KR102303635B1 - PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT - Google Patents
PROCESS FOR PREPARING (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol AND PHARMACEUTICALLY ACCEPTABLE SALT Download PDFInfo
- Publication number
- KR102303635B1 KR102303635B1 KR1020200081133A KR20200081133A KR102303635B1 KR 102303635 B1 KR102303635 B1 KR 102303635B1 KR 1020200081133 A KR1020200081133 A KR 1020200081133A KR 20200081133 A KR20200081133 A KR 20200081133A KR 102303635 B1 KR102303635 B1 KR 102303635B1
- Authority
- KR
- South Korea
- Prior art keywords
- bromo
- dimethylamino
- methoxyquinolin
- phenyl
- naphthyl
- Prior art date
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- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000004017 vitrification Methods 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B57/00—Separation of optically-active compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B63/00—Purification; Separation; Stabilisation; Use of additives
- C07B63/04—Use of additives
-
- 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pulmonology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Quinoline Compounds (AREA)
Abstract
Description
본 발명은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 이의 약제학적으로 허용 가능한 염의 제조방법에 관한 것이다. 구체적으로, 본 발명은 경제적인 제조공정과 높은 수율로 대량 생산이 가능한 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 이의 약제학적으로 허용 가능한 염의 제조방법에 관한 것이다.The present invention relates to (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2- It relates to a method for preparing ol and a pharmaceutically acceptable salt thereof. Specifically, the present invention provides (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- It relates to a method for preparing (1-naphthyl)-1-phenyl-butan-2-ol and a pharmaceutically acceptable salt thereof.
본 발명에 따른 제조방법은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 경제적인 제조공정과 높은 수율로 분리하는 방법을 포함한다.The preparation method according to the present invention is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- It includes an economical manufacturing process and a method for isolating butan-2-ol in high yield.
(1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올은 베다퀼린(bedaquiline)이라는 성분명으로 알려져 있으며 하기 화학식 A의 구조를 갖는다.(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol is veda It is known as a component name of quiline (bedaquiline) and has a structure of the following formula (A).
<화학식 A><Formula A>
베다퀼린은 결핵균(마이코박테리아)의 에너지 생산에 필수적인 ATP 합성효소를 특이적으로 억제하는 기전을 갖는 다제내성 결핵 치료제로 국제공개공보 제2004-011436호에 최초로 개시되어 있다.Bedaquiline is a multi-drug-resistant tuberculosis therapeutic agent having a mechanism of specifically inhibiting ATP synthase essential for energy production of Mycobacterium tuberculosis (mycobacteria), and was first disclosed in International Publication No. 2004-011436.
국제공개공보 제2004-011436호에는 3-벤질-6-브로모-2-메톡시퀴놀린과 3-(디메틸아미노)-1-(나프탈렌-1-일)프로판-1-온을 반응시켜 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올을 제조하는 다음의 방법이 공지되어 있다.In International Publication No. 2004-011436, 3-benzyl-6-bromo-2-methoxyquinoline is reacted with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one to 1- The following method for preparing (6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol is known has been
1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올은 두 개의 키랄성 중심을 가지므로 4개의 입체이성질체, 즉, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올이 존재한다. 1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol has two centers of chirality 4 stereoisomers, namely (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Phenyl-butan-2-ol, (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl -Butan-2-ol, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- Butan-2-ol, (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane -2-ol is present.
상기 4개의 입체이성질체 각각은 하나의 거울상 이성질체와 두 개의 부분입체 이성질체를 갖는다.Each of the four stereoisomers has one enantiomer and two diastereomers.
3-벤질-6-브로모-2-메톡시퀴놀린과 3-(디메틸아미노)-1-(나프탈렌-1-일)프로판-1-온을 반응시켜 얻어지는 4개의 입체이성질체 중 다제내성 결핵 치료제로 사용되는 물질은 베다퀼린, 즉, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올이므로, 반응 혼합물로부터 나머지 3개의 입체이성질체를 효과적으로 제거하는 공정이 필수적이라 할 수 있다.It is one of the four stereoisomers obtained by reacting 3-benzyl-6-bromo-2-methoxyquinoline with 3-(dimethylamino)-1-(naphthalen-1-yl)propan-1-one for the treatment of multidrug-resistant tuberculosis. The substance used is bedaquiline, ie (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Since it is phenyl-butan-2-ol, it can be said that a process for effectively removing the remaining three stereoisomers from the reaction mixture is essential.
국제공개공보 제2004-011436호에는 디아스테레오이성질체 A 및 디아스테레오이성질체 B의 혼합물로부터 디아스테레오이성질체 A를 컬럼 크로마토그래피 및 결정화에 의해 수득하는 방법이 공지되어 있다. 또한, 디아스테레오이성질체 A로부터 키랄 컬럼 크로마토그래피를 사용하여 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리하는 방법이 공지되어 있다. 그러나 컬럼 크로마토그래피를 사용한 정제 방법은 비용이 높으므로 대량 생산에 적합하지 않다.International Publication No. 2004-011436 discloses a method for obtaining diastereoisomer A from a mixture of diastereoisomer A and diastereoisomer B by column chromatography and crystallization. In addition, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph) from diastereoisomer A using chiral column chromatography Methods for isolating thyl)-1-phenyl-butan-2-ol are known. However, the purification method using column chromatography is expensive and not suitable for mass production.
화학학술지(J. Am. Chem. Soc. 2010, 132, 7905)에는 이트륨 복합체 등의 금속촉매를 사용한 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 입체선택적 합성 방법이 공지되어 있다. 그러나 해당 방법은 합성단계가 12단계로 길고 전체 수율이 5%로 매우 낮으며, 스케일이 mg 단위로 작아 대량 생산에 적용하기 어렵다.Chemical journal ( J. Am. Chem. Soc. 2010, 132, 7905) uses (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl) using a metal catalyst such as yttrium complex Methods for the stereoselective synthesis of -4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol are known. However, the method has a long synthesis step of 12 steps, and the overall yield is very low at 5%, and the scale is small in mg units, making it difficult to apply to mass production.
국제공개공보 제2006-125769호에는 키랄 4-하이드록시디나프토[2,1-d: 1', 2'-f][1,3,2]디옥사포스페핀 4-옥사이드 또는 그의 유도체를 분할제(resolution agent)로 사용하여 광학 분리함으로써 입체이성질체 혼합물로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리하는 방법이 공지되어 있다. 그러나 해당 방법은 결정화를 위해 반응 혼합물에 시드를 첨가하는 시딩 방법이 필요하고 순도를 높이기 위해 재결정을 실시하는 등 공정이 매우 번거롭고 생산 시간이 많이 소요되는 단점이 존재한다.International Publication No. 2006-125769 discloses chiral 4-hydroxydinaphtho [2,1-d: 1', 2'-f] [1,3,2] dioxaphosphepine 4-oxide or a derivative thereof (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1- Methods for isolating naphthyl)-1-phenyl-butan-2-ol are known. However, the method requires a seeding method of adding a seed to the reaction mixture for crystallization, and the process is very cumbersome and requires a lot of production time, such as recrystallization to increase purity.
따라서, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 상업적 규모로 대량 생산하기 위한 효과적인 제조방법이 요구된다.Thus, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol An effective manufacturing method is required for mass production on a commercial scale.
본 발명은 경제적이고 간편한 제조공정으로 제조하면서 동시에 높은 순도와 높은 수율로 제조할 수 있어 상업적 대량 생산에 적합한 베다퀼린, 즉, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 이의 약제학적으로 허용 가능한 염의 제조방법을 제공하는 것을 일 목적으로 한다.The present invention is bedaquiline suitable for commercial mass production because it can be manufactured with high purity and high yield while being manufactured by an economical and simple manufacturing process, that is, (1R,2S)-1-(6-bromo-2-methoxy An object of the present invention is to provide a method for preparing quinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a pharmaceutically acceptable salt thereof.
본 발명은 경제적이고 간편한 제조공정으로 제조하면서 동시에 높은 순도와 높은 수율로 제조할 수 있어 상업적 대량 생산에 적합한 베다퀼린, 즉, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리하는 방법을 제공하는 것을 일 목적으로 한다.The present invention is bedaquiline suitable for commercial mass production because it can be manufactured with high purity and high yield while being manufactured by an economical and simple manufacturing process, that is, (1R,2S)-1-(6-bromo-2-methoxy It is one object to provide a method for isolating quinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol.
본 발명은 키랄 옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 분할제로 사용하여, 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 광학 분리하는 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 분리방법을 제공한다.The present invention uses chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepine as a splitting agent, from a mixture of stereoisomers of 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol ( Optical separation of 1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol of (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol Separation method is provided.
일 실시예의 분리방법은 키랄 옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 분할제로 사용하므로 별도의 시딩 공정이 불요하다. 따라서, 공정 간소화가 달성되고 공정 비용이 절감될 수 있어 대량 생산에 적합하며 경제적이다.The separation method of one embodiment is a chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphosphepine as a splitting agent Therefore, a separate seeding process is unnecessary. Therefore, process simplification can be achieved and process costs can be reduced, which is suitable for mass production and economical.
일 실시예에서, 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물은 (1R, 2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, (1S, 2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, (1R, 2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S, 2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 포함할 수 있다.In one embodiment, 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol The stereoisomeric mixture is (1R, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 -ol, (1S, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2- ol, (1R, 2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1S, 2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol may include
이하, 본 명세서에서 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물은 부분입체 이성질체 A로, (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물은 부분입체 이성질체 B로 정의한다. 부분입체 이성질체 A에 포함된 두 개의 화합물은 서로 거울상 이성질체의 관계에 있고, 부분입체 이성질체 B에 포함된 두 개의 화합물은 서로 거울상 이성질체 관계에 있다. 부분입체 이성질체 A에 포함된 화합물들과 부분입체 이성질체 B에 포함된 화합물들은 서로 부분입체 이성질체 관계에 있다.Hereinafter, in the present specification (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- 2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 The mixture of -ols is diastereomer A, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- 1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 A mixture of -phenyl-butan-2-ols is defined as diastereomer B. Two compounds contained in diastereomer A are enantiomers of each other, and two compounds contained in diastereomer B are enantiomers of each other. Compounds contained in diastereomer A and compounds contained in diastereomer B are in a diastereomeric relationship with each other.
