KR20120117028A - Process for the preparation of pregabalin - Google Patents

Process for the preparation of pregabalin Download PDF

Info

Publication number
KR20120117028A
KR20120117028A KR1020110034513A KR20110034513A KR20120117028A KR 20120117028 A KR20120117028 A KR 20120117028A KR 1020110034513 A KR1020110034513 A KR 1020110034513A KR 20110034513 A KR20110034513 A KR 20110034513A KR 20120117028 A KR20120117028 A KR 20120117028A
Authority
KR
South Korea
Prior art keywords
formula
compound
pregabalin
reaction
reacting
Prior art date
Application number
KR1020110034513A
Other languages
Korean (ko)
Other versions
KR101306585B1 (en
Inventor
하현준
윤두하
Original Assignee
한국외국어대학교 연구산학협력단
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한국외국어대학교 연구산학협력단 filed Critical 한국외국어대학교 연구산학협력단
Priority to KR1020110034513A priority Critical patent/KR101306585B1/en
Publication of KR20120117028A publication Critical patent/KR20120117028A/en
Application granted granted Critical
Publication of KR101306585B1 publication Critical patent/KR101306585B1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/30—Preparation of optical isomers
    • C07C227/32—Preparation of optical isomers by stereospecific synthesis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/10—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with ester groups or with a carbon-halogen bond
    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/62—Carboxylic acid esters

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

PURPOSE: A manufacturing method of a pregabalin is provided to manufacture pure pregabalin with high stereoselctivity and high yield. CONSTITUTION: A manufacturing method of a pregabalin comprises: a step of obtaining a compound indicated in chemical formula 4 by reacting a compound indicated in chemical formula 3 with Candida antarctica lipase B or porcine liver esterase; a step of obtaining a compound indicated in chemical formula 5 by reacting the compound indicated in chemical formula 4 with magnesium nitride(Mg3N2); and a step of obtaining a compound indicated in chemical formula 1 through an amination of an amide moiety of the compound indicated in chemical formula 5.

Description

프레가발린의 제조방법{Process for the preparation of pregabalin}Process for the preparation of pregabalin

본 발명은 높은 입체 선택성을 갖는, 프레가발린의 개선된 제조방법에 관한 것이다.The present invention is directed to an improved process for preparing pregabalin with high stereoselectivity.

프레가발린은 하기 화학식 1의 구조를 갖는 광학적으로 활성인 화합물로서, 항경련제로서 사용되고 있다.Pregabalin is an optically active compound having a structure represented by the following formula (1), and is used as an anticonvulsant.

<화학식 1>&Lt; Formula 1 >

Figure pat00001
Figure pat00001

프레가발린의 다양한 제조방법이 알려져 있으며, 예를 들어 4-이소부틸다이하이드로-2H-피란-2,6(3H)-다이온을 퀴놀린(quinoline)으로 비대칭화하는 방법 (Tetrahedron: Asymmetry 18 (2007) 1481-1485), 4-이소부틸다이하이드로-2H-피란-2,6(3H)-다이온을 고리열림 반응 후, 디아스테레오머를 제조한 후 비대칭화 분리하는 방법, L-luecine을 이용하여 제조하는 방법 등이 알려져 있다(Organic Process Reserch & Development 1 (1997) 26-38). 또한 신코나를 기반으로 한 설폰아미이드 촉매를 이용하여 4-이소부틸다이하이드로-2H-피란-2,6(3H)-다이온을 비대칭화하는 방법이 알려져 있다(Adv. Synth. Catal. 2010, 352, 2211-2217). 기타, 3-시아노-5-헥사노익 산의 비대칭 수소화반응을 이용하는 방법이 개발된 바 있다(미국 특허 제6891059호).Various methods of preparing pregabalin are known, for example, asymmetry of 4-isobutyldihydro-2H-pyran-2,6 (3H) -dione with quinoline ( Tetrahedron: Asymmetry 18 ( 1481-1485 ), 4-isobutyldihydro-2H-pyran-2,6 (3H) -dione after ring-opening reaction, a diastereomer was prepared and then asymmetrically separated and separated, L-luecine And the like are known ( Organic Process Reserch & Development 1 (1997) 26-38). In addition, a method of asymmetrical 4-isobutyldihydro-2H-pyran-2,6 (3H) -dione using a sulfonamide catalyst based on syncona is known ( Adv. Synth. Catal. 2010, 352, 2211-2217). In addition, a method using asymmetric hydrogenation of 3-cyano-5-hexanoic acid has been developed (US Patent No. 6891059).

한편, Organic Process Reserch & Development 1 (1997) 26-38 은 포르신 리버 에스터라아제(porcine liver esterase, PLE)와 같은 효소를 사용하여 디프로필 3-이소부틸펜탄디오에이트를 비대칭화하여 중간체를 제조한 후, 리튬 메톡사이드 및 포름아미드를 사용하여 아미드 모이어티를 갖는 중간체를 제조한 다음, 이를 프레가발린으로 전환하는 방법을 개시한 바 있다 (하기 반응식 1 참조). Organic Process Reserch & Development 1 (1997) 26-38, on the other hand, prepared an intermediate by asymmetric dipropyl 3-isobutylpentanedioate using an enzyme such as porcine liver esterase (PLE). Thereafter, lithium methoxide and formamide have been used to prepare intermediates having amide moieties and then convert them to pregabalin (see Scheme 1 below).

