CN105294797A - Preparation method for methyltestosterone - Google Patents
Preparation method for methyltestosterone Download PDFInfo
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- CN105294797A CN105294797A CN201510787680.0A CN201510787680A CN105294797A CN 105294797 A CN105294797 A CN 105294797A CN 201510787680 A CN201510787680 A CN 201510787680A CN 105294797 A CN105294797 A CN 105294797A
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Abstract
The invention provides a preparation method for methyltestosterone. According to the preparation method, methyltestosterone is prepared by taking androstenedione as a raw material and successively performing position-3 keto protection reaction, grignard addition reaction, position-3 keto deprotection and position-17 hydrolysis reaction. The technology possesses the characteristics of being high in reaction selectivity, high in operation safety, simple and easily-realizable for industrialization, low in production cost, high in yield, applicability to industrial large-scale production.
Description
Technical field
The invention belongs to chemical pharmacy field, be specifically related to a kind of preparation method of the steroide Synrotabs as bulk drug.
Background technology
Synrotabs is as androgens medicine, and clinical being applicable to promotes the growth of male genitals and secondary sex character and maintain its normal function; Hemorrhage and transport property mammary cancer of the dysfunctional uterine of women etc.This steroide is also the important intermediate preparing the multi-medicament such as Metrostenolone, 4-chlorine Metrostenolone simultaneously, and market application is very extensive.
Prior art for raw material with 4-AD (DHT), adopts following two kinds of methods to be prepared respectively, is specially:
(1) protect 3-position ketone group through the cyaniding of 17-position, ethylene glycol, remove the obtained Synrotabs of the reactions such as 17-position cyano group, grignard addition, hydrolysis, its synthetic route is as follows:
Document " synthesis of Synrotabs " (Chinese Journal of Pharmaceuticals, 2005,36,385-386) adopts technique scheme to prepare Synrotabs, uses highly toxic product sodium cyanide, expensive raw material methyl iodide, hazardous substance anhydrous diethyl ether in building-up process; Its operational path is tediously long, produce impurity many, need by column chromatography separating purification, production cost high, preparation technology does not possess competitive edge.
(2) first to the 3-position ketone group etherification protection of 4-AD, then carry out the ketone group grignard addition of 17-position, hydrolysis reaction obtains Synrotabs.Its synthetic route is as follows:
Document " synthesis of Synrotabs " (chemical engineering and equipment, 2009,9,136) adopt technique scheme to prepare Synrotabs.Compared with (1) kind scheme, expel highly toxic product sodium cyanide, substitute anhydrous diethyl ether and methyl iodide with tetrahydrofuran (THF) and monochloro methane respectively, reduce production cost, processing safety is improved, total recovery is also promoted to 80% by 77%, but still exist in the etherificate operation of this operational path reaction not thoroughly, the excessive by product of formation reaction, need in reaction to use expensive catalyzer and triethyl orthoformate causes the more high deficiency of cost, containing the 4-AD of 5% and the 3-position of about 3% and 17 the bis ether by products of having an appointment in etherification product; In addition, due to the addition reaction of lower step grignard for avoiding water, the avoid alcohol reaction of (alcoholic solvent contains reactive hydrogen, the hydrogen meeting on-OH and Grignard reagent), all raw materials all need strictly to control moisture and weight loss on drying.Etherification product poor stability, can react at slightly biased acidic conditions and being heated and go bad.In etherate preparation process, all easily there is stock accident in multiple operating process such as solvent distillation, recrystallization, drying.
In order to ensure product Synrotabs purity and reduce production cost, need in production process that refinement treatment is carried out to etherification product, need to bis ether by product carry out acidifying recycling obtain 4-AD.
Because etherification reaction is wayward in the synthesis technique of Synrotabs, cause intermediate etherification product purity not high.Need in process of production to carry out refinement treatment to this intermediate, just and need to carry out acidification to the bis ether by product in refinement mother liquor can be used to prepare target product Synrotabs to reduce production cost.
