HU224687B1 - 16-alpha-methyl-steroides - Google Patents

Abstract

The present invention relates to novel compounds of formula (III). In the formula, the ring A contains a keto group at the 3-position, R is -CH2OR, where R 'represents an ester group, R- and R2 together form an epoxide group. According to the invention, a compound of formula (II) wherein R, R 1 and R 2 are as defined above, is treated with a methylating agent (16) (17) to hydrolyze the resulting intermediate. EN 224 687 Β1 Scope of description 6 pages (including 2 sheets)

Description

The present invention relates to novel 16α-methyl steroids.

The compounds of the invention are represented by formula (III) wherein A and B represent a group of formula (b)

R is -CH 2 -OR 'where R' is an ester-type hydroxyl protecting group and R ₁ and R ₂ together are a β-epoxy group.

The ester-type hydroxyl protecting group mentioned as R 'may be any group known to those skilled in the art, such as a C 1 -C 8 acyl group such as formyl, acetyl, propionyl, butyryl, valeryl or benzoyl.

Compounds of formula (III) are prepared by treating a compound of formula (II), wherein A, B, R, R 1, R ₂ and R ₃ are as defined above, with a methylating agent in the presence of a copper-containing catalyst. hydrolyzing the methylated enolate intermediate.

The methylating agent used is a methylated copper derivative such as CH ₃ Cu, (CH ₃ ) ₂ CuMg, (CH ₃ ) ₂ CuLi, or more preferably methyl magnesium chloride, bromide or iodide in the presence of a copper-containing catalyst. The catalyst may be a salt such as copper (II) acetate, propionate or chloride, copper (II) chloride, bromide, iodide or cyanide, or a complex such as copper acetyl acetate, copper (I), ) -dimethylsulfide bromide or copper (I) -tri (n-butyl) phosphine chloride or any similar type of complex known in the art. Copper (II) acetate and propionate are particularly preferred.

The process is carried out in a solvent, preferably an ether such as tetrahydrofuran, dioxane, tert-butyl methyl ether or dimethoxyethane. Tetrahydrofuran is particularly preferred.

The reaction is carried out at a temperature between 0 and -30 ° C, preferably at -20 ° C.

The hydrolysis of the methylated intermediate is preferably carried out by pouring the reaction mixture into an aqueous solution of mono-alkaline phosphate such as sodium or potassium phosphate, or into a slightly acidic buffer such as phosphate buffer, such as acetic acid, propionic acid or butyric acid.

The compounds are valuable industrial intermediates for the preparation of other steroids (see HU 213 683).

Compounds of formula II are known, for example, from 2 345 711, 2 883 400, 1 963 496, 2 966 504,

975 197, 3 029 233, 3 210 341, 3 377 343,

839,369, 3,976,638, 4,031,080, 4,277,409,

U.S. Patent No. 929,395; German Patent No. 2,207,420; Dutch Patent No. 69,02,507; and Belgian Patent Nos. 539,498, 540,478, 711,016, or the starting materials disclosed in these patents. it can be easily produced by professionals.

The invention is illustrated by the following non-limiting example.

Example 1

Step A: $ 9β, 1β-Epoxy-16α-methyl-20-hydroxy-21-acetyloxy-pregna-1,4,17 (20) -trien-3-one

0.1 g of copper (II) acetate monohydrate, 3.83 g of 9β, 11βepoxy-21-acetyloxy-pregna-1,4,16 (17) -triene-3,20-dione and 50 ml of tetrahydrofuran. After stirring at 15 ° C for 15 minutes under an inert gas, the solution is cooled to -20 ° C and 3.75 ml of a 3 mol / L solution of methyl magnesium bromide in ethyl ether are added slowly. The mixture was stirred at -20 ° C for 1 hour. 40 ml of a 13.6% aqueous solution of monopotassium phosphate were cooled to about 0 ° C and the above solution was added with stirring for about 5 minutes. The title compound was obtained.

IR (CHCl ₃₎ (in an inert atmosphere)

3588 + associated 3430 cm ^-1 (F): OH; 1738 cm ^-1 (shoulder), 1718 cm ^-1 (max):> = 0; 1663 cm ^-1 > = 0.1625 cm ^-1 C = C, 1607 cm ^-1 conjugated: Δ _{1-4 at} 3. Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 400 MHz, ppm):

5.17 and 5.20 (s) E + Z isomers: OH; 1.01 (d) and 1.08 (d): CH ₃ -CH; 1.08 (s) and 1.10 (s): 18-Me; 1.45:

19 Me; 2.11 (s) - 2.12 (s): OAc; 3.15 and 3.19: H _n ;

4.49 (d) and 4.67 (d) C-CH ₂ O; 6.16: H ₄ ; 6.20 (dd):

H ₂ ; 6.61 (d), 6.63 (d): Η ₃ .

