KR20120119468A - Resolution method of racemic 1,4-thiazepine compound - Google Patents

Resolution method of racemic 1,4-thiazepine compound Download PDF

Info

Publication number
KR20120119468A
KR20120119468A KR1020110037411A KR20110037411A KR20120119468A KR 20120119468 A KR20120119468 A KR 20120119468A KR 1020110037411 A KR1020110037411 A KR 1020110037411A KR 20110037411 A KR20110037411 A KR 20110037411A KR 20120119468 A KR20120119468 A KR 20120119468A
Authority
KR
South Korea
Prior art keywords
racemic
thiazepine
thiazepan
amino
compound
Prior art date
Application number
KR1020110037411A
Other languages
Korean (ko)
Other versions
KR101233139B1 (en
Inventor
오민근
김기남
서기형
권대길
Original Assignee
주식회사 한서켐
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 주식회사 한서켐 filed Critical 주식회사 한서켐
Priority to KR1020110037411A priority Critical patent/KR101233139B1/en
Publication of KR20120119468A publication Critical patent/KR20120119468A/en
Application granted granted Critical
Publication of KR101233139B1 publication Critical patent/KR101233139B1/en

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

PURPOSE: A partitioning method of racemic 1,4- thiazepine compound is provided to reduce total manufacturing cost by easily purchasing alcohol solvent and organic acid at low cost. CONSTITUTION: A partitioning method of racemic 1,4- thiazepine compound comprises the following steps: dissolving (6R)-6-amino-2-(thiophene-2-yl)-1,4-thiazepan-5-one of chemical formula 1 which is a racemic compound in an alcohol solvent of methanol, ethanol, propanol, and isopropanol; performing salt formation by adding organic acid of ascorbic acid, tartaric acid, camphorsulfonic acid; cooling the reactant getting and filtering and removing antipode which is educted as crystal; vacuum concentrating the filtrate and melting in the chloroform or the methylene chloride and dissolving into KOH or K2CO3 aqueous solution; and crystallizing thereof with acetonitrile or ethyl acetate; and obtaining (6R)-6-amino-2-(thiophene-2-yl)-1,4-thiazepan-5-one of chemical formula 2. In the first step, the used amount of the alcohol solvent is 6-15 times of the (6R)-6-amino-2-(thiophene-2-yl)-1,4-thiazepan-5-one.

Description

라세믹 1,4-티아제핀 화합물의 분할 방법{Resolution method of racemic 1,4-thiazepine compound} Solution method of racemic 1,4-thiazepine compound

본 발명은 라세믹 1,4-티아제핀 화합물의 분할 방법에 관한 것으로서, 좀더 상세하게 설명하면 키랄(Chiral) 특성을 갖는 하기 화학식 1로 표시되는 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온의 라세미 화합물을 화학적으로 광학 분할(optical resolution)하여 혈압강하제 테모카프릴(Temocapril)의 제조 중간체로 유용한 (S)-에난티오머(enantiomer)인 하기 화학식 2의 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 수득하는 새로운 분할 방법에 관한 것이다.The present invention relates to a method for cleaving a racemic 1,4-thiazepine compound, and more particularly, to (6R) -6-amino-2- (thiophene) represented by the following Chemical Formula 1 having chiral properties: (S) -enantiomer useful as an intermediate for the preparation of the antihypertensive agent, Temocapril, by chemically optical resolution of the racemic compound of 2-yl) -1,4-thiazepan-5-one and (2S, 6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one of formula (2) which is an enantiomer.

Figure pat00001
Figure pat00001

Figure pat00002
Figure pat00002

다음 화학식 3로 표시되는 테모카프릴(Temocapril)의 염산염은 안지오텐신 전환효소 억제제(ACE Inhibitor)의 일종으로 특히 당뇨 환자와 신장 기능이 약한 환자에게도 안전하게 사용할 수 있는 혈압강하제로 평가 받고 있다.Temocapapril (Temocapril) hydrochloride represented by the following formula (3) is an angiotensin converting enzyme inhibitor (ACE Inhibitor) is evaluated as a blood pressure lowering agent that can be used safely even in diabetics and patients with weak kidney function.

