CN101456888B - Method for preparing methenolone - Google Patents

Method for preparing methenolone Download PDF

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CN101456888B
CN101456888B CN2008101634297A CN200810163429A CN101456888B CN 101456888 B CN101456888 B CN 101456888B CN 2008101634297 A CN2008101634297 A CN 2008101634297A CN 200810163429 A CN200810163429 A CN 200810163429A CN 101456888 B CN101456888 B CN 101456888B
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metenolone
reaction
formula
acetic acid
dihydrotestosterone
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CN101456888A (en
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周贤言
潘联根
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Lin'an Xinlian Wire and Cable Material Co., Ltd.
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Hangzhou Tonghua Chemical Co ltd
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Abstract

The invention provides a preparation method for metenolone. The method comprises the following steps: (1) acetic acid isotestosterone of a formula(IV) is taken as a raw material; and the acetic acid isotestosterone, ethylene glycol and calcium hypochlorite are subjected to a ketal oxidation reaction at the temperature of between 60 and 65 DEG C in the organic solvent in the presence of protonic acid serving as a catalyst, so as to obtain the ketal oxide expressed by a formula (III); and (2) the ketal oxide of the formula (III) and a Grignard reagent are subjected to the Grignard reaction to obtain the metenolone of the formula (I). The method has the advantages of few processing steps, simple operation, high safety, contribution to industrialized production and high yield; and according to the separation and purification method, the metenolone is firstly converted into a metenolone acetic ester and the metenolone is obtained through alcoholysis, so that the product has high purity andgood quality.

