CN106632559B - A method of preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object - Google Patents
A method of preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object Download PDFInfo
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- CN106632559B CN106632559B CN201611134841.7A CN201611134841A CN106632559B CN 106632559 B CN106632559 B CN 106632559B CN 201611134841 A CN201611134841 A CN 201611134841A CN 106632559 B CN106632559 B CN 106632559B
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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
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Abstract
The invention discloses a kind of method preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object, this method is raw material through -17 β carboxylic acids of bromoform reaction one-step synthesis androstane-3-ketone-4-alkene using progesterone mother liquor object；The synthetic method step of the present invention is simple, and cost is relatively low, is suitable for mass industrial production, is in off-white color using -17 β carboxylic acid finished products of androstane-3-ketone-4-alkene that synthesize of the present invention, and yield >=80%, product purity >=99.5% can meet international market quality standard.
Description
Technical field
It is specially a kind of female using progesterone the present invention relates to a kind of preparation method of -17 β carboxylic acids of androstane-3-ketone-4-alkene
The method that liquid object prepares -17 β carboxylic acids of androstane-3-ketone-4-alkene.
Background technology
- 17 β carboxylic acids of androstane-3-ketone-4-alkene（4-Androsten-3-one-5-ene-17-carboxylic acid）, again
Name：- 17 Β of 3- oxo-androst -4- alkene-carboxylic acid, CAS：302-97-6, molecular formula：C20H28O3, molecular weight：316.44, structure
Formula is as follows：
Finasteride is a kind of 4- aza steroids, it is the specificity inhibition of desmoenzyme-II type 5a- reductases
Agent can inhibit hyperplasia of prostate and prevent hair loss.- 17 β carboxylic acids of androstane-3-ketone-4-alkene are that synthesis is non-
The important intermediate of that male amine；
It is raw material through over hydrogenation ﹑ bromofoms, five steps of ester ﹑ oxygen ﹑ water solutions ﹑ that domestic manufacturer, which generally uses diene alcohol ketone acetic ester,
Reaction synthesis -17 β carboxylic acids of androstane-3-ketone-4-alkene；- 17 β carboxylic acids of androstane-3-ketone-4-alkene are using contracting
It closes, Kai Huan ﹑ Huan He ﹑ Qingization ﹑ dehydrogenation four-step reaction synthesizing finasterides.
Invention content
The present invention is long for prior art route, and yield is low, and impurity is big, of high cost, and heavy-polluted feature provides a kind of conjunction
Short at route, the synthetic route of high income, spy's proposition is a kind of to prepare -17 β carboxylics of androstane-3-ketone-4-alkene using progesterone mother liquor object
The method of acid.
To achieve the above object, the technical solution adopted by the present invention is：It is a kind of to prepare androstane -3- using progesterone mother liquor object
The method of -17 β carboxylic acids of ketone -4- alkene, includes the following steps：
（1）Take the progesterone mother liquor object solid with gained during diene alcohol ketone acetic ester synthesis progesterone in reaction bulb 1#
In, the tert-butyl alcohol is added, water stirs evenly, and cooling is spare；Sodium hydroxide, water are added in reaction bulb 2#, stirs complete molten rear cooling,
Bromine, wherein Chun Du≤90% of progesterone mother liquor object is added dropwise in temperature control；
（2）It will be at the uniform velocity added dropwise in reaction bulb 1#, in the process temperature control, kept the temperature with 1 hour containing bromine solutions in reaction bulb 2#
Reaction, TLC are monitored to the reaction was complete, and aqueous solution of sodium bisulfite is added and terminates reaction, the normal pressure concentration and recovery tert-butyl alcohol adds salt
Acid, cooling crystallization are placed；Filtering, washing filter cake are drained, are discharged, being dried to obtain -17 β carboxylic acids of androstane-3-ketone-4-alkene to neutrality
Crude product；
（3）By -17 β crude carboxylic acids of androstane-3-ketone-4-alkene be added containing ethyl alcohol, methanol, dichloromethane reaction bulb 3# in,
Temperature rising reflux, cool down crystallization, and filtering is dried to obtain -17 β carboxylic acid finished products of androstane-3-ketone-4-alkene.
Further improve is：The step（1）In the tert-butyl alcohol, water quality and progesterone mother liquor object quality
Ratio is：40~42:4~5:1；Cooling temperature be：0~5℃；The ratio of the quality of sodium hydroxide, water, bromine and progesterone mother liquor object
Example be：2.4~2.5:12~13:2.5~3:1.
Further improve is：The step（2）In dropping temperature be：5 ~ 10 DEG C, reaction temperature is：10 ~ 15 DEG C,
Reaction time is：6~7h；The ratio of the quality of sodium hydrogensulfite, water and progesterone mother liquor object is：0.7~0.8:2.5~3:1.
