CN1147816A - Synthesis of 17'beta'-cyano-3-ethoxy-17'alpha-hydroxy-6-methylandrosta-3,5,9(11)-triene - Google Patents

Synthesis of 17'beta'-cyano-3-ethoxy-17'alpha-hydroxy-6-methylandrosta-3,5,9(11)-triene Download PDF

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CN1147816A
CN1147816A CN95192975A CN95192975A CN1147816A CN 1147816 A CN1147816 A CN 1147816A CN 95192975 A CN95192975 A CN 95192975A CN 95192975 A CN95192975 A CN 95192975A CN 1147816 A CN1147816 A CN 1147816A
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alpha
beta
cyanos
methyl
triolefin
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J·G·雷德
T·德彼克-克洛克
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0094—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 containing nitrile radicals, including thiocyanide radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0003—Androstane derivatives
    • C07J1/0011—Androstane derivatives substituted in position 17 by a keto group

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Abstract

17 beta -Cyano-3,17 alpha -dihydroxy-6-methylandrosta-3,5,9(11)-triene 3-ethyl ether (II) is prepared by reacting 3-hydroxy-6-methylandrosta-3,5,9(11)-trien-17-one 3- ethyl ether (I) with hydrogen cyanide at a pH of about 7 to about 11. The product is a useful intermediate in the production of pharmacologically active steroids including methylprednisolone.

Description

17 beta-cyanos-3-oxyethyl group-17 Alpha-hydroxies-6-methyl androstane-3,5,9 (11)-triolefins synthetic
Background of invention
1. invention field
The present invention relates to a kind of chemical process that the 17-ketosteroid is converted into corresponding 17 beta-cyanos-17 Alpha-hydroxy steroide.
2. description of Related Art
The 17-ketosteroid is converted into corresponding cyanalcohol (17 beta-cyanos-17 Alpha-hydroxy steroide) and is known by those of ordinary skill in the art.
United States Patent (USP) 4,500,461 and 4,548,748 disclose a kind of by using acetone cyanohydrin and potassium cyanide with Δ 4-3,17-diketone steroid is converted into the method for corresponding 17 beta-cyanos-17 Alpha-hydroxy steroide.Embodiment 1 and 25 discloses a kind of C of being used for 6The last Δ that does not have replacement 4-3, the method for the conversion of 17-diketone steroid.Embodiment 2 discloses a kind of C of being used for 6The last Δ that does not have replacement 4,9 (11)-3, the method for the conversion of 17-diketone steroid.Embodiment 26 discloses a kind of C of being used for 6The last Δ that does not have replacement 1,4-3, the method for the conversion of 17-diketone steroid.Embodiment 27 discloses a kind of 6 Alpha-Methyls-11 beta-hydroxies-Δ that is used for 4-3, the method for the conversion of 17-diketone steroid.Embodiment 28 discloses a kind of 6 Alpha-Methyls-Δ that is used for 1,4-3, the method for the conversion of 17-diketone steroid.These patents also disclose 17 beta-cyanos-3,17 alpha-dihydroxy-s-5-alkene 3-ethylidine ketal ether (embodiment 3) and 17 beta-cyanos-3,17 alpha-dihydroxy--3,5-diene 3-methyl ether (embodiment 24).Yet in both of these case, 17-ketone steroid at first is converted into corresponding 17-cyanalcohol, then the C on the A ring 3The functional group changes into ether.
United States Patent (USP) 4,921,638 disclose 17 beta-cyanos-3,17 alpha-dihydroxy-androstane-3,5,9 (11)-triolefin 3-methyl ethers (preparation 1) and 17 beta-cyanos-6-fluoro-3,17 alpha-dihydroxy-androstanes-3,5,9 (11)-triolefin 3-methyl ethers (preparation 5).In addition, United States Patent (USP) 4,921,638 (embodiment 89) disclose use potassium cyanide, sulfuric acid, first alcohol and water and have prepared 17 beta-cyanos-9 α by corresponding 17-ketone steroid, 17 alpha-dihydroxy-androstane-4-alkene-3-ketone.
