DE1195308B - Process for the preparation of 6, 17alpha-dimethyl-4, 6-pregnadiene-3, 20-dione - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C07c

German KL: 12 ο - 25/05

Number: 1195 308

File number: A 43798IV b / 12 ο

Filing date: August 9, 1963

Opening day: June 24, 1965

The present invention relates to a process for the preparation of 6,17a-dimethyl-4,6-pregnadiene-3,20-dione (VI), which is an orally active gestagenic agent and is described by R. Deghenghi and R. G a u d r y in J. Am. Chem. Soc, Vol. 83, P. 4668 (1961).

The particular advantage of the method according to the invention is the avoidance of the first Step in the synthesis of 6,17a-dimethyl-4,6-pregnadiene-3,20-dione (VI) as described in the publication cited above, namely the separation of 3 /? - Hydroxy-17a-methyl-5a, 6o-epoxyätiansäuremethylester of the corresponding 5β, 6β-Ερ-oxide.

The inventive method is characterized in that one is known per se Methods a 3 /? - hydroxy-17a-methylsteroid of the general formula

HO

s-CH ₃

(D

Process for the preparation of 6.17 dimethyl-4,6-pregnadiene-3,20-dione

Applicant:

Ayerst, McKenna & Harrison, Limited,

Saint Laurent, Quebec (Canada)

Representative:

Dr.-Ing. F. Wuesthoff, Dipl.-Ing. G. Pulse and
Dipl.-Chem. Dr. rer. mat. E. Frhr. v. Pechmann ·,
Patent Attorneys, Munich 9, S'chweigerstr. 2

Named as inventor:

Peter Frank Morand, Montreal, Quebec;

Romano Deghenghi, Westmount, Quebec

(Canada)

Claimed priority:

Canada August 11, 1962 (855 720, 855721)

has given meaning and R 1 is hydrogen atom or a lower acyl group is obtained.

wherein A is a COCH3 or COOCHs group, with hydrogen peroxide in formic acid and then with methanolic KOH, the obtained 5a, 6 /? - dihydroxy derivative of the general formula II, in which A has the meaning given above Has.

HO

S-CH ₈

s- CH ₃

(III)

(Π)

HO

OH

with an N-haloimide a dibasic low aliphatic acid, in particular N-bromosuccinimide, oxidized and optionally on it acylated, the corresponding 5a-hydroxy-6-keto derivative of the formula III, in which A is the above an-through Treatment of this compound with a methyl magnesium halide in an inert solvent depending on the conditions used, 3 / 3,5a, 6 / J-trihydroxy-6o-methyl derivatives are obtained of the formula IV, in which A has the meanings given above.

Thus, if one starts from a compound of the formula III in which A is COOCH3, and the Grignard reaction at a temperature below 35 ° C, preferably at room temperature, carries out the compound of Formula IV wherein A is COOCH3. In this case it joins education the compound of the general formula IV, wherein A

509 597/429

COCH3 is another reaction with a methyl magnesium halide under more severe conditions. If the same reaction is carried out at the boiling point of the reaction mixture, the compound of formula IV is obtained, in which A is COCH3; and if the compound of the formula III in which A is COCH3 is treated with a Grignard reagent at a temperature below 35 ° C., preferably at room temperature, the compound of formula IV in which A is COCH ₃ is obtained.

c-CH ₃

15th

(IV)

CH ₃

The Grignard reactions taking place on the compounds of the formula III are surprising and unexpected to look at. Although it is well known that a carbomethoxy or a keto group with Excess methyl magnesium halide gives the corresponding carbinol in very high yield. The fact that in the present case not a substantial amount of normal carbinol is produced, but rather that, depending on the conditions, compounds with carbomethoxy or keto group (A) from the reaction mixture obtained in very good yields is undoubtedly a new and unexpected one Observation.

The oxidation of the compound of formula IV, in which A is COCH3, with a suitable reagent, which oxidizes the 30-hydroxy group to the 3-keto group yields the 5a, 6 ^ -dihydroxy-6a, 17a-dimethylpregnan-3,20-dione of the formula V, which by known methods to the desired end product 6,17a-dimethyl-4,6-pregnadiene-3,20-dione of formula VI can be dehydrated.

CH ₃

CH ₃

The method according to the invention is explained in more detail using the following examples.