Analysis of metals:

Mg: 0.1-0.2% of the theoretical stoichiometric amount required for enolate formation.

Alkali metals: 1-2% of the theoretical stoichiometric amount required for enolate formation.

Step B: Preparation of 9β, 11β-Epoxy-16α-methyl-17α-hydroxy-21-acetyloxy-pregna-1,4-diene-3,20-dione (Reference Example)

The temperature of the enol solution obtained in step A) is allowed to rise with stirring and then 4 ml of dimethyl sulfide are added at + 15 ° C in the presence of air. While stirring, air was bubbled through while allowing the temperature to warm and the dimethylsulfide added was condensed. After 3 hours, an additional 2 mL of dimethyl sulfide was added and the bubbling of air continued for 2 hours. The mixture is extracted with ethyl acetate, the organic phase is washed with water, dried and the solvent is distilled off. The residue was chromatographed on silica gel, eluting with a 7: 3 mixture of methylene chloride and diethyl ether. 3.124 g of the expected product are obtained in crystalline form.

IR _(CHCl3);

Absorption: 3616 cm ^-1 (OH), 1747-1728 cm ^-1 (C = O), 1663-1624-1607 cm ^-1 (Δ1.4 at 3). Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm):

0.88: 16-CH ₃ ; 0.93: H in 18-CH ₃ ; 1.44: H a

19-CH ₃ ; 2.16: CH ₃ in OAc; 2.94: H a

17 in OH; 3.21 11-H; 4.69 to 5.04: 21 H _2; 6.14:

4-H; 6.20: 2-H; 6.26: 1-H.

Example 2 (reference)

Preparation of 9β, 11β-χροχί-16α-methyl-17α-hydroxy-pregna-1,4-diene-3,20-dione

The procedure of Example 1 was followed, starting from 0.02 g of copper (II) acetate monohydrate and

HU 224 687 Β1

0.649 g of 9β, 11β-epoxy-21-acetyloxy-pregna-1,4,16 (17) triene-3,20-dione in 10 ml of tetrahydrofuran and then 0.8 ml of methyl magnesium bromide (3 mol / l) were added. 1 L of ether), 8 mL of 13.6% monopotassium phosphate solution and 1.5 mL of dimethyl sulfide were used. Air was bubbled and stirred for a total of 16 hours. After extraction with ethyl acetate, the crude product is chromatographed on silica gel, eluting with 75:25 methylene chloride: ether, to give 0.326 g of the desired crystalline product. IR _(CHCl3);

Absorption: 3610 cm ^-1 (OH), 1706-1688 cm ^-1 (C = O), 1663-1625-1607 cm ^-1 (Δ1.4 at 3). Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm):

0.88: 16-CH ₃ ; 1.01 (s): 18-CH ₃ ; 1.44 (s): 19-CH ₃ ;

2.24 (s): -CO-CH ₃ ; 3.05 (s) -OH; 3.21 (s): H _n ;

6.15: H ₄ ; 6.18 (dd): H ₂ ; 6.6 (d): H ·,.

Example 3 (reference)

16alfa-Methyl-17.alpha.-hydroxy-21-acetyloxy-1,4,9 (11) -triene-3,20-dione

In the same manner as in Example 1, starting from 0.02 g of copper (II) acetate monohydrate, 0.733 g of 21-acetyloxy-pregna-1,4,9 (11), 16 (17) -tetraene- 3.20 dione in 10 ml of tetrahydrofuran was added followed by 0.77 ml of methyl magnesium bromide (3 M in ether), 7 ml of 13.6% monopotassium phosphate solution and 2.25 ml of dimethylsulfide. Air bubbling and stirring were continued for 18 hours, followed by extraction with ethyl acetate. The product was purified by chromatography on silica gel (eluent: methylene chloride / ether = 7: 3). 0.16 g of the desired crystalline product is obtained.

IR _(CHCl3);

Absorption: 3610 cm ^-1 (OH), 1747-1728 cm ^-1 (C = O), 1663-1623-1606 cm ^-1 (Δ1.4 at 3). Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm):

0.75: 13-CH ₃ ; 0.94: 16-CH ₃ ; 1.40: 10-CH ₃ ; 2.17:

CH _{3 in} OAC; 4.82 and 4.99: 2H at 21;

5.54: H at position 11; 6.05: H at 4; 6.28:

H at position 2; 7.19; H in 1 position.