J.Am.Chem.Soc., 75,650 (1953) disclose androstane-4-alkene-3, the preparation of the 17-cyanalcohol of 17-diketone with and to corresponding 3-enol ethyl ether, the conversion of 3-enol benzylic ether and 3-ethylene ketal.
Helv.Chem.Acta, 33,1093 (1950) disclose the preparation of 17 alpha-cyanos-3,17 beta-dihydroxyl androstane-5-alkene 3-ethanoyl ester.
Helv.Chem.Acta, 29,1580 (1946) disclose the preparation of the mixture of 17 beta-cyanos-3,17 alpha-dihydroxy-etioallocholane 3-ethanoyl ester and 17 alpha-cyanos-3,17 beta-dihydroxyl etioallocholane 3-ethanoyl ester.
Helv.Chem.Acta, 21,1317 (1938) disclose the use prussic acid is converted into 17-spiral shell glycolylurea with 3-acetoxyl group androstane-5-alkene-7-ketone.
Streroids, 28,89 (1976) disclose the preparation of the 17-cyanalcohol of rotex.The stereochemistry of this cyanalcohol is still uncertain.
United States Patent (USP) 3,496,169 disclose use alkyl cyano group aluminum compound prepares α-cyanalcohol from carbonyl compound.
Deutsches Wirtschafts Patent 147,669 discloses by 17-ketone steroid and alkane ketone or naphthenone cyanalcohol prepared in reaction 17 Alpha-hydroxies-17 beta-cyano steroide in the presence of alkali.This steroide is 4,5-, and 5,6-and 5 has two keys on the 10-position.The 3-position is a ketone, acetoxyl group or dimethoxy ketal.
Japanese Patent J57; 062; 296 disclose by 17 beta-cyanos-17 Alpha-hydroxy androstane-4-alkene-3-ketone or wherein 3-carbonyl and protected 17 beta-cyanos-17 of 17 Alpha-hydroxies Alpha-hydroxy androstane-4,9 (11)-diene-3-ketone prepare 17 Alpha-hydroxy Progesterone derivatives.
Japanese Patent J57,062,299 discloses by using prussic acid or its an alkali metal salt to prepare 17 beta-cyanos-17 Alpha-hydroxy androstane-4-alkene and 17 beta-cyanos-17 Alpha-hydroxy androstane-4,9 (11)-diene or its 3-acetal derivant.
Japanese Patent J57,062,300 discloses 17 beta-cyanos-17 Alpha-hydroxy androstane-4-alkene-3-ketone and 17 beta-cyanos-17 Alpha-hydroxy androstane-4,9 (11)-diene-3-ketone and 3-acetal thereof.
Tetrahedron Letters, 22,2005 (1971) have reported to have and have contained Δ 5 (10)The preparation of the cyanalcohol of the steroide A ring of-two keys.
United States Patent (USP) 4,977,255 disclose a kind of important method that is used for 17 beta-cyanos-17 Alpha-hydroxy steroide is converted into commercially important corticoid or Progesterone.17 beta-cyanos-17 Alpha-hydroxy steroide raw material prepares in preparation 1-10.Some 17-ketone steroid that is used for preparing 17 beta-cyanos-17 Alpha-hydroxy steroide contains C 6On methyl substituents (preparation 3 and 4), C 6On methylene radical substituting group (preparation 8), the Δ in the C-ring 9 (11)Unsaturated (preparation 1,5,9 and 10) and/or 3-methoxyl group-Δ 3,5-unsaturated A-ring (preparation 1,2 and 5).
Tetrahedron Letters, 313669 (1990) disclose 17 beta-cyanos-3,17 Alpha-hydroxy androstane-3,5, the preparation of 9 (11)-triolefins with and to the conversion of hydrocortisone acetic ester.
United States Patent (USP) 5,003,063 cyanalcohol (II) that discloses protection is converted into the 21-halo steroide (IV) of corresponding protection, and wherein blocking group is at C 3On.The steroide none that exemplifies be not Δ 5 (6)The C of-two keys 6On have substituting group.
CA:106:84943 and CA109:170717 disclose 3-hydroxy-androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether, and it is at C 6On do not contain and concerning producing 6-methyl intermediate, be necessary methyl.
