KR20190037172A - Production method of intermediate compound for synthesizing medicament - Google Patents
Production method of intermediate compound for synthesizing medicament Download PDFInfo
- Publication number
- KR20190037172A KR20190037172A KR1020180115838A KR20180115838A KR20190037172A KR 20190037172 A KR20190037172 A KR 20190037172A KR 1020180115838 A KR1020180115838 A KR 1020180115838A KR 20180115838 A KR20180115838 A KR 20180115838A KR 20190037172 A KR20190037172 A KR 20190037172A
- Authority
- KR
- South Korea
- Prior art keywords
- group
- formula
- compound
- reaction
- process according
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/10—Preparation of carboxylic acid amides from compounds not provided for in groups C07C231/02 - C07C231/08
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
본 발명은 디펩티딜 펩티데이즈 IV(이하, 'DPP-IV'라고도 함) 억제 당뇨병 치료제를 합성하는데 필수적 중간체인 하기 화학식 1의 제조에 사용되는 하기 화학식 2 화합물을 제조하는 방법 및 이 방법을 수행하는데 중간체로서 생성되는 하기 신규한 화학식 3 및 4의 화합물에 관한 것이다.The present invention relates to a method for producing a compound represented by the following formula (2), which is an essential intermediate for synthesizing a therapeutic agent for inhibiting dipeptidyl peptidase IV (hereinafter, also referred to as 'DPP-IV' The present invention relates to novel compounds of formulas (III) and (IV) which are produced as intermediates.
국제출원 공개 WO 06/104356호에 개시된 디펩티딜 펩티데이즈 IV(DPP-IV) 억제 당뇨병 치료제로 유용한 화합물은(국제출원 공개 WO 06/104356호의 화학식 1의 화합물 참조) DPP-IV 효소에 대해 우수한 저해 활성을 나타내어, 상기 효소로 인해 유발되는 질병인 당뇨병, 비만 등의 치료 및 예방에 효과적으로 사용될 수 있음이 알려져 있다. 이러한 DPP-IV 억제제 화합물의 제조에 있어서, 국제출원 공개 WO 06/104356호는 필수적 중간체로서 하기 화학식 1의 화합물로부터 제조하는 방법을 개시하고 있다. Compounds useful as therapeutic agents for the inhibition of dipeptidyl peptidase IV (DPP-IV) inhibition of diabetes mellitus as disclosed in International Application Publication No. WO 06/104356 (see the compound of formula 1 of WO 06/104356) DPP-IV enzyme, and is known to be effectively used for the treatment and prevention of diabetes, obesity and the like caused by the enzyme. In the preparation of such DPP-IV inhibitor compounds, International Publication No. WO 06/104356 discloses a process for preparing from compounds of formula 1 as essential intermediates.
[화학식 1][Chemical Formula 1]
한편, 상기 화학식 1의 화합물 제조에는 하기 화학식 2의 화합물이 사용되는데, 일반적으로, 화학식 2 화합물 제조를 위해 상업적으로 유용한 4-tert-Butyl (2S)-2-tert-butoxycarbonylamino-butanedioate를 출발물질로 제조하는 방법이 한국특허출원 제10-2010-0086619호에 개시되어 있으나, 1) 제조 공정이 상업용 대량 생산에 적합하지 않으며, 2) 비싼 단가와 낮은 수율로 인해 생산 원가 상승의 주요 요인이 되는 문제가 있었다.On the other hand, the formula I compound prepared is used, the following compounds of formula (2) of, generally, from the commercially available 4- tert -Butyl (2 S) -2- tert -butoxycarbonylamino-butanedioate for Preparation 2 Compounds Material Has been disclosed in Korean Patent Application No. 10-2010-0086619, but it has been found that 1) the production process is not suitable for commercial mass production, 2) it is a major factor in the increase of the production cost due to the high unit price and low yield There was a problem.
이에 본 발명자들은 선행기술의 상술한 단점들을 해결하기 위하여 집중적으로 연구를 수행하였고 아민 보호기 (P1)의 도입과 고리화 반응을 통해 카르복시산기에 보호기 (P2)를 도입하는 기술 개발을 실시하였다. 또한, 이러한 제조과정에서 생성된 중간체들이 그 자체로 신규한 화합물임을 발견하고 본 발명을 완성하게 되었다.Accordingly, the present inventors conducted intensive studies to solve the above-mentioned disadvantages of the prior art, and developed a technique of introducing a protecting group (P 2 ) into a carboxylic acid group through introduction of an amine protecting group (P 1 ) and a cyclization reaction. Further, it has been found that intermediates produced in such a production process are novel compounds in themselves, and the present invention is completed.
구체적으로 설명하면 하기 반응식 1과 같다:Specifically, the following reaction formula 1 is given:
[반응식 1][Reaction Scheme 1]
앞서 언급된 종래 기술상의 문제점을 해소하기 위하여, 본 발명자들은 가격이 저렴한 화학식 6 화합물로부터 화학식 2의 화합물을 합성하고자 시도하였다. In order to solve the above-mentioned problems in the prior art, the present inventors attempted to synthesize the compound of the formula (2) from the compound of the formula (6) which is inexpensive.
종래 기술에 따른 상기 반응식 1의 경로 1(pathway 1) (Chem. Commun., 2001, 1710-1711)의 경우 1) 30~34%의 낮은 수율과 2) Toxic한 티오닐클로라이드등의 원료 및 암모니아 가스의 사용 3) 저온반응 등이 요구되는 반면, 본 발명에 따른 제조방법에 해당하는 경로 2(pathway 2)의 경우 온화한 반응 조건과 57~61%의 높은 수율로 화학식 2 화합물을 수득할 수 있는 장점을 확보할 수 있다.In the case of pathway 1 ( Chem . Commun ., 2001, 1710-1711) of Scheme 1 according to the prior art, 1) a low yield of 30-34% and 2) a raw material such as toxic thionyl chloride and ammonia Gas 3) low-temperature reaction is required, while in the case of pathway 2 corresponding to the production method according to the present invention, it is possible to obtain a compound of formula 2 with mild reaction conditions and a high yield of 57 to 61% Advantages can be secured.
