METHODS FOR SYNTHESIZING N-(PHENYLSULFONYL)BENZAMIDE COMPOUNDS AND INTERMEDIATES THEREOF

Abstract

Disclosed is a method for synthesizing N-(phenylsulfonyl)benzamide compound and intermediate thereof. The method comprises a method for synthesizing a compound 1, comprising conducting a Buchwald-Hartwig coupling reaction as shown below with compound A and compound B in a solvent and in the presence of a base and a palladium catalyst to obtain the compound 1; wherein R is C.sub.1-C.sub.8 alkyl. The present disclosure synthesizes three intermediate compounds required by the target compound and their preparation methods for the first time. Using the method disclosed in the present disclosure to synthesize the target compound 3 has the advantages of high yield, good purity, easy-to-obtain reaction raw materials, suitable for industrial production.

##STR00001##

Claims

1. A method for synthesizing compound 1, comprising conducting a Buchwald-Hartwig coupling reaction as shown below with compound A and compound B in a solvent and in the presence of a base and a palladium catalyst to obtain compound 1; ##STR00034## wherein R is C.sub.1-C.sub.8 alkyl.

2. The method of claim 1, wherein the palladium catalyst is selected from: palladium acetate, [1,1′-bis(diphenylphosphino) ferrocene] dichloro palladium(II), tetrakis (triphenylphosphine)palladium, bis(triphenylphosphine) palladium(II) chloride, palladium on carbon, palladium hydroxide, [1,3-bis(2,6-diisopropylphenyl) imidazol-2(3H)-ylidene](3-chloro-1-pyridyl)palladium(IV) chloride, tris(dibenzylideneacetone) dipalladium, bis(di-tert-butyl(4-(dimethylaminophenyl) phosphine)dichloropalladium(II), and mixtures thereof; the base is an inorganic base, an organic base, or mixtures thereof, wherein the inorganic base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal phosphate, an alkali metal bicarbonate or a mixture thereof, and the organic base is R.sup.m1OM1, (M2)N(R.sup.n1R.sup.n2) or a mixture thereof, wherein each of M1 and M2 is an alkali metal; each of R.sup.n1 and R.sup.n2 is C.sub.1-C.sub.4 alkyl or —Si(R.sup.s1R.sup.s2R.sup.s3); and each of R.sup.m1, R.sup.s1, R.sup.s2 and R.sup.s3 is C.sub.1-C.sub.4 alkyl; a molar ratio of compound A to the base is 1:(3-10); a molar ratio of compound A to the palladium catalyst is 1:(0.01-0.5); a molar ratio of compound A to compound B is 1:(1-3); the solvent is a chlorinated alkane solvent, an aromatic hydrocarbon solvent, an ether solvent or a mixture thereof, wherein the aromatic hydrocarbon solvent is benzene, toluene, xylene, chlorobenzene or a mixture thereof; the ether solvent is diethyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether or a mixture thereof; the temperature of the Buchwald Hartwig coupling reaction is 40-100° C.; the Buchwald-Hartwig coupling reaction is conducted under the protection of a gas, wherein the gas in the gas protection is nitrogen, helium or argon; the Buchwald-Hartwig coupling reaction is conducted in the presence of a ligand or in the absence of a ligand.

3. The method of claim 1, wherein; the palladium catalyst is bis(di-tert-butyl(4-(dimethylaminophenyl phosphine) dichloropalladium(II); the base is sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium phosphate, lithium carbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, KHMDS, NaHMDS, LDA, potassium tert-pentoxide, sodium tert-pentoxide or a mixture thereof; a molar ratio of compound A to the base is 1:(4.5-8); a molar ratio of compound A to the palladium catalyst is 1:(0.05-0.2); a molar ratio of compound A to compound B is 1:(1-1.5); the solvent is a mixed solvent of an aromatic hydrocarbon solvent and an ether solvent, wherein a mass ratio of the aromatic hydrocarbon solvent to the ether solvent is 1:1-10:1; the temperature of the Buchwald Hartwig coupling reaction is 40-70° C.; when the Buchwald-Hartwig coupling reaction is conducted in the presence of the ligand, the ligand is selected from a monodentate phosphine ligand, a polydentate phosphine ligand or a mixture thereof; when the Buchwald-Hartwig coupling reaction is conducted in the presence of the ligand, a molar ratio of compound A to the ligand is 1:(0.01-0.5).

4. The method of claim 1, wherein; a salt of compound A is used to conduct the Buchwald-Hartwig coupling reaction; the salt of compound A is a salt formed by compound A and an acid; the acid is an inorganic acid or an organic acid; the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is trifluoroacetic acid.

