IL108829A - Enzymatic process for the preparation of optically pure (2R-trans)-alkyl-2-piperidinecarboxylates and use of the compounds obtained as synthesis intermediates - Google Patents
Enzymatic process for the preparation of optically pure (2R-trans)-alkyl-2-piperidinecarboxylates and use of the compounds obtained as synthesis intermediatesInfo
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- C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
- C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
Process for preparing alkyl (2R-trans)-piperidine-2-carboxylates of formula (I) <IMAGE> in which R represents a (C1-C3)alkoxy group and R3 represents a (C1-C3)alkyl group, according to which process an alkyl piperidine-2-carboxylate in the form of a racemate of trans configuration is reacted with an enzyme which specifically degrades the (2S-trans) enantiomer, leaving the (2R-trans) enantiomer essentially intact.
Description
108829/2 - 2 -^p^tf (Ώ31Ό - 2R) n33iT7 ΊΌΤΓΤ3ί* Τ^ΠΓΙ mzrmju anrnnm "•OSIN ΎΙΓΓΟ Ί*7ΐη o^^upixiprTng^g ΠΤΠΓΌ:Ι ϋ'Ί-'η πτπτπ πΤ72ρηππ ENZYMATIC PROCESS FOR THE PREPARATION OF OPTICALLY PURE (2R- TRANS ALKYL 2-PIPERIDINECARBOXYLATES AND USE OF THE COMPOUNDS OBTAINED AS SYNTHESIS INTERMEDIATES SYNTHELABO C: 18516 The present invention relates to a process for the enzymatic preparation of optically pure alkyl (2R-trans) -2--pipe idi ecarboxylatoe of formula (1) in which R represents a (Ct-C4) alkoxycarbonyl group and Rj represents a (C,-^) alkyl group.
These compounds are intermediates in the synthesis of compounds having antithrombotic activity.
Ethyl 4-methyl-2-piporidine carboxylate is described in European Patent 0,008,746 in the form of a racemate and the preparation of the (2R-trans) form is performed by preferential crystallisation using tartaric acid via the corresponding acid (4-methyl-2-piperidinecarbox lic acid).
The process according to the invention consists in a separation of the enantioroers by means of an enzyme which is capable of preferentially hydrolysing the (2S-trans) enantio er, leaving the (2R-trans) onantiomcr intact.
The process according to the invention makes it possible to obtain the optically pure (2R-trans) enantiomer in good yield and with enantiomeric excesses of between 98 and 99%.
The starting compound, in the form of a racemate and of trans configuration, is dissolved in an organic solvent such as, for example, 1, 1-dimethylethyl methyl ether, to which is added an aqueous solution buffered with a 0.01 mixture at pH 7 of sodium hydrogen phosphate and potassium dihydrogen phosphate. The pH of the reaction medium is adjusted to 7.4 and the enzyme is added. The reaction occurs in 4 to 25 hours, depending on the enzyme used, at a temperature of 20 to 37 °C and at a pH of 7.4, which is kept constant by addition of a 1 M sodium hydroxide solution with the aid of a pH-stat. The progress of the reaction is monitored by high performance liquid chromatography on a chiral phase. At the end of the reaction the pH is adjusted to 9, the insoluble material is filtered off, if necessary, and extraction is carried out using an organic solvent such as, for example, diethyl ether.
Preferred enzymes which may be used in the process of the invention in order to preferentially hydrolyse the (2S-trans) enantiomer are lipase AY, lipase N, lipase M Amano 10 (Mucor) or prozyme 6 Aspergillus from the company Amano Pharmaceutical Ltd., protease Aspergillus oryzae (Sigma) , cholesterol esterase (Boehringer) , sheep pancreas acetone powder (Sigma) or porcine type I pancreas acetone powder (Sigma) .
The starting compounds are commercially available or are described in the literature or may be prepared according to methods which are described therein or which are known to a person skilled in the art.
The following examples illustrate the process of the invention. Elemental microanalyses and the IR and N R spectra confirm the structure of the compounds obtained.
Example 1 Ethyl (2R-trans) -4-methyl-2-piperidinecarboxylate Method 1 10 g (58.5 mmol) of the racemate ethyl (trans) -4-methyl-2-piperidinecarboxylate are dissolved in 40 ml of 1, 1-dimethylethyl methyl ether and 150 ml of 0.01 M phosphate buffer (KH2P04 + Na2HP04) at pH 7.
The pH is adjusted to 7.4 with a 1 M hydrochloric acid solution and 8 g of porcine type I pancreas acetone powder (Sigma) are then added. The pH is kept constant during the 4 hours 30 minutes of reaction by addition of a 1 M sodium hydroxide solution with the aid of a pH-stat and the progress of the reaction is followed by high performance liquid chromatography on a chiral phase. After addition of 31 ml of sodium hydroxide, 100 ml of diethyl ether are added, the pH is adjusted to 9 and the mixture is filtered through Celite. The extraction is repeated- 4 times and the organic phases are combined, dried over magnesium sulphate and filtered and the solvent is evaporated off under vacuum. 4.23 g of the expected^compound are obtained in the form of an oil, with an enantiomeric excess of 98 %.