There is not one piece to disclose 3-oxyethyl group-6-methyl steroid in the above-mentioned file.
Summary of the invention
3-hydroxyl-6-methyl androstane-3,5 is disclosed, 9 (11)-triolefins-17-ketone 3-ethyl ether.
17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 is also disclosed, 9 (11)-triolefin 3-ethyl ethers.
Formula (II) compound 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 is disclosed in addition, the preparation method of 9 (11)-triolefin 3-ethyl ethers:
Figure A9519297500071
(II)
This method comprises:
(1) under the pH of about 7-about 11, makes formula (I) compound 3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether in the presence of solvent or the solvent mixture (I) contact with prussic acid (H-C ≡ N), prepare 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II) and 17 alpha-cyanos-3,17 beta-dihydroxyies-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers, wherein 17 beta-cyano isomer selective crystallizations.
Detailed description of the present invention
The inventive method is with 3-hydroxyl-6-methyl androstane-3 by reacting in the presence of acid and suitable solvent with prussiate, 5,9 (11)-triolefins-17-ketone 3-ethyl ether (I) is converted into 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II).
3-ethyl ether raw material 3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I) is by 6 Alpha-Methyl androstanes-4,9 (11)-diene-3,20 diketone (United States Patent (USP) 2,842,573, embodiment 2) by with triethyl orthoformate under nitrogen atmosphere, in the presence of pyridine hydrochloride in appropriate solvent such as ethanol the reaction and prepare.In about 40 ℃ of these reactions of heating, up to record by the TLC that uses methylene dichloride/acetone (97.5/2.5) solvent system (carrying out must ending with triethylamine before this TLC) react completely till.This reacts completely when only being left the raw material of percentum.When reacting completely, reaction mixture is cooled to 20-25 ℃, the 3-ethyl ether of expectation crystallizes out.If some 3-hydroxyl-6-methyl androstanes-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I) is existing, then preferably adds to make kind of a crystalline substance in the refrigerative reaction mixture.3-ethyl ether (I) slowly crystallization to guarantee good filtration.If this 3-ethyl ether (I) goes out to come too fast from solution, then form very thin particle, cause filtering bad.For avoiding this point, crystallization is necessary before adding water.Preferably induce by seeding.When obtaining the thickness slurry, mixture further cools off on ice bath.Add water then and stir the mixture that to record hydrolysis to undesirable 17-diethyl ketal by TLC complete.Use the triethylamine stopped reaction mixture that is in excess in pyridine hydrochloride slightly this moment.Add extra water with this 3-ethyl ether (I) of further precipitation, mixture stirred 1 hour in 5 ℃.Obtain this 3-ethyl ether by the known filtration of those of skill in the art of present technique field, wash with cold methanol.If need, can each compound in the mother liquor be converted into Δ 4-3-ketone raw material again by using hydrochloric acid (1N).
With 3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I) contacts with prussic acid under about 7 to about 11 PH.But key is the pH with reaction mixture maintains about 7 to about 11 operating restraint, and preferred about 8 to about 10, more preferably from about 9.0 to about 9.5.By using the cyanide salt (10-25%) excessive slightly easily pH to be set in this scope with respect to acid.This has just produced 17 beta-cyanos-3, the 17 alpha-dihydroxy-s-6-methyl androstane-3,5 of expectation, 9 (11)-triolefin 3-ethyl ethers (H) and 17 alpha-cyano isomer, 17 alpha-cyanos-3,17 beta-dihydroxyies-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers.This is reflected at solvent or solvent mixture and exists down and carry out, and wherein 17 beta-cyano isomer are insoluble than 17 alpha-cyano isomer, thereby the product of expecting carries out with reaction and is precipitated out.
