KR20010081367A - Process for producing Alanine derivatives - Google Patents
Process for producing Alanine derivatives Download PDFInfo
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- KR20010081367A KR20010081367A KR1020000006759A KR20000006759A KR20010081367A KR 20010081367 A KR20010081367 A KR 20010081367A KR 1020000006759 A KR1020000006759 A KR 1020000006759A KR 20000006759 A KR20000006759 A KR 20000006759A KR 20010081367 A KR20010081367 A KR 20010081367A
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- indanylglycine
- alanine
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- 238000000034 method Methods 0.000 title claims description 6
- 150000001294 alanine derivatives Chemical class 0.000 title abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims abstract description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 7
- GKQLYSROISKDLL-UHFFFAOYSA-N EEDQ Chemical group C1=CC=C2N(C(=O)OCC)C(OCC)C=CC2=C1 GKQLYSROISKDLL-UHFFFAOYSA-N 0.000 claims description 6
- 239000007822 coupling agent Substances 0.000 claims description 6
- TYRGLVWXHJRKMT-QMMMGPOBSA-N n-benzyloxycarbonyl-l-serine-betalactone Chemical compound OC(=O)[C@H](C)NC(=O)OCC1=CC=CC=C1 TYRGLVWXHJRKMT-QMMMGPOBSA-N 0.000 claims description 5
- LPBHYOYZZIFCQT-UHFFFAOYSA-N 2-methylpropyl 2-(2-methylpropoxy)-2h-quinoline-1-carboxylate Chemical compound C1=CC=C2N(C(=O)OCC(C)C)C(OCC(C)C)C=CC2=C1 LPBHYOYZZIFCQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 7
- 206010020772 Hypertension Diseases 0.000 abstract description 2
- 238000007796 conventional method Methods 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940124597 therapeutic agent Drugs 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 229960003767 alanine Drugs 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000006227 byproduct Substances 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- -1 indanylglycine ethyl ester Chemical compound 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical group 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- IRFSXVIRXMYULF-UHFFFAOYSA-N 1,2-dihydroquinoline Chemical compound C1=CC=C2C=CCNC2=C1 IRFSXVIRXMYULF-UHFFFAOYSA-N 0.000 description 1
- MKFDYOISVJDNKS-UHFFFAOYSA-N 2-(2,3-dihydro-1h-inden-1-ylamino)acetic acid Chemical compound C1=CC=C2C(NCC(=O)O)CCC2=C1 MKFDYOISVJDNKS-UHFFFAOYSA-N 0.000 description 1
- JOXAGILIYGVOIN-QHGLUPRGSA-N 2-[[(2s)-2-aminopropanoyl]-(2,3-dihydro-1h-inden-1-yl)amino]acetic acid Chemical compound C1=CC=C2C(N(CC(O)=O)C(=O)[C@@H](N)C)CCC2=C1 JOXAGILIYGVOIN-QHGLUPRGSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 229940058961 hydroxyquinoline derivative for amoebiasis and other protozoal diseases Drugs 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
Classifications
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- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K31/00—Actuating devices; Operating means; Releasing devices
- F16K31/02—Actuating devices; Operating means; Releasing devices electric; magnetic
- F16K31/06—Actuating devices; Operating means; Releasing devices electric; magnetic using a magnet, e.g. diaphragm valves, cutting off by means of a liquid
- F16K31/0644—One-way valve
- F16K31/0655—Lift valves
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K27/00—Construction of housing; Use of materials therefor
- F16K27/02—Construction of housing; Use of materials therefor of lift valves
- F16K27/029—Electromagnetically actuated valves