<반응식 1><Reaction Scheme 1>

Figure pat00002
Figure pat00002

상기 공정(A)는 포르신 리버 에스터라아제(PLE)의 효소 반응을 위해 DMSO(디메틸술폭시드)와 같은 유기용매의 사용을 필요로 한다. 그러나, DMSO는 끓는점이 매우 높아, 반응생성물의 분리정제시 DMSO를 제거하기 어려운 문제가 있다. 또한, 상기 공정(A)를 통하여 얻어지는 생성물의 광학적 순도는 85%에 불과하므로, 입체선택성이 낮은 문제가 있다. 또한, 상기 공정(B)에서 사용되는 리튬 시약은 수분에 반응성이 너무 높아 대량생산 공정에서 폭발의 위험성을 가지고 있어 사용하기가 곤란하며, 특히 공정(B)로부터 얻어지는 수율이 66%에 불과하여, 프레가발린의 산업적 대량생산 공정에 적합하지 않다.The process (A) requires the use of an organic solvent such as DMSO (dimethylsulfoxide) for the enzymatic reaction of forcin reversal esterase (PLE). However, DMSO has a high boiling point, which makes it difficult to remove DMSO during separation and purification of the reaction product. In addition, since the optical purity of the product obtained through the step (A) is only 85%, there is a problem of low stereoselectivity. In addition, the lithium reagent used in the step (B) is too high reactivity with water, there is a risk of explosion in the mass production process is difficult to use, in particular, the yield obtained from the step (B) is only 66%, Not suitable for pregabalin's industrial mass production process.

본 발명은 새로운 중간체 즉, 디알릴 3-이소부틸펜탄디오에이트를 사용하여, 무-유기용매(organic solvent-free) 조건하에서 효소반응을 수행함으로써 높은 광학적 순도로 모노-에스테르 중간체(하기 화학식 4의 화합물)를 제조한 후, 얻어진 모노-에스테르 중간체로부터 높은 수율로 아미드 모이이티를 갖는 중간체(하기 화학식 5의 화합물)를 제조하는 공정을 포함하는, 프레가발린의 개선된 제조방법을 제공한다.The present invention utilizes a novel intermediate, diallyl 3-isobutylpentanedioate, to carry out the enzymatic reaction under organic solvent-free conditions, thereby providing a mono-ester intermediate with high optical purity ( Compound), followed by a process for preparing an intermediate having a amide moiety (compound of formula 5) from the obtained mono-ester intermediate in high yield.

즉, 본 발명은 높은 입체선택성 및 높은 수율로 순수하게 프레가발린을 제조할 수 있는, 프레가발린의 제조방법을 제공하는 것을 목적으로 한다.That is, an object of the present invention is to provide a method for producing pregabalin, which can produce pregabalin purely with high stereoselectivity and high yield.

본 발명의 일 태양에 따라, (a) 화학식 3의 화합물을 칸디다 안타크티카 리파아제 B(Candida antarctica lipase B) 또는 포르신 리버 에스터라아제(porcine liver esterase)와 반응시켜 화학식 4의 화합물을 얻는 단계; (b) 단계(a)에서 얻어진 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)를 반응시켜 화학식 5의 화합물을 얻는 단계; 및 (c) 단계(b)에서 얻어진 화학식 5의 화합물의 아미드 모이어티를 아민화하여 화학식 1의 화합물을 얻는 단계를 포함하는, 화학식 1의 화합물의 제조방법이 제공된다:According to one aspect of the invention, (a) reacting a compound of formula 3 with Candida antarctica lipase B or porcine liver esterase to obtain a compound of formula 4 ; (b) reacting the compound of formula 4 obtained in step (a) with magnesium nitride (Mg 3 N 2 ) to obtain a compound of formula 5; And (c) aminating the amide moiety of the compound of formula (5) obtained in step (b) to obtain a compound of formula (1):

<화학식 1>&Lt; Formula 1 >

Figure pat00003
Figure pat00003

<화학식 3><Formula 3>

Figure pat00004
Figure pat00004

<화학식 4>&Lt; Formula 4 >

Figure pat00005
Figure pat00005

<화학식 5>&Lt; Formula 5 >

Figure pat00006
Figure pat00006

본 발명의 제조방법에 있어서, 단계(a)의 반응이 유기용매가 함유되어 있지 않은 pH 6.5?7.5 의 수성매질 중에서 바람직하게 수행될 수 있다. 또한, 단계(b)가 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)와의 반응으로부터 얻어진 조 생성물(crude product)을 디에틸 에테르 중에서 재결정함으로써 바람직하게 수행될 수 있다. 상기 화학식 3의 화합물은 화학식 2의 화합물을 알릴 할라이드와 1,8-디아자비시클로[5.4.0]운덱-7-엔 또는 암모늄 세륨 니트레이트 존재하에서 반응시킴으로써 바람직하게 얻어질 수 있다:In the production method of the present invention, the reaction of step (a) may be preferably carried out in an aqueous medium of pH 6.5 ~ 7.5 that does not contain an organic solvent. In addition, step (b) may be preferably carried out by recrystallization of the crude product obtained from the reaction of the compound of formula 4 with magnesium nitride (Mg 3 N 2 ) in diethyl ether. The compound of formula 3 may be preferably obtained by reacting the compound of formula 2 with allyl halide in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene or ammonium cerium nitrate:

<화학식 2><Formula 2>

Figure pat00007
Figure pat00007

본 발명에 따른 제조방법은 알릴기를 갖는 중간체 즉 디알릴 3-이소부틸펜탄디오에이트(화학식 3의 화합물)를 사용하여, 무-유기용매(organic solvent-free) 조건하에서 효소반응을 수행함으로써, 약 93.3%ee 의 높은 광학적 순도로 모노-에스테르 중간체를 제조할 수 있으며, 유기용매가 잔류하는 것을 근본적으로 회피할 수 있다. 또한, 얻어진 모노-에스테르 중간체(화학식 4의 화합물)를 마그네슘 나이트라이드(Mg3N2)와 반응시킴으로써 93%의 높은 수율로 아미드 모이이티를 갖는 중간체를 제조할 수 있다. 따라서, 본 발명에 따른 제조방법은 높은 입체선택성 및 높은 수율로 순수하게 프레가발린을 제조할 수 있으므로, 산업적 규모의 대량생산에 적합하다.The preparation method according to the present invention uses an intermediate having an allyl group, that is, diallyl 3-isobutylpentanedioate (compound of formula 3), by carrying out an enzymatic reaction under organic solvent-free conditions. Mono-ester intermediates can be prepared with high optical purity of 93.3% ee, essentially avoiding the residual organic solvent. In addition, an intermediate having an amide moiety can be prepared in a high yield of 93% by reacting the obtained mono-ester intermediate (compound of formula 4) with magnesium nitride (Mg 3 N 2 ). Therefore, the production method according to the present invention can produce pregabalin purely with high stereoselectivity and high yield, and is suitable for mass production on an industrial scale.

본 발명의 제조방법에 따른 프레가발린의 제조방법을 반응식으로 나타내면 하기 반응식 2와 같다.Representative method for producing pregabalin according to the preparation method of the present invention is shown in Scheme 2 below.

<반응식 2><Reaction Scheme 2>

Figure pat00008
Figure pat00008

상기 화학식 3의 화합물은 화학식 2의 화합물을 알릴 할라이드(예를 들어, 알릴 아이오다이드 등)와 1,8-디아자비시클로[5.4.0]운덱-7-엔(1,8-diazabicyclo[5.4.0]undec-7-ene) 또는 암모늄 세륨 니트레이트(ammonium cerium nitrate) 존재하에서 반응시킴으로써 제조할 수 있다. 상기 화학식 2의 화합물(3-이소부틸펜탄다이오닉 산)은 공지의 화합물로서 Organic Process Reserch & Development 1 (1997) 26-38 등에 개시된 제조방법에 따라 제조될 수 있다. 상기 화학식 2의 화합물과 알릴 할라이드의 반응은 아세토니트릴 등의 통상의 유기용매 중에서 수행될 수 있으며, 알릴 할라이드의 사용량은 약간 과량 즉, 화학식 2의 화합물 1 당량에 대하여 약 2.2 몰 당량으로 사용될 수 있다. 상기 반응은 약 0℃에서 8?12 시간 동안 반응시킴으로써 수행될 수 있다. 커플링화제로서 가해지는 상기 1,8-디아자비시클로[5.4.0]운덱-7-엔 또는 암모늄 세륨 니트레이트의 사용량은 크게 제한되는 것은 아니며, 예를 들어 화학식 2의 화합물 1 당량에 대하여 2 내지 5 당량의 범위로 사용될 수 있다. 생성물 즉, 화학식 3의 화합물은 에틸 아세테이트, 디클로로메탄 등의 유기용매를 사용하여 추출하여 분리할 수 있으며, 필요할 경우 컬럼크로마토그래피로 정제할 수 있다.The compound of Formula 3 may be selected from the group consisting of allyl halides (eg, allyl iodide, etc.) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1,8-diazabicyclo [5.4). .0] undec-7-ene) or ammonium cerium nitrate. The compound of Chemical Formula 2 (3-isobutylpentanedionic acid) may be prepared according to a manufacturing method disclosed in Organic Process Reserch & Development 1 (1997) 26-38 and the like as a known compound. The reaction of the compound of Formula 2 and allyl halide may be carried out in a conventional organic solvent such as acetonitrile, and the amount of allyl halide may be used slightly in excess, that is, about 2.2 molar equivalents based on 1 equivalent of compound of Formula 2 . The reaction may be carried out by reacting at about 0 ° C. for 8-12 hours. The amount of the 1,8-diazabicyclo [5.4.0] undec-7-ene or ammonium cerium nitrate added as the coupling agent is not particularly limited, for example, 2 to 1 equivalent of the compound of formula (2). To 5 equivalents. The product, that is, the compound of Formula 3, may be extracted and separated using an organic solvent such as ethyl acetate or dichloromethane, and may be purified by column chromatography if necessary.

본 발명의 제조방법은 상기와 같이 얻어진 화학식 3의 화합물을 높은 광학적 순도로 비대칭화하여 화학식 4의 화합물을 제조한 후, 93%의 높은 수율로 아미드 모이어티를 갖는 화학식 5를 제조한 다음, 이를 프레가발린으로 전환하는 공정을 포함한다. 즉, 본 발명은 (a) 화학식 3의 화합물을 칸디다 안타크티카 리파아제 B(Candida antarctica lipase B) 또는 포르신 리버 에스터라아제(porcine liver esterase)와 반응시켜 화학식 4의 화합물을 얻는 단계; (b) 단계(a)에서 얻어진 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)를 반응시켜 화학식 5의 화합물을 얻는 단계; 및 (c) 단계(b)에서 얻어진 화학식 5의 화합물의 아미드 모이어티를 아민화하여 화학식 1의 화합물을 얻는 단계를 포함하는, 화학식 1의 화합물의 제조방법을 제공한다.According to the preparation method of the present invention, the compound of formula 3 obtained as described above is asymmetrical with high optical purity to prepare a compound of formula 4, and then a formula 5 having an amide moiety with a high yield of 93% is obtained. Converting to pregabalin. That is, the present invention comprises the steps of: (a) reacting a compound of formula 3 with Candida antarctica lipase B or porcine liver esterase to obtain a compound of formula 4; (b) reacting the compound of formula 4 obtained in step (a) with magnesium nitride (Mg 3 N 2 ) to obtain a compound of formula 5; And (c) aminating the amide moiety of the compound of formula (5) obtained in step (b) to obtain a compound of formula (1).

