CN109627277A - A kind of preparation method of medroxyprogesterone acetate - Google Patents
A kind of preparation method of medroxyprogesterone acetate Download PDFInfo
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- CN109627277A CN109627277A CN201811554953.7A CN201811554953A CN109627277A CN 109627277 A CN109627277 A CN 109627277A CN 201811554953 A CN201811554953 A CN 201811554953A CN 109627277 A CN109627277 A CN 109627277A
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- medroxyprogesterone acetate
- methine
- palladium carbon
- acetate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J7/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms
- C07J7/0005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21
- C07J7/001—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group
- C07J7/004—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa
- C07J7/0045—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms not substituted in position 21 substituted in position 20 by a keto group substituted in position 17 alfa not substituted in position 16
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- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Polyesters Or Polycarbonates (AREA)
Abstract
The invention discloses a kind of preparation methods of medroxyprogesterone acetate, including using methine object as raw material, palladium carbon is catalyst, cyclohexene is reducing agent, it reacts in organic solvent, generates the mixture of transition intermediate and medroxyprogesterone acetate, add hydrochloric acid, make transition intermediate indexing medroxyprogesterone acetate therein, in which: the organic solvent is selected from: one of ethyl alcohol, ethyl acetate, methanol, isopropanol and acetone or any two or more mixed solvent；The temperature of the heating reaction are as follows: 40~80 DEG C.Method of the invention is without using with toxicity and irretrievable DMF, use recyclable and the alcohols of nonhazardous, esters, organic solvent of ketone instead, it is environmentally friendly, belong to a kind of friendly process route, and obtained product meets the regulation of Chinese Pharmacopoeia, can substitute existing preparation process.
Description
Technical field
The invention belongs to chemical pharmaceutical technology fields, specifically, being the preparation method about a kind of medroxyprogesterone acetate.
Background technique
Medroxyprogesterone acetate also known as peace palace flavonoids, are a kind of common drugs, are mainly used for dysmenorrhea, functional amenorrhea, function
It can property uterine hemorrhage, threatened abortion or habitual abortion, endometriosis, treatment advanced breast cancer, adenocarcinoma of endometrium
And kidney etc..Large dosage can be used as long acting injectable contraceptives.In addition to this effect is also embodied in menstrual onset because endometrium loses
After the support of estrogen and progestational hormone is fallen off, artificially complementing estrogen or progestational hormone, particularly progestational hormone can be continued, made
The endometrium of " helpless " continues to be supported, the level that maintenance thickens, such endometrium is grown in uterus securely
On wall, gets ready for the fertilization implantation of ovum, realize the purpose for postponing menstruation.
Existing medroxyprogesterone acetate preparation method be make catalyst using megestrol acetate object as raw material, palladium carbon, cyclohexene is
Reducing agent is placed in n,N-Dimethylformamide (DMF) solvent, is heated to 120 DEG C or so, generates after reacting a few hours under high temperature
Then the mixture of transition intermediate and medroxyprogesterone acetate filters off palladium carbon, reduce temperature, and hydrochloric acid is added, makes transition therein
Intermediate indexing is medroxyprogesterone acetate, finally by being refining to obtain the satisfactory medroxyprogesterone acetate of purity content.
This method needs the DMF using low toxicity, and high temperature of 120 DEG C or so, DMF are possible to remain in finished product, warp
Human body easily endangers body after taking, moreover, DMF is difficult in waste water by microbial metabolism, to cause the pollution to environment.
It is therefore desirable to develop a kind of environmentally friendly preparation method, to overcome the problems, such as environmental pollution.
Summary of the invention
The object of the invention is that the preparation method for improving existing medroxyprogesterone acetate is used with toxicity and can not be returned
The DMF of receipts is as reaction dissolvent, the problem of polluting to environment, to provide a kind of environmentally friendly medroxyprogesterone acetate
Preparation method.
To achieve the above object, the preparation method of medroxyprogesterone acetate of the invention, including using methine object as raw material, palladium
Carbon is catalyst, and cyclohexene is reducing agent, is reacted in organic solvent, and the mixing of transition intermediate and medroxyprogesterone acetate is generated
Object adds hydrochloric acid, makes transition intermediate indexing medroxyprogesterone acetate therein, in which:
The organic solvent is selected from: one of ethyl alcohol, ethyl acetate, methanol, isopropanol and acetone are two kinds any
Above mixed solvent；
The temperature of the reaction are as follows: 40~80 DEG C.