따라서, 본 발명은 DPP-IV 억제 당뇨병 치료제를 합성하는데 사용되는 중간체인 화학식 1 화합물을 제조하기 위하여 필수적으로 사용되는 화학식 2의 화합물을 상업용 대량생산에 적합하면서도, 경제적이고 고수율로 제조하는 방법을 제공하는 것을 목적으로 한다.Accordingly, the present invention provides a method for preparing a compound of formula (2), which is an essential intermediate for preparing a compound of formula (1), which is an intermediate used for synthesizing a therapeutic agent for DPP-IV inhibition of diabetes, in an economical and high- The purpose is to provide.
상기 과제를 해결하기 위하여, 본 발명은: In order to solve the above problems, the present invention provides:
1) 하기 화학식 6 화합물의 아민기에 P1기를 도입하여 아민기가 보호된 화학식 5 화합물을 수득하는 단계;1) introducing a P < 1 > group to an amine group of the following formula 6 compound to yield a compound of formula 5 wherein the amine group is protected;
2) 단계 1)에서 생성된 화학식 5의 화합물에 산 촉매하에서 축합반응을 통한 고리화 반응을 통해 화학식 4 화합물을 수득하는 단계;2) obtaining a compound of formula (IV) via a cyclization reaction by condensation reaction of the compound of formula (5) produced in step 1) with an acid catalyst;
3) 단계 2)에서 생성된 화학식 4 화합물의 카르복시산기에 P2기를 도입하여 상기 카르복시산기를 에스테르기로 전환시켜 화학식 3 화합물을 수득하는 단계; 및3) introducing a P 2 group to the carboxylic acid group of the compound of formula 4 produced in step 2) to convert the carboxylic acid group to an ester group to obtain a compound of formula 3; And
4) 단계 3)에서 생성된 화학식 3 화합물의 질소원료 화합물과 반응시켜 옥사졸리디논 탈고리화를 통해 화학식 2의 아미드 화합물을 수득하는 단계,4) reacting the compound of formula 3 with a nitrogen source compound produced in step 3) to obtain an amide compound of formula 2 via oxazolidinone decarboxylation,
를 포함하는 하기 화학식 2 화합물의 제조방법에 관한 것이다:Lt; RTI ID = 0.0 > (2) < / RTI > comprising:
[화학식 6][Chemical Formula 6]
[화학식 5][Chemical Formula 5]
[화학식 4][Chemical Formula 4]
[화학식 3](3)
[화학식 2](2)
상기 식에서 P1은 아민 보호기로서 카르보닐기, 아실기, 술포닐기, 아세틸 또는 벤질기에서 선택될 수 있는 것이며, 바람직하게 P1은 Boc (부틸옥시카보닐), Cbz (벤질옥시카보닐) 또는 Fmoc (9-플루오레닐메틸옥시카르보닐)이고, 더욱 바람직하게는 Boc이다. Wherein P 1 is selected from the group consisting of a carbonyl group, an acyl group, a sulfonyl group, an acetyl group or a benzyl group as an amine protecting group and preferably P 1 is Boc (butyloxycarbonyl), Cbz (benzyloxycarbonyl) or Fmoc 9-fluorenylmethyloxycarbonyl), more preferably Boc.
P2는 카르복시산 보호기이다. 바람직하게는 벤질기, 메틸기, 에틸기, i-프로필기 또는 i-부틸기, 더욱 바람직하게는 t-부틸기이다.P 2 is a carboxylic acid protecting group. Preferably a benzyl group, a methyl group, an ethyl group, an i-propyl group or an i-butyl group, more preferably a t-butyl group.
이하, 본 발명을 반응식에 기초하여 상세하게 설명한다. 다만, 하기 반응식은 본 발명의 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본원발명을 제한하려는 것은 아니다.Hereinafter, the present invention will be described in detail based on the reaction formula. However, the following reaction formula is intended to aid understanding of the present invention, and is not intended to limit the present invention in any sense.
본 발명에 따른 제조 방법을 구체적으로 설명하면 하기 반응식 2와 같다:The preparation method according to the present invention will be described in detail as follows.
[반응식 2][Reaction Scheme 2]
상기 반응식 2의 제 1 단계의 보호기화 반응에서 사용되는 반응 염기는 트리에틸아민, N,N-디이소프로필에틸아민 (Hunig's base), 리튬 t-부톡사이드, 포타슘 t-부톡사이드, 소듐 t-부톡사이드 및 수산화 나트륨으로 이루어지는 군 중에서 선택되는 하나 이상일 수 있다. 바람직하게는 트리에틸아민을 사용하는 것이 좋다. 반응 염기의 사용량은 화학식 6 화합물에 대해 1.0 당량 이상, 특히 2.0 내지 3.0 당량이 바람직하다. The reaction bases used in the first step of the reaction scheme 2 include triethylamine, N, N-diisopropylethylamine (Hunig's base), lithium t-butoxide, potassium t-butoxide, sodium t- Butoxide, sodium hydroxide, and the like. Preferably, triethylamine is used. The amount of the reaction base to be used is preferably 1.0 equivalents or more, particularly 2.0 to 3.0 equivalents relative to the compound of formula (VI).
또한, 반응 용매로는 이소프로필알콜, 에틸알콜, 디클로로에탄, 디클로로메탄, 테트라히드로퓨란, 아세톤 및 디옥산 등 유기반응에 통상적으로 사용될 수 있는 유기 용매를 1종 이상 선택하여 사용할 수 있으며, 또한 물과 함께 혼합용매(Co-solvent) 등을 사용할 수 있다. 특히, 이소프로필알콜 및 물의 혼합용매가 바람직하다. As the reaction solvent, at least one organic solvent which can be commonly used for organic reactions such as isopropyl alcohol, ethyl alcohol, dichloroethane, dichloromethane, tetrahydrofuran, acetone and dioxane can be selected and used. And a mixed solvent (Co-solvent) may be used. Particularly, a mixed solvent of isopropyl alcohol and water is preferable.