Summary of the invention
Object of the present invention is exactly the defect for prior art, provides a kind of preparation method of Synrotabs, and the present invention has the advantages that reaction preference is high, the processing safety of preparation technology is high, production cost is low, yield is high, be applicable to industrial scale production.Synthetic route of the present invention is as follows:
Method of the present invention specifically comprises the following steps:
(1) 3-position ketone group protection
Dropped into by 4-AD in previously prepared good mixing solutions and carry out etherification reaction, react complete, join in the aqueous solution of carbonate by etherification reaction liquid, finish and continue to stir, suction filtration, washing obtains etherate wet feed;
(2) 17-position ketone group grignard addition
Added in toluene by protection reagent and stir, in input, the dehydration of step reaction wet feed, then carries out grignard addition reaction with Grignard reagent;
(3) 3-position ketone group goes protection and 17 β-position hydrolysis
Grignard addition reaction terminates, and is added dropwise to by the mineral acid of dilute with water in grignard addition reaction liquid, and finish and continue hydrolysis insulation reaction, reaction terminates, and removes solvent, suction filtration, washing, drying, refining obtains Synrotabs.
Mixing solutions is by Acetyl Chloride 98Min. and the standby solution of Methanol in reactions steps (1), 4-AD: Acetyl Chloride 98Min.: the amount ratio of methyl alcohol is 1:1 ~ 2:10 ~ 20(g/g/ml).
Mixing solutions described in reactions steps (1) is obtained by laxative remedy: methyl alcohol is cooled to 0 DEG C, stirs lower temperature control to 0 ~ 5 DEG C and drips Acetyl Chloride 98Min., dropwises after continuing at 0 ~ 5 DEG C of stirring and obtains required mixing solutions.
Etherification reaction temperature described in reactions steps (1) is 0 ~ 5 DEG C.
Carbonate described in reactions steps (1) is sodium carbonate or sour potassium.
Protection reagent in reactions steps (2) is triethylamine or pyridine.
Mineral acid in reactions steps (3) is hydrochloric acid or sulfuric acid.
The invention has the beneficial effects as follows:
1. the low in raw material price, the reaction preference that use of etherification reaction of the present invention is high, decreases etherate refining step and bis ether by-product recovery treatment process;
2. the present invention takes to add protection reagent reflux dewatering mode before grignard addition reaction, effectively ensure that the processing safety of avoiding water reaction conditions and preparation technology of grignard addition reaction, avoids the generation of stock accident;
3. the present invention has the advantages that reaction preference is high, the processing safety of preparation technology is high, production cost is low, yield is high, be applicable to industrial scale production.
Embodiment
Illustrate the present invention with example below, these examples are intended to help to understand technique means of the present invention.But should be understood that these embodiments are exemplary, the present invention is not limited thereto.
Embodiment one
In reaction flask, drop into 400ml methyl alcohol, stir and be cooled to 0 DEG C, stir lower temperature control to 0 ~ 5 DEG C and drip 40g Acetyl Chloride 98Min., dropwise and continue at 0 ~ 5 DEG C of stirring and obtain mixing solutions for subsequent use in 15 minutes.
The 4-AD dropping into 40g in above-mentioned mixing solutions carried out etherification reaction, in 0 ~ 5 DEG C of stirring reaction 5 hours.React complete, gained etherification reaction liquid is joined the 100g salt of wormwood being chilled to 0 ~ 5 DEG C in advance and is dissolved in the solution of 3000ml water, finish and continue stirring 30 minutes, suction filtration, washing obtains 61.5 etherate wet feeds.
