WO2010150946A1 - Method for preparation of carbamic acid (r)-1-aryl-2-tetrazolyl-ethyl ester - Google Patents

Method for preparation of carbamic acid (r)-1-aryl-2-tetrazolyl-ethyl ester Download PDF

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Publication number
WO2010150946A1
WO2010150946A1 PCT/KR2009/005906 KR2009005906W WO2010150946A1 WO 2010150946 A1 WO2010150946 A1 WO 2010150946A1 KR 2009005906 W KR2009005906 W KR 2009005906W WO 2010150946 A1 WO2010150946 A1 WO 2010150946A1
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Prior art keywords
chemistry
carbon atoms
asymmetric reduction
arylketone
alcohol
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PCT/KR2009/005906
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French (fr)
Inventor
Sang Chul Lim
Moo Yong Uhm
Nahm Ryune Cho
Dae Won Lee
Ju Young Lee
Hui Ho Kim
Dong Ho Lee
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Sk Holdings Co., Ltd.
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Priority to BRPI0924997-4A priority Critical patent/BRPI0924997B1/en
Application filed by Sk Holdings Co., Ltd. filed Critical Sk Holdings Co., Ltd.
Priority to AU2009348523A priority patent/AU2009348523B2/en
Priority to MX2011013982A priority patent/MX2011013982A/en
Priority to PL09846577T priority patent/PL2445890T3/en
Priority to CN200980160004.3A priority patent/CN102803233B/en
Priority to CA2765566A priority patent/CA2765566C/en
Priority to ES09846577.6T priority patent/ES2541590T3/en
Priority to RU2012102051/04A priority patent/RU2508290C2/en
Priority to JP2012517362A priority patent/JP5683580B2/en
Priority to EP20090846577 priority patent/EP2445890B1/en
Publication of WO2010150946A1 publication Critical patent/WO2010150946A1/en
Priority to IL216786A priority patent/IL216786A/en
Priority to ZA2011/09362A priority patent/ZA201109362B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C07D257/06—Five-membered rings with nitrogen atoms directly attached to the ring carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring

Definitions

  • the present invention relates to a method for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester. More particularly, the present invention relates to a method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester, comprising the asymmetric reduction of an arylketone.
  • carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters (hereinafter referred to as "the carbamate compounds") with anticonvulsant activity are useful in the treatment of disorders of the central nervous system, especially including anxiety, depression, convulsion, epilepsy, migraines, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorders, neuropathic pain, strokes, cognitive impairment, neurodegeneration, strokes and muscle spasms.
  • the carbamate compounds are divided into two positional isomers: tetrazole-1-yl (hereinafter referred to as "1N tetrazole”) and treatzole-2-yl (hereinafter referred to as "2N tetrazole").
  • 1N tetrazole tetrazole-1-yl
  • 2N tetrazole treatzole-2-yl
  • the carbamate compounds must be in high optical purity as well as chemical purity as they are used as medications.
  • U. S. Patent Application Publication No. 2006/0258718 A1 uses the pure enantiomer (R)-aryl-oxirane as a starting material which is converted into an alcohol intermediate through a ring-opening reaction by tetrazole in the presence of a suitable base in a solvent, followed by introducing a carbamoyl group into the alcohol intermediate.
  • column chromatography is set after the formation of an alcohol intermediate or carbamate.
  • (R)-2-aryl-oxirane may be synthesized from an optically active material, such as substituted (R)-mandelic acid derivative, via various routes or obtained by asymmetric reduction-ring formation reaction of ⁇ -halo arylketone or by separation of racemic 2-aryl-oxirane mixture into its individual enantiomers.
  • an optically active material such as substituted (R)-mandelic acid derivative
  • the ring-opening reaction of (R)-2-aryl-oxirane with tetrazole is performed at relatively high temperatures because of the low nucleophilicity of the tetrazole.
  • the ring opening reaction includes highly likely risk of a runaway reaction because tetrazoles start to spontaneously degrade at 110 ⁇ 120°C.
  • an object of the present invention is to provide a novel method for preparing novel (R)-1-aryl-2-tetrazolyl-ethyl ester.
  • the present invention provides a method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl ethyl ester, represented by Chemistry Figure 1, comprising: subjecting an arylketone, represented by Chemistry Figure 2, to (R)-selective asymmetric reduction to form an alcohol compound of (R)-configuration, represented by Chemistry Figure 5; and carbamating said alcohol:
  • R 1 and R 2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of 1 to 8 carbon atoms, thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
  • one of A 1 and A 2 is CH with the other being N.
  • a method comprising (R)-selective asymmetric reduction of an arylketone represented by the following Chemistry Figure 2 and the carbamation of an alcohol compound represented by the following Chemistry Figure 5 is provided for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester, represented by the following Chemistry Figure 1.
  • R 1 and R 2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of 1 to 8 carbon atoms, thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
  • one of A 1 and A 2 is CH with the other being N.
  • the arylketone of Chemistry Figure 2 useful as a starting material in the preparation method of the present invention, may be synthesized by, for example, a substitution reaction between the arylketone of Chemistry Figure 8 and the tetrazole of Chemistry Figure 9:
  • R 1 and R 2 are as defined above;
  • X is a leaving group such as a halide or sulfonate.
  • the arylketone represented by Chemistry Figure 2 which can be synthesized by the substitution reaction with tetrazole may be in a mixture of positional isomers including 1N arylketone of the following Chemistry Figure 3 and 2N arylketone of the following Chemistry Figure 4, which can be isolated and purified through commercially available crystallization.
  • the crystallization useful in the present invention may comprise adding a solubilizing agent to the product of the substitution reaction, that is, a mixture of the positional isomers, and then adding a precipitating agent.
  • the crystallization may further comprise, after the precipitation, filtrating the precipitate, concentrating the filtrate and adding an additional precipitating agent.
  • solubilizing agent examples include acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, and lower alcohols of 1 to 4 carbon atoms, and a combination thereof.
  • the solubilizing agent may be used in an amount of from 0 to 20 ml (v/w) based on the weight (g) of the mixture of the positional isomers.
  • the addition of the solubilizing agent in an amount of zero ml (v/w) is intended to mean immediately adding the subsequent additive without dilution of the filtrate.
  • the precipitating agent examples include water, C1-C4 lower alcohol, diethylether, pentane, hexane, cyclohexane, heptane and a combination thereof, but are not limited thereto.
  • the precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w) based on the weight (g) of the mixture of positional isomers.
  • the addition of the precipitating agent in an amount of zero ml is intended to mean leaving or cooling to yield precipitates without the addition of the precipitating agent.
  • the filtrate thus obtained after the filtration step may be concentrated to increase the ratio of the precipitating agent to the solubilizing agent, thereby yielding the 2N arylketone of Chemistry Figure 4 with high purity.
  • Concentration ratio of the filtrate can be suitably determined by those of ordinary skill in the art. For example, concentration is carried until the solvent is totally removed off, then the solubilizing agent and the precipitating agent are added as mentioned above.
  • this crystallization may be commercially used without much difficulty.
  • R 1 and R 2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
  • one of A 1 and A 2 is CH with the other being N.
  • the (R)-selective asymmetric reduction can be achieved, for example, biologically or chemically.
  • the arylketone compound of Chemistry Figure 2 is converted into an alcohol compound with (R)-configuration of optically high purity by biological asymmetric reduction.
  • the biological asymmetric reduction can be achieved in a buffer containing a microbial strain capable of producing oxidoreductase, the arylketone compound of Chemistry Figure 2 and a cosubstrate at an appropriate temperature.
  • a microbial strain capable of producing oxidoreductase include yeast of the Candida genus, such as Candida parapsilosis or Candida rugosa ; yeast of the Pichia genus, such as Pichia anomala or Pichia jadinii ; yeast of the Saccharomyces genus, such as Baker's yeast, Saccharomyces cerevisiae or Saccharomyces pastorianus ; other yeast such as Rhodotorula mucilaginosa or Trigonopsis variabilis ; bacteria, such as Klebsiella pneumoniae , Enterobacter cloacae , Erwinia herbicola , Micrococcus luteus , Bacillus stearothermophilus , Rhodococc
  • the microbial strain capable of producing oxidoreductase may be used in an amount of from about 0.1 to 10 g per gram of the arylketone of Chemistry Figure 2.
  • an additional coenzyme such as nicotineamide adenine dinucleotide phosphate (NADP) or nicotineamide adenine dinucleotide (NAD) may be added to the buffer with a use amount from about 0.1 to 1 mg per gram of the arylketone of Chemistry Figure 2.
  • NADP nicotineamide adenine dinucleotide phosphate
  • NAD nicotineamide adenine dinucleotide
  • the coenzyme, NADP or NAD may be converted to its reduced form, NADPH or NADH, respectively with the aid of the oxidoreductase and/or a cosubstrate.
  • Examples of the cosubstrate include saccharides such a glucose, glycerol or sucrose; and alcohols such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 2-pentanol, 2-methylpentanol, 2-hexanol, 2-heptanol, 2-octanol, cyclopentanol, cyclohexanol, 2-methyl 2-butanol, etc.
  • alcohols such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 2-pentanol, 2-methylpentanol, 2-hexanol, 2-heptanol, 2-octanol, cyclopentanol, cyclohexanol, 2-methyl 2-butanol, etc.