구체적인 일 양태에서, 1) P1로서 부틸옥시카보닐 또는 아세틸기를 도입하는 경우에는, 디-tert-부틸디카보네이트 (Boc anhydride) 또는 아세트산무수물 (Acetic anhydride); 트리에틸아민 (TEA), N,N-디이소프로필에틸아민 (Hunig's base) 등의 염기; 반응용매로서 디클로로에탄, 디클로로메탄, 고리화 에테르 (예, 테트라히드로퓨란 (THF), 디옥산 (dioxane)), 이소프로판올(IPA)/H2O 혼합 용매 또는 THF/H2O 혼합용매가 사용될 수 있고, 2) P1로서 Fmoc (9-Fluorenylmethoxycarbonyl)기를 도입하는 경우에는 Fmoc-Cl; 염기로서 탄산나트륨 (aq Na2CO3); 반응용매로서 디옥산이 사용될 수 있고, 3) P1이 4-니트로벤젠술포닐 (Ns) 인 경우 4-니트로벤젠술포닐 클로라이드 (Ns-Cl); 트리에틸아민 또는 N,N-디이소프로필에틸아민, 수산화나트륨 등의 염기; 반응용매로서 아세톤이 사용될 수 있고, 4) P1이 카복실벤질 (Cbz)인 경우 벤질클로로퍼메이트 (benzyl chloroformate); 염기로서 탄산수소나트륨 (NaHCO3); 반응 용매로서 테트라히드로퓨란/물이 사용될 수 있다. In a specific embodiment, 1) when butyloxycarbonyl or acetyl group is introduced as P 1 , di-tert-butyl dicarbonate (Boc anhydride) or acetic anhydride; Bases such as triethylamine (TEA) and N, N-diisopropylethylamine (Hunig's base); As the reaction solvent, a mixed solvent of dichloroethane, dichloromethane, cyclized ether (e.g., tetrahydrofuran (THF), dioxane), isopropanol (IPA) / H 2 O mixed solvent or THF / H 2 O may be used 2) when Fmoc (9-Fluorenylmethoxycarbonyl) group is introduced as P 1 , Fmoc-Cl; Sodium carbonate (aq Na 2 CO 3 ) as a base; Dioxane may be used as a reaction solvent, and 3) when P 1 is 4-nitrobenzenesulfonyl (Ns), 4-nitrobenzenesulfonyl chloride (Ns-Cl); Bases such as triethylamine or N, N-diisopropylethylamine, sodium hydroxide and the like; Acetone may be used as a reaction solvent; 4) benzyl chloroformate when P 1 is carboxyl benzyl (Cbz); Sodium bicarbonate (NaHCO 3 ) as a base; Tetrahydrofuran / water may be used as a reaction solvent.
바람직하게, P1으로서 부닐옥시카르보닐로 보호시키기 위해 디-tert-부틸디카보네이트를 사용하는 경우가 수율 측면에서 바람직하며, 사용량은 화학식 6 화합물에 대해 1.0 당량 이상, 특히 1.0 내지 1.3 당량이 바람직하다. 또한, 상기 당량은 다른 보호기를 도입하기 위한 화합물, 즉, 아세트산 무수물, Fmoc-Cl, 아세틸언하이드라이드 및 벤질클로로퍼메이트들에도 동일하게 적용된다. Preferably, the use of di-tert-butyl dicarbonate as the protecting group for P 1 as the boron oxycarbonyl is preferred in terms of yield, and the amount used is preferably 1.0 equivalent or more, particularly 1.0 to 1.3 equivalent relative to the compound of formula Do. The same applies also to the compounds for introducing other protecting groups, i.e., acetic anhydride, Fmoc-Cl, acetyl anhydride and benzyl chloropermates.
제 2 단계의 고리화 반응은 산 촉매 하에 파라포름알데히드와 반응시켜 축합반응을 통해 이루어지며, 구체적으로 1) 파라포름알데히드 (paraformaldehyde), 파라톨로엔설폰산 (p-TsOH)-물, 톨루엔 또는 에틸아세테이트-벤젠, 또는 2) 파라포름알데히드, 피리듐-p-톨루엔설포네이트 (PPTS, Pyridium-p-toluenesulfonate), 톨루엔-에틸아세테이트 조건하에서 화학식 4 화합물을 얻을 수 있다. 안전성 및 경제성 측면에서, 산 촉매로 피리듐-p-톨루엔설포네이트와 반응용매는 톨루엔-에틸아세테이트 혼합용매를 사용하는 것이 바람직하다. 특히 피리듐-p-톨루엔설포네이트 사용량은 화학식 5의 화합물에 대해 0.005 당량 이상을 사용하며 바람직하게는 0.01 내지 0.02 당량을 사용한다. 제 2 단계의 반응 결과 생성된 화학식 4 화합물은 에틸아세테이트/톨루엔 혼합용매 중에서 재결정하면 고순도의 고체화합물의 상태로 수득될 수 있다. 재결정 용매의 혼합 비율에 관하여, 생성된 화학식 4 화합물에 대해 에틸아세테이트와 톨루엔을 1:7 내지 1:10의 부피비로 혼합한 혼합용매 중에서 실시할 수 있고, 바람직하게는 1:8 내지 1:9 부피비로 혼합한 혼합용매 중에서 재결정을 실시할 수 있다.The cyclization reaction in the second step is carried out by condensation reaction with paraformaldehyde under an acid catalyst. Specifically, 1) paraformaldehyde, para-toluenesulfonic acid (p-TsOH) -water, toluene Or ethyl acetate-benzene, or 2) under the conditions of paraformaldehyde, PPTS, pyridinium- p- toluenesulfonate and toluene-ethyl acetate. From the viewpoints of safety and economy, it is preferable to use pyridium-p-toluene sulfonate as an acid catalyst and a toluene-ethyl acetate mixed solvent as a reaction solvent. In particular, the amount of pyridium-p-toluenesulfonate used is 0.005 equivalents or more, preferably 0.01 to 0.02 equivalents, based on the compound of formula (5). The compound of formula (IV) produced as a result of the reaction of the second step can be obtained in the form of a solid compound of high purity by recrystallization in an ethyl acetate / toluene mixed solvent. Regarding the mixing ratio of the recrystallization solvent, the resulting compound of formula (IV) can be carried out in a mixed solvent of ethyl acetate and toluene mixed at a volume ratio of 1: 7 to 1:10, preferably 1: 8 to 1: 9 The recrystallization can be carried out in a mixed solvent mixed at a volume ratio.
