CN1887897A - Chemical synthesis of free megestrol - Google Patents
Chemical synthesis of free megestrol Download PDFInfo
- Publication number
- CN1887897A CN1887897A CN 200610052632 CN200610052632A CN1887897A CN 1887897 A CN1887897 A CN 1887897A CN 200610052632 CN200610052632 CN 200610052632 CN 200610052632 A CN200610052632 A CN 200610052632A CN 1887897 A CN1887897 A CN 1887897A
- Authority
- CN
- China
- Prior art keywords
- methyne
- megestrol
- thing
- free
- palladium
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960001786 megestrol Drugs 0.000 title claims abstract description 24
- 238000003786 synthesis reaction Methods 0.000 title claims abstract description 9
- RQZAXGRLVPAYTJ-GQFGMJRRSA-N megestrol acetate Chemical compound C1=C(C)C2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)C)[C@@]1(C)CC2 RQZAXGRLVPAYTJ-GQFGMJRRSA-N 0.000 title claims abstract 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 36
- 239000003054 catalyst Substances 0.000 claims abstract description 19
- DBPWSSGDRRHUNT-UHFFFAOYSA-N 17alpha-hydroxy progesterone Natural products C1CC2=CC(=O)CCC2(C)C2C1C1CCC(C(=O)C)(O)C1(C)CC2 DBPWSSGDRRHUNT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229950000801 hydroxyprogesterone caproate Drugs 0.000 claims abstract description 16
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000007069 methylation reaction Methods 0.000 claims abstract description 4
- DOMWKUIIPQCAJU-LJHIYBGHSA-N Hydroxyprogesterone caproate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(C)=O)(OC(=O)CCCCC)[C@@]1(C)CC2 DOMWKUIIPQCAJU-LJHIYBGHSA-N 0.000 claims abstract 3
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 35
- 238000006243 chemical reaction Methods 0.000 claims description 18
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 17
- 239000002994 raw material Substances 0.000 claims description 7
- 238000005303 weighing Methods 0.000 claims description 4
- 239000000376 reactant Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract 2
- 239000000126 substance Substances 0.000 abstract 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 230000011987 methylation Effects 0.000 abstract 1
- JBVNBBXAMBZTMQ-CEGNMAFCSA-N megestrol Chemical compound C1=CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 JBVNBBXAMBZTMQ-CEGNMAFCSA-N 0.000 description 19
- DBPWSSGDRRHUNT-CEGNMAFCSA-N 17α-hydroxyprogesterone Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)C)(O)[C@@]1(C)CC2 DBPWSSGDRRHUNT-CEGNMAFCSA-N 0.000 description 13
- 239000012141 concentrate Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000007670 refining Methods 0.000 description 7
- 239000012043 crude product Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 238000009413 insulation Methods 0.000 description 6
- 239000012452 mother liquor Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention discloses chemical synthesis of free megestrol. The initial material 17alpha-hydroxyprogesterone is first methenylated to form methenylated substance, the methenylated substance is then mixed with Pd/C catalyst, dimethylformamide and cyclohexene and reacted at 50-70 deg.c for 1-3 hr, and the product is post-treated to obtain free megestrol. The improved synthesis process of the present invention has complete methylation, less side product, high product purity, high quality stability, high yield and low production cost, and may be used in industrial production.
Description
Technical field
The present invention relates to a kind of method of synthetic free megestrol (6-methyl-4,6-diene-3, the pregnant steroid of 20-diketone-17 Alpha-hydroxy), this method is that starting raw material prepares free megestrol with 17 Alpha-hydroxy Progesterone.
Background technology
Free megestrol is the important intermediate of hormones bulk drug.
Prior art is many to be starting raw material with 17 Alpha-hydroxy Progesterone acetic esters, through methyne reaction, 6 methylate, decolorizing and refining obtains Magace, hydrolysis obtains free megestrol again.6 these step committed step Technology difficulty that methylate are big simultaneously, and side reaction is difficult to control.
The patent No. is disclose the Magace structural compounds in U.S.'s patent of invention of US3117966, US1020493 synthetic, and wherein methyneization has been conventional production method.But 6 the process that methylates wherein though also adopt palladium-carbon catalyst, adopts alcohols such as ethanol to make solvent, and a small amount of tetrahydrobenzene is as reaction promotor.Obtaining by this method is hydrolyzed behind the Magace again obtains free megestrol, disclosed technology only limits to laboratory condition, palladium-carbon catalyst activity in the alcoholic solvent reaction system is not high, cause reactant to rest on the 6-7 position and be two key conjugated system states, make the transposition that methylates not thorough, reaction times is longer, and reaction product quality is poor, and yield is lower.