  • alcohols such as methanol, ethanol, 1-propanol, isopropanol
  • the buffer useful in the biological asymmetric reduction may be PBS (phosphate buffered saline) or a solution of sodium phosphate, potassium phosphate or triethanolamine in water, for example, at a pH of 6 to 8.
  • PBS phosphate buffered saline
  • a solution of sodium phosphate, potassium phosphate or triethanolamine in water for example, at a pH of 6 to 8.
  • the biological asymmetric reduction may be carried out at from 10 to 45°C.
  • the arylketone compound of Chemistry Figure 2 is chemically converted into an alcohol compound with (R)-configuration of high optical purity under asymmetric conditions.
  • Chemical asymmetric reduction may be accomplished, for example, with a chiral borane reductant at an appropriate temperature in an organic solvent, or by asymmetric catalytic hydrogenation or asymmetric catalytic transfer hydrogenation.
  • the asymmetric catalytic hydrogenation may be conducted as follows: the 0.0004 to 0.2 equivalents of an inorganic base may be added to the solution with 0.0002 to 0.1 equivalents of (R)-bisphosphono-ruthenium (II)-(R,R)-chiral diamine complex catalyst dissolved in organic solvent such as isopropanol, methanol, ethanol or t-butylalcohol.
  • organic solvent such as isopropanol, methanol, ethanol or t-butylalcohol.
  • the arylketone compound of Chemistry Figure 2 may be added and the resultant solution may hold at about -10 to about 60°C under hydrogen pressure of 1 to 20 atm.
  • a non-limiting example of the catalyst useful in the asymmetric catalytic hydrogenation is dichloro[(R)-(+)-2,2'-bis(diphenylphosphono)1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) represented by the following Chemistry Figure 10.
  • asymmetric catalytic transfer hydrogenation it may be carried out by adding 0.001 ⁇ 0.1 equivalents of [S,S]-monosulfonatediamine-M(II) arene complex catalyst (wherein M is ruthenium or rhodium) to a solution of the arylketone compound of Chemistry Figure 2 in 5:2 formic acid-triethylamine azeotrope or isopropanol at about -10 to 60°C.
  • a non-limiting example of catalyst useful for the asymmetric catalytic transfer hydrogenation may be chloro ⁇ [(1S,2S)-(+)-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido ⁇ (p-cymene)ruthenium(II), represented by the following Chemistry Figure 11.
  • the alcohol compound obtained through the asymmetric reduction may exist as a positional isomer mixture of 1N alcohol of Chemistry Figure 6 and 2N alcohol of Chemistry Figure 7 that can be isolated and purified into individual positional isomers of high purity by crystallization:
  • the crystallization may comprise adding a solubilizing agent to the positional isomer mixture resulting from the asymmetric reduction; and adding a precipitating agent, and optionally filtering the precipitate; and concentrating the filtrate and adding an additional precipitating agent.
  • the solubilizing agent may be added in an amount of zero to 20 ml (v/w) based on the weight (g) of the positional isomer mixture.
  • Non-limiting examples of the precipitating agent include water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane, and a mixture thereof.
  • the precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w) based on the weight (g) of the positional isomer mixture.
  • 2N alcohol (7) can be obtained as a crystal form of very high purity by concentrating the filtrate and increasing the ratio of the precipitating agent to the solubilizing agent.
  • R 1 and R 2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and an alkoxy of 1 to 8 carbon atoms; and
  • one of A 1 and A 2 is CH with the other being N.
  • inorganic cyanate-organic acid, isocyanate-water, or carbonyl compound-ammonia may be employed to introduce a carbamoyl moiety.
  • the alcohol compound with (R)-configuration of Chemistry Figure 5 is dissolved in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and mixed with 1 to 4 equivalents of inorganic cyanate such as sodium cyanate and organic acid, such as methane sulfonic acid or acetic acid, followed by reacting at about -10 to 70°C.
  • organic solvent for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof.
  • isocyanate-water 1 to 4 equivalents of isocyanate, for example, chlorosulfonic isocyanate, trichloroacetyl isocyanate, trimethylsilyl isocyanate, are added to a solution of the alcohol compound with (R)-configuration of Chemistry Figure 5 in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and reacted at about -50 to 40°C. Subsequently, without purification, 1 to 20 equivalents of water were added to induce hydrolysis.
  • an organic solvent for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof
  • 1 to 4 equivalents of a carbonyl compound for example, 1,1'-carbonyldiimidazole, carbamoly chloride, disuccinyl carbonate, phosgene, triphosgene, or chloroformate, are added to a solution of the alcohol compound with (R)-configuration of Chemistry Figure 5 in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and reacted at about -10 to 70°C, followed by adding 1 to 10 equivalents of ammonia without purification.
  • a carbonyl compound for example, 1,1'-carbonyldiimidazole, carbamoly chloride, disuccinyl carbonate, phosgene, triphosgene, or chloroformate
  • the carbamate compound of Chemistry Figure 1 may be purified to higher optical and chemical purity through the following crystallization.
  • the crystallization comprises adding a solubilizing agent to the product of the carbamation; and then adding a precipitating agent, and optionally filtering the precipitate and adding an additional precipitating agent.
  • a solubilizing agent to the product of the carbamation
  • a precipitating agent for pharmaceutical use, it is preferable that there is always a final purification of the carbamated product before use, but that there can be a crystallization step earlier in the process.
  • Non-limiting examples of the solubilizing agent include acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, lower alcohol of 1 to 4 carbon atoms, and a mixture thereof. Based on the weight (g) of the reaction product, the solubilizing agent may be used in an amount of from zero to 20 ml (v/w).
  • Non-limiting examples of the precipitating agent include water, lower alcohols of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane and a mixture thereof. Based on the weight (g) of the reaction product, the precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w).
  • the method of the present invention can provide optically high pure carbamate compounds.
  • the mild reaction conditions which the method of the present invention requires ensure process safety.
  • the crystallization step applicable to large-scale production before or after the asymmetric reduction or after the carbamation results in a higher chemical purity of the carbamate compounds.
  • carbamate compounds prepared according to the present invention are very useful in the treatment of CNS disorders such as convulsion.
  • Suitable for use in the biological asymmetric reduction is a strain expressing oxidoreductase.
  • baker s yeast a strain commercially available in a freeze-dried form may be weighed properly for the reaction.
  • the strain stored in a deep freezer may be spread on LB plates medium (Bactotrypton: 1%, yeast extract: 0.5%, NaCl: 0.5%, glucose: 0.1%, agar: 1.5%) to form colonies. The one of which is then inoculated into 3 mL of an LB medium in a tube and pre-incubated at 30°C for 1 day.
  • Optical Purity (%) [(Area of R-Configuration Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100
  • Trigonopsis variabilis KCTC7263 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 1, below.
  • Trigonopsis variabilis KCTC7263 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 1, below.
  • Candida parapsilosis ATCC20179 or Candida rugosa KCTC7292 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 2, below.
  • the precipitate was dissolved in dichloromethane (73 mL) to which methanesulfonic acid (5.5 mL, 84.7 mmol) was added at 10°C, followed by the slow addition of sodium cyanate (4.24 g, 65.2 mmol).
  • the reactant mixture was stirred at 10°C for 12h and washed with 10% brine (3 x 100 mL).
  • the organic layer thus formed was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (14 mL). Heating the solution to 45°C and cooling to room temperature led to the completion of crystallization.
  • chlorosulfonyl isocyanate (6.9 mL, 79.2 mmol) was slowly added and stirred at -10°C for 2 h.
  • the slow addition of water (10 mL) induced termination of the reaction.
  • the resulting solution was concentrated under reduced pressure until about 100 mL of the solvent was removed.
  • the concentrate was diluted in ethyl acetate (200 mL) and washed with 10% brine (3 x 150 mL).
  • the organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (30 mL) to which heptane (90 mL) was slowly added, leading to the completion of crystallization.
  • carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.

Abstract

Disclosed is a method for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester, comprising the asymmetric reduction of arylketone and the carbamation of alcohol.

Description

METHOD FOR PREPARATION OF CARBAMIC ACID (R)-1-ARYL-2-TETRAZOLYL-ETHYL ESTER
The present invention relates to a method for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester. More particularly, the present invention relates to a method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester, comprising the asymmetric reduction of an arylketone.
As disclosed in U. S. Patent Application Publication No. 2006/0258718 A1, carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl esters (hereinafter referred to as "the carbamate compounds") with anticonvulsant activity are useful in the treatment of disorders of the central nervous system, especially including anxiety, depression, convulsion, epilepsy, migraines, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorders, neuropathic pain, strokes, cognitive impairment, neurodegeneration, strokes and muscle spasms.
Depending on the position of N in the tetrazole moiety thereof, the carbamate compounds are divided into two positional isomers: tetrazole-1-yl (hereinafter referred to as "1N tetrazole") and treatzole-2-yl (hereinafter referred to as "2N tetrazole"). The introduction of tetrazole for the preparation of the carbamate compounds results in a 1:1 mixture of the two positional isomers which are required to be individually isolated for pharmaceutical use.
Having chirality, the carbamate compounds must be in high optical purity as well as chemical purity as they are used as medications.
