CN105111270A - Preparation method for finasteride intermediate - Google Patents
Preparation method for finasteride intermediate Download PDFInfo
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- CN105111270A CN105111270A CN201510504675.4A CN201510504675A CN105111270A CN 105111270 A CN105111270 A CN 105111270A CN 201510504675 A CN201510504675 A CN 201510504675A CN 105111270 A CN105111270 A CN 105111270A
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Abstract
The invention relates to a preparation method for finasteride intermediate. According to the method, a product compound I, namely N-tert-butyl-3-oxo-4-olefinic-17 beta-finasteride formamide intermediate, is prepared by carrying out two steps of cyaniding and amidation on a compound II, namely androstenedione. A reaction scheme is shown in the specification. 4-androstenedione is used as a raw material, the resource is richer, and the cost is lower; the synthesis time is short, and the obtained finasteride intermediate is high in purity yield, and the HPLC is greater than or equal to 98%; and the yield is greater than or equal to 110%.
Description
Technical field
The present invention relates to the preparation method of Steroid medicine intermediates, specifically relate to a kind of preparation method of finasteride intermediate.
Background technology
Finasteride is a kind of 4-aza steroid, and it is the specific inhibitor of desmo enzyme-II type 5α-reductase, can Suppress hyperplasia of prostate and anti-loss.
Domestic manufacturer generally adopts diene alcohol ketone acetic ester to be that raw material is through over hydrogenation ﹑ water solution ﹑ ester ﹑ oxygen ﹑ water solution ﹑ amidation six-step process synthetic compound I; Chemical compounds I is again through Kai Huan ﹑ Huan He ﹑ Qingization ﹑ dehydrogenation four-step reaction synthesizing finasteride.The product that patent CN201210002148 adopts chemical compounds I to obtain through Kai Huan ﹑ cyclization is raw material, through bromo, and cancellation two step synthesizing finasteride, raw materials cost is high, and the waste water of production and quinones substance pollute large; Patent CN201210301773 adopts 3-beta-hydroxy-5 α-androstane-17 β-carboxylic acid to be raw material, and through 9 step Reactive Synthesis finasterides, synthetic route is long, and production cost is high.
Above-mentioned route utilizes diene alcohol ketone acetic ester synthesizing finasteride route long, and cost is high, pollutes large.
Therefore develop a kind of raw material resources to enrich, synthetic route is short, and the technique of the finasteride intermediate that cost is low seems most important.
Summary of the invention
The present invention enriches to develop a kind of raw material resources, and synthetic route is short, the finasteride intermediate that cost is low,
Spy provides a kind of preparation method of finasteride intermediate.
For solving the problems of the technologies described above, the technical solution used in the present invention is: a kind of preparation method of finasteride intermediate, is characterized in that: it is that amidation two-step reaction obtains chemical compounds I finasteride intermediate by compound ii and 4-AD through cyaniding, 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 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 the one in Dan Qi ﹑ Ya Qi ﹑ 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 and 4-AD.
Further improvement is: described temperature of reaction is 20 ~ 25 DEG C, and the reaction times is 3 ~ 4 hours; Elutriation water: the mass ratio=20 ~ 30:1 of compound ii and 4-AD; Bake out temperature is: 55 ~ 60 DEG C.
Further improvement is: described amidate action is, compound III added in reaction flask, add glacial acetic acid, the trimethyl carbinol stirs evenly, and slowly drips sulfuric acid, and temperature control reacts, and TLC monitoring is to reacting completely; Add sodium carbonate termination reaction, elutriation, filter, filter cake washes with water to neutrality, dries, obtains chemical compounds I finasteride intermediate.
Further improvement is: described glacial acetic acid: the trimethyl carbinol: sulfuric acid: sodium carbonate: water: the mass ratio=3 ~ 5:1.5 ~ 2:1 ~ 1.5:1.2 ~ 1.8:15 ~ 20:1 of compound III.
Further improvement is: described temperature of reaction is: 10 ~ 15 DEG C; Reaction times: 12 ~ 15h; Bake out temperature is: 50 ~ 60 DEG C.
Beneficial effect:
1) utilize compound ii 4-AD for raw material, resource is abundanter, and cost is lower.
2) generated time is short, and the chemical compounds I finasteride intermediate purity and yield of gained is high, HPLC :≤98%; Shou Shuais≤and 110%.