상기 단계(a)에서, 디알릴 에스테르 모이어티를 갖는 화합물(화학식 3의 화합물)을 사용함으로써, 높은 약 93.3%ee 의 높은 광학적 순도로 모노-에스테르 중간체(화학식 4의 화합물)을 제조할 수 있다. 상기 칸디다 안타크티카 리파아제 B(Candida antarctica lipase B, CalB) 또는 포르신 리버 에스터라아제(porcine liver esterase, PLE)는 고정화-효소(immobilized enzyme) 형태로 바람직하게 사용될 수 있다. 이들은 각각 공지의 방법으로 제조될 수 있다(예를 들어, 국제특허공개 제WO/2010/005235호, Appl Biochem Biotechnol. 2008 Mar;146(1-3):173-87 등). 또한, 상기 PLE 및 CalB는 상업적으로 구입할 수도 있으며, 예를 들어 상기 PLE는 Sigma-Aldrich 사로부터 구입할 수 있고(제품명: E3019 Esterase), CalB는 Roche Applied Science사로부터 구입할 수 있다(제품명: CHIRAZYME L-2, c.-f., lyo). 상기 효소의 사용량은 화학식 3의 화합물 0.1mmol에 대하여 110?120mg 의 범위로 사용될 수 있으나, 이에 제한되는 것은 아니다.In step (a), by using a compound having a diallyl ester moiety (compound of formula 3), a mono-ester intermediate (compound of formula 4) can be prepared with a high optical purity of about 93.3% ee high. . The Candida antarctica lipase B (CalB) or porcine liver esterase (PLE) may be preferably used in the form of an immobilized enzyme. They can each be prepared by known methods (eg, WO / 2010/005235, Appl Biochem Biotechnol . 2008 Mar; 146 (1-3): 173-87, etc.). The PLE and CalB can also be purchased commercially, for example the PLE can be purchased from Sigma-Aldrich (trade name: E3019 Esterase), and CalB can be purchased from Roche Applied Science (trade name: CHIRAZYME L-). 2, c.-f., lyo). The amount of the enzyme may be used in the range of 110 to 120 mg based on 0.1 mmol of the compound of Formula 3, but is not limited thereto.

상기 화학식 3의 화합물과 효소와의 반응은 특히 유기용매가 함유되어 있지 않은(즉, organic solvent-free) pH 6.5?7.5 의 수성매질(예를 들어, 약 pH 7의 인산완충액) 중에서 바람직하게 수행될 수 있다. 이와 같이 상기 화학식 3의 화합물과 효소와의 반응을 수성매질 중에서 수행함으로써, DMSO 등의 유기용매가 잔류하는 것을 근본적으로 회피할 수 있다. 상기 효소 반응은 실온에서 6?20 시간 동안 수행될 수 있으며, 얻어진 생성물은 에틸 아세테이트 등으로 추출하여 분리할 수 있다.The reaction of the compound of Formula 3 with the enzyme is particularly preferably performed in an aqueous medium (eg, phosphate buffer of about pH 7) having a pH of 6.5 to 7.5 which is free of organic solvent (ie, organic solvent-free). Can be. As described above, by performing the reaction between the compound of Formula 3 and the enzyme in an aqueous medium, it is possible to fundamentally avoid remaining of an organic solvent such as DMSO. The enzymatic reaction may be performed at room temperature for 6-20 hours, and the obtained product may be separated by extraction with ethyl acetate or the like.

본 발명의 제조방법은 화학식 5의 화합물은 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)를 반응시키는 단계[단계(b)]를 포함한다. 아미드 형성시약으로서 마그네슘 나이트라이드를 사용할 경우 높은 수율(약 93%)로 화학식 5의 화합물을 제조할 수 있다는 것이 밝혀졌다. 이는 종래의 제조방법에 있어서의 수율(66%)와 대조된다. In the preparation method of the present invention, the compound of Formula 5 includes reacting the compound of Formula 4 with magnesium nitride (Mg 3 N 2 ) [step (b)]. It has been found that the use of magnesium nitride as the amide forming reagent can produce the compound of formula 5 in high yield (about 93%). This is in contrast to the yield (66%) in the conventional manufacturing method.

상기 화학식 4의 화합물과 마그네슘 나이트라이드와의 반응은 메탄올 등의 극성 용매 중에서 수행될 수 있다. 상기 마그네슘 나이트라이드는 화학식 4의 화합물 1 당량에 대하여 4?5 당량, 바람직하게는 약 5 당량의 범위로 사용될 수 있다. 상기 반응은 80?85℃에서 약 16 시간 동안 수행될 수 있다. 얻어진 생성물은 바람직하게는 디에틸 에테르를 사용하여 재결정함으로써, 더욱 정제될 수 있다. 즉, 단계(b)는 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)와의 반응으로부터 얻어진 조 생성물(crude product)을 디에틸 에테르 중에서 재결정함으로써 바람직하게 수행될 수 있다. The reaction of the compound of Formula 4 with magnesium nitride may be carried out in a polar solvent such as methanol. The magnesium nitride may be used in the range of 4-5 equivalents, preferably about 5 equivalents to 1 equivalent of the compound of Formula 4. The reaction can be carried out at 80-85 ° C. for about 16 hours. The product obtained can be further purified, preferably by recrystallization with diethyl ether. That is, step (b) may be preferably carried out by recrystallization of the crude product obtained from the reaction of the compound of formula 4 with magnesium nitride (Mg 3 N 2 ) in diethyl ether.