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F16—ENGINEERING ELEMENTS AND UNITS; GENERAL MEASURES FOR PRODUCING AND MAINTAINING EFFECTIVE FUNCTIONING OF MACHINES OR INSTALLATIONS; THERMAL INSULATION IN GENERAL
- F16K—VALVES; TAPS; COCKS; ACTUATING-FLOATS; DEVICES FOR VENTING OR AERATING
- F16K31/00—Actuating devices; Operating means; Releasing devices
- F16K31/02—Actuating devices; Operating means; Releasing devices electric; magnetic
- F16K31/06—Actuating devices; Operating means; Releasing devices electric; magnetic using a magnet, e.g. diaphragm valves, cutting off by means of a liquid
- F16K31/08—Actuating devices; Operating means; Releasing devices electric; magnetic using a magnet, e.g. diaphragm valves, cutting off by means of a liquid using a permanent magnet
-
- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01F—MAGNETS; INDUCTANCES; TRANSFORMERS; SELECTION OF MATERIALS FOR THEIR MAGNETIC PROPERTIES
- H01F7/00—Magnets
- H01F7/06—Electromagnets; Actuators including electromagnets
- H01F7/08—Electromagnets; Actuators including electromagnets with armatures
- H01F7/16—Rectilinearly-movable armatures
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- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Mechanical Engineering (AREA)
- Physics & Mathematics (AREA)
- Electromagnetism (AREA)
- Peptides Or Proteins (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
본 발명은 고혈압 치료제인 염산 델라프릴의 제조에 유용한 중간체인 하기 화학식(1)의 알라닌 유도체의 제조방법에 관한 것이다:The present invention relates to a process for preparing an alanine derivative of formula (1) which is an intermediate useful for the preparation of delaapril hydrochloride, a therapeutic agent for hypertension:
상기 식에서, R은 에틸 또는 t-부틸기를 나타낸다.Wherein R represents an ethyl or t-butyl group.
또한 본 발명은 종래 방법들에 비해, 상온에서 반응의 진행이 가능하고, 고수율로 제조할 수 있으며, 또한 재현성이 뛰어나 상업생산이 매우 용이한 제조방법이다.In addition, the present invention, compared to the conventional methods, the reaction can be carried out at room temperature, can be produced in high yield, and also has excellent reproducibility and is a very easy production method.
Description
본 발명은 고혈압 치료제인 염산 델라프릴의 제조에 유용한 중간체인 하기 화학식(1)의 구조를 갖는 알라닌 유도체의 제조방법에 관한 것이다:The present invention relates to a method for preparing an alanine derivative having the structure of formula (1), which is an intermediate useful for the preparation of delaapril hydrochloride, a therapeutic agent for hypertension:
상기 식에서, R은 알킬기이고, 에틸 또는 t-부틸기로 대표된다.Wherein R is an alkyl group and is represented by ethyl or t-butyl group.
알라닌 유도체를 제조하기 위한 여러가지 실험이 보고되어 있다.Various experiments have been reported for preparing alanine derivatives.
USP 4385051호에는 하기 반응식과 같이 인다닐글리신 에틸에스테르와 N-카르보벤질옥시-L-알라닌을 커플링제(coupling agent)로서 이소부틸 클로로포르메이트를 사용하여 반응시켜 화학식(1)의 N-카르보벤질옥시-L-알라닐-N-인다닐글리신 에틸에스테르를 제조하는 방법이 기재되어 있다:USP 4385051 reacts indanylglycine ethyl ester with N-carbobenzyloxy-L-alanine using isobutyl chloroformate as a coupling agent as shown in the following reaction scheme to form N-carramide of formula (1). A process for preparing bobenzyloxy-L-alanyl-N-indanilglycine ethylester is described:
또한 일본특허 공개공보 57-179414호에는 인다닐글리신 t-부틸에스테르와 N-카르보벤질옥시-L-알라닌을 커플링제로서 에틸 클로로포르메이트를 사용하여 반응시켜 N-카르보벤질옥시-L-알라닐-N-인다닐글리신 t-부틸에스테르를 제조하는 방법이 기재되어 있다.In addition, Japanese Patent Laid-Open No. 57-179414 discloses indanylglycine t-butylester and N-carbobenzyloxy-L-alanine by using ethyl chloroformate as a coupling agent to react N-carbenzyloxy-L- A process for preparing alanyl-N-indanylglycine t-butylester is described.