5. The method of claim 4, wherein the salt of compound A dissociates to form compound A ##STR00035##

6. The method of claim 5, wherein the base is an alkali metal carbonate, an alkali metal bicarbonate, an alkali metal phosphate, an alkali metal hydrogen phosphate or a mixture thereof; an amount of the base renders the pH value in the reaction solution between 8 and 9; the solvent is a mixed solvent of water and an organic solvent, wherein the organic solvent is a chlorinated alkane solvent, an aromatic hydrocarbon solvent or a mixture thereof; the chlorinated alkane solvent is dichloromethane, chloroform, 1,2-dichloroethane or a mixture thereof; the aromatic hydrocarbon solvent is benzene, toluene, xylene, chlorobenzene or a mixture thereof; a mass ratio of water to the organic solvent is 1:1-1:20.

7. The method in claim 5 further comprising conducting a reaction as shown below with compound A-7 in a solvent and in the presence of an acid to obtain the salt of compound A; ##STR00036##

8. The method of claim 7, wherein the acid is an inorganic acid or an organic acid, wherein the inorganic acid is hydrochloric acid, sulfuric acid or phosphoric acid; the organic acid is trifluoroacetic acid; a mass ratio of compound A-7 to the acid is 1:(1-10); the solvent is water, a C.sub.1-C.sub.6 alcohol solvent, a chlorinated alkane solvent, an ether solvent, an ester solvent or a mixture thereof, wherein the C.sub.1-C.sub.6 alcohol solvent is methanol, ethanol, isopropanol, tert-butanol, n-butanol or a mixture thereof; the chlorinated alkane solvent is dichloromethane, chloroform, 1,2-dichloroethane or a mixture thereof; the ether solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether or a mixture thereof; a mass ratio of compound A-7 to the solvent is 1:(1-10); the reaction temperature is 30-100° C.

9. The method of claim 7, further comprising conducting a Borch reduction as shown below with compound A-6 and 1-Boc-piperazine in a solvent and in the presence of a reducing agent to obtain compound A-7; ##STR00037##

10. The method of claim 9, wherein, the reducing agent is a metal borohydride; a molar ratio of compound A-6 to the reducing agent is 1:(1-10), preferably 1:(3-10); the solvent is a chlorinated alkane solvent, an ether solvent, a nitrile solvent, an ester solvent or a mixture thereof, wherein the chlorinated alkane solvent is dichloromethane, chloroform, 1,2-dichloroethane or a mixture thereof; the ether solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether or a mixture thereof; the nitrile solvent is acetonitrile; the ester solvent is ethyl acetate, isopropyl acetate or a mixture thereof; a molar ratio of compound A-6 to 1-Boc-piperazine is 1:(1-5); the temperature of the Borch reduction is room temperature to 50° C.; is the reduction is conducted under the protection of a gas, wherein the gas in the gas protection is nitrogen, helium or argon.

11. The method of claim 9, further comprising conducting a coupling reaction as shown below with compound A-5 and 4-chloro phenylboronic acid in a solvent and in the presence of a palladium catalyst and a base to obtain compound A-6 under the protection of a gas; ##STR00038##

12. The method of claim 11, wherein, the gas in the gas protection is nitrogen, helium or argon; the palladium catalyst is palladium acetate, [1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II), tetrakis (triphenylphosphine)palladium, bis(triphenylphosphine) palladium(II) chloride, palladium on carbon, palladium hydroxide, [1,3-bis(2,6-diisopropylphenyl)imidazol-2(31H)-ylidene](3-chloro-1-pyridyl)palladium(IV) chloride, tris(dibenzylideneacetone) dipalladium, bis(di-tert-butyl(4-(dimethylaminophenyl)phosphine)dichloropalladium(II), or a mixture thereof; a molar ratio of compound A-5 to the palladium catalyst is 1:(0.001-0.05); a molar ratio of compound A-5 to 4-chlorophenylboric acid is 1:(0.8-2.5); the base is an inorganic base, wherein the inorganic base is an alkali metal carbonate; a molar ratio of compound A-5 to the base is 1:(1-5); the solvent is water, a C.sub.1-C.sub.6 alcohol solvent, an ether solvent or a mixture thereof, wherein for the mixed solvent, a mass ratio of the ether solvent to water and the alcohol solvent is (1-50):(1-50):1; the C.sub.1-C.sub.6 alcohol solvent is methanol, ethanol, isopropanol, tert-butanol, n-butanol or a mixture thereof; the ether solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, ethylene glycol dimethyl ether or a mixture thereof; the temperature of the coupling reaction is 30-70° C.; the reaction is conducted in the presence of a fluorine-containing additive, wherein the fluorine-containing additive is tetrabutylammonium fluoride, cesium fluoride, potassium fluoride or a mixture thereof; a molar ratio of tie-compound A-5 to the fluorine-containing additive is 1:(0.1-1).