제 3 단계의 에스테르화 반응에서는 화학식 4 화합물에 P2가 도입되면서 카르복시산기가 에스테르기로 전환되어, 화학식 3 화합물이 생성된다. 이 때, t-부틸알콜, 이소프로필알콜, 에틸알콜, 메틸알콜 또는 테트라히드로퓨란등의 단일용매 또는 이들을 혼합한 혼합용매를 사용하고, 촉매량 (화학식 4의 화합물에 대해 0.05 내지 0.2 당량 범위이며, 바람직하게는 0.1 당량)의 4-디(메틸아미노)피리딘을 사용할 수 있다. 도입하고자 하는 P2에 따라, 반응 용매, 시약, 온도 조건 등을 달리할 수 있다. 예컨대 P2가 t-부틸기인 경우 1.0 내지 2.0 당량의 디-tert-부틸디카보네이트를 사용하며, 상온 내지 60℃ 정도의 온도 범위, 바람직하게는 40℃ 내지 50℃의 온도 범위에서 제 3 단계를 수행할 수 있다. In the esterification reaction in the third step, P 2 is introduced into the compound of formula (IV), and the carboxylic acid group is converted to an ester group to produce the compound of formula (III). In this case, a single solvent such as t-butyl alcohol, isopropyl alcohol, ethyl alcohol, methyl alcohol or tetrahydrofuran, or a mixed solvent obtained by mixing these solvents is used, and the amount of the catalyst (0.05 to 0.2 equivalent weight, Preferably 0.1 equivalent) of 4-di (methylamino) pyridine can be used. Depending on the P 2 to be introduced, the reaction solvent, the reagent, the temperature condition, and the like may be different. For example, when P 2 is a t-butyl group, 1.0 to 2.0 equivalents of di-tert-butyl dicarbonate is used, and the third step is carried out at a temperature ranging from room temperature to 60 ° C, preferably 40 ° C to 50 ° C Can be performed.
제 4 단계의 옥사졸리디논 탈고리화 반응에서는 옥사졸리디논 구조의 화학식 3 화합물과 질소원료 화합물이 반응하여 탈고리화되어 아마이드 화합물인 화학식 2 화합물을 수득한다. 이때, 반응 용매로는 t-부틸알콜, 메틸알콜, 에틸알콜, n-부틸알콜 및 n-프로판올로 이루어진 군으로부터 선택되는 용매를 사용할 수 있고, 바람직하게는 반응속도를 단축하고 불순물의 생성을 최소화 할 수 있는 이소프로필알콜을 사용할 수 있다. 상기 질소원료 화합물은 암모니아수 (25 % 내지 30 % 농도)를 사용하는 것이 바람직하며 사용량은 화학식 2 화합물에 대해 1.0 폴드(fold) (fold: ml/g) 이상이며, 바람직하게 1.2 내지 1.5 폴드를 사용하며 또한 암모니아 가스를 사용할 수도 있으며, 이때 사용량은 화학식 2의 화합물에 대해 1.0 내지 2.0 당량이 바람직하다. 반응 온도는 상온에서 환류 범위이며 불순물의 생성과 반응속도를 고려하여 60℃ 내지 80℃ 이 바람직하다. 반응 완료 후 반응용매를 감압증류하여 제거하고 추출용매로 톨루엔 또는 에틸아세테이트를 사용하여 추출할 수 있다. 이후, 수산화나트륨 수용액 및 염산 수용액에서 세척한 후 추출용매를 감압증류하면 고순도의 화학식 2 화합물을 수득할 수 있다. In the oxazolidinone decarboxylation reaction in the fourth step, the compound of Formula 3 of the oxazolidinone structure is reacted with the nitrogen source compound to be decyclized to obtain the compound of Formula 2 as an amide compound. At this time, as the reaction solvent, a solvent selected from the group consisting of t-butyl alcohol, methyl alcohol, ethyl alcohol, n-butyl alcohol and n-propanol can be used. Preferably, the reaction rate is shortened and the generation of impurities is minimized Isopropyl alcohol can be used. It is preferable to use ammonia water (concentration of 25% to 30%) as the nitrogen source compound. The amount of the nitrogen source compound used is 1.0 fold (fold: ml / g) or more and preferably 1.2 to 1.5 folds Ammonia gas may also be used, and the amount of the ammonia gas to be used is preferably 1.0 to 2.0 equivalents based on the compound of formula (2). The reaction temperature is a reflux range at room temperature and is preferably 60 to 80 ° C in consideration of the formation of impurities and the reaction rate. After completion of the reaction, the reaction solvent may be distilled off under reduced pressure, and extracted with toluene or ethyl acetate as an extraction solvent. Thereafter, the compound is washed with an aqueous solution of sodium hydroxide and an aqueous solution of hydrochloric acid, and the extracting solvent is distilled off under reduced pressure to obtain a compound of the formula (2) with high purity.
이하 제조예 및 실시예를 통하여 본 발명을 더욱 상세하게 설명하지만, 본 발명의 이해를 돕기 위한 것일 뿐, 어떤 의미로든 본 발명의 범위가 이들에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following Preparation Examples and Examples, but the present invention is not limited thereto in any sense.
본 발명에 따른 제조방법은, DPP-IV 억제를 통한 경구용 인슐린 비의존성 당뇨병 치료제 중간체인 상기 화학식 2 화합물을, 1) 옥사졸리디논 고리화 반응 및 아마이드로 전환하는 탈고리화 반응을 통해 높은 순도로 생산할 수 있고, 2) 제조공정의 안정화를 통해 수율 증가 및 생산성 증대가 가능하며, 그리고 3) 값싼 시료의 출발물질을 사용하여 원재료비 절감 등의 개선효과를 성취할 수 있다는 장점을 가져 매우 유용하다.The preparation method according to the present invention is a process for preparing a compound of the formula (2), which is an intermediate for the treatment of non-insulin dependent diabetes mellitus through DPP-IV inhibition, by: 1) deprotecting by oxazolidinone cyclization and amide, , 2) it is possible to increase the yield and productivity by stabilizing the production process, and 3) it is possible to achieve the improvement effects such as reduction of the raw material cost by using the starting material of the inexpensive sample, which is very useful .