Further improve is：The step（2）In hydrochloric acid and the ratio of quality of progesterone mother liquor object be：2.2~
2.5:1, recrystallization temperature is：20 ~ 25 DEG C, time of repose is：2~4h；Drying temperature is：70~80℃.
Further improve is：The step（3）In ethyl alcohol, methanol, dichloromethane quality and androstane -3- ketone -4-
- 17 β crude carboxylic acid mass ratios of alkene are 1 ~ 1.2:1~1.2:0.5~0.8:1；The temperature rising reflux time is：0.5 ~ 1h, recrystallization temperature
For：20 ~ 25 DEG C, the crystallization time is：2 ~ 4h, drying temperature are：70~80℃.
Advantageous effect：
The present invention is the easily operated, efficient androstane -3- ketone -4- of one kind provided in view of the shortcomings of the prior art
The preparation method of -17 β carboxylic acids of alkene, involved this method advantage are as follows：
1）Synthetic route is short, low raw-material cost, high income.
2）- 17 β carboxylic acid finished products of androstane-3-ketone-4-alkene can meet in off-white color, yield >=80%, product purity >=99.5%
International market quality standard.
Specific implementation mode
Embodiment one：
（1）It takes with the progesterone mother liquor object solid of gained during diene alcohol ketone acetic ester synthesis progesterone（Progesterone is pure
Degree：90%）The 4000g tert-butyl alcohols are added in reaction bulb 1# in 100g, and 400g water stirs evenly, be cooled to 0 DEG C it is spare；In reaction bulb
Be added 240g sodium hydroxides, 1200g water in 2#, stirring it is complete it is molten after be cooled to 0 DEG C, 250g bromines are added dropwise, be added dropwise process temperature control 5 ~
10℃；
（2）It will be at the uniform velocity added dropwise in reaction bulb 1# with 1 hour containing bromine solutions in reaction bulb 2#, temperature control 5 during dropwise addition ~
10 DEG C, 10 DEG C of insulation reaction 7h, TLC are monitored to the reaction was complete, and aqueous solution of sodium bisulfite is added（Sodium hydrogensulfite：70g, water：
250g）Reaction is terminated, 220g hydrochloric acid is added in the normal pressure concentration and recovery tert-butyl alcohol, is cooled to 20 DEG C of crystallizations and places 2h；Filtering, washing
Filter cake is drained, discharges to neutrality, and 70 DEG C are dried to obtain -17 β crude carboxylic acids of 95g androstane-3-ketone-4-alkenes；
（3）Ethyl alcohol containing 95g, 95g methanol, 48g dichloromethane is added in 95g androstane-3-ketone-4-alkenes -17 β crude carboxylic acids
In reaction bulb 3#, temperature rising reflux 0.5h is cooled to 20 DEG C, crystallization 2h, and filtering is dried to obtain -17 β of 80g androstane-3-ketone-4-alkenes
Carboxylic acid finished product, purity：99.5%, yield 80%.
Embodiment two：
（1）It takes with the progesterone mother liquor object solid of gained during diene alcohol ketone acetic ester synthesis progesterone（Progesterone is pure
Degree：92%）The 4200g tert-butyl alcohols are added in reaction bulb 1# in 100g, and 500g water stirs evenly, be cooled to 5 DEG C it is spare；In reaction bulb
Be added 250g sodium hydroxides, 1300g water in 2#, stirring it is complete it is molten after be cooled to 5 DEG C, 300g bromines are added dropwise, be added dropwise process temperature control 5 ~
10℃。
（2）Reaction bulb 2# was at the uniform velocity added dropwise to 1 hour in reaction bulb 1# containing bromine solutions, temperature control 5 ~ 10 during dropwise addition
DEG C, 15 DEG C of insulation reaction 6h, TLC are monitored to the reaction was complete, and aqueous solution of sodium bisulfite is added（Sodium hydrogensulfite：80g, water：
300g）Reaction is terminated, 250g hydrochloric acid is added in the normal pressure concentration and recovery tert-butyl alcohol, is cooled to 25 DEG C of crystallizations and places 4h；Filtering, washing
Filter cake is drained, discharges to neutrality, and 80 DEG C are dried to obtain -17 β crude carboxylic acids of 98g androstane-3-ketone-4-alkenes；
（3）Ethyl alcohol containing 117g, 117g methanol, 78g dichloromethane is added in -17 β crude carboxylic acids of 98g androstane-3-ketone-4-alkenes
Reaction bulb 3# in, temperature rising reflux 1h is cooled to 25 DEG C, crystallization 4h, and filtering is dried to obtain -17 β of 82g androstane-3-ketone-4-alkenes
Carboxylic acid finished product, purity：99.7%, yield：82%.