클로로포르메이트 유도체를 사용한 펩티드 유도체의 제조방법은 여러 논문 및 특허에서 일반적으로 사용되는 방법으로 알려져 왔으나, 상기 화학식(1)의 N-카르보벤질옥시-L-알라닐-N-인다닐글리신 에스테르 유도체를 경우에 있어서는 다음과 같은 여러 가지 문제점을 가지고 있다.A method for preparing a peptide derivative using a chloroformate derivative has been known as a method generally used in various papers and patents, but the N-carbenzyloxy-L-alanyl-N-indanilglycine ester of the formula (1) In the case of the derivative, there are various problems as follows.
즉, 용매에 대한 인다닐 유도체의 용해도가 낮아 반응 용매로 메탄올 또는 에탄올을 사용해야 하기 때문에 에틸 클로로포르메이트나 이소부틸 클로로포르메이트의 안정성이 저하되어 부생성물이 다량 생성되어 수율이 낮고, 반응 중에 생성되는 염산을 중화하기 위해 4급 아민의 사용시 사용량 및 투입 시점을 정확히 조절해야 하기 때문에 반응상의 재현성이 떨어지게 되는 단점이 있으며, 또한 클로로포르메이트 유도체의 낮은 안정성을 보완하기 위해 0℃ 이하의 낮은 온도에서 반응을 시켜야 하기 때문에 경제성이 떨어지는 문제점을 가지고 있다.That is, since the solubility of the indanyl derivative in the solvent is low, methanol or ethanol should be used as the reaction solvent, the stability of ethyl chloroformate or isobutyl chloroformate is lowered, so that a large amount of by-products are produced, and the yield is low. The use of quaternary amines in order to neutralize the hydrochloric acid is required to precisely control the amount of use and the timing of the input, there is a disadvantage that the reproducibility of the reaction is poor, and also to compensate for the low stability of the chloroformate derivative at a low temperature below 0 ℃ It has a problem of low economic feasibility because it has to react.
이에, 본 발명자는 상기 종래기술의 문제점을 해결하고자 연구를 거듭한 결과, 히드로퀴놀린계 화합물을 커플링제로 사용하여 알라닌 유도체를 제조할 경우, 안정성의 증가로 인해 수율이 높고, 반응 중 생성되는 부산물을 반응계로부터 쉽게 제거할 수 있으며, 또한 별도의 4급 아민을 사용하지 않아도 반응이 효과적으로 진행된다는 것을 발견하여 본 발명을 완성하였다.Thus, the present inventors conducted a study to solve the problems of the prior art, when producing an alanine derivative using a hydroquinoline-based compound as a coupling agent, the yield is high due to increased stability, by-products generated during the reaction The present invention was completed by finding that the reaction can be easily removed from the reaction system and that the reaction proceeds effectively without using a quaternary amine.
따라서, 본 발명의 목적은 상기 화학식(1)의 알라닌 유도체 제조에 유용한 제조방법을 제공하는 것이다.Accordingly, it is an object of the present invention to provide a preparation method useful for preparing alanine derivatives of the above formula (1).
본 발명은 하기 화학식(2)의 인다닐글리신 알킬에스테르와 화학식(3)의 N-카르보벤질옥시-L-알라닌을 커플링제로서 히드록시퀴놀린 유도체를 사용하여 반응시켜 하기 화학식(1)의 알라닌 유도체인 N-카르보벤질옥시-L-알라닐-N-인다닐글리신 알킬에스테르를 제조하는 방법에 관한 것이다.The present invention is obtained by reacting an indanylglycine alkyl ester of formula (2) with N-carbobenzyloxy-L-alanine of formula (3) using a hydroxyquinoline derivative as a coupling agent to produce alanine of formula (1) The present invention relates to a method for producing an N-carbobenzyloxy-L-alanyl-N-indanylglycine alkyl ester as a derivative.
본 발명에 의해 알라닌 유도체를 제조하는 방법은 하기 반응식과 같다:The process for preparing alanine derivatives according to the present invention is shown in the following scheme:
상기 식에서, R은 에틸 또는 t-부틸기를 나타낸다.Wherein R represents an ethyl or t-butyl group.
상기 반응에서 커플링제로 사용되는 히드록시퀴놀린 유도체는 1-에톡시카르보닐-2-에톡시-1,2-디히드로퀴놀린(EEDQ) 또는 1-이소부틸옥시카르보닐-2-이소부틸옥시-1,2-디히드로퀴놀린(IIDQ)을 사용하는 것이 바람직하다.The hydroxyquinoline derivative used as the coupling agent in the reaction is 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) or 1-isobutyloxycarbonyl-2-isobutyloxy- Preference is given to using 1,2-dihydroquinoline (IIDQ).
또한 상기 반응에서 히드록시퀴놀린 유도체를 0.5 내지 3당량 사용하는 것이 바람직하며, 더욱 바람직하게는 1 내지 2당량을 사용하는 것이 좋다.It is also preferable to use 0.5 to 3 equivalents of hydroxyquinoline derivatives in the reaction, more preferably 1 to 2 equivalents.
또한 본 발명의 제조방법에 사용되는 용매로는 디메틸포름아미드, 테트라히드로푸란 및 염화메틸렌을 사용하는 것이 바람직하나, 본 발명에 제한된 것은 아니다.In addition, it is preferable to use dimethylformamide, tetrahydrofuran and methylene chloride as a solvent used in the production method of the present invention, but is not limited to the present invention.
상기 반응은 0 내지 100℃의 반응온도에서 약 5 내지 10시간 동안 수행하는 것이 바람직하고, 20 내지 40℃의 반응온도에서 8시간 동안 반응을 수행하는 것이 더욱 바람직하다.The reaction is preferably carried out at a reaction temperature of 0 to 100 ° C. for about 5 to 10 hours, and more preferably at 8 to 8 hours at a reaction temperature of 20 to 40 ° C.
상기 반응온도보다 온도가 낮으면 반응성이 떨어지고, 상기 반응온도보다 온도가 높으면 부반응이 일어나며, 또한 상기한 반응시간보다 시간이 짧으면 반응수율이 떨어지고, 상기 반응시간보다 시간이 길어지면 수율의 향상 없이 반응시간만 길어지므로 경제성이 떨어진다.If the temperature is lower than the reaction temperature, the reactivity decreases, and if the temperature is higher than the reaction temperature, a side reaction occurs, and if the time is shorter than the reaction time, the reaction yield drops, and if the time is longer than the reaction time, the reaction is not improved. It only takes longer, so it is less economical
반응이 완결되면, 물을 첨가하여 반응을 중지시키고, 층분리 및 감압증류를 통해 생성되는 고체를 여과한 후, 정제공정을 거쳐 고순도의 알라닌 유도체를 수득하게 된다.When the reaction is completed, water is added to stop the reaction, and the solid produced through layer separation and distillation under reduced pressure is filtered and then purified to obtain alanine derivative of high purity.
이하, 본 발명은 하기 실시예에 의해 상세히 설명될 것이나, 본 발명이 이에 한정되는 것은 아니다.Hereinafter, the present invention will be described in detail by the following examples, but the present invention is not limited thereto.
실시예 1: N-카르보벤질옥시-L-알라닐-N-인다닐글리신 t-부틸에스테르의 제조Example 1 Preparation of N-Carbobenzyloxy-L-alanyl-N-indanylglycine t-butylester
디메틸포름아미드 200ml에 인다닐글리신 t-부틸에스테르 33g, N-카르보벤질옥시-L-알라닌 31.7g 및 1-에톡시카르보닐-2-에톡시-1,2-디히드로퀴놀린(EEDQ) 33g을 첨가한 후, 상온에서 8시간 동안 반응시켰다. 반응이 완료되면, 반응용매를 감압증류하여 제거하고, 여기에 염화메틸렌 200ml와 10% 시트르산 수용액 100ml를 첨가한 후, 30분간 교반시킨 다음, 유기층을 분리해 내고, 5% 탄산나트륨 수용액 100ml 및 물 100ml로 세척하였다. 황산마그네슘으로 수분을 제거한 후, 용매를 감압하여 목적 화합물 52.3g을 얻었다(수율: 88%).33 g of indanylglycine t-butyl ester, 31.7 g of N-carbenzyloxy-L-alanine and 33 g of 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) in 200 ml of dimethylformamide After the addition, the reaction was carried out at room temperature for 8 hours. After the reaction was completed, the reaction solvent was removed by distillation under reduced pressure, 200 ml of methylene chloride and 100 ml of 10% citric acid solution were added thereto, followed by stirring for 30 minutes, and then the organic layer was separated, 100 ml of 5% aqueous sodium carbonate solution and 100 ml of water. Washed with. After the removal of water with magnesium sulfate, the solvent was depressurized to obtain 52.3 g of the target compound (yield: 88%).