실시예 1: N-(t-부톡시카보닐)-L-아스파틱산 (N-(tert-butoxycarbonyl)-L-aspartic acid)의 합성 Example 1: Synthesis of N- (t-butoxycarbonyl) -L-aspartic acid (N- (tert-butoxycarbonyl) -L-aspartic acid)
출발물질 L-아스파틱산 500 kg, 이소프로필알콜 785 kg, H2O 250 kg, 트라이에틸아민 760.3 kg을 상온에서 반응기에 부가한 후, 40oC 반응 온도를 유지하면서 디-tert-부틸디카보네이트 901.9 kg을 천천히 적가 하였다. 반응이 완료된 후, 실온으로 냉각 하고, 메틸 tert-부틸메틸이써 (MTBE) 740 kg, 19.7 % NaOH 수용액을 pH가 9가 되도록 20 ℃ 이하의 온도를 유지하면서 적가하고 교반한 후 층분리 하였다. 수층을 tert-부틸메틸이써 1110 kg으로 한번 더 세척해주고 층분리 하였다. 17.9 % 염산 수용액을 pH가 약 3이 되도록 20 oC 이하의 온도를 유지하면서 적가하고 교반한 후 층분리하여 유기층은 감압 증류하여 표제화합물 832.3 kg을 제조하였다. (수율: 95%)The starting material L- lactic acids aspartate 500 kg, was added to isopropyl alcohol and 785 kg, H 2 O 250 kg , triethylamine reactor 760.3 kg at room temperature, while maintaining a reaction temperature of 40 o C di -tert- butyl dicarbonate 901.9 kg was slowly added dropwise. After completion of the reaction, the reaction mixture was cooled to room temperature, 740 kg of methyl tert-butyl methyl ether (MTBE) and 19.7% NaOH aqueous solution were added dropwise while maintaining the temperature below 20 ° C so that the pH was 9, and the mixture was then layered. The aqueous layer was washed once with 1110 kg of tert-butyl methyl ether and layered. A 17.9% hydrochloric acid aqueous solution was added dropwise thereto at a temperature of 20 ° C or lower to adjust the pH to about 3, and the mixture was stirred. The organic layer was separated by vacuum distillation to obtain 832.3 kg of the title compound. (Yield: 95%).
1H NMR (DMSO-d6, 300 MHz) δ 12.5 (br, 2 H), 6.97 (d, J = 8.4 Hz, 1 H), 4.24 (m, 1 H), 2.65 (dd, J = 16.3,5.6 Hz, 1 H), 2.50 (dd, J = 16.0, 7.9 Hz, 1 H), 1.36 (s, 9 H) 1 H), 4.24 (m, 1H), 2.65 (dd, J = 16.3, 5.6 (d, J = Hz, 1 H), 2.50 (dd, J = 16.0,7.9 Hz, 1H), 1.36 (s, 9 H)
실시예 2: 2-[(4S)-3-(t-부틸옥시카르보닐)-5-옥소-1,3-옥사졸란-4-일]아세트산 (2-[(4S)-3-(tert-butyloxycarbonyl)-5-oxo-1,3-oxazolan-4-yl]acetic acid )의 합성 Example 2: Synthesis of 2 - [(4S) -3- (tert-butyloxycarbonyl) -5-oxo-1,3-oxazolan-4- -butyloxycarbonyl) -5-oxo-1,3-oxazolan-4-yl] acetic acid)
실시예 1에서 제조된 출발물질 N-(t-부톡시카보닐)-L-아스파틱산 832.3 kg, 톨루엔 3294.6 kg, 에틸아세테이트 2118.2 kg, 포름알데히드 214.3 kg, 피리듐-p-톨루엔설포네이트 (PPTS) 9.44 kg 및 마그네슘설페이트 (MgSO4) 217.2 kg을 상온에서 투입한 후 승온하여 환류하에서 반응을 진행하였다. 이때 반응 중에 생성되는 물은 반응완결 및 수율에 영향을 미치기 때문에 Dean-stark 설비를 갖추고 실시하였다. 반응 완료 후 마그네슘설페이트를 여과하여 제거하고 여과액은 에틸아세테이트 762.5 kg과 15.5 % 암모늄클로라이드 수용액 879.8 kg을 사용하여 세척하여 층분리 하였다. 유기층은 물 737 kg을 사용하여 세척 및 층분리하고, 유기층은 감압증류한 후 농축액의 에틸아세테이트 함량을 고려하여 톨루엔/에틸아세테이트 혼합용매 비율 8 내지 9/1 (v/v)에서 재결정 공정을 실시하여 고체로 생성된 표제화합물을 여과하고 톨루엔으로 세척한 후 건조하여 표제화합물을 673.9 kg을 제조하였다. (수율: 77%)832.3 kg of the starting material N- (t-butoxycarbonyl) -L-aspartic acid prepared in Example 1, 3294.6 kg of toluene, 2118.2 kg of ethyl acetate, 214.3 kg of formaldehyde, ) And 217.2 kg of magnesium sulfate (MgSO 4 ) were charged at room temperature, and then the reaction was carried out under reflux. At this time, the water produced during the reaction was carried out with Dean-stark equipment since it affects the completion of the reaction and the yield. After completion of the reaction, the magnesium sulfate was removed by filtration, and the filtrate was separated by washing with 762.5 kg of ethyl acetate and 879.8 kg of 15.5% ammonium chloride aqueous solution. The organic layer was washed and layered using 737 kg of water and the organic layer was subjected to a recrystallization process at a toluene / ethyl acetate mixed solvent ratio of 8 to 9/1 (v / v) in consideration of the ethyl acetate content of the concentrate after distillation under reduced pressure The title compound was isolated by filtration, washed with toluene and dried to give 673.9 kg of the title compound. (Yield: 77%)
1H NMR (DMSO-d6, 500 MHz) δ 12.8 (br, 2 H), 5.42 (s, J = 1 H), 5.16 (s, 1 H), 4.41 (s, 1 H), 2.79 (m, 1 H), 1.47 (s, 9 H) 1 H NMR (DMSO-d 6, 500 MHz)? 12.8 (br, 2 H), 5.42 (s, J = 1 H), 5.16 1 H), 1.47 (s, 9 H)
