AU2362895A - SYNTHESIS OF 17B CYANO-3-ETHOXY-17a-HYDROXY-6-METHYLANDROSTA-3,5,9-(11)-TRIEN 9(11)-triene - Google Patents

SYNTHESIS OF 17B CYANO-3-ETHOXY-17a-HYDROXY-6-METHYLANDROSTA-3,5,9-(11)-TRIEN 9(11)-triene

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AU2362895A
AU2362895A AU23628/95A AU2362895A AU2362895A AU 2362895 A AU2362895 A AU 2362895A AU 23628/95 A AU23628/95 A AU 23628/95A AU 2362895 A AU2362895 A AU 2362895A AU 2362895 A AU2362895 A AU 2362895A
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cyano
methylandrosta
ethyl ether
triene
dihydroxy
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AU684946B2 (en
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Therese Debiak-Krook
John Gregory Reid
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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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Toxicology (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

SYNTHESIS OF 17B-CYANO-3-ETHOXY-17α-HYDROXY-6-
METHYLA]SrDROSTA-3.5.9(ll)-TRIENE
BACKGROUND OF THE INVENTION
1. Field of the Invention The present invention is a chemical process for the transformation of a 17- keto steroid to the corresponding 17β-cyano-17α-hydroxy steroid.
2. Description of the Related Art The transformation of 17-keto steroids to the corresponding cyanohydrins (17β-cyano-17α-hydroxy steroids) is known to those skilled in the art. US Patents 4,500,461 and 4,548,748 discloses a process for transforming Δ4-
3,17-diketo steroids to the corresponding 17β-cyano-17α-hydroxy steroid by use of acetone cyanohydrin and potassium cyanide. EXAMPLES 1 and 25 discloses a process for the transformation of a Δ4-3,17-diketo steroid without substitution at C6. EXAMPLE 2 discloses a process for the transformation of a Δ '9(11^-3,17-diketo steroid without substitution at Cg. EXAMPLE 26 discloses a process for the transformation of a Δ1,4-3,17-diketo steroid without substitution at Cg. EXAMPLE 27 discloses a process for the transformation of a 6α-methyl-llβ-hydroxy-Δ4-3,17- diketo steroid. EXAMPLE 28 discloses a process for the transformation of a 6α- methyl-Δ1,4-3,17-diketo steroid. These patents also disclose 17β-cyano-3,17α- dihydroxy-5-ene 3-ethylidine ketal ethers (EXAMPLE 3) and 17β-cyano-3,17α- dihydroxy-3,5-diene 3-methyl ethers (EXAMPLE 24). However, in both cases the 17- keto steroid was first transformed to the corresponding 17-cyanohydrin and then the C3 functionality in the A-ring was transformed into the ether.
US Patent 4,921,638 discloses 17β-cyano-3,17α-dihydroxyandrosta-3,5,9(ll)- triene 3-methyl ether (Preparation 1) and 17β-cyano-6-fluoro-3,17α- dihydroxyandrosta-3,5,9(ll)-triene 3-methyl ether (Preparation 5). In addition, US Patent 4,921,638 (EXAMPLE 89) discloses the production of 17β-cyano-9α,17α- dihydroxyandrost-4-en-3-one from the corresponding 17-keto steroid using potassium cyanide, sulfuric acid, methanol and water. J. Am. Chem. Soc, 75, 650 (1953) discloses the preparation of the 17- cyanohydrin of androst-4-ene-3,17-dione and its conversion to the corresponding 3- enol ethyl ether, the 3-enol benzyl ether and the 3-ethylene glycol ketal.
Helv. Chem. Ada, 33, 1093 (1950) discloses the preparation of 17α-cyano- 3,17β-dihydroxyandrost-5-ene 3-acetyl ester. Helv. Chim. Ada, 29, 1580 (1946) discloses the preparation of a mixture of
17β-cyano-3,17α-dihydroxyandrostane 3-acetyl and 17α-cyano-3,17β- dihydroxyandrostane 3-acetyl esters.
Helv. Chim. Ada, 21, 1317 (1938) discloses 3-acetoxyandrost-5-en-17-one to the 17- spirohydantoin using hydrogen cyanide.
Steroids, 28, 89 (1976) discloses the preparation of the 17-cyanohydrin of androstenedione. The stereochemistry of the cyanohydrin was not determined.