Prussic acid is by mixing a kind of cyanide salt and a certain amount of pK aBe lower than approximately 7, preferably be lower than 6 acid and preparation on the spot easily.Preferred prussiate is sodium cyanide or potassium cyanide, but because preferably it is added with the aqueous solution, so the specific form of this prussiate is unimportant, as long as it is solvable.This acid is for prussiate (C ≡ N -) to be transformed into prussic acid (H-C ≡ N) be essential, prussic acid is active specy in the formation of 17-cyanalcohol.Should acid be carboxylic acid preferably.Suitable acid comprises the mineral acid example hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, sulfuric acid, hydrofluoric acid, perchloric acid, nitric acid and phosphoric acid; Carboxylic acid such as acetate, formic acid, propionic acid, phenylformic acid, Mono Chloro Acetic Acid, dichloro acetic acid, trichoroacetic acid(TCA), PIVALIC ACID CRUDE (25), thylhexoic acid and other organic acids such as p-TSA, methylsulfonic acid and camphorsulfonic acid or its equivalent.Specifically be which kind of acid is unimportant, as long as it is enough acidity with prussiate (C ≡ N -) be converted into prussic acid (H-C ≡ N).In addition, prussic acid can be by unsettled cyanohydrin compound such as market on sale and acetone cyanohydrin that be usually used in this purpose obtain.
The character of solvent or solvent mixture is very crucial.For successfully carrying out this reaction, product 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II) must precipitations, and 17 alpha-cyano isomer are retained in the solution.Therefore, solvent or solvent system must make product 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5, and 9 (11)-triolefin 3-ethyl ethers (II) are insoluble than 17 alpha-cyano isomer in reaction mixture.3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I) steroide raw material and cyanide salt must have some solvability at least in solvent or solvent mixture.In order to realize 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5, the precipitation of 9 (11)-triolefins-3-ethyl ether (II) if need, can be regulated solvent so that more voluminous thing precipitation in reaction process.Preferred solvent or solvent mixture contain at least 50% alcohol.Preferred this alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, ethylene glycol and propylene glycol.Preferred alcohol is methyl alcohol.Suitable Non-alchoholic solvents comprises water, methylene dichloride, toluene, tetrahydrofuran (THF) or its mixture.
This reaction should be carried out to about 70 ℃ temperature (in closed system) at about 0 ℃; Preferred about 10 ℃ to about 45 ℃; More preferably from about 20 ℃ to about 40 ℃.At high temperature closed system is necessary to preventing that prussic acid from steaming.Preferably under about 30-35 ℃, reacted about 1 hour, be cooled to about 20-25 ℃ then.
When reacting completely, preferably add entry and stir the short period of time as 30 minutes.17 beta-cyanos-3, the 17 alpha-dihydroxy-s-6-methyl androstane-3,5 of expectation, 9 (11)-triolefin 3-ethyl ether (II) products slowly crystallize out.If some product (II) is existing, then preferably make the crystallization of reaction mixture seed.
React completely in case record, end to be lower than 7 to pH with acetate by TLC.This moment, reaction mixture was warmed to about 50 ℃ and add THF and dissolve until all solids.Be important to note that and emit a large amount of prussic acid this moment.After all solids dissolving, in about 3 minutes, add entry.If adding is too fast, crystal is with too little and filtration, and washing and drying are more difficult.Stir this mixture down at 50 ℃, cooling then (to-10 ℃ approximately), restir filters, and washing is also dry, with 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 that hydrate obtains expecting, 9 (11)-triolefin 3-ethyl ethers (II).If wish to obtain anhydrous form, should be at dry this compound more than 50 ℃.
17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II) are equal to its hydrate and solvate.
17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II) are useful in the production of 6-methyl steroid such as methyl prednisolone, referring to United States Patent (USP) 4,500,461,4,548,748 and 4,977,255.
Definition and custom
The used term of whole file that following definition and explanation are used for comprising specification sheets and claims.
Definition
All temperature are degree centigrade.
TLC refers to tlc.
HPLC refers to high pressure lipuid chromatography (HPLC).
THF refers to tetrahydrofuran (THF).
When use solvent to the time, solvent for use is than being volume/volume (v/v).
When the solubleness of using solid in solvent, the ratio of solid and solvent is weight/volume (wt/v).
Prussic acid refers to HCN (H-C ≡ N).