13. The method of claim 11, further comprising conducting a formylation reaction as shown below with compound A-4 in the presence of DMF and POCl.sub.3 to obtain compound A-5; ##STR00039##

14. The method of claim 13, wherein a molar ratio of compound A-4 to POCl.sub.3 is 1:(1-5); a molar ratio of compound A-4 to DMF is 1:(1-5); the solvent is a chlorinated alkane solvent or a mixture thereof; the temperature of the formylation reaction is the reflux temperature of the solvent under normal pressure.

15. The method of claim 13, further comprising conducting a reduction reaction as shown below with compound A-3 in a solvent and in the presence of an organic acid, hydrogen and a metal catalyst to obtain compound A-4; ##STR00040##

16. The method of claim 15, wherein; the organic acid is methanesulfonic acid, p-toluenesulfonic acid, acetic acid or a mixture thereof; a molar ratio of compound A-3 to the organic acid is 1:(0.01-0.5); the metal catalyst is palladium, platinum, palladium on carbon, palladium acetate, palladium hydroxide or a mixture thereof; a mass ratio of compound A-3 to the metal catalyst is 1:(0.01-0.1); the solvent is water, a C.sub.1-C.sub.6 alcohol solvent or a mixture thereof, wherein the C.sub.1-C.sub.6 alcohol solvent is methanol, ethanol, isopropanol, tert-butanol, n-butanol or a mixture thereof; the temperature of the reduction reaction is 50-100° C.; the pressure of hydrogen is 0.5-0.6 MPa.

17. The method of claim 1, further comprising conducting a nucleophilic substitution reaction as shown below with compound B-1 and 5-hydroxy-7-azaindole in a solvent and in the presence of a base to obtain compound B; ##STR00041## wherein R is C.sub.1-C.sub.8 alkyl.

18. The method of claim 17, wherein the base is an inorganic base, an organic base or a mixture thereof, wherein the inorganic base is potassium phosphate, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydride or a mixture thereof; the organic base is potassium tert-butoxide, sodium tert-butoxide or a mixture thereof; a molar ratio of compound B-1 to the base is 1:(1-5); the solvent is a nitrile solvent, an amide solvent or a mixture thereof; a molar ratio of compound B-1 to 5-hydroxy-7-azaindole is 1:(1-5); the temperature of the nucleophilic substitution reaction is 50-100° C.

19. The method of claim 17, further comprising conducting an esterification reaction as shown below with 2-fluoro-4-bromobenzoic acid and alcohol ROH in a solvent and in the presence of a condensing agent to obtain compound B-1; ##STR00042## wherein R is C.sub.1-C.sub.8 alkyl.

20. The method of claim 19, wherein; the condensing agent is EDC.HCl, CDI, DCC, HOBt, HOAT or a mixture thereof; a molar ratio of 2-fluoro-4-bromobenzoic acid to the condensing agent is 1:(1-5); the solvent is a chlorinated alkane solvent; a molar ratio of 2-fluoro-4-bromobenzoic acid to the alcohol is 1:(1-10); the temperature of the esterification reaction is room temperature to 50° C.

21. A method for synthesizing compound 2, which refers to either method 1 or method 2: method 1 comprises conducting a hydrolysis reaction as shown below with compound 1 in a solvent and in the presence of an acid or a base to obtain compound 2; ##STR00043## wherein R is C.sub.1-C.sub.8 alkyl; method 2 comprises conducting a Buchwald-Hartwig coupling reaction as shown below with compound C and compound A in a solvent and in the presence of a base and a palladium catalyst to obtain compound 2; ##STR00044##

22. The method of claim 21, wherein in the method 1, the acid is an inorganic acid, an organic acid or a mixture thereof, wherein the inorganic acid is hydrochloric acid, sulfuric acid or a mixture thereof; the organic acid is acetic acid, trifluoroacetic acid or a mixture thereof; a molar ratio of the acid to compound A is 1:(0.5-1); in the method 1, the base is an inorganic base, an organic base or a mixture thereof, wherein; the inorganic base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate or a mixture thereof; the organic base is triethylamine, pyridine, DBU, DIPEA, triethylenediamine, DBN, DMAP, N-methylmorpholine, tetramethylethylenediamine, potassium tert-butoxide, tert-butanol sodium, n-butyllithium, KHMDS, NaHMDS, LDA, potassium tert-pentoxide, sodium tert-pentoxide or a mixture thereof; a molar ratio of the base to compound A is 1:(0.5-1); in the method 1, the solvent is water, an ether solvent or a mixture thereof, wherein; the ether solvent is diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether or a mixture thereof; in the method 1, the temperature of the hydrolysis reaction is room temperature to 60° C.