18g magnesium chips, 400ml tetrahydrofuran (THF), 0.1g iodine grain is added in reaction flask, stirring is warming up to 40 DEG C, starts from 40 DEG C ~ 45 DEG C and passes into monochloro methane until magnesium chips total overall reaction is complete, continue at 40 DEG C ~ 45 DEG C insulation reaction 1 hour, be cooled to less than 10 DEG C, obtain Grignard reagent;
Added by 1.5ml pyridine in 400ml toluene, stir 5 minutes, in input, step reacts the 61.5 etherate wet feeds obtained, and temperature rising reflux divides water 1 little of dividing a water purification to divide, and is cooled to 20 DEG C ~ 25 DEG C.The toluene solution of etherate is added dropwise in above-mentioned grignard reagent, controls dropping temperature 10 DEG C ~ 15 DEG C.Finish, continue at 40 DEG C ~ 45 DEG C insulation reaction 24 hours.React complete, cooling, drip 40ml water, then be added dropwise to 400ml methyl alcohol in 10 DEG C ~ 15 DEG C in 10 DEG C ~ 15 DEG C, then continuing at 10 DEG C ~ 15 DEG C droppings by 60ml mass percent concentration is the hydrochloric acid of 36% and the solution of 120ml water preparation, and adjust pH is 2 ~ 3.Finish intensification, in 50 DEG C ~ 55 DEG C reactions 2 hours.React completely, be cooled to less than 30 DEG C, concentrating under reduced pressure, added by concentrating residues mashed prod in the water being chilled to 0 DEG C ~ 5 DEG C in advance, continue stirring 0.5 hour, leave standstill more than 2 hours, suction filtration, is washed to neutrality, and drying obtains crude product.Gained crude product obtains Synrotabs 34.1g with ethyl acetate decolorizing and refining again, HPLC purity 98.9%.
Embodiment two
In reaction flask, drop into 800ml methyl alcohol, stir and be cooled to 0 DEG C, stir lower temperature control to 0 ~ 5 DEG C and drip 80g Acetyl Chloride 98Min., dropwise and continue at 0 ~ 5 DEG C of stirring and obtain mixing solutions for subsequent use in 30 minutes.
The 4-AD dropping into 40g in above-mentioned mixing solutions carried out etherification reaction, in 0 ~ 5 DEG C of stirring reaction 4.5 hours.React complete, gained etherification reaction liquid is joined the 110g sodium carbonate being chilled to 0 ~ 5 DEG C in advance and is dissolved in the solution of 4000ml water, finish and continue stirring 30 minutes, suction filtration, washing obtains 61.0 etherate wet feeds.
18g magnesium chips, 400ml tetrahydrofuran (THF), 0.1g iodine grain is added in reaction flask, stirring is warming up to 40 DEG C, starts from 40 DEG C ~ 45 DEG C and passes into monochloro methane until magnesium chips total overall reaction is complete, continue at 40 DEG C ~ 45 DEG C insulation reaction 1 hour, be cooled to less than 10 DEG C, obtain Grignard reagent;
Added by 1.2ml triethylamine in 400ml toluene, stir 5 minutes, in input, step reacts the 61.5 etherate wet feeds obtained, and temperature rising reflux divides water 1 little of dividing a water purification to divide, and is cooled to 20 DEG C ~ 25 DEG C.The toluene solution of etherate is added dropwise in above-mentioned grignard reagent, controls dropping temperature 10 DEG C ~ 15 DEG C.Finish, continue at 40 DEG C ~ 45 DEG C insulation reaction 24 hours.React complete, cooling, drip 40ml water in 10 DEG C ~ 15 DEG C, then be added dropwise to 400ml methyl alcohol in 10 DEG C ~ 15 DEG C, then continue at 10 DEG C ~ 15 DEG C drip by 15ml mass percent concentration be 98% sulfuric acid and the solution adjust pH prepared of 60ml water be 2 ~ 3.Finish intensification, in 50 DEG C ~ 55 DEG C reactions 2 hours.React completely, be cooled to less than 30 DEG C, concentrating under reduced pressure, added by concentrating residues mashed prod in the water being chilled to 0 DEG C ~ 5 DEG C in advance, continue stirring 0.5 hour, leave standstill more than 2 hours, suction filtration, is washed to neutrality, and drying obtains crude product.Gained crude product obtains Synrotabs 33.9g with ethyl acetate decolorizing and refining again, HPLC purity 99.0%.