부분입체 이성질체 A는 라세미 혼합물일 수 있다. 부분입체 이성질체 B는 라세미 혼합물일 수 있다.Diastereomer A may be a racemic mixture. Diastereomer B may be a racemic mixture.
일 실시예에 따르면, 상기 입체이성질체 혼합물에서 상기 입체이성질체 혼합물의 전체 중량을 기준으로 한 부분입체 이성질체 A의 중량 비율은 약 90 중량% 이상일 수 있다. 그러나, 실시예가 이에 한정되는 것은 아니며 약 70 중량% 이상, 또는 약 80 중량% 이상일 수 있다.According to one embodiment, in the stereoisomer mixture, the weight ratio of diastereomer A based on the total weight of the stereoisomer mixture may be about 90% by weight or more. However, embodiments are not limited thereto, and may be about 70% by weight or more, or about 80% by weight or more.
일 실시예에서, 키랄 옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀은 하기 화학식 1로 표시될 수 있다.In one embodiment, chiral octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine is represented by Formula 1 can be displayed as
[화학식 1][Formula 1]
상기 화학식 1에서 R1 내지 R4는 각각 독립적으로 수소 원자, 중수소 원자, 할로겐 원자, 아릴기로 치환되거나 또는 비치환된 탄소수 1 이상 5 이하의 알킬기 또는 알킬기로 치환되거나 또는 비치환된 고리형성 탄소수 6 이상 12 이하의 아릴기일 수 있다. 상기 알킬기에 치환된 아릴기의 종류로는 고리형성 탄소수 6 이상 12 이하의 아릴기를 들 수 있고, 상기 아릴기에 치환된 알킬기의 종류로는 탄소수 1 이상 5 이하의 알킬기를 들 수 있다. In Formula 1, R 1 to R 4 are each independently a hydrogen atom, a deuterium atom, a halogen atom, or an unsubstituted or unsubstituted alkyl group having 1 to 5 carbon atoms or an alkyl group substituted or unsubstituted with 6 ring carbon atoms It may be an aryl group of 12 or more. The type of the aryl group substituted with the alkyl group may include an aryl group having 6 to 12 ring carbon atoms, and the type of the alkyl group substituted for the aryl group may include an alkyl group having 1 to 5 carbon atoms.
상기 탄소수 1 이상 5 이하의 알킬기의 종류로는 메틸기, 에틸기, 프로필기, iso-프로필기, n-부틸기, iso-부틸기, sec-부틸기, tert-부틸기, n-펜틸기, iso-펜틸기, neo-펜틸기 tert-펜틸기 또는 sec-펜틸기 등을 들 수 있다. Examples of the alkyl group having 1 to 5 carbon atoms include methyl group, ethyl group, propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, iso -pentyl group, neo-pentyl group, tert-pentyl group, sec-pentyl group, etc. are mentioned.
상기 고리형성 탄소수 6 이상 12 이하의 아릴기의 종류로는 페닐기, 나프틸기 또는 바이페닐기 등을 들 수 있다.Examples of the aryl group having 6 to 12 ring carbon atoms include a phenyl group, a naphthyl group, or a biphenyl group.
상기 할로겐 원자는 F, Cl, Br 또는 I일 수 있다.The halogen atom may be F, Cl, Br or I.
a 및 b는 각각 독립적으로 1 이상 2 이하의 정수일 수 있다. 예를 들어 a 및 b는 1일 수 있다. c 및 d는 각각 독립적으로 1 이상 8 이하의 정수일 수 있다. 예를 들어, c 및 d는 각각 독립적으로 1 이상 4 이하, 1 이상 2 이하의 정수이거나 또는 1 일 수 있다.a and b may each independently be an integer of 1 or more and 2 or less. For example, a and b may be 1. c and d may each independently be an integer of 1 or more and 8 or less. For example, c and d may each independently be an integer of 1 or more and 4 or less, or 1 or more and 2 or less, or 1 may be.
R1이 복수 개인 경우, 복수 개의 R1은 서로 동일하거나 상이할 수 있다. R2 내지 R4가 복수 개인 경우에도 R1과 동일한 설명이 적용될 수 있다. 일 실시예에서, 상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀, 또는 (11bS)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀일 수 있다. 예를 들어, 상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀일 수 있다.When R 1 a plurality individual, a plurality of R 1 s may be the same or different from each other. Even when R 2 to R 4 are plural, the same description as that of R 1 may be applied. In one embodiment, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d: 1',2'-f][1,3,2]dioxaphospepine, or (11bS)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4 -oxide-dinaphtho[2,1-d:1',2'-f][1,3,2]dioxaphospepine. For example, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.
일 실시예에서, 상기 분리방법은 (a) 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물 및 상기 분할제를 유기용매에 가하여 고체 상태의 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 포함하는 혼합물을 제조하는 단계를 포함할 수 있다.In one embodiment, the separation method comprises (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1 -Phenylbutan-2-ol stereoisomer mixture and the resolving agent were added to an organic solvent to form (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4- preparing a mixture comprising dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a salt of the resolving agent.
상기 단계 (a) 에서 상기 유기용매는 극성 양성자성 용매, 극성 비양성자성 용매 및 이들의 혼합용매로 이루어진 군에서 선택되는 적어도 하나를 포함할 수 있다.In step (a), the organic solvent may include at least one selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof.
상기 유기용매는 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염의 입체이성질체들에 대하여 서로 다른 용해도를 나타내는 것일 수 있다.The organic solvent is 1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and a splitting agent. It may be to show different solubility with respect to the stereoisomers of the salt.
구체적으로 상기 유기용매는 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염에 대해 상대적으로 낮은 용해도를 나타내고, (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염, (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염 각각에 대하여 상대적으로 높은 용해도를 나타내는 것일 수 있다.Specifically, the organic solvent is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane Relatively low solubility in salts of -2-ol and resolving agents, (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- (1-naphthyl)-1-phenyl-butan-2-ol and salt of resolving agent, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethyl Salts of amino-2-(1-naphthyl)-1-phenyl-butan-2-ol and splitting agent and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl) -4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and salts of the splitting agent may each exhibit relatively high solubility.
상기 극성 양성자성 용매는 메탄올, 에탄올, 이소프로필알코올, n-부틸알코올, sec-부틸알코올, t-부틸알코올 및 이들의 혼합용매로 구성된 군에서 선택되는 적어도 하나를 포함할 수 있다.The polar protic solvent may include at least one selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, and a mixed solvent thereof.
상기 극성 비양성자성 용매는 에틸아세테이트, 아세토니트릴, 아세톤, 메틸에틸케톤, 메틸이소부틸케톤, 테트라하이드로퓨란, 디메틸설폭사이드, 디메틸포름아미드, 디메틸아세트아미드, N-메틸-2-피롤리돈 및 이들의 혼합용매로 구성된 군에서 선택되는 적어도 하나를 포함할 수 있다.The polar aprotic solvent is ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and It may include at least one selected from the group consisting of these mixed solvents.
예를 들어, 상기 유기용매는 상기 극성 양성자성 용매 만을 포함할 수 있다. 예를 들어, 상기 유기용매는 메탄올 만을 포함할 수 있다. 예를 들어, 상기 유기용매는 상기 혼합용매를 포함할 수 있다. 상기 혼합용매는 극성 양성자성 용매로 메탄올을 포함할 수 있다. 상기 혼합용매는 극성 비양성자성 용매로 테트라하이드로퓨란, 디메틸포름아미드 및 N-메틸-2-피롤리돈 중 선택되는 적어도 하나를 포함할 수 있다. 상기 혼합용매는 극성 양성자성 용매로 메탄올을 포함하고, 극성 비양성자성 용매로 테트라하이드로퓨란, 디메틸포름아미드 및 N-메틸-2-피롤리돈 중 선택되는 적어도 하나를 포함할 수 있다. 예를 들어, 상기 혼합용매는 극성 양성자성 용매로 메탄올을 포함하고 극성 비양성자성 용매로 디메틸포름아미드를 포함할 수 있다.For example, the organic solvent may include only the polar protic solvent. For example, the organic solvent may include only methanol. For example, the organic solvent may include the mixed solvent. The mixed solvent may include methanol as a polar protic solvent. The mixed solvent may include at least one selected from tetrahydrofuran, dimethylformamide, and N-methyl-2-pyrrolidone as a polar aprotic solvent. The mixed solvent may include methanol as the polar protic solvent, and at least one selected from tetrahydrofuran, dimethylformamide, and N-methyl-2-pyrrolidone as the polar aprotic solvent. For example, the mixed solvent may include methanol as the polar protic solvent and dimethylformamide as the polar aprotic solvent.
상기 혼합용매에서 상기 극성 양성자성 용매 대 상기 극성 비양성자성 용매의 부피 비율은 용매의 종류에 따라 상이할 수 있으나, 10:0.5 내지 10:2, 10:0.7 내지 10:2, 10:0.9 내지 10:2, 10:1 내지 10:2, 10:0.5 내지 10:1.5, 10:0.7 내지 10:1.5, 10:0.9 내지 10:1.5 또는 10:1 내지 10:1.5일 수 있다. 예를 들어, 상기 극성 양성자성 용매 대 상기 극성 비양성자성 용매의 부피 비율은 약 10:1일 수 있다.The volume ratio of the polar protic solvent to the polar aprotic solvent in the mixed solvent may be different depending on the type of solvent, but 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10:1 to 10:2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5 or 10:1 to 10:1.5. For example, the volume ratio of the polar protic solvent to the polar aprotic solvent may be about 10:1.
