CN101982472A - Synthesis process of levonorgestrel by methoxydienone - Google Patents
Synthesis process of levonorgestrel by methoxydienone Download PDFInfo
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- CN101982472A CN101982472A CN 201010289509 CN201010289509A CN101982472A CN 101982472 A CN101982472 A CN 101982472A CN 201010289509 CN201010289509 CN 201010289509 CN 201010289509 A CN201010289509 A CN 201010289509A CN 101982472 A CN101982472 A CN 101982472A
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Abstract
The invention relates to a synthesis process of levonorgestrel, in particular to a synthesis process of levonorgestrel by methoxydienone. The synthesis process of the levonorgestrel uses the methoxydienone as a raw material which reacts with an alkynyllithium ammine complex to prepare an acetylide, and then the acetylide is hydrolyzed to obtain the levonorgestrel. The chemical structural formula in the process route is shown in the specification. The synthesis process has simple and easily controlled industrial production conditions, fast reaction speed, and low production cost. The synthesis process of the invention enhances the yield, further ensures the product quality, and solves the problems of the existing production processes that the solubility of the acetylene gas in the tetrahydrofuran is limited which results in the waste of the acetylene gas in a large amount, and the acetylene gas reacts with the potassium hydroxide to generate water, which has an influence on the reaction progress and can not meet the requirement of the industrial production of the levonorgestrel.
Description
Technical field:
The present invention relates to a kind of synthesis technique of Levonorgestrel, be specifically related to the technology of the synthetic Levonorgestrel of a kind of Wo Shi thing.
Background technology:
Levonorgestrel is a known compound, and its chemical name is (-)-13-ethyl-17-hydroxyl-18,19-dinor--17 α-pregnant steroid-4-alkene-20-alkynes-3-ketone, English name Levonorgestrel.Levonorgestrel is a kind of quick-acting, short-term oral contraceptive, and contraception mechanism is significantly to suppress ovulation and stop nidation, and uterine neck mucus denseness is increased, and the sperm penetration resistance increases, thereby brings into play quick-acting contraceptive efficacy.The production technique of existing Levonorgestrel is: acetylene gas is fed in the tetrahydrofuran (THF) that is dissolved with potassium hydroxide to saturated, the saturated acetylene solution of tetrahydrofuran (THF) is made in cooling; With the Wo Shi oxide compound is raw material, and it is dissolved in the saturated acetylene solution of making solution in tetrahydrofuran (THF) and the acetone and being added drop-wise to tetrahydrofuran (THF), is stirred to reaction and finishes; Add water a little, tell organic layer, organic layer is acidified to pH value 1～2 with dilute hydrochloric acid, the intensification hydrolysis can obtain Levonorgestrel.Its synthesis route is: as follows with the synthesis route that chemical structural formula is described:
There is certain defective in above-mentioned this production technique, mainly shows: the solubleness of acetylene gas in tetrahydrofuran (THF) is limited, causes a large amount of acetylene gas wastes, and acetylene gas and potassium hydroxide water generation reaction, can influence the process of reaction.After feeding acetylene gas, in the tetrahydrofuran solution of potassium hydroxide, form mashed prod, cause reaction not gone down at all, can't satisfy the demand of Levonorgestrel suitability for industrialized production.
Summary of the invention:
The objective of the invention is to: provide a kind of and solve acetylene gas and potassium hydroxide water generation reaction in the existing production technique and cause reacting the problem of carrying out of being difficult to.It is fast that speed is carried out in reaction, and production cost is low, the yield height, and quality product can be guaranteed, the technology of the synthetic Levonorgestrel of the Wo Shi thing of suitability for industrialized production characteristics preferably.