US Patent 3,496,169 discloses the preparation of the α-cyanohydrin from carbonyl compounds using alkylcyanoaluminum compounds.
East German Patent 147,669 discloses the preparation of a 17α-hydroxy-17β- cyano steroids by reaction of a 17-keto-steroid with an alkanone or a cycloalkanone cyanohydrin in the presence of a base. The steroid had a double bond at 4,5-, 5,6- and 5,10- positions. The 3-position was a ketone, acetoxy or dimethoxyketal.
Japanese Patent J5 7,062,296 discloses preparation of 17α- hydroxyprogesterone derivatives from 17β-cyano-17α-hydroxyandrost-4-en-3-one or 17β-cyano-17α-hydroxyandrosta-4,9(ll)-dien-3-one in which the 3-carbonyl and 17α- hydroxy groups are protected.
Japanese Patent J5 7,062,299 discloses the preparation of 17β-cyano-17α- hydroxyandrost-4-ene and 17β-cyano-17α-hydroxyandrosta-4,9(ll)-diene or their 3- acetal derivatives by use of either hydrogen cyanide or an alkali metal salt thereof.
Japanese Patent J5 7,062,300 discloses 17β-cyano-17α-hydroxyandrost-4-en-3- one and 17β-cyano-17α-hydroxyandrosta-4,9(ll)-dien-3-one and the 3-acetals thereof.
Tetrahedron Letters, 22, 2005 (1971) reported the preparation of a cyanohydrin with a steroid A-ring containing a Δ ' -double bond.
US Patent 4,977,255 discloses an important process for the transformation of 17β-cyano-17α-hydroxy steroids into commercially important corticoids or progesterones. The 17β-cyano-17α-hydroxy steroid starting materials were prepared in PREPARATIONS 1 thru 10. Some of the 17-keto steroids used to make the 17β- cyano-17α-hydroxy steroids contained methyl substitution at Cg (PREPARATIONS 3 and 4), methylene substitution at Cg (PREPARATION 8), Δ9(11)-unsaturation in the C-ring (PREPARATIONS 1, 5, 9 and 10) and/or a 3-methoxy-Δ3'5-unsaturated A-ring (PREPARATIONS 1, 2 and 5).
Tetrahedron Letters, 31 3669( 1990) discloses the preparation of 17β-cyano- 3,17α-dihydroxyandrosta-3,5,9(ll)-triene and its conversion to hydrocortisone acetate.
US Patent 5,003,063 discloses the conversion of protected cyanohydrins (II) to the corresponding protected 21-halo steroid (IV) where the protecting groups are at C3. None of the steroids exemplified had a substituent at Cg other than a Δ5^- double bond.
CA: 106:84943 and CA 109:170717 disclose 3-hydroxyandrosta-3,5,9(ll)-trien- 17-one 3-ethyl ether which does not contain the methyl group at Cg which is necessary to produce the 6-methyl intermediate.
None of the above documents disclose 3-ethoxy-6-methylsteroids. SUMMARY OF INVENTION
Disclosed is 3-hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether.
Also disclosed is 17β-cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether.
Further disclosed is a process for the preparation of 17β-cyano-3,17α- dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether, the compound of formula (ID
which comprises:
(1) contacting 3-hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether, the compound of formula (I)
CH,
with hydrogen cyanide (H-C≡N) at a pH of about 7 to about 11 to produce the 17β- cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) and 17α- cyano-3,17β-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether in the presence of a solvent or solvent mixture in which the 17β-cyano isomer selectively crystallizes.
DETAILED DESCRIPTION OF THE INVENTION The process of the present invention is the transformation of 3-hydroxy-6- methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether (I) to 17β-cyano-3,17α-dihydroxy- 6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) by reaction with cyanide in the presence of an acid and a suitable solvent.