Figure pat00003
Figure pat00003

그리고, 상기 화학식 1의 (6R)-6-아미노-2-( 티오펜-2-일)-1,4-티아제판-5-온(이하,‘라세믹 1,4-티아제핀’으로 약칭하기도 함)은 키랄(Chiral) 특성을 갖는 라세미 화합물로서, (S)-에난티오머(enantiomer)인 상기 화학식 2의 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온(이하, ‘S형 1,4-티아제핀’으로 약칭하기도 함)은 상기 테모카프릴의 제조 중간체로 매우 유용하다.In addition, (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one (hereinafter, abbreviated as 'racemic 1,4-thiazepine') of Chemical Formula 1 (Hereinafter also referred to) is a racemic compound having chiral properties, and is (S) -enantiomer of (2S, 6R) -6-amino-2- (thiophen-2-yl of Chemical Formula 2). ) -1,4-thiazepan-5-one (hereinafter also abbreviated as 'S-type 1,4-thiazepine') is very useful as an intermediate for preparing temocapryl.

종래에도 일본 특허공개 제87(소62)-161775호에는 실리카겔을 이용한 컬럼 크로마토그래피 분할법으로 상기 라세믹 1,4-티아제핀 화합물을 분리하고, 그 분획물을 과량의 알콜로 재결정하여 S형 1,4-티아제핀을 회수하는 방법이 소개되어 있다.Conventionally, Japanese Patent Application Laid-Open No. 87 (So 62) -161775 discloses the racemic 1,4-thiazepine compound by column chromatography using silica gel, and the fractions are recrystallized with excess alcohol to form S type 1, A method for recovering 4-thiazepine is introduced.

그러나, 상기와 같은 종래의 크로마토그래피 분할법에서는 고가의 실리카겔을 20V/kg 정도 사용해야 하기 때문에 많은 비용이 소요되고, 그럼에도 불구하고 원하는 (S)-에난티오머가 확실히 분리되지 않아서 이를 다시 메탄올로 재결정해야 하는 번거러움이 있으며, 나아가 목적물질의 수율이 35% 정도로 매우 저조하여 이에 대한 개선의 필요성이 요구되어 왔다.
However, in the conventional chromatographic separation method described above, an expensive silica gel needs to be used at about 20 V / kg, which is expensive. Nevertheless, the desired (S) -enantiomer is not separated from each other so that it must be recrystallized from methanol. There is a hassle, and the yield of the target material is very low, about 35%, and there is a need for improvement.

이에 본 발명이 해결하고자 하는 기술적 과제는 상기 라세믹 1,4-티아제핀 화합물을 분할하는데 있어서 많은 시간과 비용이 소요되는 실리카겔 컬럼을 사용하지 않고, 저렴한 유기산을 이용한 화학적 분할법을 사용하여 보다 간편한 공정과 저렴한 비용으로 대량생산에 적합한 새로운 S형 1,4-티아제핀의 분할 방법을 제공하는 것이다.
Accordingly, the technical problem to be solved by the present invention is a simpler process using a chemical separation method using an inexpensive organic acid, without using a silica gel column, which requires a lot of time and cost in dividing the racemic 1,4-thiazepine compound. It is to provide a new method of dividing S-type 1,4-thiazepine which is suitable for mass production at low cost.

본 발명은 혈압강하제 테모카프릴(Temocapril)의 제조 중간체로 유용한 다음 화학식 2의 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온의 분할 방법에 있어서,The present invention provides (2S, 6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5- of Formula 2, useful as an intermediate for the preparation of the antihypertensive agent, Temocapril. In the division method of on,

a) 라세믹 화합물인 다음 화학식 1의 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 메탄올, 에탄올, 프로판올, 이소프로판올 중에서 선택된 어느 하나 이상의 알콜 용매에 용해하고, 여기에 아스크로빈산, 타르타르산, 캄포 술폰산 중에서 선택된 어느 하나 이상의 유기산을 첨가하여 염 형성반응(Salt formation)을 실시하는 단계와;a) (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one of the following formula (1) which is a racemic compound selected from methanol, ethanol, propanol and isopropanol Dissolving in at least one alcohol solvent and adding at least one organic acid selected from ascrobinic acid, tartaric acid, and camphor sulfonic acid to conduct salt formation;

b) 상기 a) 단계에서 얻어진 반응물을 냉각하여 결정으로 석출된 대장체(antipode)를 여과 및 제거하는 단계와;b) filtering and removing the antipode precipitated as crystals by cooling the reactant obtained in step a);

c) 상기 b) 단계에서 얻어진 여액을 진공 농축하고 클로로포름이나 메틸렌클로라이드에 녹인 후 KOH 또는 K2CO3 수용액으로 해리시킨 다음, 아세토니트릴 혹은 에틸아세테이트로 결정화 하는 단계; 로 이루어지는 것을 특징으로 한다.c) concentrating the filtrate obtained in step b) in chloroform or methylene chloride, dissociating with aqueous KOH or K 2 CO 3 solution, and then crystallizing with acetonitrile or ethyl acetate; .