Embodiment
Need not further instruction, can believe that the one skilled in the art can use above stated specification the most fully to implement the present invention.How following detailed embodiment explanation prepares all cpds and/or carries out the whole bag of tricks of the present invention, and should think it only is illustrative, and never limits aforementioned open.The one skilled in the art will recognize the suitable variation that reactant and reaction conditions and technology are done rapidly.Preparation 13-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I)
With 6 Alpha-Methyl androstane-4,9 (11)-diene-3,7-diketone (United States Patent (USP) 2,842,573-embodiment 2,50g), pyridine hydrochloride (0.56g), (decompression removes devaporation and uses nitrogen replacement for 1.4 equivalents, 39ml) slurryization for dehydrated alcohol (100ml) and triethyl orthoformate.At 40 times stirring heating mixtures up to by TLC (methylene dichloride/acetone; 97.5/2.5) record and react completely.Mixture is cooled to 20-25 ℃, by adding kind of crystalline substance and using the slow crystallization of the further refrigerative mixture of water-bath to obtain product.Slowly add entry (2 equivalents, 6ml) and stir the mixture up to by TLC (methylene dichloride/acetone; 97.5/2.5) record and react completely.When reacting completely, (0.04 equivalent, 1ml) stopped reaction add entry (40ml), and stir the mixture 1 hour at 5 ℃ with triethylamine.Rapid filtering mixt is with cold (20 ℃) methyl alcohol (2 * 50ml) washing leaching cakes.One night of 40 drying under reduced pressure filter cakes, obtain title compound, R f=0.67 (methylene dichloride/acetone; 97.5/2.5).
Can be removed and reclaim raw material by merging mother liquor and methanol wash liquid and concentrating volume is reduced to most organic solvents.Add methyl alcohol (25ml) and use the nitrogen purge mixture.Add hydrochloric acid (12N, 5ml) and stir the mixture.Filtering-depositing and water and cold methanol washing.At one night of dry cake in vacuum drying oven, obtain title compound, HPLC R t=4.70 minutes (acetonitrile/water, 90/10, flow velocity 1.5ml/min, C18 Nucloesil post).Preparation 23-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone
The 3-methyl ether
By preparation 1 usual procedure and do nonessential change, but from methyl alcohol and trimethyl orthoformate, obtain title compound, R f=0.71 (methylene dichloride/acetone, 97.5/2.5); HPLCRt=5.56 minute (acetonitrile/water, 90/10, flow velocity 1.5ml/min, C18 Nucloesil post).Preparation 33-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-
Ketone 3-propyl ether
By preparation 1 usual procedure and do nonessential change, but from propyl alcohol and tripropyl orthoformate, obtain title compound, HPLCR t=8.52 minutes (acetonitrile/water, 90/10, flow velocity 1.5ml/min, C18 Nucloesil post).Embodiment 117 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II)
With 3-hydroxyl-6-methyl androstane-3,5, (50g), potassium cyanide (19.95g) and methyl alcohol (120ml) merge and clean with nitrogen/depressurized system (3x) 9 (11)-triolefins-17-ketone 3-ethyl ether, are heated to 35-40 ℃ in closed system for I, preparation 1.Decompression is removed steam and is added acetate (14ml) through syringe.Nitrogen slowly is released in the vacuum, in case reach environmental stress with regard to closed container.In 35 ℃ of stirred reaction mixtures 1 hour, again in 20-25 ℃ of stirring.Reduce pressure up to reaching environmental stress with nitrogen replacement once more.Add water (9ml) and stirred the mixture 30 minutes.If no solid comes out, then make this mixture seed crystallization from solution.Seal flask once more and be lower than for 3% (a common night) up to observe raw material by HPLC 25 ℃ of stirrings.When reacting completely, end to the reaction mixture ventilation and with acetate (4ml) with nitrogen.Warm reaction mixture also slowly adds THF (about 45-50ml) to about 50 ℃ and dissolves up to all solids.Necessary careful operation is because emit a large amount of prussic acid.After all solids dissolving, at least 3 minutes, add entry (33ml).Stirred the mixture 5 minutes in 50 ℃, in 3 two hours, slowly cool to-10 ℃ then.Stirred the mixture 3 two hours and filtered in-10 ℃.With aqueous methanol (50%, 2 * 50ml) washing leaching cake that is cooled to 10.One night of dry cake under nitrogen pressure.This moment, product was a hydrate.Require drying temperature greater than 50 ℃ to remove water of hydration and to obtain title compound, HPLC=6.70 minute (acetonitrile/water, 80/20); Productive rate (chemistry) 92.4%; HPLC shows about 1% raw material of residue.Raw material is removed during crystallization.Embodiment 217 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-methyl ethers
Mix 3-hydroxyl-6-methyl androstane-3,5, (preparation 2,9.3g), potassium cyanide (4.2g) and methyl alcohol (18ml) also are heated to 35 ℃ to 9 (11)-triolefins-17-ketone 3-methyl ether.With nitrogen purge mixture and decompression.In flask, use decompression to add acetate (3.0ml).Reaction mixture maintains 45-48 ℃.After 1 hour 45 minutes, make the crystallization of mixture seed with the cyanalcohol that derives from the expectation of testing previously.