Preferred embodiment in accordance with the present invention, the quality proportioning range of the methine object and palladium carbon usage amount are as follows: 1:0.1
~1:1.
According to a further advantageous embodiment of the invention, the quality proportioning range of the methine object and cyclohexene usage amount
Are as follows: 1:0.05~1:5.
According to the present invention, the reaction for heating reaction or is heated to reflux state；Further, the time of the reaction
It is 3~7 hours.
According to the present invention, the method also includes refining obtained medroxyprogesterone acetate.
Further, the purification successively includes the steps that crystallisation by cooling, filtering, decoloration and recrystallization；Wherein,
The decoloration uses the mixed solvent of the mixed solvent or ethyl acetate and ethyl alcohol of methylene chloride and methanol.
The preparation method of medroxyprogesterone acetate of the invention has the advantages that
1, due to without using with toxicity and irretrievable DMF, using recyclable and nonhazardous instead alcohols, esters,
Organic solvent of ketone, thus it is environmentally friendly, belong to a kind of friendly process route.
2, reaction temperature is compared existing lower using the technique of DMF, and obtained product meets the regulation of Chinese Pharmacopoeia, can
To substitute existing preparation process.
Specific embodiment
Below by way of specific embodiment, the preparation method of medroxyprogesterone acetate of the invention is described in further details.
It should be understood that following embodiment is merely to illustrate the present invention not for limiting the scope of the invention.
The present invention will using the alcohols of recyclable nonhazardous, esters, organic solvent of ketone without using the solvent DMF of low toxicity
Methine object and palladium carbon, cyclohexene are heated to 40~80 DEG C or so, instead in alcohols, esters, ketone or their in the mixed solvent
The mixture for generating transition intermediate and medroxyprogesterone acetate after a few hours is answered, palladium carbon is then filtered off, reduces temperature, salt is added
Acid makes transition intermediate indexing medroxyprogesterone acetate therein, finally by being refining to obtain the satisfactory vinegar of purity content
The process route of sour Medroxyprogesterone, preparation is as follows:
Raw material used in following embodiment --- methine object can pass through commercially available acquisition (product name: 6 α-secondary first
- 17 α acetate progesterone of base), it can also be synthesized according to existing known method.
Embodiment 1
10g methine object, 400ml ethyl alcohol, 4g palladium carbon (5%, moisture 30%), 1ml cyclohexene are added to tri- mouthfuls of 500ml
In bottle, heating water bath flows back 5 hours to 76~80 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, and hydrochloric acid 2ml is added, stirs
It mixes 2 hours, recycling ethyl alcohol is concentrated under reduced pressure, then crystallisation by cooling 1 hour, filters to obtain white solid, and white solid uses dichloromethane again
Alkane and methanol mixed solvent decoloration, recrystallization, are obtained by filtration fine work medroxyprogesterone acetate, purity 98.6%, content 98%, impurity
< 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meet Chinese Pharmacopoeia CP2015.
Embodiment 2
10g methine object, 200ml ethyl alcohol, 8g palladium carbon (5%, moisture 60%), 7.5ml cyclohexene are added to 500ml tri-
In mouth bottle, heating water bath flows back 3 hours to 76~80 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, and hydrochloric acid 2ml is added,
Recycling ethyl alcohol is concentrated under reduced pressure in stirring 2 hours, and then crystallisation by cooling 1 hour, filters to obtain white solid, and white solid uses dichloro again
Methane and methanol mixed solvent decoloration, recrystallization, are obtained by filtration fine work medroxyprogesterone acetate, purity 98.6%, and content 98% is miscellaneous
Matter < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meet Chinese Pharmacopoeia CP2015.
Embodiment 3
10g methine object, 400ml ethyl acetate, 4g palladium carbon (5%, moisture 60%), 2.5ml cyclohexene are added to
In 500ml there-necked flask, heating water bath flows back 7 hours to 70~78 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, is added
Hydrochloric acid 2ml is stirred 2 hours, recycling ethyl alcohol is concentrated under reduced pressure, then crystallisation by cooling 1 hour, filters to obtain white solid, white solid
Ethyl acetate and ethanol decolorization, recrystallization are used again, is obtained by filtration fine work medroxyprogesterone acetate, and purity 98.6%, content 98% is miscellaneous
Matter < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meet Chinese Pharmacopoeia CP2015.
