CN112940062A - Preparation method of 16-dehydroprogesterone - Google Patents
Preparation method of 16-dehydroprogesterone Download PDFInfo
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- CN112940062A CN112940062A CN202110201587.2A CN202110201587A CN112940062A CN 112940062 A CN112940062 A CN 112940062A CN 202110201587 A CN202110201587 A CN 202110201587A CN 112940062 A CN112940062 A CN 112940062A
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- Prior art keywords
- dehydroprogesterone
- reaction
- hydroxyprogesterone
- water
- toluene
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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
- C07J7/0015—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 not substituted in position 17 alfa
- C07J7/002—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 not substituted in position 17 alfa not substituted in position 16
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a preparation method of 16-dehydroprogesterone, and belongs to the technical field of organic synthesis. The preparation method of 16-dehydroprogesterone provided by the invention comprises the following steps: mixing 17 alpha-hydroxyprogesterone, toluene, water, acetic acid and semicarbazide hydrochloride, and carrying out elimination reaction to obtain the 16-dehydroprogesterone. The method provided by the invention has the advantages of low cost and high product yield and purity, and is suitable for industrial large-scale production. Specifically, the 17 alpha-hydroxyprogesterone is used as a raw material, and the raw material is low in price; toluene and water are used as solvents, semicarbazide hydrochloride is used as an elimination reagent, acetic acid is used as a catalyst, a reaction system is divided into a toluene layer and a water layer, the elimination reaction is specifically carried out in the water layer, and a product generated by the reaction is extracted to the toluene layer, so that the phenomenon that the yield and the purity of the product are influenced due to impurities generated by excessive reaction of the product is avoided.
Description
Technical Field
The invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of 16-dehydroprogesterone.
Background
The 16-dehydroprogesterone is white or white-like crystalline powder, is an important steroid drug intermediate, can be used for synthesizing steroid drugs such as progesterone, hydrocortisone, dexamethasone, betamethasone and the like, and has a structural formula shown as a formula I:
patent application CN106977570A discloses a method for preparing 16-dehydroprogesterone, specifically, 17 alpha-hydroxyprogesterone is used as a raw material, esterification reaction is firstly carried out, ester group on 3-position is converted into ketone group through hydrolysis reaction, and finally reaction is carried out at 240-300 ℃ under the action of a removing reagent to obtain 16-dehydroprogesterone. However, the method has complex process and high temperature during elimination, and is not suitable for industrial large-scale production.
Disclosure of Invention
The invention aims to provide a preparation method of 16-dehydroprogesterone, which is simple to operate, can obtain the 16-dehydroprogesterone through one-step elimination reaction at a lower temperature, and is suitable for industrial large-scale production.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of 16-dehydroprogesterone, which comprises the following steps:
mixing 17 alpha-hydroxyprogesterone, toluene, water, acetic acid and semicarbazide hydrochloride, and carrying out elimination reaction to obtain the 16-dehydroprogesterone.
Preferably, the dosage ratio of the 17 alpha-hydroxyprogesterone to the toluene is 1 g: (5-10) mL.
Preferably, the dosage ratio of the 17 alpha-hydroxyprogesterone to the water is 1 g: (0.3-1) mL.
Preferably, the dosage ratio of the 17 alpha-hydroxyprogesterone to the acetic acid is 1 g: (0.3-1) mL.
Preferably, the mass ratio of the 17 alpha-hydroxyprogesterone to the semicarbazide hydrochloride is 1: (0.1-0.2).
Preferably, the temperature of the elimination reaction is 80-90 ℃ and the time is 4-8 h.
Preferably, the elimination reaction further comprises:
and standing and layering a product system obtained after the elimination reaction, washing the obtained toluene layer with water, concentrating to be dry, and refining residues obtained by concentration by using ethyl acetate to obtain the 16-dehydroprogesterone.
Preferably, the method of refining comprises:
and dissolving the residues with ethyl acetate, concentrating the obtained solution, cooling the obtained concentrated solution, separating out solid materials, and sequentially filtering and drying to obtain the 16-dehydroprogesterone.
The invention provides a preparation method of 16-dehydroprogesterone, which comprises the following steps: mixing 17 alpha-hydroxyprogesterone, toluene, water, acetic acid and semicarbazide hydrochloride, and carrying out elimination reaction to obtain the 16-dehydroprogesterone. The method provided by the invention is simple to operate, low in cost, high in product yield and purity, and suitable for industrial large-scale production. Specifically, the 17 alpha-hydroxyprogesterone is used as a raw material, and the raw material is low in price; toluene and water are used as solvents, semicarbazide hydrochloride is used as an elimination reagent, acetic acid is used as a catalyst, and 16-dehydroprogesterone can be obtained through one-step elimination reaction at a lower temperature (80-90 ℃); the reaction system is divided into a toluene layer and a water layer, the elimination reaction is carried out in the water layer, and the product generated by the reaction is extracted to the toluene layer, so that the product is prevented from being excessively reacted to generate impurities, and the yield and the purity of the product are prevented from being influenced.