Yield = 42 % [a 22 (C = 2.66 ethanol) Method 2 1.21 g (7.08 mmol) of the racemate ethyl (trans) -4-methyl-2-piperidinecarboxylate are suspended in 30 ml of 0.01 M phosphate buffer ( H2P04 + Na2HP04) at pH 7. The pH is adjusted to 7 with a 1 M hydrochloric acid solution and 1.5 g of Prozyme 6 (Amano) are then added. The pH is kept constant during the 22 hours of reaction by addition of a 1 M sodium hydroxide solution with the aid of a pH-stat and the progress of the reaction is followed by high performance liquid chromatography on a chiral phase. After 22 hours, the pH is adjusted to 9 and the chiral ester is extracted with 4 times 40 ml of diethyl ether. The organic phases are combined, dried over magnesium sulphate and filtered and the solvent is evaporated off under vacuum. 430 mg of the expected compound are obtained in the form of an oil, with an enantiomeric excess of 96 %.
Yield = 35 % Example 2 Ethyl (2R-trans) -4-ethyl-2-piperidinecarboxylate 1 g (5.4 mmol) of the racemate ethyl (trans) -4-ethyl-2-piperidinecarboxylate is dissolved in 58 ml of toluene. 58 ml of 0.01 M phosphate buffer (KH2P04 + Na2HP04) at pH 7 and 1.3 g of porcine type I pancreas acetone powder (Sigma) are added. The progress of the reaction is followed by high performance liquid chromatography on a chiral column and at the end of 4 hours 50 ml of diethyl ether are added, the pH is adjusted to 9 and the solution is filtered through Celite. The extraction is repeated 4 times and the organic phases are combined, dried over magnesium sulphate, filtered and evaporated under vacuum. 500 mg of product are obtained in the form of an oil, with an enantiomeric excess of 99 %.
Yield = 50 % [a]*0 = -13.45° (c = 1.13; chloroform) The derivatives of formula (1) obtained according to the process of the invention are useful for the synthesis of trifluoroacetates of formula (2) in which R2 represents either a carboxylic group or a sodium carboxylate group or an amide group of formula -CONP^Rg or a group -CH2OR4 or a group -CN4R4, R being a hydrogen atom or a (Cj-C^) alky) group and R5 being a hydrogen atom, a (C,-^) alky] group, a hydroxyl group, a (C,-^) alkoxy group or a phenylmethoxy group and Rj represents a (Cj-C alky} group, in the (2U-trans) form.
The compounds of formula (2) in which R2 represents a group -CONR4Rs where R4 is a hydrogen atom or a (C-C alkyl group and R5 ie a hydrogen atom, a (Ct-C4) alkyl group, a hydroxyl group, a .(.Cj-C^) alkoxy group or a phenylmethoxy group may thus be prepared in the following way: a compound of formula (1) is treated with bis(l,l-dimethylethyl) dicarbonate in a solvent such as dichloromethane under standard conditions. A compound protected on the nitrogen is obtained, which is saponified with an aqueous sodium hydroxide solution and then reacted with an amine of formula HN 4R5, in which R4 and 5 are as defined above, to obtain an amide? the reaction is carried out in the presence of a base such as, for example, 4-methylmorpholine or N,N-diisopropylethylamine ("Hunig's base") and a coupling agent such as, for example, [ (benzotriafcol-l-yl ) oxy)trie(di eth lamino) hosphonium hexafluorophosphate or isobutyl chlorofor ate.
Trifluoroacetic acid is then reacted with the amide obtained, in dichloromethane, in the optional presence of methoxybeiiKene.
The compounds of formula (2) in which R2 represents a group -CH2OR4 where R4 is a hydrogen atom, may be synthesised in the following way: a compound of formula (1) is treated with bis (1, 1-dimethylethyl) dicarbonate in a solvent such as dichloromethane under standard conditions. A compound protected on the nitrogen is obtained, which is saponified with an aqueous sodium hydroxide solution, and the carboxyl functionality is then reduced either by the mixed anhydride method described by Valerio R.M. et al. in Synthesis, 1988, 786 or by the action of borane-dimethyl sulphide in a solvent such as tetrahydrofuran. The amine is then deprotected by the action of trifluoroacetic acid.
The compounds of formula (2) in which Rj represents a group -CH2OR4 where R4 is a (C,-C4) alkyl group may be synthesised in the following way: a compound of formula (1) is treated with bis (1,1-dimethy1ethyl) dicarbonate in a solvent such as dichloromethane under standard conditions. A compound protected on the nitrogen is obtained, which is saponified with an aqueous sodium hydroxide solution; the product is then reacted with an alkyl halide, preferably an alkyl iodide, in the presence of a base such as, for example, sodium hydride, and the compound thus obtained is then treated with trifluoroacetic acid in dichloromethane.