예를 들어, 메탄올 및 디메틸포름아미드를 포함하는 혼합용매에서 메탄올 및 디메틸포름아미드의 부피 비율은 10:0.5 내지 10:2, 10:0.7 내지 10:2, 10:0.9 내지 10:2, 10:1 내지 10:2, 10:0.5 내지 10:1.5, 10:0.7 내지 10:1.5, 10:0.9 내지 10:1.5 또는 10:1 내지 10:1.5일 수 있다.For example, in a mixed solvent containing methanol and dimethylformamide, the volume ratio of methanol and dimethylformamide is 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10: 1 to 10:2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5 or 10:1 to 10:1.5.
상기 혼합용매에서 상기 극성 양성자성 용매의 부피(ml) 대 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)의 비율은 5:1 내지 30:1, 8:1 내지 25:1, 10:1 내지 20:1 또는 15:1 내지 25:1일 수 있다. 예를 들어, 상기 혼합용매에서 상기 극성 양성자성 용매의 부피(ml) 대 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)의 비율은 10:1 또는 20:1일 수 있다. 상기 혼합용매에서 상기 극성 비양성자성 용매의 부피(ml) 대 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)의 비율은 0.5:1 내지 3:1, 0.8:1 내지 2.5:1, 1:1 내지 2:1 또는 1.5:1 내지 2.5:1일 수 있다. 상기 혼합용매에서 상기 극성 비양성자성 용매의 부피(ml) 대 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)의 비율은 예를 들어 1:1 또는 2:1일 수 있다. 예를 들어, 상기 극성 양성자성 용매의 부피(ml):상기 극성 비양성자성 용매의 부피(ml):상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)은, 5:0.5:1 내지 30:3:1, 8:0.8:1 내지 25:2.5:1, 10:1:1 내지 20:2:1 또는 15:1.5:1 내지 25:2.5:1일 수 있다. 예를 들어, 상기 극성 양성자성 용매의 부피(ml):상기 극성 비양성자성 용매의 부피(ml):상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)은 10:1:1 또는 20:2:1일 수 있다.Volume (ml) of the polar protic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl) )-1-phenylbutan-2-ol, the ratio of the mass (g) of the mixture of stereoisomers is from 5:1 to 30:1, from 8:1 to 25:1, from 10:1 to 20:1 or from 15:1 to It could be 25:1. For example, the volume (ml) of the polar protic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene) The ratio of the mass (g) of the mixture of stereoisomers of -1-yl)-1-phenylbutan-2-ol may be 10:1 or 20:1. Volume (ml) of the polar aprotic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- The ratio of the mass (g) of the mixture of stereoisomers of yl)-1-phenylbutan-2-ol is 0.5:1 to 3:1, 0.8:1 to 2.5:1, 1:1 to 2:1 or 1.5:1 to 2.5:1. Volume (ml) of the polar aprotic solvent in the mixed solvent versus the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- The ratio of the mass (g) of the stereoisomeric mixture of yl)-1-phenylbutan-2-ol may be, for example, 1:1 or 2:1. For example, the volume of the polar protic solvent (ml): the volume of the polar aprotic solvent (ml): the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-( The mass (g) of a mixture of stereoisomers of dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol is from 5:0.5:1 to 30:3:1, 8:0.8:1 to 25:2.5:1, 10:1:1 to 20:2:1 or 15:1.5:1 to 25:2.5:1. For example, the volume of the polar protic solvent (ml): the volume of the polar aprotic solvent (ml): the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-( The mass (g) of a mixture of stereoisomers of dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol may be 10:1:1 or 20:2:1.
상기 유기용매의 부피(ml)대 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)의 비율은 5.5:1 내지 33:1, 8.8:1 내지 27.5:1, 11:1 내지 22:1 또는 16.5:1 내지 27.5:1일 수 있다.Volume (ml) of the organic solvent vs. 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane The ratio of the mass (g) of the mixture of stereoisomers of -2-ol may be 5.5:1 to 33:1, 8.8:1 to 27.5:1, 11:1 to 22:1 or 16.5:1 to 27.5:1 .
상기 단계 (a)에서 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염은 상기 유기용매에 대해 용해도가 낮으므로 고체 상태로 수득 될 수 있다.In step (a), the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- Butan-2-ol and the salt of the splitting agent have low solubility in the organic solvent, and thus may be obtained in a solid state.
상기 단계 (a)에서 (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염, (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염 및 (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염 각각은 상기 유기용매에 대해 상대적으로 용해도가 높으므로 유기용매에 용해될 수 있다.(1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane in step (a) above Salt of -2-ol and splitting agent, (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-butan-2-ol and salts of resolving agents and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph Since each of tyl)-1-phenyl-butan-2-ol and the salt of the splitting agent has relatively high solubility in the organic solvent, it can be dissolved in the organic solvent.
따라서, 일 실시예의 분리방법에 따르면, 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염이 선택적으로 분리 될 수 있다.일 실시예의 염에서 상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀일 수 있다.Therefore, according to the separation method of one embodiment, the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- Salts of 1-phenyl-butan-2-ol and the resolving agent may be optionally isolated. In one embodiment, the resolving agent is (11bR)-8,9,10,11,12,13,14,15. -octahydro-4-hydroxy-4-oxide- dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.
예를 들어, 상기 단계 (a)는 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물 및 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 10:0.5 내지 10:2, 10:0.7 내지 10:2, 10:0.9 내지 10:2, 10:1 내지 10:2, 10:0.5 내지 10:1.5, 10:0.7 내지 10:1.5, 10:0.9 내지 10:1.5 또는 10:1 내지 10:1.5의 부피 비율의 메탄올 및 디메틸포름아미드의 혼합용매에 가하여 고체 상태의 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀 의 염을 포함하는 혼합물을 제조하는 단계를 포함할 수 있다. 여기서, 메탄올의 부피(ml):디메틸포름아미드의 부피(ml):1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 질량(g)은, 5:0.5:1 내지 30:3:1, 8:0.8:1 내지 25:2.5:1, 10:1:1 내지 20:2:1 또는 15:1.5:1 내지 25:2.5:1일 수 있고, 예를 들어 10:1:1 또는 20:2:1일 수 있다.For example, in step (a), the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl Stereoisomeric mixture of butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d :1',2'-f][1,3,2]dioxaphosphepine 10:0.5 to 10:2, 10:0.7 to 10:2, 10:0.9 to 10:2, 10:1 to 10 :2, 10:0.5 to 10:1.5, 10:0.7 to 10:1.5, 10:0.9 to 10:1.5, or 10:1 to 10:1.5 by volume ratio of methanol and dimethylformamide in a mixed solvent of of (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][ 1,3,2] preparing a mixture containing a salt of dioxaphospepine. where, volume of methanol (ml): volume of dimethylformamide (ml): 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1 The mass (g) of a mixture of stereoisomers of -yl)-1-phenylbutan-2-ol is 5:0.5:1 to 30:3:1, 8:0.8:1 to 25:2.5:1, 10:1 :1 to 20:2:1 or 15:1.5:1 to 25:2.5:1, for example 10:1:1 or 20:2:1.
상기 단계 (a)는 상기 혼합물을 교반하는 단계를 포함할 수 있다. 상기 교반하는 단계는 약 60℃ 이상 약 100℃ 이하의 온도(예를 들어 약 80℃)에서, 약 30분 이상 약 3 시간 이하(예를 들어, 약 1시간)의 시간 동안 진행될 수 있다.Step (a) may include stirring the mixture. The stirring may be performed at a temperature of about 60° C. or more and about 100° C. or less (eg, about 80° C.) for a time of about 30 minutes or more and about 3 hours or less (eg, about 1 hour).
일 실시예에서, 상기 단계 (a)는 상기 혼합물을 교반한 후, 0 이상 5℃ 이하로 냉각하고, 약 30분 이상 약 3시간 이하의 시간 동안 교반하는 단계를 더 포함할 수 있다.In one embodiment, the step (a) may further include stirring the mixture, cooling the mixture to 0 or more and 5° C. or less, and stirring for a time of about 30 minutes or more and about 3 hours or less.
상기 단계 (a)는 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 여과 및 세척하는 단계를 포함할 수 있다.Step (a) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- filtering and washing the butan-2-ol and the salt of the resolving agent.
일 실시예의 분리방법은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 정제하는 단계를 더 포함할 수 있다.The separation method of one embodiment is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane It may further comprise the step of purifying the salt of the -2-ol and the resolving agent.
상기 정제 단계는 (aa) 여과된 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 유기용매에 가하는 단계를 더 포함할 수 있다. 상기 정제 단계에서 유기용매는 전술한 극성 양성자성 용매, 극성 비양성자성 용매 또는 혼합용매일 수 있다. 상기 단계 (a) 및 상기 정제 단계에서 유기용매는 동일한 것일 수 있다.The purification step was (aa) filtered (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- The method may further include adding phenyl-butan-2-ol and a salt of the resolving agent to an organic solvent. In the purification step, the organic solvent may be the above-described polar protic solvent, polar aprotic solvent, or mixed solvent. In the step (a) and the purification step, the organic solvent may be the same.
상기 정제 단계는 교반하는 단계를 포함할 수 있다. 상기 교반하는 단계는 약 60℃ 이상 약 100℃ 이하의 온도(예를 들어 약 80℃)에서, 약 15분 이상 약 1 시간 이하(예를 들어, 약 30분)의 시간 동안 진행될 수 있다. 일 실시예에서, 상기 정제 단계는 상기 교반하는 단계 이후, 상기 혼합물을 0 이상 5℃ 이하로 냉각하고, 약 30분 이상 약 3시간 이하의 시간 동안 교반하는 단계를 더 포함할 수 있다.The purification step may include stirring. The stirring may be performed at a temperature of about 60° C. or more and about 100° C. or less (eg, about 80° C.) for a time of about 15 minutes or more and about 1 hour or less (eg, about 30 minutes). In one embodiment, the refining step may further include, after the stirring step, cooling the mixture to 0 or more and 5°C or less, and stirring for about 30 minutes or more and about 3 hours or less.