Furthermore, the method provided by the invention adopts a small amount of solvent, has high concentration of raw materials in a reaction system and short reaction time, and is beneficial to improving the production efficiency and shortening the production period.
Furthermore, the method provided by the invention has the advantages that after the reaction is finished, the water layer contains impurities with high polarity, and the water layer can be removed by standing and layering the product system obtained after the reaction, so that the operation is simple, the step of further refining to remove the impurities with high polarity is omitted, and the purity of the product is favorably improved.
Furthermore, the method provided by the invention can recycle toluene by concentrating the toluene layer, has no pollution to the environment, and is suitable for large-scale industrial production.
Detailed Description
The invention provides a preparation method of 16-dehydroprogesterone, which comprises the following steps:
mixing 17 alpha-hydroxyprogesterone, toluene, water, acetic acid and semicarbazide hydrochloride, and carrying out elimination reaction to obtain the 16-dehydroprogesterone.
The reaction formula for preparing 16-dehydroprogesterone in the invention is specifically as follows:
in the present invention, the ratio of the amount of 17 α -hydroxyprogesterone to toluene is preferably 1 g: (5-10) mL, more preferably 1 g: (6-8) mL; the dosage ratio of the 17 alpha-hydroxyprogesterone to the water is preferably 1 g: (0.3-1) mL, more preferably 1 g: (0.4-0.5) mL. In the invention, the toluene and the water are used as solvents, the reaction system is divided into a toluene layer and a water layer, the elimination reaction is carried out in the water layer, and the product generated by the reaction is extracted to the toluene layer, so that the phenomenon that the product is excessively reacted to generate impurities, which affects the yield and the purity of the product is avoided.
In the present invention, the amount ratio of 17 α -hydroxyprogesterone to acetic acid is preferably 1 g: (0.3-1) mL, more preferably 1 g: (0.4-0.5) mL. In the invention, the acetic acid is a catalyst, so that an acidic environment can be provided, and the reaction efficiency is improved.
In the present invention, the mass ratio of the 17 α -hydroxyprogesterone to the semicarbazide hydrochloride is preferably 1: (0.1 to 0.2), and specifically may be 1: 0.1, 1: 0.15 or 1: 0.2. in the invention, the semicarbazide hydrochloride is an elimination reagent, and under the action of the elimination reagent, the 17 alpha-hydroxyprogesterone is dehydrated to obtain the 16-dehydroprogesterone.
The mixing mode of the 17 alpha-hydroxyprogesterone, the toluene, the water, the acetic acid and the semicarbazide hydrochloride is not particularly limited, and all the components can be uniformly mixed.
In the invention, the temperature of the elimination reaction is preferably 80-90 ℃, and the time is preferably 4-8 h, and more preferably 6 h.
In the present invention, it is preferable that the elimination reaction further comprises: and standing and layering a product system obtained after the elimination reaction, washing the obtained toluene layer with water, concentrating to be dry, and refining residues obtained by concentration by using ethyl acetate to obtain the 16-dehydroprogesterone. In the present invention, the number of times of washing with water and the specific operation method are not particularly limited, and a method known to those skilled in the art may be used. The method of concentration in the present invention is not particularly limited, and a method known to those skilled in the art may be used. In the invention, the toluene obtained by concentration can be recycled and used in the elimination reaction, has no pollution to the environment, and is suitable for large-scale industrial production.
In the present invention, the method for refining the residue with ethyl acetate preferably comprises: and dissolving the residues with ethyl acetate, concentrating the obtained solution, cooling the obtained concentrated solution, separating out solid materials, and sequentially filtering and drying to obtain the 16-dehydroprogesterone. In the invention, most of ethyl acetate is removed in the process of concentrating the solution obtained by dissolving, the obtained concentrated solution contains a small amount of ethyl acetate, solid materials can be separated out in the system by cooling, the system is filtered, and the filter cake is dried to obtain the 16-dehydroprogesterone.
The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
500mL of toluene, 100g of 17 alpha-hydroxyprogesterone, 30mL of acetic acid, 30mL of water and 10g of semicarbazide hydrochloride are added into a reactor, and the temperature of the system is controlled to be 80-90 ℃ for reaction for 6 hours; and (3) after the reaction is finished, standing and layering the obtained product system, removing a water layer, washing a toluene layer for 2 times, concentrating to be dry, dissolving the obtained residue with ethyl acetate, concentrating to remove most of ethyl acetate, cooling the obtained concentrated solution, separating out a solid material, and sequentially filtering and drying to obtain 82.1g of 16-dehydroprogesterone with the purity of 99.3%.