23. A method for synthesizing compound 3, comprising conducting an amidation reaction as shown below with compound 2 and compound D in the presence of a condensing agent, a base and a catalyst to obtain compound 3; ##STR00045##

24. The method of claim 23, wherein the condensing agent is DCC, EDC.HCl, CDI, HATU, HBTU, TBTU, HOBT, HOAT or a mixture thereof; a molar ratio of compound 2 to the condensing agent is 1:(1-2); the base is an inorganic base, an organic base or a mixture thereof; wherein the inorganic base is an alkali metal hydroxide, an alkali metal carbonate, an alkali metal bicarbonate or a mixture thereof; the organic base is triethylamine, N,N-diisopropylethylamine, pyridine or a mixture thereof; a molar ratio of compound 2 to the base is 1:(1-5); the catalyst is DMAP; a mass ratio of compound 2 to the catalyst is 1:(0.1-1); a molar ratio of compound 2 to compound D is 1:(0.8-1.5); the temperature of the amidation reaction is 20-50° C.;

25. The method claim 23, further comprising conducting a reaction as shown below with compound D-1 and (S)-2-aminomethyl-1,4-dioxane hydrochloride in a solvent and in the presence of a base to obtain compound D; ##STR00046## wherein X is halogen.

26. The method of claim 25, wherein; the solvent is a nitrile solvent; the base is an inorganic base, an organic base or a mixture thereof, wherein the inorganic base is an alkali metal hydroxide, an alkali metal carbonate or a mixture thereof; a molar ratio of compound D-1 to the base is 1:(1-10); a molar ratio of compound D-1 to (S)-2-aminomethyl-1,4-dioxane hydrochloride is 1:(1-2); the reaction temperature is room temperature to the solvent reflux temperature under normal pressure.

27. A method for synthesizing the salt of compound A, comprising conducting a reaction as shown below with compound A-7 in a solvent and in the presence of an acid to obtain the salt of compound A; ##STR00047##

28. A method for synthesizing compound B, comprising conducting a nucleophilic substitution reaction as shown below with compound B-1 and 5-hydroxy-7-azaindole in the presence of a solvent and a base to obtain compound B; ##STR00048## wherein R is C.sub.1-C.sub.8 alkyl; the conditions of the method for synthesizing the salt of the compound B are the same as those defined in claim 18.

29. A method for synthesizing compound D, comprising conducting a reaction as shown below with compound D-1 and (S)-2-aminomethyl-1,4-dioxane hydrochloride in a solvent and in the presence of a base to obtain compound D; ##STR00049## wherein X is halogen; the conditions of the method for synthesizing the salt of the compound D are the same as those defined in claim 24.

30. A compound or a pharmaceutically acceptable salts thereof selected from one of the following: ##STR00050## ##STR00051##

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0138] The following examples further illustrate the present disclosure, but the present disclosure is not limited thereto. In the following examples, the experimental methods without specific conditions are selected according to conventional methods and conditions, or according to product specifications.

[0139] In the following examples, if the temperature is not specified, it means that it is conducted at room temperature.

Example 1 Synthesis of Hydrochloride Salt of the Compound A

[0140] ##STR00027##

[0141] Step 1 Synthesis of the Compound A-2

[0142] At room temperature, methyl tert-butyl ether (126 mL) was added to a reactor, cyclobutanone (18 g) and triethyl phosphonoacetate (57 g) were added successively under stirring, the reaction temperature was raised to about 50° C.-60° C., potassium hydroxide (17 g) was added. After the addition was completed, the reaction mixture was cooled to room temperature and stirred for 10-12 hours, a sample was taken and in-process control of the reaction was performed. After the reaction was completed, the reaction was quenched with dilute hydrochloric acid. After separation, the aqueous phase was extracted with methyl tert-butyl ether, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and 35 g of the compound A-2 was obtained as a yellow oil.