The present invention realizes above-mentioned purpose by the following technical solutions:
The technology of the synthetic Levonorgestrel of a kind of Wo Shi thing is characterized in that it comprises the steps:
The preparation of the first step alkynyl lithium ammonia complex:
A, liquefied ammonia is injected in three mouthfuls of reaction flasks and the control bottle in temperature at-55～-50 ℃, whipped state adds metallic lithium down,, add-on is every 50mL liquefied ammonia 1g lithium, the joining day is 20min;
After b, metallic lithium were dissolved in liquefied ammonia fully, temperature fed acetylene gas at-50 ℃ by the flow of 4L/min in the control bottle in bottle, to liquid ammonia solution by black-and-blue become canescence after, continue to feed acetylene gas 5min again;
C, heat up with normal-temperature water, continue volatilization liquefied ammonia, add wherein a kind of with methyl tertiary butyl ether, toluene or the tetrahydrofuran (THF) of the liquefied ammonia equal volume of volatilizing simultaneously, make its reaction in the reaction flask outside;
D, the reaction solution volume in adding methyl tertiary butyl ether or tetrahydrofuran (THF) reaction flask reach and the preceding whiles such as volume of liquefied ammonia volatilization, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, change in another reaction flask the alkynyl lithium complex for preparing standby again; After perhaps adding temperature in the toluene reaction flask and reaching 10 ℃, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, change in another reaction flask the alkynyl lithium complex for preparing standby again;
The alkynyl addition reaction of second step:
A, the Wo Shi oxide compound is dissolved in wherein a kind of solvent of methyl tertiary butyl ether, toluene or tetrahydrofuran (THF) and stirs, add-on is that every liter of solvent adds Wo Shi oxide compound 90g, make Wo Shi oxide compound methyl tertbutyl ethereal solution, or Wo Shi oxide compound toluene solution, or Wo Shi oxide compound tetrahydrofuran solution;
B, standby alkynyl lithium complex is cooled to-20 ℃, temperature control-20 ℃ the method that employing drips is with Wo Shi oxide compound methyl tertbutyl ethereal solution, or Wo Shi oxide compound toluene solution, or Wo Shi oxide compound tetrahydrofuran solution joins in the alkynyl lithium complex, stir while dripping in the dropping process, the dropping time is 30min; Obtain the alkynyl affixture.
The preparation of the 3rd step Levonorgestrel:
The hydrochloric acid of a, adding 10% in the good alkynyl affixture of above-mentioned reaction, make the pH value be adjusted to 1～2, temperature is controlled at-10～-5 ℃ in the adjustment process, with 20min to 22min temperature slowly is warming up to 60 ℃ after adjustment is finished, and keeps 60 ℃ of temperature reflux 1h to complete hydrolysis; Be cooled to 0 ℃ after hydrolysis is finished, make its standing demix;
After b, standing demix are finished, lower floor's water is used methyl tertiary butyl ether again, or toluene, or tetrahydrofuran (THF) extracted organic phase at twice, add-on is pressed the weight of Wo Shi oxide compound and is calculated, and ratio is 4.4mL/g, merges all organic phases after extraction is finished, again organic phase water Xian is neutral to the pH value, the 300mm Hg that reduces pressure then concentrates organic phase;
C, add ethyl acetate again in the organic phase enriched material, add-on is pressed the weight of Wo Shi oxide compound and is calculated, and ratio is 22mL/g, be heated to 60 ℃ dissolved the back will slowly be cooled to 10 ℃ with 20min to 22min, insulated and stirred 30min, suction filtration again, dry the product Levonorgestrel.
The chemical structural formula of the synthesis technique of this Levonorgestrel is:
The present invention's beneficial effect compared with prior art is:
The synthesis technique of this Levonorgestrel is to be raw material with the Wo Shi thing, generates the alkynyl affixture with the ammonia complex reaction of alkynyl lithium.This synthetic technological condition is simple, and commercial production conditions is easy to control, and it is fast that speed is carried out in reaction, and production cost is low, has improved yield, has further guaranteed quality product.Solve acetylene gas and potassium hydroxide water generation reaction in the existing production technique and caused reacting the problem of carrying out of being difficult to.
Embodiment:
The present invention is that employing Wo Shi thing is a raw material, reacts with alkynyl lithium ammonia complex, generates acetylide, again the acetylide hydrolysis is obtained Levonorgestrel.The chemical structural formula of its synthesis technique is:
That the invention will be further described is as follows below by specific embodiment:
Embodiment 1
The preparation of the first step alkynyl lithium ammonia complex:
A, the liquefied ammonia of 500ml is injected in three mouthfuls of reaction flasks of 1000ml, and temperature is at-55～-50 ℃ in the control bottle, whipped state adds the 10.5g metallic lithium down, and the joining day is 20min;
After b, metallic lithium were dissolved in liquefied ammonia fully, temperature fed acetylene gas at-50 ℃ by the flow of 4L/min in the control bottle in bottle, until liquid ammonia solution by black-and-blue become canescence after, feed acetylene gas 5min again;
C, heat up with normal-temperature water, continue volatilization liquefied ammonia, add the 600ml methyl tertiary butyl ether simultaneously, make its reaction in the reaction flask outside;
After d, the reaction solution volume in adding methyl tertiary butyl ether afterreaction bottle reach 500ml, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, the alkynyl lithium complex for preparing is changed in the reaction flask of another 10L standby.
