KR920003100B1 - (-)-6,6-디메틸바이싸이클로[3.3.1]엡트-2-엔-2-메탄올 유도체의 제조방법 - Google Patents
(-)-6,6-디메틸바이싸이클로[3.3.1]엡트-2-엔-2-메탄올 유도체의 제조방법 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
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- 150000002118 epoxides Chemical class 0.000 claims description 7
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
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- TVZRAEYQIKYCPH-UHFFFAOYSA-N 3-(trimethylsilyl)propane-1-sulfonic acid Chemical compound C[Si](C)(C)CCCS(O)(=O)=O TVZRAEYQIKYCPH-UHFFFAOYSA-N 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
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- VLYIFKVQCHXFQK-UHFFFAOYSA-N [4-(hydroxymethyl)cyclohex-3-en-1-yl]methanol Chemical compound OCC1CCC(CO)=CC1 VLYIFKVQCHXFQK-UHFFFAOYSA-N 0.000 description 1
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- 238000006703 hydration reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
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- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-N propane-1-sulfonic acid Chemical compound CCCS(O)(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-N 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
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- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- 229910052623 talc Inorganic materials 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
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- 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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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/48—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by oxidation reactions with formation of hydroxy groups
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- C07C2602/00—Systems containing two condensed rings
- C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
- C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms
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Abstract
내용 없음.
Description
본 발명은 다음 구조식을 가진 화합물 α, α-디메틸-5-하이드록시-3 싸이클로헥센-1, 4-디메탄올을 제조하는 방법에 관한 것이다.
약호 1446 C10H18O3분자량 186.24; m.p.114-116℃(-)-6, 6-디메틸바이싸이클로[3.3.1]엡트-2-엔-메탄올((-)미르레놀로 공지, 1981-1982 Aldrich-Europe Catalog Handbook of Fine Chemicals, N°18.841-7 참고)은 m-클로로벤조산 또는 과초산(40℃ 아세트용액)과 같은 과산으로 처리하여 에폭사이드를 형성할 수 있다고 발견되었다.
에폭사이드는 특히 산 수용체로서 작용하는 무수 탄산나트륨의 존재하에 무수 메틸렌 클로라이드(에탄올유리) 매체내에 과초산이 작용된때 얻어진다. 반응 매체내에서 에폭시화와 함께 여과 또는 물 용해 및 형성된 에폭사이드의 클로로메틸렌 용액의 분리에 의하여 제거될 수 있는 초산나트륨 및 무수 중탄산나트륨의 동일몰량 염 혼합물이 형성된다. 분리된 유기 클로로메틸렌 용액은 감압하에 증발에 의하여 농축되어 농축된 에폭사이드를 얻는다. 일반식(2)의 (-)-6, 6-디메틸바이싸이클로[3.3.1]엡트-2-엔-2-에탄올의 에폭사이드를 얻은 후에 1°부터 20℃온도에서 희석된 강산(H2SO4, H3PO4의 1% 용액) 또는 약산(H2CO3, H2SO3)의 존재하에 수성 매체내에서 얻어질 수 있는, 수화 생성물을 조사한다. 그렇게 본 발명의 물질인 일반식(1)의 생성물을 얻는다.
일반식(1)의 생성물은 기관지 분비액에 대한 점액제로서 흥미있는 약리학적 활성을 갖고 있어, 기관지폐의 급성뿐만 아니라 만성 질병에 대한 신규의 치료약의 구성 요소가 될 수 있다.
약호 1470의 합성 개요
원소분석
이론치(%) : C ; 64.49%, H ; 9.74%, O ; 25.77%
실험치(%) : C ; 64.37%, H ; 9.92%
C ; 64.40%, H ; 9.94%
C ; 64.35%, H ; 9.86%
I.R.nujol(분산액 : ㎝-1) : 3290νOH, 1140; 1057; 1025; 1011; 1005; 963 ; 930; 835; 특성적 밴드 N.M.R(D2O용매 ; D.S.S. 기준물질; oppm) : 6.0중심 c.a.(1H; =CH), 4.33 중심 c.a.(1H; CH-OH; W½=7.5H2), 4.12 c.a.(2H; CH2-OH), 2.43 ÷1.32 c.a.(5H; CH2-CH-CH2), 1.22 s.(6H; 같은 탄소상의 CH3).
c.a. = 복합흡수, W=중간 높이에서 광폭, D.S.S.=3(트리메틸실릴), 프로판-설폰산, 나트륨염. M.S.(사중극 ; 전자 충격, 직접 삽입, 80eV, 70㎃, m/z) : 168[(M-18)+, 1%]; 153[M-18-15)+, 3%]; 151(2%); 150(10%); 137(8%); 135(13%); 126(11%); 122(4%); 114(11%); 110%(10%); 109(9%); 108(17%); 107(16%); 106(5%); 105(3%); 97(5%); 96(9%); 95(41%); 94(5%); 93(12%); 92(23%);91(22%); 82(9%); 81(275); 80(9%); 79(44%); 78(11%); 77(15%); 69(17%); 57(16%); (기본피크).
표 1-약호 1470의 기관지의 분비 촉진제 활성
다음은 약호 1470 및 다른 공지의 표준 물질로 처리했을때 기관지 점액 분비의 평균 증가 %이다. 또한, 다양한 복용얄 및 두 투약 방법을 사용하여 약호 1470으로 처리하였을때, 모든 토끼 수에 대한 기관지 분비액이 증가한 토기 수가 기록되었다.
[실시예]
300㎖메틸렌 클로라이드내에 30g(-)-6, 6-디메틸바이싸이클로-[3.3.1]엡트-2-엔-2-메탄올의 용액에 34g의 무수 탄산나트륨을 부가한다. 결과 혼합물은 5°에서 10℃까지 냉각하고 격렬한 교반하에 60㎖의 40% 과초산을 부가한다. 부가의 말기에, 냉각을 중단하고 혼합물은 12시간 이상 상온에서 교반 방치한다. 반응 혼합물은 물로 희석하고 유기상은 분리하고 물로 세척하고 탈수하고 증발 건조시켜 31.5g(95%)의 에폭사이드를 얻는다. 상기 화합물에 60㎖ 물 및 10g 고체 이산화탄소를 부가하고, 결과 혼합물을 3시간 격렬히 교반한다. 염화나트뮬으로 포화된 물로 희석하고 에틸아세테이트로 반복 추출한다. 결합된 유기상의 소량의 물로 세척하고 무수화(anhydrified)하고 약 100㎖ 부피로 농축한다. 침전은 흡입 여과해 14g(38%) 백색 결정성 생성물(m.p. 114-116℃를 얻는다. 일반식(1)의 화합물의 점액 분비 촉진제로서의 활성에 관하여, 본 발명은 복용 단위로 일반식(1)을 포함하는 제약학적 조성물을 또한 제공한다. 상기의 활성성분을 포함하는 제약학적 형태는 근육내, 정맥내 및 경구투여뿐만 아니라 연무질(aerosol)-형태인데 상세히 말하면 : 캡슐, 정제, 카세내의 과립 형태, 시럽 및 직장투여 행태인 좌약이다.
상기 형태에서 통상적인 부형제는 일반식(1)의 화합물과 결합한다.
고체 경구투여 형태(정제,캡슐,과립 형태)에서 바람직한 부 형태는 : 침전된 실리카, 탈크, 캡슐 또는 마그네슘 스테아테이트같은 제약학적 형태의 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 연무 형태에서, 일반식(1)의 화합물은 등장 용액으로 되고 냉각 살균 또는 고온 살균된다.
Claims (1)
- 40% 아세트 용액내의 과초산을 사용하여 무수 탄산나트뮬의 존재하에 5°∼10℃의 온도에서 에탄올 유리된 무수 메틸렌 클로라이드 매체에서(-)-6,6-디메틸바이싸이클로[3.3.1]엡트-2-엔-메탄올을 에폭시화하고, 염으로부터 분리하여 얻어진 순수한 에폭사이드를 약한 산수성 매체내의 1°∼20℃ 온도에서 수화시키고 그것을 염화나트륨 용액의 존재하에 에틸아세테이트로 추출하고 유기상을 농축하여 결정 형태로 얻는 것을 특징으로 하는, 다음 일반식(1)의 α, α-디메틸-5-하이드록시-3-싸이클로헥센-1,4-디메탄올의 제조방법.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22258/84A IT1196214B (it) | 1984-08-08 | 1984-08-08 | Derivato del(-)-6,6-dimetilbiciclo(3.3.1)ept-2-ene-2-metanolo ad attivita' mucosecretolitica,procedimento per la sua preparazione e sue composizioni farmaceutiche |
| IT22258A/84 | 1984-08-08 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR860001776A KR860001776A (ko) | 1986-03-22 |
| KR920003100B1 true KR920003100B1 (ko) | 1992-04-18 |
Family
ID=11193772
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019850005645A KR920003100B1 (ko) | 1984-08-08 | 1985-08-06 | (-)-6,6-디메틸바이싸이클로[3.3.1]엡트-2-엔-2-메탄올 유도체의 제조방법 |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4605792A (ko) |
| EP (1) | EP0177673B1 (ko) |
| JP (1) | JPS6147431A (ko) |
| KR (1) | KR920003100B1 (ko) |
| AT (1) | ATE66667T1 (ko) |
| DE (1) | DE3583910D1 (ko) |
| IT (1) | IT1196214B (ko) |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA649603A (en) * | 1962-10-02 | J. Durbetaki Anthony | Preparation of sobrerol | |
| US2883398A (en) * | 1957-12-31 | 1959-04-21 | Union Carbide Corp | Epoxy-vinyl monomers and method of preparing the same |
| US2949489A (en) * | 1958-06-23 | 1960-08-16 | Fmc Corp | Preparation of sobrerol |
| CH568951A5 (ko) * | 1970-04-17 | 1975-11-14 | Corvi Camillo Spa | |
| CH549006A (de) * | 1971-02-11 | 1974-05-15 | Corvi Camillo Lab Biochimici F | Verfahren zur herstellung von (alpha)-pinenoxyd. |
-
1984
- 1984-08-08 IT IT22258/84A patent/IT1196214B/it active
-
1985
- 1985-06-07 US US06/742,574 patent/US4605792A/en not_active Expired - Fee Related
- 1985-06-19 DE DE8585107580T patent/DE3583910D1/de not_active Expired - Fee Related
- 1985-06-19 EP EP85107580A patent/EP0177673B1/en not_active Expired - Lifetime
- 1985-06-19 AT AT85107580T patent/ATE66667T1/de not_active IP Right Cessation
- 1985-08-05 JP JP60171262A patent/JPS6147431A/ja active Granted
- 1985-08-06 KR KR1019850005645A patent/KR920003100B1/ko active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| EP0177673A3 (en) | 1986-07-16 |
| EP0177673B1 (en) | 1991-08-28 |
| JPS6147431A (ja) | 1986-03-07 |
| EP0177673A2 (en) | 1986-04-16 |
| ATE66667T1 (de) | 1991-09-15 |
| IT8422258A0 (it) | 1984-08-08 |
| JPS647056B2 (ko) | 1989-02-07 |
| US4605792A (en) | 1986-08-12 |
| IT1196214B (it) | 1988-11-16 |
| KR860001776A (ko) | 1986-03-22 |
| DE3583910D1 (de) | 1991-10-02 |
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