[0143] Step 2 Synthesis of the Compound A-3

[0144] At room temperature, THF (400 mL) was added to a reactor, sodium hydride (24 g) was added at first, and then diethyl acetonedicarboxylate (61 g) was added, the mixture was stirred, after that the compound A-2 (35 g) and anhydrous ethanol (12 g) were added. Then the reaction solution was heated to 60° C.-70° C., stirred for 1-2 hours, then cooled to room temperature, added with methanol and 20% potassium hydroxide aqueous solution (280 g) successively. And the mixture was heated to 60° C.-70° C. and continued to stir for 12 hours, then cooled to room temperature, added with methyl tert-butyl ether for extraction, the organic phase was discarded to obtain an aqueous phase, which was acidified with concentrated hydrochloric acid at 40° C. Then the reaction solution was heated to 45° C.-50° C. and stirred for 3 hours. After the reaction was completed, the reaction solution was cooled to 0° C.-10° C., filtered and concentrated to obtain a crude product by slurrying with demineralized water, concentrated, dried under vacuum to obtain the compound 3 as an off-white solid (18 g, yield 53%).

[0145] .sup.1HNMR (300 MHz, CDCl.sub.3): δ ppm 2.94 (2H, d, J=1.6), 2.52 (2H, s), 1.79-2.03 (6H, m).

[0146] Step 3 Synthesis of the Compound A-4

[0147] Methanol (121 g) was added to a hydrogenation reactor, compound A-3 (20 g, 0.132 mol) was added, and the mixture was dissolved by stirring. Then acetic acid (0.845 g, 0.014 mol) and 10% Pd/C (1.41 g) were added successively. The mixture was replaced with nitrogen, then replaced with hydrogen, and a hydrogenation reduction was conducted for 3-4 hours, a sample was taken and in-process control of the reaction was performed until the reaction was completed. After filtration, the filtrate was concentrated to dryness to obtain a residue. Then dichloromethane and water were added and separated to obtain an organic phase, then dichloromethane was added to extract the aqueous phase. The organic phases were combined, washed with water until the pH of the aqueous phase was 5-6, dried over anhydrous sodium sulfate, filtered, and the filtrate was fractionated at atmospheric pressure, the distillate at 45-50° C. was collected to obtain 13 g of colorless transparent liquid, with a GC purity of 89%, and a yield of 73.4%.

[0148] .sup.1HNMR (400 MHz, CDCl.sub.3): δ ppm 2.38 (2H, s), 2.19-2.22 (2H, m), 1.75-1.89 (10H, m).

[0149] Step 4 Synthesis of the Compound A-5

[0150] DMF (29 g, 0.40 mol) and CH.sub.2Cl.sub.2 (161 g) were added to a reactor, POCl.sub.3 (54 g, 0.35 mol) was added dropwise at −5-5° C. in an ice-water bath with stirring. After the addition was completed, the reaction was heated to 25° C.-35° C. and stirred at 25° C.-35° C. for 1 hour, and then cooled to −5° C.-5° C., and a solution of the compound A-4 (20 g, 0.15 mol) in CH.sub.2Cl.sub.2 (20 g) was slowly added dropwise. After the addition, the reaction was heated and refluxed for 2-4 hours, then cooled to −10 to 0° C., added dropwise with 20% NaOH aqueous solution, adjusted the pH of the aqueous phase to 5-6, raised to room temperature and stirred for 20-30 minutes, separated. The aqueous phase was extracted with dichloromethane. The organic phase was washed with water and dried over anhydrous sodium sulfate, the filtrate was concentrated to dryness to obtain 24.6 g of oil, and the oil was directly conducted the next reaction without purification.

[0151] Step 5 Synthesis of the Compound A-6

[0152] The compound A-5 (25 g, 0.135 mol), ethylene glycol dimethyl ether (131 g), water (61 g) and ethanol (35 g) were added to a reactor successively. The mixture was stirred for 20-30 minutes, added with potassium carbonate (54 g, 0.39 mol), replaced with nitrogen, added with Pd(PPh.sub.3).sub.2Cl.sub.2 (0.9 g, 0.0013 mol) under the protection of nitrogen, heated to 40° C.-50° C., added dropwise with a solution of p-chlorophenylboronic acid (p-chlorophenylboronic acid (16 g, 0.103 mol)+DME (26 g)+EtOH (6 g)+H.sub.2O (12 g)). After the addition, the reaction temperature was maintained for 1-2 hours. After the reaction was completed, the reaction solution was cooled to 0° C.-10° C., added with water and methyl tert-butyl ether, and separated at room temperature. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 22 g of oil.

