CN1557828A - Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives - Google Patents
Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives Download PDFInfo
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Abstract
The present invention belongs to the field of chemical synthesis technology, and relates to preparation process of compound 17beta-substitute-1-methyl-5alpha-androst-1-alkenyl-3-ketone (methenolone) and its derivative. The present invention prepares methenolone with 17beta-acetoxy-5alpha-androst-1-alkenyl-3-ketone as material and through five reaction steps of epoxidation, hydrogenolysis, ketalization, oxidation and Gridnard reaction. The 17beta-hydroxyl may be acidated, etherified and esterified into various methenolone derivatives. The present invention has the advantages of no environmental pollution caused by diazotitation, direct alkali oxidation after epoxidation, catalytic hydrogenolysis and ketalization without separation, simple operation program, high total product yield and high product purity.
Description
Technical field
The invention belongs to the field of chemical synthesis, relate to the preparation method of compound 17 beta substitution-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone) and derivative thereof.
Background technology
Metenolone has another name called methylene hydrogen dragon, and chemistry 17 beta-hydroxies by name-1-methyl-5 α-androstane-1-alkene-3-ketone are a kind of stronger protein anabolic hormone, and its biggest advantage is minimum to the side effect of liver.Relevant prior art is, Wiechert R equals nineteen sixty and synthesized the Metenolone acetic ester, and synthetic route is suc as formula 1:
Above-mentioned synthetic route is brief, and step is few, but has following defective, and diazomethane reaction is to serious environment pollution, and the by product of denitrification reaction is more, and difficulty removes, and product yield is not high.
Summary of the invention
The purpose of this invention is to provide a kind of easyly, environmental pollution is light, the preparation method of the synthetic Metenolone acetic ester that by product is few, and the inventive method reaction is ripe, and condition is not harsh, can obtain higher yield and very high yield.
The inventive method is at diazomethane reaction in the synthetic route of Wiechert R etc., the deficiency that product yield is not high, adopting 17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone is raw material, makes the compound Metenolone and the derivative thereof of following formula through epoxy, hydrogenolysis, ketalization, oxidation, grignard reaction 5 step reaction.
R=-H in the formula,
R wherein
1=-CH
3,-C
2H
5,-C
3H
7,-CH
2C
6H
5
The synthetic route of through type (I), adopting 17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone is raw material, 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
2/ palladium-lime carbonate catalytic hydrogenolysis makes 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester; Then under the catalysis of tosic 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 makes 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (claiming Metenolone again) through Ge Shi-dehydration continuous reaction again.
The synthetic route of through type (II), the employing Metenolone is a raw material, makes 17 β-acetoxyl group-1-methyl-5 α-androstane-1-alkene-3-ketone (claiming the Metenolone acetic ester again) through acetylize.
The synthetic route of through type (III), the employing Metenolone is a raw material, makes 17 β-propionyloxy-1-methyl-5 α-androstane-1-alkene-3-ketone (claiming the propionic acid Metenolone again) through propionylization.
The synthetic route of through type (IV), the employing Metenolone is a raw material, makes 17 β-oenanthyl Oxy-1-methyl-5 α-androstane-1-alkene-3-ketone (metenolone enanthate) through oenanthylization.
By the synthetic route of formula V, the employing Metenolone is a raw material, makes 17 β-undecanoyl Oxy-1-methyl-5 α-androstane-1-alkene-3-ketone (undeeanoic acid Metenolone) through undecanoylization.
Through type (VI)) synthetic route, the employing Metenolone is a raw material, with 2,3-dihydro-4H-pyrans reaction makes Metenolone 17-tetrahydropyrans-2-ether.
The synthetic route of through type (VII), the employing Metenolone is a raw material, makes the Metenolone methyl carbonic through the methyl carbonic acid esterification.
The synthetic route of through type (VIII), the employing Metenolone is a raw material, makes Metenolone ethyl carbonate ester through the ethyl carbonate esterification.
The synthetic route of through type (IX), the employing Metenolone is a raw material, makes the Metenolone propyl carbonate through propyl carbonateization.
The synthetic route of through type (X), the employing Metenolone is a raw material, makes Metenolone benzyl carbonic ether through the esterification of benzyl carbonic acid.
The present invention prepares 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone) and derivative thereof by following step:
1) epoxidation reaction: a.17 beta-acetoxyl group-5 α-androstane-1-alkene-3-ketone is dissolved in the methyl alcohol, stirs and is cooled to 5～15 ℃; B. add hydrogen peroxide, stir; C.15～20 ℃ following dropping sodium solution, stirring reaction; D. pour in the water, place, filter, washing makes 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone.
2) hydrogenolysis: a. is with 1 α, and 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone is dissolved in ethanol, adds palladium-lime carbonate, and with the hydrogen ventilation, (hydrogen pressure is a normal pressure～70bar) to stir logical hydrogen down at 25～50 ℃ then; B. reaction finishes, and stops logical hydrogen, reacting liquid filtering, washing with alcohol; C. concentrating under reduced pressure cools off, and filters, and makes 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester.
3) ketal reaction: α a.1 adds benzene, tosic acid and ethylene glycol, reflux water-dividing in the reactor of water trap is housed in 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester; B. be cooled to room temperature, add pyridine; C. be evaporated to driedly, make 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester.
4) oxidizing reaction: a.3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester is dissolved in pyridine; B. stir under the room temperature and add chromic acid solution down; C. at room temperature reaction; D. pour in the sodium sulfite aqueous solution, placement is spent the night, and filters, and washing makes 17 α-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone.
5) Ge Shi-dehydration continuous reaction: a. adds tetrahydrofuran (THF) in magnesium rod, methyl iodide, and the stirring at room reaction refluxes; B. be cooled to room temperature, add 17 α-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone and benzene refluxes; C. be cooled to room temperature, add concentrated hydrochloric acid, the remaining Grignard reagent of water destruct; D. tell the benzene layer, the water layer benzene extraction, the combined benzene layer, washing is evaporated to dried; E. add methyl alcohol, sulfuric acid refluxes; F. pour in the water, separate out crystallization, filter, washing, drying makes 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone).
6) acetylization reaction: a. is dissolved in Metenolone in the pyridine, adds aceticanhydride, and placement is spent the night; B. pour next day in the water, filter, washing, drying, ethyl alcohol recrystallization makes 17 β-acetoxyl group-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone acetic ester).
7) propionyl reaction: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings; Add propionic anhydride in room temperature, the stirring at room reaction; B. pour in the frozen water, place, filter, washing is drained, drying, and ethyl alcohol recrystallization makes 17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 17-propionic ester (propionic acid Metenolone).
8) oenanthyl reaction: a. is dissolved in pyridine with Metenolone, is lower than under 30～50 ℃ the condition at the control temperature of charge, adds oenanthyl chloro, and in 25-30 ℃ of reaction, placement is spent the night; B. pour next day in the water, place; C. elutriation liquid chloroform extraction, chloroform solution is used hydrochloric acid, water, yellow soda ash and water washing successively, tells chloroform layer, be evaporated to no chloroform, pour methyl alcohol, continue to be concentrated into solvent-free, pour methyl alcohol once more, continue to be concentrated into solvent-free, add methyl alcohol, freeze overnight is separated out crystallization, filters, the small amount of methanol washing, drain, 40～60 ℃ of dryings make 17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 17-heptanoate (metenolone enanthate).
9) undecanoyl reaction: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings, adds undecanoyl chlorine, room temperature reaction in room temperature; B. pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes 17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 17-undecylate (undeeanoic acid Metenolone).
10) etherification reaction: a. adds pyridine and tosic acid in chloroform, stirring at room adds Metenolone, under agitation adds 2,3-dihydro-4H-pyrans, back flow reaction after molten entirely; B. reaction is finished, and washing is evaporated to several solvent-free, pour methyl alcohol, continue to be concentrated into several solvent-free, pour methyl alcohol, continue to be concentrated into several solvent-free, pour methyl alcohol, cool overnight is filtered, the ice methanol wash, drain, washing with water, the dry Metenolone 17-tetrahydropyrans-2-ether (Metenolone tetrahydropyranyl ethers) that gets the white crystals shape to neutrality.
11) methyl carbonic acid esterification reaction: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings, in 5～15 ℃ of dropping methyl-chloroformates, reacts in stirring at room; B. pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, recrystallizing methanol makes the Metenolone methyl carbonic.
12) ethyl carbonate esterification: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings, in 5～15 ℃ of dropping Vinyl chloroformates, reacts in stirring at room; B. pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes Metenolone ethyl carbonate ester.
13) propyl carbonate reaction: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings, in 5～15 ℃ of dropping propyl chloroformates, reacts in stirring at room; B. pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes the Metenolone propyl carbonate.
14) benzyl carbonic acid esterification: a. is dissolved in Metenolone in the pyridine, is stirred to whole dissolvings, in 5～15 ℃ of dropping chloroformic acid benzyl esters, reacts in stirring at room; B. pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes Metenolone benzyl carbonic ether.
The present invention has following advantage: avoided the pollution of diazotization reaction to environment 1.; 2. use the catalytic hydrogenolysis catalyzer of suitable active, make 1 α, the yield of 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester reaches 70%; 3. do not add separation behind the employing ketal reaction and directly enter oxidizing reaction, reduced the unnecessary loss that produces because of aftertreatment, simplified schedule of operation, improved reaction yield.4. can pass through acidylate by Metenolone, esterification, etherificate etc. and synthetic various derivatives.
Embodiment:
Embodiment 1
Prepare 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone
17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone 46g is dissolved among the methyl alcohol 460ml, stirs and be cooled to 10 ℃.Add 30-35% superoxol 50.6ml, stir,, added in about 15 minutes dripping 10% sodium hydroxide-methanol solution 13.1ml below 18 ℃.Continue reaction 45 minutes.Pour in the 2000ml water, stir, placement is spent the night.Filter next day, is washed to neutrality, making beating, thoroughly washing, dry 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone 42g of getting.
Embodiment 2
Prepare 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester
At 1 α, add 95% ethanol 1260mL, palladium-lime carbonate 12.6g among 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone 42g.With hydrogen ventilation 3 times, 40 ℃ of stirrings were led to hydrogen 8～10 hours under the hydrogen pressure of 40bar then.Reaction finishes, and stops logical hydrogen.Reacting liquid filtering, the catalyzer washing with alcohol merges reaction solution, is evaporated to pasty state, cool overnight.Filter next day, the small amount of ethanol washing is drained, and drying makes 1 α of 29.6g, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester, mp190～192 ℃.MS：348(M
+)。
Embodiment 3
Preparation 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester
At 1 α, add benzene 930ml, ethylene glycol 93ml and tosic acid 0.31g among 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester 29.6g.Reflux water-dividing reacted completely in about 2 hours.Be chilled to room temperature.Add pyridine 15.5ml, tell the benzene layer.Ethylene glycol layer benzene extraction.The combined benzene layer is washed to neutrality, is concentrated into dried.Get 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester is treated oxidation.
Embodiment 4
Prepare 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone
3,3-enedioxy generation-5 α-etioallocholane-1 α adds pyridine 93ml in the 17-isoallopregnane-3 17-acetic ester, be stirred to molten entirely.So temperature is agitation and dropping chromic anhydride-aqueous solution (chromic anhydride 9.3g, water 15.5ml) down.Add the back in 40 ℃ of reactions 5 hours.Reaction is finished, and pours among the water 930ml that contains S-WAT 21.7g, and placement is spent the night.Filter next day, is washed to neutrality, drains, the dry 17 β-acetoxy-3 that gets, 3-enedioxy generation-5 α-etioallocholane-1-ketone 32g.Crude product is through re-crystallizing in ethyl acetate, mp175～178 ℃; MS (m/z) 392 (M
+).
Embodiment 5
Prepare 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone)
In magnesium rod 2.93g, add tetrahydrofuran (THF) 244mL, methyl iodide 28.4g.Stirring at room reaction 1 hour refluxed 15 minutes, was cooled to room temperature.Add 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone (crude product) 32g and benzene 600mL.Temperature rising reflux 30 minutes is cooled to room temperature.Add concentrated hydrochloric acid 85.4mL, water 488mL destroys remaining Grignard reagent, tells the benzene layer then.The water layer benzene extraction.The combined benzene layer is washed to neutrality, is evaporated to dried (oily matter).Add methyl alcohol 390mL, 30% sulfuric acid 30mL.Refluxed 1 hour, and poured in the 1000mL water, separate out crystallization, filter, be washed to neutrality, ethyl alcohol recrystallization is used in dry back, makes 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone) 18g.
