WO2012059798A2 - NOVEL METHOD FOR RACEMIZATION OF OPTICALLY PURE β-CYANO ESTER TO CORRESPONDING RACEMIC β-CYANO ACID - Google Patents
NOVEL METHOD FOR RACEMIZATION OF OPTICALLY PURE β-CYANO ESTER TO CORRESPONDING RACEMIC β-CYANO ACID Download PDFInfo
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- WO2012059798A2 WO2012059798A2 PCT/IB2011/000485 IB2011000485W WO2012059798A2 WO 2012059798 A2 WO2012059798 A2 WO 2012059798A2 IB 2011000485 W IB2011000485 W IB 2011000485W WO 2012059798 A2 WO2012059798 A2 WO 2012059798A2
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- GYAZXRQVMSVZQX-UHFFFAOYSA-N CC(C)(Cc1ccccc1)C#N Chemical compound CC(C)(Cc1ccccc1)C#N GYAZXRQVMSVZQX-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- This invention relates to process for racemization of ( ?)-3-cyano-5-methyl hexanoic acid ethyl ester (VII) in presence of a base to obtain directly (&S)-3-cyano-5-methyl hexanoic acid (III).
- This invention provides a method for racemization of optically active ⁇ - cyano ester directly to corresponding racemic ⁇ - cyano acid.
- this invention provides a novel, highly cost effective, operation friendly, "green” process for racemization of (R) - 3-cyano-5-methyl-hexanoic acid ethyl ester (VII) to .
- the object of the present invention is to provide a process for recycling of ( ?)-3-cyano-5- methyl-hexanoic acid (V) via converting into corresponding ester i.e. (i?)-3-cyano-5-methyl- hexanoic acid ethyl ester (VII), followed by racemization to obtain (RS) - 3-cyano-5-methyl- hexanoic acid (III), which could be reused for resolution through diastereomeric salt formation with cinchonidine, thereby improving the atom economy and hence further reduce the cost for the synthesis of (S)-pregabalin.
- the present invention is directed towards racemization of (ft)-3-cyano-5 -methyl hexanoic acid ethyl ester (VII) to (i?S)-3-cyano-5-methyl hexanoic acid (III) with a base, which is directly utilized for resolution with cinchonidine as mentioned hereinbefore.
- the invention is summarized below in scheme C.
- the substrates reported in literature and mentioned above contain only one electron withdrawing group i.e. nitrile, hence, when above said substrates were subjected to racemization in presence of catalytic amount of base, proton which is attached to carbon bearing optically active center i.e. "Ha”, which is a to cyano functionality only gets abstracted, which results into isomerization of said nitrile substrates.
- Retention time for (R) -3-cyano-5-methylhexanoic acid ethyl ester (VII) is 30.10 min and for (S) -3-cyano-5-methylhexanoic acid ethyl ester (II) is 31.09 min.
- Product was also characterized by NMR and IR having the following spectral data.
- racemization of (R) -3-cyano-5-methylhexanoic acid (V) to (RS) -3-cyano-5- methylhexanoic acid (III) comprised of the following steps: compound (V) was converted into corresponding ester i.e. compound (VII) through esterification reaction such as "mixed-anhydride” technique employing ethylchloroformate/ triethylamine with ethanol or through Steglich Esterification or acid catalyzed esterification or esterification by any other conventional methods.
- compound (VII) was racemized to obtain compound (III) in presence of alkali metal alkoxides in a mixture of organic solvent e.g. methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2% ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol.
- organic solvent e.g. methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2% ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol.
- Alkali metal alkoxides used such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, potassium tert- butoxide preferably sodium methoxide, sodium ethoxide; more preferably sodium ethoxide.
- Aprotic solvent used such as dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran, methyl tert-butyl ether and N-Me ' thyl-2- ⁇ pyrrolidone preferably dimethyl sulfoxide and methyl tert-butyl ether.