본 발명의 제조방법은 또한 단계(b)에서 얻어진 화학식 5의 화합물의 아미드 모이어티를 아민화하여 화학식 1의 화합물(즉, 프레가발린)을 얻는 단계[즉, 단계(c)]를 포함한다. 상기 단계(c)의 반응은 호프만 전이(Hoffman rearrangement)를 이용한 공지의 방법(Organic Process Reserch & Development 1 (1997) 26-38 등)에 따라 수행될 수 있다. The process of the invention also comprises the step of aminating the amide moiety of the compound of formula 5 obtained in step (b) to obtain a compound of formula 1 (ie pregabalin) (ie step (c)). . The reaction of step (c) can be carried out according to a known method using Hoffman rearrangement ( Organic Process Reserch & Development 1 (1997) 26-38, etc.).

이하, 본 발명을 실시예를 통하여 더욱 상세히 설명한다. 그러나, 하기 실시예는 본 발명을 예시하기 위한 것으로 본 발명을 제한하는 것이 아니다.Hereinafter, the present invention will be described in more detail with reference to examples. However, the following examples are intended to illustrate the invention and not to limit the invention.

실시예 1. 디알릴 3-이소부틸펜탄디오에이트의 제조Example 1 Preparation of Diallyl 3-isobutylpentanedioate

둥근바닥 플라스크에 3-이소부틸펜탄디오익 산 0.8902g을 넣고 아세토나이트릴 10ml을 가하여 용해시켰다. 상기 용액을 0℃에서 교반하면서 1,8-디아자비시클로[5.4.0]운덱-7-엔(1,8-diazabicyclo[5.4.0]undec-7-ene) 1.7mL을 가하고, 15분 후 알릴 아이오다이드 0.95mL를 가하였다. TLC상 출발물질의 스팟이 사라졌을 때(반응시간: 약 12시간), 반응혼합물에 증류수 50ml 및 디클로로메탄 100 ml를 가한 다음, 유기층을 분리하였다. 남아있는 수층에 디클로로메탄 100 ml를 가하여 2회 추출하였다. 유기층을 모두 합하여 무수 황산마그네슘으로 수분을 제거한 후, 여과하였다. 여액을 감압농축하여 용매를 완전히 제거한 후, 컬럼 크로마토그래피(용리액: 에틸 아세테이트:n-헥산 = 1:15, v/v)로 정제하여 표제 화합물을 제조하였다.0.8902 g of 3-isobutylpentanedioic acid was added to a round bottom flask, and 10 ml of acetonitrile was added to dissolve it. 1.7 mL of 1,8-diazabicyclo [5.4.0] undec-7-ene was added while stirring the solution at 0 ° C., and after 15 minutes, 0.95 mL of allyl iodide was added. When the spot of starting material disappeared on TLC (reaction time: about 12 hours), 50 ml of distilled water and 100 ml of dichloromethane were added to the reaction mixture, and the organic layer was separated. 100 ml of dichloromethane was added to the remaining aqueous layer and extracted twice. The organic layers were combined, the water was removed with anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to completely remove the solvent, and then purified by column chromatography (eluent: ethyl acetate: n-hexane = 1:15, v / v) to prepare the title compound.

수율: 93%. Yield 93%.

1H NMR (200MHz; CDCl3; J/Hz); d 0.89 (6H, d, J=6.6Hz, (CH 3 )2CH), 1.21 (2H, t. J = 6.2Hz, CHCH 2 CH), 1.63 (1H, m,(CH3)2 CH) 2.39 (5H, m, CH 2 CO2Allyl, CH2 CH(CH2)2), 4.57 (4H, d, J = 5.6Hz, OCH 2 CHCH2), 5.26 (4H, dd, J = 14, 15.6 Hz, OCH2CHCH 2 ), 5.26 (4H, ddt, J = 5.6, 14, 15.6Hz, OCH2 CHCH2). 1 H NMR (200 MHz; CDCl 3 ; J / Hz); d 0.89 (6H, d, J = 6.6 Hz, ( CH 3 ) 2 CH), 1.21 (2H, t. J = 6.2 Hz, CH CH 2 CH), 1.63 (1H, m, (CH 3 ) 2 CH ) 2.39 (5H, m, CH 2 CO 2 Allyl, CH 2 CH (CH 2 ) 2 ), 4.57 (4H, d, J = 5.6 Hz, O CH 2 CHCH 2 ), 5.26 (4H, dd, J = 14, 15.6 Hz, OCH 2 CH CH 2 ), 5.26 (4H, ddt, J = 5.6, 14, 15.6 Hz, OCH 2 CH CH 2 ).

13C NMR (50MHz; CDCl3; J/Hz); 171.9, 132.0, 118.0 64.8, 43.2, 38.4, 29.7, 25.0, 22.4. 13 C NMR (50 MHz; CDCl 3 ; J / Hz); 171.9, 132.0, 118.0 64.8, 43.2, 38.4, 29.7, 25.0, 22.4.

MS(ES+) m/z 291.02 (M+ +Na).
MS (ES &lt; + &gt;) m / z 291.02 (M + + Na).

