WO2019002344A1

WO2019002344A1 - Method for preparation of alpha-methyl-l-proline

Info

Publication number: WO2019002344A1
Application number: PCT/EP2018/067198
Authority: WO
Inventors: Purong ZHENG; Ruiliang Lu; Zhihua Huang; Yijun Zhang
Original assignee: Lonza Guangzhou Nansha Ltd.; Lonza Ltd
Priority date: 2017-06-29
Filing date: 2018-06-27
Publication date: 2019-01-03

Abstract

The invention discloses a method for preparation of alpha-methyl-L-proline starting from proline and comprising three steps, first a conversion with chloral, then a conversion with methyl bromide and then a conversion with aqueous HCl.

Description

METHOD FOR PREPARATION OF ALPHA- ME THYL-L-PROLINE

The invention discloses a method for preparation of alpha-methyl-L-proline starting from proline and comprising three steps, first a conversion with chloral, then a conversion with methyl bromide and then a conversion with aqueous HC1.

BACKGROUND OF THE INVENTION

Alpha-methyl-L-proline can be used e.g. as a peptidomimetic and allows the preparation of conformationally restricted peptides. Wang et al, Synlett 1999, 1, 33-36, discloses the preparation of N-formyl alpha-methyl-L- proline methyl ester by conversion of proline with chloral to 2-trichloromethyloxazolidinone, which then is methylated with methyl iodide to 4-methyl-2-trichloromethyloxazolidinone, which then is converted by treatment with sodium methoxide to the N-formyl alpha-methyl- L-proline methyl ester.

Wang reports for the methylation with methyl iodide a yield of 58%.

Comparative Examples la, lb, lc and Id confirm that when using acetonitrile the yield is considerably lower than when using toluene.

WO 2012/019430 Al discloses a reaction of proline with chloral to 2- trichloromethyloxazolidinone in chloroform with a yield of 67%; then the 2- trichloromethyloxazolidinone is methylated with methyl iodide with a yield of 75%, then the methylated 2-trichloromethyloxazolidinone is converted with SOCb to alpha-methyl-L- proline methyl ester with a yield of 70%. F. J. Sayago et al. in Tetrahedron, 2008, 64, 84-91, is an overview article and discloses in scheme 3 on page 86 the the preparation of alpha-alkyl-L-proline starting from L-proline.

CN 102372698 A in paragraphs [0464] to [0476] discloses the preparation of 2-methyl- proline methyl ester starting from L-proline. Chloroform is used as solvent in STEP1, the reaction of proline with chloral, which gives a yield of 67%.

W0 2013/182972 Al discloses on page 110 in example 5.1 the compound alpha-methyl-L- proline hydrochloride. There was a need for a method for preparation of alpha-methyl-L-proline which shows higher yield.

Unexpectedly it was found that

when the conversion of L-proline with chloral was done in toluene and acetic acid, then the yield was 85%; whereas when using acetonitrile instead of toluene the yield was only between 41%, 71% and less than 80%, see our Comparative Examples la, lb, lc and Id, and the yield of 71% required twice as much volume of acetonitrile compared with the volume of toluene which gave a yield of 85%;

when in the methylation step methyl bromide was used instead of methyl iodide, then a yield of 76% was observed, and not only of 58% as reported by Wang when using methyl iodide; and

when the conversion of the methylated 2-trichloromethyloxazolidinone was done with

aqueous cone HC1 the yield was 78%.

The method allows for reactions in relatively smaller reaction volumes and with shorter reaction times.

The following abbreviations are used, if not otherwise stated:

BuLi butyllithium, specifically n-butyllithium if not otherwise stated

chloral trichloroacetaldehyde, MW 147.4 g/mol

chloral hydrate MW 165.4 g/mo 1

compound of formula (1) CAS Number 42856-71-3, alpha-methyl-L-proline

LDA Lithium diisopropylamide, CAS Number 4111 -54-0

compound of formula (4) L-proline, CAS Number 147-85-3, (S)-Pyrrolidine-2-carboxylic acid

THF tetrahydrofuran

wt% percent by weight

SUMMARY OF THE INVENTION

Subject of the invention is a method for the preparation of compound of formula (4)

comprising the steps STEP1, the step STEP2 and the step STEP3;