Claims (5)
1. a kind of method preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object, which is characterized in that including with
Lower step：
（1）Take the progesterone mother liquor object solid with gained during diene alcohol ketone acetic ester synthesis progesterone in reaction bulb 1#,
The tert-butyl alcohol is added, water stirs evenly, and cooling is spare；Sodium hydroxide, water, the complete molten rear cooling of stirring, control are added in reaction bulb 2#
Bromine, wherein Chun Du≤90% of progesterone mother liquor object is added dropwise in temperature；
（2）It will be at the uniform velocity added dropwise in reaction bulb 1# with 1 hour containing bromine solutions in reaction bulb 2#, in the process temperature control, insulation reaction,
TLC is monitored to the reaction was complete, and aqueous solution of sodium bisulfite is added and terminates reaction, and the normal pressure concentration and recovery tert-butyl alcohol adds hydrochloric acid, cools down
Crystallization is placed；Filtering, washing filter cake are drained, are discharged, being dried to obtain -17 β crude carboxylic acids of androstane-3-ketone-4-alkene to neutrality；
（3）By -17 β crude carboxylic acids of androstane-3-ketone-4-alkene be added containing ethyl alcohol, methanol, dichloromethane reaction bulb 3# in, heating
Reflux, cool down crystallization, and filtering is dried to obtain -17 β carboxylic acid finished products of androstane-3-ketone-4-alkene.
2. a kind of side preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object according to claim 1
Method, which is characterized in that the step（1）In the tert-butyl alcohol, the quality of water and the ratio of quality of progesterone mother liquor object be：40~
42:4~5:1；Cooling temperature be：0~5℃；The ratio of the quality of sodium hydroxide, water, bromine and progesterone mother liquor object is：2.4~
2.5:12~13:2.5~3:1。
3. a kind of side preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object according to claim 1
Method, which is characterized in that the step（2）In dropping temperature be：5 ~ 10 DEG C, reaction temperature is：10 ~ 15 DEG C, the reaction time is：
6 ~ 7h, sodium hydrogensulfite, water and progesterone mother liquor object the ratio of quality be：0.7~0.8:2.5~3:1.
4. a kind of side preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object according to claim 1
Method, which is characterized in that the step（2）In hydrochloric acid and the ratio of quality of progesterone mother liquor object be：2.2~2.5:1, crystallization
Temperature is：20 ~ 25 DEG C, time of repose is：2~4h；Drying temperature is：70~80℃.
5. a kind of side preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object according to claim 1
Method, which is characterized in that the step（3）In ethyl alcohol, methanol, dichloromethane quality and -17 β carboxylic acids of androstane-3-ketone-4-alkene it is thick
Quality ratio is 1 ~ 1.2:1~1.2:0.5~0.8:1；The temperature rising reflux time is：0.5 ~ 1h, recrystallization temperature are：20 ~ 25 DEG C, analysis
The brilliant time is：2 ~ 4h, drying temperature are：70~80℃.
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| CN201611134841.7A CN106632559B (en) | 2016-12-11 | 2016-12-11 | A method of preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object |
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| CN201611134841.7A CN106632559B (en) | 2016-12-11 | 2016-12-11 | A method of preparing -17 β carboxylic acids of androstane-3-ketone-4-alkene using progesterone mother liquor object |
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| CN106632559B true CN106632559B (en) | 2018-10-30 |
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Citations (3)
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|---|---|---|---|---|
| CN1306005A (en) * | 2001-01-18 | 2001-08-01 | 湖南正清制药集团股份有限公司 | Process for preparing medicine |
| CN1980950A (en) * | 2004-07-05 | 2007-06-13 | 隆萨股份公司 | Process for the preparation of 4-azasteroids |
| CN101863956A (en) * | 2010-06-04 | 2010-10-20 | 上海应用技术学院 | Method for synthesizing finasteride |
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2016
- 2016-12-11 CN CN201611134841.7A patent/CN106632559B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1306005A (en) * | 2001-01-18 | 2001-08-01 | 湖南正清制药集团股份有限公司 | Process for preparing medicine |
| CN1980950A (en) * | 2004-07-05 | 2007-06-13 | 隆萨股份公司 | Process for the preparation of 4-azasteroids |
| CN101863956A (en) * | 2010-06-04 | 2010-10-20 | 上海应用技术学院 | Method for synthesizing finasteride |
Non-Patent Citations (2)
| Title |
|---|
| Progesterone–adenine hybrids as bivalent inhibitors of P-glycoprotein-mediated multidrug efflux: Design, synthesis, characterization and biological evaluation;Wael Zeinyeh等;《Steroids》;20120731;第77卷;1171-1191 * |
| 合成非那雄胺的新方法;姚志艺等;《中国新药杂志》;20111231;第20卷(第22期);2248-2250 * |
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