CN105085596A - Preparation method of progesterone carboxylate - Google Patents
Preparation method of progesterone carboxylate Download PDFInfo
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- CN105085596A CN105085596A CN201510504672.0A CN201510504672A CN105085596A CN 105085596 A CN105085596 A CN 105085596A CN 201510504672 A CN201510504672 A CN 201510504672A CN 105085596 A CN105085596 A CN 105085596A
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- Prior art keywords
- carboxylic acid
- preparation
- compound
- reaction
- progesterone
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
- C07J3/005—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom the carbon atom being part of a carboxylic function
Abstract
The invention relates to a preparation method of progesterone carboxylate, which comprises the following step: by using a compound II 4-androstenedione as the raw material, carrying out cyanation and carboxylation to obtain the compound I progesterone carboxylate. The reaction is disclosed in the specification. By using the raw material 4-androstenedione with better price advantage, the method has the advantages of short synthesis route, low cost and high product yield. The product compound I progesterone carboxylate has the advantages of short synthesis time and high purity and yield of the synthesized intermediate; the HPLC (high performance liquid chromatography) is greater than or equal to 98%; and the total yield is greater than or equal to 95%. By using the compound II 4-androstenedione as the raw material, the method has the characteristics of more abundant resources and lower cost.
Description
Technical field
The present invention relates to the preparation method of Steroid medicine intermediates, specifically relate to a kind of preparation method of carboxylic acid Progesterone.
Background technology
Carboxylic acid Progesterone, chemical name: 3-oxo-androst-4-alkene-17 Β-carboxylic acid.English name: 4-Androsten-3-one-5-ene-17-carboxylicacid; Molecular formula: C20H28O3; Molecular weight: 316.44.It is the important intermediate of synthesizing steroid hormone bulk drug.Domestic manufacturer generally adopts diene alcohol ketone acetic ester to be that raw material is hydrolyzed five step Reactive Synthesis chemical compounds Is and carboxylic acid Progesterone through over hydrogenation ﹑ water solution ﹑ ester ﹑ oxygen ﹑.Synthetic route is as follows:
。
Above-mentioned route utilizes diene alcohol ketone acetic ester synthesis of carboxylic acid Progesterone route long, and cost is high, pollutes large, and therefore develop a kind of raw material resources and enrich, synthetic route is short, and the technique of the carboxylic acid Progesterone that cost is low seems most important.
Summary of the invention
The present invention is long in order to solve diene alcohol ketone acetic ester synthesis of carboxylic acid Progesterone route, and cost is high, heavy-polluted problem, and the special preparation method proposing a kind of carboxylic acid Progesterone, raw material resources are enriched, and synthetic route is short, and cost is low.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method of carboxylic acid Progesterone, it is characterized in that: be that compound ii and 4-AD are obtained chemical compounds I and carboxylic acid Progesterone through cyaniding, Carboxylation two-step reaction, reaction scheme is as follows:
。
Further improvement is: described cyanogenation is, under protection of inert gas, compound ii and 4-AD, potassium tert.-butoxide, glycol dimethyl ether and the trimethyl carbinol is stirred, and is cooled to-10 DEG C ~ 0 DEG C; Slowly add Methyl benzenesulfonyl methyl isocyanide in mixing solutions, add and carry out insulation reaction, stir 3 ~ 4 hours, TLC monitoring is to reacting completely, and elutriation, suction filtration, dries and obtain compound III and 3-oxo-4-alkene-17-cyano group.
Further improvement is: described rare gas element is nitrogen, argon gas, the one in helium, preferred nitrogen.
Further improvement is: described to Methyl benzenesulfonyl methyl isocyanide: potassium tert.-butoxide: glycol dimethyl ether: the trimethyl carbinol: the mass ratio=1.5 ~ 2:2 ~ 3:40 ~ 45:12 ~ 15:1 of compound ii.
Further improvement is: described temperature of reaction is 20 ~ 25 DEG C, and the reaction times is: 3 ~ 4h; Elutriation water: the mass ratio=20 ~ 30:1 of compound ii; Bake out temperature is: 55 ~ 60 DEG C.