[0153] Step 6 Synthesis of the Compound A-7

[0154] 1-Boc-piperazine (32 g, 0.13 mol) was added to a reactor, replaced with nitrogen, then the compound A-6 (22 g, 0.085 mol) and dichloromethane (200 g) were added, and the reaction solution was stirred at 25-35° C. for 40-60 minutes, NaBH(OAc).sub.3 (84 g, 0.40 mol) was added in batches at 25-35° C. After the addition, the reaction was continued for 2-3 hours, then cooled to −5-5° C., added with water and 20% NaOH aqueous solution slowly, adjusted the pH to 7-8, and separated. The organic phase was added with activated carbon and stirred under reflux for 0.5-1.5 hours, filtered while hot, and the filtrate was concentrated to dryness under reduced pressure. The crude product is recrystallized with acetonitrile and filtered to obtain a solid and dried under vacuum.

[0155] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm: 7.38 (2H, d, J=8.4), 7.09 (2H, d, J=8.4), 3.23 (4H, m), 2.69 (2H, s), 2.16 (2H, m), 2.03 (2H, m), 1.73-1.88 (6H, m), 1.63 (2H, t, J.sub.1=12.4, J.sub.2=6.4), 1.35 (9H, s).

[0156] A total yield of the compound A-4 to the compound A-7 was about 79%.

[0157] Step 7 Synthesis of the Hydrochloride Salt of the Compound A

[0158] The compound A-7 (33 g) and isopropanol (260 g) were added to a reactor, the reaction temperature was controlled at 0-30° C., then concentrated hydrochloric acid (28 g) was added dropwise. After the addition, the reaction solution was raised to 60-70° C., stirred, a sample was taken and in-process control of the reaction was performed until the reaction was completed. The reaction solution was cooled to 0-10° C., filtered to obtain 36 g of a crude product, the crude product was recrystallized with a mixed solvent of isopropanol (180 g) and water (13 g), filtered, and the solid was dried under vacuum at 45-50° C. to obtain the hydrochloride salt of the compound A (31 g).

[0159] .sup.1HNMR: (400 MHz, DMSO): δ ppm 11.62 (1H, s), 9.79 (1H, s), 9.46 (1H, s), 9.46 (2H, d, J=8.4), 7.18 (2H, d, J=8.0), 3.38-3.53 (8H, m), 2.88 (2H, s), 2.42 (2H, m), 2.33 (2H, m), 1.73-1.93 (6H, m), 1.69 (2H, t, J.sub.1=12.4, J.sub.2=6.4).

Example 2 Synthesis of the Compound B

[0160] ##STR00028##

[0161] Step 1 Synthesis of the Compound B-1 (Tert-Amyl 2-Fluoro-4-Bromobenzoate)

[0162] 2-Fluoro-4-bromobenzoic acid (30 g, 0.138 mol), dichloromethane (240 mL), EDC.HCl (52 g, 0.271 mol), HOBt (33 g, 0.244 mol) and tert-amyl alcohol (72 g, 0.818 mol) were added to a three-neck flask, the mixture was stirred at room temperature, a sample was taken and in-process control of the reaction was performed until the reaction was completed. The reaction mixture was adjusted to pH 1-2 with dilute hydrochloric acid, separated, the organic phase was washed with saturated NaHCO.sub.3 solution, saturated brine successively, and dried over anhydrous sodium sulfate, filtered and concentrated to dryness to obtain 33 g of oil, with a yield of 84% and a purity of 97%.

[0163] .sup.1HNMR (400 MHz, CDCl.sub.3): δ ppm 7.75 (1H, t, J=8.0), 7.68 (1H, d, J=10.4), 7.54 (1H, dd, J.sub.1=8.4, J.sub.2=2.0), 1.83 (2H, q, J.sub.1=22.4, J.sub.2=15.2, J.sub.3=7.6), 1.39 (6H, s), 0.90 (1H, t, J=7.2).

[0164] Step 2 Synthesis of the Compound B

[0165] 5-Hydroxy-7-azaindole (5 g, 0.037 mol), the compound B-1 (10 g, 0.035 mol), a mixed solvent of DMF and acetonitrile (70 mL/70 mL) and potassium phosphate (10 g) were added to a three-neck flask, the reaction temperature was controlled at 90-95° C. under the protection of N.sub.2, a sample was taken and in-process control of the reaction was performed until the reaction was completed. The reaction solution was cooled to 10° C., water (400 mL) was added, a solid was precipitated. The mixture was stirred for 5 hours, filtered with suction, and the filter cake was washed with water. In addition, ethyl acetate (300 mL) was added to dissolve the filter cake, then the solution was washed with saturated brine, separated, and the organic phase was concentrated to dryness to obtain 12.89 g of a crude product. The crude product was recrystallized with ethyl acetate and n-heptane and filtered. The filter cake was dried at 40° C. to obtain the compound B (10.94 g) with a yield of 78%.