The compounds of formula (2) in which Rj represents a group -CN4R4 in which R4 is a hydrogen atom may be synthesised in the following way: a compound of formula (1) is treated with bis ( \, 1-dimethylethyl) dicarbonate in a solvent such as dichloromethane under standard conditions. A compound protected on the nitrogen is obtained, which is saponified with an aqueous sodium hydroxide solution. The compound thus obtained is condensed with aqueous ammonia in the presence of a base such as, for example, 4-methylmorpholine and a coupling agent such as, for example, isobutyl chloroformate in a solvent such as tetrahydrofuran. The carboxamide thus obtained is dehydrated with phosphorus oxychloride to give a nitrile which is heated in the presence of sodium azide and ammonium chloride in a solvent such as, for example, dimethylfor amide. A tetrazolyl derivative is obtained which is treated with trifluoroacetic acid.
The compounds of formula (2) in which R2 represents a group -CN4R4 where 4 is a (C^C^) alkyl group may be synthesised in the following way: a compound of formula (1) is treated with bis ( 1,1-dimethylethyl) dicarbonate in a solvent such as dichloromethane under standard conditions. A compound protected on the nitrogen is obtained, which is saponified with an aqueous sodium hydroxide solution. The compound thus obtained is condensed with aqueous ammonia in the presence of a base such as, for example, 4-methylmorpholine and a coupling agent such as, for example, isobutyl chloroformate in a solvent such as tetrahydrofuran. The carboxamide thus obtained is dehydrated with phosphorus oxychloride to give a nitrile which is heated in the presence of sodium azide and ammonium chloride in a solvent such as, for example, dimethylformamide. The tetrazolyl derivative obtained is then condensed with an alkyl halide, preferably an alkyl iodide, then the compound obtained is treated with trifluoroacetic acid.
Examples 3 to 5 which follow "illustrate the use of compounds of formula (1) for the synthesis of compounds of formula (2) .
Example 3 (2R-trans) -N-Ethyl-4-methyl-2-piperidinecarboxamide trifluoroacetate 3.1. (2R-trans) -4-methyl-l, 2-piperidinedicarboxylic acid 1-(1, 1-dimethy1ethyl) ester 510 mg (3 mmol) of ethyl (2R-trans) -4-methyl-2-piperidinecarboxylate are placed in 10 ml of dichloromethane and 654 mg (3 mmol) of bis (1,1-dimethylethyl) dicarbonate are added, under nitrogen, at 0°C. The temperature of the reaction medium is allowed to return to room temperature overnight, the solvent is evaporated and the residue is taken up in 4 ml of ethanol and 3 ml of a 1 N sodium hydroxide solution. The mixture is left overnight at room temperature, then a further 3 ml of 1 N sodium hydroxide solution are added. The reaction medium is then evaporated and the residue is taken up with water and washed with ether. The medium is acidified with 1 N hydrochloric acid and then extracted twice with ether. The organic phases are rinsed with 10 ml of a saturated sodium chloride solution and dried over magnesium sulphate. 0.68 g of product is obtained.
Melting point = 87-90 "C Yield = 97 % 3.2. 1, 1-dimethylethyl (2R-trans) -2- [ (ethylamino) carbonyl]-4-methyl-l-piperidinecarboxylate 1 g (4.11 mmol) of the 1-(1, 1-dimethylethyl) ester of (2R-trans) -4-methyl-l, 2-piperidinedicarboxylic acid is dissolved in 15 ml of tetrahydrofuran. 0.45 ml (4 mmol) of 4-methylmorpholine is added under argon and at room temperature, then the mixture is cooled to a temperature between -10 and -15°C. 0.53 ml (4 mmol) of 2-methylpropyl chlorofor ate is then added, followed by 0.278 g (6 mmol) of ethanamine dissolved in 3 ml of tetrahydrofuran. The medium is allowed to return to room temperature and the tetrahydrofuran is then evaporated. The residue is taken up with 100 ml of ether and is successively washed with 50 ml of 1 N hydrochloric acid, 50 ml of water and finally 50 ml of a saturated sodium hydrogen carbonate solution. The resultant solution is dried over magnesium sulphate. 1.06 g of product are obtained.
Yield = 95 % 3.3. (2R-trans) -N-ethyl-4-methyl-2-piperidinecarboxamide trifluoroacetate 4 0.352 g (1.3 mmol) of 1 , 1-dimethylethyl (2R-trans) -2- [ (ethylamino) carbonyl] -4-methyl-l-piperidine carboxylate is dissolved in 5.4 ml of dichloromethane. 5.4 ml of trifluoroacetic acid are added under argon and at O'C. The medium is allowed to return to room temperature and the solvent is then evaporated off. The residue is taken up in 50 ml of dichloromethane and the solvent is again evaporated off. 0.686 g of crude product is obtained.