Altogether after 4 hours, cooling mixture.After 1 hour, mixture is 27 ℃ and takes out sample.Analysis is presented in the mixture surplus 9% the raw material of having an appointment.Detect supernatant liquid simultaneously.Seldom see raw material, this shows raw material and product coprecipitation.
Go up slurry heating to 35 ℃ and stir a night.Do not see variation after stirring a night.Use acetate (1.5ml) stopped reaction then, mixture is cooled to 25 ℃.The filtering solid also washs with cold methanol.Use the HPLC analyzing crystal, find to contain 8% raw material of having an appointment.By being dissolved in, solid makes its recrystallize in the toluene and methanol then.Distillation for removing methanol also leaches gained crystal, R f=0.3 (acetone/methylene dichloride, 2/98).Crystal is analyzed the raw material that still there is about 5-6% in demonstration.Recrystallize can not be removed raw material.Embodiment 317 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-propyl ethers
Merge 3-hydroxyl-6-methyl androstane-3,5, (preparation 3,10.0g), potassium cyanide (4.7g) and methyl alcohol (15ml) also clean 9 (11)-triolefins-17-ketone 3-propyl ether.Heated mixt to 45.Add acetate (3.5ml) with nitrogen, then decompression.Discharge decompression with nitrogen then, and make the flask decompression once more.After mixture is even, adds water (4ml) and make the crystallization of mixture seed.After 30 minutes, observe slurry.Behind the restir 30 minutes, cooling mixture to 32.After 1 hour, add water (4ml).Behind the restir 45 minutes, end mixture with acetate (1.5ml).Add tetrahydrofuran (THF) (10ml) and heated mixt to 40 ℃.Add water and make the product precipitation, but observe oily matter.Add methyl alcohol and seed crystal, obtain crystal then.Slowly stir the mixture a night, cooling is also filtered.After washing (methanol) and the drying, obtain title compound, output 6.5g.Embodiment 43-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether (I)
With 6 Alpha-Methyl androstane-4,9 (11)-diene-3, (United States Patent (USP) 2,842,573, embodiment 2,50g) mix with ethanol (130ml) and use nitrogen purge for the 20-diketone.Be dissolved in pyridine hydrochloride (0.56g) in the ethanol (20ml) and be added in steroide/alcohol mixture.Reaction mixture is remained on 35-40 ℃ also to be stirred up to react completely (by the TLC monitoring).When reacting completely, cooling mixture is to 0-5 ℃.Add water (6ml) and under 0-5 ℃, stir the mixture and separate fully (by the TLC monitoring) up to turning one's coat.Separate when turning one's coat when complete, add triethylamine (1.2ml).
Under nitrogen in 55-60 ℃ of stirring and refluxing mixture.When steroide is solution, removes water-bath and make reaction mixture be cooled to 20-25 ℃.In 30 minutes, add entry (60ml).Cooling mixture is to 0-5 ℃ when finishing, and stirs 60 minutes.Filtering mixt, (2%, in cold (5 to-10 ℃) methyl alcohol, 60ml) washing and dry obtains title compound with triethylamine.Embodiment 517 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II)
Under nitrogen, mix 3-hydroxyl-6-methyl androstane-3,5, and 9 (11)-triolefins-17-ketone 3-ethyl ether (I, embodiment 4, and 40g), potassium cyanide (17.6g) and methyl alcohol (96ml) also stir under 20-25 ℃.Add acetate (12.35ml) and under agitation warm mixture to 35 ℃.In 35-40 ℃ of stirred reaction mixture 45 minutes, be cooled to 20-25 then.Add water (10.8ml) and stir the mixture to react completely (measuring) by HPLC.When reacting completely, end mixture with acetate (3.85ml).When temperature of reaction is 20-25 ℃, add THF (20ml), add water (20ml) then, stirred the mixture 5 minutes at 20-25, be cooled to-10 ℃ then and stirred 1-2 hour.Filtering mixt then, (50%, 2 * 40ml) washing, drying obtains title compound, because of it is temperature sensitive property hydrate, so＜0 ℃ of storage with 10 ℃ aqueous methanol.