STEP1 comprises a reaction REAC1,

in REAC1 compound of formula (1)

is reacted with chloral to provide compound of formula (2);

REAC1 is done in toluene as solvent and in the presence of acetic acid;

STEP2 comprises a reaction REAC2A and a reaction REAC2B, REAC2B is done after REAC2A;

in REAC2A compound of formula (2) is reacted with lithium diisopropylamide;

in REAC2B the reaction product of REAC2A is reacted with methyl bromide to provide compound of formula (3);

STEP3 comprises a reaction REAC3, in REAC3 compound of formula (3) is reacted with HC1 and water to provide compound of formula (4). DETAILED DESCRIPTION OF THE INVENTION

In REACl the chloral can be used in anhydrous form or as chloral hydrate, preferably chloral hydrate is used. Preferably, compound of formula (2), which is used in STEP2, has been prepared in STEP1. Preferably, compound of formula (3), which is used in STEP3, has been prepared in STEP2.

Preferably, the molar amount of chloral in REACl is from 1 to 2 times, more preferably from 1.2 to 1.7 times, of the molar amount of compound of formula (1).

Preferably, the weight of toluene in REACl is from 2 to 20 times, more preferably from 4 to 15 times, even more preferably from 5 to 12 times, of the weight of compound of formula (1).

Preferably, the volume of toluene in REACl is from 125 to 5 time, more preferably from 50 to 7.5 time, even more preferably from 33.5 to 8.5 time, of the volume of acetic acid in REACl .

Preferably, the reaction temperature TEMPI of REACl is from 50 to 80°C, more preferably from 65 to 70°C.

Preferably, the pressure PRESS 1 during REACl is adjusted according to the vapor pressure of the reaction mixture at the desired TEMPI of REACl . This can be done by applying vacuum, by purging with an inert gas such as nitrogen, applying pressure with an inert gas such as nitrogen, or by a combination of these measures. More preferably, the pressure is adjusted by applying vacuum in order to effect the desired distillation during REACl at the desired TEMP 1. Also a nitrogen purge can be applied during the distillation of REAC 1.

Preferably, the reaction time TIMEl of REACl is from 2 h to 10 h, more preferably from 4 h to 8 h.

Preferably during REACl the reaction mixture is submitted to a distillation DIST1;

more preferably, the volume of the reaction mixture is kept constant during DIST1 by continuously adding a mixture MIXTOLAA, MIXTOLAA is a mxiture of toluene and acetic acid; preferably, MIXTOLAA is a mixture of toluene and acetic acid with a ratio (v/v) of toluene : acetic acid in MIXTOLAA of from 25 : 5 to 25 : 0.2, more preferably of from 25 : 2 to 25 : 0.5, even more preferably of from 25 : 1.5 to 25 : 0.75. More preferably, REACl is started in a mixture of toluene and acetic acid wherein the volume of toluene is from 5 to 15 times, more preferably from 7.5 to 12.5 times, even more preferably from 8.5 to 11.5 times, of the volume of acetic acid.

After REACl, compound of formula (2) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods of purification. It is assumed that in REAC2A, when compound of formula (2) is reacted with lithium diisopropylamide, then the Li salt of compound of formula (2) is formed.

It is assumed that in REAC2B it is the Li salt of compound of formula (2) formed in

REAC2A that is reacted with methyl bromide to provide compound of formula (3). Preferably, the molar amount of lithium diisopropylamide in REAC2A is from 1 to 2 times, more preferably from 1.2 to 1.7 times, of the molar amount of compound of formula (2).

REAC2A or REAC2B or both can be done in the presence of diisopropylamine.

Preferably, the molar amount of diisopropylamine is from 0.1 to 0.5 times, more preferably from 0.15 to 0.4 times, of the molar amount of lithium diisopropylamide.

REAC2A or REAC2B or both can done in a solvent SOLV2, SOLV2 is THF or methyl THF, preferably SOLV2 is THF.

Preferably, both REAC2A and REAC2B are done in the same solvent SOLV2, more preferably both REAC2A and REAC2B are done in THF.

Preferably, the weight of SOLV2 is from 2 to 20 times, more preferably from 4 to 15 times, even more preferably from 5 to 12 times, even more preferably from 6 to 12 times, of the weight of compound of formula (2). Preferably, the lithium diisopropylamide is used in form of a solution in SOLV2. Preferably, when lithium diisopropylamide is used in form of said solution in SOLV2, the weight of SOLV2 in said solution is from 5 to 15 times, more preferably from 6 to 12 times, of the weight of lithium diisopropylamide.