Example 4 (2R-trans) -4-Methyl-N- (phenylmethoxy) -2-piperidinecarboxamide trifluoroacetate 4.1. 1, 1-dimethylethyl (2R-trans) -4-methyl-2- [ [ (phenylmethoxy) amino] carbonyl ]-l- piperidinecarbox late 1 g (4.03 mmol) of the 1- (1, 1-dimethylethyl) ester of (2R-trans) -4-methyl-l, 2-piperidinedicarboxylic acid is placed in 15 ml of tetrahydrofuran under nitrogen. The solution is cooled to -15 °C and 0.47 ml (4 mmol) of 4-methylmorpholine and 0.56 ml (4 mmol) of 2-methylpropyl chloroformate are added. The mixture is stirred for 5 minutes and 0.755 g (4.7 mmol) of O- (phenylmethyl) hydroxylamine hydrochloride dissolved in a mixture of 5 ml of tetrahydrofuran and 0.52 ml of 4-methylmorpholine is added. After stirring overnight at room temperature the reaction medium is poured into 3 volumes of ethyl acetate. The mixture is successively washed with 50 ml of 0.1 N hydrochloric acid, 50 ml of water, 50 ml of sodium hydrogen carbonate, 50 ml of water and finally with 50 ml of a saturated sodium chloride solution. The resultant solution is dried over magnesium sulphate and the residue is recrystallised by trituration in ether. 0.95 g of product is obtained.
Melting point = 107-108 °C 4.2. (2R-trans) -4-methyl-N- (phenylmethoxy) -2- piperidinecarboxamide trifluoroacetate A solution of 450 mg (1.4 mmol) of 1,1-dimethylethyl (2R-trans) -4-methyl-2-[ [ (phenylmethoxy) amino] carbonyl]-l-piperidinecarboxylate in a mixture of 5 ml of trifluoroacetic acid and 5 ml of dichloromethane is stirred for 15 minutes at O'C. The solvent is evaporated off, the residue is taken up with 10 ml of benzene and the solvent is again evaporated off. 700 mg of product are obtained in the form of an oil.
Example 5 (2R-trans) -4- ethyl-2- ( lH-tetrazol-5-yl) piperidine trifluoroacetate t 5.1. 1, 1-dimethylethyl (2R-trans) -2- (aminocarbonyl) -4- methyl-l-piperidinecarboxylate 1 g (4.03 mmol) of the 1- (1, 1-dimethylethyl) ester of (2R-trans) -4-methyl-l, 2-piperidinedicarboxylic acid is placed in 15 ml of tetrahydrofuran under nitrogen. The reaction medium is cooled to -15 °C and 0.47 ml (4 mmol) of 4-methylmorpholine and then 0.56 ml (4 mmol) of 2-methylpropyl chloroformate are added. The » mixture is stirred for 5 minutes and then an excess of aqueous ammonia is added. The mixture is allowed to return to room temperature, then the reaction medium is stirred for 1 hour. It is poured into 3 volumes of ethyl acetate and the resulting mixture is successively washed with 50 ml of 0.1 N hydrochloric acid, 50 ml of water, 50 ml of a sodium hydrogen carbonate solution, 50 ml of water and finally with 50 ml of a saturated sodium chloride solution. The mixture is dried over magnesium sulphate and the solvent is evaporated off. 1 g of product is obtained in the form of an opaque oil, which is used as it is in the following step. 5.2. 1, 1-dimethylethyl (2R-trans) -2-cyano-4-methyl-l- piperidinecarboxylate 1 g (4 mmol) of 1, 1-dimethylethyl (2R-trans) -2- (aminocarbonyl) -4-methyl-l- piperidinecarboxylate is taken up in 5 ml of pyridine, the mixture is cooled to -5°C and 0.52 ml of phosphoryl chloride in 1 ml of dichloromethane is added dropwise. The reaction medium is stirred for 1 hour and then poured onto ice and extracted with 100 ml of diethyl ether. The solvent is evaporated off and the residue is purified by chromatography on a column of silica gel, eluting with dichloromethane. 0.7 g of product in the form of an oil is obtained, which is used as it is in the following step. 5.3. (2R-trans) -4-methyl-2- (lH-tetrazol-5-yl) piperidine 0.7 g (3.1 mmol) of 1, 1-dimethylethyl (2R-trans) -2-cyano-4-methyl-l-piperidinecarboxylate are placed into a sealed tube and 1.5 ml of dimethylformamide, 212 mg (3 mmol) of sodium azide and 180 mg (4 mmol) of ammonium chloride are added. The reaction medium is heated to 100 °C for 24 hours and the solvent is then evaporated off. The residue is taken up in a mixture of sodium carbonate and diethyl ether, the organic phase is collected, the pH is adjusted to 2 with 1 N hydrochloric acid and the mixture is extracted with diethyl ether. The organic phase is recovered and dried over magnesium sulphate and the solvent is evaporated off. 0.3 g of product in the form of an oil is obtained, which is used as it is in the following step. 5.4. (2R-trans) -4-methyl-2- (lH-tetrazol-5-yl) piperidine trifluoroacetate 242 mg (0.9 mmol) of (2R-trans) -4-methyl-2- (1H-tetrazol-5-yl) piperidine are dissolved in 2 ml of dichloromethane under nitrogen, and 2 ml of trifluoroacetic acid are added. The mixture is stirred for 1 hour at room temperature, the solvent is evaporated off and the residue is taken up with dichloromethane. The solvent is again evaporated off. 355 mg of product in the form of an oil are obtained.