The alkynyl addition reaction of second step:
A, be dissolved in 450g Wo Shi oxide compound in the 5L methyl tertiary butyl ether and stir, make Wo Shi oxide compound methyl tertiary butyl ether solution for standby;
B, standby alkynyl lithium complex is cooled to-20 ℃, temperature control-20 ℃ the method that employing drips joins standby Wo Shi oxide compound methyl tertbutyl ethereal solution in the alkynyl lithium complex, stir while dripping in the dropping process, the dropping time is 30min, obtains the alkynyl affixture.
The preparation of the 3rd step Levonorgestrel:
The hydrochloric acid of a, adding 10% in the good alkynyl affixture of above-mentioned reaction makes the pH value be adjusted to 1～2, and temperature is controlled at-10～-5 ℃ in the adjustment process, slowly is warming up to 60 ℃ with 20min after adjustment is finished, and keeps 60 ℃ of temperature reflux 1h to complete hydrolysis; Be cooled to 0 ℃ after hydrolysis is finished, make its standing demix;
After b, standing demix were finished, lower floor's water was used 2000mL methyl tertiary butyl ether extracted organic phase at twice again, merged all organic phases after extraction is finished, and again organic phase water Xian was neutral to the pH value, was decompressed to 300mm Hg then and concentrated organic phase;
C, in the organic phase enriched material, add the 10L ethyl acetate again, be heated to 60 ℃ and dissolve and then slowly be cooled to 10 ℃ with 20min, insulated and stirred 30min, suction filtration again, dry product Levonorgestrel (375g, 80%).
Embodiment 2
The preparation of the first step alkynyl lithium ammonia complex:
A, the liquefied ammonia of 500ml is injected in three mouthfuls of reaction flasks of 1000ml, and temperature is at-55～-50 ℃ in the control bottle, whipped state adds the 11g metallic lithium down, and the joining day is 20min;
After b, metallic lithium were dissolved in liquefied ammonia fully, temperature fed acetylene gas at-50 ℃ by the flow of 4L/min in the control bottle in bottle, until liquid ammonia solution by black-and-blue become canescence after, feed acetylene gas 5min again;
C, heat up with normal-temperature water, continue volatilization liquefied ammonia, add 500ml toluene simultaneously, make its reaction in the reaction flask outside;
After d, the reacting liquid temperature in adding toluene afterreaction bottle reach 10 ℃, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, the alkynyl lithium complex for preparing is changed in the reaction flask of another 10L standby.
The alkynyl addition reaction of second step:
A, be dissolved in 450g Wo Shi oxide compound in the 5L toluene and stir, it is standby to make Wo Shi oxide compound toluene solution;
B, standby alkynyl lithium complex is cooled to-20 ℃, temperature control-20 ℃ the method that employing drips joins standby Wo Shi oxide compound toluene solution in the alkynyl lithium complex, stir while dripping in the dropping process, the dropping time is 30min, obtains the alkynyl affixture.
The preparation of the 3rd step Levonorgestrel:
The hydrochloric acid of a, adding 10% in the good alkynyl affixture of above-mentioned reaction makes the pH value be adjusted to 1～2, and temperature is controlled at-10～-5 ℃ in the adjustment process, slowly is warming up to 60 ℃ with 20min after adjustment is finished, and keeps 60 ℃ of temperature reflux 1h to complete hydrolysis; Be cooled to 0 ℃ after hydrolysis is finished, make its standing demix;
After b, standing demix were finished, lower floor's water was used 2000mL toluene extracted organic phase at twice again, merged all organic phases after extraction is finished, and again organic phase water Xian was neutral to the pH value, was decompressed to 300mm Hg then and concentrated organic phase;
C, in the organic phase enriched material, add the 10L ethyl acetate again, be heated to 60 ℃ and dissolve and then slowly be cooled to 10 ℃ with 20min, insulated and stirred 30min, suction filtration again, dry product Levonorgestrel (352g, 75%).