Description

A kind of preparation method of Metenolone
(1) technical field
The present invention relates to a kind of preparation method of Metenolone.
(2) background technology
Metenolone, have another name called methylene hydrogen dragon, chemistry 17 beta-hydroxies by name-1-methyl-5 α-androstane-1-alkene 3-ketone are a kind of stronger protein anabolic hormones, a kind of bulk drug and intermediate as steroid hormone class medicine, be mainly used in the protein assimilating drug manufacture, can promote protein anabolism, reduce protein and decompose low thanking, promote the process of amino acid synthetic protein, suppress amino acid and resolve into the process of urea, and can promote muscularly, physique strengthens; Also have and impel calcium, the phosphoric deposition in osseous tissue, promote the formation of matter between osteocyte, the accelerated bone calcification, promote the newborn and granulation formation of tissue, impel physiological actions such as wound and ulcer healing and reduction blood cholesterol levels, be widely used in fields such as various chronic consumption disease treatments, wound healing, physique enhancing health care.Along with improving constantly of people's living standard, good health and a long life have become the common objective that people pursue, for this reason, all having exhausted with all strength in the research of the steroid drugs of countries in the world and the production, all is steroid hormone medicine production big country as states such as the U.S., Germany, Britain, Japan, France, Italy, India.Therefore, the Development and Production of Metenolone series product has vast market prospect and social effect.
Chinese patent CN200410015949.5 provides the preparation method of a kind of Metenolone and derivative thereof, and it is as follows to relate to the Metenolone preparation process:
Figure G2008101634297D00011
Figure G2008101634297D00021
This method is to be raw material with 17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone (the different testosterone of acetic acid), carries out epoxidation reaction in the presence of alkaline hydrogen peroxide, makes 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone; Use H again 2/ palladium-lime carbonate catalytic hydrogenolysis makes 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester; In the back under Catalyzed by p-Toluenesulfonic Acid in benzene with the ethylene glycol azeotropic dehydration, make 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester; Do not add then to be separated in the pyridine and carry out oxidation with chromic acid, make 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone is after Ge Shi-dehydration continuous reaction makes 17 beta-hydroxies-1-methyl 5 α-androstane-1-alkene-3-ketone (being Metenolone).This method steps complexity, and need hydrogen to participate in hydrogenolysis, the danger coefficient height, it is low to make Metenolone purity, is unfavorable for suitability for industrialized production.
(3) summary of the invention
The object of the invention provides that a kind of step is simple, environmental pollution is little, safety coefficient is high, the high-quality measured Metenolone preparation method of product purity.
The technical solution used in the present invention is:
A kind of preparation method of Metenolone, described method comprises: (1) is raw material with the different testosterone of acetic acid shown in the formula (IV), in the presence of the catalyzer protonic acid, in organic solvent, carry out the ketal oxidizing reaction with ethylene glycol and Losantin in 60～65 ℃, obtain the ketal oxide compound shown in the formula (III); Described protonic acid is one of following: tosic acid, Phenylsulfonic acid, chlorsulfonic acid etc.; Described organic solvent is one of following or wherein two or more mixture: benzene, toluene, tetracol phenixin; (2) ketal oxide compound shown in the formula (III) and Grignard reagent carry out grignard reaction, make the Metenolone shown in the formula (I); Ethylene glycol, Losantin and Grignard reagent consumption are advisable for being enough to that different testosterone of acetic acid and ketal oxide compound are fully reacted, also can be excessive.The grignard reaction process can be referring to CN200410015949.5.
It is as follows to relate to reaction formula:
Figure G2008101634297D00031
(2) grignard reaction:
CH 3I+Mg＝CH 3MgI；
Figure G2008101634297D00032
Preferably, the middle different testosterone of acetic acid of described step (1) is 1: 1.0～1.2: 0.5～0.6 with the ratio of oxalic acid, Losantin amount of substance.Described organic solvent is preferably benzene.
The present invention is a raw material with the different testosterone of acetic acid, carrying out single step reaction with ethylene glycol and Losantin can obtain the ketal oxide compound shown in the formula (III) and (real reoxidize for first condensation, but owing to do not need purifying intermediate products, can be considered single step reaction), than CN200410015949.5 (needing for 4 steps), reduced reactions steps greatly by the ketal oxide compound shown in the different testosterone synthesis type of acetic acid (III), simplified operation, and do not need hydrogen and participate in, the processing safety height is beneficial to suitability for industrialized production.