Embodiment
Embodiment one:
(1) cyaniding
Under nitrogen protection, by 20g compound ii, 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 18.5g compound III and 3-oxo-4-alkene-17-cyano group for 55 DEG C;
(2) amidation
Add in reaction flask by 18.5g compound III 3-oxo-4-alkene-17-cyano group, add 55.5g glacial acetic acid, the 27.8g trimethyl carbinol stirs evenly, and slowly drips 18.5g sulfuric acid, and temperature control 10 DEG C reaction 15h, TLC monitoring is to reacting completely.Add 22.2g sodium carbonate termination reaction, add 278ml water elutriation, filter, filter cake washes with water to neutrality, dries to constant weight, obtains 22.2g chemical compounds I finasteride intermediate for 50 DEG C; Total recovery: 111%; HPLC:98.3%.
Embodiment two:
(1) cyaniding
Under nitrogen protection, by 50g compound ii, and 150g potassium tert.-butoxide joins in 2250g glycol dimethyl ether and the 750g trimethyl carbinol, is cooled to 0 DEG C under stirring; Slowly add 100g to Methyl benzenesulfonyl methyl isocyanide, add, be warming up to 25 DEG C, stir 3h, TLC is complete to raw material reaction, frozen water elutriation, and suction filtration obtains off-white color solid, be washed to neutrality, dry to constant weight, obtain 46g compound III and 3-oxo-4-alkene-17-cyano group for 60 DEG C;
(2) amidation
Add in reaction flask by 46g compound III and 3-oxo-4-alkene-17-cyano group, add 230g glacial acetic acid, the 92g trimethyl carbinol stirs evenly, and slowly drips 69g sulfuric acid, and temperature control 15 DEG C reaction 12h, TLC monitoring is to reacting completely.Add 82.2g sodium carbonate termination reaction.Add 920ml water elutriation, filter, filter cake washes with water to neutrality, dries to constant weight, obtains 56g chemical compounds I finasteride intermediate, total recovery: 112% for 60 DEG C; HPLC:98.5%.
Claims (8)
1. a preparation method for finasteride intermediate, is characterized in that: it is that amidation two step obtains product Compound I i.e. finasteride intermediate, and reaction scheme is as follows by compound ii and 4-AD through cyaniding:
。
2. the preparation method of a kind of finasteride intermediate 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 are stirred, and be 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 finasteride intermediate 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 finasteride intermediate 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 and 4-AD.
5. the preparation method of a kind of finasteride intermediate according to claim 2, it is characterized in that: described temperature of reaction is 20 ~ 25 DEG C, the reaction times is 3 ~ 4 hours; Elutriation water: the mass ratio=20 ~ 30:1 of compound ii and 4-AD; Bake out temperature is: 55 ~ 60 DEG C.
6. the preparation method of a kind of finasteride intermediate according to claim 1, is characterized in that: described acid amides reaction is compound III added in reaction flask, add glacial acetic acid, the trimethyl carbinol stirs evenly, and slowly drips sulfuric acid, temperature control reacts, and TLC monitoring is to reacting completely; Add sodium carbonate termination reaction; Elutriation, filter, filter cake washes with water to neutrality, dries and obtains chemical compounds I and finasteride intermediate.
7. the preparation method of a kind of finasteride intermediate according to claim 6, is characterized in that: described glacial acetic acid: the trimethyl carbinol: sulfuric acid: sodium carbonate: water: the mass ratio=3 ~ 5:1.5 ~ 2:1 ~ 1.5:1.2 ~ 1.8:15 ~ 20:1 of compound III.
8. the preparation method of a kind of finasteride intermediate according to claim 6, is characterized in that: described temperature of reaction is: 10 ~ 15 DEG C; Reaction times: 12 ~ 15h; Bake out temperature is: 50 ~ 60 DEG C.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510504675.4A CN105111270A (en) | 2015-08-18 | 2015-08-18 | Preparation method for finasteride intermediate |
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| CN201510504675.4A CN105111270A (en) | 2015-08-18 | 2015-08-18 | Preparation method for finasteride intermediate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988210A (en) * | 2017-12-30 | 2019-07-09 | 天津药业研究院有限公司 | A kind of preparation method of progesterone and progesterone intermediate |
-
2015
- 2015-08-18 CN CN201510504675.4A patent/CN105111270A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 叶景泉: "非那雄胺的合成", 《中国优秀博硕士学位论文全文数据库 (硕士) 工程科技Ⅰ辑》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109988210A (en) * | 2017-12-30 | 2019-07-09 | 天津药业研究院有限公司 | A kind of preparation method of progesterone and progesterone intermediate |
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Application publication date: 20151202 |