실시예 3: t-부틸 (4S)-4-(t-부틸옥시카르보닐메틸)-5-옥소-1,3-옥사졸란-3-카르복실레이트 (tert-butyl (4S)-4-(tert-butyloxycarbonylmethyl)-5-oxo-1,3-oxazolane-3-carboxylate)의 합성Example 3: Synthesis of t-butyl (4S) -4- (tert-butyloxycarbonylmethyl) -5-oxo-1,3-oxazolone- tert-butyloxycarbonylmethyl) -5-oxo-1,3-oxazolane-3-carboxylate
반응기에, 실시예 2에서 제조된 2-[(4S)-3-(t-부틸옥시카르보닐)-5-옥소-1,3-옥사졸란-4-일]아세트산 650 kg, t-부틸알콜 906.8 kg 및 4-디메틸아미노피리딘 (DMAP) 32.4 kg을 투입하고 40oC에서 디-tert-부틸디카보네이트 578.5 kg을 천천히 적가한 후 45~55oC 범위로 승온하여 1시간 이상 교반하였다. 반응종료 확인을 위한 분석을 실시한 후 완결되지 않을 경우 디-tert-부틸디카보네이트를 추가 투입하여 반응을 완료시켰다. 반응완료 후 감압증류하여 t-부틸알콜을 제거하고 t-부틸알콜이 증류되면서 냉각 콘덴서에 t-부틸알콜 결정이 생성되는 것을 막기 위해 에틸아세테이트 350 kg을 투입 후 감압증류를 완료한 후 에틸아세테이트 1750 kg을 투입하고 25 oC 이하에서 5.3 % 암모늄클로라이드 수용액을 투입한 후 교반을 실시하고 층분리하여 유기층을 감압증류를 실시하여 얻은 표제 화합물은 바로 다음 반응단계에 사용하였다. 650 kg of 2 - [(4S) -3- (t-butyloxycarbonyl) -5-oxo-1,3-oxazolan-4-yl] acetic acid prepared in Example 2, And DMAP (32.4 kg) were added. Then, 578.5 kg of di-tert-butyl dicarbonate was slowly added dropwise at 40 ° C, and the temperature was raised to 45-55 ° C and the mixture was stirred for 1 hour or more. After completion of the reaction for confirming the completion of the reaction, if not completed, the reaction was completed by addition of di-tert-butyl dicarbonate. After completion of the reaction, the reaction mixture was distilled under reduced pressure to remove t-butyl alcohol. In order to prevent the formation of t-butyl alcohol crystals in the cooling condenser due to the distillation of t-butyl alcohol, 350 kg of ethyl acetate was added. After vacuum distillation, ethyl acetate 1750 kg, and 5.3% ammonium chloride aqueous solution was added at 25 ° C or lower. The mixture was stirred and separated, and the organic layer was subjected to vacuum distillation. The title compound was used in the next reaction step.
DP09: 1H NMR (400 MHz, DMSO-d6) δ 1.44 (s, 9H), 1.54 (s, 9H), 2.96 (m, 1H), 4.41 (s, 1H), 5.27, (d, J=4.0 Hz, 1H), 5.41 (d, J=4.0 Hz, 1H). DP09: 1 H NMR (400 MHz , DMSO-d 6) δ 1.44 (s, 9H), 1.54 (s, 9H), 2.96 (m, 1H), 4.41 (s, 1H), 5.27, (d, J = 4.0 Hz, 1 H), 5.41 (d, J = 4.0 Hz, 1 H).
실시예 4: t-부틸 (3S)-3-부톡시카르보닐아미노-3-카르보닐프로판노에이트 (tert-butyl (3S)-3-butoxycarbonylamino-3-carbonylpropaneoate)의 합성Example 4 Synthesis of t-butyl (3S) -3-butoxycarbonylamino-3-carbonylpropanoate (tert-butyl (3S) -3-butoxycarbonylamino-3-carbonylpropaneoate)
실시예 3에서 얻은 t-부틸 (4S)-4-(t-부틸옥시카르보닐메틸)-5-옥소-1,3-옥사졸란-3-카르복실레이트와 이소프로필알콜 2824.4 kg 및 28 % 암모니아수용액 719.6 kg을 투입한 후 70 oC에서 5시간 이상 교반하였다. 반응 완료 후 감압증류를 실시하고 농축액에 에틸아세테이트 2075.5 kg을 투입하여 교반한 후 정제수 650 kg, 에틸아세테이트 125 kg, 3.84 % 수산화나트륨 수용액 325 kg을 투입/교반/정치후 층분리하고 유기층은 정제수 650 kg, 3.6 % 염산 수용액 324.7 kg으로 세척 후 층분리 및 농축을 실시하여 표제화합물을 580.8 kg을 얻었다. (최종 수율: 76%) (4S) -4- (t-butyloxycarbonylmethyl) -5-oxo-1,3-oxazolone-3-carboxylate obtained in Example 3, 2824.4 kg of isopropyl alcohol and 28% 719.6 kg of aqueous solution was added thereto, followed by stirring at 70 ° C for 5 hours or more. After completion of the reaction, distillation under reduced pressure was carried out. 2075.5 kg of ethyl acetate was added to the concentrate, and the mixture was stirred. Then, 650 kg of purified water, 125 kg of ethyl acetate and 325 kg of 3.84% aqueous sodium hydroxide solution were added / kg, 3.6% aqueous hydrochloric acid solution (324.7 kg), followed by layer separation and concentration to obtain 580.8 kg of the title compound. (Final yield: 76%)
DP56: 1H NMR (400 MHz, CDCl3) δ 1.29 (s, 18H), 2.64 (dd, J=6.0, 16.8 Hz, 1H), 2.83 (dd, J=5.2, 16.4 Hz, 1H), 4.48 (bs, 1H), 5.79 (br d, J=7.6 Hz, 1H), 6.06 (bs, 1H), 6.63 (bs, 1H). DP56: 1 H NMR (400 MHz , CDCl 3) δ 1.29 (s, 18H), 2.64 (dd, J = 6.0, 16.8 Hz, 1H), 2.83 (dd, J = 5.2, 16.4 Hz, 1H), 4.48 ( bs, 1H), 5.79 (br d, J = 7.6 Hz, 1H), 6.06 (bs, 1H), 6.63 (bs, 1H).