Further improvement is: described carboxylic acid reaction is: compound III added in reaction flask, add sulphuric acid soln, and temperature control reacts, and TLC monitoring is complete to raw material reaction, elutriation, and suction filtration, is washed to neutrality, dries and obtains chemical compounds I and carboxylic acid Progesterone.
Further improvement is: described sulphuric acid soln is: 50% sulfuric acid, sulphuric acid soln: the mass ratio=8 ~ 10:1 of compound III.
Further improvement is: described temperature of reaction is: 50 ~ 60 DEG C, and the reaction times is: 2 ~ 3h, elutriation water: the mass ratio=15 ~ 20:1 of compound III, and bake out temperature is: 60 ~ 70 DEG C.
Beneficial effect:
Product Compound I of the present invention i.e. carboxylic acid Progesterone, generated time is short, and synthetic intermediate purity and yield is high, HPLC≤98%; Zong Shou Shuais≤and 95%; Utilize compound ii 4-AD for raw material, resource is abundanter, and cost is lower.
Embodiment
Embodiment one:
(1) cyaniding
Under nitrogen protection, by 20g compound ii and 4-AD, and 40g potassium tert.-butoxide joins in 800g glycol dimethyl ether and the 240g trimethyl carbinol, is cooled to-10 DEG C under stirring; Slowly add 30g to Methyl benzenesulfonyl methyl isocyanide, add, be warming up to 20 DEG C, stir 4h, TLC complete to raw material reaction; Frozen water elutriation, suction filtration obtains off-white color solid, is washed to neutrality, dries to constant weight, obtains 18g compound III and 3-oxo-4-alkene-17-cyano group for 55 DEG C.
(2) Carboxylation
Add in reaction flask by 18g compound III and 3-oxo-4-alkene-17-cyano group, add 144g50% sulphuric acid soln, temperature control 50 DEG C reaction, TLC monitoring is complete to raw material reaction; Add 270g elutriation, suction filtration, massive laundering, to neutral, dried and is obtained 19.8g chemical compounds I and carboxylic acid Progesterone; Total recovery: 99%; HPLC:98.4%.
Embodiment two:
(1) cyaniding
Under nitrogen protection, by 20g compound ii and 4-AD, and 60g potassium tert.-butoxide joins in 900g glycol dimethyl ether and the 300g trimethyl carbinol, be cooled to 0 DEG C under stirring, slowly add 40g to Methyl benzenesulfonyl methyl isocyanide, add, be warming up to 25 DEG C, stir 3h, TLC complete to raw material reaction; Frozen water elutriation, suction filtration obtains off-white color solid, is washed to neutrality, dries to constant weight, obtains 18.2g compound III and 3-oxo-4-alkene-17-cyano group for 60 DEG C.
(2) Carboxylation
18.2g compound III and 3-oxo-4-alkene-17-cyano group are added in reaction flask, adds 182g50% sulphuric acid soln, temperature control 60 DEG C reaction, TLC monitoring is complete to raw material reaction, adds 364g water, elutriation suction filtration, massive laundering, to neutral, dried and is obtained 19.5g chemical compounds I and carboxylic acid Progesterone; Total recovery: 97.5%; HPLC:98.1%.
Claims (8)
1. a preparation method for carboxylic acid Progesterone, is characterized in that: it is that Carboxylation two steps obtain product Compound I i.e. carboxylic acid Progesterone, and reaction scheme is as follows by compound ii and 4-AD through cyaniding:
。
2. the preparation method of a kind of carboxylic acid Progesterone according to claim 1, it is characterized in that, described cyanogenation is: under protection of inert gas, compound ii and 4-AD, potassium tert.-butoxide, glycol dimethyl ether and the trimethyl carbinol is stirred, and is cooled to-10 DEG C ~ 0 DEG C; Slowly add Methyl benzenesulfonyl methyl isocyanide in mixing solutions, add and carry out insulation reaction, stir 3 ~ 4 hours, TLC monitoring is to reacting completely, and elutriation, suction filtration, dries and obtain compound III and 3-oxo-4-alkene-17-cyano group.