[화학식 1][Formula 1]

Figure pat00004
Figure pat00004

[화학식 2][Formula 2]

Figure pat00005

Figure pat00005

본 발명에서 출발물질인 라세믹 1,4-티아제핀 화합물을 광학분할하기 위해 사용하는 상기 알콜 용매와 유기산은 시중에서 저렴한 비용으로 쉽게 구입할 수 있는 것들이기 때문에 전체적인 제조원가가 매우 저렴한 효과가 있다. The alcohol solvent and the organic acid used to optically divide the racemic 1,4-thiazepine compound, which is a starting material in the present invention, can be easily purchased at low cost in the market, and thus, the overall manufacturing cost is very low.

또한 본 발명은 화학적 분할법으로서 고가의 실리카겔 컬럼을 사용하는 종래의 크로마토그래피 분할법에 비해 전체적인 공정이 매우 간편하면서도 고순도의 목적물질을 수득할 수 있으며, 특히 대량생산에 적합한 효과가 있다.
In addition, the present invention is very simple compared to the conventional chromatographic splitting method using an expensive silica gel column as a chemical splitting method, it is possible to obtain a high-purity target material, and is particularly suitable for mass production.

도 1은 본 발명에 따라 수득된 S형 1,4-티아제핀의 핵자기공명 데이터,
도 2은 본 발명에서 출발물질인 라세믹 1,4-티아제핀의 HPLC 데이터,
도 3은 본 발명에서 대장체(antipode)인 R형 1,4-티아제핀의 HPLC 데이터,
도 4은 본 발명에 따라 수득된 S형 1,4-티아제핀의 HPLC 데이터이다.1 is nuclear magnetic resonance data of S type 1,4-thiazepine obtained according to the present invention,
2 is HPLC data of racemic 1,4-thiazepine which is a starting material in the present invention,
3 is HPLC data of an R-type 1,4-thiazepine, which is an antipode in the present invention,
4 is HPLC data of S-type 1,4-thiazepine obtained according to the present invention.

본 발명에 따른 라세믹 1,4-티아제핀 화합물의 분할 방법을 하나의 반응식으로 표시하면 다음 반응식 1과 같다.
The division method of the racemic 1,4-thiazepine compound according to the present invention is represented by the following scheme 1.

[반응식 1][Reaction Scheme 1]

Figure pat00006
Figure pat00006

상기 반응식 1에서 보는 바와 같이, 본 발명의 출발물질인 라세믹 1,4-티아제핀은 아스크로빈산과 같은 유기산과 반응하여 염을 형성하는데, 이때 두 가지 염 형태 중 (R)-에난티오머의 염은 알콜 용매에 잘 녹지 않는 반면, (S)-에난티오머의 염은 알콜 용매에 잘 녹는 경향이 있다. As shown in Scheme 1, racemic 1,4-thiazepine, which is a starting material of the present invention, reacts with an organic acid such as ascorbic acid to form a salt, wherein (R) -enantiomer of the two salt forms The salts of are insoluble in alcohol solvents, whereas the salts of (S) -enantiomers tend to dissolve well in alcohol solvents.

본 발명은 상기 두 에난티오머가 서로 다른 용해도 특성을 갖은 성질을 이용하여 (R)-에난티오머를 알콜 용매 중에서 결정으로 석출시켜 제거하고, (S)-에난티오머가 염 형태로 녹아 있는 여액만을 농축 한 후 상기 유기산을 해리시켜서 광학적으로 순수한 (S)-에난티오머인 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 수득하는 것이다.
The present invention utilizes a property in which the two enantiomers have different solubility characteristics to remove (R) -enantiomer as crystals in an alcohol solvent, and only the filtrate in which (S) -enantiomer is dissolved in salt form. After concentration, the organic acid is dissociated to give (2S, 6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one which is an optically pure (S) -enantiomer. To obtain.

상기와 같은 본 발명을 좀 더 상세히 설명하면, 먼저 라세믹 화합물인 상기 화학식 1의 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 메탄올, 에탄올, 프로판올, 이소프로판올 중에서 선택된 어느 하나 이상의 알콜 용매에 용해하고, 여기에 아스크로빈산(ascorbic acid), 타르타르산(tartaric acid), 캄포 술폰산(camphor sulfonic acid) 중에서 선택된 어느 하나 이상의 유기산을 첨가하여 염 형성반응(Salt formation)을 실시한다. In more detail, the present invention as described above, the (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one of the general formula (1) is a racemic compound Is dissolved in one or more alcohol solvents selected from methanol, ethanol, propanol, and isopropanol, and at least one organic acid selected from ascorbic acid, tartaric acid, and camphor sulfonic acid. The salt formation reaction is carried out by addition.