Claims (17)
2) 단계 1)에서 생성된 화학식 5의 화합물에 산 촉매 하에서 축합반응을 통한 고리화 반응을 통해 화학식 4 화합물을 수득하는 단계;
3) 단계 2)에서 생성된 화학식 4 화합물의 카르복시산기에 보호기 P2를 도입하여 상기 카르복시산기를 에스테르기로 전환시켜 화학식 3 화합물을 수득하는 단계; 및
4) 단계 3)에서 생성된 화학식 3 화합물의 질소원료 화합물과 반응시켜 옥사졸리디논 탈고리화를 통해 화학식 2의 아미드 화합물을 수득하는 단계,
를 포함하는 화학식 2 화합물의 제조방법:
[화학식 6]
[화학식 5]
[화학식 4]
[화학식 3]
[화학식 2]
상기 식에서,
P1은 아민 보호기로서 카르보닐기, 아실기, 술포닐기, 아세틸 또는 벤질기이고,
P2는 카르복시산 보호기이다. 1) introducing a protecting group P < 1 > into the amine group of the compound of formula 6 to obtain a compound of formula 5 wherein the amine group is protected;
2) obtaining a compound of formula (IV) via a cyclization reaction by condensation reaction of the compound of formula (5) produced in step 1) with an acid catalyst;
3) introducing a protecting group P 2 into the carboxylic acid group of the compound of formula 4 produced in step 2) to convert the carboxylic acid group into an ester group to obtain a compound of formula 3; And
4) reacting the compound of formula 3 with a nitrogen source compound produced in step 3) to obtain an amide compound of formula 2 via oxazolidinone decarboxylation,
: ≪ / RTI >
[Chemical Formula 6]
[Chemical Formula 5]
[Chemical Formula 4]
(3)
(2)
In this formula,
P 1 is an amine protecting group such as a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group,
P 2 is a carboxylic acid protecting group.
(1) 파라포름알데히드 (paraformaldehyde); 산 촉매로서 파라톨로엔설폰산 (p-TsOH)-H2O; 및 반응 용매로서 톨루엔 또는 에틸아세테이트-벤젠을 사용하거나, 또는
(2) 파라포름알데히드 (paraformaldehyde); 산 촉매로서 피리듐-p-톨루엔설포네이트 (PPTS, Pyridium-p-toluenesulfonate); 및 반응 용매로서 톨루엔-에틸아세테이트를 사용하는 것을 특징으로 하는, 제조방법. The method according to claim 1, wherein the step (2)
(1) paraformaldehyde; Paratoluenesulfonic acid (p-TsOH) -H 2 O as an acid catalyst; And toluene or ethyl acetate-benzene as the reaction solvent, or
(2) paraformaldehyde; Pyridium- p -toluenesulfonate (PPTS, Pyridium- p- toluenesulfonate) as an acid catalyst; And toluene-ethyl acetate is used as a reaction solvent.
[화학식 4]
상기 식에서,
P1은 카르보닐기, 아실기, 술포닐기, 아세틸 또는 벤질기를 나타낸다.A compound of formula 4:
[Chemical Formula 4]
In this formula,
P 1 represents a carbonyl group, an acyl group, a sulfonyl group, an acetyl or a benzyl group.
[화학식 3]
상기 식에서.
P1은 카르보닐기, 아실기, 술포닐기, 아세틸 또는 벤질기이고;
P2는 벤질기, 메틸기, 에틸기, i-프로필기 또는 t-부틸기를 나타낸다.A compound of formula (3)
(3)
Gt;
P 1 is a carbonyl group, an acyl group, a sulfonyl group, an acetyl or benzyl group;
P 2 represents a benzyl group, a methyl group, an ethyl group, an i-propyl group or a t-butyl group.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2018/011565 WO2019066578A1 (en) | 2017-09-28 | 2018-09-28 | Process for preparing intermediate compound for pharmaceutical synthesis |
| PE2020000587A PE20201169A1 (en) | 2017-09-28 | 2018-09-28 | METHOD OF PRODUCTION OF AN INTERMEDIATE COMPOUND TO SYNTHESIZE A MEDICINAL PRODUCT |
| BR112020006063-1A BR112020006063B1 (en) | 2017-09-28 | 2018-09-28 | METHOD FOR PREPARING AN INTERMEDIATE COMPOUND FOR SYNTHESISTING ANTIDIABETTIC DRUGS |
| RU2020114741A RU2742765C1 (en) | 2017-09-28 | 2018-09-28 | Method for preparing intermediate compound for synthesis of medicinal agent |
| MX2020003543A MX2020003543A (en) | 2017-09-28 | 2018-09-28 | Process for preparing intermediate compound for pharmaceutical synthesis. |
| CL2020000807A CL2020000807A1 (en) | 2017-09-28 | 2020-03-27 | Production method of an intermediate compound to synthesize a drug. |
| PH12020550170A PH12020550170A1 (en) | 2017-09-28 | 2020-03-27 | Production method of intermediate compound for synthesizing medicament |
| CONC2020/0005226A CO2020005226A2 (en) | 2017-09-28 | 2020-04-27 | Production method of an intermediate compound to synthesize a drug |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20170126119 | 2017-09-28 | ||
| KR1020170126119 | 2017-09-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20190037172A true KR20190037172A (en) | 2019-04-05 |
| KR102152445B1 KR102152445B1 (en) | 2020-09-04 |
Family
ID=66104057
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020180115838A KR102152445B1 (en) | 2017-09-28 | 2018-09-28 | Production method of intermediate compound for synthesizing medicament |
Country Status (8)
| Country | Link |
|---|---|
| KR (1) | KR102152445B1 (en) |
| CN (1) | CN111164071A (en) |
| BR (1) | BR112020006063B1 (en) |
| CL (1) | CL2020000807A1 (en) |
| CO (1) | CO2020005226A2 (en) |
| PE (1) | PE20201169A1 (en) |
| PH (1) | PH12020550170A1 (en) |