Embodiment 3
The preparation of the first step alkynyl lithium ammonia complex:
A, the liquefied ammonia of 500ml is injected in three mouthfuls of reaction flasks of 1000ml, and temperature is at-55～-50 ℃ in the control bottle, whipped state adds the 10.5g metallic lithium down, and the joining day is 20min;
After b, metallic lithium were dissolved in liquefied ammonia fully, temperature fed acetylene gas at-50 ℃ by the flow of 4L/min in the control bottle in bottle, until liquid ammonia solution by black-and-blue become canescence after, feed acetylene gas 5min again;
C, heat up with normal-temperature water, continue volatilization liquefied ammonia, add the 600ml tetrahydrofuran (THF) simultaneously, make its reaction in the reaction flask outside;
After d, the reaction solution volume in adding tetrahydrofuran (THF) afterreaction bottle reach 500ml, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, the alkynyl lithium complex for preparing is changed in the reaction flask of another 10L standby.
The alkynyl addition reaction of second step:
A, be dissolved in 450g Wo Shi oxide compound in the 5L tetrahydrofuran (THF) and stir, it is standby to make Wo Shi oxide compound tetrahydrofuran solution;
B, standby alkynyl lithium complex is cooled to-20 ℃, temperature control-20 ℃ the method that employing drips joins standby Wo Shi oxide compound tetrahydrofuran solution in the alkynyl lithium complex, stir while dripping in the dropping process, the dropping time is 30min, obtains the alkynyl affixture;
The preparation of the 3rd step Levonorgestrel:
The hydrochloric acid of a, adding 10% in the good alkynyl affixture of above-mentioned reaction makes the pH value be adjusted to 1～2, and temperature is controlled at-10～-5 ℃ in the adjustment process, slowly is warming up to 60 ℃ with 20min after adjustment is finished, and keeps 60 ℃ of temperature reflux 1h to complete hydrolysis; Be cooled to 0 ℃ after hydrolysis is finished, make its standing demix;
After b, standing demix were finished, lower floor's water was used 2000mL tetrahydrofuran (THF) extracted organic phase at twice again, merged all organic phases after extraction is finished, and again organic phase water Xian was neutral to the pH value, was decompressed to 300mm Hg then and concentrated organic phase;
C, in the organic phase enriched material, add the 10L ethyl acetate again, be heated to 60 ℃ and dissolve and then slowly be cooled to 10 ℃ with 20min, insulated and stirred 30min, suction filtration again, dry product Levonorgestrel (337g, 72%).
Claims (1)
1. the technology of the synthetic Levonorgestrel of Wo Shi thing is characterized in that it comprises the steps:
The preparation of the first step alkynyl lithium ammonia complex:
A, liquefied ammonia is injected in three mouthfuls of reaction flasks and the control bottle in temperature at-55～-50 ℃, whipped state adds metallic lithium down,, add-on is every 50mL liquefied ammonia 1g lithium, the joining day is 20min;
After b, metallic lithium were dissolved in liquefied ammonia fully, temperature fed acetylene gas at-50 ℃ by the flow of 4L/min in the control bottle in bottle, to liquid ammonia solution by black-and-blue become canescence after, continue to feed acetylene gas 5min again;
C, heat up with normal-temperature water, continue volatilization liquefied ammonia, add wherein a kind of with methyl tertiary butyl ether, toluene or the tetrahydrofuran (THF) of the liquefied ammonia equal volume of volatilizing simultaneously, make its reaction in the reaction flask outside;
D, the reaction solution volume in adding methyl tertiary butyl ether or tetrahydrofuran (THF) reaction flask reach and the preceding whiles such as volume of liquefied ammonia volatilization, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, change in another reaction flask the alkynyl lithium complex for preparing standby again; After perhaps adding temperature in the toluene reaction flask and reaching 10 ℃, make the reacting liquid temperature in the reaction flask reduce to-20 ℃ by add refrigerant at reaction flask, continue to feed acetylene gas 30min again and obtain the alkynyl lithium complex, change in another reaction flask the alkynyl lithium complex for preparing standby again;