이때, 상기 알콜 용액의 사용량은 출발물질인 상기 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온1,4-티아제핀에 대하여 6~15배량을 사용하는 것이 바람직하다. 만일 상기 알콜 용액의 사용량이 상기 출발물질의 6배량 미만이면, 출발물질과 유기산이 제대로 용해되지 않아 반응이 완결되지 않고, 또한 (S)-에난티오머가 결정으로 석출되어 dr값(diastereomer ratio)이 떨어지는 문제가 있다. 이처럼 (S)-에난티오머가 석출되고 나면 이를 다시 결정화하기가 어렵기 때문에 (S)-에난티오머가 석출되지 않도록 알콜 용매의 양을 조절하는 것이 매우 중요하다.
In this case, the amount of the alcohol solution used is 6 to the (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one 1,4-thiazepine as starting material. It is preferable to use ˜15 times the amount. If the amount of the alcohol solution is less than 6 times the amount of the starting material, the starting material and the organic acid are not dissolved properly, so that the reaction is not completed, and (S) -enantiomer is precipitated as a crystal so that the drster (diastereomer ratio) is decreased. There is a problem falling. It is very important to adjust the amount of the alcohol solvent so that the (S) -enantiomer does not precipitate because it is difficult to crystallize it again after the (S) -enantiomer is precipitated.

또한, 반대로 상기 알콜 용액의 사용량이 출발물질의 15배량을 초과하면 염 형성 후 대장체(antipode) 즉, (R)-에난티오머가 결정으로 석출이 되지 않고 용매에 용해되어 dr값(diastereomer ratio)이 떨어지는 문제가 있다. 그래서 염 형성반응에서 (R)-에난티오머를 제거하지 못하면 다음 반응에서 제거할 수 없기 때문에 용매의 사용량을 조절하여 대장체인 (R)-에난티오머를 결정으로 석출, 제거하는 것이 매우 중요하다. On the contrary, if the amount of the alcohol solution exceeds 15 times the amount of the starting material, the antipode, that is, the (R) -enantiomer, is dissolved in the solvent and does not precipitate as a crystal after salt formation, so that the dr value (diastereomer ratio) There is a problem with this falling. Therefore, if the (R) -enantiomer cannot be removed in the salt formation reaction, it cannot be removed in the next reaction. Therefore, it is very important to precipitate and remove the large (R) -enantiomer as a crystal by controlling the amount of solvent used. .

그리고, 상기 유기산의 사용량은 상기 출발물질에 대하여 0.5~1.2 당량 사용하는 것이 바람직하다. 만일 상기 유기산의 사용량이 0.5당량 미만이면, (S)-에난티오머가 전부 염이 되지 않아 수율이 떨어지며, 반대로 1.2당량을 초과하면 반응 후 잔류한 유기산이 많아 염기로 제거할 때 염기를 과량 사용해야 하는 문제가 있다.
In addition, the amount of the organic acid is preferably used in 0.5 to 1.2 equivalents based on the starting material. If the amount of the organic acid used is less than 0.5 equivalents, the yield decreases because all of the (S) -enantiomers do not become salts. On the contrary, when the amount of the organic acids exceeds 1.2 equivalents, there is a large amount of organic acids remaining after the reaction. there is a problem.

한편, 상기 염 형성반응은 30~40℃의 온도에서 1~3시간 동안 진행하는 것이 바람직하다. 이때, 상기 반응온도가 30℃ 미만이면, 활성화 에너지가 적어서 염을 형성하는데 시간이 오래 걸리고 반응성이 낮기 때문에 수율이 떨어지는 문제가 있다. 반대로 40℃를 초과하면 반응온도가 너무 높아서 (R)-에난티오머 중 일부가 결정으로 석출되지 않는 문제가 발생한다. On the other hand, the salt formation reaction is preferably carried out for 1 to 3 hours at a temperature of 30 ~ 40 ℃. At this time, if the reaction temperature is less than 30 ℃, there is a problem that the yield is low because the activation energy is low, it takes a long time to form a salt and the reactivity is low. On the contrary, if it exceeds 40 ° C, the reaction temperature is so high that some of the (R) -enantiomers do not precipitate as crystals.