Embodiment 4
10g methine object, 400ml isopropanol, 4g palladium carbon (5%, moisture 40%), 5ml cyclohexene are added to 500ml tri-
In mouth bottle, heating water bath flows back 6 hours to 70~78 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, and hydrochloric acid 2ml is added,
Recycling ethyl alcohol is concentrated under reduced pressure in stirring 2 hours, and then crystallisation by cooling 1 hour, filters to obtain white solid, and white solid uses acetic acid again
Ethyl ester and ethanol decolorization, recrystallization, are obtained by filtration fine work medroxyprogesterone acetate, purity 98.7%, content 98%, impurity < 4, always
Miscellaneous < 1.5%, dissolvent residual, fusing point meet Chinese Pharmacopoeia CP2015.
Embodiment 5
10g methine object, 400ml methanol, 10g palladium carbon (5%, moisture 30%), 0.5ml cyclohexene are added to 500ml tri-
In mouth bottle, heating water bath flows back 5 hours to 76~80 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, and hydrochloric acid 2ml is added,
Recycling methanol is concentrated under reduced pressure in stirring 2 hours, and then crystallisation by cooling 1 hour, filters to obtain white solid, and white solid uses dichloro again
Methane and methanol mixed solvent decoloration, recrystallization, are obtained by filtration fine work medroxyprogesterone acetate, purity 98.6%, and content 98% is miscellaneous
Matter < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meets Chinese Pharmacopoeia CP2015.
Embodiment 6
10g methine object, 400ml acetone, 10g palladium carbon (5%, moisture 30%), 2ml cyclohexene are added to tri- mouthfuls of 500ml
In bottle, heating water bath reacts 5 hours to 40~70 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C, and hydrochloric acid 2ml is added, stirs
It mixes 2 hours, recycling acetone is concentrated under reduced pressure, then crystallisation by cooling 1 hour, filters to obtain white solid, and white solid uses dichloromethane again
Alkane and methanol mixed solvent decoloration, recrystallization, are obtained by filtration fine work medroxyprogesterone acetate, purity 98.6%, content 98%, impurity
< 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meets Chinese Pharmacopoeia CP2015.
Embodiment 7
10g methine object, 50ml acetone, 350ml ethyl acetate, 1g palladium carbon (5%, moisture 30%), 10ml cyclohexene add
Entering into 500ml there-necked flask, heating water bath reacts 5 hours to 70~80 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C,
Hydrochloric acid 2ml is added, stirs 2 hours, recycling acetoneand ethyl acetate is concentrated under reduced pressure, then crystallisation by cooling 1 hour, filters white
Solid, white solid use methylene chloride and methanol mixed solvent to decolourize, recrystallize again, fine work medroxyprogesterone acetate are obtained by filtration,
Purity 98.6%, content 98%, impurity < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meets Chinese Pharmacopoeia CP2015.
Embodiment 8
10g methine object, 200ml methanol, 200ml ethyl acetate, 5g palladium carbon (5%, moisture 30%), 20ml cyclohexene,
It is added in 500ml there-necked flask, heating water bath reacts 3 hours to 40~70 DEG C, is filtered to remove palladium carbon, reaction solution is cooled to 30
DEG C, hydrochloric acid 2ml is added, stirs 2 hours, recycling methanol and ethyl acetate is concentrated under reduced pressure, then crystallisation by cooling 1 hour, is filtered
White solid, white solid use ethyl acetate and alcohol mixed solvent to decolourize, recrystallize again, it is pregnant that fine work tumer hydroxyl are obtained by filtration
Ketone, purity 98.6%, content 98%, impurity < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meets Chinese Pharmacopoeia
CP2015。
Embodiment 9
10g methine object, 200ml ethyl alcohol, 200ml isopropanol, 6g palladium carbon (5%, moisture 30%), 50ml cyclohexene add
Entering into 500ml there-necked flask, heating water bath reacts 3 hours to 40~70 DEG C, is filtered to remove palladium carbon, and reaction solution is cooled to 30 DEG C,
Hydrochloric acid 2ml is added, stirs 2 hours, recycling ethyl alcohol and isopropanol is concentrated under reduced pressure, then crystallisation by cooling 1 hour, filters white solid
Body, white solid uses ethyl acetate and alcohol mixed solvent to decolourize, recrystallize again, fine work medroxyprogesterone acetate is obtained by filtration, pure
Degree 98.6%, content 98%, impurity < 4, total miscellaneous < 1.5%, dissolvent residual, fusing point meets Chinese Pharmacopoeia CP2015.