[0166] .sup.1HNMR (400 MHz, CDCl.sub.3): δ ppm 11.76 (1H, s), 8.05 (1H, d, J=2.4), 7.68 (1H, d, J=8.4), 7.62 (1H, d, J=2.8), 7.54 (1H, t, J.sub.1=6, J.sub.2=2.8), 7.41 (1H, dd, J.sub.1=8.4, J.sub.2=1.6), 7.04 (1H, d, J=2.0), 6.44 (1H, q, J.sub.1=4.8, J.sub.2=3.2, J.sub.3=2), 1.75 (2H, q, J.sub.1=22.4, J.sub.2=14.8, J.sub.3=7.6), 1.39 (6H, s), 0.82 (1H, t, J=7.2).

Example 3 Synthesis of the Compound D

[0167] ##STR00029##

[0168] Acetonitrile (1.2 L), (S)-2-aminomethyl-1,4-dioxane hydrochloride (60 g, 0.39 mol), 4-chloro-3-nitrobenzene sulfonamide (92 g, 0.39 mol) and N, N-diisopropylethylenediamine (152 g, 1.17 molmol) were added to a reactor successively, the reaction solution was heated to the reflux temperature of acetonitrile, a sample was taken and in-process control of the reaction was performed until the reaction was completed. The reaction solution was cooled to room temperature, stirred for 30 minutes, filtered, and the filter cake was dried under vacuum at 50° C. to obtain the compound D with a yield of 78% and a purity of not less than 99%.

[0169] .sup.1HNMR (400 MHz, CDCl.sub.3): δ ppm 8.53 (1H, t, J=5.2), 8.48 (1H, d, J=2.0), 7.84 (1H, dd, J.sub.1=9.2, J.sub.2=2), 7.35 (2H, s), 7.27 (1H, d, J=8.8), 3.77-3.81 (3H, m), 3.40-3.67 (5H, m), 3.32-3.35 (1H, m).

Example 4 Synthesis of the Compound 3

[0170] ##STR00030## ##STR00031##

[0171] Step 1 Synthesis of the Compound 1

[0172] The hydrochloride salt of the compound A (2.5 g) and water (12 g) were added to a reactor. The mixture was stirred to dissolve, added with toluene (14 g), added with saturated sodium bicarbonate aqueous solution, adjusted the pH of the aqueous phase to 8-9, separated to obtain a toluene phase, the aqueous phase was extracted with toluene (14 g). The toluene phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and water was removed with toluene to obtain the compound A (2 g).

[0173] Toluene (10.30 g), tetrahydrofuran (5.90 g), the compound B (2.87 g) were added to a reactor, replaced with nitrogen, bis(di-tert-butyl(4-(dimethylaminophenyl)phosphine)dichloropalladium(II) (0.54 g, 7 mmol) and sodium tert-pentoxide (2.91 g) were added under the protection of nitrogen. The reaction mixture was heated and stirred for about 1.0 hour, and then cooled to room temperature. The reaction solution was adjusted to pH with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was stirred with N-acetyl-L-cysteine sodium bicarbonate aqueous solution (N-acetyl-L-cysteine:sodium bicarbonate:water=1:1.1:12.8 mass ratio) three times, separated, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 3.4 g of the compound 1 with a yield of 70%.

[0174] .sup.1HNMR (400 MHz, d-DMSO): δ ppm 11.58 (1H, s), 7.96 (1H, d, J=2.4), 7.66 (1H, d, J=8.8), 7.46 (1H, m), 7.35 (3H, m), 7.08 (2H, d, J=8.4), 6.75 (1H, dd, J.sub.1=9.2, J.sub.2=1.2), 6.36 (2H, m), 3.11 (4H, m), 2.71 (2H, m), 2.26 (2H, m), 2.18 (6H, m), 1.62-1.88 (8H, m), 1.58 (2H, m), 1.28 (6H, s), 0.71-0.75 (3H, t, J=7.6).

[0175] Step 2 Synthesis of the Compound 2

[0176] A solution of the compound 1 (20 g) dissolved in tetrahydrofuran (140 g) was added to a reactor, then potassium tert-butoxide (16 g) and water (16 g) were added slowly, the reaction solution was heated to 50-60° C., a sample was taken and in-process control of the reaction was performed until the reaction was completed. The reaction solution was cooled to 10-20° C., adjusted the pH of the reaction solution to 4-4.5 with 1N hydrochloric acid, extracted with ethyl acetate. The organic phase was washed with a freshly prepared L-cysteine sodium bicarbonate aqueous solution (L-cysteine:sodium bicarbonate:purified water=1:1.5:17.3; mass ratio) for 5 times, each wash was stirred for 1-2 hours, then the organic phase was washed with saturated brine aqueous solution, separated, dried with anhydrous sodium sulfate, filtered, washed with ethyl acetate, concentrated under reduced pressure until a large amount of solids were precipitated, filtered. The filter cake was washed with ethyl acetate, and dried under vacuum to obtain 14 g of the compound 2 with a yield of 80%.