또한, 상기 염 형성 반응시간이 1시간 미만이면 반응이 완결되지 않을 우려가 있고, 반대로 3시간을 초과하면 대장체(antipode)인 (R)-에난티오머 이외에 (S)-에난티오머 까지 일부 결정으로 석출이 되며, 석출된 (S)-에난티오머는 회수가 어렵기 때문에 수율이 떨어지며 문제가 있다.In addition, when the salt formation reaction time is less than 1 hour, the reaction may not be completed. On the contrary, when the salt formation reaction time is longer than 3 hours, a part of (S) -enantiomer in addition to (R) -enantiomer, which is an antipode, may be used. Precipitates due to crystals, and the precipitated (S) -enantiomer is problematic in that the yield is poor because it is difficult to recover.

이렇게 하여 염 형성 반응이 완료되면, 얻어진 반응물을 20℃ 정도로 냉각하고, 결정으로 석출된 대장체(antipode), 즉 (R)-에난티오머를 여과하여 제거한다.
In this way, when the salt formation reaction is completed, the obtained reactant is cooled to about 20 ° C., and an antipode, ie, (R) -enantiomer, precipitated as crystals is removed by filtration.

마지막으로 대장체가 제거된 여액을 진공 농축하고, 클로로포름 또는 메틸렌클로라이드에 용해한다. 그리고 KOH 또는 K2CO3 수용액으로 해리하여 염을 풀고 추출하여 수층을 분리 제거한 후 유기층을 농축한다. 이어 농축물을 아세토니트릴 혹은 에틸아세테이트로 현탁 시키고, 서서히 숙성하면 (S)-에난티오머인 상기 화학식 2의 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온이 수득된다.
Finally, the filtrate from which the colon is removed is concentrated in vacuo and dissolved in chloroform or methylene chloride. After dissociation with an aqueous KOH or K 2 CO 3 solution, salts are extracted, extracted, and the aqueous layer is separated and concentrated. The concentrate is then suspended with acetonitrile or ethyl acetate and slowly aged to yield (S) -enantiomer (2S, 6R) -6-amino-2- (thiophen-2-yl) -1 , 4-thiazepan-5-one is obtained.

이와 같이, 본 발명에서는 출발물질인 라세믹 1,4-티아제핀을 시중에서 저렴한 비용으로 손쉽게 구입할 수 있는 유기산과 반응시켜서 염을 형성하고, 그로부터 원하지 않는 대장체(antipode) 결정을 제거한 다음, 아세토니트릴이나 에틸아세테이트과 같은 유기용매로 결정화하는 화학적 광학분할방법으로 고순도의 S형 1,4-티아제핀을 수득할 수 있다.
As such, in the present invention, the racemic 1,4-thiazepine, which is a starting material, is reacted with a commercially available organic acid, which is readily available at low cost, to form a salt, to remove unwanted antipode crystals therefrom, and then to aceto. S-type 1,4-thiazepine of high purity can be obtained by chemical optical splitting method of crystallization with an organic solvent such as nitrile or ethyl acetate.

이하, 본 발명에 대한 실시예를 기술하면 다음과 같다. 하기 실시예들은 본 발명에 대한 이해를 돕기 위한 것이기 때문에 하기 실시예들로 인해서 본 발명의 권리범위가 제한되는 것은 아니다.
Hereinafter, an embodiment of the present invention will be described. The following examples are provided to aid understanding of the present invention, and thus the scope of the present invention is not limited by the following examples.

[실시예 1] Example 1

세척이 완료된 반응용기에 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을1,4-티아제핀 72g을 에탄올 1000mL에 용해하고, 여기에 L-아스크로빈산 39.6g을 정제수 100mL에 용해하여 30분 동안 적가한 후, 이를 2시간 동안 35℃에서 교반한다.72 g of 1,4-thiazepine was dissolved in 1000 mL of ethanol in (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one in a washing reaction vessel, Here, 39.6 g of L-ascorbic acid was dissolved in 100 mL of purified water, and added dropwise thereto for 30 minutes, followed by stirring at 35 ° C. for 2 hours.

이어 상기 반응물을 20℃ 로 냉각하고, 결정물을 여과하여 제거한 다음, 여액을 진공 농축하고 농축된 잔사를 클로로포름 500 mL에 용해한다.The reaction is then cooled to 20 ° C., the crystals are filtered off, the filtrate is concentrated in vacuo and the concentrated residue is dissolved in 500 mL of chloroform.