Claims (6)
1. a preparation method for Synrotabs, comprises the steps:
This synthetic route is made up of following steps:
(1) 3-position ketone group protection
Dropped into by 4-AD in previously prepared good mixing solutions and carry out etherification reaction, react complete, join in the aqueous solution of carbonate by etherification reaction liquid, finish and continue to stir, suction filtration, washing obtains etherate wet feed;
(2) 17-position ketone group grignard addition
Added in toluene by protection reagent and stir, in input, the dehydration of step reaction wet feed, then carries out grignard addition reaction with Grignard reagent;
(3) 3-position ketone group goes protection and 17 β-position hydrolysis
Grignard addition reaction terminates, and is added dropwise to by the mineral acid of dilute with water in grignard addition reaction liquid, and finish and continue hydrolysis insulation reaction, reaction terminates, and removes solvent, suction filtration, washing, drying, refining obtains Synrotabs;
It is characterized in that: wherein mixing solutions is by Acetyl Chloride 98Min. and the standby solution of Methanol in reactions steps (1), 4-AD: Acetyl Chloride 98Min.: the amount ratio of methyl alcohol is 1:1 ~ 2:10 ~ 20(g/g/ml).
2. preparation method as claimed in claim 1, it is characterized in that: the mixing solutions described in reactions steps (1) is obtained by laxative remedy: methyl alcohol is cooled to 0 DEG C, stir lower temperature control to 0 ~ 5 DEG C and drip Acetyl Chloride 98Min., dropwise after continuing at 0 ~ 5 DEG C of stirring and obtain required mixing solutions.
3. preparation method as claimed in claim 1, is characterized in that: the etherification reaction temperature described in reactions steps (1) is 0 ~ 5 DEG C.
4. preparation method as claimed in claim 1, is characterized in that: the carbonate described in reactions steps (1) is sodium carbonate or salt of wormwood.
5. preparation method as claimed in claim 1, is characterized in that: the protection reagent in reactions steps (2) is triethylamine or pyridine.
6. preparation method as claimed in claim 1, is characterized in that: the mineral acid in reactions steps (3) is hydrochloric acid or sulfuric acid.
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| CN201510787680.0A CN105294797A (en) | 2015-11-17 | 2015-11-17 | Preparation method for methyltestosterone |
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| CN201510787680.0A CN105294797A (en) | 2015-11-17 | 2015-11-17 | Preparation method for methyltestosterone |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749463A (en) * | 2016-11-07 | 2017-05-31 | 华中药业股份有限公司 | A kind of method that methyltestosterone is reclaimed in the mother liquor from methyltestosterone |
| CN109096354A (en) * | 2018-09-12 | 2018-12-28 | 湖北竹溪人福药业有限责任公司 | A kind of testosterone intermediate mother liquor recycling method |
| CN109456378A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A method of preparing danabol product |
| CN109456379A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol product |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012529A (en) * | 2012-09-26 | 2013-04-03 | 宜城市共同药业有限公司 | Method for synthesizing high-yield nandrolone |
-
2015
- 2015-11-17 CN CN201510787680.0A patent/CN105294797A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012529A (en) * | 2012-09-26 | 2013-04-03 | 宜城市共同药业有限公司 | Method for synthesizing high-yield nandrolone |
Non-Patent Citations (2)
| Title |
|---|
| MANAS K.BASU ET AL.: "A New Molecular Iodine-Catalyzed Acetalization of Carbonyl Compounds", 《SYNLETT》 * |
| 刘泺: "甲睾酮的合成", 《中国医药工业杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106749463A (en) * | 2016-11-07 | 2017-05-31 | 华中药业股份有限公司 | A kind of method that methyltestosterone is reclaimed in the mother liquor from methyltestosterone |
| CN109096354A (en) * | 2018-09-12 | 2018-12-28 | 湖北竹溪人福药业有限责任公司 | A kind of testosterone intermediate mother liquor recycling method |
| CN109456378A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A method of preparing danabol product |
| CN109456379A (en) * | 2018-12-18 | 2019-03-12 | 湖南科瑞生物制药股份有限公司 | A kind of preparation method of danabol product |
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Application publication date: 20160203 |