실시예 2. (S)-3-(2-알릴옥시-2-옥소에틸)-5-메틸헥사노익 산의 제조Example 2. Preparation of (S) -3- (2-allyloxy-2-oxoethyl) -5-methylhexanoic acid

둥근바닥 플라스크에 실시예 1에서 제조한 디알릴 3-이소부틸펜탄디오에이트 0.1744g을 넣고, 인산완충액(pH=7) 7mL을 가하여 용해시켰다. pH 메터(pH meter)를 용액 속에 설치하고, 상기 용액을 교반하면서, 고정화된 칸디다 안타크티카 리파아제 B(Candida antarctica lipase B, CalB)(CHIRAZYME L-2, c.-f., lyo, Roche Applied Science) 180mg을 가하였다. 반응이 진행되는 동안 pH 변화를 보정하기 위해 0.25M NaOH 용액을 가하여 pH를 7로 유지시켰다. 출발물질의 스팟이 사라졌을 때(반응시간: 약 6시간), 반응혼합물에 에틸 아세테이트 50ml를 가하여 3회 추출하였다. 얻어진 유기층을 무수 황산마그네슘으로 수분을 제거한 후, 여과하였다. 여액을 감압 농축하여 용매를 완전히 제거하여 표제화합물을 제조하였다.0.1744 g of diallyl 3-isobutylpentanedioate prepared in Example 1 was added to a round bottom flask, and 7 mL of phosphate buffer solution (pH = 7) was added to dissolve it. A pH meter was placed in the solution and the solution was stirred while immobilized Candida antarctica lipase B (CalB) (CHIRAZYME L-2, c.-f., lyo, Roche Applied). Science) 180 mg was added. To correct the pH change during the reaction, 0.25M NaOH solution was added to maintain the pH at 7. When the spot of starting material disappeared (reaction time: about 6 hours), 50 ml of ethyl acetate was added to the reaction mixture and extracted three times. The obtained organic layer was filtered after removing water with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure to completely remove the solvent to prepare the title compound.

수율: >99%. Yield:> 99%.

광학적 순도: 93.3%ee. [a]D = 2.169 (c=0.507, 클로로포름). Optical purity: 93.3% ee. [a] D = 2.169 (c = 0.507, Chloroform).

1H NMR (200MHz; CDCl3; J/Hz); d 0.86 (6H, d, J=6.4Hz, (CH 3 )2CH), 1.19 (2H, m. CHCH 2 CH), 1.60 (1H, m,(CH3)2 CH) 2.37 (5H, m, CH 2 CO2Allyl, CH 2 CO2H CH2 CH(CH2)2), 4.54 (2H, d, J = 5.6Hz, OCH 2 CHCH2), 5.23 (2H, dd, J = 14, 15.6 Hz, OCH2CHCH 2 ), 5.86 (2H, ddt, J = 5.6, 14, 15.6Hz, OCH2 CHCH2), 10.52 (1H, s, CO2 H). 1 H NMR (200 MHz; CDCl 3 ; J / Hz); d 0.86 (6H, d, J = 6.4 Hz, ( CH 3 ) 2 CH), 1.19 (2H, m.CH CH 2 CH), 1.60 (1H, m, (CH 3 ) 2 CH ) 2.37 (5H, m , CH 2 CO 2 Allyl, CH 2 CO 2 H CH 2 CH (CH 2 ) 2 ), 4.54 (2H, d, J = 5.6 Hz, O CH 2 CHCH 2 ), 5.23 (2H, dd, J = 14, 15.6 Hz, OCH 2 CH CH 2 ), 5.86 (2H, ddt, J = 5.6, 14, 15.6 Hz, OCH 2 CH CH 2 ), 10.52 (1H, s, CO 2 H ).

13C NMR (50MHz; CDCl3; J/Hz); 178.9, 172.3, 132.1, 118.5, 65.2, 43.4, 38.6, 38.5, 29.7, 25.2, 22.6. 13 C NMR (50 MHz; CDCl 3 ; J / Hz); 178.9, 172.3, 132.1, 118.5, 65.2, 43.4, 38.6, 38.5, 29.7, 25.2, 22.6.

MS (m/z) m/z 250.92 (M+ +Na, 100%).
MS (m / z) m / z 250.92 (M + + Na, 100%).

실시예 3. (R)-3-(2-아미노-2-옥소에틸)-5-메틸헥사노익 산의 제조.Example 3. Preparation of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid.

실시예 2에서 얻어진 (S)-3-(2-알릴옥시-2-옥소에틸)-5-메틸헥사노익 산 70.1mg을 실링튜브(pressure tube)에 MeOH 1.3mL를 가하여 용해시켰다. 상기 용액에 Mg3N2(마그네슘 나이트라이드) 0.1549g을 가한 후, 80?85℃에서 16시간 동안 교반하였다. 출발물질이 TLC에서 사라졌을 때, 6N HCl을 이용하여 pH를 3으로 조절한 후, 반응혼합물에 에틸 아세테이트 100ml를 가하여 3회 추출하였다. 얻어진 유기층을 무수 황산마그네슘으로 수분을 제거한 후, 여과하였다. 여액을 감압 농축한 후, 디에틸 에테르 2mL에 용해시켜 재결정하여, 표제 화합물을 제조하였다.70.1 mg of (S) -3- (2-allyloxy-2-oxoethyl) -5-methylhexanoic acid obtained in Example 2 was dissolved by adding 1.3 mL of MeOH to a pressure tube. 0.1549 g of Mg 3 N 2 (magnesium nitride) was added to the solution, followed by stirring at 80 ° C to 85 ° C for 16 hours. When the starting material disappeared in TLC, the pH was adjusted to 3 using 6N HCl, and then extracted three times by adding 100 ml of ethyl acetate to the reaction mixture. The obtained organic layer was filtered after removing water with anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, then dissolved in 2 mL of diethyl ether and recrystallized to give the title compound.

수율: 93%. Yield 93%.