The alkynyl addition reaction of second step:
A, the Wo Shi oxide compound is dissolved in wherein a kind of solvent of methyl tertiary butyl ether, toluene or tetrahydrofuran (THF) and stirs, add-on is that every liter of solvent adds Wo Shi oxide compound 90g, make Wo Shi oxide compound methyl tertbutyl ethereal solution, or Wo Shi oxide compound toluene solution, or Wo Shi oxide compound tetrahydrofuran solution;
B, standby alkynyl lithium complex is cooled to-20 ℃, temperature control-20 ℃ the method that employing drips is with Wo Shi oxide compound methyl tertbutyl ethereal solution, or Wo Shi oxide compound toluene solution, or Wo Shi oxide compound tetrahydrofuran solution joins in the alkynyl lithium complex, stir while dripping in the dropping process, the dropping time is 30min; Obtain the alkynyl affixture;
The preparation of the 3rd step Levonorgestrel:
The hydrochloric acid of a, adding 10% in the good alkynyl affixture of above-mentioned reaction, make the pH value be adjusted to 1～2, temperature is controlled at-10～-5 ℃ in the adjustment process, with 20min to 22min temperature slowly is warming up to 60 ℃ after adjustment is finished, and keeps 60 ℃ of temperature reflux 1h to complete hydrolysis; Be cooled to 0 ℃ after hydrolysis is finished, make its standing demix;
After b, standing demix are finished, lower floor's water is used methyl tertiary butyl ether again, or toluene, or tetrahydrofuran (THF) extracted organic phase at twice, add-on is pressed the weight of Wo Shi oxide compound and is calculated, and ratio is 4.4mL/g, merges all organic phases after extraction is finished, again organic phase water Xian is neutral to the pH value, the 300mm Hg that reduces pressure then concentrates organic phase;
C, add ethyl acetate again in the organic phase enriched material, add-on is pressed the weight of Wo Shi oxide compound and is calculated, and ratio is 22mL/g, be heated to 60 ℃ dissolved the back will slowly be cooled to 10 ℃ with 20min to 22min, insulated and stirred 30min, suction filtration again, dry the product Levonorgestrel;
The chemical structural formula of described Levonorgestrel operational path is:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057121A (en) * | 2019-12-31 | 2020-04-24 | 湖北葛店人福药业有限责任公司 | Recycling method and application of levonorgestrel mother liquor |
| CN111606962A (en) * | 2020-06-08 | 2020-09-01 | 浙江神洲药业有限公司 | Synthesis method of levonorgestrel |
-
2010
- 2010-09-17 CN CN2010102895094A patent/CN101982472B/en active Active
Non-Patent Citations (2)
| Title |
|---|
| 《HELVETICA CHIMICA ACTA》 19851231 Helmut Baier, et al. 117. Totalsynthese von (-)-Norgestrel') 第1054-1068页 1 第68卷, * |
| 《Tetrahedron》 20100408 Fung Fuh Wong, et al. One-pot ethynylation and catalytic desilylation in synthesis of mestranol and levonorgestrel 第4068-4072页 1 第66卷, * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111057121A (en) * | 2019-12-31 | 2020-04-24 | 湖北葛店人福药业有限责任公司 | Recycling method and application of levonorgestrel mother liquor |
| CN111057121B (en) * | 2019-12-31 | 2022-05-06 | 湖北葛店人福药业有限责任公司 | Recycling method and application of levonorgestrel mother liquor |
| CN111606962A (en) * | 2020-06-08 | 2020-09-01 | 浙江神洲药业有限公司 | Synthesis method of levonorgestrel |
| CN111606962B (en) * | 2020-06-08 | 2021-03-02 | 浙江神洲药业有限公司 | Synthesis method of levonorgestrel |
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Effective date of registration: 20120903 Address after: 434000 Dongfang Avenue, Jingzhou Development Zone, Hubei Patentee after: Nenter & Co., Inc. Address before: 434000 Dongfang Avenue, Jingzhou Development Zone, Jingzhou, Hubei Patentee before: Hubei Nengte Technology Co., Ltd. |
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Address after: 434000 Dongfang Avenue, Jingzhou Development Zone, Hubei Province Patentee after: Nenter AND Co., Inc. Address before: 434000 Dongfang Avenue, Jingzhou Development Zone, Hubei Province Patentee before: Nenter & Co., Inc. |