In this regard, U. S. Patent Application Publication No. 2006/0258718 A1 uses the pure enantiomer (R)-aryl-oxirane as a starting material which is converted into an alcohol intermediate through a ring-opening reaction by tetrazole in the presence of a suitable base in a solvent, followed by introducing a carbamoyl group into the alcohol intermediate. For isolation and purification of the 1N and 2N positional isomers thus produced, column chromatography is set after the formation of an alcohol intermediate or carbamate.
For use in the preparation, (R)-2-aryl-oxirane may be synthesized from an optically active material, such as substituted (R)-mandelic acid derivative, via various routes or obtained by asymmetric reduction-ring formation reaction of α-halo arylketone or by separation of racemic 2-aryl-oxirane mixture into its individual enantiomers. As such, (R)-2-aryl-oxirane is an expensive compound.
In addition, the ring-opening reaction of (R)-2-aryl-oxirane with tetrazole is performed at relatively high temperatures because of the low nucleophilicity of the tetrazole. However, the ring opening reaction includes highly likely risk of a runaway reaction because tetrazoles start to spontaneously degrade at 110 ~ 120℃.
In terms of a selection of reaction, as there are two reaction sites in each (R)-2-aryl-oxirane and tetrazole, the ring-opening reaction therebetween affords the substitution of 1N- or 2N-tetrazole at the benzyl or terminal position, resulting in a mixture of a total of 4 positional isomers. Therefore, individual positional isomers are low in production yield and difficult to isolate and purify.
Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and an object of the present invention is to provide a novel method for preparing novel (R)-1-aryl-2-tetrazolyl-ethyl ester.
In order to accomplish the above object, the present invention provides a method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl ethyl ester, represented by Chemistry Figure 1, comprising: subjecting an arylketone, represented by Chemistry Figure 2, to (R)-selective asymmetric reduction to form an alcohol compound of (R)-configuration, represented by Chemistry Figure 5; and carbamating said alcohol:
ChemistryFigure 1
Figure PCTKR2009005906-appb-C000001
ChemistryFigure 2
Figure PCTKR2009005906-appb-C000002
ChemistryFigure 5
Figure PCTKR2009005906-appb-C000003
wherein,
R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of 1 to 8 carbon atoms, thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
one of A1 and A2 is CH with the other being N.
An economical advantage is given to the synthesis of the arylketone of Chemistry Figure 2 from the compounds represented by Chemistry Figures 8 and 9 because they are commercially available, cheap compounds. In addition, the substitution reaction can be carried out in relatively mild conditions, compared to the ring-opening reaction between (R)-2-aryl-oxirane and tetrazole. The method according to the present invention is therefore certain of process safety although employing potentially explosive tetrazole, and ensures high production yield and easy purification, with the production of no unnecessary positional isomers at benzyl positions.
In accordance with an embodiment of the present invention, a method comprising (R)-selective asymmetric reduction of an arylketone represented by the following Chemistry Figure 2 and the carbamation of an alcohol compound represented by the following Chemistry Figure 5 is provided for the preparation of carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester, represented by the following Chemistry Figure 1.
[Chemistry Figure 1]
Figure PCTKR2009005906-appb-I000001
[Chemistry Figure 2]
Figure PCTKR2009005906-appb-I000002
[Chemistry Figure 5]
Figure PCTKR2009005906-appb-I000003
wherein,
R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, alkyl of 1 to 8 carbon atoms, thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
one of A1 and A2 is CH with the other being N.
The arylketone of Chemistry Figure 2, useful as a starting material in the preparation method of the present invention, may be synthesized by, for example, a substitution reaction between the arylketone of Chemistry Figure 8 and the tetrazole of Chemistry Figure 9:
ChemistryFigure 8
Figure PCTKR2009005906-appb-C000004
ChemistryFigure 9
Figure PCTKR2009005906-appb-C000005
wherein,
R1 and R2 are as defined above; and
X is a leaving group such as a halide or sulfonate.
An economical advantage is given to the synthesis of the arylketone of Chemistry Figure 2 from the compounds represented by Chemistry Figures 8 and 9 because they are commercially available, cheap compounds. In addition, the substitution reaction can be carried out in relatively mild conditions, compared to the ring-opening reaction between (R)-2-aryl-oxirane and tetrazole. The method according to the present invention is therefore certain of process safety although employing potentially explosive tetrazole, and ensures high production yield and easy purification, with the production of no unnecessary positional isomers at benzyl positions.
The arylketone represented by Chemistry Figure 2 which can be synthesized by the substitution reaction with tetrazole may be in a mixture of positional isomers including 1N arylketone of the following Chemistry Figure 3 and 2N arylketone of the following Chemistry Figure 4, which can be isolated and purified through commercially available crystallization.
ChemistryFigure 3
Figure PCTKR2009005906-appb-C000006
ChemistryFigure 4
Figure PCTKR2009005906-appb-C000007
The crystallization useful in the present invention may comprise adding a solubilizing agent to the product of the substitution reaction, that is, a mixture of the positional isomers, and then adding a precipitating agent. Optionally, the crystallization may further comprise, after the precipitation, filtrating the precipitate, concentrating the filtrate and adding an additional precipitating agent.
Illustrative, non-limiting examples of the solubilizing agent include acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, and lower alcohols of 1 to 4 carbon atoms, and a combination thereof. The solubilizing agent may be used in an amount of from 0 to 20 ml (v/w) based on the weight (g) of the mixture of the positional isomers. As used herein, the addition of the solubilizing agent in an amount of zero ml (v/w) is intended to mean immediately adding the subsequent additive without dilution of the filtrate.
Examples of the precipitating agent include water, C1-C4 lower alcohol, diethylether, pentane, hexane, cyclohexane, heptane and a combination thereof, but are not limited thereto. The precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w) based on the weight (g) of the mixture of positional isomers. As used herein, the addition of the precipitating agent in an amount of zero ml is intended to mean leaving or cooling to yield precipitates without the addition of the precipitating agent.
The filtration of the precipitates thus obtained by the addition of the precipitating agent yields the 1N arylketone of Chemistry Figure 3 as a crystal with high purity.
On the other hand, the filtrate thus obtained after the filtration step may be concentrated to increase the ratio of the precipitating agent to the solubilizing agent, thereby yielding the 2N arylketone of Chemistry Figure 4 with high purity. Concentration ratio of the filtrate can be suitably determined by those of ordinary skill in the art. For example, concentration is carried until the solvent is totally removed off, then the solubilizing agent and the precipitating agent are added as mentioned above.
Unlike column chromatography, this crystallization may be commercially used without much difficulty.
(R)-Selective asymmetric reduction allows for the conversion of the arylketone of Chemistry Figure 2 into the alcohol compound with (R)-configuration, represented by the following Chemistry Figure 5.
[Chemistry Figure 2]
Figure PCTKR2009005906-appb-I000004
[Chemistry Figure 5]
Figure PCTKR2009005906-appb-I000005
wherein,
R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and alkoxy of 1 to 8 carbon atoms; and
one of A1 and A2 is CH with the other being N.
The (R)-selective asymmetric reduction can be achieved, for example, biologically or chemically.
In the method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester according to an embodiment of the present invention, the arylketone compound of Chemistry Figure 2 is converted into an alcohol compound with (R)-configuration of optically high purity by biological asymmetric reduction.
The biological asymmetric reduction can be achieved in a buffer containing a microbial strain capable of producing oxidoreductase, the arylketone compound of Chemistry Figure 2 and a cosubstrate at an appropriate temperature. Examples of the microbial strain capable of producing oxidoreductase include yeast of the Candida genus, such as Candida parapsilosis or Candida rugosa; yeast of the Pichia genus, such as Pichia anomala or Pichia jadinii; yeast of the Saccharomyces genus, such as Baker's yeast, Saccharomyces cerevisiae or Saccharomyces pastorianus; other yeast such as Rhodotorula mucilaginosa or Trigonopsis variabilis; bacteria, such as Klebsiella pneumoniae, Enterobacter cloacae, Erwinia herbicola, Micrococcus luteus, Bacillus stearothermophilus, Rhodococcus erythropolis or Rhodococcus rhodochrous; fungi, such as Mucor racemosus or Geotrichum candidum, etc.
The microbial strain capable of producing oxidoreductase may be used in an amount of from about 0.1 to 10 g per gram of the arylketone of Chemistry Figure 2.
To enhance the rate of the biological asymmetric reduction, an additional coenzyme such as nicotineamide adenine dinucleotide phosphate (NADP) or nicotineamide adenine dinucleotide (NAD) may be added to the buffer with a use amount from about 0.1 to 1 mg per gram of the arylketone of Chemistry Figure 2.
The coenzyme, NADP or NAD may be converted to its reduced form, NADPH or NADH, respectively with the aid of the oxidoreductase and/or a cosubstrate.
Examples of the cosubstrate include saccharides such a glucose, glycerol or sucrose; and alcohols such as methanol, ethanol, 1-propanol, isopropanol, 1-butanol, 2-butanol, 2-pentanol, 2-methylpentanol, 2-hexanol, 2-heptanol, 2-octanol, cyclopentanol, cyclohexanol, 2-methyl 2-butanol, etc. Among the alcohols mentioned beforehand, methanol, 1-propanol, 1-butanol and 2-methyl 2-butanol are preferable.
The buffer useful in the biological asymmetric reduction may be PBS (phosphate buffered saline) or a solution of sodium phosphate, potassium phosphate or triethanolamine in water, for example, at a pH of 6 to 8.