여기에 10% KOH 수용액 200 mL를 투입하고 30분간 교반한 다음, 이를 층 분리하여 5% 소금물 300mL로 세척하고, 유기용매층을 탈수 후 감압 농축하면 조품의 S형 1,4-티아제핀이 얻어진다. 200 mL of 10% KOH aqueous solution was added thereto, stirred for 30 minutes, and the layers were separated and washed with 300 mL of 5% brine. The organic solvent layer was dehydrated and concentrated under reduced pressure to obtain a crude S-type 1,4-thiazepine. Lose.

상기 조품의 S형 1,4-티아제핀을 에틸아세테이트 100 ml에 현탁하고, 20℃에서 1시간 교반 숙성한 후 여과 및 진공건조하면 광학적으로 순수한 S형 1,4-티아제핀 화합물 29.9g(수득률 83%)이 수득된다.
The crude S-type 1,4-thiazepine was suspended in 100 ml of ethyl acetate, stirred and aged at 20 ° C. for 1 hour, and then filtered and vacuum dried to obtain optically pure S-type 1,4-thiazepine compound 29.9 g (yield) 83%) is obtained.

[실시예 2~3] [Examples 2 to 3]

상기 실시예 1에서 L-아스크로빈산 대신에 다음 표 1과 같은 유기산을 사용하는 것 이외에는 상기 실시예 1과 동일한 방법으로 실시하여 S형 1,4-티아제핀 화합물 제조하였다. 이때, 각 실시예에서 얻어진 목적물질의 수율을 다음 표 1과 같다.
The S-type 1,4-thiazepine compound was prepared in the same manner as in Example 1 except for using the organic acid shown in Table 1 in place of L-ascorbic acid in Example 1. In this case, the yield of the target material obtained in each example is shown in Table 1 below.

실시 예Example 유기산Organic acid 수율yield 22 타르타르산Tartaric acid 69%69% 33 캄포 술폰산Campo sulfonic acid 73%73%

[NMR 및 HPLC 분석]NMR and HPLC Analysis

가. 핵자기공명(end. Nuclear magnetic resonance ( NMRNMR ) 데이터 분석Data analysis

상기 실시예에서 얻어진 S형 1,4-티아제핀에 대한 핵자기공명 데이터를 분석한 결과, 도 1에서 보는 바와 같이 1H NMR(200Mz, CDCl3)d 7.17-7.14(d, J= 6, 2H), 7.05-7.00(m, 2H), 6.51(brs, 1H), 4.32-4.01(m, 2H), 3.98-3.89(m, 1H), 3.78-3.67(m, 1H), 3.10-2.98(m, 1H), 2.72-2.64(dd,J=2,J=14, 1H), 1.83(brs, 2H)에서 각각 피크를 보였다. 이때, 핵자기공명(NMR)의 측정조건은 다음과 같다.As a result of analyzing the nuclear magnetic resonance data for the S-type 1,4-thiazepine obtained in the above example, as shown in FIG. 1, 1 H NMR (200Mz, CDCl 3 ) d 7.17-7.14 (d, J = 6, 2H), 7.05-7.00 (m, 2H), 6.51 (brs, 1H), 4.32-4.01 (m, 2H), 3.98-3.89 (m, 1H), 3.78-3.67 (m, 1H), 3.10-2.98 ( m, 1H), 2.72-2.64 (dd, J = 2, J = 14, 1H) and 1.83 (brs, 2H), respectively. At this time, the measurement conditions of nuclear magnetic resonance (NMR) are as follows.

1) 장치 : Bruker AC NMR 2001) Apparatus: Bruker AC NMR 200

2) 측정 범위: -1.0 ~ 10 ppm2) Measuring range: -1.0 to 10 ppm

3) 스캔 횟수: 16
3) Number of scans: 16

나. I. HPLCHPLC 분석 analysis

상기 실시예에서 얻어진 S형 1,4-티아제핀을 HPLC로 분석한 결과, 도 4에서 보는 바와 같이 디아스테레오머(Diastereomer)-A (2S,6R)과 디아스테레오머-B (2R,6R)의 피크가 각각 7.4분, 5.5분에 나타났으며, 이성체 비율은 96.5%이다. S-type 1,4-thiazepine obtained in the above Example was analyzed by HPLC, and as shown in FIG. 4, diastereomer-A (2S, 6R) and diastereomer-B (2R, 6R) Peaks were found at 7.4 and 5.5 minutes, respectively, and the isomer ratio was 96.5%.

또한, 도 2와 도 3은 각각 분할 공정 이전의 라세믹 1,4-디아제핀과, 대장체(antipode)인 R형 1,4-티아제핀의 HPLC데이터를 나타낸 것이다. 이 때, HPLC의 측정조건은 다음과 같다.2 and 3 show HPLC data of racemic 1,4-diazepine and R-type 1,4-thiazepine, which is an antipode, before the dividing process, respectively. At this time, HPLC measurement conditions are as follows.