Embodiment 6
Prepare 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone 17-acetic ester (Metenolone acetic ester)
17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone 10g is dissolved among the pyridine 20ml, is stirred to whole dissolvings.Add acetic anhydride 8ml in room temperature, stirring at room reaction 4 hours.Pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying gets 17-hydroxyl-1-methyl-5-etioallocholane-1-alkene-3-ketone 17-acetic ester crude product.Get 17 β-acetoxyl group-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone acetic ester) 10g with recrystallizing methanol.Content 99% (HPLC); Mp140～141 ℃; UV
Max(MeOH) 240nm (ε 13300) (mp137 ~ 138.5 ℃; UV: ε
240=13300); [α]
D 25=+56 °; MS:344 (M
+);
1HNMR: δ=0.85 (s, 3H, C
18-CH
3), 1.08 (s, 3H, C
19-CH
3), 2.06 (s, 3H, C
1-CH
3), 4.61 (t, 1H, C
17 α-H, J8Hz), 5.71 (s, 1H, C
2-H).
Embodiment 7
Prepare 17 β-propionyloxy-1-methyl-5 α-androstane-1-alkene-3-ketone (propionic acid Metenolone)
17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone 10g is dissolved among the pyridine 20ml, is stirred to whole dissolvings.Add propionic anhydride 9ml in room temperature, stirring at room reaction 4 hours.Pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying gets 17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 17-propionic ester 12g.Get propionic acid acid Metenolone 10g with re-crystallizing in ethyl acetate.
Embodiment 8
Prepare 17 β-oenanthyl Oxy-1-methyl-5 α-androstane-1-alkene-3-ketone (metenolone enanthate)
Metenolone 10g is dissolved in pyridine 20ml, is lower than under 40 ℃ the condition at the control temperature of charge, add oenanthyl chloro 11g, in 25-30 ℃ of reaction 3 hours, placement was spent the night.Pour next day in the water, placed 2 hours.Elutriation liquid is abandoned it afterwards 4 times with chloroform extraction.Chloroform solution is used hydrochloric acid, water, yellow soda ash and water washing successively, tells chloroform layer, is evaporated to no chloroform, pour methyl alcohol, continue to be concentrated into solvent-free, pour methyl alcohol once more, continue to be concentrated into solvent-free, add methyl alcohol, freeze overnight is separated out crystallization, filter, 50 ℃ of dryings are drained in the small amount of methanol washing.Get metenolone enanthate 11g.
Embodiment 9
Prepare 17 β-undecanoyl Oxy-1-methyl-5 α-androstane-1-alkene-3-ketone (undeeanoic acid Metenolone)
17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 10g is dissolved among the pyridine 20ml, is stirred to whole dissolvings.Add undecanoyl chlorine 12g, 4 hours in room temperature.Pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying gets 17 beta-hydroxies-1-methyl-5 α-etioallocholane-1-alkene-3-ketone 17-undecylate 14g.Get undeeanoic acid Metenolone 12g with recrystallizing methanol.
Embodiment 10
Preparation Metenolone 17-tetrahydropyrans-2-ether (Metenolone tetrahydropyranyl ethers)
Add pyridine 1g and tosic acid 1g in chloroform 10ml, stirring at room 10 minutes adds Metenolone 10g, under agitation adds 2,3-dihydro-4H-pyrans 6g, back flow reaction 3 hours after molten entirely.Reaction is finished, and washing is evaporated to several solvent-freely, pours methyl alcohol, continues to be concentrated into several solvent-free, pours methyl alcohol, continues to be concentrated into several solvent-free, pours methyl alcohol 10ml, and cool overnight is filtered, and the ice methanol wash is drained, and is washing with water to neutrality.The dry Metenolone 17-tetrahydropyrans-2-ether 10g that gets the white crystals shape.
Embodiment 11
Preparation Metenolone alkane carbonic ether
Metenolone 10g is dissolved among the pyridine 20ml, is stirred to whole dissolvings.In 10 ℃ of dropping chloro-formic ester 11～14ml, added in about 15 minutes.Then in stirring at room reaction 4 hours.Pour in the frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying gets Metenolone alkyl carbonate 12～15g.Get elaboration with ethyl alcohol recrystallization.(product comprises methyl carbonic, ethyl carbonate ester, propyl carbonate and benzyl carbonic ether).