Table A
Figure A9519297500141

Claims (11)

1.3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether.
2.17 beta-cyano-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers.
3. a preparation formula (II) compound 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5, the method for 9 (11)-triolefin 3-ethyl ethers
Figure A9519297500021
(II) this method comprises:
(1) under the pH of about 7-about 11, makes formula (I) compound 3-hydroxyl-6-methyl androstane-3,5,9 (11)-triolefins-17-ketone 3-ethyl ether in the presence of solvent or the solvent mixture
Figure A9519297500022
(I) contact with prussic acid (H-C ≡ N), prepare 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers (II) and 17 alpha-cyanos-3,17 beta-dihydroxyies-6-methyl androstane-3,5,9 (11)-triolefin 3-ethyl ethers, wherein 17 beta-cyano isomer selective crystallizations.
4. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 3, the method for 9 (11)-triolefin 3-ethyl ethers, wherein prussic acid is by making cyanide salt (C ≡ N -) contact less than 7 acid and form on the spot with pKa.
5. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 4, the method for 9 (11)-triolefin 3-ethyl ethers, cyanide salt or be sodium or be potassium wherein, and acid is selected from mineral acid and organic acid.
6. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 3, the method for 9 (11)-triolefin 3-ethyl ethers, wherein prussic acid is provided by unsettled cyanohydrin compound.
7. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 3, the method for 9 (11)-triolefin 3-ethyl ethers, wherein solvent contains at least 50% alcohol.
8. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 7, the method for 9 (11)-triolefin 3-ethyl ethers, wherein alcohol is selected from methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, the trimethyl carbinol, ethylene glycol and propylene glycol.
9. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to Claim 8, the method for 9 (11)-triolefin 3-ethyl ethers, wherein alcohol is methyl alcohol.
10. preparation 17 beta-cyanos-3,17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 3, the method for 9 (11)-triolefin 3-ethyl ethers, wherein solvent contains some water.
11. preparation 17 beta-cyanos-3, the 17 alpha-dihydroxy-s-6-methyl androstane-3,5 according to claim 3, the method for 9 (11)-triolefin 3-ethyl ethers, wherein pH is lower than 7 acid with pKa and maintains about 7 to about 11 scope.
CN95192975A 1994-05-09 1995-05-02 Synthesis of 17'beta'-cyano-3-ethoxy-17'alpha-hydroxy-6-methylandrosta-3,5,9(11)-triene Pending CN1147816A (en)

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CN112898365A (en) * 2021-03-08 2021-06-04 营口德瑞化工有限公司 Synthesis method of 17 beta-cyano-17 alpha-hydroxyandrost-4-en-3-one

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FR2468617A1 (en) * 1979-10-26 1981-05-08 Roussel Uclaf NOVEL CHLORINATED ACETYLENIC DERIVATIVES OF ANDROST-4-ENE, THEIR PREPARATION PROCESS, AND THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
EP0153001B1 (en) * 1984-02-03 1992-03-11 The Upjohn Company Steroids having an enamide or enimide group and their preparation
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CN112898365A (en) * 2021-03-08 2021-06-04 营口德瑞化工有限公司 Synthesis method of 17 beta-cyano-17 alpha-hydroxyandrost-4-en-3-one
CN112898365B (en) * 2021-03-08 2023-02-28 营口德瑞化工有限公司 Synthesis method of 17 beta-cyano-17 alpha-hydroxyandrost-4-en-3-one

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