Summary of the invention
The invention provides a kind of is the directly synthetic free megestrol of starting raw material with 17 Alpha-hydroxy Progesterone directly, can reduce the reaction step number, improves reaction yield.
The reaction principle of the chemical synthesis process of free megestrol of the present invention is:
A kind of chemical synthesis process of free megestrol is a starting raw material with 17 Alpha-hydroxy Progesterone (I), obtains methyne thing (II) through the methyne reaction, obtains free megestrol (III) through 6 methylation reactions again.
Synthetic method of the present invention is made up of following steps:
(1) takes by weighing 17 Alpha-hydroxy Progesterone, 1 weight part, carry out the methyne reaction, obtain the methyne thing;
(2) press the row weight part and take by weighing dimethyl formamide, 5% palladium-carbon catalyst, tetrahydrobenzene:
Dimethyl formamide 10-12 weight part, 5% palladium-carbon catalyst 0.4-0.6 weight part, tetrahydrobenzene 0.4-0.6 weight part;
(3) the methyne thing that (1) is obtained, dimethyl formamide, 5% palladium-carbon catalyst, tetrahydrobenzene drop into retort, mix the back under 50-70 ℃ of temperature, react 1-3 hour;
(4) reactant is carried out aftertreatment, obtain free megestrol.
Palladium-carbon catalyst has 1%, 5% etc. according to the common specification of its effective content, and the specification of the palladium-carbon catalyst that the present invention adopts is 5%, if select for use other specifications to convert consumption by effective content.
It is the synthetic method of starting raw material with 17 Alpha-hydroxy Progesterone acetic esters that the present invention changes traditional, and adopting 17 Alpha-hydroxy Progesterone is starting raw material, reduces the reaction step number, improves reaction yield.Adopt dimethyl formamide to substitute alcohols of the prior art, improved the catalytic activity of palladium-carbon catalyst greatly, accelerated speed of response, make more thorough that methylation reaction carries out, reduced the generation of by product as solvent.
The present invention has determined the rational catalyst usage quantity, takes into account cost and yield.
The free megestrol that synthetic method of the present invention obtains has the advantage of the few and product purity height (up to more than 98%) of by product, and synthetic method is simple to operate, reaction conditions is gentle, be easy to realize industrialization.
Embodiment
Embodiment 1:
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In dimethyl formamide 260L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1200ml was in 70 ℃ of insulations 1.5 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 1 hour, dry free megestrol crude product, obtain 16.1KG after refining, yield is 70.0%.
Embodiment 2:
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In dimethyl formamide 240L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1200ml was in 60 ℃ of insulations 3 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 0.5 hour, dry free megestrol crude product, obtain 16.6KG after refining, yield is 72.2%.
Embodiment 3:
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In dimethyl formamide 260L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1100ml was in 55 ℃ of insulations 2.5 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 0.5 hour, dry free megestrol crude product, obtain 16.4KG after refining, yield is 71.3%.
Embodiment 4:
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In dimethyl formamide 250L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1150ml was in 50 ℃ of insulations 3 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 1 hour, dry free megestrol crude product, obtain 16.8KG after refining, yield is 73.0%.
Comparative Examples 1:(adopts alcohol to make solvent)
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In ethanol 260L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1200ml was in 60 ℃ of insulations 3 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 1 hour, dry free megestrol crude product, obtain 10.4KG after refining, yield is 45.2%.
Comparative Examples 2:(adopts alcohol to make solvent)
17 Alpha-hydroxy Progesterone 30KG through the methyne reaction, obtain methyne thing 23KG.In ethanol 260L suction retort, drop into methyne thing 23KG, 5% palladium-carbon catalyst 12KG, tetrahydrobenzene 1200ml was in 50 ℃ of insulations 12 hours, filter, concentrate while filtering, the weight that concentrates the back mother liquor is chilled to below 5 ℃ centrifugal for 1.5 times of the methyne thing weight that drops into, with 50 ℃ of warm water washings 1 hour, dry free megestrol crude product, obtain 11.2KG after refining, yield is 48.7%.
Claims (2)
1. the chemical synthesis process of a free megestrol is a starting raw material with 17 Alpha-hydroxy Progesterone, obtains methyne thing, methyne thing and obtain free megestrol through methylation reaction again after methyneization.