- Protic solvent used such as methanol, ethanol, propanol and butanol, preferably ethanol. Ratio of aprotic solvent to protic solvent varied from 1:99 to 99:1, preferably ratio used was 99: 1. The quantity of base used was 1.25 mol/per mole of substrate. l) 2 % Ethanol
- the enantiomeric excess (ee) for (S) - 3-cyano-5-methyl-hexanoic acid ethyl ester is determined by Gas-Liquid chromatography using a Shimadzu GC 2010 system equipped with a chiral column (Chiraledex (20m x 0.25mm x 0.12mm)), and FID detector.
- the enantiomeric excess (ee) for (S) or (R) - 3-cyano-5-methyl-hexanoic acid is determined via converting into corresponding ester and analyzed on Gas-Liquid chromatography using a Shimadzu GC 2010 system equipped with a chiral column (Chiraledex (20m x 0.25mm x 0.12mm)), and FID detector.
- NMR spectra are obtained at 200 and 400 MHz Bruker instruments, with CDC1 3 as solvent unless otherwise stated. Chemical shifts (3) are given in ppm relative to tetramethylsilane ( ⁇ - 0 ppm). IR spectra are recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm '1 . Mass analyses are performed on Shimadzu LCMS 201 OA instrument.
- Example 1 Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through Steglich Esterification.
- a reactor equipped with overheard stirring is charged with 50 mL of dichloromethane 50 mL, ethanol (1.24 g), (R) - 3-cyano-5-methylhexanoic acid (2.1 g) and DCC (5.58 g) at 0 °C. The mixture is stirred for 1 h at 0 °C. Further it is stirred for 12 h at 25 °C. The extent of reaction is monitored on GC for chiral purity for (R) 3-cyano-5-methylhexanoic acid ethyl ester (1.8 g).
- Example 2 Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through mixed-anhydride.
- a reactor equipped with overheard stirring is charged with 100 mL of dichloromethane, (R) - 3- cyano-5-methylhexanoic acid (26.2 g) and triethyl amine (34.1 g) and resulting reaction mixture was cooled to 0 °C.
- a solution of ethyl chloroformate (27.5 g) in dichloromethane (l OOmL) was slowly added to the above reaction mixture over a period of 30 min at 0°C and stirred further for 3 h at 25 °C.
- reaction mixture was cooled to 0°C and ethanol (15.5 g) was added slowly over period of 20-25 min and resultant reaction mixture was further stirred for 1 h at 25 °C.
- the reaction was quenched by adding 100 ml water and organic layer was separated. Aqueous layer was further extracted with dichloromethane (2*100ml).Combined organic layer was dried over sodium sulfate and solvent was evaporated under reduced pressure to obtain (R) 3-cyano-5- methylhexanoic acid ethyl ester (30.1 g) as yellow oil.
- Example 3 Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) in presence of sulfuric acid.
- a reactor equipped with overheard stirring is charged with ethanol (100 mL), (R) - 3-cyano-5- methylhexanoic acid (25.0 g) and concentrated sulfuric acid (0.25 g) and resulting reaction mixture was refluxed for 6 h. After which reaction was cooled to 25 °C, solvent was evaporated under reduced pressure to obtain crude (R) - 3 -cyano-5 -methylhexanoic acid ethyl ester.
- Example 4 Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in dimethyl sulfoxide and 2 % ethanol.
- Example 6 Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methyIhexanoic acid (III) in dimethyl formamide and 2 % ethanol
- Example 8 Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in methyl-i'eri'-butyl ether
- a reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), dimethoxy ethane (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C.
- reaction mixture was cooled to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 40 °C.
- Organic layer was separated and aqueous phase was extracted with methyl tert-butyl ether (100 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3- cyano-5 -methylhexanoic acid (2.2 g, analyzed chiral GC by converting in to ethyl ester) brown color oil.
- Example 9 Racemization of enantiomerically enriched (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3-cyano-5-methylhexanoic acid (III) in 2-methyl tetrahydrofuran
Abstract
A novel process for racemization of (R)-3-cyano-5 -methyl hexanoic acid ethyl ester directly to (RS)-3-cyano-5 -methyl hexanoic acid has been developed through a base catalyzed mechanism in a specific solvent system.
Description
NOVEL METHOD FOR RACEMIZATION OF OPTICALLY PURE β-CYANO
ESTER TO CORRESPONDING RACEMIC B-CYANO ACID
Field of the Invention:
This invention relates to process for racemization of ( ?)-3-cyano-5-methyl hexanoic acid ethyl ester (VII) in presence of a base to obtain directly (&S)-3-cyano-5-methyl hexanoic acid (III).
Background of the Invention:
The PCT application number PCT/IN2010/000440 dated 28 June 2010 entitled "Improved synthesis of optically pure (S) - 3-cyano-5-methyl-hexanoic acid alkyl ester, an intermediate of (S)-pregabalin" of the present applicant reports the lipase catalyzed kinetic resolution of (RS) - 3-cyano-5-methyl-hexanoic acid ethyl ester (I) to obtain (S)- 3-cyano-5-methyl- hexanoic acid ethyl ester (II) , which was further converted to (S)-pregabalin (VI)· In the copending Indian patent Application No. 1235/KOL/2010 dated November 4, 2010, entitled "Novel, cost effective, green and industrial process for synthesis of (5)-pregabalin" of the present applicant, the inventors demonstrated the process for resolution of (RS) - 3-cyano-5- methyl-hexanoic acid (III) with cinchonidine through diastereomeric salt formation to obtain (S) - 3 -cyano-5 -methyl-hexanoic acid (IV), which was also further converted into (S)- pregabalin. The disclosers of above said patents, including prior art are incorporated herein by reference.
In both the above processes (R) - 3 -cyano-5 -methyl-hexanoic acid (V) was obtained as an undcsired isomer. The processes disclosed in the above said patents i.e. PCT/IN2010/000440 and co-pending Indian patent Application No. 1235/KOL/2010 dated November 4, 2010, entitled "Novel, cost effective, green and industrial process for synthesis of (S)-pregabalin" are summarized in scheme A.
Scheme A
It is evident from the prior art that whichever process is utilized for resolution to obtain optically pure (S) -3-cyano-5-methyl hexanoic acid (IV), about 50 % of undesired isomer i.e. (R) -3-cyano-5-methyl hexanoic acid (V) will get produced.
Hence, it is imperative that for improvement of overall process efficiency, "atom economy" and cost, the undesired isomer i.e. (R) - 3-cyano-5-methyl-hexanoic acid (V) has to be isomerised through racemization to (RS) - 3-cyano-5-methyl-hexanoic acid (III), which could be resolved through subsequent identical processes described in application entitled "Novel, cost effective, green and industrial process for synthesis of (S)-pregabalin" of the present applicant.
In PCT application number PCT/IN2010/000440 dated 28 June 2010, process for racemization of (R) - 3 -cyano-5 -methyl-hexanoic acid ethyl ester (VII) to (RS) - 3-cyano-5- methyl-hexanoic acid ethyl ester (I) was disclosed in presence of catalytic amount of base such as sodium ethoxide and ethanol as a solvent and summarized in scheme B
Scheme B
Racemization of nitrile compounds in presence of base (JACS, 1961, 83, 3678-3687; J. Org. Chem. 1974, 39, 1705-1707) has been reported for benzylic substrates such as (+)-2-methyl- 3 -phenyl propionitrile (VIII), (-)-2-phenylbutyronitrile (IX) and (-) 2,2- diphenylcyclopropylnitrile (X).
(+)-2-methyl-3 -phenyl propionitrile (VIII)
(-) 2,2-diphenylcyclopropylnitrile (X)
"*" denotes carbon bearing optical center.
Although, iri the said publications, racemization of benzylic nitrile substrates has been reported but there is no report for the racemization of substrate containing both carboxyl and cyano functionality i.e. β- cyano esters.
This invention provides a method for racemization of optically active β- cyano ester directly to corresponding racemic β- cyano acid. To the knowledge of the inventors, there is no report available for isomerization of (J?) - 3- cyano-5-methyi-hexanoic acid ethyl ester (VII) to (RS) - 3-cyano-5-methyl-hexanoic acid (III).
Thus, this invention provides a novel, highly cost effective, operation friendly, "green" process for racemization of (R) - 3-cyano-5-methyl-hexanoic acid ethyl ester (VII) to . (RS) - 3-cyano-5-methyl-hexanoic acid (III).
Objects of the Invention:
The object of the present invention is to provide a process for recycling of ( ?)-3-cyano-5- methyl-hexanoic acid (V) via converting into corresponding ester i.e. (i?)-3-cyano-5-methyl- hexanoic acid ethyl ester (VII), followed by racemization to obtain (RS) - 3-cyano-5-methyl- hexanoic acid (III), which could be reused for resolution through diastereomeric salt formation with cinchonidine, thereby improving the atom economy and hence further reduce the cost for the synthesis of (S)-pregabalin.
Summary of Invention:
The present invention is directed towards racemization of (ft)-3-cyano-5 -methyl hexanoic acid ethyl ester (VII) to (i?S)-3-cyano-5-methyl hexanoic acid (III) with a base, which is directly utilized for resolution with cinchonidine as mentioned hereinbefore. The invention is summarized below in scheme C.
1) 2 % Ethanol
Dry solvetnt
(VII) (in)
Racemic Mixture (Yield=95%) Sc heme C
The processes for isomerization of (R)-3-cyano-5-methyl hexanoic acid (VII)
(i?)-3-cyano-5 -methyl hexanoic acid ethyl ester (VII) and 2% absolute ethanol was heated at 70 °C for 4 hours in organic solvent such as dimethyl sulfoxide, N,N, dimethylformamide, N- methyl-2-pyrrolidone, 2-methyl tetrahydrofuran, dimethoxy ethane and methyl tert-butyl ether preferably 2-methyl tetrahydrofuran, dimethoxy ethane, methyl fert-butyl ether in
presence of a base such as alkali earth metal alkoxides e.g; sodium ethoxide, potassium tert- butoxide, sodium methoxide to obtain (J?S -3-cyano-5-methyl-hexanoic acid (III).
Detailed Description of the Invention:
It is worthwhile to note that, the substrates reported in literature and mentioned above contain only one electron withdrawing group i.e. nitrile, hence, when above said substrates were subjected to racemization in presence of catalytic amount of base, proton which is attached to carbon bearing optically active center i.e. "Ha", which is a to cyano functionality only gets abstracted, which results into isomerization of said nitrile substrates.
In case of substrates like β- cyano ester i.e. 3 -cyano-5 -methyl hexanoic acid ethyl ester (XI), where, two vicinal protons are present as shown in the following structure i.e. "Ha" which is a to carboxyl and "Hb" which is a to cyano functionality, it is difficult to predict which proton will get abstracted in conditions reported in literature.
However, surprisingly it was observed that, when (R) -3 -cyano-5 -methylhexanoic acid ethyl ester (VII) was treated with more than 1 equivalent of base such as sodium ethoxide, in dimethyl sulfoxide and 2 % ethanol, the product was (RS) -3-cyano-5-methylhexanoic acid (III). The product was analyzed by Gas-Liquid chromatography using a Shimadzu GC 2010 system equipped with a chiral column: Chiraledex (20m x 0.25mm x 0.12mm) and FID detector by converting into ester. Retention time for (R) -3-cyano-5-methylhexanoic acid ethyl ester (VII) is 30.10 min and for (S) -3-cyano-5-methylhexanoic acid ethyl ester (II) is
31.09 min. Product was also characterized by NMR and IR having the following spectral data.
NMR spectra (CDC13, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.36-1.38 (d, 1H), 1.59-1.66 (m, 1H), 1.79-1.85 (m, 1H), 2.59-2.61 (dd, 1H), 2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H) and IR Spectra (neat): 31 18, 2961, 2935, 2875, 2642, 2244, 1715, 1470, 1174, 11 13 cm'1.
Moreover, it is to be noted that the solvent system reported in the literature such as dimethyl sulfoxide/ 2% ethanol could be replaced with other solvent systems such as 2-methyl tetrahydrofuran/ 2% ethanol, methyl tert-butyl ether/ 2% ethanol, dimethoxy ethane/ 2% ethanol, dimethyl formamide 1 2 % ethanol, and N-Methyl-2-pyrrolidone/ 2 % ethanol without effecting the efficiency of the process and also it is to be noted that water content in the solvent used for reaction is in the range of 0.05 to 0.65 %. Further, it was observed that when (i?)-3-cyano-5-methyl hexanoic acid was treated under similar experimental conditions used for (/?)-3-cyano-5 -methyl hexanoic acid ethyl ester, it did not undergo racemization.
To the best of knowledge of the inventors, there are no reports available for one step racemization of (R) -3-cyano-5-methylhexanoic acid ester (VII) to (RS) -3-cyano-5- methylhexanoic acid (III).
One might rationalize the formation of (RS) -3- cyano-5-methylhexanoic acid (III) from (R) - 3- cyano-5-methylhexanoic acid ester (VII) with the help of following plausible reaction mechanism (Scheme D), which proceeds via a cyclopropanone intermediate.
Scheme D
In literature formation of cyclopropanone through Dieckmann type condensation has been reported as shown in scheme E (Tetrahedron: Asymmetry 13 (2002) 563-567). The present proposed reaction mechanism is akin to Dieckmann condensation.
Scheme E
Thus, racemization of (R) -3-cyano-5-methylhexanoic acid (V) to (RS) -3-cyano-5- methylhexanoic acid (III) comprised of the following steps:
compound (V) was converted into corresponding ester i.e. compound (VII) through esterification reaction such as "mixed-anhydride" technique employing ethylchloroformate/ triethylamine with ethanol or through Steglich Esterification or acid catalyzed esterification or esterification by any other conventional methods.
compound (VII) was racemized to obtain compound (III) in presence of alkali metal alkoxides in a mixture of organic solvent e.g. methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2% ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol. Alkali metal alkoxides used such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, potassium tert- butoxide preferably sodium methoxide, sodium ethoxide; more preferably sodium ethoxide. Aprotic solvent used such as dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran, methyl tert-butyl ether and N-Me'thyl-2-■ pyrrolidone preferably dimethyl sulfoxide and methyl tert-butyl ether. Protic solvent used such as methanol, ethanol, propanol and butanol, preferably ethanol. Ratio of aprotic solvent to protic solvent varied from 1:99 to 99:1, preferably ratio used was 99: 1. The quantity of base used was 1.25 mol/per mole of substrate.
l) 2 % Ethanol
(VII) (in)
Nomenclatures used for the compounds mentioned herein are as understood from the CambridgeSoft® ChemOffice software ChemDraw Ultra version 6.0.1.
Analytical Methods:
The enantiomeric excess (ee) for (S) - 3-cyano-5-methyl-hexanoic acid ethyl ester is determined by Gas-Liquid chromatography using a Shimadzu GC 2010 system equipped with a chiral column (Chiraledex (20m x 0.25mm x 0.12mm)), and FID detector.
The enantiomeric excess (ee) for (S) or (R) - 3-cyano-5-methyl-hexanoic acid is determined via converting into corresponding ester and analyzed on Gas-Liquid chromatography using a Shimadzu GC 2010 system equipped with a chiral column (Chiraledex (20m x 0.25mm x 0.12mm)), and FID detector.
NMR spectra are obtained at 200 and 400 MHz Bruker instruments, with CDC13 as solvent unless otherwise stated. Chemical shifts (3) are given in ppm relative to tetramethylsilane (δ - 0 ppm). IR spectra are recorded on Perkin Elmer Spectrum (Model: Spectrum 100) and absorption bands are given in cm'1. Mass analyses are performed on Shimadzu LCMS 201 OA instrument.
Example 1: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through Steglich Esterification.
A reactor equipped with overheard stirring is charged with 50 mL of dichloromethane 50 mL, ethanol (1.24 g), (R) - 3-cyano-5-methylhexanoic acid (2.1 g) and DCC (5.58 g) at 0 °C. The mixture is stirred for 1 h at 0 °C. Further it is stirred for 12 h at 25 °C. The extent of reaction is monitored on GC for chiral purity for (R) 3-cyano-5-methylhexanoic acid ethyl ester (1.8 g).
FTIR (neat): 2961, 2242, 1738, 1469, 1182, 1023 cm-1.
1H NMR (CDC13, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.22-1.24 (m, 4H), 1.58 (m, 1H), 1.83 (m, 1H), 2.49 (dd, 1H), 2.65 (dd, 1H), 2.98-3.06 (m, 1H), 4.17 (q, 2H). 13C NMR (CDC13, 50 MHz): 14.1, 21.2, 22.8, 25.8, 26.0, 37.1, 40.7, 61.4, 121.1, 169.7.
MS (EI): C10H17NO2: 183; [M+H20] +: 201.05.
Example 2: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) through mixed-anhydride. A reactor equipped with overheard stirring is charged with 100 mL of dichloromethane, (R) - 3- cyano-5-methylhexanoic acid (26.2 g) and triethyl amine (34.1 g) and resulting reaction mixture was cooled to 0 °C. A solution of ethyl chloroformate (27.5 g) in dichloromethane (l OOmL) was slowly added to the above reaction mixture over a period of 30 min at 0°C and stirred further for 3 h at 25 °C.
After which reaction mixture was cooled to 0°C and ethanol (15.5 g) was added slowly over period of 20-25 min and resultant reaction mixture was further stirred for 1 h at 25 °C. The reaction was quenched by adding 100 ml water and organic layer was separated. Aqueous layer was further extracted with dichloromethane (2*100ml).Combined organic layer was dried over sodium sulfate and solvent was evaporated under reduced pressure to obtain (R) 3-cyano-5- methylhexanoic acid ethyl ester (30.1 g) as yellow oil.
Example 3: Synthesis of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) in presence of sulfuric acid.
A reactor equipped with overheard stirring is charged with ethanol (100 mL), (R) - 3-cyano-5- methylhexanoic acid (25.0 g) and concentrated sulfuric acid (0.25 g) and resulting reaction mixture was refluxed for 6 h. After which reaction was cooled to 25 °C, solvent was evaporated under reduced pressure to obtain crude (R) - 3 -cyano-5 -methylhexanoic acid ethyl ester. Crude (R) - 3-cyano-5-methylhexanoic acid ethyl ester was dissolved in di-iso-propyl ether (100 mL) and washed with 10 % aqueous solution of sodium bicarbonate. Organic layer was dried over sodium sulfate and solvent was evaporated under reduced pressure to obtain (R) 3-cyano-5- methylhexanoic acid ethyl ester (30.1 g) as yellow oil.
Example 4: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in dimethyl sulfoxide and 2 % ethanol.
A reactor equipped with overheard stirring is charged with (R) 3 -cyano-5 methylhexanoic acid ethyl ester (15.8 g, 0.086 mol), dimethyl sulfoxide (158 ml), ethanol (4 mL ) and sodium ethoxide (7.35 g, 0.10 mol) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 30 °C. The aqueous phase was extracted with methyl tert-butyl ether (3 x 200 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (12.5 g 95 % yield and analyzed chiral GC by converting in to ethyl ester) light brown color oil.
FTIR (neat): 31 18, 2961 , 2935, 2875, 2642, 2244, 1715, 1470, 1 174, 11 13 cm"1
1H NMR (CDCb, 200 MHz): δ 0.95 (d, 3H), 0.96 (d, 3H), 1.36-1.38 (d, 1H), 1.59-1.66 (m, 1H), 1.79-1.85 (m, 1H), 2.59-2.61 (dd, 1H), 2.69-2.75 (dd, 1H), 2.98-3.04 (m, 1H).
MS (EI): C8H13N02: 155.19; [M-H] ': 154.00; [M+H] +: 156.15
Example 5: Racemization of (R) 3-cyano-5-methyIhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in N-methyl pyrrolidine and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), N-methyl pyrrolidine (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 40 °C. The aqueous phase was extracted with methyl fert-butyl ether (3 x 100 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.4 g, analyzed chiral GC by converting in to ethyl ester) brown color oil.
Example 6: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methyIhexanoic acid (III) in dimethyl formamide and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), dimethyl formamide (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 40 °C. The aqueous phase was extracted with methyl tert-butyl ether (3 x 100 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.1 g, analyzed chiral GC by converting in to ethyl ester) brown color oil. Example 7: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in dimethoxy ethane and 2 % ethanol
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), dimethoxy ethane (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled
to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 40 °C. The aqueous phase was extracted with methyl tert-butyl ether (3 x 100 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3-cyano-5-methylhexanoic acid (2.2 g, analyzed chiral GC by converting in to ethyl ester) brown color oil.
Example 8: Racemization of (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3- cyano-5-methylhexanoic acid (III) in methyl-i'eri'-butyl ether A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), dimethoxy ethane (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled to room temperature neutralized with acetic acid and treated with water (200 mL) in small portions to maintain the temperature below 40 °C. Organic layer was separated and aqueous phase was extracted with methyl tert-butyl ether (100 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to give (RS) - 3- cyano-5 -methylhexanoic acid (2.2 g, analyzed chiral GC by converting in to ethyl ester) brown color oil. Example 9: Racemization of enantiomerically enriched (R) 3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) 3-cyano-5-methylhexanoic acid (III) in 2-methyl tetrahydrofuran
A reactor equipped with overheard stirring is charged with (R) 3-cyano-5 methylhexanoic acid ethyl ester (3.0 g), 2-methyl tetrahydrofuran (30 ml), ethanol (0.6 mL ) and sodium ethoxide (1.4 g) and resulting reaction mixture was stirred for 4 h at 75 °C. After which reaction mixture was cooled to room temperature neutralized with acetic acid and solvent was evaporated under reduced pressure to obtain residue. Residue was further suspended in water (200 mL) and aqueous phase was extracted with methyl tert-butyl ether (3 x 300 mL), organic phases were combined and dried over sodium sulfate and solvent was evaporated under reduced pressure to
give (RS) - 3-cyano-5-methylhexanoic acid (2.0 g, analyzed chiral GC by converting in to ethyl ester) brown color oil.
Claims
A process of racemization of (R) -3-cyano-5-methylhexanoic acid (V) to obtain (SR) -3- cyano-5-methylhexanoic acid (III) comprising
) conversion of (R) -3-cyano-5-methylhexanoic acid (V) into corresponding ester (VII) through esterification reaction such as "mixed-anhydride" technique employing ethylchloroformate/ triethylamine with ethanol or through Steglich esterification or acid catalyzed esterification or esterification by any other conventional methods;
(V) (VII) ii) treatment of compound (VII) with alkali metal alkoxides in a mixture of protic and aprotic polar solvents, wherein aprotic polar solvent is selected from dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran, methyl tert-butyl ether and N-Methyl-2-pyrrolidone preferably dimethyl sulfoxide and methyl tert-butyl ether; and protic polar solvent is selected from methanol, ethanol, propanol and butanol.
(VII) (III)
The process as claimed in claim 1, wherein the solvent in step (ii) is selected from methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2%
ethanol, dimethylformamide doped with 2% ethanol, dimethoxyemane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol.
3) The process as claimed in claim 1, wherein alkali metal alkoxide in step (ii) is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide', lithium methoxide, lithium ethoxide, and potassium tert-butoxide.
4) A process for conversion of (R) -3-cyano-5-methylhexanoic acid ethyl ester (VII) to (RS) -3-cyano-5-methylhexanoic acid (III) comprising treatment of compound (VII) with alkali metal alkoxides in a mixture of protic and aprotic polar solvents, wherein aprotic polar solvent is selected from dimethyl sulfoxide, dimethylformamide, dimethoxyethane, 2-methyl tetrahydrofuran, methyl tert-butyl ether and N-Methyl-2-pyrrolidone preferably dimethyl sulfoxide and methyl tert-butyl ether; and protic polar solvent is selected from methanol, ethanol, propanol and butanol.
5) The process as claimed in claim 4, wherein the solvent is selected from methyl tert-butyl ether doped with 2% ethanol, dimethyl sulfoxide doped with 2% ethanol, dimethylformamide doped with 2% ethanol, dimethoxyethane doped with 2% ethanol, 2-methyl tetrahydrofuran doped with 2% ethanol and N-Methyl-2-pyrrolidone doped with 2% ethanol.
6) The process as claimed in claim 1, wherein the alkali metal alkoxide is selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, and potassium tert-butoxide.
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Non-Patent Citations (3)
| Title |
|---|
| J.ORG. CHEM., vol. 39, 1974, pages 1705 - 1707 |
| JACS, vol. 83, 1961, pages 3678 - 3687 |
| TETRAHEDRON: ASYMMETRY, vol. 13, 2002, pages 563 - 567 |
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