Example!

hydroxy-na-rne
methoxyandrostane

60

5 g of 17a - methyl -17/3 - carbomethoxyandrost - 5 - en-3 /? - ol (I, A = COOCH ₃ ) were dissolved in 50 ml of formic acid and heated on the steam bath for 10 minutes. The solution was cooled to room temperature, whereby a crystalline precipitate formed

65 fell. The mixture was stirred, 5 ml of 30% strength hydrogen peroxide were added and the mixture was left to stand at room temperature for 2 hours. The clear solution was poured into 300 ml of water and the deposited solid was filtered off. This was dissolved in warm methanol and heated on the steam bath for 10 minutes with 15.8 ml of 10% strength methanolic potassium hydroxide solution. Then additional 2 ml of potassium hydroxide solution were added, the solution was cooled and diluted with water to give ₍₃ II, A = COOCH), mp 245-255 ⁰ C, gave a solid. A second crystallization was obtained from the mother liquors. Repeated recrystallization from acetone gave an analytical sample, mp 262 to 265 ° C .; [a] 2 -2.1 °.

Analysis for C22H.36O5:
Calculated ... C 69.44, H9.54 ^_0/0;
found ... C 69.28. H 9.2.6%.

5.2 g S

methoxyandrostane (II, A = COOCH ₃ ) were dissolved in 105 ml of methanol, and 105 ml of ether and 84 ml of water were added. Then 5.2 g of N-bromosuccinimide were added with stirring, and the clear solution was left to stand in the refrigerator for 3 hours. The ether was evaporated off under reduced pressure at room temperature, a crystalline solid (III, A = COOCH ₃ , R = H), melting point 268 to 272 ° C., separating out.

This substance was dissolved in 15 ml of pyridine and 7.5 ml of acetic anhydride and heated on the steam bath for half an hour. The reaction product (III, A = COOCH3, R = COCH ₃ ) crystallized from aqueous ethanol in flakes, mp 237-239 ° C. An analysis sample melted at 241 to 243 ⁰ C.

Analysis for
Calculated
found

y-l 7a-methyl-l7 /? - carbomethoxyandrostan-6-one

C 68.59, H 8.62%;
C 69.05, H 8.72%.

c) 3 / ?, 5a, 6j9-trihydroxy-6a, 17a-dimethyl-17 _j-8 carbomethoxyandrostan

1.004 g of 3/3 - acetoxy - 5a - hydroxy - 17a - methyl-17 /? - carbomethoxyandrostan-6-one (III, A = COOCH ₃ , R = COCH3) were dissolved in 25 ml of dry benzene and 10 ml (3 mol) of a methylmagnesium bromide solution in ether added. The mixture was diluted with 25 ml of dry tetrahydrofuran and allowed to stand at room temperature for 20 hours, excess Grignard reagent was decomposed by adding a saturated solution of ammonium chloride, the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined extracts were washed with ammonium chloride solution and water and worked up in the usual manner to give a white solid (IV, A = _COOCH3) was obtained, which melted after a single recrystallization from aqueous methanol at 242-243 ⁰ C. The infrared spectrum of this compound indicated the presence of a carbomethoxy group (1730 cm " ¹ ), the disappearance of the 6-keto group and the presence of an ester group (1727 cm" ¹ ). The substance was used for the next step without further purification.

d) 3 | tf, 5a, 6/3-trihydroxy-6a, 17a-dimethylpregnan-20-one

737 mg of crude 3 / i, 5a, 6 / S-trihydroxy-6a, 17a-dimethyl-17 /? - carbomethoxyandrostane (IV, A = COOCHa) were dissolved in 25 ml of dry benzene and 25 ml of tetrahydrofuran (freshly distilled over lithium aluminum hydride) . The solution was stirred under dry N2 and 10 ml (3 mol) of a methyl magnesium bromide solution was added over 10 minutes. The ether and tetrahydrofuran were then almost completely distilled off, and the resulting solution was refluxed for 3 hours (a solid separated out during the reaction). The reaction mixture was cooled and worked up as in the previous example to give a white solid (IV, A = COCHs). Its infrared spectrum indicated the presence of a 20-keto group (1690 cm- ^x ). After recrystallization, the compound melted at 238 to 240 ^° C.

Analysis for C ₂₃ H ₃₈ O ₄ · H ₂ O:

Calculated ... C 69.60, H 10.17%;

found ... C69.09, H 10.15%.