The 3-ethyl ether starting material, 3-hydroxy-6-methylandrosta-3,5,9(ll)- trien-17-one 3-ethyl ether (I) is prepared from 6α-methylandrost-4,9(ll)-diene-3,20- dione (US Patent 2,842,573, EXAMPLE 2) by reaction with triethylorthoformate in a suitable solvent such as ethanol in the presence of pyridine hydrochloride under a nitrogen atmosphere. The reaction is heated at about 40° until the reaction is complete as monitored by TLC using a methylene chloride/acetone (97.5/2.5) solvent system (a triethylamine quench is necessary before performing the TLC). The reaction is complete when only a few percent of starting material is left. When the reaction is complete, the reaction mixture is cooled to 20-25° and the desired 3-ethyl ether crystallizes out. If some 3-hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3- ethyl ether (I) is available, it is preferred to seed the cooled reaction mixture. The 3- ethyl ether (I) must be crystallized slowly to assure good filtration. If the 3-ethyl ether (I) comes out of solution too fast, very fine particles are formed resulting in a poor filtration. To avoid this, crystallization prior to water addition is necessary. It is best induced by seeding. When a thick slurry is obtained, the mixture is cooled further on an ice bath. Water is then added and the mixture is stirred until the hydrolysis of the undesired 17-diethyl ketal is complete as measured by TLC. At this point the reaction mixture is quenched with a slight excess of triethylamine over the pyridine hydrochloride. Additional water is added to further precipitate the 3-ethyl ether (I) and the mixture stirred at 5° for one hour. The 3-ethyl ether is obtained by filtration as is known to those skilled in the art, washing with cold methanol. Various compounds in the mother liquor can be reconverted to the Δ -3- keto starting material, if desired, by using hydrochloric acid (1 N). The 3-hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether (I) is contacted with hydrogen cyanide at a pH of about 7 to about 11. It is critical to maintain the pH of the reaction mixture in the operable range of about 7 to about 11, preferably from about 8 to about 10, more preferred is from about 9.0 to about 9.5. The pH is conveniently set in this range by using a slight excess of cyanide salt relative to acid (10-25%). This produces the desired 17β-cyano-3,17α-dihydroxy-6- methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) and the 17α-cyano isomer, 17α- cyano-3,17β-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether. The reaction is performed in the presence of a solvent or solvent mixture in which the 17β-cyano isomer is less soluble than the 17α-cyano isomer so that the desired product precipitates out as the reaction proceeds. The hydrogen cyanide is conveniently prepared in situ by combining a salt of cyanide amount of an acid with a pKa of less than about 7; it is preferred that the pKg be less than 6. It is preferred that the cyanide initially be either sodium or potassium cyanide however since it is preferred to add it as an aqueous solution the particular form of the cyanide is not important as long as it is soluble. The acid is necessary to convert the cyanide (C≡N") to hydrogen cyanide (H-C≡N) which is the active species in the formation of the 17-cyanohydrin. It is preferred that the acid be a carboxylic acid. Suitable acids include inorganic acids such as hydrochloric, hydrobromic, hydriodic, sulfuric, hydrofluoric, perchloric, nitric and phosphoric; carboxylic acids such as acetic acid, formic, propionic, benzoic, chloroacetic, dichloroacetic, trichloroacetic, pivalic, ethylhexanoic and other organic acids such as p-TSA, methanesulfonic and camphorsulfonic or their equivalent. The particular acid is not important as long as it is sufficiently acidic to transform the cyanide (C≡N") to hydrogen cyanide (H-C≡N). Alternatively, the hydrogen cyanide may be contributed by a labile cyanohydrin compound such as acetone cyanohydrin which is commercially available and commonly used for this purpose.
The nature of the solvent or solvent mixture is critical. For the reaction to succeed the 17β-cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) product must precipitate while the 17α-cyano isomer remains in solution. Therefore, the solvent or solvent system must be such that the 17β-cyano-3,17α- dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) is less soluble in the reaction mixture than the 17α-cyano isomer. The 3-hydroxy-6-methylandrosta- 3,5,9(ll)-trien-17-one 3-ethyl ether (I) steroid starting material and cyanide salt must have at least some solubility in the solvent or solvent mixture. To effectuate precipitation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) the solvent can be adjusted during the reaction, if necessary, to cause more product to precipitate. It is preferred that the solvent or solvent mixture contain at least 50% of an alcohol. It is preferred that the alcohol be selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, t-butanol, ethylene glycol and propylene glycol. The preferred alcohol is methanol. Suitable non- alcoholic solvents include water, methylene chloride, toluene, tetrahydrofuran or mixture thereof. The reaction should be performed in a temperature range of from about 0° to about 70° (in a sealed system); preferable from about 10° to about 45°; more preferably from about 20° to about 40°. At elevated temperatures a sealed system is necessary to prevent the hydrogen cyanide from being distilled off. It is preferred to run the reaction for about one hour at about 30-35°, then reduce the temperature to about 20-25°.
When the reaction is complete, it is preferred to add water and stir for a short period such as 30 min. The desired 17β-cyano-3,17α-dihydroxy-6- methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) product slowly crystallizes out. If some product (II) is available, it is preferred to seed the reaction mixture.
Once the reaction is complete as measured by TLC, it is quenched with (acetic) acid to a pH of less than 7. At this point the reaction is warmed to about 50° and THF is added until all the solids dissolve. It is important to note that at this point large amounts of hydrogen cyanide are evolved. When all the solids have dissolved, water is added over a period of about three minutes. If it is added to fast, the crystals will be too small and filtration and washing and drying will be more difficult. The mixture is stirred at 50°, then cooled (to about -10°) stirred more, filtered, washed and dried to give the desired 17β-cyano-3,17α-dihydroxy-6- methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) as a hydrate. If the anhydrous form is desired, the compound should be dried at above 50°.
17β-Cyano-3, 17α-dihydroxy-6-methylandrosta-3,5,9( 1 l)-triene 3-ethyl ether (II) is equivalent to hydrates and solvates thereof.
17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) is useful in the production of 6-methyl steroids such as methylprednisolone, see US Patents 4,500,461, 4,548,748 and 4,977,255.
DEFINITIONS AND CONVENTIONS The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
DEFINITIONS All temperatures are in degrees Centigrade.
TLC refers to thin-layer chromatography. HPLC refers to high pressure liquid chromatography. THF refers to tetrahydrofuran. When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight volume (wt v).
Hydrogen cyanide refers to HCN (H-C≡N).
EXAMPLES Without further elaboration, it is believed that one skilled in the art can, using the preceding description, practice the present invention to its fullest extent. The following detailed examples describe how to prepare the various compounds and/or perform the various processes of the invention and are to be construed as merely illustrative, and not limitations of the preceding disclosure in any way whatsoever. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
PREPARATION 1 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether (I) 6α-Methylandrost-4,9(ll)-diene-3,17-dione (US Patent 2,842,573 - EXAMPLE 2, 50 g), pyridine hydrochloride (0.56 g), absolute ethanol (100 ml) and triethylorthoformate (1.4 eq, 39 ml) are slurried and the vapors are removed under reduced pressure and replaced with nitrogen. The mixture is heated with stirring at 40° until the reaction is complete, as measured by TLC (methylene chloride acetone; 97.5/2.5). The mixture is cooled to 20-25° and the product is obtained by seeding and slow crystallization with the mixture being cooled further with an ice bath. Water (2 eq, 6 ml) is slowly added and the mixture stirred until the reaction is complete as measured by TLC (methylene chloride/acetone; 97.5/2.5). When complete, the reaction is quenched with triethylamine (0.04 eq, 1 ml), water (40 ml) is added and the mixture stirred at 5° for one hour. The mixture is filtered rapidly, the cake is washed with cold (-20°) methanol (2 x 50 ml). The filter cake is dried at 40° under reduced pressure overnight to give the title compound, Rf = 0.67 (methylene chloride/acetone; 97.5/2.5).
The starting material may be recovered by combining the mother liquors and the methanol washes and concentrating to reduce the volume to the point that most of the organic solvents are removed. Methanol (25 ml) is added and the mixture is purged with nitrogen. Hydrochloric acid (12 N, 5 ml) is added and the mixture is stirred. The precipitate is filtered and washed with water and cold methanol. The filter cake is dried in a vacuum oven overnight to give the title compound, HPLC Rt = 4.70 in (acetonitrile/water, 90/10, flow rate 1.5 ml/min, column C18 Nucloesil). PREPARATION 2 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-methyl ether Following the general procedure of PREPARATION 1 and making non-critical variations but starting with methanol and trimethylorthoformate, the title compound is obtained, Rf = 0.71 (methylene chloride/acetone, 97.5/2 5); HPLC R^. = 5.56 min (acetonitrile water, 90/10, flow rate 1.5 ml min, column C18 Nucloesil). PREPARATION 3 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-propyl ether Following the general procedure of PREPARATION 1 and making non-critical variations but starting with propanol and tripropylorthoformate, the title compound is obtained, HPLC Rj. = 8.52 min (acetonitrile/water, 90/10, flow rate 1.5 ml/min, column C18 Nucloesil).