[0177] The compound 2 can also be synthesized by one-pot method,

##STR00032##

[0178] Toluene (4.9 g) and tetrahydrofuran (2.4 g) were added to a reactor, then the compound A (0.7 g) and the compound C (0.9 g) were added, bis(di-tert-butyl(4-(dimethylaminophenyl)phosphine)dichloropalladium(II) (0.08 g) and sodium tert-pentoxide (2.2 g) were added under the protection of nitrogen. The reaction solution was heated to 60° C. and stirred for 20 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and adjusted the pH to 5.0-5.5 with 1N hydrochloric acid, then added with ethyl acetate to extract, separated, the organic phase was stirred with N-acetyl-L-cysteine sodium bicarbonate solution (N-acetyl-L-cysteine:sodium bicarbonate:water=1:1.1:12.8 mass ratio) for 3 times, separated, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (mobile phase:dichloromethane:methanol=20:1), 0.72 g of the compound 2 was obtained with a yield of 47%.

[0179] .sup.1HNMR (400 MHz, d-DMSO): δ ppm: 11.62 (1H, s), 7.99 (1H, d, J=2.4), 7.75 (1H, d, J=8.8), 7.46 (1H, t, J.sub.1=6.0, J.sub.2=2.8), 7.39 (1H, d, J=2.8), 7.33 (2H, J=2.8), 7.05 (2H, d, J=8.0), 6.70 (1H, dd, J.sub.1=8.8, J.sub.2=2.0), 6.35 (1H, t, J.sub.1=4.4, J.sub.2=2.4), 6.33 (1H, d, J=1.6), 3.08 (4H, m), 2.68 (2H, s), 2.15-2.23 (8H, m), 1.67-1.87 (6H, m), 1.58-1.61 (2H, m).

[0180] Step 3 Synthesis of the Compound 3

##STR00033##

[0181] The compound D (2.6 g, 0.008 mol), DMAP (2 g, 0.016 mol) and NMP (15 mL) were added to a reactor. The reaction system was stirred at room temperature for 0.5 hour until the system was clear, added with EDC.HCl (2.2 g), added with a mixed solution of the compound 2 (compound 2+triethylamine+dichloromethane=5 g (0.009 mol)+1.6 g+75 mL). The reaction mixture was stirred overnight, added with N,N-dimethylethylenediamine (1.8 g) to quench the reaction, stirred at room temperature for 4-5 hours, washed with water and 10% acetic acid aqueous solution successively, and adjusted the pH to about 7 with 6% sodium bicarbonate aqueous solution, the organic phase was concentrated and added with 1,4-dioxane until the solution was clear, stirred for 0.5 hour, crystallized under natural cooling, stirred at room temperature overnight, and filtered to obtain 7 g of a crude product.

[0182] Recrystallization method of the compound 3: at room temperature, dichloromethane (30 mL) was added to dissolve the crude product, added with 1,4-dioxane (95 mL) dropwise in 0.5 hour, stirred for 1 hour, concentrated, and cooled naturally to 20° C., filtered and washed the filter cake with 1,4-dioxane to obtain 6 g of the compound 3 with a yield of 78%.

[0183] .sup.1HNMR (400 MHz, d-DMSO): δ ppm 11.70 (1H, s), 11.35 (1H, br), 8.59 (2H, m), 8.05 (1H, d, J=2.6), 7.84 (1H, dd, J.sub.1=9.2, J.sub.2=2.3), 7.51 (3H, m), 7.33 (2H, d, J=8.4), 7.10 (1H, d, J=9.2), 7.04 (2H, d, J=8.4), 6.66 (1H, dd, J.sub.1=8.8, J.sub.2=1.2), 6.39 (1H, dd, J.sub.1=3.6, J.sub.2=2.0), 6.19 (1H, d, J=1.2), 3.77-3.82 (3H, m), 3.64 (1H, t, J=11.2), 3.62 (1H, dd, J.sub.1=10.8, J.sub.2=2.4), 3.30-3.52 (4H, m), 3.06 (4H, m), 2.72 (2H, m), 2.13-2.23 (8H, m), 1.67-1.86 (6H, m), 1.58 (2H, m).