Preferably, the reaction temperature TEMP2A of REAC2A is from -90 to -50°C, more preferably from -80 to -60°C.

The pressure PRESS2A during REAC2A can be the vapor pressure of the reaction mixture at the chosen TEMP2A of REAC2A. Or the pressure can be adjusted by applying vacuum or by applying pressure with an inert gas such as nitrogen, as the case may be.

Preferably, the reaction time TIME2A of REAC2A is from 1 min to 2 h, more preferably from 5 min to 1 h, even more preferably from 10 min to 50 min.

Preferably, the molar amount of methyl bromide in REAC2B is from 1 to 10 times, more preferably from 2 to 7 times, more preferably from 3 to 5 times, of the molar amount of compound of formula (2).

The methyl bromide can be used neat or in form of a solution in SOLV2.

Preferably, when methyl bromide is used in form of a solution in SOLV2, this solution has a content of from 10 to 50 wt%, more preferably of from 20 to 30 wt%, the wt% being based on the total weight of the solution of methyl bromide in SOLV2.

Preferably, the reaction temperature TEMP2B of REAC2B is from -90 to -50°C, more preferably from -80 to -60°C.

The pressure PRESS2B during REAC2B can be the vapor pressure of the reaction mixture at the chosen TEMP2B of REAC2B. Or PRESS2B can be adjusted by applying vacuum or by applying pressure with an inert gas such as nitrogen, as the case may be.

Preferably, the reaction time TIME2B of REAC2B is from 1 h to 10 h, more preferably from 2 h to 7 h, even more preferably from 3 h to 5 h. After REAC2B, compound of formula (3) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods of purification. Preferably, the molar amount of HCl in REAC3 is from 1 to 10 times, more preferably from 2 to 7 times, even more preferably from 3 to 5 times, of the molar amount of compound of formula (3).

Preferably, REAC3 is done in the presence of water, more preferably, the molar amount of water is at least 1 time of the molar amount of compound of formula (3).

More preferably, the water and the HCl, which are required in REAC3, are provided by using HCl in form of an aqueous solution, more preferably the HCl is used as aqueous HCl cone. Preferably, REAC3 is done in toluene as solvent.

Preferably, the weight of toluene is from 1 to 10 times, more preferably from 1.5 to 7.5 times, even more preferably from 1.5 to 5 times, of the weight of compound of formula (3). Preferably, the reaction temperature TEMP3 of REAC3 is from 50 to 100°C, more preferably from 60 to 90°C.

The pressure PRESS3 during REAC3 can be the vapor pressure of the reaction mixture at the chosen TEMP3 of REAC3. Or PRESS3 can be adjusted by applying vacuum, by purging with an inert gas such as nitrogen, applying pressure with an inert gas such as nitrogen, or by a combination of these measures.

Preferably, the reaction time TIME3 of REAC3 is from 1 h to 10 h, more preferably from 1 h to 7 h, even more preferably from 2 to 5 h.

After REAC3, compound of formula (4) can be isolated and purified by conventional methods, which are known to those skilled in the art. These conventional methods include extraction, distillation, preferably fractional distillation, which can be done under reduced pressure, crystallization, chromatography, filtration, washing or any combination of these methods of purification. Both compound of formula (1) and compound of formula (4) are amino acids which can be present in their deprotonated form, in their protonated form or in their zwitterionic form. This is known to the skilled person and depends essentially on the pH of a solution or of a suspension containing them, or, in case of solid substance, on the pH at which they were isolated e.g. from a solution or from a suspension. Therefore compound of formula (1) and compound of formula (4) in present invention comprise all three forms: deprotonated form, protonated form or zwitterionic form.