The biological asymmetric reduction may be carried out at from 10 to 45℃.
In addition to being economical and environment-friendly, the biological selective reduction allows for very high enantioselectivity. Thus, an alcohol compound with an (R)-configuration of high optical purity can be obtained in the presence of the enzyme under the above-mentioned reaction conditions.
In the method for preparing carbamic acid (R)-1-aryl-2-tetrazolyl-ethyl ester according to another embodiment of the present invention, the arylketone compound of Chemistry Figure 2 is chemically converted into an alcohol compound with (R)-configuration of high optical purity under asymmetric conditions.
Chemical asymmetric reduction may be accomplished, for example, with a chiral borane reductant at an appropriate temperature in an organic solvent, or by asymmetric catalytic hydrogenation or asymmetric catalytic transfer hydrogenation.
As concerns the use of a chiral borane reductant, 1 to 4 equivalents of sodium (-)-B-chlorodiisopinochampheylborane (hereinafter referred to as "(-)-DIP-Cl") or (R)-2-methyl-CBS-oxazaborolidine/borane (hereinafter referred to as "(R)-CBS/BH3") are added to a solution of the arylketone compound of Chemistry Figure 2 in an organic solvent such as diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and the reaction may be conducted at about -10 to about 60℃.
The asymmetric catalytic hydrogenation may be conducted as follows: the 0.0004 to 0.2 equivalents of an inorganic base may be added to the solution with 0.0002 to 0.1 equivalents of (R)-bisphosphono-ruthenium (II)-(R,R)-chiral diamine complex catalyst dissolved in organic solvent such as isopropanol, methanol, ethanol or t-butylalcohol. The arylketone compound of Chemistry Figure 2 may be added and the resultant solution may hold at about -10 to about 60℃ under hydrogen pressure of 1 to 20 atm. A non-limiting example of the catalyst useful in the asymmetric catalytic hydrogenation is dichloro[(R)-(+)-2,2'-bis(diphenylphosphono)1,1'-binaphthyl][(1R,2R)-(+)-1,2-diphenylethylenediamine]ruthenium(II) represented by the following Chemistry Figure 10.
ChemistryFigure 10
Figure PCTKR2009005906-appb-C000008
Turning to the asymmetric catalytic transfer hydrogenation, it may be carried out by adding 0.001 ~ 0.1 equivalents of [S,S]-monosulfonatediamine-M(II) arene complex catalyst (wherein M is ruthenium or rhodium) to a solution of the arylketone compound of Chemistry Figure 2 in 5:2 formic acid-triethylamine azeotrope or isopropanol at about -10 to 60℃. A non-limiting example of catalyst useful for the asymmetric catalytic transfer hydrogenation may be chloro｛[(1S,2S)-(+)-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido｝(p-cymene)ruthenium(II), represented by the following Chemistry Figure 11.
ChemistryFigure 11
Figure PCTKR2009005906-appb-C000009
The alcohol compound obtained through the asymmetric reduction may exist as a positional isomer mixture of 1N alcohol of Chemistry Figure 6 and 2N alcohol of Chemistry Figure 7 that can be isolated and purified into individual positional isomers of high purity by crystallization:
ChemistryFigure 6
Figure PCTKR2009005906-appb-C000010
ChemistryFigure 7
Figure PCTKR2009005906-appb-C000011
The crystallization may comprise adding a solubilizing agent to the positional isomer mixture resulting from the asymmetric reduction; and adding a precipitating agent, and optionally filtering the precipitate; and concentrating the filtrate and adding an additional precipitating agent.
Examples of the solubilizing agent useful in the crystallization include acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, lower alcohol of 1 to 4 carbon atoms, and a mixture thereof, but are not limited thereto. The solubilizing agent may be added in an amount of zero to 20 ml (v/w) based on the weight (g) of the positional isomer mixture.
Non-limiting examples of the precipitating agent include water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane, and a mixture thereof. The precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w) based on the weight (g) of the positional isomer mixture.
Following the addition of the precipitating agent, filtration may yield 1N alcohol (6) as a precipitate of high purity.
Furthermore, 2N alcohol (7) can be obtained as a crystal form of very high purity by concentrating the filtrate and increasing the ratio of the precipitating agent to the solubilizing agent.
These crystallization steps may be omitted when the positional isomers of arylketone of Chemistry Figure 2 are already isolated and purified.
The introduction of a carbomoyl moiety into the alcohol compound with (R)-configuration of Chemistry Figure 5 leads to carbamate with (R)-configuration, represented by Chemistry Figure 1:
[Chemistry Figure 5]
Figure PCTKR2009005906-appb-I000006
[Chemistry Figure 1]
Figure PCTKR2009005906-appb-I000007
wherein,
R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and an alkoxy of 1 to 8 carbon atoms; and
one of A1 and A2 is CH with the other being N.
In the carbamation step, for example, inorganic cyanate-organic acid, isocyanate-water, or carbonyl compound-ammonia may be employed to introduce a carbamoyl moiety.
For the carbamation with inorganic cyanate-organic acid, the alcohol compound with (R)-configuration of Chemistry Figure 5 is dissolved in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and mixed with 1 to 4 equivalents of inorganic cyanate such as sodium cyanate and organic acid, such as methane sulfonic acid or acetic acid, followed by reacting at about -10 to 70℃.
With regard to use of the isocyanate-water, 1 to 4 equivalents of isocyanate, for example, chlorosulfonic isocyanate, trichloroacetyl isocyanate, trimethylsilyl isocyanate, are added to a solution of the alcohol compound with (R)-configuration of Chemistry Figure 5 in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and reacted at about -50 to 40℃. Subsequently, without purification, 1 to 20 equivalents of water were added to induce hydrolysis.
With regard to use of the carbonyl compound-ammonia,
1 to 4 equivalents of a carbonyl compound, for example, 1,1'-carbonyldiimidazole, carbamoly chloride, disuccinyl carbonate, phosgene, triphosgene, or chloroformate, are added to a solution of the alcohol compound with (R)-configuration of Chemistry Figure 5 in an organic solvent, for example, diethylether, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, chloroform or a mixture thereof, and reacted at about -10 to 70℃, followed by adding 1 to 10 equivalents of ammonia without purification.
After the carbamation, the carbamate compound of Chemistry Figure 1 thus obtained may be purified to higher optical and chemical purity through the following crystallization. The crystallization comprises adding a solubilizing agent to the product of the carbamation; and then adding a precipitating agent, and optionally filtering the precipitate and adding an additional precipitating agent. For pharmaceutical use, it is preferable that there is always a final purification of the carbamated product before use, but that there can be a crystallization step earlier in the process.
Non-limiting examples of the solubilizing agent include acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, lower alcohol of 1 to 4 carbon atoms, and a mixture thereof. Based on the weight (g) of the reaction product, the solubilizing agent may be used in an amount of from zero to 20 ml (v/w).
Non-limiting examples of the precipitating agent include water, lower alcohols of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane and a mixture thereof. Based on the weight (g) of the reaction product, the precipitating agent may be slowly added in an amount of from zero to 40 ml (v/w). Comprising biological or chemical asymmetric reduction, the method of the present invention can provide optically high pure carbamate compounds. In addition, the mild reaction conditions which the method of the present invention requires ensure process safety. Furthermore, the crystallization step applicable to large-scale production before or after the asymmetric reduction or after the carbamation results in a higher chemical purity of the carbamate compounds.
As demonstrated in the following examples, the carbamate compounds prepared according to the present invention are very useful in the treatment of CNS disorders such as convulsion.
A better understanding of the present invention may be obtained through the following examples which are set forth to illustrate, but are not to be construed as limiting the present invention.
EXAMPLES
Preparation of Tetrazole Arylketones
Preparation Example 1: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one
To a suspension of 2-bromo-2'-chloroacetophenone (228.3 g, 0.978 mol) and potassium carbonate (161.6 g, 1.170 mol) in acetonitrile (2000 mL) was added a 35 w/w% 1H-tetrazole dimethylformamide solution (215.1 g, 1.080 mol) at room temperature. These reactants were stirred for 2 h at 45℃ and distilled under reduced pressure to remove about 1500 mL of the solvent. The concentrate was diluted in ethylacetate (2000 mL) and washed with 10% brine (3 x 2000 mL). The organic layer thus separated was distilled under reduced pressure to afford 216.4 g of an oily solid residue. To a solution of the solid residue in ethylacetate (432 mL) was slowly added heptane (600 mL). The precipitate thus formed was filtered at room temperature and washed to yield 90.1 g (0.405 mol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (hereinafter referred to as "1N ketone").
1H-NMR(CDCl3)d8.87(s, 1H), d7.77(d, 1H), d7.39-7.62(m, 3H), d5.98(s, 2H)
Preparation Example 2: Preparation of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one
After the filtration of Preparation Example 1, the filtrate was concentrated and dissolved in isopropanol (100 mL), and to which heptane (400 mL) was then added to complete the crystallization. Filtering and washing at 5℃ afforded 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one (hereinafter referred to as "2N ketone") as a solid. 94.7 g (0.425 mol).