| RU (1) | RU2742765C1 (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120060139A (en) * | 2010-09-03 | 2012-06-11 | 주식회사 엘지생명과학 | Production method of intermediate compound for synthesizing medicament |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6267097A (en) * | 1985-09-18 | 1987-03-26 | Nippon Kayaku Co Ltd | Novel process for production of alpha-aspartyl-phenylalanine ester |
| IT1248486B (en) * | 1990-05-24 | 1995-01-19 | Roberto Pellicciari | THERAPEUTIC AGENT ACTIVITIES ON THE CENTRAL NERVOUS SYSTEM |
| EP1745784A1 (en) * | 2005-06-27 | 2007-01-24 | Ferrer Internacional, S.A. | Oxazolidinone derivatives and use thereof as antibiotics |
| US8524936B2 (en) * | 2011-05-18 | 2013-09-03 | Milan Soukup | Manufacturing process for sitagliptin from L-aspartic acid |
-
2018
- 2018-09-28 KR KR1020180115838A patent/KR102152445B1/en active IP Right Grant
- 2018-09-28 BR BR112020006063-1A patent/BR112020006063B1/en active IP Right Grant
- 2018-09-28 CN CN201880063056.8A patent/CN111164071A/en active Pending
- 2018-09-28 PE PE2020000587A patent/PE20201169A1/en unknown
- 2018-09-28 RU RU2020114741A patent/RU2742765C1/en active
-
2020
- 2020-03-27 CL CL2020000807A patent/CL2020000807A1/en unknown
- 2020-03-27 PH PH12020550170A patent/PH12020550170A1/en unknown
- 2020-04-27 CO CONC2020/0005226A patent/CO2020005226A2/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20120060139A (en) * | 2010-09-03 | 2012-06-11 | 주식회사 엘지생명과학 | Production method of intermediate compound for synthesizing medicament |
Non-Patent Citations (4)
| Title |
|---|
| Synthesis, 1991, 1991권, 11호, 페이지 935-936* * |
| Tetrahedron Letters, 1993, 34권, 46호, 페이지 7409-7412* * |
| Tetrahedron Letters, 2001, 42권, 페이지 5319-5321* * |
| The Journal of Organic Chemistry, 2011, 76권, 페이지 6825-6831* * |
Also Published As
| Publication number | Publication date |
|---|---|
| BR112020006063B1 (en) | 2024-01-16 |
| CO2020005226A2 (en) | 2020-06-09 |
| BR112020006063A2 (en) | 2020-09-29 |
| PE20201169A1 (en) | 2020-10-28 |
| KR102152445B1 (en) | 2020-09-04 |
| PH12020550170A1 (en) | 2021-03-01 |
| CN111164071A (en) | 2020-05-15 |
| CL2020000807A1 (en) | 2020-08-07 |
| RU2742765C1 (en) | 2021-02-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2510395C2 (en) | Method of producing docetaxel | |
| EP3481201B1 (en) | Processes for the preparation of 4-alkoxy-3-(acyl or alkyl)oxypicolinamides | |
| RU2730006C1 (en) | Method of producing 5r-[(benzyloxy)amino]piperidine-2s-carboxylic acid or derivative thereof | |
| CN114031543A (en) | Preparation method of intermediate of palovaried | |
| TWI438188B (en) | Production method of intermediate compound for synthesizing medicament | |
| CN114478690A (en) | Preparation method of 6, 6-dimethyl-3-azabicyclo [3.1.0] hexane derivative | |
| JP5548129B2 (en) | Asymmetric organic catalyst | |
| US9771317B2 (en) | Process for preparing lacosamide and related compounds | |
| KR102068754B1 (en) | Production Method of Intermediate Compound for Synthesizing Medicament | |
| JP6781030B2 (en) | L-carnosine derivative or salt thereof, and method for producing L-carnosine or salt thereof | |
| KR102152445B1 (en) | Production method of intermediate compound for synthesizing medicament | |
| CN114591299A (en) | Paroviride intermediate and preparation and application thereof | |
| RU2362766C2 (en) | Method of obtaining benzylamine derivative and acylbenzylamine derivative | |
| WO2019066578A1 (en) | Process for preparing intermediate compound for pharmaceutical synthesis | |
| JP5704763B2 (en) | Production of trans-4-aminocyclopent-2-ene-1-carboxylic acid derivative | |
| JP5191385B2 (en) | Succinic acid diester derivative, process for its preparation and use of said derivative in pharmaceutical manufacture | |
| KR0136706B1 (en) | Process for 3-amino pyrrolidine derivatives | |
| KR102589305B1 (en) | Improved manufacturing method of sitagliptin phosphate salt | |
| WO2024092892A1 (en) | Edoxaban intermediate and preparation method therefor | |
| JP5279449B2 (en) | Process for producing 5- {4- [2- (5-ethyl-2-pyridyl) ethoxy] benzyl} -2,4-thiazolidinedione hydrochloride | |
| Mohalid et al. | Chemical exploration of 4-hydroxybenzylated 3-substituted tetramic acid | |
| KR100566896B1 (en) | Processes for the preparation of an optically active 5,6-dioxopiperazine-2-carboxylic acid derivative | |
| US20080242861A1 (en) | Synthesis of amino-protected cyclohexane-1,4-diyldimethanamine and its derivatives | |
| US20100010225A1 (en) | Isoquinuclidine derivative and method for manufacturing 1-cyclohexene-1-carboxylic acid derivative using the same | |
| JP2018131415A (en) | Method for producing l-carnosine derivative and its salt |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant |