METHOD FOR PREPARING SUBSTITUTED 4-AMINOINDANE DERIVATIVES

Abstract

The present invention relates to a method for preparing substituted 4-aminoindane derivatives of the general formula (I)

##STR00001##

by rearrangement of compounds of the formula (II) in HF, wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 have the definitions as specified in the description.

Claims

1. Process for preparing substituted 4-aminoindane derivative of general formula (I) ##STR00008## in which R.sup.1 is hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.2, R.sup.3 each are mutually independently hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.4 is CO(C.sub.1-C.sub.4)-alkyl, R.sup.5 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl, comprising reacting a compound of Formula (II) ##STR00009## with anhydrous hydrogen fluoride.

2. The process according to claim 1, wherein R.sup.1 is hydrogen or (C.sub.1-C.sub.4)-alkyl R.sup.2 and R.sup.3 each are mutually independently hydrogen or (C.sub.1-C.sub.4)-alkyl, R.sup.4 is CO(C.sub.1-C.sub.4-alkyl), R.sup.5 is hydrogen or (C.sub.1-C.sub.4)-alkyl.

3. The process according to, claim 1, wherein R.sup.1 is hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl, R.sup.2 and R.sup.3 each are mutually independently methyl, ethyl, n-propyl, isopropyl or n-butyl, R.sup.4 is COCH.sub.3, R.sup.5 is hydrogen or methyl.

4. The process according to claim 1, wherein R.sup.1, R.sup.2 and R.sup.3 each are methyl, R.sup.4 is COCH.sub.3, R.sup.5 is hydrogen.

5. The process according to claim 1, wherein the process is carried out at a temperature in the range of from 0 C. and 50 C. .

6. The process according to claim 1, wherein the process is carried out at a temperature in the range of from 0 C. and 40 C. .

7. The process according to claim 1, wherein the process is carried out at a temperature in the range of from 0 C. and 30 C. .

8. The process according to claim 1, wherein the process is carried out at a temperature in the range of from 10 C. and 20 C. .

9. The process according to claim 1, wherein the amount of used hydrogen fluoride is in the range of 1 to 100 molar equivalents, optionally 5 to 30 molar equivalents, especially optionally 5 to 20 molar equivalents based on the total amount of compound of formula (II).

10. The process according to claim 1, wherein the reaction time of hydrogen fluoride with compounds of formula (II) is between 1 and 24 hours, optionally between 10 and 22 hours.

11. Process for preparation of a compound of formula (III) ##STR00010## Wherein R.sup.1 is hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.2, R.sup.3 each are mutually independently hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl, R.sup.4 is CO(C.sub.1C.sub.4)-alkyl, R.sup.5 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl, comprising the process according to claim 1 and further comprising hydrolyzing the compound of formula (I) in water to obtain the compound of formula (III).

12. The process according to claim 11, wherein the process is carried out at a temperature in the range of from 50 C. to 100 C.

Description

DETAILED DESCRIPTION OF THE PROCESS

[0029] 1-Acyl-trialkyl-3,4-dihydro-1H-quinolines of the formula (II) are known and can be prepared according to WO 2014/103811 (Reference Example 1-1 of WO 2014/103811).

[0030] The present inventive process is generally carried out at a temperature in the range of from 10 C. to 80 C., preferably in the range of from 0 C. to 50 C., more preferably in the range of from 0 C. to 40 C., most preferably in the range of from 0 C. to 30 C. and especially preferably at a temperature in the range of from 10 C. to 20 C.

[0031] The process is generally conducted at normal pressure or at elevated pressure in an autoclave.

[0032] The amount of anhydrous HF may be varied over a wide range but is preferably in the range of 1 to 100 molar equivalents, particularly preferably 5 to 30 molar equivalents and especially preferably 5 to 20 molar equivalents, in each case based on the total amount of compounds of the formula (II).

[0033] HF can be used in anhydrous form, as a solution in organic solvents (ethers, such as tetrahydrofuran (THF)) or as aqueous solution. Preferably, the process according to the invention is carried out in anhydrous HF.

[0034] The processes is preferably carried out without additional organic solvent, using anhydrous HF as a reagent and as solvent. But it is possible to replace a part of anhydrous HF by an organic solvent, in particular by ethers such as THF, dioxane, diethyl ether, diglyme, methyl tert-butyl ether (MTBE), tert-amyl methyl ether (TAME), dimethyl ether, 2-methyl-THF; nitriles such as acetonitrile (ACN) or butyronitrile; ketones such as acetone, methyl isobutyl ketone (MIBK); aromatic hydrocarbons such as toluene, anisole, xylenes, mesitylene; esters such as ethyl acetate, isopropyl acetate, butyl acetate, pentyl acetate; alcohols such as methanol, ethanol, propanol, butanol, ethylene glycol; carbonates such as ethylene carbonate, propylene carbonate; amides such as N,N-dimethylacetamide (DMAc), N,N-dimethylformamide (DMF), N-methylpyrrolidone; halohydrocarbons and halogenated aromatic hydrocarbons, particularly chlorohydrocarbons such as tetrachloroethylene, tetrachloroethane, dichloropropane, methylene chloride (dichloromethane, DCM), dichlorobutane, chloroform, carbon tetrachloride, trichloroethane, trichloroethylene, pentachloroethane, difluorobenzene, 1,2-dichloroethane, chlorobenzene, bromobenzene, dichlorobenzene, especially 1,2-dichlorobenzene, chlorotoluene, trichlorobenzene; fluorinated aliphatic and aromatic compounds such as trichlorotrifluoroethane, benzotrifluoride or 4-chlorobenzotrifluoride.

[0035] Preferably, HF is used in anhydrous form, optionally as solution in organic solvents, more preferably HF is used in anhydrous form with a boiling point of 20 C. (i.e. without any organic solvents and free of water).

[0036] The reaction time in anhydrous HF is not critical and it can generally be varied from 1 to 24 hours (h), preferably from 10 to 22 h.

[0037] According to the invention the starting material, i.e. a compound according to formula (II), is mixed with anhydrous HF and stirred for a certain time under a certain temperature as defined above. For the isolation of the product the excess of anhydrous HF preferably is removed using distillation and the (precipitated) product of formula (I) is obtained (filtered off).

[0038] Depending on the work up and isolation method of the reaction mixture obtained after reaction of the compound of the formula (II) with anhydrous HF, it is possible to get either a compound of the formula (I), wherein R.sub.4 is CO(C.sub.1-C.sub.4-alkyl), or a compound of the formula (III), wherein R4 is hydrogen, i.e. a free amine as illustrated in the process scheme and also in the preparation examples 1 and 2 below.

[0039] The compound of the formula (I) wherein R.sub.4 is CO(C.sub.1-C.sub.4-alkyl) is isolated from the reaction mixture as a solid upon removal of HF via distillation. The solid is washed with cold water (5-10 C.) to remove the traces of HF and dried. In order to prepare a compound of the formula (III) wherein R.sub.4 is H, water is added to the precipitate after the removal of HF and this mixture is heated to a temperature in the range of from 50 C. to 100 C., preferably in the range of from 60 C. to 100 C., especially preferably at a temperature in the range of from 80 C. to 100 C. for 6 to 10 h. After transformation, the pH of the medium is adjusted to 8 upon addition of aqueous solution of NaOH, the product is filtered off or extracted with organic solvent and dried. The amount of water may be varied over a wide range but is preferably in the range of from 1 to 100 molar equivalents, particularly preferably in the range of from 5 to 30 molar equivalents and especially preferably in the range of from 5 to 20 molar equivalents, in each case based on the total amount of compounds of the formula (I). The work up and isolation is generally conducted at normal pressure.

##STR00004##

wherein in formulae (I), (II) and (III) the substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 each have the general, preferred, particularly preferred or especially preferred meanings which have already been mentioned for these substituents in connection with the description of the compounds of the formulae (I), (II) and (III).

[0040] In the following, preferred embodiment of the present invention are described.

[0041] A first preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl,
R.sup.2, R.sup.3 each are mutually independently hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl,
R.sup.4 is CO(C.sub.1-C.sub.4)-alkyl,
R.sup.5 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above, is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0042] A second preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is methyl,
R.sup.2, R.sup.3 each are mutually independently hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl,
R.sup.4 is CO(C.sub.1-C.sub.4)-alkyl,
R.sup.5 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0043] A third preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is (C.sub.2-C.sub.8)-alkyl,
R.sup.2, R.sup.3 each are mutually independently hydrogen, (C.sub.1-C.sub.8)-alkyl or (C.sub.3-C.sub.8)-cycloalkyl,
R.sup.4 is CO(C.sub.1-C.sub.4)-alkyl,
R.sup.5 is hydrogen, halogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0044] A fourth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is hydrogen or (C.sub.1-C.sub.4)-alkyl
R.sup.2 and R.sup.3 each are mutually independently hydrogen or (C.sub.1-C.sub.4)-alkyl,
R.sup.4 is CO(C.sub.1-C.sub.4-alkyl),
R.sup.5 is hydrogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0045] A fifth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is methyl,
R.sup.2 and R.sup.3 each are mutually independently hydrogen or (C.sub.1-C.sub.4)-alkyl,
R.sup.4 is CO(C.sub.1-C.sub.4-alkyl),
R.sup.5 is hydrogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0046] A sixth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 (C.sub.2-C.sub.4)-alkyl,
R.sup.2 and R.sup.3 each are mutually independently hydrogen or (C.sub.1-C.sub.4)-alkyl,
R.sup.4 is CO(C.sub.1-C.sub.4-alkyl),
R.sup.5 is hydrogen or (C.sub.1-C.sub.4)-alkyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0047] A seventh preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 hydrogen, methyl, ethyl, n-propyl, isopropyl or n-butyl,
R.sup.2 and R.sup.3 each are mutually independently methyl, ethyl, n-propyl, isopropyl or n-butyl,
R.sup.4 is CO-CH.sub.3 (i.e. acetyl),
R.sup.5 is hydrogen or methyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1 , R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0048] An eighth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is methyl,
R.sup.2 and R.sup.3 each are mutually independently methyl, ethyl, n-propyl, isopropyl or n-butyl,
R.sup.4 is COCH.sub.3,
R.sup.5 is hydrogen or methyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0049] A ninth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1 is ethyl, n-propyl, isopropyl or n-butyl,

[0050] R.sup.2 and R.sup.3 each are mutually independently methyl, ethyl, n-propyl, isopropyl or n-butyl,

R.sup.4 is COCH.sub.3,
R.sup.5 is hydrogen or methyl,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0051] A tenth preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.2 and R.sup.3 each are methyl,
R.sup.4 is COCH.sub.3,
R.sup.5 is hydrogen,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

[0052] An eleventh preferred embodiment is the process for preparing substituted 4-aminoindane derivatives of the general formula (I) as defined above, in which

R.sup.1is n-propyl,
R.sup.2 and R.sup.3 each are methyl,
R.sup.4 is COCH.sub.3
R.sup.5 is hydrogen,
characterized in that a compound of the Formula (II) as defined above is reacted with anhydrous HF at a temperature in the range of from 0 C. to 30 C., wherein the definitions of the residues R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 listed in the formula (II) are the same as in the formula (I).

PREPARATION EXAMPLES

Example 1: Synthesis of N-(1,1,3-trimethylindan-4-yl)acetamide (a Compound of Formula (I))

[0053] ##STR00005##

[0054] 80 g of anhydrous hydrogen fluoride (HF) was initially charged in a 250 mL teflon reactor and cooled to 0 C. 21.7 g (0.1 mol) of 1-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone were added and the reaction mixture was allowed to warm slowly to 15 C. within 1 h. The reaction mixture was stirred at this temperature for 20 h and 70-75 g of HF was then distilled off and recovered. The solid which precipitated was filtered off and washed three times with 20 ml of cold water and dried to give 21 g of N-(1,1,3-trimethylindan-4-yl)acetamide (97% yield) as pale yellow solid with a melting point (m.p.) of 115-116 C.