The same compound could also be obtained by adding 25.0 g of 3 / S, 5a-dihydroxy-17a-methyl - Π β - carbomethoxyandrostan - 6 - one (III, A = COOCH ₃ , R = H) or 25.0 g Dissolved its 3jS acetate (III, A = COOCH3, R = COCH ₃ ) in 1250 ml of dry tetrahydrofuran (freshly distilled over lithium aluminum hydride) and added 2000 ml of dry benzene, stirred the solution and added 750 ml (3 mol) of a methylmagnesium bromide solution in ether . The mixture was stirred at room temperature for 16 hours; a further 375 ml (3 mol) of a methylmagnesium bromide solution in ether were then added and 1250 ml of the solvent mixture were distilled off. The remaining mixture was refluxed for 5 hours and worked up as above, the compound IV (A = COCH ₃ ) being obtained in the form of a colorless oil.

e) 5a, 6 / i-dihydroxy-6a, 17 <z-dimethylpregnane-3,20-dione

45

650 mg raw S ^^
Pregnan-20-one (IV, A = COCH ₃ ) was dissolved in 150 ml of acetone freshly distilled over potassium permanganate and the solution was cooled in an ice-water bath while stirring. Then 8N chromic acid solution was added in excess and stirring was continued at room temperature for 4 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with dilute sodium bicarbonate solution and with water and dried over magnesium sulfate. After removal of the solvent a white solid remained (V). This crude product was used for the next stage. Its infrared spectrum showed a strong band at 1705 cm ^x . A sample was heated to a mp of 243 to 245 ° C (decomposition); [a] i ⁴ -16.9 ° (c = 0.83%, ethanol-pyridine), recrystallized.

65 Analysis for C23H36O4:

Calculated ... C 73.36, H 9.64%;
found ... C 73.23, H 9.65%.

f) 6,17a-dimethyl-4,6-pregnadiene-3,20-dione
553 mg of 5a, 6jS-dihydroxy-6a, 17a-dimethylpregnan-3,20-dione (V) were dissolved in 60 ml of absolute ethanol and two drops of concentrated hydrochloric acid were added. This solution was heated on a steam bath for 45 minutes, cooled, diluted with water and extracted with ether. The combined extracts were washed with dilute sodium bicarbonate solution and with water and then dried over magnesium sulfate. After removal of the solvent, a syrup remained, the ultraviolet spectrum of which indicated ^{the presence of a zl 4} ' ^{6 ketone.} Eluting this material over 25 g of aluminum oxide (W ο e 1 m, No. 3) with hexane-benzene (1: 1) yielded a crystalline substance, mp 138-141 ° C., which, after recrystallizing once from ether, yielded an infrared spectrum which was identical to that of an authentic sample of 6,17a-dimethyl-4,6-pregnadiene-3,20-dione (VI).

Example 2

a) 3 ^, 5a, 6 | S-Trihydroxy-17 <z-methylpregnan-20-one 8.7 g of 17a-methylpregnenolone (I, A = COCH ₃ ), which according to Plattner et al., HeIv. Chim. Acta, Vol. 32, p. 270 (1949), were heated in 52 ml of formic acid on the steam bath for 15 minutes. The solution was cooled and 8.7 ml of 30% hydrogen peroxide were added. The mixture was left to stand at room temperature for 4 hours. Water was then added, the precipitated solid was dissolved in 60 ml of warm methanol and the solution was neutralized with 10% strength methanolic potassium hydroxide solution. At dilution with water a crystalline solid precipitated out which after one recrystallization from aqueous methanol, melted at 278 to 280 ⁰ C (II, A = COCH3).

b) S / S-acetoxy-Sa-hydroxy-na-methylpregnan-6,20-dione

The above 3β, 5a, 6β - trihydroxy -17a - methylpregnan-20-one (II, A = COCH3) was dissolved in 360 ml of methanol, and 360 ml of ether and 220 ml of water were added to the solution. The solution was stirred and 10 g of N-bromosuccinimide were added. After the latter was dissolved, the mixture was left to stand in the refrigerator for 2 hours. A small amount of saturated sodium bicarbonate solution was then added to remove the orange color of the solution. The ether was removed from the solution under reduced pressure at room temperature. It was then diluted with water, a crystalline solid (III, A = COCH ₃ , R = H) being obtained.

