KR920001788B1 - (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온에서 유도된 디아스테레오머 혼합물의 제조 방법 - Google Patents
(-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온에서 유도된 디아스테레오머 혼합물의 제조 방법 Download PDFInfo
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- KR920001788B1 KR920001788B1 KR1019850005443A KR850005443A KR920001788B1 KR 920001788 B1 KR920001788 B1 KR 920001788B1 KR 1019850005443 A KR1019850005443 A KR 1019850005443A KR 850005443 A KR850005443 A KR 850005443A KR 920001788 B1 KR920001788 B1 KR 920001788B1
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- cyclohexene
- hydroxy
- mixture
- methanol
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- LJAOOBNHPFKCDR-UHFFFAOYSA-K chromium(3+) trichloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Cr+3] LJAOOBNHPFKCDR-UHFFFAOYSA-K 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/36—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal
- C07C29/38—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones
- C07C29/40—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring increasing the number of carbon atoms by reactions with formation of hydroxy groups, which may occur via intermediates being derivatives of hydroxy, e.g. O-metal by reaction with aldehydes or ketones with compounds containing carbon-to-metal bonds
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/10—Expectorants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C35/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic
- C07C35/08—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings
- C07C35/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring monocyclic containing a six-membered rings with unsaturation at least in the ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
- C07C45/292—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups with chromium derivatives
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- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
Abstract
내용 없음.
Description
본 발명은 다음 구조식을 가진 (1) (1S-5R) 5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로히센-1-메탄올(약호 1516) 및 (2) (1S-5S) 5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로히센-1-메탄올(약호 1517)을 제조하는 방법에 관한 것이다.
약호 1517인 구조식(2)의 화합물 55.55% 및 약호 1516인 구조식(1)의 화합물 44.44%가 m.p. 77-100℃이고 약호 1483인 화합물(3)을 구성한다.
본 발명의 활성 물질의 제조에 대한 출발 화합물은 (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온이다.
문헌에 공지되어 있는 상기 화합물은 다음 구조식을 갖고 카본(Carvone)수화물, 하이드록시카보탄-아세톤이라 불린다(Rupe 및 Schlochoff, Ber. 1905 Vol.38페이지 1719; Harry Schmidt, Chem. Ber. 1953, 11, 페이지 1442)
상업적으로 유용하지 않은 상기 물질은 (-) 트랜스-5-하이드록시-α,α-4,5-트리메틸-3-싸이클로헥센-1-메탄올((-)-트랜스-소브레롤)을 존스(Jones) 시약으로 산화하여 합성되었다.
* Jones 시약
26.72의 CrO3를 45ml물에 용해하고, 교반하면서 23ml틴의 농축된 H2SO4를 조심스럽게 부가하고, 혼합물은 물로 100ml를 만든다.
출발 물질을 제조하는 방법 :
일반식 (4)의 (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온
800ml 아세톤내에 현탁된 20g (-) 트랜스-1-소브레롤에, 얼음 물에 냉각하면서, 격렬한 기계 교반(침전하는 크로뮴 염은 출발 소브레롤과 결합하는 경향이 있기 때문에 중요하다)하에 55ml Jones 시약을 오렌지 색을 띨때까지 적가한다. 약 1시간 동안 교반을 계속하고 과량의 크로뮴(4)는 이소프로판올에 의해 파괴되고(혼합물은 다시 암녹색이 된다). 혼합물은 탈광수로 회석한다. 혼합물은 에틸 아세테이트로 완전히 (4×500m1) 추출하고, Na2SO4로 건조하고, 증발 건조하여, 3 : 1 싸이클로헥산/에틸 아세테이트로 용출하는 400g 실리카겔 크로마토그래프한다. 14g(-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로 헥센-1-온을 얻는다.
약호 1483(약호 1516+약호 1517)의 합성 개요
[실시예 1]
약호 1483인 혼합물(3)의 제조
-30 에서 냉각된, 에틸 에테르내의 10g (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온의 용액에 교반하면서 에틸 에테르내의 100m1 5% 메틸리튬 용액을 천천히 부가한다. 혼합물은 12시간 동안 상온에서 교반하면서 방치하고, 물로 희석하고, 에테르성 상은 분리하고, 다시 그 상을 물로 세척하고, 무수 황산 나트륨 상에서 건조시키고, 증발 건조한다. 잔사는 이소프로필 에테르내에서 세분하여, 9g(82%) 디아스테레오머의 혼합물(m.p.77-100℃)을 얻는다. 이것은 6 : 4 싸이클로헥산/에틸 아세테이트로 용출하는 실리카겔 컬럼 크로마토그래피에 의하여 분리된다. mp 101-104℃ 이고 높은 이동률(Rf)인 5g 약호 1517 및 mP 114-116℃ 이고 낮은 이동률인 4g 약호 1516을 얻는다.
약호/1517
IR(nujol 분산액 ; cm-') : 3440 및 3360 v OH 1163; 1088; 1003; 989; 920; 810 특징적 밴드
NMR(90MHz,용매 : CDCI3; TMS 기준물질; δppm); 5.39 중심 c.a. (1H=CH) 2.15+1.35 c.a.(8H : CH2-CH-CH2및 CH3-C=) 1.33 s(3H; CH3-C-OH) 1,2 s(6H; 같은 탄소상의 CH3) c.a.=복합흡수 s=단일선 TMS=테트라메틸실란.
NMR(300MHz,CDCl3용매) : C(5)- CH3ax=0.75HZ(대표적인 트랜스-이축결합)
MS(사중극, 전자충격, 직접 삽입, (80ev, 및 80mA, m/z) : 156[(m-18)+, 14%], 151[(M-18-15)+,24%]; 133(6%); 123(24%); 111(7%); 110(6%); 109(58%); 108(52%); 107(30%); 105(5%); 95(18%); 94(10%); 93(81%); 91(22%); 83(12%); 81(15%); 79(12%); 77(17%); 67(15%); 59(기본 피크).
계산치(%) : C; 71.70, H : 10.94, O : 17.36
실측치(%) : C; 71.80, H : 10.87
C; 71.89, H : 10.79
C; 71.81, H : 10.82
약호/1516
IR(nujol 분산액; cm-1) : 3310ν OH 1285; 1150; 1086; 1059; 973; 923; 874; 811 특징적 밴드
NMR(90MHz; 용매 : CDCl3; TMS 기준물질; δppm) : 5.47 중심 c.a.(1H,CH=) 2.3÷1.1 c.a.(7H,CH2-CH-CH2및 (CH3)2-C-
) 1.73 b.s.(3H,CH3-C=C) 1.3 s.(3H,C=C-C-
) 1.2 및 1.17 2s.(6H, 같은 탄소상의 CH3) TMS=테트라메틸실란 s.=단일선, 2s.=2단일선, c.a.=복합흡수, b.s.=광폭 단일선
MS(사중극; 직접 삽입; 전자 충격 (80eV, 및 80mA, m/z) : 169[(M-15)+, 1%], 166[(M-18)+; 5%]; 151[(M-18-15)+; 17%]; 148(3%); 133(3.5%); 123(23%); 111(6%); 109(43%); 108(13%); 107(12%); 105(4%); 95(9%); 93(39%); 91(12%); 83(10%); 81(9%); 77(11%); 67(11%); 59(기본 피크).
의외로, 만약 상기 방법으로 제조된 (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-싸이클로헥센-1-온이 중성 용액내의 메틸리튬으로 처리된다면, 이것은 본 발명 물질의 하나인 디아스테레오머(약호 1483)의 혼합물(3)으로 전환됨이 발견되었다. 또한 혼합물은 크로마토그래피하여 개별 성분인 (1)=약호 1516 및 (2)=약호 1517로 분리될 수 있다.
상기의 분석적으로 동일한 성분(1) 및 (2)도 또한 본 발명의 물질이다.
혼합물(3) 및 그것의 성분(1) 및 (2)는 약리학적으로 검사될때, 기관지 분비액의 점액 성질을 보여, 이것은 기관지 폐의 병치료에 적용될 수 있는 약임을 지적한다.
표 1 약호 1483의 기관지의 분비 촉진제 활성
다음은 약호 1483뿐만 아니라 기타 공지의 표준 물질로 처리했을때 기관지 점액 분비의 평균 증가 %이다. 또한 다양한 복용량 및 두 투약 방법을 사용하여 약호 1483으로 처리했을때, 모든 토끼수에 대한 기관지 분비액이 증가한 토끼 수가 기록되었다.
(1) 및 (2)의 혼합물(3)(약호 1483)의 점액 분비 촉진제로서의 활성에 관하여, 본 발명은 복용 단위로 화합물(3)을 포함하는 제약학적 조성물을 또한 제공한다. 활성 성분의 상기 혼합물을 포함하는 제약하적 형태는 경우 투여뿐만 아니라 주사 및 연무질(aersol)형태인데, 상세히 말하면, 캡슐, 정제, 카세내의 과립형태, 시럽 및 직장 투여 형태인 좌약이다.
상기의 형태에서, 통상적인 부형제는 혼합물(3)과 결합한다.
고체 경구형태(정제, 캡슐, 과립형태)에서, 바람직한 부형제는 : 침전된 실리카, 탈크, 캘슘 또는 마그네슘 스테아레이트같은 제약학적 제제에 대한 모든 담체 물질을 가진 락토스, 전분, 셀룰로우스 및 그들의 유도체이다.
시럽 형태에서, 활성 화합물은 방향제 및 보호제의 첨가로 당(Sugar)용액(설탕, 포도당, 소비톨)내에 용해된다.
좌약 형태에서, 주요 부형제는 지방산의 트리글리세라이드로 구성되고, 순수하거나 또는 옥시에틸화된 유도체와 혼합물이다.
주사 또는 연무형태에서, 혼합물(3)은 등장 용액으로 되고 냉각 살균 또는 고온 살균된다.
Claims (2)
- 에틸 에테르내의 (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온을 -30℃에서 5% 메틸리튬의 에테르 용액과 반응시키고, 반응 혼합물을 12시간동안 상온에서 연속적으로 교반하고, 물로 세척하고, 증발 건조하고, 이소프로필 에테르로 정제하여 디아스테레오머 혼합물을 얻는 것을 특징으로 하는, 44.44%(1S-5R)-5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올 및 55.55%(1S-5S)-5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올로 구성된 디아스테레오머 혼합물을 제조하는 방법.
- 44.44%(1S-5R)-5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올 및 55.55%(1S-5S)-5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올로 구성된 디아스테레오머 혼합물이 6 : 4 싸이클로헥산/에틸 아세테이트로 용출하는 실리카 겔 크로마토그래피에 의해서 분리되는 것을 특징으로 하는, (1S-5R)-5-하이드록시-α,α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올 및 (1S-5S)-5-하이드록시-α, α-4,5-테트라메틸-3-싸이클로헥센-1-메탄올인 디아스테레오머를 제조하는 방법.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22257-A/84 | 1984-08-08 | ||
| IT22257A/84 | 1984-08-08 | ||
| IT22257/84A IT1180220B (it) | 1984-08-08 | 1984-08-08 | Miscela di composti diastereoisomeri, ottenuti da (-)-5-(1-idrossi-1-metiletil)-2-metil-2-cicloesen-1-one, avente attivita' mucosecretolitica, procedimento per la sua preparazione e composizioni farmaceutiche che la contengono |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR860001778A KR860001778A (ko) | 1986-03-22 |
| KR920001788B1 true KR920001788B1 (ko) | 1992-03-02 |
Family
ID=11193758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019850005443A KR920001788B1 (ko) | 1984-08-08 | 1985-07-29 | (-)-5-(1-하이드록시-1-메틸에틸)-2-메틸-2-싸이클로헥센-1-온에서 유도된 디아스테레오머 혼합물의 제조 방법 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4596894A (ko) |
| EP (1) | EP0170839B1 (ko) |
| JP (1) | JPS6147432A (ko) |
| KR (1) | KR920001788B1 (ko) |
| AT (1) | ATE45939T1 (ko) |
| DE (1) | DE3572649D1 (ko) |
| IT (1) | IT1180220B (ko) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10347484B2 (en) | 2015-08-25 | 2019-07-09 | Samsung Display Co., Ltd. | Laser crystallizing apparatus |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH681060A5 (ko) * | 1990-08-22 | 1993-01-15 | Riace Ets |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2949489A (en) * | 1958-06-23 | 1960-08-16 | Fmc Corp | Preparation of sobrerol |
| CH568951A5 (ko) * | 1970-04-17 | 1975-11-14 | Corvi Camillo Spa |
-
1984
- 1984-08-08 IT IT22257/84A patent/IT1180220B/it active
-
1985
- 1985-06-19 EP EP85107579A patent/EP0170839B1/en not_active Expired
- 1985-06-19 US US06/746,559 patent/US4596894A/en not_active Expired - Fee Related
- 1985-06-19 AT AT85107579T patent/ATE45939T1/de not_active IP Right Cessation
- 1985-06-19 DE DE8585107579T patent/DE3572649D1/de not_active Expired
- 1985-07-29 KR KR1019850005443A patent/KR920001788B1/ko active IP Right Grant
- 1985-08-07 JP JP60172534A patent/JPS6147432A/ja active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10347484B2 (en) | 2015-08-25 | 2019-07-09 | Samsung Display Co., Ltd. | Laser crystallizing apparatus |
Also Published As
| Publication number | Publication date |
|---|---|
| IT8422257A0 (it) | 1984-08-08 |
| DE3572649D1 (en) | 1989-10-05 |
| JPS647057B2 (ko) | 1989-02-07 |
| JPS6147432A (ja) | 1986-03-07 |
| US4596894A (en) | 1986-06-24 |
| EP0170839A3 (en) | 1987-06-03 |
| IT1180220B (it) | 1987-09-23 |
| ATE45939T1 (de) | 1989-09-15 |
| EP0170839A2 (en) | 1986-02-12 |
| EP0170839B1 (en) | 1989-08-30 |
| KR860001778A (ko) | 1986-03-22 |
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