The different testosterone of described acetic acid can adopt commercial commodity, also can prepare: be raw material (a) with the acetic acid dihydrotestosterone shown in the formula (VI) by following method, obtain the tetrapropylammonium acetate dihydrotestosterone shown in the formula V with bromine reaction under-10～0 ℃ in chloroform, described acetic acid dihydrotestosterone is 1: 1.0～1.2 with the ratio of bromine amount of substance; (b) the tetrapropylammonium acetate dihydrotestosterone shown in the formula V is dissolved among the DMF, under the methanol solution effect at catalyst n aOH under 120～160 ℃, with calcium carbonate reaction, obtain the different testosterone of described acetic acid, described tetrapropylammonium acetate dihydrotestosterone is 1: 0.5～0.6 with the ratio of lime carbonate amount of substance; Bromine and lime carbonate consumption are advisable for being enough to that acetic acid dihydrotestosterone and tetrapropylammonium acetate dihydrotestosterone are fully reacted, also can be excessive.
Figure G2008101634297D00041
The HBr that this step produces can remove by following reaction:
2HBr+Na 2CO 3＝2NaBr+CO 2+H 2O；
Figure G2008101634297D00042
Excessive CaCO in this step 3Can remove by following reaction:
CaCO 3+2HCl＝CaCl 2+CO 2+H 2O；
For obtaining the Metenolone of higher degree, described method also can further comprise the purification step of product Metenolone: the Metenolone dissolving crude product that (A) grignard reaction is obtained obtains the Metenolone acetic ester shown in the formula (II) with the aceticanhydride reaction in pyridine; (B) the Metenolone acetic ester shown in the formula (II) is dissolved in the methyl alcohol, carries out alcoholysis reaction in 95～100 ℃ under the effect of catalyzer 98% vitriol oil, and after reaction finished, the reaction solution separation and purification obtained the Metenolone after refining;
Preferably, the mass ratio of described step (A) Metenolone crude product and pyridine, aceticanhydride is: 1: 5: 0.5-0.6.
Preferably, the consumption of methyl alcohol is counted 3～4mL/g with Metenolone acetic ester quality in the described step (B).
Described purification procedures is as follows: the reaction solution concentrating under reduced pressure reclaims methyl alcohol, adds the entry elutriation, and is centrifugal, dry, acetone recrystallization, and oven dry obtains described Metenolone after refining.
Concrete, described method step is in the following order carried out:
(1) bromination reaction: acetic acid dihydrotestosterone and bromine carry out bromination reaction in-10 ℃ in chloroform, obtain the tetrapropylammonium acetate dihydrotestosterone; Described acetic acid dihydrotestosterone is 1: 1.0～1.2 with the ratio of bromine amount of substance; Reaction finishes the back and uses in the yellow soda ash and the hydrogen bromide that generates, and adopts the underpressure distillation mode to reclaim chloroform, makes the solvent recrystallization reaction product with methyl alcohol then, and oven dry obtains the tetrapropylammonium acetate dihydrotestosterone.Concentrating under reduced pressure reclaims most of methyl alcohol, and mother liquor is made solid waste and handled after repeatedly applying mechanically;
(2) dehydrobromination reaction: the tetrapropylammonium acetate dihydrotestosterone with calcium carbonate reaction, obtains the different testosterone of acetic acid under the methanol solution effect at catalyst n aOH under 150 ℃; Described tetrapropylammonium acetate dihydrotestosterone is 1: 0.5～0.6 with the ratio of lime carbonate amount of substance;
(3) ketal oxidizing reaction: the different testosterone of acetic acid is dissolved in the benzene, under the effect of catalyzer tosic acid, carries out the ketal oxidizing reaction with ethylene glycol and Losantin, obtains the ketal oxide compound shown in the formula (III); The different testosterone of described acetic acid is 1: 1.0～1.2: 0.5～0.6 with the ratio of oxalic acid, Losantin amount of substance; Can reclaim benzene by steam distillation method after reaction finishes, use recrystallizing methanol, oven dry obtains the ketal oxide compound, the most of methyl alcohol of reclaim under reduced pressure, and mother liquor is handled as solid waste after repeatedly applying mechanically;
(4) grignard reaction: the ketal oxide dissolution shown in the formula (III) is carried out grignard reaction with Grignard reagent in benzene, and grignard reaction finishes the back and adds concentrated hydrochloric acid to there not being precipitation, reclaims benzene, recrystallizing methanol, and oven dry obtains the Metenolone crude product;
(5) acetylization reaction: the Metenolone dissolving crude product is reacted with aceticanhydride in pyridine, generate the Metenolone acetic ester, add the entry elutriation, use acetone recrystallization, oven dry obtains the Metenolone acetic ester, and Metenolone with aceticanhydride amount of substance ratio is: 1: 1.5;
(6) alcoholysis reaction: the Metenolone acetic ester is dissolved in the methyl alcohol, carries out alcoholysis reaction, reaction end afterreaction liquid concentrating under reduced pressure recovery methyl alcohol in 95～100 ℃ under the effect of catalyzer 98% vitriol oil, add the entry elutriation, centrifugal, dry, acetone recrystallization, oven dry obtains described Metenolone; Described Metenolone acetic ester is 1: 1.0～1.2 with the ratio of methyl alcohol amount of substance.
It is as follows that aforesaid method relates to operational path:
Figure G2008101634297D00061
Figure G2008101634297D00071
Beneficial effect of the present invention is mainly reflected in: with the different testosterone of acetic acid shown in the formula (IV) is raw material, directly obtain the ketal oxide compound shown in the formula (III) and carry out grignard reaction with Grignard reagent again, described Metenolone, processing step is few, simple to operate, safe, be beneficial to suitability for industrialized production, the product yield height; Adopt separation purification method of the present invention, earlier Metenolone is converted into after the Metenolone acetic ester again that alcoholysis obtains Metenolone, product purity height (98.0～102.0%), quality are good.
(4) description of drawings
Fig. 1 is a process flow sheet of the present invention.
(5) embodiment
The present invention is described further below in conjunction with specific embodiment, but protection scope of the present invention is not limited in this:
Embodiment 1:
(1) bromination reaction:
In acetic acid dihydrotestosterone 30g dissolving 100mL chloroform, add the 28mL bromine, under-10 ℃, carry out bromination reaction, wash organic phase with water, chloroform is reclaimed in underpressure distillation, and methyl alcohol is the solvent recrystallization reaction product, and oven dry obtains tetrapropylammonium acetate dihydrotestosterone 39.4g; The hydrogen bromide that produces in the reaction process is handled with yellow soda ash, and the mother liquor concentrating under reduced pressure reclaims most of methyl alcohol, handles as solid waste after repeatedly applying mechanically, and this step bromination reaction yield is 88.9%.
(2) dehydrobromination reaction:
Step (1) gained tetrapropylammonium acetate dihydrotestosterone is dissolved among the 200mLDMF, add the methanol solution (NaOH6g that contains 6gNaOH, methyl alcohol 20mL) as catalyzer, add lime carbonate 6g dehydrobromination down in 150 ℃, reclaim catalyzer and part DMF (about 150mL) back and add 200mL water elutriation, centrifugal, oven dry obtains the different testosterone of acetic acid; Excess calcium carbonate salt acid treatment, the yield of this step dehydrobromination reaction is 99.6%.
(3) ketal oxidizing reaction:
The different testosterone of step (2) gained acetic acid is dissolved in the 200mL benzene, add the 7g tosic acid as catalyzer, and adding ethylene glycol 15mL, Losantin 8g carry out the ketal oxidizing reaction under 75 ℃, steam distillation method reclaims benzene, use recrystallizing methanol, oven dry obtains the ketal oxide compound shown in the formula (III); The mother liquor concentrating under reduced pressure reclaims most of methyl alcohol, does the solid waste processing after repeatedly applying mechanically, and this step ketal oxidization-hydrogenation ratio is 88.5%.
(4) grignard reaction:
Magnesium rod 10g adds 30mL tetrahydrofuran (THF) (THF), methyl iodide 16g, stirring at room reaction 2h, and temperature rising reflux 20min is cooled to room temperature, obtains Grignard reagent;
Step (3) gained ketal oxide dissolution in 150mL benzene, is added the 30mL Grignard reagent and carry out grignard reaction under 70 ℃, add concentrated hydrochloric acid (mass concentration 36.5%) then to there not being precipitation, remove THF, steam distillation method reclaims benzene, recrystallizing methanol, oven dry obtains the Metenolone crude product; The mother liquor concentrating under reduced pressure reclaims most of methyl alcohol, handles as solid waste after repeatedly applying mechanically, and this step grignard reaction yield is 14%.
(5) acetylization reaction:
Step (3) gained Metenolone dissolving crude product in the 120mL pyridine, is added the 15g aceticanhydride and carry out acetylization reaction under 28 ℃, add the entry elutriation, use acetone recrystallization, oven dry obtains the Metenolone acetic ester; The mother liquor concentrating under reduced pressure reclaims most of acetone, handles as solid waste after repeatedly applying mechanically, and this step acetylization reaction yield is 87.7%.
(6) alcoholysis reaction:
Step (5) gained Metenolone acetic ester is dissolved in the 150mL methyl alcohol, add 98% vitriol oil 6g as catalyzer, under 97 ℃, carry out alcoholysis reaction, reaction finishes afterreaction liquid concentrating under reduced pressure and reclaims most of methyl alcohol (about 120mL), add 100mL water elutriation, acetone recrystallization, oven dry obtains described Metenolone; The mother liquor concentrating under reduced pressure reclaims most of acetone, handles as solid waste after repeatedly applying mechanically, and this step alcoholysis reaction yield is 95.4%.
The main quality index of products therefrom Metenolone is as follows:
Molten point: m.p.130 ℃-140 ℃;
Specific optical rotation: (a) D 20+ 55-+59 0
Weight loss on drying :≤0.2%
Ignition residue :≤0.05%
Content: 98.0%～102.0%.

Claims (9)

1. the preparation method of a Metenolone, described method comprises: (1) is raw material with the different testosterone of acetic acid shown in the formula (IV), in the presence of the catalyzer protonic acid, in organic solvent, under 60～65 ℃, carry out the ketal oxidizing reaction with ethylene glycol and Losantin, obtain the ketal oxide compound shown in the formula (III); Described protonic acid is one of following: tosic acid, Phenylsulfonic acid, chlorsulfonic acid; Described organic solvent is one of following or wherein two or more mixture: benzene, toluene, tetracol phenixin; (2) ketal oxide compound shown in the formula (III) and Grignard reagent carry out grignard reaction, make the Metenolone shown in the formula (I);
Figure FSB00000539929800011
2. the preparation method of Metenolone as claimed in claim 1 is characterized in that the middle different testosterone of acetic acid of described step (1) and the ratio of ethylene glycol, Losantin amount of substance are 1: 1.0～1.2: 0.5～0.6.
3. the preparation method of Metenolone as claimed in claim 2 is characterized in that described organic solvent is a benzene.
4. the method for claim 1, it is characterized in that the different testosterone of described acetic acid is prepared by following method: be raw material (a) with the acetic acid dihydrotestosterone shown in the formula (VI), obtain the tetrapropylammonium acetate dihydrotestosterone shown in the formula V with bromine reaction under-10～0 ℃ in chloroform, described acetic acid dihydrotestosterone is 1: 1.0～1.2 with the ratio of bromine amount of substance; (b) the tetrapropylammonium acetate dihydrotestosterone shown in the formula V is dissolved among the DMF, under the methanol solution effect at catalyst n aOH under 120～160 ℃, with calcium carbonate reaction, obtain the different testosterone of described acetic acid, described tetrapropylammonium acetate dihydrotestosterone is 1: 0.5～0.6 with the ratio of lime carbonate amount of substance;
Figure FSB00000539929800021
5. the method for claim 1, it is characterized in that described method also comprises the purification step of product Metenolone: the Metenolone dissolving crude product that (A) grignard reaction is obtained obtains the Metenolone acetic ester shown in the formula (II) with the aceticanhydride reaction in pyridine; (B) the Metenolone acetic ester shown in the formula (II) is dissolved in the methyl alcohol, is carrying out alcoholysis reaction under the effect of catalyzer 98% vitriol oil under 95～100 ℃, after reaction finishes, and the Metenolone after the reaction solution separation and purification obtains making with extra care;
Figure FSB00000539929800022
6. method as claimed in claim 5, the mass ratio that it is characterized in that described step (A) Metenolone crude product and pyridine, aceticanhydride is 1: 5: 0.5～0.6.
7. method as claimed in claim 5 is characterized in that the consumption of methyl alcohol in the described step (B) is counted 3～4mL/g with Metenolone acetic ester quality.
8. method as claimed in claim 5 is characterized in that purification procedures is as follows: the reaction solution concentrating under reduced pressure reclaims methyl alcohol, adds the entry elutriation, and is centrifugal, dry, acetone recrystallization, and oven dry obtains described Metenolone after refining.
9. the preparation method of a Metenolone, it is characterized in that described method in the following order step carry out:
(1) bromination reaction: acetic acid dihydrotestosterone shown in the formula (VI) and bromine carry out bromination reaction in-10 ℃ in chloroform, obtain the tetrapropylammonium acetate dihydrotestosterone shown in the formula V; Described acetic acid dihydrotestosterone is 1: 1.0～1.2 with the ratio of bromine amount of substance;
(2) dehydrobromination reaction: the tetrapropylammonium acetate dihydrotestosterone shown in the formula V with calcium carbonate reaction, obtains the different testosterone of acetic acid shown in the formula (IV) under the methanol solution effect at catalyst n aOH under 150 ℃; Described tetrapropylammonium acetate dihydrotestosterone is 1: 0.5～0.6 with the ratio of lime carbonate amount of substance;
(3) ketal oxidizing reaction: the different testosterone of acetic acid shown in the formula (IV) is dissolved in the benzene, under the effect of catalyzer tosic acid, in 60～65 ℃ down and ethylene glycol and Losantin carry out the ketal oxidizing reaction, obtain the ketal oxide compound shown in the formula (III); The different testosterone of described acetic acid is 1: 1.0～1.2: 0.5～0.6 with the ratio of ethylene glycol, Losantin amount of substance;
(4) grignard reaction: the ketal oxide dissolution shown in the formula (III) is carried out grignard reaction with Grignard reagent in benzene, and grignard reaction finishes the back and adds concentrated hydrochloric acid to there not being precipitation, reclaims benzene, recrystallizing methanol, and oven dry obtains the Metenolone crude product;
(5) acetylization reaction: the Metenolone dissolving crude product is reacted with aceticanhydride in pyridine, generate the Metenolone acetic ester, add the entry elutriation, use acetone recrystallization, oven dry obtains the Metenolone acetic ester shown in the formula (II), and Metenolone is 1: 1.5 with aceticanhydride amount of substance ratio;
(6) alcoholysis reaction: the Metenolone acetic ester shown in the formula (II) is dissolved in the methyl alcohol, under the effect of catalyzer 98% vitriol oil, carry out alcoholysis reaction in 95～100 ℃, reaction finishes afterreaction liquid concentrating under reduced pressure and reclaims methyl alcohol, add the entry elutriation, centrifugal, dry, acetone recrystallization, oven dry obtains the Metenolone shown in the formula (I); Described Metenolone acetic ester is 1: 1.0～1.2 with the ratio of methyl alcohol amount of substance;
Figure FSB00000539929800031
Figure FSB00000539929800041
CN2008101634297A 2008-12-19 2008-12-19 Method for preparing methenolone Expired - Fee Related CN101456888B (en)

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CN114560903B (en) * 2022-03-09 2023-08-01 绍兴市上虞区武汉理工大学高等研究院 Preparation method of abiraterone derivative and cytotoxicity evaluation thereof
CN114773420A (en) * 2022-03-30 2022-07-22 湖北武当安泰药业有限公司 Preparation method of 3-hydroxyandrost-1-ene-17-one

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183815A (en) * 1991-01-22 1993-02-02 Merck & Co., Inc. Bone acting agents
CN1557828A (en) * 2004-01-19 2004-12-29 复旦大学 Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5183815A (en) * 1991-01-22 1993-02-02 Merck & Co., Inc. Bone acting agents
CN1557828A (en) * 2004-01-19 2004-12-29 复旦大学 Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives

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