1H-NMR(CDCl3) d8.62(s, 1H), d7.72(d, 1H), d7.35-7.55(m, 3H), d6.17(s, 2H)
Preparation of Alcohol Compound of (R)-Configuration by Biological Asymmetric Reduction
Suitable for use in the biological asymmetric reduction is a strain expressing oxidoreductase. Like baker s yeast (Jenico), a strain commercially available in a freeze-dried form may be weighed properly for the reaction. As like other micorbial strans, the strain stored in a deep freezer (Revco) may be spread on LB plates medium (Bactotrypton: 1%, yeast extract: 0.5%, NaCl: 0.5%, glucose: 0.1%, agar: 1.5%) to form colonies. The one of which is then inoculated into 3 mL of an LB medium in a tube and pre-incubated at 30℃ for 1 day. After completion of the pre-incubation, it was scaled up to 300 mL of LB medium in 1L Erlenmeyer flask, followed by incubation at 30℃ for 2 days. Centrifugation precipitates the strain into a pellet which is quantified for use in the reaction.
Preparation Example 3: Preparation of 1N Alcohol with Rhodotorula mucilaginosa
1-(2-Chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one (100mg, 0.449mmol), prepared in Preparation Example 1, was incubated at room temperature for 4 days with nicotinamide adenine dinucleotide (NAD, 0.5 mg) in the presence of Rhodotorula mucilaginosa KCTC7117 (500 mg), a microbial strain producing oxidoreductase, in PBS (10mL, pH7.0) containing 5% (w/v) glycerol, after which extraction with ethylacetate (1 mL) gave an alcohol of R-configuration, that is, (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (hereinafter referred to as "1N alcohol"). Conversion rates and optical purities of products are listed in Table 1, below. Conversion rates (%), purities (%) and optical purities of products were measured using HPLC and calculated using the following equations.
Conversion Rate (%) = [(Area of Product)/(Area of Reactant + Area of Product)]x100
Purity (%) = (Area of Product)/(Area of All Peaks on HPLC)] x 100
Optical Purity (%) = [(Area of R-Configuration Area of S-Configuration)/(Area of R-Configuration + Area of S-Configuration)] x 100
1H-NMR(CDCl3) d8.74(s, 1H), d7.21-7.63(m, 4H), d5.57(m, 1H), d4.90(d, 1H), d4.50(d, 1H), d3.18(d, 1H)
Preparation Example 4: Preparation of 2N Alcohol with Rhodotorula mucilaginosa
The same procedure as in Preparation Example 3 was repeated, with the exception that 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-one, prepared in Preparation Example 2, was used instead of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-one, to afford (R)-1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (hereinafter referred to as "2N alcohol"). The conversion rate and optical purity of the product are given in Table 1, below.
1H-NMR(CDCl3) d8.55(s, 1H), d7.28-7.66(m, 4H), d5.73(d, 1H), d4.98(d, 1H), d4.83(d, 1H), d3.38(br, 1H)
Preparation Example 5: Preparation of 1N Alcohol with Trigonopsis variabilis
The same procedure as in Preparation Example 3 was repeated, with the exception that Trigonopsis variabilis KCTC7263 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 1, below.
Preparation Example 6: Preparation of 2N Alcohol with Trigonopsis variabilis
The same procedure as in Preparation Example 4 was repeated, with the exception that Trigonopsis variabilis KCTC7263 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 1, below.
Table 1
Figure PCTKR2009005906-appb-T000001
Preparation Examples 7 and 8: Preparation of 1N Alcohol with Yeasts of Candida Genus
The same procedure as in Preparation Example 3 was repeated, with the exception that Candida parapsilosis ATCC20179 or Candida rugosa KCTC7292 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 2, below.
Preparation Examples 9 and 10: Preparation of 2N Alcohol with Yeasts of Candida Genus
The same procedure as in Preparation Example 4 was repeated, with the exception that Candida parapsilosis ATCC20179 or Candida rugosa KCTC7292 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 2, below.
Table 2
Figure PCTKR2009005906-appb-T000002
Preparation Examples 11 and 12: Preparation of 1N Alcohol with Yeasts of Pichia Genus
The same procedure as in Preparation Example 3 was repeated, with the exception that Pichia anomala KCTC1206 or Pichia jadinii KCTC7008 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 3, below.
Preparation Examples 13 and 14: Preparation of 2N Alcohol with Yeasts of Pichia Genus
The same procedure as in Preparation Example 4 was repeated, with the exception that Pichia anomala KCTC1206 or Pichia jadinii KCTC7008 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 3, below.
Table 3
Figure PCTKR2009005906-appb-T000003
Preparation Examples 15 to 20: Preparation of 1N Alcohol with Yeast of Saccharomyces Genus
The same procedure as in Preparation Example 4 was repeated, with the exception that Baker's yeast, Saccharomyces cerevisiae KCTC7108, Saccharomyces cerevisiae KCTC1205, Saccharomyces cerevisiae KCTC7107, Saccharomyces cerevisiae KCTC1552 or Saccharomyces pastorianus KCTC1218 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 4, below.
Preparation Example 21 to 26: Preparation of 2N Alcohol with Yeasts of Saccharomyces Genus
The same procedure as in Preparation Example 4 was repeated, with the exception that Baker's yeast, Saccharomyces cerevisiae KCTC7108, Saccharomyces cerevisiae KCTC1205, Saccharomyces cerevisiae KCTC7107, Saccharomyces cerevisiae KCTC1552 or Saccharomyces pastorianus KCTC1218 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Its conversion rate and optical purity are given in Table 4, below.
Table 4
Figure PCTKR2009005906-appb-T000004
Preparation Examples 27 to 30: Preparation of 1N Alcohol with Bacteria
The same procedure as in Preparation Example 3 was repeated, with the exception that Klebsiella pneumoniae IFO3319, Bacillus stearothermophilus KCTC1752, Rhodococcus erythropolis KCCM40452 or Rhodococcus rhodochrous ATCC21197 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Their conversion rates and optical purities are given in Table 5, below.
Preparation Examples 31 to 37: Preparation of 2N Alcohol with Bacteria
The same procedure as in Preparation Example 4 was repeated, with the exception that Klebsiella pneumoniae IFO3319, Enterobacter cloacae KCTC2361, Erwinia herbicola KCTC2104, Micrococcus luteus KCTC1071, Bacillus stearothermophilus KCTC1752, Rhodococcus erythropolis KCCM40452 or Rhodococcus rhodochrous ATCC21197 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Their conversion rates and optical purities are given in Table 5, below.
Table 5
Figure PCTKR2009005906-appb-T000005
Preparation Examples 38 and 39: Preparation of 1N Alcohol with Fungi
The same procedure as in Preparation Example 3 was repeated, with the exception that Mucor racemosus KCTC6119, Geotrichum candidum KCTC6195, Geotrichum candidum IFO5767 or Geotrichum candidum IFO4597 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 1N alcohol of R-configuration. Their conversion rates and optical purities are given in Table 6, below.
Preparation Examples 40 to 42: Preparation of 2N Alcohol with Fungi
The same procedure as in Preparation Example 4 was repeated, with the exception that Mucor racemosus KCTC6119, Geotrichum candidum KCTC6195, Geotrichum candidum IFO5767 or Geotrichum candidum IFO4597 was used as a strain producing an oxidoreductase, instead of Rhodotorula mucilaginosa KCTC7117, to afford 2N alcohol of R-configuration. Their conversion rates and optical purities are given in Table 6, below.
Table 6
Figure PCTKR2009005906-appb-T000006
Preparation of Alcohol Compound of (R)-Configuration by Chemical Asymmetric Reduction
Preparation Examples 43 and 44: Preparation of 1N Alcohol with Chiral Borane Reductant
To a solution of 1N ketone (100 mg, 0.449 mmol), prepared in Preparation Example 1, in tetrahydrofuran (1 mL) was added 2 equivalents of a chiral borane reductant, such as (-)-B-chlorodiisopinocampheylborane or (R)-2-methyl-CBS-oxazaborolidine/borane, at 0℃. Stirring at room temperature for 24h was followed by extraction with ethyl acetate (1 mL) to give the results of Table 7, below.
Preparation Examples 45 and 46: Preparation of 2N Alcohol with Chiral Borane Reductant
To a solution of 2N ketone (100 mg, 0.449 mmol), prepared in Preparation Example 2, in tetrahydrofuran (1 mL) was added 2 equivalents of a chiral borane reductant, such as (-)-B-chlorodiisopinocampheylborane or (R)-2-methyl-CBS-oxazaborolidine/borane, at 0℃. Stirring at room temperature for 24h was followed by extraction with ethyl acetate (1 mL) to give the results of Table 7, below.
Table 7
Figure PCTKR2009005906-appb-T000007
Preparation Examples 47 and 48: Preparation of 1N and 2N Alcohols with Asymmetric Catalytic Transfer Hydrogenation
The 1N ketone prepared in Preparation Example 1 or 2N ketone prepared in Preparation Example 2 (222 mg, 1.0 mmol) was dissolved in a 5:2 formic acid-triethylamine azeotrope (1.4 mL) and subjected to an argon environment. After the solution was cooled to 0℃ in the argon environment, chloro｛[(1S,2S)-(+)-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido｝(p-cymene)ruthenium(II) (2 mg, 0.00 3mmol) of Chemistry Figure 11 was added thereto. Stirring at room temperature for 48 h was followed by extraction with ethyl acetate (2 mL) to give the results of Table 8, below.