This solid was dissolved in 20 ml of pyridine and 10 ml of acetic anhydride and heated on the steam bath for 30 minutes. The solution was cooled and diluted with water, a solid separating out which, on crystallization from warm aqueous ethanol, gave the monoacetate (III, A = COCH ₃ , R = COCH 3). An analysis sample showed a temperature of 230 to 232 ° C; [a] f -63 ° (ethanol); _7mas in cm- ¹ : 3440, 3380, 1737, 1705.

Analysis for Calculated Found C 71.43, H 8.74%;
C 71.29, H 8.77%.

c) 3i?, 5a, 6 ^ -Trihydroxy-6a, 17a-dimethylpregnan-20-one

3.7 g of 3β, 5α-dihydroxy-17α-methylpregnan-6,20-dione (III, A = COCH ₃ , R = H) were dissolved in 90 ml of dry benzene and 90 ml of dry tetrahydrofuran. This solution was stirred in an ice-water bath and cooled while 27 ml (3 moles) of an ether solution of methyl magnesium bromide was added. After half an hour, a further 40 ml of tetrahydrofuran were added and the solution was stirred at room temperature for 18 hours.

The reaction mixture was poured into 150 ml of saturated ammonium chloride solution with stirring, and the organic layer was separated. The aqueous solution was extracted with ethyl acetate and the combined extracts washed with ammonium chloride solution and with water. After drying the organic solution over magnesium sulfate, the solvent was removed and the residue recrystallized from aqueous acetone, said substance IV (A = COCH3), mp was 238-240 ⁰ C is obtained.

d) 6,17a-dimethyl-4,6-pregnadiene-3.20-dione

513 mg of 3β.5a, 6β- trihydroxy-6α, 17α-dimethylpregnan-20-one (IV, A = COCH ₃ ) were dissolved in 250 ml of purified acetone and cooled in an ice-water bath. The solution was stirred vigorously, an excess of 8N chromic acid solution was added and, when the addition was complete, the mixture was stirred for a further 4 minutes. Then the reaction mixture was poured into 400 ml of water and extracted with ether. The combined extracts were washed with sodium bicarbonate solution and water and dried over magnesium sulfate. The solvent was removed under reduced pressure, leaving a yellowish semi-solid mass (V).

A portion of this residue (444 mg) was dissolved in 20 ml of absolute ethanol and a few drops of concentrated hydrochloric acid were added. The solution was heated on a steam bath for ½ hours, cooled, diluted with water and worked up in the usual way by ether extraction. , / Ϊ-unsaturated ketone indicated ketone ⁶ (εζ9ΐ = 19400), and from about 7% α a - a yellowish rubber, the ultraviolet spectrum, the presence of about 92% of a J ⁴ was obtained. Chromatography of this material on alumina gave a substance whose infrared spectrum was identical to that of 6J7a-dimethyl-4,6-pregnadiene-3,20-dione (VI).

55

Claims (2)

Patent claims: 1. Process for the preparation of 6,17a-dimethyl-4,6-pregnadiene-3,20-dione, characterized in that one after per se known methods a compound of the general formula I HO GH ₃ (D wherein A is a COCH ₃ or COOCHa group. reacted with hydrogen peroxide in formic acid and then with methanolic KOH, the resulting compound of general formula II HO --CH ₃ (Π) HO OH wherein A has the meaning given above, with an N-haloimide a divalent one lower aliphatic acid, the resulting compound of general formula III RO CH ₃ (III) HO where A has the meaning given above and R = H, optionally acylated to the 3 / i-acyloxy compound and a compound of the general formula III, where A = COCH ₃ or COOCH ₃ and R = H or an acyl radical, with a methyl magnesium halide in an inert solvent, optionally in two stages, the 3ß, 5a, 6ß-TnhydTOxy-6a, \ 7a-di methyIpregnan-20-one obtained with a suitable reagent which oxidizes the 3 /? -hydroxy group to the 3-keto group, converts and the obtained 5a, 6 ^ -dihydroxy-oa, 17a-dimethylpregnan-3 ^ 0-dione in 4 (5) - and 6 (7) position dehydrated. 2. The method according to claim 1, characterized in that a compound of the general formula III, wherein A = COOCH ₃ and R = H or an acyl radical, with a methyl magnesium halide in an inert solvent at a temperature below 35 ⁰ C and then, with the addition of further methyl magnesium halide, reacts at the boiling point of the mixture.