Example 4 (reference)

9alpha-Fluoro-11beta-hydroxy-16alpha-methyl17alpha-hydroxy-21-acetyloxy-pregna-1,4-diene-3,20-dione

In the same manner as in Example 1, the starting material was 0.02 g of copper (II) acetate monohydrate and 0.805 g of 9alpha-fluoro-11beta-hydroxy-21-acetyloxypropegna-1,4,16 (17) triene. 3,20-Dione was added in 10 ml of tetrahydrofuran followed by 1.5 ml of methyl magnesium bromide (3 M in ether), 8 ml of 13.6% monopotassium phosphate solution and 1.6 ml of dimethylsulfide. . Air bubbling and stirring were continued for a total of 17 hours, followed by extraction with ethyl acetate. The product was purified by chromatography on silica gel (eluent: methylene chloride: ethyl acetate = 7: 3). 0.276 g of the desired crystalline product are obtained. IR _(CHCl3);

Absorption: 3450-3360 cm ^-1 (OH), 1740 cm ^-1 (C = O / acetate), 1720 cm ^-1 (unconjugated C = O)

1660 cm ^-1 (conjugated C = O).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm):

0.93 (d): 16-CH ₃ ; 1.07: 13-CH ₃ ; 1.57: 10-CH ₃ ;

2.17: _CH3 in OAC; 3.39: 17 alpha-OH and 11 beta-OH; 4.38: 11alpha-H; 4.92: 2H at 21; 6.11: H at 4; 6.33: H at 2; 7.25: H in 1-position.

Example 5 (reference)

9-alpha-Fluoro-11beta, 21-diacetyloxy-16-alpha-methyl-17-alpha-hydroxy-pregna-1,4-diene-3,20-dione The procedure described in Example 1 was followed by starting with 0.02 g of copper (II). acetate monohydrate and 0.889 9 alpha-fluoro-11 beta, 21-diacetyloxy-pregna-1,4,16 (17) -triene-3,20-dione in 10 ml of tetrahydrofuran followed by 0.78 ml of methyl magnesium bromide (3 M in ether), 8 mL of 13.6% monopotassium phosphate solution and 1.6 mL of dimethyl sulfide were used. Air bubbling and stirring were continued for 18 hours, followed by extraction with ethyl acetate. The product was purified by chromatography on silica gel (eluent: methylene chloride: ethyl ether = 75:25) to give 0.634 g of the desired crystalline product.

IR _(CHCl3);

Absorption: 3615 cm ^-1 (OH), 1746 cm ^-1 (-OAC),

1730 cm ^-1 (unconjugated C = O), 1668-1631 and

1610 cm ^-1 ; (Δ1,4 at 3).

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , 300 MHz, ppm):

0.93 (d): _CH3 in position 16 and 0.93 (s): _CH3 13helyzetben; 1.58: _CH3 in position 10; 2.13 to 2.15: _CH3 in Ac; 2.74: 17alpha-OH; 4.71-4.99: 2H. At position 21; 5.42: H in Halfa position; 6.11: H at 4; 6.33: H at 2; 6.82: H in 1-position.

Example 6 (reference)

9beta, 11beta-Epoxy-16alpha-methyl-17alpha-hydroxy21-acetyloxy-pregna-1,4-diene-3,20-dione

In the same manner as in Example 1, 0.766 g of 9,11-epoxy derivative and 0.02 g of copper (II) acetate monohydrate in 10 ml of tetrahydrofuran were used, followed by 0.8 ml of methyl magnesium bromide (3 mol / l). 1 mL of ether) and 8 mL of phosphate buffer solution (1 mol of phosphoric acid to 1.2 mol of sodium carbonate) was used.

After stirring for 5 minutes in an inert gas atmosphere at 0 ° C, the temperature was allowed to rise to + 18 ° C, bubbling and stirring was continued for 30 minutes, and tetrahydrothiophene (1.2 ml) was added. Air was bubbled through the reaction mixture for an additional 4 hours, then additional tetrahydrothiophene (0.4 mL) was added and stirring and bubbling continued. Finally, it is extracted with ethyl acetate, the organic phase is washed with water, dried and the solvent is distilled off. The crude product was purified by chromatography on silica gel (eluent: methylene chloride: ether = 7: 3). 0.6075 g of the desired product is obtained, which is identical to the product of Example 1.

Claims (1)

A compound of formula (III) wherein A and B represent a group of formula (b) R is -CH ₂ -OR ', wherein R' is an ester-type hydroxyl protecting group and R ₁ and R ₂ together are a β-epoxy group.