Examples

Example 1 - 2-trichloromethyloxazolidinone, compound of formula (1)

300 mL toluene, 30 mL acetic acid, 30.0 g L-proline (0.26 mol) and 64.7 g chloral hydrate (0.39 mol) were mixed, the resulting suspension was heated to 65°C and distilled with vacuum (nitrogen purge works also instead of vacuum) while maintaining the temperature in the range of from 57 to 63°C and while adding simultaneously toluene : AcOH 25: 1 (v/v) for keeping an approximately constant volume. The azeotropic distillation continued for 6 h. The resulting mixture was cooled to 35°C and filtered through a silica gel cartridge (30.0 g of silica gel, 100 to 200 M, M means mesh and is determined according to the norm ISO 9001); 50 mL toluene were used for washing the filter cake. The combined filtrate was concentrated at 25 to 30°C under vacuum until no more distillate was observed. 50 mL heptane was added and the resulting mixture was concentrated to dryness again.

150 mL heptane were added, the resulting suspension was stirred for 20 to 30 min at 20 to 30°C. The suspension was filtered, the resulting filter cake was washed with 30 mL heptane and then dried under vacuum at 30°C to provide compound of formula (1) as a white solid. Molar yield with respect to L-proline was 85%.

Example 2 - Methylation of 2-trichloromethyloxazolidinone, compound of formula (2) 15 mL THF and 3.95 g diisopropylamine were mixed and cooled to 0°C. 19.5 mL 1.6 M n- BuLi/THF were added while maintaining the temperature in the range from 0 to 5°C. Then the solution of the resulting Lithium diisoproylamide was warmed to 20 to 30°C.

4.95 g of compound of formula (1), prepared according to example 1, and 25 mL THF were mixed and cooled to -75 to -70°C. The solution of the Lithium diisopropylamide was added in ca. 30 min while maintaining the temperature in the range of from -75 to -65 °C.

30.0 g of a solution of 25 wt-% methyl bromide in THF was added while maintaining the temperature in the range of from -75 to -65 °C.

The resulting suspension was stirred for 4 h.

The suspension was warmed to -35°C. 30 mL of a solution of 12.5 wt-% of N¾ in H₂0 was added in 30 min while stirring. Two phases separated. The organic phase was washed with 20 mL aqueous saturated NaCl solution. The aqueous phases from the separation and the washing were combined and were extracted with 60 mL ethylacetate. The organic phases from the washing and from the extraction were combined and filtered through a silica gel cartridge (5.0g, 100 to 200M, M means mesh and is determined according to the norm ISO 9001). 50 mL toluene were used for washing the silica gel cartridge. The filtrate was concentrated to dryness at 35°C under vacuum to get compound of formula (2) as an oil which was used directly in subsequent reaction. Molar yield with respect to compound of formula (1) was 76%.

Example 3 - alpha-methyl-L-proline, compound of formula (3)

4.00 g of compound of formula (2), prepared according to example 2, 10 mL toluene and 5.0 mL aqueous cone. HCl were mixed. The resulting mixture was heated to 75°C and was stirred at 75°C for 3 h. The resulting mixture was concentrated to dryness at 35°C under vacuum. 10 mL toluene were added and concentrated to dryness again.10 mL acetone were added and concentrated to dryness again. 20 mL acetone were added and the resulting suspension was stirred for 1 h. The suspension was filtered to provide compound of formula (3) as a white solid, which was dried under vacuum at 35°C. Molar yield with respect to compound of formula (2) was 78%.

Comparative Example la - 2-trichloromethyloxazolidinone, compound of formula (1) 10 times of volume of acetonitrile (instead of toluene) with respect to mass of L-proline

200 mL dry acetonitrile, 20.0 g L-proline (0.17 mol) and 40.6 g chloral hydrate (0.24 mol) were mixed, the resulting suspension was heated to 65°C and distilled with vacuum (nitrogen purge works also instead of vacuum) while maintaining the temperature in the range of from 57 to 63°C and while adding simultaneously dry acetonitrile for keeping an approximately constant volume. The azeotropic distillation continued for 7 h. The resulting mixture was concentrated to dryness and 50 mL ethanol were added, the resulting suspension was stirred for 20 to 30 min at 20 to 30°C. The suspension was filtered, the resulting filter cake was washed with 5 mL ethanol and then dried under vacuum at 30°C to provide compound of formula (1) as a light-colored off- white solid.

Molar yield with respect to L-proline was 41%.