상기 정제 단계는 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 여과 및 세척하는 단계를 포함할 수 있다. 상기 정제 단계를 통해 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염의 순도를 높일 수 있다.The purification step is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- filtering and washing the 2-ol and the salt of the resolving agent. (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- It is possible to increase the purity of the salt of the 2-ol and the splitting agent.
일 실시예에 따르면, 상기 단계 (a)에서 상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀일 수 있다.According to one embodiment, in the step (a), the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d:1',2'-f][1,3,2]dioxaphospepine.
일 실시예에서, 상기 분리방법은 (b) (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 상기 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 제조하는 단계를 더 포함할 수 있다. 상기 단계 (b)는 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 상기 분할제의 염으로부터(1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 유리화하는 단계일 수 있다.In one embodiment, the separation method comprises (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( The method may further include preparing 1-naphthyl)-1-phenyl-butan-2-ol. Step (b) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- from (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents It may be a step of liberating -1-phenyl-butan-2-ol.
일 실시예에서, 상기 단계 (b)는 상기 결정화된 염을 포함하는 현탁액을 제조하는 단계; 및 상기 현탁액에 탄산염 또는 인산염을 첨가하는 단계를 포함할 수 있다.In one embodiment, the step (b) comprises the steps of preparing a suspension comprising the crystallized salt; and adding carbonate or phosphate to the suspension.
일 실시예에서, 상기 단계 (b)에서 상기 현탁액의 용매는 비극성 유기용매를 포함할 수 있다. 예를 들어, 상기 현탁액의 용매는 톨루엔을 포함할 수 있다. 일 실시예에서, 현탁액의 용매로 톨루엔과 같은 비극성 유기용매를 사용하는 경우 유연 물질의 발생을 감소시킬 수 있다.In one embodiment, the solvent of the suspension in step (b) may include a non-polar organic solvent. For example, the solvent of the suspension may include toluene. In one embodiment, when a non-polar organic solvent such as toluene is used as a solvent of the suspension, the generation of related substances can be reduced.
일 실시예에서, 상기 탄산염은 K2CO3, KHCO3, Na2CO3 및 NaHCO3 중 선택되는 적어도 하나일 수 있다. 상기 인산염은 Na3PO4 및 Na2HPO4 중 선택되는 적어도 하나일 수 있다. 예를 들어, 상기 단계(b)에서 상기 현탁액에 탄산염이 첨가될 수 있다. 예를 들어, 탄산염으로 K2CO3가 첨가될 수 있다.In one embodiment, the carbonate may be at least one selected from K 2 CO 3 , KHCO 3 , Na 2 CO 3 and NaHCO 3 . The phosphate salt may be at least one selected from Na 3 PO 4 and Na 2 HPO 4 . For example, carbonate may be added to the suspension in step (b). For example, K 2 CO 3 may be added as carbonate.
상기 단계 (b)는 상기 탄산염 또는 인산염 수용액을 상기 단계 (b)의 현탁액에 첨가 및 교반하고, 층분리하여 수층을 제거하는 단계를 포함할 수 있다. 이후, 탄산염 또는 인산염 수용액을 첨가 및 교반하고, 층분리하여 수층을 제거하는 단계가 적어도 한번 더 진행될 수 있다. 상기 단계 (b)는 상기 수층을 제거하고 남은 유기층을 세척, 탈수, 여과 및 농축하는 단계를 포함할 수 있다. 상기 단계 (b)는 농축 단계에서 얻은 농축액으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 결정화하는 단계일 수 있다.The step (b) may include adding and stirring the carbonate or phosphate aqueous solution to the suspension of step (b), and separating the layers to remove the aqueous layer. Thereafter, the steps of adding and stirring a carbonate or phosphate aqueous solution and separating the layers to remove the aqueous layer may be performed at least once more. The step (b) may include washing, dehydrating, filtering and concentrating the organic layer remaining after removing the aqueous layer. Step (b) is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from the concentrate obtained in the concentration step. It may be a step of crystallizing -1-phenyl-butan-2-ol.
일 실시예에 따르면, 본 발명은 분할제로 키랄 옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 사용하며, 별도의 시딩 공정 없이도 높은 광학 순도를 갖는 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리할 수 있다. 이에 따라 공정이 단순화되고 비용이 절감되면서도, 높은 순도로 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리할 수 있다. 특히, 일 실시예의 분리 방법에 따르면 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 상업적 규모로 대량 생산 할 수 있다.구체적으로, 일 실시예의 분리 방법에 따를 때, 99% 이상의 높은 순도를 갖는 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 고수율로 수득할 수 있다.According to one embodiment, the present invention is a splitting agent chiral octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxa (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1) using phospepine and having high optical purity without a separate seeding process -naphthyl)-1-phenyl-butan-2-ol can be isolated. This simplifies the process and reduces costs, but with high purity (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph Tyl)-1-phenyl-butan-2-ol can be isolated. In particular, according to the separation method of an embodiment, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- Phenyl-butan-2-ol can be mass-produced on a commercial scale. Specifically, according to the separation method of one embodiment, (1R,2S)-1-(6-bromo- having a high purity of 99% or more 2-Methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol can be obtained in high yield.
일 실시예에서, 상기 입체이성질체의 혼합물은, (a1) 3-벤질-6-브로모-2-메톡시퀴놀린을 염기 및 3-(디메틸아미노)-1'-프로피오나프톤과 반응시킨 후 산을 첨가하는 단계 및 (b1) 상기 단계 (a1)에서 수득한 반응 혼합물을 결정화하여 결정을 생성하는 단계를 포함하는 입체이성질체 혼합물의 제조 방법에 의해 수득 되는 것일 수 있다.In one embodiment, the mixture of stereoisomers is prepared by reacting (a1) 3-benzyl-6-bromo-2-methoxyquinoline with a base and 3-(dimethylamino)-1'-propionaphthone followed by an acid. and (b1) crystallizing the reaction mixture obtained in step (a1) to produce crystals.
입체이성질체 혼합물의 제조 단계는 (c1) 상기 단계 (b1)의 결정으로부터 (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물을 제거하여 입체이성질체 혼합 용액을 수득하는 단계를 더 포함할 수 있다.The step of preparing a stereoisomeric mixture is (c1) from the crystal of step (b1) above (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- (1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( The method may further include removing the mixture of 1-naphthyl)-1-phenyl-butan-2-ol to obtain a stereoisomer mixture solution.
일 실시예에서, 상기 단계 (c1)은 상기 단계 (b1)의 결정을 에탄올; 및 에틸아세테이트, 테트라하이드로퓨란 및 디클로로메탄 중 선택되는 적어도 하나를 포함하는 혼합용매에 가하는 단계를 포함할 수 있다.In one embodiment, the step (c1) is ethanol; and adding to a mixed solvent containing at least one selected from among ethyl acetate, tetrahydrofuran and dichloromethane.
일 실시예에 따르면, 상기 단계 (a1)에서 상기 산은 아세트산일 수 있다. 상기 단계 (a1)에서 상기 염기는 n-부틸리튬일 수 있다. 일 실시예에서, 염기로 n-부틸리튬을 사용하는 경우, 대량생산에 적용되는 경우에도 우수한 수율을 달성할 수 있다.According to one embodiment, the acid in step (a1) may be acetic acid. In step (a1), the base may be n-butyllithium. In one embodiment, when n-butyllithium is used as the base, excellent yield can be achieved even when applied to mass production.
단계 (a1)은 약 -80℃ 이상 약 -70℃ 이하에서 n-부틸리튬을 포함하는 용액을 3-벤질-6-브로모-2-메톡시퀴놀린을 포함하는 용액에 적가하여 반응액을 준비하는 단계, 상기 반응액을 약 -80℃ 이상 약 -70℃ 이하에서 3-(디메틸아미노)-1'-프로피오나프톤을 포함하는 용액에 적가하고 교반하는 단계, 상기 교반액을 약 0℃ 이상 5℃ 이하로 가온 한 후 산을 첨가하여 교반하는 단계를 포함할 수 있다.Step (a1) prepares a reaction solution by dropwise adding a solution containing n-butyllithium to a solution containing 3-benzyl-6-bromo-2-methoxyquinoline at about -80° C. or more and about -70° C. or less adding the reaction solution dropwise to a solution containing 3-(dimethylamino)-1'-propionaphthone at about -80° C. or more and about -70° C. or less and stirring, and stirring the stirring solution at about 0° C. or more It may include the step of stirring by adding an acid after heating to 5 ℃ or less.
상기 단계 (b1)은 상기 단계 (a1)에서 수득한 반응 혼합물에 물을 첨가하여 교반하는 단계, 유기층을 분리 후 탈수하여 농축하는 단계 및 농축물에 유기용매를 가하여 교반하는 단계를 포함할 수 있다. 상기 농축물에 유기용매(예를 들어, 에틸 아세테이트 및 에탄올의 혼합용매)를 가하여 교반하는 단계는, 약 50 ℃ 이상 90 ℃ 이하(예를 들어, 약 75℃ 이상 80℃ 이하)로 가온 교반하는 제1 교반단계 및 상온(예를 들어 약 15℃ 이상 약 30 ℃이하, 또는 약 25℃)으로 냉각하여 교반하는 제2 교반 단계를 포함할 수 있다.The step (b1) may include adding water to the reaction mixture obtained in step (a1) and stirring, separating the organic layer, dehydrating and concentrating, and adding an organic solvent to the concentrate and stirring. . The step of stirring by adding an organic solvent (for example, a mixed solvent of ethyl acetate and ethanol) to the concentrate includes heating and stirring to about 50 ℃ or more and 90 ℃ or less (eg, about 75 ℃ or more and 80 ℃ or less). It may include a first stirring step and a second stirring step of stirring by cooling to room temperature (eg, about 15 ℃ to about 30 ℃ or less, or about 25 ℃).