광학적 순도: 99.9%ee Optical Purity: 99.9% ee

1H NMR (200MHz; DMSO-d 6; J/Hz) d 0.80 (6H, d, J=6.4Hz, (CH 3 )2CH), 1.07 (2H, t. J = 6.4, CHCH 2 CH), 1.57 (1H, m,(CH3)2 CH) 1.97-2.22 (5H, m, CH 2 CO2H, CH 2 CONH2 CH2 CH(CH2)2), 6.77 (1H, s, CONH2), 6.37 (1H, s, CONH2). 1 H NMR (200 MHz; DMSO- d 6 ; J / Hz) d 0.80 (6H, d, J = 6.4 Hz, ( CH 3 ) 2 CH), 1.07 (2H, t. J = 6.4, CH CH 2 CH) , 1.57 (1H, m, (CH 3 ) 2 CH ) 1.97-2.22 (5H, m, CH 2 CO 2 H, CH 2 CONH 2 CH 2 CH (CH 2 ) 2 ), 6.77 (1H, s, CONH 2 ) , 6.37 (1H, s, CONH 2 ).

13C NMR (50MHz; DMSO-d 6; J/Hz); 174.7, 174.6, 43.8, 40.4, 30.4, 25.2, 23.3, 23.3. 13 C NMR (50 MHz; DMSO- d 6 ; J / Hz); 174.7, 174.6, 43.8, 40.4, 30.4, 25.2, 23.3, 23.3.

MS (m/z) m/z 209.88 (M+ +Na).
MS (m / z) m / z 209.88 (M + + Na).

실시예 4. 프레가발린의 제조.Example 4. Preparation of Pregabalin.

환류콘덴서가 장착된 둥근바닥 플라스크에 실시예 3에서 얻어진 (R)-3-(2-아미노-2-옥소에틸)-5-메틸헥사노익 산 140.8mg을 가하고, 증류수 7.5mL 및 50% 수산화나트륨 수용액 0.15mL을 0℃에서 가하여 용해시켰다. 또다른 둥근바닥 플라스크에 증류수 21mL와 50% 수산화나트륨 수용액 0.56mL을 가하고 0℃에서 브로민 0.144g을 용핵시켰다. 얻어진 브로민 용액을 상기 (R)-3-(2-아미노-2-옥소에틸)-5-메틸헥사노익 산의 용액에 적가하였다. 반응 혼합물을 80℃에서 10분 동안 교반한 다음, 45℃로 냉각하고, 37% HCl 0.16mL를 적가하였다. 적가 완료 후, 반응 혼합물을 2 시간 동안 환류시킨 다음, 실온으로 냉각한 후, 여과하였다. 얻어진 고체를 감압건조하여 표제화합물을 제조하였다. To a round bottom flask equipped with a reflux condenser, 140.8 mg of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid obtained in Example 3 was added, and 7.5 mL of distilled water and 50% sodium hydroxide were added. 0.15 mL of aqueous solution was added at 0 ° C. to dissolve. In another round bottom flask, 21 mL of distilled water and 0.56 mL of 50% aqueous sodium hydroxide solution were added, and 0.144 g of bromine was lysed at 0 ° C. The obtained bromine solution was added dropwise to the solution of (R) -3- (2-amino-2-oxoethyl) -5-methylhexanoic acid. The reaction mixture was stirred at 80 ° C. for 10 minutes, then cooled to 45 ° C. and 0.16 mL of 37% HCl was added dropwise. After completion of the dropwise addition, the reaction mixture was refluxed for 2 hours, then cooled to room temperature and filtered. The obtained solid was dried under reduced pressure to give the title compound.

수율: 65%. Yield 65%.

1H NMR (200MHz; D2O; J/Hz) d 0.88 (6H, d, J=6.4Hz, (CH 3 )2CH), 1.21 (2H, t. J = 6.4, CHCH 2 CH), 1.52-1.75 (1H, m,(CH3)2 CH) 2.1-2.4 (3H, m, CH 2 CO2H, CH2 CH(CH2)2), 2.89-3.06 (2H, m, CH2NH2). 1 H NMR (200 MHz; D 2 O; J / Hz) d 0.88 (6H, d, J = 6.4 Hz, ( CH 3 ) 2 CH), 1.21 (2H, t. J = 6.4, CH CH 2 CH), 1.52-1.75 (1H, m, (CH 3 ) 2 CH ) 2.1-2.4 (3H, m, CH 2 CO 2 H, CH 2 CH (CH 2 ) 2 ), 2.89-3.06 (2H, m, CH 2 NH 2 ).

Claims (4)

(a) 화학식 3의 화합물을 칸디다 안타크티카 리파아제 B(Candida antarctica lipase B) 또는 포르신 리버 에스터라아제(porcine liver esterase)와 반응시켜 화학식 4의 화합물을 얻는 단계;
(b) 단계(a)에서 얻어진 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)를 반응시켜 화학식 5의 화합물을 얻는 단계; 및
(c) 단계(b)에서 얻어진 화학식 5의 화합물의 아미드 모이어티를 아민화하여 화학식 1의 화합물을 얻는 단계를 포함하는, 화학식 1의 화합물의 제조방법:
<화학식 1>
Figure pat00009

<화학식 3>
Figure pat00010

<화학식 4>
Figure pat00011

<화학식 5>
Figure pat00012
(a) reacting a compound of Formula 3 with Candida antarctica lipase B or porcine liver esterase to obtain a compound of Formula 4;
(b) reacting the compound of formula 4 obtained in step (a) with magnesium nitride (Mg 3 N 2 ) to obtain a compound of formula 5; And
(c) aminating the amide moiety of the compound of formula 5 obtained in step (b) to obtain a compound of formula 1;
&Lt; Formula 1 >
Figure pat00009