2, chemical synthesis process according to claim 1, it is characterized in that: chemical synthesis process is made up of following steps:
(1) takes by weighing 17 Alpha-hydroxy Progesterone, 1 weight part, carry out the methyne reaction, obtain the methyne thing;
(2) press the row weight part and take by weighing dimethyl formamide, 5% palladium-carbon catalyst, tetrahydrobenzene:
Dimethyl formamide 10-12 weight part, 5% palladium-carbon catalyst 0.4-0.6 weight part, tetrahydrobenzene 0.4-0.6 weight part;
(3) the methyne thing that (1) is obtained, dimethyl formamide, 5% palladium-carbon catalyst, tetrahydrobenzene drop into retort, mix the back under 50-70 ℃ of temperature, react 1-3 hour;
(4) reactant is carried out aftertreatment, obtain free megestrol.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100526328A CN100398553C (en) | 2006-07-24 | 2006-07-24 | Chemical synthesis of free megestrol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100526328A CN100398553C (en) | 2006-07-24 | 2006-07-24 | Chemical synthesis of free megestrol |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1887897A true CN1887897A (en) | 2007-01-03 |
| CN100398553C CN100398553C (en) | 2008-07-02 |
Family
ID=37577179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100526328A Expired - Fee Related CN100398553C (en) | 2006-07-24 | 2006-07-24 | Chemical synthesis of free megestrol |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100398553C (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087136A (en) * | 2012-11-06 | 2013-05-08 | 湖南科源生物制品有限公司 | Novel process for preparing progesterone |
| CN113583074A (en) * | 2021-06-28 | 2021-11-02 | 佳尔科生物科技南通有限公司 | Novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and precursor thereof |
| CN114057821A (en) * | 2021-11-30 | 2022-02-18 | 黑龙江中医药大学 | Preparation method of medroxyprogesterone acetate for perimenopausal syndrome |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3004508C2 (en) * | 1980-02-05 | 1981-12-10 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | Process for the preparation of 6-methylene steroids |
| US4346037A (en) * | 1981-07-10 | 1982-08-24 | The Upjohn Company | Base catalyzed acylation with enol esters |
| FR2676740B1 (en) * | 1991-05-23 | 1993-11-05 | Roussel Uclaf | NOVEL STEROUID DERIVATIVES OF PREGNA-4,9 (11), 17 (20) -TRIE-3-ONE, THEIR PREPARATION, THEIR APPLICATION TO THE PREPARATION OF PREGNA-4,9 (11), 16-TRIENE- STEROUID COMPOUNDS 3.20-DIONE AND NEW INTERMEDIATES. |
| US6828120B2 (en) * | 2001-06-18 | 2004-12-07 | Pharmacia And Upjohn Company | Process to prepare 11β, 17α,21-trihydroxy-6α-methylpregna-1,4-diene-3,20-dione 21-acetate |
-
2006
- 2006-07-24 CN CNB2006100526328A patent/CN100398553C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103087136A (en) * | 2012-11-06 | 2013-05-08 | 湖南科源生物制品有限公司 | Novel process for preparing progesterone |
| CN113583074A (en) * | 2021-06-28 | 2021-11-02 | 佳尔科生物科技南通有限公司 | Novel preparation method of 6-methyl-17 alpha-hydroxyprogesterone and precursor thereof |
| CN114057821A (en) * | 2021-11-30 | 2022-02-18 | 黑龙江中医药大学 | Preparation method of medroxyprogesterone acetate for perimenopausal syndrome |
| CN114057821B (en) * | 2021-11-30 | 2022-12-09 | 黑龙江中医药大学 | Preparation method of medroxyprogesterone acetate for perimenopausal syndrome |
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| Publication number | Publication date |
|---|---|
| CN100398553C (en) | 2008-07-02 |
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| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| EE01 | Entry into force of recordation of patent licensing contract |
Application publication date: 20070103 Assignee: Taizhou Taifa Pharmaceuticals Co., Ltd. Assignor: Wang Jiazhen Contract record no.: 2010330000450 Denomination of invention: Chemical synthesis of free megestrol Granted publication date: 20080702 License type: Exclusive License Record date: 20100409 |
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| ASS | Succession or assignment of patent right |
Owner name: TAIZHOU TAIFA PHARMACEUTICAL CO., LTD. Free format text: FORMER OWNER: WANG JIAZHEN Effective date: 20130620 |
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| C41 | Transfer of patent application or patent right or utility model | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20130620 Address after: 317300 No. 14 Industrial East Road, Xianju County, Zhejiang, Taizhou Patentee after: Taizhou Taifa Pharmaceuticals Co., Ltd. Address before: The 317300 industry in Zhejiang province Xianju County Road No. 14 Taizhou Baida Pharmaceutical Co Ltd Patentee before: Wang Jiazhen |
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| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20080702 Termination date: 20150724 |
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| EXPY | Termination of patent right or utility model |