Comparative Example lb - 2-trichloromethyloxazolidinone, compound of formula (1) 5 times of volume of acetonitrile (instead of toluene) with respect to mass of L-proline

100 mL dry acetonitrile, 20.0 g L-proline (0.17 mol) and 40.6 g chloral hydrate (0.24 mol) were mixed, the resulting suspension was heated to 65°C and distilled with vacuum (nitrogen purge works also instead of vacuum) while maintaining the temperature in the range of from 57 to 63°C and while adding simultaneously dry acetonitrile for keeping an approximately constant volume. The azeotropic distillation continued for 7 h.

'H-NMR showed the reaction conversion was less than 50%. Comparative Example lc - 2-trichloromethyloxazolidinone, compound of formula (1) 20 times of volume of acetonitrile (instead of toluene) with respect to mass of L-proline

200 mL dry acetonitrile, 10.0 g L-proline (0.08 mol) and 20.0 g chloral hydrate (0.12 mol) were mixed, the resulting suspension was heated to 65°C and distilled with vacuum (nitrogen purge works also instead of vacuum) while maintaining the temperature in the range of from 57 to 63°C and while adding simultaneously dry acetonitrile for keeping an approximately constant volume. The azeotropic distillation continued for 7 h. The resulting mixture was concentrated to dryness and 25 mL ethanol were added, the resulting suspension was stirred for 20 to 30 min at 20 to 30°C. The suspension was filtered, the resulting filter cake was washed with 5 mL ethanol and then dried under vacuum at 30°C to provide compound of formula (1) as a light-colored off- white solid.

Molar yield with respect to L-proline was 71%.

Comparative Example Id - 2-trichloromethyloxazolidinone, compound of formula (1) Acetic acid and 10 times of volume of acetonitrile (instead of toluene) with respect to mass of L-proline

10 mL dry acetonitrile, 1.0 mL acetic acid, 1.01 g L-proline (0.009 mol) and 2.12 g chloral hydrate (0.012 mol) were mixed, the resulting suspension was heated to 65 °C and distilled with vacuum (nitrogen purge works also instead of vacuum) while maintaining the temperature in the range of from 57 to 63°C and while adding simultaneously dry acetonitrile for keeping an approximately constant volume. The azeotropic distillation continued for 7 h. IPC by 'H-NMR showed the reaction conversion was less than 80%.

Comparative Example 3a - alpha-methyl-L-proline, compound of formula (3)

No toluene present in REAC3

4.00 g of compound of formula (2), prepared according to example 2, 20.0 mL aqueous cone. HCl, and 60 mL H₂0 were mixed. The resulting mixture was heated to 100°C and was stirred at 100°C for 3 h. The resulting mixture was concentrated to dryness at 50°C under vacuum. 20 mL acetone were added and concentrated to dryness again. 20 mL acetone were added and concentrated to dryness again. 20 mL acetone were added and the resulting suspension was stirred for 1 h. The suspension was filtered to provide compound of formula (3) as a white solid, which was dried under vacuum at 35°C.

Molar yield with respect to compound of formula (2) was 67%.

Claims

1. Method for the preparation of compound of formula (4)

comprising the steps STEP1, the step STEP2 and the step STEP3;

STEP1 comprises a reaction REAC1,

in REAC1 compound of formula (1)

is reacted with chloral to provide compound of formula (2);

REAC1 is done in toluene as solvent and in the presence of acetic acid; STEP2 comprises a reaction REAC2A and a reaction REAC2B, REAC2B is done after REAC2A;

in REAC2A compound of formula (2) is reacted with lithium diisopropylamide;

STEP3 comprises a reaction REAC3, in REAC3 compound of formula (3) is reacted with HCl and water to provide compound of formula (4).

2. Method according to claim 1, wherein

in REAC1 the chloral is used as chloral hydrate.

3. Method according to claim 1 or 2, wherein

REAC2A or REAC2B are done in a solvent SOLV2, SOLV2 is THF or methyl THF.

4. Method according to claim 3, wherein

both REAC2A and REAC2B are done in the solvent SOLV2, SOLV2 is THF.

5. Method according to claim 3 or 4, wherein

the lithium diisopropylamide as defined in claim 1 is used in form of a solution in SOLV2.

6. Method according to claim 3 or 4, wherein

the methyl bromide as defined in claim 1 is used in form of a solution in SOLV2.

7. Method according to one or more of claims 1 to 6, wherein

the water and the HCl, as defined in claim 1, are provided by using HCl in form of an aqueous solution.