3. the preparation method of a kind of carboxylic acid Progesterone according to claim 2, is characterized in that, described rare gas element is the one in Dan Qi ﹑ Ya Qi ﹑ helium, preferred nitrogen.
4. the preparation method of a kind of carboxylic acid Progesterone according to claim 2, is characterized in that, described to Methyl benzenesulfonyl methyl isocyanide: potassium tert.-butoxide: glycol dimethyl ether: the trimethyl carbinol: the mass ratio=1.5 ~ 2:2 ~ 3:40 ~ 45:12 ~ 15:1 of compound ii.
5. the preparation method of a kind of carboxylic acid Progesterone according to claim 2, it is characterized in that, described temperature of reaction is: 20 ~ 25 DEG C; Reaction times is: 3 ~ 4h; Elutriation water: the mass ratio=20 ~ 30:1 of compound ii; Bake out temperature is: 55 ~ 60 DEG C.
6. the preparation method of a kind of carboxylic acid Progesterone according to claim 1, it is characterized in that, described carboxylic acid reaction is: compound III added in reaction flask, add sulphuric acid soln, and temperature control reacts, and TLC monitoring is complete to raw material reaction; Add water elutriation, and suction filtration is washed to neutrality, dries and obtain chemical compounds I and carboxylic acid Progesterone.
7. the preparation method of a kind of carboxylic acid Progesterone according to claim 6, is characterized in that, described sulphuric acid soln is 50% sulfuric acid, sulphuric acid soln: the mass ratio=8 ~ 10:1 of compound III.
8. the preparation method of a kind of carboxylic acid Progesterone according to claim 6, it is characterized in that, temperature of reaction is: 50 ~ 60 DEG C; Reaction times is: 2 ~ 3h; Elutriation water: the mass ratio=15 ~ 20:1 of compound III; Bake out temperature is: 60 ~ 70 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510504672.0A CN105085596A (en) | 2015-08-18 | 2015-08-18 | Preparation method of progesterone carboxylate |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510504672.0A CN105085596A (en) | 2015-08-18 | 2015-08-18 | Preparation method of progesterone carboxylate |
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| CN105085596A true CN105085596A (en) | 2015-11-25 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2374683A (en) * | 1944-02-10 | 1945-05-01 | Glidden Co | Dehalogenation of steroids |
| WO2005067627A2 (en) * | 2004-01-07 | 2005-07-28 | E-L Management Corporation | Cosmetic composition and method for retarding hair growth |
| CN101679479A (en) * | 2007-06-12 | 2010-03-24 | 拜耳先灵医药股份有限公司 | 17ss-cyano-19-androst-4-ene derivative, use thereof and medicaments containing said derivative |
| CN101679478A (en) * | 2007-06-12 | 2010-03-24 | 拜耳先灵医药股份有限公司 | 17ss-cyano-19-nor-androst-4-ene derivative, use thereof and medicaments containing said derivative |
-
2015
- 2015-08-18 CN CN201510504672.0A patent/CN105085596A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2374683A (en) * | 1944-02-10 | 1945-05-01 | Glidden Co | Dehalogenation of steroids |
| WO2005067627A2 (en) * | 2004-01-07 | 2005-07-28 | E-L Management Corporation | Cosmetic composition and method for retarding hair growth |
| CN101679479A (en) * | 2007-06-12 | 2010-03-24 | 拜耳先灵医药股份有限公司 | 17ss-cyano-19-androst-4-ene derivative, use thereof and medicaments containing said derivative |
| CN101679478A (en) * | 2007-06-12 | 2010-03-24 | 拜耳先灵医药股份有限公司 | 17ss-cyano-19-nor-androst-4-ene derivative, use thereof and medicaments containing said derivative |
Non-Patent Citations (1)
| Title |
|---|
| MARIA KRISTINA PARR ET AL.: "《Unexpected contribution of cytochrome P450 enzymes CYP11B2 and CYP21，as well as CYP3A4 in xenobiotic androgen elimination – Insights from metandienone metabolism》", 《TOXICOLOGY LETTERS》 * |
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Application publication date: 20151125 |
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