Table 8
Figure PCTKR2009005906-appb-T000008
Preparation of Carbamate
Preparation Example 49: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-1-yl)ethyl ester
To PBS (1000mL, pH 7.0) containing 5%(w/v) glycerol were added baker's yeast (50 g) and 1N ketone (10 g, 44.9 mmol) prepared in preparation example 1, together with nicotineamide adenine dinucleotide (NAD, 1 mg). The resulting reaction suspension was stirred at 30℃ for 4 days and mixed with ethyl acetate (500 mL). After being separated, the organic layer thus formed was washed with 10% brine (3 x 500 mL). To the organic layer was added magnesium sulfate, followed by filtering the resulting suspension. The filtrate was distilled under reduced pressure to afford 8.5 g of a solid residue which was then dissolved at 45℃ in ethyl acetate (10 mL) and cooled to room temperature. Slow addition of heptane (20 mL) led to crystallization. The precipitate thus formed was filtered and washed to give 7.32 g (32.6 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-1-yl)ethan-1-ol (optical purity 99.9%). The precipitate was dissolved in dichloromethane (73 mL) to which methanesulfonic acid (5.5 mL, 84.7 mmol) was added at 10℃, followed by the slow addition of sodium cyanate (4.24 g, 65.2 mmol). The reactant mixture was stirred at 10℃ for 12h and washed with 10% brine (3 x 100 mL). The organic layer thus formed was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (14 mL). Heating the solution to 45℃ and cooling to room temperature led to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 7.84 g (29.3 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-1-yl)ethyl ester (purity >99.0%, optical purity >99.0%).
1H-NMR(Acetone-d6) d9.14(s, 1H), d7.31-7.59(m, 4H), 6.42(m, 1H), d6.0-6.75(Br, 2H), d4.90(d, 1H), d5.03(m, 2H)
Preparation Example 50: Preparation of Carbamic Acid (R)-1-(2-Chlorophenyl)-2-(tetrazol-2-yl)ethyl ester
The 2N ketone (15.5 g, 69.6 mmol), prepared in Preparation Example 2, was dissolved in a 5:2 formic acid-triethylamine azeotrope (60 mL) and subjected to an argon environment. To this solution was added chloro｛[(1S,2S)-(+)-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido｝(p-cymene)ruthenium(II) of Chemistry Figure 11 (140 mg, 0.220 mmol), followed by stirring at room temperature for 48 h. The solution was diluted in ethylacetate (200 mL) and washed with 10% brine (3 x 100 mL). The organic layer thus formed was dried over magnesium sulfate and filtered and the filtrate was distilled under reduced pressure to give 14.8 g (65.9 mmol) of 1-(2-chlorophenyl)-2-(1,2,3,4-tetrazol-2-yl)ethan-1-ol (optical purity 87.8%) as an oily residue. To this was added tetrahydrofuran (150 mL). After cooling to -15℃, chlorosulfonyl isocyanate (6.9 mL, 79.2 mmol) was slowly added and stirred at -10℃ for 2 h. The slow addition of water (10 mL) induced termination of the reaction. The resulting solution was concentrated under reduced pressure until about 100 mL of the solvent was removed. The concentrate was diluted in ethyl acetate (200 mL) and washed with 10% brine (3 x 150 mL). The organic layer was concentrated under reduced pressure and the concentrate was dissolved in isopropanol (30 mL) to which heptane (90 mL) was slowly added, leading to the completion of crystallization. The precipitate thus obtained was filtered and washed to afford 15.4 g (57.5 mmol) of carbamic acid (R)-1-(2-chlorophenyl)-2-(tetrazol-2-yl)ethyl ester (purity >99.0%, optical purity>99.0%).
1H-NMR(Acetone-d6) d8.74(s, 1H), d7.38-7.54(m, 4H), d6.59(m, 1H), d6.16(Br, 2H), d4.90(d, 1H), d5.09(m, 2H)
As described hitherto, carbamate compounds with high optical and chemical purity can be produced with an economical benefit in accordance with the present invention.
Although the preferred embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as disclosed in the accompanying claims.

Claims (18)

  1. A method for preparing carbamic acid aryl-2-tetrazolyl ethyl ester, represented by Chemistry Figure 1, comprising:
    subjecting an arylketone, represented by Chemistry Figure 2, to (R)-selective asymmetric reduction to form an alcohol compound of (R)-configuration, represented by Chemistry Figure 5; and
    carbamating said alcohol:
    [Chemistry Figure 1]
    Figure PCTKR2009005906-appb-I000008
    [Chemistry Figure 2]
    Figure PCTKR2009005906-appb-I000009
    [Chemistry Figure 5]
    Figure PCTKR2009005906-appb-I000010
    wherein,
    R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and an alkoxy of 1 to 8 carbon atoms; and
    one of A1 and A2 is CH with the other being N.
  2. The method according to claim 1, wherein the (R)-selective asymmetric reduction is achieved by biological asymmetric reduction or chemical asymmetric reduction.
  3. The method according to claim 2, wherein the biological asymmetric reduction is carried out in a buffer containing the arylketone of Chemistry Figure 2, a microbial strain capable of producing oxidoreductase, and a cosubstrate.
  4. The method according to claim 3, wherein the microbial strain is selected from a group consisting of yeasts of Candida genus including Candida parapsilosis and Candida rugosa; yeasts of Pichia genus including Pichia anomala and Pichia jadinii; yeasts of Saccharomyces genus including Baker's yeast, Saccharomyces cerevisiae and Saccharomyces pastorianus; yeasts including Rhodotorula mucilaginosa and Trigonopsis variabilis; bacteria including Klebsiella pneumoniae, Enterobacter cloacae, Erwinia herbicola, Micrococcus luteus, Bacillus stearothermophilus, Rhodococcus erythropolis and Rhodococcus rhodochrous; fungi including Mucor racemosus and Geotrichum candidum; and a combination thereof.
  5. The method according to claim 2, wherein the chemical asymmetric reduction is achieved with a chiral borane reductant or by asymmetric catalytic hydrogenation or asymmetric catalytic transfer hydrogenation.
  6. The method according to claim 5, wherein the chiral borane reductant is (-)-B-chlorodiisopinocampheylborane or (R)-2-methyl-CBS-oxazaborolidine/borane.
  7. The method according to claim 5, wherein the asymmetric catalytic hydrogenation is carried out by reacting the arylketone of Chemistry Figure 2 with hydrogen gas in the presence of (R)-bisphosphono-ruthenium(II)-(R,R)-chiral diamine complex catalyst.
  8. The method according to claim 5, wherein the asymmetric catalytic transfer hydrogenation is carried out by reacting the arylketone of Chemistry Figure 2 with formic acid triethylamine or isopropanol-inorganic base in the presence of a [S,S]-monosulfonatediamine-M(II)-arene complex catalyst system, wherein M represents ruthenium or rhodium.
  9. The method according to claim 1, wherein the carbamating step is carried out by reacting the alcohol compound of (R)-configuration of Chemistry Figure 5 with inorganic cyanate and an organic acid.
  10. The method according to claim 1, wherein the carbamating step is carried out by hydrolyzing a product resulting from reaction between the alcohol compound of (R)-configuration of Chemistry Figure 5 and an isocyanate compound selected from the group consisting of chlorosulfonic isocyanate, trichloroacetyl isocyanate and trimethylsilyl isocyanate.
  11. The method according to claim 1, wherein the carbamating step is carried out by introducing ammonia into a product resulting from reaction between the alcohol compound of (R)-configuration of Chemistry Figure 5 and a carbonyl compound comprising 1,1'-carbodiimidazole, carbamoylhalide, disuccinyl carbonate, phosgene, triphosgene or chloroformate.
  12. The method according to claim 1, further comprising a crystallizing step after at least one of the (R)-selective asymmetric reduction step and the carbamating step.
  13. The method according to claim 12, wherein the crystallizing step comprises:
    adding to a reaction product a solubilizing agent selected from among acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, a lower alcohol of 1 to 4 carbon atoms and a mixture thereof; and
    adding a precipitating agent thereto selected from the group consisting of water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptane and a mixture thereof.
  14. The method according to claim 1, additionally including the step of preparing the arylketone of Chemistry Figure 2 is prepared by substitution reaction between an arylketone of the following Chemistry Figure 8 with a tetrazole of the following Chemistry Figure 9:
    [Chemistry Figure 8]
    Figure PCTKR2009005906-appb-I000011
    [Chemistry Figure 9]
    Figure PCTKR2009005906-appb-I000012
    wherein,
    R1 and R2 are as defined in claim 1; and
    X is a leaving group selected from among a halide and a sulfonate;
  15. A method according to claim 14, further comprising a crystallizing step comprising:
    adding a solubilizing agent selected from among acetone, acetonitrile, tetrahydrofuran, ethylacetate, dichloromethane, chloroform, 1,4-dioxane, a lower alcohol of 1 to 4 carbon atoms and a mixture thereof to a product obtained by the substitution reaction; and
    adding a precipitating agent selected from water, a lower alcohol of 1 to 4 carbon atoms, diethylether, pentane, hexane, cyclohexane, heptanes and a mixture thereof.
