CN1041829C - Synthetic technology of 17a-acetylene estriol-3-cyclopentana ether - Google Patents
Synthetic technology of 17a-acetylene estriol-3-cyclopentana ether Download PDFInfo
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- CN1041829C CN1041829C CN93107394A CN93107394A CN1041829C CN 1041829 C CN1041829 C CN 1041829C CN 93107394 A CN93107394 A CN 93107394A CN 93107394 A CN93107394 A CN 93107394A CN 1041829 C CN1041829 C CN 1041829C
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- amyl ether
- acetylene
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- phenolic ketone
- female phenolic
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Abstract
The present invention provides a novel technology for synthesizing 17 alpha-ethynylestriol-3-cyclopentyl ether of a steroid hormone medicament. The existing preparation method has long reaction route, seven reaction steps, many byproducts and complicated separation and operation. The present invention takes estrone as raw material, and the reaction is completed by four steps. Simultaneously, the stereoselectivity of the 17 alpha-ethynylation and the yield of 3-hydroxy cyclopentyl ether are greatly enhanced.
Description
The present invention relates to the preparation method of known compound 17 α-acetylene trihydroxy-oestrin-3-ring amyl ether.
17 α-acetylene trihydroxy-oestrin-3-ring amyl ether is a kind of steroidal estrogens medicine, and commodity are called nilestriol (Nilestriol).Existing preparation method through enol esterification, epoxidation, rearrangement reaction, obtains 3,16 α-diacetoxy-1 from female phenolic ketone (I), 3,5 (10)-female steroids triolefin-17-ketone (V), (Leeds et al, J.Am, Chem.Soc.76,2943-8,1954).V and ethynyl magnesium bromide reaction obtain 17 α-acetylene trihydroxy-oestrin (VI) and 17 β-acetylene trihydroxy-oestrin isomer (VII) mixture (Englefried et al, Azneim.Forsch.16:1518-21,1966), VII generates ketal thing (IX) through the acetone reaction of contracting, use column chromatography, obtain 17 pure α-acetylene trihydroxy-oestrin (VI), VI and sodium methylate reaction make 3 hydroxyl salifies, obtain 17 α-acetylene trihydroxy-oestrin-3-ring amyl ether (VIII) (Kraay et al with the bromocyclopentane reaction then, U.S.Pant3868452,1975).(see figure 1)
Existing preparation method's weak point mainly contains 3 points: the one, and reaction scheme is long, from the female phenolic ketone of raw material (I) to target compound 17 α-acetylene trihydroxy-oestrin-3-ring amyl ether (VIII) must be through the reaction of seven steps, intermediate enol acetyl thing (II) and epoxy material (III) instability, side reactions such as deacetylation take place easily, for obtaining pure rearrangement product (V), need acetylize again; Two is 17 α ethinylations reactions owing to adopt lattice for reagent, and addition reaction is sterically hindered big, generates 17 more β-acetylene steric isomer (VII), with the acetone that contracts react and column chromatography for separation complicated operation, productive rate low; The 3rd, when encircling the amyl ether reaction at last, substitution reaction takes place on ethynyl easily, increase by product, influence overall yield and quality product.
The present invention proposes the variation route of preparation 17 a α-acetylene trihydroxy-oestrin-3-ring amyl ether (VIII), be raw material promptly with female phenolic ketone (I), through following four-step reaction: the one, use the Anhydrous potassium carbonate salify earlier, then with bromocyclopentane ring amyl etherization, make female phenolic ketone-3-and encircle amyl ether (X); The 2nd, X is reacted with cupric bromide in methanol solution, makes the female phenolic ketone of 16 α-bromo--3-and encircles amyl ether (XII); The 3rd, XII issues unboiled water in alkaline condition and separates reaction in dimethyl formamide solution, makes 16 Alpha-hydroxies-female phenolic ketone-3-and encircles amyl ether (XII); The 4th, XII is reacted with the acetylene lithium in tetrahydrofuran solution, makes 17 α-acetylene trihydroxy-oestrin-3-and encircles amyl ether (VIII).(synthetic route is seen Fig. 2)
The preparation method of the present invention 17 α-acetylene-trihydroxy-oestrin-3-ring amyl ether, its advantage is: (1) reactions steps goes on foot from seven than existing preparation method and foreshortened to for four steps; (2) ring amyl ether employing Anhydrous potassium carbonate replaces the sodium methylate salify, moves on to the foremost from final step and carries out, and makes yield bring up to 96% from 56%; (3) 16 α hydroxylations adopt the cupric bromide bromination, use basic hydrolysis then, and are stronger than adopting enol esterification, epoxidation, rearrangement transposition stereospecificity; (4) ethinylation adopts acetylene lithium replace ethine magnesium bromide that stereoselectivity α/β was increased to 9: 1 from 6: 4.
Embodiment:
1. the preparation of female phenolic ketone-3-ring amyl ether (x)
The 50 female phenolic ketones of gram (I) are dissolved in the 1500ml dehydrated alcohol, add 75 gram Anhydrous potassium carbonates, and under agitation reflux is 3 hours, drip 100 gram bromocyclopentanes, continue reflux 12 hours, check response situation with the silica gel thin sheet chromatography.Filtered while hot after reaction finishes, concentrating under reduced pressure reclaims ethanol, and residuum is separated out white solid after room temperature placement, cooling, filter, and drying gets 60 grams.
2.16 the preparation of the female phenolic ketone of α-bromo--3-ring amyl ether (XI)
The female phenolic ketone of 80 grams-3-ring amyl ether (X) is dissolved in 1600ml methyl alcohol, adds 224 gram cupric bromides, under agitation in 50-65 ℃ of reaction 4 hours.Pour 4 times into and measure in the frozen water, separate out white solid, filter, wash with water to neutrality, be dissolved in the chloroform, anhydrous sodium sulfate drying is used in washing, and concentrating under reduced pressure adds methyl alcohol, separates out white solid, filters, and drying gets 65 grams.Mass spectrum (M/e): 418 (M
++ 2), 416 (M
+).
3.16 the preparation of Alpha-hydroxy-female phenolic ketone-3-ring amyl ether (XII).
The female phenolic ketone of 50 gram 16 α-bromo--3-ring amyl ether (XI) is dissolved in the 2000ml dimethyl formamide, adds 500ml 0.3N sodium hydroxide solution, and under agitation room temperature reaction is 1 hour.Then, add the 1N hcl acidifying, add frozen water simultaneously, separate out white solid, filter, washing, drying gets crude product.Crude product is dissolved in ethyl acetate, filters, and concentrates, separates out crystallization, and filtration, drying get elaboration 30 grams.Mass spectrum (M/e): 354 (M
+); Nuclear-magnetism: 0.99 (18-CH
3), 4.41 (16 β H), 4.71 (cyclopentyloxy) ppm; Infrared (KBr) 3430,1730,1610,1570,1500cm
-1
4.17 the preparation of α-acetylene-trihydroxy-oestrin-3-ring amyl ether (VIII)
20 gram metallic lithiums drip 200 in-20 ℃ and restrain bromination of n-butane in the 800ml anhydrous diethyl ether, in-5 ℃ of logical acetylene gass, react 3 hours.In 0 ℃ of tetrahydrofuran solution that drips 30 gram 16 Alpha-hydroxies-female phenolic ketone-3-ring amyl ethers (XII), continue to be warming up to 30 ℃, reacted 3 hours.Use hcl acidifying, ethyl acetate extraction, washing, anhydrous sodium sulfate drying, concentrating under reduced pressure adds an amount of sherwood oil, separates out solid, and cooling is filtered, and gets crude product.Crude product dehydrated alcohol recrystallization gets 16 grams.Mp160-2 ℃; Mass spectrum (M/e): 380 (M
+); Nuclear-magnetism: 0.93 (18-CH), 2.84 (C ≡ CH).
Claims (1)
1. a method for preparing 17 α-acetylene-trihydroxy-oestrin-3-ring amyl ether is characterized in that with female phenolic ketone be raw material, gets through four-step reaction:
A. in ethanol solution, make 3 hydroxyl salifies of female phenolic ketone with Anhydrous potassium carbonate earlier, with the reaction of bromocyclopentane initial ring amyl ether, make female phenolic ketone-3-and encircle amyl ether then;
B. in methanol solution, make female phenolic ketone-3-ring amyl ether the female phenolic ketone of 16 α-bromo--3-take place encircle amyl ether with cupric bromide;
C. in dimethyl formamide solution, make the female phenolic ketone of 16 α-bromo--3-ring amyl ether generation hydrolysis reaction, make 16 Alpha-hydroxies-female phenolic ketone-3-and encircle amyl ether with 0.1～0.5N sodium hydroxide solution;
D. in tetrahydrofuran solution, make 16 Alpha-hydroxies-female phenolic ketone-3-ring amyl ether 17 ketone group generation addition reactions, make 17 α-acetylene-trihydroxy-oestrin-3-and encircle amyl ether with the acetylene lithium.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93107394A CN1041829C (en) | 1993-06-28 | 1993-06-28 | Synthetic technology of 17a-acetylene estriol-3-cyclopentana ether |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN93107394A CN1041829C (en) | 1993-06-28 | 1993-06-28 | Synthetic technology of 17a-acetylene estriol-3-cyclopentana ether |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1087644A CN1087644A (en) | 1994-06-08 |
| CN1041829C true CN1041829C (en) | 1999-01-27 |
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ID=4986678
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93107394A Expired - Fee Related CN1041829C (en) | 1993-06-28 | 1993-06-28 | Synthetic technology of 17a-acetylene estriol-3-cyclopentana ether |
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|---|---|
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Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109369765B (en) * | 2018-12-10 | 2021-01-26 | 华南理工大学 | Preparation method of murine cholic acid |
| CN109705182B (en) * | 2019-01-24 | 2021-08-31 | 上海新华联制药有限公司 | Preparation method of nilestriol |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3868452A (en) * | 1971-04-23 | 1975-02-25 | Lilly Co Eli | 17Alpha-ethynylestriol 3-Cyclopentyl ether |
| EP0365421A1 (en) * | 1988-10-19 | 1990-04-25 | La Region Wallonne | Specific ligands for estrogenic and progestagenic steroidal hormone receptors, their use and synthesis intermediates |
-
1993
- 1993-06-28 CN CN93107394A patent/CN1041829C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3868452A (en) * | 1971-04-23 | 1975-02-25 | Lilly Co Eli | 17Alpha-ethynylestriol 3-Cyclopentyl ether |
| EP0365421A1 (en) * | 1988-10-19 | 1990-04-25 | La Region Wallonne | Specific ligands for estrogenic and progestagenic steroidal hormone receptors, their use and synthesis intermediates |
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|---|---|
| CN1087644A (en) | 1994-06-08 |
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