EXAMPLE 1 17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3- ethyl ether (II) 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether (I, PREPARATION 1, 50 g), potassium cyanide (19.95 g) and methanol (120 ml) are combined and purged with a nitrogen/reduced pressure system (3 x) and heated to 35-40° in a sealed system. The vapors are removed under reduced pressure and acetic acid (14 ml) is added via a syringe. The vacuum is slowly release to nitrogen and once ambient pressure is reached the vessel is sealed. The reaction mixture is stirred for one hour at 35° and then at 20-25°. The reduced pressure is again replaced by nitrogen until ambient pressure is reached. Water (9 ml) is added and the mixture stirred for 30 min. If no solids are out of solution, the mixture is seeded. The flask is resealed and stirred at 25° until less than 3% starting material is observed by HPLC (usually overnight). When the reaction is complete, the reaction mixture is vented with nitrogen and quenched with acetic acid (4 ml). The reaction is warmed to about 50° and THF (about 45 - 50 ml) is slowly added until all the solids are dissolved. Care must be exercised as large amounts of hydrogen cyanide are evolved. When all the solids are dissolved water (33 ml) is added over at least three minutes. The mixture is stirred for five min at 50° and then cooled slowly over a period of a couple of hours to - 10°. The mixture is stirred at - 10° for a couple of hours and filtered. The filtered cake is washed with aqueous methanol (50%, 2 x 50 ml) cooled to 10°. The filter cake is dried overnight on the nitrogen press. At this point the product is the hydrate. Drying temperatures of greater than 50° are required to remove the water of hydration and give the title compound, HPLC = 6.70 min (acetonitrile/water, 80/20); yield (chemical) 92.4%; HPLC indicates about 1% starting material remains. Upon recrystaUization the starting material is removed. EXAMPLE 2 17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3- methyl ether 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-methyl ether (PREPARATION 2, 9.3 g), potassium cyanide (4.2 g) and methanol (18 ml) are mixed and heated to 35°. The mixture is purged with nitrogen and subjected to reduce pressure. Acetic acid (3.0 ml) is added using reduced pressure in the flask. The reaction is maintained at 45-48°. After 1 hr 45 min, the mixture is seeded with the desired cyanohydrin obtained from previous experiments.
After a total of four hours, the mixture is cooled. One hr later, the mixture is at 27° and a sample is taken. Analysis discloses about 9% of the starting material remains in the mixture. The supernatant is checked at the same time. Very little of the starting material is seen, indicating that the starting material coprecipitates ' with the product.
The slurry is heated back up to 35° and stirred overnight. No change is noticed after the overnight stirring. The reaction is then quenched with acetic acid (1.5 ml) and the mixture is cooled to 25°. The solids are filtered off and washed with cold methanol. The crystals are analyzed by HPLC and found to contain about 8% starting material. The solids are then recrystallized by dissolving them in toluene/methanol. The methanol is removed by distillation and the resulting crystals are filtered off, Rf = 0.3 (acetone/methylene chloride, 2/98) . The assay on the crystals indicates that about 5-6% of starting material is still present. RecrystaUization does not remove the starting material.