  16. A method for preparing an alcohol compound, represented by the following Chemistry Figure 5, through (R)-selective asymmetric reduction of an arylketone, represented by the following Chemistry Figure 2, wherein the (R)-selective asymmetric reduction is achieved by biological asymmetric reduction or chemical asymmetric reduction:
    [Chemistry Figure 2]
    Figure PCTKR2009005906-appb-I000013
    [Chemistry Figure 5]
    Figure PCTKR2009005906-appb-I000014
    wherein,
    R1 and R2 are independently selected from a group consisting of hydrogen, halogen, perfluoroalkyl, an alkyl of 1 to 8 carbon atoms, a thioalkoxy of 1 to 8 carbon atoms, and an alkoxy of 1 to 8 carbon atoms; and
    one of A1 and A2 is CH with the other being N.
  17. The method according to claim 16, wherein the biological asymmetric reduction is carried out in a buffer containing the arylketone of Chemistry Figure 2, a microbial strain capable of producing oxidoreductase, and a cosubstrate.
  18. The method according to claim 16, wherein the chemical asymmetric reduction is achieved with a chiral borane reductant or by asymmetric catalytic hydrogenation or asymmetric catalytic transfer hydrogenation.
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Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2488505A2 (en) * 2009-10-15 2012-08-22 SK Biopharmaceuticals Co., Ltd. Method for preparation of carbamic acid (r)-1-aryl-2-tetrazolyl-ethyl ester
WO2017200316A1 (en) 2016-05-19 2017-11-23 에스케이바이오팜 주식회사 Use of carbamate compound in order to preventatively treat headaches
WO2017200317A1 (en) 2016-05-19 2017-11-23 에스케이바이오팜 주식회사 Use of carbamate compound for preventing or treating trigeminal neuralgia
WO2018111002A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Orally disintegrated tablet comprising carbamate compound
WO2018111006A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Use of carbamate compound for prevention, alleviation, or treatment of demyelinating disease
WO2018111009A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Use of carbamate compound for preventing, alleviating, or treating tremors or tremor syndrome
WO2018111000A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Parenteral liquid preparation comprising carbamate compound
WO2018111003A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Use of carbamate compound for prevention, alleviation or treatment of pruritus
WO2018111008A1 (en) 2016-12-14 2018-06-21 에스케이바이오팜 주식회사 Use of carbamate compounds for prevention, alleviation or treatment of bipolar disorder
WO2019098628A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Use of carbamate compound for preventing, alleviating or treating absence seizure or epilepsy showing absence seizure
WO2019098634A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Blend containing carbamate compound for prevention, mitigation, or treatment of schizophrenia
WO2019098632A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Use of carbamate compound for preventing, alleviating or treating myotonia
WO2019098626A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Use of carbamate compound for preventing or treating diseases associated with increase in late sodium current
WO2019098633A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Use of a carbamate compound to prevent, alleviate or treat visceralgia or pain arising from visceral disease
WO2019098630A1 (en) 2017-11-14 2019-05-23 에스케이바이오팜 주식회사 Use of carbamate compound for reducing or treating developmental disorders including fragile x syndrome, angelman syndrome or rett syndrome
WO2020060252A1 (en) 2018-09-21 2020-03-26 에스케이바이오팜 주식회사 Use of carbamate compound for prevention, alleviation, or treatment of concurrent seizures
WO2020060251A1 (en) 2018-09-21 2020-03-26 에스케이바이오팜 주식회사 Carbamate compound and use of formulation comprising same in preventing, alleviating, or treating acute stress disorder or post-traumatic stress disorder
WO2020080866A1 (en) 2018-10-19 2020-04-23 에스케이바이오팜 주식회사 Use of carbamate compound for preventing, alleviating or treating diabetic peripheral neuropathy or chemotherapy-induced peripheral neuropathy
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WO2021101295A1 (en) 2019-11-22 2021-05-27 에스케이바이오팜 주식회사 Oral pharmaceutical composition comprising carbamate compound and preparation method therefor
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RU2772465C2 (en) * 2017-11-14 2022-05-20 ЭсКей БАЙОФАРМАСЬЮТИКАЛЗ КО., ЛТД. Mixture containing carbamate compound for prevention, relief or treatment of schizophrenia
ES2931000A1 (en) * 2022-07-14 2022-12-22 Univ Madrid Complutense Process for the preparation of cenobamate (Machine-translation by Google Translate, not legally binding)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10611737B1 (en) * 2019-10-24 2020-04-07 Sk Biopharmaceuticals Co., Ltd. Method for preparing aryl 2-tetrazol-2-yl ketone with improved selectivity
CN110982757B (en) * 2019-12-30 2021-04-06 浙江工业大学 Enterobacter cloacae ZJPH1903 and application
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WO2023152711A1 (en) * 2022-02-12 2023-08-17 Metrochem Api Pvt Ltd Process for the preparation of cenobamate and intermediates thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287634A (en) * 1997-04-11 1998-10-27 Otsuka Pharmaceut Co Ltd Benzene derivatives
JPH11130761A (en) * 1997-10-24 1999-05-18 Otsuka Pharmaceut Co Ltd Benzothiazole derivative
WO2006112685A1 (en) * 2005-04-22 2006-10-26 Sk Holdings Co., Ltd. Neurotherapeutic azole compounds

Family Cites Families (74)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61134339A (en) 1984-12-05 1986-06-21 Seitetsu Kagaku Co Ltd Optically active alcohol produced by stereospecific reduction of alpha-diketone and production thereof
JPH054943A (en) 1990-08-30 1993-01-14 Sagami Chem Res Center Optically active beta,delta-diketo-acid ester and reduced material thereof
WO1993004052A1 (en) * 1991-08-22 1993-03-04 Warner-Lambert Company Amide tetrazole acat inhibitors
EP0538693A3 (en) 1991-10-23 1994-08-17 Squibb & Sons Inc Stereoselective preparation of halophenyl alcohols
CA2117482C (en) 1992-03-13 2005-02-15 Maria-Regina Kula New ketonic ester reductases, its preparation and use for enzymatic redox reactions
WO1994007888A1 (en) 1992-09-25 1994-04-14 Chiroscience Limited Chiral compounds and their use
CA2103932A1 (en) 1992-11-05 1994-05-06 Ramesh N. Patel Stereoselective reduction of ketones
JPH0759592A (en) 1993-08-25 1995-03-07 Osaka City Production of optically active diol
JP3574682B2 (en) 1993-09-24 2004-10-06 ダイセル化学工業株式会社 Novel enzymes, methods for producing the enzymes, DNAs encoding the enzymes, transformants containing the DNAs, methods for producing optically active alcohols and the like using the enzymes
PL177372B1 (en) 1995-03-30 1999-11-30 Akad Rolnicza Method of obtaining optically active aromatic alcohols
DE19610984A1 (en) 1996-03-21 1997-09-25 Boehringer Mannheim Gmbh Alcohol dehydrogenase and its use for the enzymatic production of chiral hydroxy compounds
JPH1094399A (en) 1996-09-24 1998-04-14 Fukui Pref Gov Sangyo Shinko Zaidan Production of optically active alcohol using enzyme
IL131241A0 (en) 1997-02-07 2001-01-28 Kaneka Corp Novel carbonyl reductase gene coding same and method for using such reductase and gene
DE19707008A1 (en) 1997-02-21 1998-08-27 Basf Ag Process for the preparation of enantiomerically pure alcohols
JPH10248591A (en) 1997-03-06 1998-09-22 Sumitomo Chem Co Ltd Production of optically active alcohol
JP2000236883A (en) 1998-12-21 2000-09-05 Daicel Chem Ind Ltd New carbonyl reductase, production of the enzyme, dna coding for the enzyme, and production of alcohol using the same
EP1153919A4 (en) 1999-02-16 2002-10-02 Kaneka Corp Substituted acetylpyridine derivatives and process for the preparation of intermediates for optically active beta3 agonist by the use of the same
KR100512080B1 (en) 1999-12-03 2005-09-02 카네카 코포레이션 Novel carbonyl reductase, gene thereof and method of using the same
DE10037101A1 (en) 2000-07-27 2002-02-07 Degussa Recombinantly produced enzymes with improved NAD (H) acceptance
KR20030085012A (en) 2001-03-22 2003-11-01 브리스톨-마이어스스퀴브컴파니 Stereoselective Reduction of Substituted Acetophenone
DE10119274A1 (en) 2001-04-20 2002-10-31 Juelich Enzyme Products Gmbh Enzymatic process for the enantioselective reduction of keto compounds
JP4630486B2 (en) 2001-05-28 2011-02-09 ダイセル化学工業株式会社 Novel (R) -2,3-butanediol dehydrogenase, method for producing the same, and method for producing optically active alcohol using the same