(3)
Figure pat00010

&Lt; Formula 4 >
Figure pat00011

&Lt; Formula 5 >
Figure pat00012
 제1항에 있어서, 단계(a)의 반응이 유기용매가 함유되어 있지 않은 pH 6.5?7.5 의 수성매질 중에서 수행되는 것을 특징으로 하는 제조방법.The process according to claim 1, wherein the reaction of step (a) is carried out in an aqueous medium having a pH of 6.5 to 7.5 without containing an organic solvent. 제1항에 있어서, 단계(b)가 화학식 4의 화합물과 마그네슘 나이트라이드(Mg3N2)와의 반응으로부터 얻어진 조 생성물(crude product)을 디에틸 에테르 중에서 재결정함으로써 수행되는 것을 특징으로 하는 제조방법.The process according to claim 1, wherein step (b) is carried out by recrystallization of a crude product obtained from the reaction of the compound of formula 4 with magnesium nitride (Mg 3 N 2 ) in diethyl ether. . 제1항 내지 제3항 중 어느 한 항에 있어서, 상기 화학식 3의 화합물이 화학식 2의 화합물을 알릴 할라이드와 1,8-디아자비시클로[5.4.0]운덱-7-엔 또는 암모늄 세륨 니트레이트 존재하에서 반응시킴으로써 얻어지는 것을 특징으로 하는 제조방법:
<화학식 2>
Figure pat00013
4. A compound according to any one of claims 1 to 3, wherein the compound of formula (3) is an allyl halide with 1,8-diazabicyclo [5.4.0] undec-7-ene or ammonium cerium nitrate A process for the production which is obtained by reacting in the presence of:
(2)
Figure pat00013
KR1020110034513A 2011-04-14 2011-04-14 Process for the preparation of pregabalin KR101306585B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020110034513A KR101306585B1 (en) 2011-04-14 2011-04-14 Process for the preparation of pregabalin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020110034513A KR101306585B1 (en) 2011-04-14 2011-04-14 Process for the preparation of pregabalin

Publications (2)

Publication Number Publication Date
KR20120117028A true KR20120117028A (en) 2012-10-24
KR101306585B1 KR101306585B1 (en) 2013-09-10

Family

ID=47285054

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020110034513A KR101306585B1 (en) 2011-04-14 2011-04-14 Process for the preparation of pregabalin

Country Status (1)

Country Link
KR (1) KR101306585B1 (en)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5616793A (en) * 1995-06-02 1997-04-01 Warner-Lambert Company Methods of making (S)-3-(aminomethyl)-5-methylhexanoic acid
CN102102114B (en) * 2004-06-21 2013-08-14 沃尼尔·朗伯有限责任公司 Preparation of pregabalin and related compounds
BRPI0702897A2 (en) * 2006-05-31 2011-03-15 Teva Pharmaceutical Ind Ltda process for preparing a pregabalin intermediate
KR100846419B1 (en) * 2007-08-10 2008-07-15 한국과학기술원 Novel method for preparing pregabalin

Also Published As

Publication number Publication date
KR101306585B1 (en) 2013-09-10

Similar Documents

Publication Publication Date Title
KR102630456B1 (en) Method of manufacturing brivaracetam
JP5683761B1 (en) Method for producing optically active bicyclic γ-amino acid derivative
KR20050113292A (en) Process for the preparation of optically pure 4-hydroxy-2-oxo-1-pyrrolidineacetamide
CN111153818B (en) Method for preparing antiviral drug Tamiflu intermediate tert-butylamine derivative I
JP6474392B2 (en) Method for preparing an intermediate for the preparation of oseltamivir phosphate
EA019285B1 (en) Process for the stereoselective enzymatic hydrolysis of 5-methyl-3-nitromethyl-hexanoic acid ester
AU2020365314A1 (en) Process for producing acyloxymethyl esters of (4S)-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridin-3-carboxylic acid
US20090143615A1 (en) Process for the Preparation of (S)(+)-3-(Aminomethyl)-5-Methylhexanoic Acid
US6417403B1 (en) Process for preparing chiral (s)-2,3-disubstituted-1-propylamine derivatives
JP2009502750A (en) Nebivolol manufacturing method
KR101306585B1 (en) Process for the preparation of pregabalin
CN102010355B (en) Method for synthesizing (1R, 2R)-1-p-methyl sulfone phenyl-2-amino-1,3-propanediol
US20070032542A1 (en) Process for the preparation of enantiopure pyrrolidin-2-one derivatives
US8063244B2 (en) Process for the synthesis of pregabalin
KR100915551B1 (en) Process for the efficient preparation of 3-hydroxy pyrrolidine and derivatives thereof
JP4800482B2 (en) (2S, 4R, 9S) -Octahydro-1H-indole-2-carboxylic acid production method and intermediates thereof
JP2004534040A (en) Stereoselective synthesis of 2-hydroxy-4-phenylbutyrate
WO2006008170A1 (en) Process for the preparation of (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionamide and (2r, 3r)-2-hydroxy-3-amino-3-aryl-propionic acid alkyl ester
JP3333184B2 (en) Process for producing (S) -3,4-epoxybutyrate having optical activity
US6365755B1 (en) Ammonium 3,5,6-trihydroxyhexanoate derivatives and preparation process thereof
JP2000063321A (en) Production of long-chain beta-hydroxycarboxylic acid of high optical purity
WO2006031179A1 (en) Process for preparation of phtalimide
KR20090118557A (en) Process for the preparation of a chiral intermediate for the preparation of hmg-coa reductase inhibitors
WO2007126258A1 (en) The method of making optically active 2-halo-2-(n-substituted phenyl)acetic acid esters and 2-halo-2-(n-substituted phenyl)acetic acids by enzymatic method
JP4187822B2 (en) Process for producing optically active 4-hydroxy-2-pyrrolidone

Legal Events

Date Code Title Description
A201 Request for examination
E701 Decision to grant or registration of patent right
GRNT Written decision to grant
FPAY Annual fee payment

Payment date: 20160825

Year of fee payment: 4

FPAY Annual fee payment

Payment date: 20170817

Year of fee payment: 5

LAPS Lapse due to unpaid annual fee