1) 장치 : Agilent technologies 1260 infinity HPLC system1) Device: Agilent technologies 1260 infinity HPLC system

2) 컬럼: 옥타데실 실릴화 실리카겔(4.6x150mm,5μm)2) Column: octadecylsilylated silica gel (4.6 x 150 mm, 5 m)

3) 이동상 : 88:12, 0.147M KH2PO4 buffer solution:Acetonitrile3) Mobile phase: 88:12, 0.147M KH 2 PO 4 buffer solution: Acetonitrile

4) 컬럼온도 : 40 oC4) Column temperature: 40 o C

5) 검출기 : 자외부 흡광광도계5) Detector: Ultraviolet absorptiometer

6) 측정파장 : 235 nm6) Measurement wavelength: 235 nm

7) 측정범위: 30분7) Measurement range: 30 minutes

Claims (4)

a) 라세믹 화합물인 다음 화학식 1의 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 메탄올, 에탄올, 프로판올, 이소프로판올 중에서 선택된 어느 하나 이상의 알콜 용매에 용해하고, 여기에 아스크로빈산, 타르타르산, 캄포 술폰산 중에서 선택된 어느 하나 이상의 유기산을 첨가하여 염 형성반응(Salt formation)을 실시하는 단계와;
b) 상기 a) 단계에서 얻어진 반응물을 냉각하여 결정으로 석출된 대장체(antipode)를 여과 및 제거하는 단계와;
c) 상기 b) 단계에서 얻어진 여액을 진공 농축하고 클로로포름이나 메틸렌클로라이드에 녹인 후 KOH 또는 K2CO3 수용액으로 해리시킨 다음, 아세토니트릴 혹은 에틸아세테이트로 결정화하여 다음 화학식 2의 (2S,6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온을 수득하는 단계; 로 이루어지는 것을 특징으로 하는 라세믹 1,4-티아제핀 화합물의 분할 방법.
[화학식 1]
Figure pat00007

[화학식 2]
Figure pat00008

a) (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one of the following formula (1) which is a racemic compound selected from methanol, ethanol, propanol and isopropanol Dissolving in at least one alcohol solvent and adding at least one organic acid selected from ascrobinic acid, tartaric acid, and camphor sulfonic acid to conduct salt formation;
b) filtering and removing the antipode precipitated as crystals by cooling the reactant obtained in step a);
c) The filtrate obtained in step b) was concentrated in vacuo, dissolved in chloroform or methylene chloride, dissociated with aqueous KOH or K 2 CO 3 solution, and then crystallized with acetonitrile or ethyl acetate to give (2S, 6R)- Obtaining 6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one; A method of dividing a racemic 1,4-thiazepine compound, characterized by consisting of:
[Formula 1]
Figure pat00007

(2)
Figure pat00008

 제1항에 있어서, 상기 a) 단계에서 상기 알콜 용매의 사용량은 상기 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온1,4-티아제핀에 대하여 6~15배량 인 것을 특징으로 하는 라세믹 1,4-티아제핀 화합물의 분할 방법.
The method of claim 1, wherein the amount of the alcohol solvent used in step a) is (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one1,4 -It is 6-15 times with respect to thiazepine, The splitting method of the racemic 1, 4- thiazepine compound characterized by the above-mentioned.
제1항에 있어서, 상기 a) 단계에서 상기 유기산의 사용량은 상기 (6R)-6-아미노-2-(티오펜-2-일)-1,4-티아제판-5-온1,4-티아제핀에 대하여 0.5~1.2 당량인 것을 특징으로 하는 라세믹 1,4-티아제핀 화합물의 분할 방법.
The method of claim 1, wherein the amount of the organic acid used in step a) is (6R) -6-amino-2- (thiophen-2-yl) -1,4-thiazepan-5-one 1,4- A method for dividing a racemic 1,4-thiazepine compound, which is 0.5 to 1.2 equivalents based on thiazepine.
제1항에 있어서, 상기 a) 단계에서 염 형성반응(Salt formation)은 30~40℃의 온도에서 1~3시간 동안 진행하는 것을 특징으로 하는 라세믹 1,4-티아제핀 화합물의 분할 방법. The method of claim 1, wherein the salt formation reaction in the step a) (Salt formation) is a division method of racemic 1,4-thiazepine compound, characterized in that for 1 to 3 hours at a temperature of 30 ~ 40 ℃.
KR1020110037411A 2011-04-21 2011-04-21 Resolution method of racemic 1,4-thiazepine compound KR101233139B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020110037411A KR101233139B1 (en) 2011-04-21 2011-04-21 Resolution method of racemic 1,4-thiazepine compound

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
KR1020110037411A KR101233139B1 (en) 2011-04-21 2011-04-21 Resolution method of racemic 1,4-thiazepine compound

Publications (2)

Publication Number Publication Date
KR20120119468A true KR20120119468A (en) 2012-10-31
KR101233139B1 KR101233139B1 (en) 2013-02-21

Family

ID=47286706

Family Applications (1)

Application Number Title Priority Date Filing Date
KR1020110037411A KR101233139B1 (en) 2011-04-21 2011-04-21 Resolution method of racemic 1,4-thiazepine compound

Country Status (1)

Country Link
KR (1) KR101233139B1 (en)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU1435151A3 (en) * 1984-04-10 1988-10-30 Санкио Компани Лимитед (Фирма) Method of producing derivatives of perhydrothiazepin or acid-additive pharmaceutically acceptable salts thereof
US4652561A (en) * 1986-02-26 1987-03-24 Hoffmann-La Roche Inc. Naphtho[1,2-b]-1,4-thiazepinones
US5075440A (en) 1990-05-03 1991-12-24 Ortho Pharmaceutical Corporation Novel pyrido[2,3-f](1,4)thiazepines and pyrido[3,2-b](1,5)benzothiazepines

Also Published As

Publication number Publication date
KR101233139B1 (en) 2013-02-21

Similar Documents

Publication Publication Date Title
KR100641534B1 (en) Process of esomeprazole and salts thereof
CN116751136A (en) Novel preparation method of oxo-pyridine compound and key intermediate
KR101233139B1 (en) Resolution method of racemic 1,4-thiazepine compound
WO2011010579A1 (en) Process for production of optically active nipecotamide
EP4177243A1 (en) Preparation method for aromatic ether compound
BR112013010115B1 (en) separation process of triazine-derived enantiomers using tartaric acid
CN109803961B (en) Process for producing (R) -5- (3, 4-difluorophenyl) -5- [ (3-methyl-2-oxopyridin-1 (2H) -yl) methyl ] imidazolidine-2, 4-dione and intermediate for production thereof
Hirose et al. Resolution of α-methylbenzylamine via diastereomeric salt formation using the naturally based reagent N-tosyl-(S)-phenylalanine together with a solvent switch technique
EP2345655A1 (en) A process for racemisation of 6-(5-chloropyridin-2-yl)-7-(4-methyl-1-piperazinyl)carbonyloxy-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine
EP3356372B1 (en) Novel process for preparing thienopyrimidine compound and intermediates used therein
KR101374939B1 (en) Novel intermediate salts for preparing itopride hydrochloride, methods for preparing thereof and methods for preparing itopride hydrochloride using thereof
KR0144575B1 (en) Procecs for the separation of enantiomers of benzopyran derivative
KR20100063915A (en) Method of preparing s-(-)-amlodipine with high optical purity and intermediate compound produced during the same
KR20120022421A (en) Novel n-methylbenzylamine salt of rosuvastatin and process for the preparation thereof
JP2616211B2 (en) Preparation of optically active 1,2-propanediamine
CN116730861A (en) Novel preparation method of oxo-pyridine compound and key intermediate
JP5704182B2 (en) Process for producing optically active tetrahydrofuran-2-carboxylic acid
KR100503639B1 (en) A purification process of Tamsulosin
CN116874387A (en) Novel preparation method of oxo-pyridine compound and key intermediate
JP3563480B2 (en) Method for producing optically active substance, and optically active sulfonium compound
KR101392993B1 (en) A preparing method of chiral 1,4-thiazepin phenyl butanoate compound
KR20060125218A (en) The optical resolution method of benzoxazine derivative
CN115368317A (en) Improved method for preparing aripiprazole intermediate
KR20030047466A (en) Optical resolution of racemic piperidine carboxylic acid derivative
CN117510398A (en) Preparation method of (3R, 4R)/(3S, 4S) -N-BOC-4-amino-3-hydroxy piperidine with high optical purity

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: 20160201

Year of fee payment: 4

FPAY Annual fee payment

Payment date: 20180205

Year of fee payment: 6

FPAY Annual fee payment

Payment date: 20190211

Year of fee payment: 7

FPAY Annual fee payment

Payment date: 20200205

Year of fee payment: 8