IR 스펙트럼 υmax(cm-1): 1720, 1640IR spectrum max (cm -1 ): 1720, 1640
실시예 2: N-카르보벤질옥시-L-알라닐-N-인다닐글리신 에틸에스테르의 제조Example 2: Preparation of N-Carbobenzyloxy-L-alanyl-N-indanylglycine ethyl ester
염화메틸렌 200ml에 인다닐글리신 에틸에스테르 21.9g, N-카르보벤질옥시-L-알라닌 22.3g과 1-이소부틸옥시카르보닐-2-이소부틸옥시-1,2-디히드로퀴놀린(IIDQ) 30.3g을 첨가한 후, 상온에서 7시간 동안 반응시켰다. 반응이 완료되면, 10% 시트르산 수용액 100ml를 첨가한 후, 30분간 교반시킨 다음, 유기층을 분리해 내고, 5% 탄산나트륨 수용액 100ml 및 물 100ml로 세척하였다. 황산마그네슘으로 수분을 제거한 다음, 용매를 감압하여 목적 화합물 38.2g을 얻었다(수율: 90%).In 200 ml of methylene chloride, 21.9 g of indanylglycine ethyl ester, 22.3 g of N-carbobenzyloxy-L-alanine and 1-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ) 30.3 After the addition of g, it was reacted at room temperature for 7 hours. After the reaction was completed, 100 ml of 10% aqueous citric acid solution was added and stirred for 30 minutes, and then the organic layer was separated and washed with 100 ml of 5% aqueous sodium carbonate solution and 100 ml of water. Water was removed with magnesium sulfate, and then the solvent was distilled off to obtain 38.2 g of the target compound (yield: 90%).
IR 스펙트럼 υmax(cm-1): 1730, 1630IR spectrum max (cm -1 ): 1730, 1630
비교예 1: N-카르보벤질옥시-L-알라닐-N-인다닐글리신 t-부틸에스테르의 제조(일본특허 공개공보 57-179141호에 따라 제조)Comparative Example 1: Preparation of N-carbobenzyloxy-L-alanyl-N-indanylglycine t-butylester (prepared according to Japanese Patent Laid-Open No. 57-179141)
테트라히드로푸란 200ml에 N-카르보벤질옥시-L-알라닌 21.8g과 트리에틸아민 12.3ml를 넣고, -15℃로 냉각한 후, 이소부틸 클로로포르메이트 13.1ml를 서서히 적가하고, 30분 교반하였다. 여기에, 인다닐글리신 t-부틸에스테르 22g을 100ml의 클로로포름에 녹여 -10℃이하에서 적가한 후, 상온에서 2시간 동안 교반시켰다. 여기에 물 500ml를 첨가한 후, 30분간 교반시킨 다음, 유기층을 분리해 내고, 감압증류하여 생성물을 농축시켰다. 다시 에틸아세테이트 300ml에 녹이고, 5% 인산 수용액 100ml, 물 100ml 및 5% 탄산나트륨 수용액 200ml를 사용하여 세척한 후, 에틸아세테이트 층을 분리하였다. 황산마그네슘으로 수분을 제거한 다음, 용매를 감압하여 생성물 23.3g을 얻었다(수율: 58%).21.8 g of N-carbenzyloxy-L-alanine and 12.3 ml of triethylamine were added to 200 ml of tetrahydrofuran, and after cooling to -15 ° C, 13.1 ml of isobutyl chloroformate was slowly added dropwise and stirred for 30 minutes. . Herein, 22 g of indanylglycine t-butyl ester was dissolved in 100 ml of chloroform and added dropwise at −10 ° C. or lower, followed by stirring at room temperature for 2 hours. 500 ml of water was added thereto, stirred for 30 minutes, the organic layer was separated, and the product was concentrated under reduced pressure. The resultant was dissolved in 300 ml of ethyl acetate, washed with 100 ml of 5% phosphoric acid aqueous solution, 100 ml of water, and 200 ml of 5% sodium carbonate aqueous solution, and then the ethyl acetate layer was separated. Water was removed with magnesium sulfate, and then the solvent was distilled off to obtain 23.3 g of a product (yield: 58%).
비교예 2: N-카르보벤질옥시-L-알라닐-N-인다닐글리신 에틸에스테르의 제조(미국 특허 4385051호에 따라 제조)Comparative Example 2: Preparation of N-carbobenzyloxy-L-alanyl-N-indanylglycine ethyl ester (prepared according to US Patent 4385051)
테트라히드로푸란 200ml에 N-카르보벤질옥시-L-알라닌 22.3g과 트리에틸아민 14ml를 넣고, -10℃로 냉각한 후, 이소부틸 클로로메이트 13.1ml를 천천히 적가하고, 30분간 교반하였다. 인다닐글리신 에틸에스테르 24.1g과 트리에틸아민 14ml를 200ml의 클로로포름에 녹여 -10℃ 이하에서 적가한 후, 상온에서 밤새 방치시켰다. 여기에 물 500ml를 첨가한 후, 30분간 교반시킨 다음, 유기층을 분리해내고, 감압증류하여 생성물을 농축시켰다. 다시 에틸아세테이트 300ml에 녹이고, 10% 염산 수용액 100ml, 물 100ml 및 5% 탄산나트륨 수용액 200ml를 사용하여 세척한 후, 에틸아세테이트층을 분리하였다. 황산마그네슘으로 수분을 제거한 다음, 용매를 감압하여 얻은 생성물을 메탄올 100ml에 녹이고, 2N 수산화나트륨 수용액 75ml를 첨가하고, 상온에서 2시간 동안 교반시켰다. 이후, 10% 염산수용액을 사용하여 산성화시키고, 에틸아세테이트 500ml로 추출하여 얻은 유기층을 감압증류하여 최종 목적생성물 24.1g을 얻었다(수율 57%).22.3 g of N-carbenzyloxy-L-alanine and 14 ml of triethylamine were added to 200 ml of tetrahydrofuran, and after cooling to -10 degreeC, 13.1 ml of isobutyl chloromates were slowly added dropwise, and stirred for 30 minutes. 24.1 g of indanyl glycine ethyl ester and 14 ml of triethylamine were dissolved in 200 ml of chloroform and added dropwise at -10 占 폚 or lower, and then left at room temperature overnight. 500 ml of water was added thereto, followed by stirring for 30 minutes, and then the organic layer was separated and distilled under reduced pressure to concentrate the product. The resultant was dissolved in 300 ml of ethyl acetate, washed with 100 ml of 10% hydrochloric acid aqueous solution, 100 ml of water, and 200 ml of 5% sodium carbonate aqueous solution, and then the ethyl acetate layer was separated. After removing water with magnesium sulfate, the product obtained by depressurizing the solvent was dissolved in 100 ml of methanol, 75 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 2 hours. Thereafter, the resultant was acidified using an aqueous 10% hydrochloric acid solution, and the organic layer obtained by extraction with 500 ml of ethyl acetate was distilled under reduced pressure to obtain 24.1 g of a final target product (yield 57%).
본 발명은 종래 방법들에 비해, 상온에서 반응의 진행이 가능하고, 부산물의 생성이 적어 고수율로 제조가 가능하며, 또한 재현성이 뛰어나 상업생산이 매우 용이한 제조방법이다.Compared to the conventional methods, the present invention enables the reaction to proceed at room temperature, produces less by-products, and can be manufactured in high yield, and also has excellent reproducibility.
Claims (4)
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| KR1020000006759A KR20010081367A (en) | 2000-02-14 | 2000-02-14 | Process for producing Alanine derivatives |
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