JP2003230398A (en) 2001-12-07 2003-08-19 Daicel Chem Ind Ltd Method for producing optically active alcohol
ATE406447T1 (en) 2002-03-19 2008-09-15 Mitsubishi Chem Corp NEW CARBONYL REDUCTASE, THE GENE CODING IT AND METHOD FOR THE PRODUCTION OF OPTICALLY-ACTIVE ALCOHOLS THEREFROM
JP2003289895A (en) 2002-04-03 2003-10-14 Sumitomo Chem Co Ltd Method for producing optically active alcohol compound by asymmetric reduction of methylenedioxyphenyl group- having ketone compound
EP1505155B1 (en) 2002-04-30 2008-12-03 Kaneka Corporation Carbonyl reductase, gene thereof and use of the same
US7056540B2 (en) 2002-10-29 2006-06-06 Council Of Scientific And Industrial Research Enzymatic process for the preparation of optically active alcohols from ketones using tuberous root Daucus carota
JP4366097B2 (en) 2003-02-28 2009-11-18 住友化学株式会社 Reductase gene and its use
JP4295531B2 (en) 2003-03-10 2009-07-15 三菱化学株式会社 Novel carbonyl reductase, DNA encoding the same, and method for producing optically active alcohol using the same
DE10315760A1 (en) 2003-04-07 2004-10-21 Basf Ag L-carnitine dehydrogenases, their derivatives and a process for the preparation of substituted (S) -alkanols
JP2004313033A (en) 2003-04-14 2004-11-11 Daiichi Fine Chemical Co Ltd New carbonyl reductase, gene encoding the same and use thereof
JP4213524B2 (en) 2003-04-17 2009-01-21 ダイセル化学工業株式会社 Novel carbonyl reductase, polynucleotide containing DNA encoding the enzyme, method for producing the same, and method for producing optically active alcohol using the same
JP4294382B2 (en) 2003-06-06 2009-07-08 ダイセル化学工業株式会社 (2S, 3S) -2,3-butanediol dehydrogenase
DE10327454A1 (en) 2003-06-18 2005-01-20 Juelich Enzyme Products Gmbh Oxidoreductase from Pichia capsulata
JP4205496B2 (en) 2003-06-19 2009-01-07 三菱化学株式会社 Novel carbonyl reductase, DNA encoding the same, and method for producing optically active alcohol using the same
DE102004037669A1 (en) 2003-08-13 2005-03-10 Juelich Enzyme Products Gmbh New (R)- and (S)-enantiomers of 1,4-dichloro-butan-2-ol, useful as chiral intermediates for pharmaceuticals, obtained by enzymatic reduction of 1,4-dichloro-butan-2-one in presence of NADH or NADPH
SG128684A1 (en) 2003-10-31 2007-01-30 Daiichi Fine Chem Co Ltd Novel sequence and utilization thereof
DE10354779A1 (en) 2003-11-21 2005-06-23 Juelich Enzyme Products Gmbh Oxidoreductase from Metschnikowia zobellii
KR20070013269A (en) 2004-02-04 2007-01-30 가부시키가이샤 에이피아이 코포레이션 Process for producing optically active alcohol and carboxylic acid
JP2005218348A (en) 2004-02-05 2005-08-18 Daicel Chem Ind Ltd METHOD FOR PRODUCING OPTICALLY ACTIVE alpha-HYDROXY AMIDE
DE102004022686A1 (en) 2004-05-05 2005-11-24 Basf Ag Process for the preparation of optically active alcohols
AT413541B (en) 2004-05-10 2006-03-15 Iep Gmbh PROCESS FOR THE PREPARATION OF 2-BUTANOL
JP2007274901A (en) 2004-05-12 2007-10-25 Taisho Pharmaceut Co Ltd Method for producing optically active propargyl alcohol
DE102004029112B4 (en) 2004-06-11 2007-06-21 Julich Chiral Solutions Gmbh Alcohol dehydrogenase for the stereoselective recovery of hydroxy compounds
US8008461B2 (en) 2004-10-27 2011-08-30 Kaneka Corporation Carbonyl reductase, gene therefor and use thereof
AT501928B1 (en) 2004-10-27 2010-09-15 Iep Gmbh PROCESS FOR THE PREPARATION OF CHIRAL ALCOHOLS
DE102004059376A1 (en) 2004-12-09 2006-06-22 Consortium für elektrochemische Industrie GmbH GDH mutant with improved chemical stability
US20060177913A1 (en) 2005-02-08 2006-08-10 Consortium Fur Elektrochemische Industrie Gmbh Process for enantioselective enzymatic reduction of keto compounds
AT501496B1 (en) 2005-02-21 2007-03-15 Iep Gmbh METHOD FOR THE ENANTIOSELECTIVE ENZYMATIC REDUCTION OF KETOVER BINDINGS
WO2006090814A1 (en) 2005-02-25 2006-08-31 Kaneka Corporation Process for producing optically active secondary alcohol
DE102005010804A1 (en) 2005-03-07 2006-09-14 Basf Ag Process for the preparation of optically active alcohols
US7393667B2 (en) 2005-05-31 2008-07-01 Bristol-Myers Squibb Company Stereoselective reduction process for the preparation of pyrrolotriazine compounds
AT502395B1 (en) 2005-07-27 2007-03-15 Iep Gmbh OXIDOREDUCETASES FOR THE STEREOSELECTIVE REDUCTION OF KETOVER BINDINGS
JP4745762B2 (en) 2005-09-02 2011-08-10 住友化学株式会社 Reductase and its use
DE102005044736A1 (en) 2005-09-19 2007-03-22 Basf Ag New dehydrogenases, their derivatives and a process for the preparation of optically active alkanols
AT502185B1 (en) 2005-09-23 2007-02-15 Iep Gmbh Enantioselective enzymatic reduction of keto compound comprises treating a liquid, two-phase mixture with an oxidoreductase in the presence of co-factors to obtain a chiral hydroxy compound
AT503017B1 (en) 2005-12-19 2007-07-15 Iep Gmbh METHOD FOR THE ENANTIOSELECTIVE ENZYMATIC REDUCTION OF HYDROXYKETOVER BINDINGS
JP5005672B2 (en) 2006-02-28 2012-08-22 株式会社カネカ Novel carbonyl reductase, gene thereof, and method for producing optically active alcohol using them
WO2007099994A1 (en) 2006-03-02 2007-09-07 Kaneka Corporation Novel carbonyl reductase, gene for the reductase, vector, transformant, and method for production of optically active alcohol utilizing these materials
DE102006010994A1 (en) 2006-03-09 2007-09-13 Wacker Chemie Ag Process for the enzymatic preparation of chiral alcohols
ATE529507T1 (en) 2006-03-31 2011-11-15 Kaneka Corp METHOD FOR PRODUCING ERYTHRO- OR THREO-2-AMINO-3-HYDROXYPROPIONIC ACID ESTERS, NOVEL CARBONYL REDUCTASE, REDUCTASE GENE, VECTOR, TRANSFORMANT AND METHOD FOR PRODUCING OPTICALLY ACTIVE ALCOHOL USING SAME
CN101501202A (en) 2006-06-05 2009-08-05 大赛璐化学工业株式会社 Process for production of optically active alcohol
JP4903512B2 (en) 2006-07-13 2012-03-28 住友化学株式会社 Expression vector containing reductase gene
WO2008035187A2 (en) 2006-09-21 2008-03-27 Dow Global Technologies Inc. Alcohol dehydrogenase from agromyces sp. and a method of producing a chiral secondary alcohol using same
DE102006055047A1 (en) 2006-11-22 2008-05-29 Wacker Chemie Ag Preparing chiral secondary diol, useful as a catalyst dehydrogenase, comprises reducing a diketone compound to dihydroxy compound, separating the obtained ketone and isolating the formed secondary diols
DE102006056526A1 (en) 2006-11-30 2008-06-05 Archimica Gmbh Process for the stereoselective synthesis of chiral epoxides by ADH reduction of alpha-leaving group-substituted ketones and cyclization
AT504542B1 (en) 2006-12-07 2008-09-15 Iep Gmbh METHOD FOR THE ENANTIOSELECTIVE ENZYMATIC REDUCTION OF SECODION DERIVATIVES
US8338146B2 (en) 2007-06-20 2012-12-25 Basf Se Method for producing optically active alcohols using an Azoarcus sp. EbN1 dehydrogenase
TWI601825B (en) 2007-09-27 2017-10-11 Ｉｅｐ有限公司 Process for the enantioselective enzymatic reduction of intermediates
DE102007052112A1 (en) 2007-10-30 2009-05-07 Chiracon Gmbh Plant biocatalysts for the preparation of optically active hydroxy compounds
WO2009070822A2 (en) 2007-12-05 2009-06-11 Angewandte Biokatalyse Kompetenzzentrum Gmbh Recombinant pichia pastoris cell
CN101314787A (en) 2008-06-24 2008-12-03 江苏华荣生物科技有限公司 Method for preparing optical activity chirality secondary alcohol with rhodotorula reductase formulation
CN101319236A (en) 2008-07-01 2008-12-10 江南大学 Method for biological catalysis of unsymmetrical reduction carbon based compound in water/ion liquid diphasic system
CN101358183B (en) 2008-09-03 2010-07-14 华东理工大学 Red bean carbonyl reductase, preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH10287634A (en) * 1997-04-11 1998-10-27 Otsuka Pharmaceut Co Ltd Benzene derivatives
JPH11130761A (en) * 1997-10-24 1999-05-18 Otsuka Pharmaceut Co Ltd Benzothiazole derivative
WO2006112685A1 (en) * 2005-04-22 2006-10-26 Sk Holdings Co., Ltd. Neurotherapeutic azole compounds
US20060258718A1 (en) 2005-04-22 2006-11-16 Choi Yong M Neurotherapeutic azole compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2445890A4

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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US11033531B2 (en) 2016-12-14 2021-06-15 Sk Biopharmaceuticals Co., Ltd. Use of carbamate compound for preventing, alleviating, or treating tremors or tremor syndrome
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US11717509B2 (en) 2017-11-14 2023-08-08 Sk Biopharmaceuticals Co., Ltd. Blend containing carbamate compound for prevention, mitigation, or treatment of schizophrenia
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