Claims (4)
1. one kind prepares the compound Metenolone of following formula and the method for derivative thereof, it is characterized in that with 17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone be raw material, makes through epoxy, hydrogenolysis, ketalization, oxidation and grignard reaction 5 step reaction.
R=-H in the formula,
R wherein
1=-CH
3,-C
2H
5,-C
3H
7,-CH
2C
6H
5
2, according to the method for claim 1, it is characterized in that described 5 steps reaction is,
With 17 beta-acetoxyl group-5 α-androstanes-1-alkene-3-ketone is raw material, and epoxidation reaction in the presence of alkaline hydrogen peroxide makes 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone; With H2/ palladium-lime carbonate or palladium-charcoal, or the active nickel catalytic hydrogenolysis, make 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester; Under the catalysis of tosic 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; Carry out oxidation with chromic acid in pyridine, make 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone makes 17 beta-hydroxies-1-methyl-5 α-androstane-1-alkene-3-ketone (Metenolone) through Ge Shi-dehydration continuous reaction again.
3, according to the method for claim 1, it is characterized in that with the Metenolone being raw material, make the Metenolone acetic ester through acetylize; Make the propionic acid Metenolone through propionylization; Make metenolone enanthate through oenanthylization; Make the undeeanoic acid Metenolone through undecanoylization; With 2,3-dihydro-4H-pyrans is reacted into Metenolone tetrahydropyrans-2-ether; Make the Metenolone methyl carbonic through the methyl-chloroformate acidylate; Make Metenolone ethyl carbonate ester through the Vinyl chloroformate acidylate; Make the Metenolone propyl carbonate through the propyl chloroformate acidylate; Make Metenolone benzyl carbonic ether through the chloroformic acid benzyl ester acidylate.
4,, it is characterized in that being undertaken by following step according to the method for claim 1-3
(1) epoxidation reaction: a.17 beta-acetoxyl group-5 α-androstane-1-alkene-3-ketone is dissolved in the methyl alcohol, stirring is cooled to 5～15 ℃, b. add hydrogen peroxide, stir, c.15～20 ℃ following dropping sodium solution stirs, d. place in the water, filter, washing makes 1 α, 2 alpha-epoxy-17 beta-hydroxy-s-5-etioallocholane-3-ketone;
(2) hydrogenolysis: a. is with 1 α, and 2 alpha-epoxy-17 beta-hydroxy-s-5 α-etioallocholane-3-ketone is dissolved in ethanol, adds palladium-lime carbonate, after the hydrogen ventilation, 25～50 ℃ are stirred logical hydrogen down, and the b. reaction finishes, stop logical hydrogen, reacting liquid filtering, washing with alcohol, c. concentrating under reduced pressure, cooling, filter, make 1 α, 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester;
(3) ketal reaction: α a.1, add benzene in 17 beta-dihydroxyies-5 α-etioallocholane-3-ketone 17-acetic ester, tosic acid and ethylene glycol, reflux water-dividing, b. is cooled to room temperature, adds pyridine, c. be evaporated to dried, make 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester;
(4) oxidizing reaction: a. is with 3,3-enedioxy generation-5 α-etioallocholane-1 α, 17-isoallopregnane-3 17-acetic ester is dissolved in pyridine, b. stirring at room adds chromic acid solution, and c. room temperature reaction, d. pour in the sodium sulfite aqueous solution, placement is spent the night, filter, washing makes 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone;
(5) Ge Shi-dehydration continuous reaction: add tetrahydrofuran (THF) in a. magnesium rod, methyl iodide, stirring at room reaction, reflux, b. is cooled to room temperature, adds 17 β-acetoxy-3,3-enedioxy generation-5 α-etioallocholane-1-ketone and benzene refluxes, and c. is cooled to room temperature, add concentrated hydrochloric acid, the remaining Grignard reagent of water destruct, d. tells the benzene layer, the water layer benzene extraction, combined benzene layer, washing, be evaporated to dried, e. add methyl alcohol, sulfuric acid refluxes, f. pour in the water, separate out crystallization, filter, washing, drying makes Metenolone;