Example 2
Adding 800mL of toluene, 100g of 17 alpha-hydroxyprogesterone, 50mL of acetic acid, 50mL of water and 15g of semicarbazide hydrochloride into a reactor, and controlling the temperature of the system to be 80-90 ℃ for reacting for 6 hours; and (3) after the reaction is finished, standing and layering the obtained product system, removing a water layer, washing a toluene layer for 2 times, concentrating to be dry, dissolving the obtained residue with ethyl acetate, concentrating to remove most of ethyl acetate, cooling the obtained concentrated solution, separating out a solid material, and sequentially filtering and drying to obtain 82.2g of 16-dehydroprogesterone with the purity of 99.1%.
Example 3
1000mL of toluene, 100g of 17 alpha-hydroxyprogesterone, 100mL of acetic acid, 100mL of water and 20g of semicarbazide hydrochloride are added into a reactor, and the temperature of the system is controlled to be 80-90 ℃ for reaction for 6 hours; and (3) after the reaction is finished, standing and layering the obtained product system, removing a water layer, washing a toluene layer for 2 times, concentrating to be dry, dissolving the obtained residue with ethyl acetate, concentrating to remove most of ethyl acetate, cooling the obtained concentrated solution, separating out a solid material, and sequentially filtering and drying to obtain 81.9g of 16-dehydroprogesterone with the purity of 99.2%.
Comparative example 1
Under the protection of argon, adding 330mL of acetic acid, 10g of 17 alpha-hydroxyprogesterone and 22mL of 5 wt% semicarbazide hydrochloride aqueous solution into a reactor, controlling the temperature of the system at 80-85 ℃ for reaction for 4.2h, heating to 85 ℃, and reacting for 5.5 h; after the reaction is finished, water is added into the obtained system, solid materials are separated out, and the solid materials are sequentially filtered and dried to obtain 8.0g of 16-dehydroprogesterone with the purity of 67.9%.
As can be seen from comparative example 1, the method has the advantages of long reaction time, low product yield and purity, large consumption of acetic acid as a solvent, difficult recovery and high cost, and is not beneficial to large-scale industrial production.
Comparative example 2
Adding 10g of 17 alpha-hydroxyprogesterone, 400mL of tetrahydrofuran, 135g of n-butyric acid and 1.08g of semicarbazide hydrochloride into a reactor, and carrying out heat preservation reaction at 66 ℃ for 16 h; after the reaction is finished, cooling the obtained product system to 0 ℃, adding a sodium hydroxide aqueous solution with the concentration of 20 wt% for neutralization to be neutral, continuously stirring for 1h, carrying out reduced pressure concentration on the obtained system until no distillate exists, cooling the obtained residue to 0 ℃, carrying out suction filtration, and washing and drying the obtained solid material in sequence to obtain 7.7g of 16-dehydroprogesterone with the purity of 42.5%.
As can be seen from comparative example 2, the method has the advantages of long reaction time, low product yield and purity, large dosage and high cost due to the adoption of tetrahydrofuran as a solvent, and is not beneficial to large-scale industrial production.
Comparative example 3
Adding 10g of 17 alpha-hydroxyprogesterone, 400mL of dichloromethane, 135g of n-butyric acid and 1.08g of semicarbazide hydrochloride into a reactor, and carrying out heat preservation reaction at 40 ℃ for 16 h; after the reaction is finished, cooling the obtained product system to 0 ℃, adding a sodium hydroxide aqueous solution with the concentration of 20 wt% for neutralization to be neutral, continuously stirring for 1h, carrying out reduced pressure concentration on the obtained system until no distillate exists, cooling the obtained residue to 0 ℃, carrying out suction filtration, and washing and drying the obtained solid material in sequence to obtain 7.7g of 16-dehydroprogesterone with the purity of 36.1%.
As can be seen from comparative example 3, the method has the advantages of long reaction time, low product yield and purity, large dosage and high cost due to the adoption of dichloromethane as a solvent, and is not beneficial to large-scale industrial production.
Comparative example 4
Adding 80mL of tetrahydrofuran, 10g of 17 alpha-hydroxyprogesterone, 5mL of acetic acid, 5mL of water and 1.5g of semicarbazide hydrochloride into a reactor, carrying out heat preservation reaction for 16h at 66 ℃, cooling an obtained product system to 0 ℃ after the reaction is finished, adding a 20 wt% sodium hydroxide aqueous solution for neutralization to neutrality, continuing stirring for 1h, concentrating the obtained system under reduced pressure until no distillate exists, cooling the obtained residue to 0 ℃, and washing and drying the obtained solid material in sequence to obtain 7.8g of 16-dehydroprogesterone with the purity of 24.4%.