[0055] .sup.1H NMR (DMSO) : 9.31; (s,1H), 7.22; (d, 1H), 7.12; (t, 1H), 6.95; (d, 1H), 3.40; (m, 1H), 2.13; (dd, 1H) 2.03; (s, 3H), 1.51; (dd, 1H), 1.28; (s, 3H), 1.18; (d,3H), 1.15; (s, 3H) ppm.

[0056] Likewise, the compound N-(1,1-dimethyl-3-propylindan-4-yl)acetamide , wherein R.sup.1 is propyl, could be obtained with this process.

[0057] Compared to the processes known from EP 0654464 and Cliffe et al. (J. Chem. Soc. (C), 1966, 514-517: The Acid-catalyzed Rearrangement of Tetrahydroquinoline Derivatives) the process according to the invention leads to a decreased amount of waste:

[0058] According to EP 0654464, 55 g of the starting material were used in reaction with 50 ml (i.e. 90 g) of concentrated H.sub.2SO.sub.4. To isolate the product (4-amino-1,1,3-trimethylindane), 50 ml (i.e. 50 g) of water and 150 ml of ammonia (35% solution in water; i.e. 150 g) were added (to form ammonia sulfate) and the product was isolated upon extraction. In conclusion, for 22 g of the obtained product 290 g liquid waste (water solution of ammonium sulfate) were produced which equals 1 g of desired product per 13 g of liquid waste.

[0059] Cliffe et al. describe the rearrangement of quinolines into aminoindane derivatives upon heating with H.sub.2SO.sub.4. For the preparation of 1 g of the product 10 g of H.sub.2SO.sub.4 (concentrated) are needed producing after work up at least 50-100 g of diluted H.sub.2SO.sub.4. Although not explicitly disclosed in the document, this diluted H.sub.2SO.sub.4 should be completely neutralized in order to isolate the desired aminoindane derivatives, which easily form a water soluble salt with H.sub.2SO.sub.4. In conclusion, also the process according to Cliffe et al. presumably produces higher amounts of liquid waste per unit of product.

[0060] Contrary to that, the process according to the present invention consumes maximum 1 equivalent of anhydrous HF based on the total amount of employed reactant and the excess of HF used for the rearrangement can be completely recovered.

Example 2 (reference example): Synthesis of 1,1,3-trimethyl-indan-4-amine (a Compound of Formula (III))

[0061] ##STR00006##

[0062] 80 g of anhydrous hydrogen fluoride was initially charged in a 250 mL teflon reactor and cooled to 0 C. 21.7 g (0.1 mol) of 1-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone were added and the reaction mixture allowed to warm slowly to 19 C. The reaction mixture was stirred at this temperature for 20 h and 70-75 g of HF was then distilled off 60 g of water were added and the mixture was heated for 6 h at 100 C. Then the pH of the solution was adjusted to 8 with 4-5 ml of 40% NaOH solution in water and the product extracted with ethylacetate. Organic solvent was evaporated to give 15.7 (90%) of 1,1,3-trimethyl-indan-4-amine as pale yellow oil.

[0063] Mass spectra: m/z 175.

[0064] Likewise, the compound 1,1-dimethyl-3-propylindan-4-amine, wherein R.sup.1 is propyl, could be obtained with this process.

Example 3 (Reference Example): Synthesis of 1,1,3-trimethyl-indan-4-amine (a Compound of Formula (III)) with HF Recovery

[0065] ##STR00007##

[0066] 80 g of anhydrous hydrogen fluoride was initially charged in a 250 mL teflon reactor and cooled to 0 C. 21.7 g (0.1 mol) of 1-(2,2,4-trimethyl-3,4-dihydroquinolin-1-yl)ethanone were added and the reaction mixture allowed to warm slowly to 19 C. The reaction mixture was stirred at this temperature for 20 h and 70 ml Toluene were added. HF was then distilled off under normal pressure at 30-40 C. collecting (75-78 g) of HF. 60 g of water were added and two phase mixture was heated for 6 hat 100 C. Then the pH of the solution was adjusted to 8 with 2-3 ml of 40% NaOH solution in water, organic phase separated and toluene removed in vacuum to give 16 g of 1,1,3-trimethyl-indan-4-amine as pale yellow oil.