상기 단계 (c1)은 상기 단계 (b1)의 결정을 상기 테트라하이드로퓨란을 포함하는 용매에 현탁시키는 단계, 상기 현탁액에 에탄올을 첨가하는 단계, 교반하는 단계 및 교반 후 여과하여 입체이성질체 혼합 용액을 수득하는 단계를 포함할 수 있다.In step (c1), the crystal of step (b1) is suspended in a solvent containing tetrahydrofuran, adding ethanol to the suspension, stirring, and filtering after stirring to obtain a stereoisomeric mixture solution may include the step of
일 실시예에서, (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물을 포함하는 결정이 제거되므로, (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물 의 비율이 높은 입체이성질체 혼합물을 수득할 수 있다. 따라서, 상기 입체이성질체 혼합물로부터 보다 더 고순도 및 고수율로 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 분리할 수 있다.In one embodiment, (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- 2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 Since crystals containing a mixture of -ols are removed, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) -1-phenyl-butan-2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- A mixture of stereoisomers with a high proportion of the mixture of 1-phenyl-butan-2-ol can be obtained. Thus, (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph) in higher purity and higher yield from the stereoisomeric mixture Tyl)-1-phenyl-butan-2-ol can be isolated.
일 실시예에 따르면, 상기 (c1) 단계에서 부분입체 이성질체 (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물의 제거 비율은 상기 단계 (b1) 단계에서 수득한 결정에 포함된 (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물의 전체 중량을 기준으로 약 80 중량% 이상 또는 약 90 중량% 이상일 수 있다.According to one embodiment, in the step (c1), the diastereomer (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1- Naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naph The removal ratio of the mixture of tyl)-1-phenyl-butan-2-ol is determined by the (1R,2R)-1-(6-bromo-2-methoxyquinoline included in the crystal obtained in step (b1) above. -3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinoline- 3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol, based on the total weight of the mixture, may be at least about 80% by weight or at least about 90% by weight.
일 실시예의 분리방법은, (d1) 상기 단계 (c1)에서 수득한 입체 이성질체 혼합 용액에 포함된 입체 이성질체 혼합물을 결정화하는 단계를 더 포함할 수 있다. 일 실시예의 분리 방법은 상기 (d1) 단계에서 수득한 결정화된 입체 이성질체 혼합물은 여과하는 단계, 여과된 결정을 건조하는 단계를 포함할 수 있다. 수득한 결정은 결정 전체 중량을 기준으로 상기 부분입체 이성질체 A를 80 중량% 이상 또는 90 중량% 이상 포함할 수 있다.The separation method of an embodiment may further include (d1) crystallizing the stereoisomer mixture contained in the stereoisomer mixture solution obtained in step (c1). The separation method of an embodiment may include filtering the crystallized stereoisomer mixture obtained in step (d1), and drying the filtered crystals. The obtained crystal may contain 80 wt% or more or 90 wt% or more of the diastereomer A based on the total weight of the crystal.
상기 단계 (b1) 및 상기 단계 (d1)의 결정화 단계는 에탄올; 또는 에틸아세테이트 및 에탄올의 혼합용매를 사용하는 단계일 수 있다.The crystallization step of step (b1) and step (d1) is ethanol; Alternatively, it may be a step of using a mixed solvent of ethyl acetate and ethanol.
부분입체 이성질체 A는 상기 단계 (c1)에서 사용되는 유기용매에 대한 용해도가 상대적으로 높을 수 있고, 부분입체 이성질체 B는 상기 단계 (c1)에서 사용되는 유기용매에 대한 용해도가 상대적으로 낮을 수 있다. 예를 들어, 상기 단계 (c1)에서 사용되는 유기용매는 에탄올; 및 에틸아세테이트, 테트라하이드로퓨란 및 디클로로메탄 중 선택되는 적어도 하나를 포함하는 혼합용매일 수 있다. 예를 들어, 상기 단계 (c1)에서 사용되는 유기용매는 에탄올 및 테트라하이드로퓨란의 혼합용매일 수 있다. 즉, 일 실시예에 따르면 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물을 제조할 때, 부분입체 이성질체 A는 혼합용매에 다수 용해되고 부분입체 이성질체 B는 다수 결정 상태로 남아있을 수 있다. 이후, 남아있는 결정을 제거하고 혼합용매에 남아있는 부분입체 이성질체 A를 포함하는 입체이성질체 혼합물을 재결정 시키므로 부분입체 이성질체 A의 비율이 높은 입체이성질체 혼합물을 얻을 수 있다. 따라서, 별도의 시딩 공정이 불요하므로 공정 단계가 간소화되면서도 부분입체 이성질체 A의 비율이 높은 입체 이성질체 혼합물을 수득할 수 있다.Diastereomer A may have relatively high solubility in the organic solvent used in step (c1), and diastereomer B may have relatively low solubility in the organic solvent used in step (c1). For example, the organic solvent used in step (c1) is ethanol; And it may be a mixed solvent comprising at least one selected from ethyl acetate, tetrahydrofuran and dichloromethane. For example, the organic solvent used in step (c1) may be a mixed solvent of ethanol and tetrahydrofuran. That is, according to an embodiment, 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2- When preparing a stereoisomeric mixture of ol, diastereomer A may be dissolved in a large number in the mixed solvent and diastereomer B may remain in a majority crystalline state. Thereafter, the remaining crystals are removed and the stereoisomer mixture containing the diastereomer A remaining in the mixed solvent is recrystallized to obtain a stereoisomeric mixture having a high ratio of the diastereomer A. Accordingly, since a separate seeding process is not required, a stereoisomer mixture having a high ratio of diastereomer A can be obtained while simplifying the process step.
본 발명의 일 실시예에 따른 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올, 또는 이의 약제학적으로 허용 가능한 염의 제조방법은 전술한 키랄 옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 분할제로 사용하여, 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 광학 분리하는 단계를 포함할 수 있다.(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl according to an embodiment of the present invention -Butan-2-ol, or a method for preparing a pharmaceutically acceptable salt thereof is chiral octahydro-4-hydroxy-4-oxide-dinaphtho [2,1-d: 1 ', 2'-f] 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalene-1- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1) from a mixture of stereoisomers of yl)-1-phenylbutan-2-ol optical separation of -naphthyl)-1-phenyl-butan-2-ol.
일 실시예에서, 상기 광학 분리하는 단계에는 전술한 분리단계와 동일한 설명이 적용될 수 있다.In one embodiment, the same description as the above-described separation step may be applied to the optical separation step.
예를 들어, 상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀일 수 있다.For example, the splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1 ',2'-f][1,3,2]dioxaphospepine.
상기 광학 분리하는 단계는, (a) 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물 및 상기 분할제를 유기용매에 가하여 고체 상태의 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 포함하는 혼합물을 제조하는 단계를 포함할 수 있다. 상기 단계 (a)에서 상기 유기용매는 메탄올, 또는 메탄올 및 디메틸포름아미드를 포함할 수 있다. 상기 단계 (a)에서 상기 메탄올 및 상기 디메틸포름아미드의 부피 비율은 전술한 것과 동일할 수 있다. 예를 들어, 상기 메탄올 및 상기 디메틸포름아미드의 부피 비율은 10:0.5 내지 10:2일 수 있다.The optical separation step is, (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenyl (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino in a solid state by adding the stereoisomeric mixture of butan-2-ol and the resolving agent to an organic solvent preparing a mixture comprising -2-(1-naphthyl)-1-phenyl-butan-2-ol and a salt of the resolving agent. In step (a), the organic solvent may include methanol, or methanol and dimethylformamide. In step (a), the volume ratio of the methanol and the dimethylformamide may be the same as described above. For example, the volume ratio of the methanol and the dimethylformamide may be 10:0.5 to 10:2.
상기 제조방법은 (b) (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 상기 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 제조하는 단계를 더 포함할 수 있다. 상기 단계 (b)는 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 상기 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 유리화하는 단계일 수 있다.The preparation method is (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents The method may further include preparing -1-phenyl-butan-2-ol. Step (b) is the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from butan-2-ol and salts of the above resolving agents It may be a step of liberating -1-phenyl-butan-2-ol.
상기 제조방법은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 산과 반응시키는 단계를 더 포함할 수 있다.The preparation method is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 - It may further comprise the step of reacting an ol with an acid.
상기 산과 반응시키는 단계는, 유리된 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 유기용매(예를 들어, 이소프로필알코올)에 가하여 교반한 후, 산을 가하여 환류 및 교반하는 단계를 포함할 수 있다.The step of reacting with the acid is the free (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1- The method may include adding phenyl-butan-2-ol to an organic solvent (eg, isopropyl alcohol) and stirring, then adding an acid to reflux and stirring.
일 실시예에서 상기 산은 염산, 브롬산, 인산 또는 황산과 같은 무기산; 아세트산, 트리플루오로아세트산, 구연산, 말레인산, 수산, 호박산, 벤조산, 주석산, 푸마르산, 만델산, 아스코르브산 또는 말산과 같은 유기 카르복실산, 메탄설폰산 또는 파라-톨루엔설폰산과 같은 설폰산; 또는 기타 약제학적으로 허용 가능한 염을 형성할 수 있는 것으로 알려진 다양한 산일 수 있다. 예를 들어, 상기 산은 푸마르산일 수 있다.In one embodiment, the acid is an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, sulfonic acid such as methanesulfonic acid or para-toluenesulfonic acid; or other various acids known to form pharmaceutically acceptable salts. For example, the acid may be fumaric acid.
상기 산과 반응시킨 용액을 여과, 세척 및 냉각하여 교반하고, 고체를 여과하고 건조하여 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 염을 수득할 수 있다.The solution reacted with the acid was filtered, washed, cooled and stirred, the solid was filtered and dried (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino A salt of -2-(1-naphthyl)-1-phenyl-butan-2-ol can be obtained.