As can be seen from comparative example 4, the reaction system using tetrahydrofuran and water as solvents is a homogeneous system, the reaction temperature can only reach 66 ℃ at most, and the temperature is low, so that the reaction is slow, the impurities are more, and the product purity is low; the reaction system adopting toluene and water as solvents is a two-phase system, the elimination reaction is carried out in a water layer, and the product generated by the reaction is extracted to a toluene layer, so that the product yield and purity are prevented from being influenced by impurities generated by excessive reaction.
Comparative example 5
Adding 80mL of dichloromethane, 10g of 17 alpha-hydroxyprogesterone, 5mL of acetic acid, 5mL of water and 1.5g of semicarbazide hydrochloride into a reactor, and carrying out heat preservation reaction at 40 ℃ for 16 h; and (3) after the reaction is finished, standing the obtained product system, removing a water layer, washing an organic layer for 2 times, concentrating to be dry, adding water for water precipitation, carrying out suction filtration on the obtained system, and washing and drying the obtained solid material in sequence to obtain 7.9g of 16-dehydroprogesterone with the purity of 46.7%.
As can be seen from comparative example 5, the reaction system using methylene chloride and water as solvents is a two-phase system, but the reaction temperature is only up to 40 ℃ at most, and the temperature is low, resulting in slow reaction, more impurities and low product purity.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.
Claims (8)
1. A preparation method of 16-dehydroprogesterone is characterized by comprising the following steps:
mixing 17 alpha-hydroxyprogesterone, toluene, water, acetic acid and semicarbazide hydrochloride, and carrying out elimination reaction to obtain the 16-dehydroprogesterone.
2. The process according to claim 1, wherein the 17 α -hydroxyprogesterone is present in a ratio of 1g to toluene: (5-10) mL.
3. The process according to claim 1, wherein the 17 α -hydroxyprogesterone is used in a ratio of 1g to water: (0.3-1) mL.
4. The process according to claim 1, wherein the 17 α -hydroxyprogesterone is used in a ratio of 1g to acetic acid: (0.3-1) mL.
5. The process according to claim 1, wherein the mass ratio of 17 α -hydroxyprogesterone to semicarbazide hydrochloride is 1: (0.1-0.2).
6. The method according to any one of claims 1 to 5, wherein the temperature of the elimination reaction is 80 to 90 ℃ and the time is 4 to 8 hours.
7. The method of claim 6, further comprising, after the elimination reaction:
and standing and layering a product system obtained after the elimination reaction, washing the obtained toluene layer with water, concentrating to be dry, and refining residues obtained by concentration by using ethyl acetate to obtain the 16-dehydroprogesterone.
8. The production method according to claim 7, wherein the refining method comprises:
and dissolving the residues with ethyl acetate, concentrating the obtained solution, cooling the obtained concentrated solution, separating out solid materials, and sequentially filtering and drying to obtain the 16-dehydroprogesterone.
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| CN202110201587.2A CN112940062B (en) | 2021-02-23 | 2021-02-23 | Preparation method of 16-dehydroprogesterone |
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| CN202110201587.2A CN112940062B (en) | 2021-02-23 | 2021-02-23 | Preparation method of 16-dehydroprogesterone |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104311619A (en) * | 2014-07-08 | 2015-01-28 | 仙居县圃瑞药业有限公司 | Method for synthesizing progesterone by series process |
| CN105164108A (en) * | 2013-03-14 | 2015-12-16 | 阿奎诺克斯药物（加拿大）公司 | SHIP1 modulators and methods related thereto |
| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
| CN107286216A (en) * | 2016-03-31 | 2017-10-24 | 天津金耀集团有限公司 | Preparation method with multiple alkene steroidal compounds |
-
2021
- 2021-02-23 CN CN202110201587.2A patent/CN112940062B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105164108A (en) * | 2013-03-14 | 2015-12-16 | 阿奎诺克斯药物（加拿大）公司 | SHIP1 modulators and methods related thereto |
| CN104311619A (en) * | 2014-07-08 | 2015-01-28 | 仙居县圃瑞药业有限公司 | Method for synthesizing progesterone by series process |
| CN105348351A (en) * | 2015-11-16 | 2016-02-24 | 浙江仙琚制药股份有限公司 | Method for preparing tetraene methyl CAS |
| CN107286216A (en) * | 2016-03-31 | 2017-10-24 | 天津金耀集团有限公司 | Preparation method with multiple alkene steroidal compounds |
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