Note: in above embodiments, the reaction temperature of heating water bath, lower limit temperature is temperature when reaction starts timing,
Ceiling temperature is the maximum temperature of reaction process.
Claims (8)
1. a kind of preparation method of medroxyprogesterone acetate, including using methine object as raw material, palladium carbon is catalyst, cyclohexene is also
Former agent, reacts in organic solvent, generates the mixture of transition intermediate and medroxyprogesterone acetate, adds hydrochloric acid, make wherein
Transition intermediate indexing be medroxyprogesterone acetate, it is characterised in that:
The organic solvent is selected from: one of ethyl alcohol, ethyl acetate, methanol, isopropanol and acetone are any two or more
Mixed solvent；
The temperature of the reaction are as follows: 40~80 DEG C.
2. preparation method according to claim 1, which is characterized in that the mass ratio of the methine object and palladium carbon usage amount
Range are as follows: 1:0.1~1:1.
3. preparation method according to claim 1, which is characterized in that the quality of the methine object and cyclohexene usage amount
Volume ratio range are as follows: 1:0.05~1:5.
4. preparation method according to claim 1, which is characterized in that the reaction is heating reaction or is heated to reflux shape
State.
5. the preparation method according to claim 4, which is characterized in that the time of the reaction is 3~7 hours.
6. preparation method according to claim 1, which is characterized in that the method also includes pregnant to obtained tumer hydroxyl
The step of ketone is refined.
7. preparation method according to claim 6, which is characterized in that the purification successively include crystallisation by cooling, filtering,
The step of decoloration and recrystallization.
8. preparation method according to claim 7, which is characterized in that the described decoloration is mixed using methylene chloride and methanol
The mixed solvent of bonding solvent or ethyl acetate and ethyl alcohol.
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Citations (9)
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|---|---|---|---|---|
| US3290322A (en) * | 1965-02-12 | 1966-12-06 | Phytogen Prod Inc | Oxidation of steroids |
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| US20090012321A1 (en) * | 2007-06-06 | 2009-01-08 | Klaus Annen | Process for preparing 17alpha-acetoxy-6-methylenepregn-4-ene-3,20-dione, medroxyprogesterone acetate and megestrol acetate |
| CN106866766A (en) * | 2017-02-14 | 2017-06-20 | 岳阳环宇药业有限公司 | The preparation method and preparation system of a kind of medroxyprogesterone acetate |
| CN107573395A (en) * | 2017-09-04 | 2018-01-12 | 江苏远大信谊药业有限公司 | A kind of preparation method of medroxyproges-terone acetate |
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|---|---|---|---|---|
| US3290322A (en) * | 1965-02-12 | 1966-12-06 | Phytogen Prod Inc | Oxidation of steroids |
| GB1203733A (en) * | 1967-03-07 | 1970-09-03 | Yehuda Mazur | PREPARATION OF delta< >-3-KETO STEROIDS |
| US4154748A (en) * | 1978-01-20 | 1979-05-15 | The Upjohn Company | Phosphate catalyzed acylation of steroidal tertiary alcohols |
| WO2008145318A2 (en) * | 2007-05-31 | 2008-12-04 | Bayer Schering Pharma Ag | USE OF α, β-UNSATURATED CARBONYL COMPOUNDS AS QUENCHING REAGENTS FOR BIRCH REDUCTION |
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| CN106866766A (en) * | 2017-02-14 | 2017-06-20 | 岳阳环宇药业有限公司 | The preparation method and preparation system of a kind of medroxyprogesterone acetate |
| CN107573395A (en) * | 2017-09-04 | 2018-01-12 | 江苏远大信谊药业有限公司 | A kind of preparation method of medroxyproges-terone acetate |
| CN108912193A (en) * | 2018-07-25 | 2018-11-30 | 岳阳环宇药业有限公司 | A kind of medroxyprogesterone acetate production technology and process units |
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