(6) acetylization reaction: a. Metenolone is dissolved in the pyridine, adds aceticanhydride, and placement is spent the night, and b. pours in the water, filter, and washing, drying, ethyl alcohol recrystallization makes the Metenolone acetic ester;
(7) propionyl reaction: a. Metenolone is dissolved in the pyridine, and stirring and dissolving adds propionic anhydride, the stirring at room reaction, and b. pours frozen water, places, and filters, and washing is drained, drying, ethyl alcohol recrystallization makes the propionic acid Metenolone;
(8) oenanthyl reaction: a. Metenolone is dissolved in pyridine, and the control temperature of charge is lower than 30～50 ℃, adds oenanthyl chloro, 25-30 ℃ of reaction, placement is spent the night, and b. pours in the water, place, c. elutriation liquid chloroform extraction, chloroform solution is used hydrochloric acid, water, yellow soda ash and water washing successively, tell chloroform layer, be evaporated to no chloroform, pour methyl alcohol, continue to be concentrated into solvent-free, pour methyl alcohol again, be concentrated into solvent-freely, add methyl alcohol, freeze overnight, separate out crystallization, filter, methanol wash is drained, 40～60 ℃ of dryings make metenolone enanthate;
(9) undecanoyl reaction: a. is dissolved in Metenolone in the pyridine, is stirred to dissolving, adds undecanoyl chlorine, room temperature reaction, and b. pours frozen water, places, and filters, and is washed to non-pyridine, drain, drying, ethyl alcohol recrystallization makes the undeeanoic acid Metenolone;
(10) etherification reaction: a. adds pyridine and tosic acid in chloroform, stirring at room adds Metenolone, and complete molten back adds 2 under stirring, 3-dihydro-4H-pyrans, back flow reaction, the b. reaction is finished, washing, be evaporated to several solvent-freely, pour methyl alcohol, continue to be concentrated into several solvent-free, pour methyl alcohol, continue to be concentrated into several solvent-free, pour methyl alcohol, cool overnight is filtered, the ice methanol wash, drain, be washed to neutrality, the dry Metenolone tetrahydropyranyl ethers that gets;
(11) methyl carbonic acid esterification reaction: a. Metenolone is dissolved in the pyridine, is stirred to dissolving, drips methyl-chloroformate, the stirring at room reaction in 5～15 ℃, b. pour frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, recrystallizing methanol makes the Metenolone methyl carbonic;
(12) ethyl carbonate esterification: a. is dissolved in Metenolone in the pyridine, is stirred to dissolving, drips Vinyl chloroformate, the stirring at room reaction in 5～15 ℃; B. pour frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes Metenolone ethyl carbonate ester;
(13) propyl carbonate reaction: a. Metenolone is dissolved in the pyridine, is stirred to dissolving, drips propyl chloroformate, the stirring at room reaction in 5～15 ℃, b. pour frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes the Metenolone propyl carbonate;
(14) benzyl carbonic acid esterification: a. Metenolone is dissolved in the pyridine, is stirred to dissolving, drips chloroformic acid benzyl ester, the stirring at room reaction in 5～15 ℃, b. pour frozen water, place, filter, be washed to the non-pyridine flavor, drain, drying, ethyl alcohol recrystallization makes Metenolone benzyl carbonic ether.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2004100159495A CN1557828A (en) | 2004-01-19 | 2004-01-19 | Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives |
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| CNA2004100159495A CN1557828A (en) | 2004-01-19 | 2004-01-19 | Process for preparing 17-beta-subsituted-1-methyl-5-alpha-androst-1-en-3-ones and their derivatives |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456888B (en) * | 2008-12-19 | 2011-10-05 | 杭州同化科技有限公司 | Method for preparing methenolone |
| CN102964417A (en) * | 2012-11-30 | 2013-03-13 | 华中药业股份有限公司 | Synthetic method of 17-hydroxy tetrahydropyran ether steroid |
-
2004
- 2004-01-19 CN CNA2004100159495A patent/CN1557828A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101456888B (en) * | 2008-12-19 | 2011-10-05 | 杭州同化科技有限公司 | Method for preparing methenolone |
| CN102964417A (en) * | 2012-11-30 | 2013-03-13 | 华中药业股份有限公司 | Synthetic method of 17-hydroxy tetrahydropyran ether steroid |
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