HU220081B - Pregna-1,4-diene-3,20-dione derivatives and their manufacturing - Google Patents

Abstract

The present invention relates to novel 9,11,16,16,17-dihydroxy or -16,17- [isopropylidene-bis (oxy)] pregna-1,4-diene-3,20-dione derivatives. Refers to 9-halo-11-formyloxy-pregna-1,4-diene-3,20-dione-21-OR derivatives wherein R is hydrogen, acyl, alkoxycarbonyl, alkenyl of up to 8 carbon atoms; oxycarbonyl, aralkoxycarbonyl, alkylsulfonyl or arylsulfonyl. ŕ

Description

The present invention relates to novel pregna-1,4-diene-3,20-dione intermediates.

The use of the new intermediates in the preparation of pregna-1,4-diene-3,20-dione derivatives of the general formula (F) is described in our patent application HU-212 197. In the formula (F), R is hydrogen, acyl, alkoxycarbonyl, alkenyloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl or arylsulfonyl having up to 8 carbon atoms and A is isopropylidene or butylidene.

Pregna-1,4-diene-3,20-dione derivatives are described in DE-A-2 360 444 and the preparation of such compounds is described in DE-3 143 757. In the processes described in these documents, the first step is to ketalize.

In our experiments, it has been found that these compounds can be prepared by other than known methods via more stable intermediates. The present invention relates to these novel intermediates.

The present invention thus relates to novel compounds of formula III wherein:

R is hydrogen, acyl, alkoxycarbonyl, alkenyloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl or arylsulfonyl, containing up to 8 carbon atoms,

THE; and A ₂ is hydrogen, or A 1 and A ₂ together form a group> C (CH ₃ ) ₂ .

The present invention also relates to a process for the preparation of compounds of formula III.

The process comprises treating a compound of formula II wherein R is as defined above with a chlorinating or brominating agent and a formyloxylating agent in an acidic medium to give a compound of formula III wherein R is as defined above, and Fish means chlorine or bromine, and A; and A ₂ is hydrogen, the compound of formula (III) thus obtained is optionally treated with acetone in the presence of a strong acid to give a compound of formula (III), wherein R and Hal are as defined above, and A ₁ and A ₂ CH ₃ ) ₂ forms a group.

When R is acyl, it is preferably formyl, acetyl, propionyl, butyryl, pivaloyl or succinyl.

When R is an alkoxycarbonyl, alkenyloxycarbonyl or aralkoxycarbonyl group, it is preferably benzyloxycarbonyl, allyloxycarbonyl, tert-butyloxycarbonyl, ethoxycarbonyl-. or methoxycarbonyl.

When R is an alkylsulfonyl group, it is preferably a methylsulfonyl group.

When R is an arylsulfonyl group, it is preferably a phenylsulfonyl group.

The process of the present invention preferably uses a compound of formula II wherein R is a C 1 -C 8 acyl group, more preferably an acetyl group.

In the process of the present invention, the chlorinating or brominating agent is an N-chloro or N-bromoamide, in particular N-chloro or N-bromoacetamide, succinimide or flalimide, or Ν, Ν-dichloro or N, N-dibromo. dimethylhydantoin is used. Particular preference is given to tert-butyl hypochlorite or hypobromite. The formyloxylating agent is preferably dimethylformamide or formic acid.

As described above, the reaction is carried out in an acidic medium. Thus, when dimethylformamide is used, the reaction is more preferably carried out in the presence of a strong acid such as perchloric acid or fluoroboric acid. When formic acid is used, it is used either alone or in a buffered medium in the presence of sodium or potassium formate and, if necessary, an acid such as hydrochloric acid is added.

The starting compounds of formula (II) used in the process of the invention are described, for example, in U.S. Patent No. 2,998,433 or U.S. Patent 3,047,468, or may be prepared from intermediates described in these patents by methods known to those skilled in the art.

The following examples illustrate the invention without limiting it.

Example 1 (9α, 11β, 16α) -21- (Acetyloxy) -16,17-dihydroxy-9-bromo-11-formyloxy-pregna-1,4-diene-3,20-dione g. 16a) -21- (Acetyloxy) -16,17-dihydroxypregna-1,4,9 (11) -triene-3,20-dione and 480 cm ^{3 of} dimethylformamide are stirred at room temperature in the dark. 42.64 g of N-bromosuccinimide are then added with stirring at + 5 / + 10 ° C. While stirring for a further 30 minutes while the temperature was raised to + 20 / + 22 ° C, a solution of 42.6 cm ^{3 of} 55 ° C perchloric acid in 107 cm ^{3 of} water was added. The reaction mixture was stirred at room temperature for 3 hours 30 minutes and then poured into ice-water. The precipitated crystals are filtered off, washed with water and dried.

102.3 g of the expected product are obtained, which can be recrystallized from dimethylformamide by addition of water, separation of the crystals and trituration with methanol.

Mp 260 ° C (dec.).

[.alpha.] D @ 20 = +11.5 DEG ± 3 DEG (c = 1%, DMF).

Example 2 (9α, 11β, 16α) -21 - (Acetyloxy) -9-bromo-11 - (formyloxy) -16,17 - [(1-methylethylidene) bis (oxy)] - pregnane, 4-diene-3,20-dione

200 g of the product obtained in Example 1, 75 cm ^{3 of} isopropenyl acetate and 1 liter of acetone are stirred at 20 ° C in the presence of an inert gas and 1 cm ^{3 of} 55 ° C perchloric acid is added. The reaction mixture was refluxed for 3 hours, then cooled to 20 ° C and 80 cm ^{3 of} tertiaryamine was added. The reaction mixture was concentrated in vacuo at 30 ° C and then acetone was distilled off by adding 600 cm ^{3 of} methanol at constant volume. Then, at 30 ° C was slowly added 200 cm ³ of water are added and cooled to 0 / + 5 ° C, and the precipitated crystals were filtered. The crystals were washed with methanol-water and dried.

211.4 g of the expected product are obtained.

Melting point: 207.5 ° C.

1 H NMR (CDCl _{3, 3} MHz ppm) 18CH ₃ : 0.86 (s); 19CH ₃ : 1.24 (s); twin diCH ₃ : 1.51-1.57 (s); CH ₃ CO: 2.17 (s); COCH ₂ -O: 4.74-4.97 (d); H _n 5.93 (ti); H ₄ : 6.09 (ti); H ₁₆ : 5.00 (d); H ₂ : 6.34 (dd); Hi: 6.84 (d); CHO: 8.13 (s).

Claims (4)

PATENT CLAIMS Compounds of formula (III) wherein R is hydrogen, acyl, alkoxycarbonyl, alkenyloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl or arylsulfonyl group containing up to 8 carbon atoms, A ₁ and A _2. is hydrogen or A ₁ and A ₂ together form a group> C (CH ₃ ) ₂ . 2. A process for the preparation of a compound of formula III wherein R, A ₁ and A ₂ are as defined in claim 1, wherein the compound of formula II is treated with an chlorinating or brominating agent and a formyloxylating agent in an acidic medium, and, if desired, treating the compound of formula (III) thus obtained, wherein A ₁ and A ₂ are hydrogen, with acetone in the presence of a strong acid. 3. A process according to claim 2 wherein the chlorinating or brominating agent is N-chloro or Nbromoacetamide, succinimide or phthalimide or Ν, Ν-dichloro or Ν, Ν-dibromo-dimethylhydantoin, or tert-butyl hypochlorite or hypobromite. A process according to claim 2 wherein the formyloxylating agent is dimethylformamide or formic acid.