filter cake was leached with ethanol and vacuum dried to obtain (+)-halofuginone, which was a white solid (12.1 g, yield 80.6%, HPLC purity 98.5%, EE=99.6%).
[0471] [60 ].sub.D=+18.52° (c=0.53, DMSO)
[0472] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 8.23 (s, 1H), 8.22 (s, 1H), 8.15 (s, 1H), 4.99 (d, J=2.8 Hz, 2H), 4.79 (d, J=5.8 Hz, 1H), 2.98 (dt, J=15.3, 4.7 Hz, 2H), 2.78 (d, J=12.3 Hz, 1H), 2.64 (td, J=8.9, 3.8 Hz, 1H), 2.44 (dd, J=15.5, 8.7 Hz, 1H), 2.36 (td, J =12.1, 2.7 Hz, 1H), 1.95-1.83 (m, 1H), 1.56 (dt, J=13.3, 3.2 Hz, 1H), 1.34 (qt, J=12.4, 3.7 Hz, 1H), 1.28-1.13 (m, 1H).
[0473] .sup.13C NMR (126 MHz, DMSO-d.sub.6) δ 200.7, 158.6, 149.5, 147.2, 132.4, 131.8, 128.4, 126.8, 121.7, 66.7, 56.2, 54.4, 43.0, 30.5, 20.1.
[0474] HRMS (m/z): calc. for C.sub.16H.sub.18BrClN.sub.3O.sub.3 [M+H].sup.+=414.0220/416.0200; found, 414.0214/416.0195
[0475] The above-described various technical features in the embodiments can be combined in various ways. The above-described embodiments do not describe all the possible combinations of the technical features to provide a concise description. However, those combinations which are not described should be within the scope of the description as long as no contradiction occurs in the combinations of these technical features.
[0476] The above-described embodiments represent only several embodiments of the present invention, which are described in specific detail but should not be construed as limitations on the scope of the claims. It should be noted that modifications and improvements can be made for those skilled in the art without departing from the spirit of the invention, all of which fall within the scope of the present invention. Accordingly, the scope of the present invention should be subject to the appended claims.