The compounds of formulae (1) and (2) are of use for the synthesis of compounds having antithrombotic activity, such as those described in European Patent No. 0,008,746 such as, for example, argatroban, and for the synthesis of the compounds described in European Patent Application No. 0,565,396, the structure of which compounds contains a piperidine of formula (3) in which R1 represents either a (C.,-^) alkoxycarbonyl group, or a carboxyl group, or a sodium carboxylate group, or an amide group of formula -CONR4R5, or a group -CH2OR4, or a group -CN4R4, R4 being a hydrogen atom or a (C^-C^) alkyl group and Rj being a hydrogen atom, a (C,-C4) alkyl group, a hydroxyl group, a (C^-C^) alkoxy group or a phenylmethoxy cjroup and Rj represents a group, in the (2R-trans) form.
Examples 6 and 7 which follow illustrate the synthesis of compounds described in European Patent Application No. 0,565,396 from the compounds of for ul (1) or (2).
Example 6 (2R-trans)-N-Ethyl-l*-i5~(lH-imidazol-4-yl)~2-[ [ (3-methyl-1,2,3 , 4~tetrahydroquinol-8-yl ) sulphonyl ]amino] ~3 -oxopentyl] 4~methyl-2~piperidinecarboxamide hydrochloride 6.1. (2R-^rans)-N-ethyl-4-methyl-l-[2-[t (3-methyl- 1,2, 3, -tetrahydroquinol-8-yl) sulphonyl ]amino]-l- oxo-5-[ 1- (triphcnylmethyl) -lH-imidazol-4- yl]pentyl-2-piperidinecarboxamide 0.221 g (1.3 mmol) of (2R-trans) -N~ethyl-4-methyl~2~piperidinecarboxamide t ifluoroacetate obtained according to the method described in Example 3 is dissolved in 30 ml of dichloro ethane. 0.635 g (1 mmol) of (S)-a-[ [ (3-mothyl-l,2,3,4-tctrahydroquinol-8-yl) sulphonyl] ami no) - - (triphenylmethy ) -3H-imida?.ole-4-pentanoic acid obtained according to the method described in European Patent Application No. 0,565,396, 0.406 g (1.10 mmol) of [ (benzotriazol-l-y1 ) oxy) trie (di ethylamino) phosphoniu hexafluorophosphate and 1.04 ml (6 mmol) of Ν,Ν-diisopropylethylamine are added under argon and at 0°C. The mixture is allowed to return to room temperature overnight, then it is successively washed with 10 ml of 1 N hydrochloric acid and with 10 ml of a saturated sodium hydrogen carbonate solution. The resultant solution is dried over magnesium sulphate. 0.337 g of product is obtained.
Melting point = 30-40 °C Yield = 43 % 6.2. (2R-trans) -N-ethyl-l-[5-(lH-imidazol-4-yl) -2-[ [ (3- methyl-1 ,2,3, 4-tetrahydroquinol-8- yl) sulphonyl] amino] -1-oxopentyl ] -4-methyl-2- piperidinecarboxamide hydrochloride 0.332 g (0.422 mmol) of (2R-trans) -N-ethyl-4-methyl-1- [ 2- [ [ (3-methyl-l ,2,3, 4-tetrahydroquinol-8-yl) sulphonyl ] amino] -l-oxo-5- [ 1- (triphenylmethyl) -1H-imidazol-4-yl]pentyl-2-piperidinecarboxamide is dissolved in 3.7 ml of acetic acid, and 0.7 ml of water and 3 ml of tetrahydrofuran are then added. The mixture is heated to reflux for one hour. It is evaporated to dryness and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane/ethanol gradient (90/10 to 85/15) . 0.225 g of product is obtained in the base form.
The hydrochloride is prepared by dissolving 0.225 g of base in 4.1 ml of 0.1 N hydrochloric acid in isopropyl alcohol . The solvent is evaporated off the residue is taken up with ether. The mixture filtered and the filtrate is dried. 0.200 g of hydrochloride is obtained.
Melting point = 105-110 °C (decomposition) [a]*0 = +33.2° (c = 0.2; methanol) Example 7 Sodium complex of sodium [2R-[1(S) f 2a, 4β] ] -4-methyl-l- [2-[[ (3-methyl-l,2,3,4-tetrahydroquinol-8-yl) sulphonyl ] amino] -l-oxo-5- ( lH-imidazol-4-yl) pentyl ] - 2-piperidinecarboxylate 7.1. ethyl [2R-[1 (S) , 2a, 40] ] -4-methyl-l- [ 2- [ [ (3-methyl- 1,2,3, 4-tetrahydroquinol-8-yl) sulphonyl ] amino] -1- oxo-5- (lH-imidazol-4-yl) pentyl] -2- piperidinecarboxylate 7.1.1. triphenyl[ [ (1-triphenylmethyl) -lH-imidazol-4- yl]methyl ]phosphonium chloride To 670 ml of a solution of 105.5 g (294 mmol) of 4- (chloromethyl) -1- (triphenylmethyl) -1H-imidazole in dimethylformamide are added 77.7 g (296 mmol) of triphenylphosphine. The mixture is heated at 80 "C for 3 hours. The solvent is evaporated off and the crude product is taken up in ether and triturated. The precipitate is filtered off and dried under vacuum over phosphorus pentoxide. 162 g of product are obtained in the form of yellowish crystals.
Melting point = 210 °C Yield = 89 % 7.1.2. 1, 1-dimethylethyl (S,E)-2- [ [ (phenylmethoxy) carbonyl ] amino] -5- [ 1- (triphenylmethyl) -lH-imidazol-4-yl] -4- pentenoate Into a three-necked round-bottomed flask, under argon, are introduced 50.93 g (820 mmol) of triphenyl[ [ (1-triphenylmethyl) -lH-imidazol-4-yl]methyl ]phosphonium chloride dissolved in 333 ml of tetrahydrofuran. 51.2 ml of a 1.6 M solution of n-butyllithium in hexane (820 mmol) are added dropwise at -70 °C. After stirring for 30 minutes at -70 °C, the reaction medium is rapidly poured into 270 ml of a 0.253 M solution, cooled to -70°C, of 1 , 1-dimethylethyl (S) -4-oxo-2-[ [ (phenylmethoxy) carbonyl] amino]butanoate (683 mmol) in tetrahydrofuran. The mixture is allowed to return to room temperature overnight. The mixture is hydrolysed with 280 ml of a saturated aqueous sodium chloride solution. The organic phase is separated from the aqueous phase and the latter is extracted with twice 140 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a hexane/ethyl acetate gradient.
A mixture of the cis and trans olefins is obtained.
For the cis form: melting point = 66 °C Rf = 0.30 [hexane/ethyl acetate 60/40)] For the trans form: Rf = 0.15 [hexane/ethyl acetate (60/40)] Yield = 40 % 7.1.3. 1, 1-dimethylethyl (S) -2-amino-5- [ 1- (triphenylmethyl) -lH-imidazol-4-yl]pentanoate hydrochloride 5.83 g (9.50 mmol) of 1 , 1-dimethylethyl (S,E)- 2~[ [ (phenylmethoxy)carbonyl]amino]-5-[l-(triphenylmethyl) -lH-imidazol-4-yl]-4-pentenoate in the cis form are dissolved in 120 ml of ethanol. A catalytic hydrogenation is carried out for 5 hours at 0.3 MPa, in the presence of palladium on charcoal as catalyst. The catalyst is filtered off over a Celite/silica mixture and the solvent is evaporated off. 4.32 g of product are collected, which are dissolved in 90 ml of hot "hydrochloric" isopropyl alcohol (HC1 = 0.1 N) . The solvent is evaporated off and the product is precipitated with ether and dried under vacuum. 3.62 g of product are obtained.
Melting point = 73 °C Yield = 73 % 7.1.4. 1, l-dimethylethyl (S) -2-[ [ (3-methylquinol-8- yl) sulphonyl ] amino] -5- [ 1- (triphenylmethyl) - lH-imidazol-4-yl ] pentanoate 1.76 g (7.28 mmol) of 8- (chlorosulphonyl) -3-methylquinoline dissolved in 50 ml of chloroform are added to 3.8 g (7.26 mmol) of 1, l-dimethylethyl (S)-2-amino-5- [ 1- (triphenylmethyl) -lH-imidazol-4-yl]pentanoate hydrochloride in the presence of 2.1 ml (14.5 mmol) of triethylamine, at 5°C. The reaction medium is left stirring for 3 hours, the organic phase is separated off and washed with a 0.1 N hydrochloric acid solution and evaporated. The crude product is purified by chromatography on a column of silica gel, eluting with an ethanol/dichloromethane (5/95) mixture 3.6 g of product are obtained.
Melting point = 56°C Yield = 72 % 7.1.5. (S)-2-[ [ (3-methylquinol-8- yl) sulphonyl] amino] -5- [l-(triphenylmethyl) - lH-imidazol-4-yl]pentanoic acid Gaseous hydrochloric acid is bubbled for 15 minutes into a solution of 2.33 g (3.39 mmol) of 1, l-dimethylethyl (S) -2-[ [ (3-methylquinol-8-yl ) sulphonyl ] amino] -5- [ 1- (triphenylmethyl ) -lH-imidazol 4-yl ] pentanoate in 34 ml of benzene, cooled to 0°C, under nitrogen. The reaction medium is allowed to return to room temperature and stirring is maintained for 2 hours at this temperature. The solvent is evaporated off under vacuum and the residue is purified by chromatography on a column of silica gel, eluting with an ethanol/dichloromethane (20/80) mixture. 1.42 g of product are obtained in the form of a whitish powder.
Melting point = 170 °C Yield = 66 % 7.1.6. ethyl [2R-[1(S) ,2a, 40] ] -4-methyl-l- [2- [ [ (3- methylquinol-8-yl) sulphonyl ] amino] -l-oxo-5- [1- (triphenylmethyl) -lH-imidazol-4- yl ] pentyl ] -2-piperidinecarboxylate To a suspension of 2.23 g (3.53 mmol) of (S)-2-[ [ (3-methylquinol-8-yl) sulphonyl] amino] -5-[1-(triphenylmethyl) -lH-imidazol-4-yl]pentanoic acid in 50 ml of acetonitrile are added at 0°C, under nitrogen, 1.56 g (3.53 mmol) of [ (benzotriazol-1-yl) oxy] tris (dimethylamino) phosphonium hexafluorophosphate, 0.78 ml (7.06 mmol) of 4-methylmorpholine, 0.61 g (3.57 mmol) of ethyl (2R-trans) -4-methy1-2-piperidinecarboxylate and 30 ml of dichloromethane. The mixture is left stirring at room temperature for 5 hours. The reaction medium is hydrolysed with a saturated sodium chloride solution and extracted with chloroform. The organic phase is successively washed with a 0.1 N hydrochloric acid solution, a saturated sodium hydrogen carbonate solution, water and finally a sodium chloride solution. It is dried over magnesium sulphate and the crude product obtained is purified by chromatography on a column of silica gel, eluting with an ethanol/ dichloromethane (5/95) mixture. < 1.94 g of product are obtained.
Rf = 0.68 (dichloromethane/ethanol 95/5) Yield = 70 % 7.1.7. ethyl [2R-[1(S) ,2a, 4)3] ] -4-methyl-l- [ 2- [ [ (3- methyl-1, 2 , 3 , 4-tetrahydroquinol-8- yl) sulphonyl] amino] -l-oxo-5- (lH-imidazol-4- yl) pentyl ] -2-piperidinecarboxylate hydrochloride To 1.94 g (2.47 mmol) of ethyl [2R-[1(S) ,2a,4jS] ] -4-methyl-l- [2- [ [ (3-methylquinol-8-yl) sulphonyl] amino] -l-oxo-5- [ 1- (triphenylmethyl) -1H-imidazol-4-yl]pentyl] -2-piperidinecarboxylate are added 70 ml of ethanol and 17 ml of acetic acid. A catalytic hydrogenation is carried out in the presence of palladium on charcoal, at 80 °C for 6 hours. The mixture is filtered and the solvent is evaporated off. The residue obtained is taken up with 1 N hydrochloric acid, washed with ether and extracted with ethyl acetate. 1.05 g of product are obtained.
Melting point = 104 "C (hydrochloride) Yield = 78 % [a]*0 = +101° (c = 0.2; methanol) 7.2. sodium complex of sodium [2R-[1(S) , 2a, 4/3] ]-4- methyl-l-[2-[ [ (3-methy1-1, 2 , 3 , 4-tetrahydroquinol- 8-yl ) sulphonyl ] amino] -1-οχο-τ5- ( lH-imidazol-4- yl) pentyl] -2-piperidinecarboxylate To a solution of 0.201 g (0.4 mmol) of ethyl [2R-[1(S) ,2a, 4)3] ] -4-methyl-l- [2- [ [ (3-methyl-l , 2 , 3 , 4-tetrahydroquinol-8-yl) sulphonyl ] amino] -l-oxo-5- ( 1H-imidazol-4-yl) pentyl] -2-piperidinecarboxylate is added, at room temperature, under argon, 0.4 ml of a titrated 1 N sodium hydroxide solution. The reaction medium is stirred at room temperature for 36 hours and the reaction is followed by thin layer chromatography. When the reaction has finished, the reaction medium is heated to 55 °C for 7 hours. It is allowed to cool and 1 ml of ethanol and 50 ml of ether are added. After trituration, a whitish precipitate is obtained which is filtered and dried. 170 mg of product are obtained in the form of a white powder.
Melting point = 215 °C Yield = 86 % [α]ξ° = +67.2° (c = 0.1; methanol)
Claims (7)
1. Process for the preparation of optically pure alkyl (2R-trans)~2-piperidinecarboxylates of formula (1) in which R represents a (c,-C alkoxycarbonyl group and Rj represents a (C,-^) alkyl group, which process is characterized in that an alkyl 2-piperidinecarboxylate in the form of a racemate of trans configuration is reacted with an enzyme which specifically degrades the (2S-trans) enantiomer, leaving the (2R-transj enantiomer largely intact.
2. Process according to Claim 1, characterized in that the enzyme is chosen from lipase ΛΥ, lipase N, lipase M Amano 10 (Mucor) , prozymo 6 Aspergillus from the company Amano Pharmaceutical Ltd., protease Aspergillus oryzae (Sigma) , cholesterol esterase (Boehringer) , sheep pancreas acetone powder (Sigma) and porcine type J pancreas acetone powder (Sigma) .
3. Process according to either of Claims 1 and 2, characterized in that the enzyme is prozymo 6 Aspergillus from the company Amano Pharmaceutical Ltd.
4. Process according to either of Claims 1 and 2, characterized in that the enzyme is porcine type I 108829/2 26 (Sigma) .
5. A process according to Claim 1 substantially as hereinbefore described in Example 1 or 2.
6. An alkyl (2R-trans) -2-piperidinecarbox late of the formula (1) when obtained by a process according to any one of Claims 1 to 5.
7. Use of a compound according to Claim 6 for the preparation of a compound having antithrombotic activity, the structure 108829/2 27 in which R, represents either a (C^-C alkoxycarbonyl group, or a carboxyl group, or a sodium carboxylate group, or an amide group of formula -CONR4R5, or a group -C1I20R4 , or a group alkyl group and R5 being a hydrogen atom, a (C,-C4) alkyl group, a hydroxyl group, a alkoxy group or a phenylntethoxy group and Rj represents a (Cj-C4) alkyl group, in the (2Rrtrans) form, substanti al ly as descri bed in the speci fication. For the Appl icant, Sa . C: 18516
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9302434A FR2702220B1 (en) | 1993-03-03 | 1993-03-03 | Enzymatic duplication of 4-alkyl-2-piperidine-carboxylate derivatives and use of the compounds obtained, as synthesis intermediates. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL108829A0 IL108829A0 (en) | 1994-06-24 |
| IL108829A true IL108829A (en) | 1999-03-12 |
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| Application Number | Title | Priority Date | Filing Date |
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| IL10882994A IL108829A (en) | 1993-03-03 | 1994-03-02 | Enzymatic process for the preparation of optically pure (2R-trans)-alkyl-2-piperidinecarboxylates and use of the compounds obtained as synthesis intermediates |
Country Status (10)
| Country | Link |
|---|---|
| EP (1) | EP0614986B1 (en) |
| JP (1) | JPH06296498A (en) |
| KR (1) | KR940021737A (en) |
| CN (1) | CN1100143A (en) |
| AT (1) | ATE182368T1 (en) |
| CA (1) | CA2116833A1 (en) |
| DE (1) | DE69419547D1 (en) |
| FI (1) | FI940999A (en) |
| FR (1) | FR2702220B1 (en) |
| IL (1) | IL108829A (en) |
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|---|---|---|---|---|
| FR2718439B3 (en) * | 1994-04-12 | 1996-02-09 | Synthelabo | Pipecolic acid derivatives, their preparation and their use as synthesis intermediates. |
| US5840733A (en) * | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| GB9924882D0 (en) * | 1999-10-20 | 1999-12-22 | Smithkline Beecham Plc | Novel process |
| FR2804682B1 (en) * | 2000-02-09 | 2002-05-03 | Rhodia Chimie Sa | PROCESS FOR THE DIASTEREOSELECTIVE PREPARATION OF PIPERIDINES FUNCTIONALIZED IN POSITIONS 2 AND 4 FOR USE AS SYNTHESIS INTERMEDIATES |
| US7091355B2 (en) | 2000-12-29 | 2006-08-15 | Dow Global Technologies Inc. | Chiral scaffolds and their preparation |
| CN101712645B (en) * | 2009-11-20 | 2013-08-28 | 重庆威尔德·浩瑞医药化工有限公司 | Preparation method for (2R, 4R)-4-substituted-2-piperidine carboxylic acid compound and intermediate thereof |
| CN102952065A (en) * | 2011-08-24 | 2013-03-06 | 重庆华邦胜凯制药有限公司 | Resolution method for cis-2,3-pyridine diformate |
| CN102719512B (en) * | 2012-06-21 | 2014-06-11 | 浙江工业大学 | Preparation method for R-2-(4- hydroxyphenoxy) propionate |
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| IE48623B1 (en) * | 1978-08-31 | 1985-03-20 | Mitsubishi Chem Ind | Alpha-(n-arylsulfonyl-l-argininamides,processes for their preparation and pharmaceutical compositions containing these substances |
| EP0151110B1 (en) * | 1983-08-01 | 1989-03-01 | Astra Läkemedel Aktiebolag | L-n-n-propylpipecolic acid-2,6-xylidide and method for preparing the same |
| JPH0641075A (en) * | 1990-09-01 | 1994-02-15 | Kazuo Achinami | New 1,4-dihydropyridine compound and its production |
-
1993
- 1993-03-03 FR FR9302434A patent/FR2702220B1/en not_active Expired - Fee Related
-
1994
- 1994-02-23 EP EP94400381A patent/EP0614986B1/en not_active Expired - Lifetime
- 1994-02-23 AT AT94400381T patent/ATE182368T1/en not_active IP Right Cessation
- 1994-02-23 DE DE69419547T patent/DE69419547D1/en not_active Expired - Lifetime
- 1994-03-02 FI FI940999A patent/FI940999A/en unknown
- 1994-03-02 CN CN94102250A patent/CN1100143A/en active Pending
- 1994-03-02 IL IL10882994A patent/IL108829A/en active IP Right Grant
- 1994-03-02 CA CA002116833A patent/CA2116833A1/en not_active Abandoned
- 1994-03-02 JP JP6032202A patent/JPH06296498A/en active Pending
- 1994-03-02 KR KR1019940004000A patent/KR940021737A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| FR2702220B1 (en) | 1995-05-12 |
| EP0614986B1 (en) | 1999-07-21 |
| EP0614986A1 (en) | 1994-09-14 |
| FI940999A0 (en) | 1994-03-02 |
| DE69419547D1 (en) | 1999-08-26 |
| FI940999A (en) | 1994-09-04 |
| ATE182368T1 (en) | 1999-08-15 |
| FR2702220A1 (en) | 1994-09-09 |
| JPH06296498A (en) | 1994-10-25 |
| IL108829A0 (en) | 1994-06-24 |
| CN1100143A (en) | 1995-03-15 |
| KR940021737A (en) | 1994-10-19 |
| CA2116833A1 (en) | 1994-09-04 |
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