EXAMPLE 3 17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3- propyl ether 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-propyl ether
(PREPARATION 3, 10.0 g), potassium cyanide (4.7 g) and methanol (15 ml) are combined and purged. The mixture is heated to 45°. Acetic acid (3.5 ml) is charged with nitrogen and then subjected to reduced pressure. The reduced pressure is then released to nitrogen and the flask again subjected to reduced pressure. When the mixture is homogeneous, water (4 ml) is added and the mixture is seeded. After 30 min, a slurry is observed. After additional 30 min stirring, the mixture is cooled to 32°. An hour later, water (4 ml) is added. After 45 min additional stirring, the mixture is quenched with acetic acid (1.5 ml). Tetrahydrofuran is added (10 ml) and the mixture is heated to 40°. Water is added to precipitate the product but an oU is observed. Methanol and seed crystals are added foUowing which crystals are obtained. The mixture is stirred slowly overnight, cooled and filtered. After washing (methanol/water) and drying, the title compound is obtained, 6.5 g yields. EXAMPLE 4 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether
(I) 6α-Methylandrost-4,9(ll)-diene-3,20-dione (US Patent 2,842,573, Example 2, 50 g) is mixed with ethanol (130 ml) and purged with nitrogen. Pyridine hydrochloride (0.56 g) is dissolved in ethanol (20 ml) and added to the steroid/ethanol mixture. The reaction mixture is kept at 35-40° and stirred until the reaction is complete (as monitored by TLC). When the reaction is complete, the mixture is cooled to 0-5°. Water (6 ml) is added and the mixture stirred at 0-5° until the back hydrolysis is complete (as measured by TLC). When the back hydrolysis is complete, triethylamine (1.2 ml) is added.
The mixture is refluxed at 55 to 60° under nitrogen with stirring. When the steroid is in solution, the water bath is removed and the reaction mixture is aUowed to cool to 20-25°. Water (60 ml) is added over 30 minutes. When complete the mixture is cooled to 0 to 5° and stirred for 60 minutes. The mixture is filtered, washed with triethylamine (2% in cold (-5 to -10°) methanol, 60 ml) and dried to give the title compound.
EXAMPLE 5 17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3- ethyl ether (II) 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether (I,
EXAMPLE 4, 40 g), potassium cyanide (17.6 g) and methanol (96 ml) are mixed under nitrogen and stirred at 20-25°. Acetic acid (12.35 ml) is added and the mixture warmed to 35° with stirring. The reaction mixture is stirred at 35-40° for 45 minutes then cooled to 20-25°. Water (10.8 ml) is added and the mixture stirred untU the reaction is complete (as measured by HPLC). When the reaction is complete, the mixture is quenched with acetic acid (3.85 ml). When the reaction temperature is 20-25°, THF (20 ml) followed by water (20 ml) water is added and the mixture stirred for 5 min at 20-25° then cooled to -10° for 1-2 hr. The mixture is then filtered, washed with aqueous methanol (50%, 2 x 40 ml) at 10° and dried to give the title compound which because it is a temperature sensitive hydrate, is stored at < 0°. CHART A
10 CH,
15 I I I i

Claims (11)

1. 3-Hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether.
2. 17β-Cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether.
3. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether, the compound of formula (II)
CH, which comprises:
(1) contacting 3-hydroxy-6-methylandrosta-3,5,9(ll)-trien-17-one 3-ethyl ether, the compound of formula (I)
CHa
with hydrogen cyanide (H-C≡N) at a pH of about 7 to about 11 to produce the 17β- cyano-3,17α-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether (II) and 17α- cyano-3,17β-dihydroxy-6-methylandrosta-3,5,9(ll)-triene 3-ethyl ether in the presence of a solvent or solvent mixture in which the 17β-cyano isomer selectively crystallizes.
4. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 3 where the hydrogen cyanide is formed in situ by contacting a cyanide salt (C≡N") and an acid with a pKa of less than 7.
5. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(1 l)-triene 3-ethyl ether according to claim 4 where the cyanide salt is either sodium or potassium and the acid is selected from the group consisting of inorganic and organic acids.
6. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 3 where the hydrogen cyanide is contributed by a labUe cyanohydrin compound.
7. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 3 where the solvent contains at least 50% of an alcohol.
8. A process for the preparation of 17β-<_yano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 7 where the alcohol is selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, t-butanol, ethylene glycol and propylene glycol.
9. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(1 l)-triene 3-ethyl ether according to claim 8 where the alcohol is methanol.
10. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 3 where the solvent contains some water.
11. A process for the preparation of 17β-cyano-3,17α-dihydroxy-6-methylandrosta- 3,5,9(ll)-triene 3-ethyl ether according to claim 3 where the pH is maintained in the range of about 7 to about 11 with an acid which has a pKa less than 7.
AU23628/95A 1994-05-09 1995-05-02 SYNTHESIS OF 17B CYANO-3-ETHOXY-17a-HYDROXY-6-METHYLANDROSTA-3,5,9-(11)-TRIEN 9(11)-triene Expired - Fee Related AU684946B2 (en)

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