일 실시예에서, 상기 약제학적으로 허용 가능한 염의 비제한적인 예로는, 염산, 브롬산, 인산 또는 황산과 같은 무기산과의 염; 아세트산, 트리플루오로아세트산, 구연산, 말레인산, 수산, 호박산, 벤조산, 주석산, 푸마르산, 만델산, 아스코르브산 또는 말산과 같은 유기 카르복실산이나, 메탄설폰산 또는 파라-톨루엔설폰산과 같은 설폰산과의 염; 혹은 기타 약제학적으로 허용 가능한 염을 형성할 수 있는 것으로 알려진 다양한 산과의 염 등을 포함할 수 있다.In one embodiment, non-limiting examples of the pharmaceutically acceptable salt include a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; Salts with organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid or malic acid, or sulfonic acids such as methanesulfonic acid or para-toluenesulfonic acid ; or salts with various acids known to form other pharmaceutically acceptable salts.
일 실시예에서, 상기 약제학적으로 허용 가능한 염은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 푸마르산염일 수 있다.In one embodiment, the pharmaceutically acceptable salt is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) )-1-phenyl-butan-2-ol fumarate.
본 발명에 따른 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 이의 약제학적으로 허용가능한 염의 제조방법은 경제적이고 간편하면서, 유연 물질의 발생이 감소되고, 동시에 높은 순도와 높은 수율로 제조할 수 있어 상업적 대량 생산에 적합하다.(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 according to the invention The production method of -ol and a pharmaceutically acceptable salt thereof is economical and convenient, and the generation of related substances is reduced, and at the same time, it can be prepared with high purity and high yield, so it is suitable for commercial mass production.
본 발명에 따른 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 분리방법은 경제적이고 간편하면서, 유연 물질의 발생이 감소되고, 동시에 높은 순도와 높은 수율로 제조할 수 있어 상업적 대량 생산에 적합하다.(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 according to the invention - The separation method of ol is economical and simple, and the generation of related substances is reduced, and at the same time, it can be manufactured with high purity and high yield, so it is suitable for commercial mass production.
이하, 본 발명의 이해를 돕기 위하여 실시예를 들어 상세하게 설명하기로 한다. 다만 하기의 실시예는 본 발명의 내용을 예시하는 것일 뿐 본 발명의 범위가 하기 실시예에 한정되는 것은 아니다. 본 발명의 실시예는 당업계에서 평균적인 지식을 가진 자에게 본 발명을 보다 완전하게 설명하기 위해 제공되는 것이다.Hereinafter, to help the understanding of the present invention, examples will be described in detail. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The embodiments of the present invention are provided to more completely explain the present invention to those of ordinary skill in the art.
<측정방법><Measuring method>
하기의 측정방법은 본 발명에 따른 각각의 실시예에 공통적으로 적용된다.The following measuring methods are commonly applied to each Example according to the present invention.
1. 순도 분석1. Purity analysis
화합물의 순도는 Agilent Technologies 1260 Infinity를 이용한 고성능 액상 크로마토그래피(HPLC)로 측정하였다. 정지상(Agilent SB-CN C18, 250 x 4.6mm, 5um)과 이동상 A(0.1% 인산 수용액)와 이동상 B(메탄올: 아세토니트릴: 이소프로판올= 45: 45: 10)를 사용하였다.The purity of the compounds was determined by high performance liquid chromatography (HPLC) using an Agilent Technologies 1260 Infinity. A stationary phase (Agilent SB-CN C18, 250 x 4.6 mm, 5 μm), a mobile phase A (0.1% aqueous phosphoric acid solution) and a mobile phase B (methanol: acetonitrile: isopropanol = 45: 45: 10) were used.
2. 광학순도 분석2. Optical Purity Analysis
화합물의 광학순도는 Agilent Technologies 1260 Infinity를 이용한 고성능 액상 크로마토그래피(HPLC)로 측정하였다. 정지상(Cyclobond I RSP-250 x 4.6mm, 5um)과 아세트산으로 pH 7로 조절한 이동상(메탄올: 물: 암모늄 아세테이트= 60mL: 40mL: 0.154g)을 사용하였다.The optical purity of the compound was determined by high performance liquid chromatography (HPLC) using an Agilent Technologies 1260 Infinity. A stationary phase (Cyclobond I RSP-250 x 4.6 mm, 5 μm) and a mobile phase adjusted to pH 7 with acetic acid (methanol: water: ammonium acetate = 60 mL: 40 mL: 0.154 g) were used.
<실시예 1> 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물의 제조<Example 1> 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol Preparation of stereoisomeric mixtures
3-(디메틸아미노)-1'-프로피오나프톤 염산염 (50.6g; 192mmol)에 물 (60 mL)를 넣어 용해시키고 톨루엔 (500 mL)을 가하여 희석시킨 후 상온에서 교반하여 반응액 A를 제조하였다. 수산화 나트륨 (8.23g; 206mmol)을 물 (60 mL)에 용해시키고 상온으로 냉각시킨 후 반응액 A에 가하고 30분간 교반하였다. 유기층을 분리한 후 물 (60 mL)로 세척하고 무수 황산나트륨 (25g)으로 탈수하였다. 탈수된 용액을 감압여과하고 외부온도 45℃에서 감압 농축하였다. 농축액을 상온에서 2시간 동안 진공 건조하여, 수득물 A를 얻었다.3-(dimethylamino)-1'-propionaphthone hydrochloride (50.6 g; 192 mmol) was dissolved in water (60 mL), diluted with toluene (500 mL), and stirred at room temperature to prepare a reaction solution A . Sodium hydroxide (8.23 g; 206 mmol) was dissolved in water (60 mL), cooled to room temperature, added to reaction solution A, and stirred for 30 minutes. The organic layer was separated, washed with water (60 mL), and dehydrated over anhydrous sodium sulfate (25 g). The dehydrated solution was filtered under reduced pressure and concentrated under reduced pressure at an external temperature of 45°C. The concentrate was vacuum dried at room temperature for 2 hours to obtain a product A.
질소로 충진한 제1 반응부에 테트라하이드로퓨란 (300 mL)을 넣고 디에틸아민 (12.6 mL; 122 mmol) 및 N,N,N',N'-테트라메틸에틸렌다이아민 (18.2 mL; 122 mmol)을 가한 후 -20℃로 냉각시키고 n-부틸리튬 (1.6 M, 76 mL; 122 mmol)을 가하고 30분간 교반한 후 -70 ~ -80℃로 냉각하여 시약을 제조 하였다. 제2 반응부에 3-벤질-6-브로모-2-메톡시퀴놀린 (30 g; 91 mmol)을 넣고 테트라하이드로퓨란 (300 mL)을 가하여 용해시킨 후 질소 분위기 하에서 -70 ~ -80℃로 냉각하여 반응액 B를 제조하였다. 제1 반응부에서 제조된 시약을 반응액 B에 서서히 적가한 후 1시간 교반하여 반응액 C를 제조하였다. 수득물 A에 톨루엔 (300 mL)을 가하여 희석시키고 질소 분위기 하에서 -70 ~ -80℃로 냉각시킨 후 반응액 C에 서서히 적가하고 24시간 교반하여 반응액 D를 얻었다. 이후, 반응액 D를 0 ~ 5℃로 가온 한 후 아세트산 (13.1 mL; 229 mmol)을 테트라하이드로퓨란 (15 mL)에 희석한 액을 서서히 가하고 동온에서 1시간 교반하였다. 이후, 물 (150 mL)을 가하고 0 ~ 5℃에서 1시간 교반하였다. 유기층을 분리한 후 무수 황산나트륨 (45 g)으로 탈수하고 외부온도 45℃에서 감압 농축하여 농축물 A를 얻었다. 농축물 A에 에탄올 (90 mL)을 가하고 추가로 동온에서 농축하여 농축물 B를 얻었다. 농축물 B에 에틸아세테이트 (30 mL)를 가하여 희석시킨 후 에탄올 (270 mL)을 가하고 질소 분위기 하에서 외부온도 75 ~ 80℃에서 1시간 가온 교반하였다. 상온으로 냉각시킨 후 동온에서 2시간 교반하여 부분입체 이성질체 A 및 부분입체 이성질체 B를 포함하는 결정을 생성하였다. 생성된 결정을 감압 여과하고 에탄올 (90 mL)로 세척하고 탈수하였다. 세척 및 탈수한 결정을 내부온도 30℃에서 밤새 진공건조하였다. 건조된 결정에 테트라하이드로퓨란 (480 mL)을 가하여 현탁시킨 후 에탄올 (480 mL)을 가하고 질소 분위기 하에서 상온에서 1시간 교반하고, 결정을 감압 여과하고 에탄올 (90 mL)로 세척하고 여과액을 외부온도 45℃에서 감압 농축하였다. 농축물에 에틸아세테이트 (32 mL)를 가하여 현탁시킨 후 에탄올 (320 mL)을 가하고 질소 분위기 하에서 상온에서 1시간 교반하여 부분입체 이성질체 A를 높은 비율로 포함하는 결정을 생성하였다. 생성된 결정을 감압 여과하고 에탄올 (90 mL)로 세척하고 탈수하였다. 이후, 수득한 결정을 내부온도 30℃에서 밤새 진공건조하여 백색의 분말 18.8 g을 수득하였다. 수율: 37%, 부분입체 이성질체 A: 93.9% (w/w), 부분입체 이성질체 B 4.2% (w/w).Tetrahydrofuran (300 mL) was added to the first reaction part filled with nitrogen, diethylamine (12.6 mL; 122 mmol) and N,N,N',N'-tetramethylethylenediamine (18.2 mL; 122 mmol) ), cooled to -20 °C, n-butyllithium (1.6 M, 76 mL; 122 mmol) was added, stirred for 30 minutes, and cooled to -70 ~ -80 °C to prepare a reagent. After adding 3-benzyl-6-bromo-2-methoxyquinoline (30 g; 91 mmol) to the second reaction part, tetrahydrofuran (300 mL) was added to dissolve it, and then heated to -70 to -80°C under a nitrogen atmosphere. After cooling, a reaction solution B was prepared. The reagent prepared in the first reaction part was slowly added dropwise to the reaction solution B and stirred for 1 hour to prepare a reaction solution C. The obtained product A was diluted by adding toluene (300 mL), cooled to -70 ~ -80°C under a nitrogen atmosphere, and then slowly added dropwise to the reaction solution C and stirred for 24 hours to obtain a reaction solution D. Then, after heating the reaction solution D to 0 ~ 5 ℃ acetic acid (13.1 mL; 229 mmol) diluted in tetrahydrofuran (15 mL) was slowly added and stirred at the same temperature for 1 hour. Then, water (150 mL) was added and the mixture was stirred at 0-5° C. for 1 hour. After separating the organic layer, it was dehydrated with anhydrous sodium sulfate (45 g) and concentrated under reduced pressure at an external temperature of 45° C. to obtain a concentrate A. Ethanol (90 mL) was added to Concentrate A and further concentrated at the same temperature to obtain Concentrate B. After dilution by adding ethyl acetate (30 mL) to Concentrate B, ethanol (270 mL) was added thereto, followed by heating and stirring for 1 hour at an external temperature of 75 to 80° C. under a nitrogen atmosphere. After cooling to room temperature, the mixture was stirred at the same temperature for 2 hours to produce crystals containing diastereomer A and diastereomer B. The resulting crystals were filtered under reduced pressure, washed with ethanol (90 mL), and dehydrated. The washed and dehydrated crystals were vacuum-dried overnight at an internal temperature of 30°C. After adding tetrahydrofuran (480 mL) to the dried crystals to suspend them, ethanol (480 mL) was added and stirred for 1 hour at room temperature under a nitrogen atmosphere, the crystals were filtered under reduced pressure, washed with ethanol (90 mL), and the filtrate was removed from the outside. Concentrated under reduced pressure at a temperature of 45°C. Ethyl acetate (32 mL) was added to the concentrate to suspend it, and ethanol (320 mL) was added thereto, followed by stirring at room temperature under a nitrogen atmosphere for 1 hour to produce crystals containing diastereomer A in a high proportion. The resulting crystals were filtered under reduced pressure, washed with ethanol (90 mL), and dehydrated. Thereafter, the obtained crystals were vacuum dried overnight at an internal temperature of 30° C. to obtain 18.8 g of a white powder. Yield: 37%, diastereomer A: 93.9% (w/w), diastereomer B 4.2% (w/w).
<실시예 2> 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 분리<Example 2> 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane-2 from a stereoisomeric mixture -separation of ol
A. (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염 제조 A. (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and salt preparation of splitting agent
실시예 1에서 수득한 분말 (2.8g; 5.04mmol)을 반응부에 투입하고 메탄올 (56mL) 및 디메틸포름아미드 (5.6mL)를 가하여 교반하였다. (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀을 가한 후 80℃로 승온하여 1시간 교반하였다. 이후, 상온으로 냉각 후 다시 0~5℃로 냉각하여 90분간 교반하였다. 고체를 여과한 후 메탄올 (14mL)로 세척하였다. 세척한 고체를 메탄올 (21mL) 및 디메틸포름아미드 (2.1mL)에 현탁 후 80℃로 승온하여 30분간 교반하였다. 혼합물을 상온으로 냉각 후 다시 0~5℃로 냉각하여 90분간 교반하였다. 고체를 여과한 후 메탄올 (10mL)로 세척하였다. 세척한 고체를 30℃ 진공 하에서 건조하여 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀의 염 1.96g을 수득하였다. 수율: 43%, 순도: 93.3%, 광학순도: 99.9%.The powder (2.8g; 5.04mmol) obtained in Example 1 was added to the reaction unit, and methanol (56mL) and dimethylformamide (5.6mL) were added thereto, followed by stirring. (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d:1',2'-f][ After adding 1,3,2] dioxaphospepine, the temperature was raised to 80° C. and stirred for 1 hour. Thereafter, after cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (14 mL). The washed solid was suspended in methanol (21 mL) and dimethylformamide (2.1 mL), and the temperature was raised to 80° C. and stirred for 30 minutes. The mixture was cooled to room temperature and then cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (10 mL). The washed solid was dried under vacuum at 30° C. (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1 -phenyl-butan-2-ol and (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dinaphtho[2,1-d: 1.96 g of a salt of 1',2'-f][1,3,2]dioxaphospepine was obtained. Yield: 43%, purity: 93.3%, optical purity: 99.9%.
B. (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 유리화 B. (1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane from the salt of the resolving agent -2-ol vitrification
단계 A에서 수득한 고체 (1.9g; 2.08mmol)를 반응부에 투입하고 톨루엔 (38mL)을 가하여 교반하였다. 탄산칼륨 (0.86g; 6.25mmol)을 물 (38mL)에 용해하여 반응부에 투입 후 10분간 교반하였다. 층분리하여 수층을 제거하고, 유기층을 물 (38mL), brine (38mL) 순으로 세척하였다. 무수 황산나트륨으로 탈수 여과 후 55℃에서 감압 농축하였다. 농축물에 에틸아세테이트 (1mL) 및 메탄올 (10mL)을 가한 후 50℃에서 1시간 교반하였다. 상온으로 냉각 후 다시 0~5℃로 냉각하여 90분간 교반하였다. 고체를 여과한 후 메탄올 (5mL)로 세척하였다. 30℃ 진공 하에서 건조하여 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 0.78g을 수득하였다. 수율: 67%, 순도: 97.6%.The solid obtained in step A (1.9 g; 2.08 mmol) was added to the reaction unit, and toluene (38 mL) was added thereto, followed by stirring. Potassium carbonate (0.86 g; 6.25 mmol) was dissolved in water (38 mL) and added to the reaction unit, followed by stirring for 10 minutes. The layers were separated to remove the aqueous layer, and the organic layer was washed with water (38 mL) and brine (38 mL) in that order. After dehydration and filtration over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure at 55°C. Ethyl acetate (1 mL) and methanol (10 mL) were added to the concentrate, followed by stirring at 50° C. for 1 hour. After cooling to room temperature, the mixture was cooled to 0-5° C. and stirred for 90 minutes. The solid was filtered and washed with methanol (5 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane 0.78 g of -2-ol was obtained. Yield: 67%, purity: 97.6%.
<실시예 3> (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 푸마르산염의 제조<Example 3> (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane- Preparation of 2-ol fumarate
실시예 2의 단계 B에서 수득한 고체 (0.75g; 1.35mmol)를 반응부에 투입하고 이소프로필알코올 (15mL)을 가하여 교반하였다. 푸마르산 (0.17g; 1.43mmol)을 가한 후 1시간 환류 교반하였다. 혼합물을 여과 후 이소프로필알코올 (3.8mL)로 세척하였다. 혼합물을 0~5℃로 냉각하여 2시간 교반하였다. 고체를 여과한 후 이소프로필알코올 (3.8mL)로 세척하였다. 30℃ 진공 하에서 건조하여 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 푸마르산염 0.78g을 수득하였다. 수율: 86%, 순도: 99.9%, 광학순도: 100%.The solid (0.75 g; 1.35 mmol) obtained in step B of Example 2 was added to the reaction unit, and isopropyl alcohol (15 mL) was added thereto and stirred. After adding fumaric acid (0.17 g; 1.43 mmol), the mixture was stirred under reflux for 1 hour. The mixture was filtered and washed with isopropyl alcohol (3.8 mL). The mixture was cooled to 0-5 °C and stirred for 2 hours. The solid was filtered and washed with isopropyl alcohol (3.8 mL). Drying under vacuum at 30°C (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butane 0.78 g of -2-ol fumarate was obtained. Yield: 86%, purity: 99.9%, optical purity: 100%.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시예일뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다. As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, it is clear that these specific descriptions are only preferred embodiments, and the scope of the present invention is not limited thereby. will be. Accordingly, it is intended that the substantial scope of the present invention be defined by the appended claims and their equivalents.
Claims (24)
Using chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine as a splitting agent, 1- ( From a mixture of stereoisomers of 6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S Optical separation of )-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol (1R Separation of ,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol.
상기 분할제는 하기 화학식 1로 표시되는 분리방법:
[화학식 1]
상기 화학식 1에서,
R1 내지 R4는 각각 독립적으로 수소 원자, 중수소 원자, 할로겐 원자, 아릴기로 치환되거나 또는 비치환된 탄소수 1 이상 5 이하의 알킬기 또는 알킬기로 치환되거나 또는 비치환된 고리형성 탄소수 6 이상 12 이하의 아릴기이고,
a 및 b는 각각 독립적으로 1 이상 2 이하의 정수이고,
c 및 d는 각각 독립적으로 1 이상 8 이하의 정수이다.
According to claim 1,
The splitting agent is a separation method represented by the following formula (1):
[Formula 1]
In Formula 1,
R 1 to R 4 are each independently a hydrogen atom, a deuterium atom, a halogen atom, an alkyl group having 1 or more and 5 or less carbon atoms substituted or unsubstituted with an aryl group, or an alkyl group substituted or unsubstituted with 6 or more ring carbon atoms and not more than 12 carbon atoms an aryl group,
a and b are each independently an integer of 1 or more and 2 or less,
c and d are each independently an integer of 1 or more and 8 or less.
상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀인 분리방법.
According to claim 1,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f][1,3,2] Dioxaphospepine Isolation method.
상기 분리방법은 (a) 상기 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물 및 상기 분할제를 유기용매에 가하여 고체 상태의 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 포함하는 혼합물을 제조하는 단계를 포함하는 것인 분리방법.
According to claim 1,
The separation method is (a) the 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane-2 (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- in a solid state by adding the stereoisomeric mixture of -ol and the resolving agent to an organic solvent A separation method comprising the step of preparing a mixture comprising (1-naphthyl)-1-phenyl-butan-2-ol and a salt of a resolving agent.
상기 단계 (a) 에서 상기 유기용매는 극성 양성자성 용매, 극성 비양성자성 용매 및 이들의 혼합용매로 이루어진 군에서 선택되는 적어도 하나를 포함하고,
상기 극성 양성자성 용매는 메탄올, 에탄올, 이소프로필알코올, n-부틸알코올, sec-부틸알코올, t-부틸알코올 및 이들의 혼합용매로 구성된 군에서 선택되는 적어도 하나를 포함하고,
상기 극성 비양성자성 용매는 에틸아세테이트, 아세토니트릴, 아세톤, 메틸에틸케톤, 메틸이소부틸케톤, 테트라하이드로퓨란, 디메틸설폭사이드, 디메틸포름아미드, 디메틸아세트아미드, N-메틸-2-피롤리돈 및 이들의 혼합용매로 구성된 군에서 선택되는 적어도 하나를 포함하는 것인 분리방법.
5. The method of claim 4,
In the step (a), the organic solvent comprises at least one selected from the group consisting of a polar protic solvent, a polar aprotic solvent, and a mixed solvent thereof,
The polar protic solvent comprises at least one selected from the group consisting of methanol, ethanol, isopropyl alcohol, n-butyl alcohol, sec-butyl alcohol, t-butyl alcohol, and a mixed solvent thereof,
The polar aprotic solvent is ethyl acetate, acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methyl-2-pyrrolidone and Separation method comprising at least one selected from the group consisting of a mixed solvent thereof.
상기 유기용매는 메탄올을 포함하거나 또는 메탄올 및 상기 극성 비양성자성 용매의 혼합용매를 포함하고,
상기 극성 비양성자성 용매는 테트라하이드로퓨란, 디메틸포름아미드 및 N-메틸-2-피롤리돈 중 선택되는 적어도 하나를 포함하는 분리방법.
6. The method of claim 5,
The organic solvent includes methanol or a mixed solvent of methanol and the polar aprotic solvent,
The polar aprotic solvent is a separation method comprising at least one selected from tetrahydrofuran, dimethylformamide and N-methyl-2-pyrrolidone.
상기 혼합용매에서 상기 메탄올 대 상기 극성 비양성자성 용매의 부피 비율은 10:0.5 내지 10:2인 분리방법.
7. The method of claim 6,
The volume ratio of the methanol to the polar aprotic solvent in the mixed solvent is 10:0.5 to 10:2.
상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀인 분리방법.
5. The method of claim 4,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f][1,3,2] Dioxaphospepine Isolation method.
상기 분리방법은 (b) 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 제조하는 단계를 더 포함하는 것인 분리방법.
5. The method of claim 4,
The separation method is (b) the (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl) from salts of -butan-2-ol and resolving agent Separation method further comprising the step of preparing -1-phenyl-butan-2-ol.
상기 단계 (b)는
상기 염의 현탁액을 제조하는 단계; 및
상기 현탁액에 탄산염 또는 인산염 중 적어도 하나를 첨가하는 단계를 포함하는 것인 분리방법.
10. The method of claim 9,
The step (b) is
preparing a suspension of the salt; and
Separation method comprising the step of adding at least one of carbonate or phosphate to the suspension.
상기 단계 (b)에서 상기 현탁액의 용매는 비극성 유기용매인 분리방법.
11. The method of claim 10,
In step (b), the solvent of the suspension is a non-polar organic solvent.
상기 입체이성질체 혼합물에서 상기 입체이성질체 혼합물의 전체 중량을 기준으로 한 상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 중량 비율은 90 중량% 이상인 분리방법.
According to claim 1,
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-( 1-Naphthyl)-1-phenyl-butan-2-ol and (1S,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1 -Naphthyl)-1-phenyl-butan-2-ol in a weight ratio of 90% by weight or more.
상기 입체이성질체의 혼합물은
(a1) 3-벤질-6-브로모-2-메톡시퀴놀린을 염기 및 3-(디메틸아미노)-1'-프로피오나프톤과 반응시킨 후 산을 첨가하는 단계; 및
(b1) 상기 단계 (a1)에서 수득한 반응 혼합물을 결정화하여 결정을 생성하는 단계를 포함하는 입체이성질체 혼합물의 제조 방법에 의해 수득 되는 것인 분리방법.
According to claim 1,
The mixture of stereoisomers is
(a1) reacting 3-benzyl-6-bromo-2-methoxyquinoline with a base and 3-(dimethylamino)-1'-propionaphthone, followed by addition of an acid; and
(b1) a separation method obtained by a method for preparing a stereoisomeric mixture comprising the step of crystallizing the reaction mixture obtained in step (a1) to produce crystals.
상기 입체이성질체 혼합물의 제조 방법은 (c1) 상기 단계 (b1)의 결정으로부터 (1R,2R)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 (1S,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올의 혼합물을 제거하여 입체이성질체 혼합 용액을 수득하는 단계를 더 포함하는 것인 분리방법.
14. The method of claim 13,
The method for preparing the stereoisomeric mixture is (c1) (1R,2R)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2 from the crystal in step (b1). -(1-naphthyl)-1-phenyl-butan-2-ol and (1S,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2- The separation method further comprising the step of removing the mixture of (1-naphthyl)-1-phenyl-butan-2-ol to obtain a mixture of stereoisomers.
상기 단계 (c1)은 상기 단계 (b1)의 결정을 에탄올; 및 에틸아세테이트, 테트라하이드로퓨란 및 디클로로메탄 중 선택되는 적어도 하나를 포함하는 혼합용매에 가하는 단계를 포함하는 것인 분리방법.
15. The method of claim 14,
The step (c1) is ethanol; and adding to a mixed solvent comprising at least one selected from ethyl acetate, tetrahydrofuran and dichloromethane.
(d1) 상기 단계 (c1)에서 수득한 입체 이성질체 혼합 용액에 포함된 입체이성질체 혼합물을 결정화하는 단계를 더 포함하는 것인 분리방법.
15. The method of claim 14,
(d1) The separation method further comprising the step of crystallizing the stereoisomer mixture contained in the stereoisomer mixture solution obtained in step (c1).
상기 단계 (b1) 및 상기 단계 (d1)의 결정화 단계는 에탄올; 또는 에틸아세테이트 및 에탄올의 혼합용매를 사용하는 것인 분리방법.
17. The method of claim 16,
The crystallization step of step (b1) and step (d1) is ethanol; Or a separation method using a mixed solvent of ethyl acetate and ethanol.
Using chiral octahydro-4-hydroxy-4-oxide-dynaphtho [2,1-d: 1 ', 2'-f] [1,3,2] dioxaphospepine as a splitting agent, 1- ( From a mixture of stereoisomers of 6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutan-2-ol (1R,2S optical separation of )-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol; (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol comprising , or a method for preparing a pharmaceutically acceptable salt thereof.
상기 분할제는 (11bR)-8,9,10,11,12,13,14,15-옥타하이드로-4-하이드록시-4-옥사이드-디나프토[2,1-d:1',2'-f][1,3,2]디옥사포스페핀인 제조방법
19. The method of claim 18,
The splitting agent is (11bR)-8,9,10,11,12,13,14,15-octahydro-4-hydroxy-4-oxide-dynaphtho[2,1-d:1 ',2' -f] [1,3,2] dioxaphospephine production method
상기 광학 분리하는 단계는 (a) 1-(6-브로모-2-메톡시퀴놀린-3-일)-4-(디메틸아미노)-2-(나프탈렌-1-일)-1-페닐부탄-2-올의 입체이성질체 혼합물 및 상기 분할제를 유기용매에 가하여 고체 상태의 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염을 포함하는 혼합물을 제조하는 단계를 포함하는 것인 제조방법.
19. The method of claim 18,
The optical separation step is (a) 1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-(naphthalen-1-yl)-1-phenylbutane- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2 in a solid state by adding the stereoisomeric mixture of 2-ol and the resolving agent to an organic solvent -(1-naphthyl)-1-phenyl-butan-2-ol and a preparation method comprising the step of preparing a mixture comprising a salt of the resolving agent.
상기 단계 (a)에서 상기 유기용매는 메탄올, 또는 메탄올 및 디메틸포름아미드를 포함하고,
상기 메탄올 및 상기 디메틸포름아미드의 부피 비율은 10:0.5 내지 10:2인 제조방법.
21. The method of claim 20,
In step (a), the organic solvent includes methanol, or methanol and dimethylformamide,
The volume ratio of the methanol and the dimethylformamide is 10:0.5 to 10:2.
상기 제조방법은 (b) (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 및 분할제의 염으로부터 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 유리화하는 단계를 더 포함하는 것인 제조방법.
21. The method of claim 20,
The preparation method is (b) (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)- from salts of butan-2-ol and resolving agent The method further comprising the step of liberating 1-phenyl-butan-2-ol.
상기 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올을 산과 반응시키는 단계를 더 포함하는 것인 제조방법.
19. The method of claim 18,
(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol The method further comprising the step of reacting with an acid.
상기 약제학적으로 허용 가능한 염은 (1R,2S)-1-(6-브로모-2-메톡시퀴놀린-3-일)-4-디메틸아미노-2-(1-나프틸)-1-페닐-부탄-2-올 푸마르산염인 제조방법.19. The method of claim 18,
The pharmaceutically acceptable salt is (1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl -Butan-2-ol fumarate production method.
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| ZA2021/03567A ZA202103567B (en) | 2020-07-01 | 2021-05-26 | Process for preparing (1r,2s)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl-butan-2-ol and pharmaceutically acceptable salt thereof |
| UAA202103258A UA125989C2 (en) | 2020-07-01 | 2021-06-11 | Method for the preparation of (1r,2s)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-dimethylamino-2-(1-naphthyl)-1-phenylbutan-2-ol and its pharmaceutically acceptable salt |
| CN202110703065.2A CN114085185B (en) | 2020-07-01 | 2021-06-24 | Method for preparing bedaquiline and pharmaceutically acceptable salts thereof |
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| CN107857727B (en) * | 2017-10-26 | 2019-10-18 | 江苏天和制药有限公司 | A kind of preparation method of (1R, 2S) and (1S, 2R)-Bei Da quinoline |
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