DE1068257B - Process for the production of Pnegnatrientrionen - Google Patents

Description

ΓΑ

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

kl. 12 ο 25/05

INTERNAT. KL. C 07 C

C 0 7 J ν -

EXPLAINING PUBLICATION 1068 257

M37822IVb / 12o

REGISTRATION DATE: MAY 30, 1958

NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: NOVEMBER 5, 1959

It was found that 4,6,8-pregnatriene-17a, 21-diol-3,11,20-trione as well as its 21-ester with lower aliphatic carboxylic acids excellent adrenal cortical hormone effect own.

It has also been found that these compounds can be prepared by sequential treatment of an o-dehydrohydrocortisone ^ l-acylate with dehydrating, HOBr-supplying, oxidizing and dehydrohalogenating and optionally saponifying agents.

The invention accordingly provides a process for the production of pregnatrientrions, which consists in adding a 4,6-pregnadiene-II / 9,17a, 21-triol-3,20-dione-21-acylate in a manner known per se Treated dehydrating agents, the thus prepared 4,6,9 (1 l) -Pregnatrien-17a, 21-diol-3,20-dione-21-acylate, preferably by the action of an N-bromo-carboxamide, in the 9a Bromo-l 1 / I-hydroxyl derivative is converted into 9 <z-bromo-4,6-pregnadiene-17a, 21-diol-3, 11, 20-trione by treatment with a mild oxidizing agent, preferably by the action of chromic anhydride -21-acylate and the latter by treatment with dehydrohalogenating agents, preferably by the action of a tertiary organic base, in 4,6,8-pregnatriene-17a, 21-diol- IO

Process for the preparation of Pregnatrientrions

Applicant:

E. Merck Aktiengesellschaft, Darmstadt, Frankfurter Str. 250

Dipl.-Chem. Dr. Klaus Brückner, Darmstadt, has been named as the inventor

3, ll, 20-trione-21-acylate converted and, if appropriate, the latter compound by methods customary per se by treatment with saponifying agents in 4,6,8-pregnatrien-17a, 21 -diol-3,11,20-trione converts.

The reaction proceeds according to the following equation:

CHgOAc CH ₂ OAc

HO

CH ₂ OAc ü}

CH ₂ OR

CH ₂ OH

Compound I can be dehydrated to give trione II in good yield by using thionyl chloride / pyridine as a dehydrating agent. Of course, all other common dehydrating agents, such as 2. B. POQ ₃ / pyridine, etc., can also be used to remove the water. For the addition a ° of the 9a-bromine atom and the 1 ^ -hydroxyl group, an N-bromo-carboxamide, such as. B. N-bromosticcinimide or N-bromacetamide. It has proven advantageous to carry out the addition of HO Br in the presence of a strong acid, preferably perchloric acid. The subsequent oxidation of the 1 ^ -hydroxyl group to the 11-carbonyl group succeeds in good yield by treatment with chromic anhydride in pyridine. This oxidation can also be carried out using chromic anhydride in acetone or in glacial acetic acid. Pyridine is particularly suitable for the splitting off of H Br, but also other tertiary bases, such as. B. lutidine, collidine, PicoJin, etc. are useful. The saponification of the ester V to the free alcohol VI is achieved by the usual methods, for. B. by treatment with sodium hydrogen carbonate.

The compounds II to VI are in the literature so far not described. The required starting material o-dehydrohydrocortisone ^ l-acylate is known Methods by treating hydrocortisone-21-acylate accessible with chloranil.

The new compounds are to be used as chemotherapeutic agents.

example
Dehydration

28.3 g 4,6-pregnadien-3,20-dione-l l ^ iya ^
Tat are dissolved in 283 ecm pyridine, treated with 4.2 ecm thionyl chloride and heated on the steam bath for 30 minutes. The reaction mixture is then cooled, poured into water, the precipitate is filtered off with suction, washed and recrystallized from methanol. 4,6,9 (11) -Pregnatriene-3,20-dione-17a, 21-diol-21-acetate (II) melts at 194 ° C.

H O Br addition

55

13 g of 4,6,9 (U) -Pregnatriene-3,20-dione-17a, 21-diol-21st-acetate (II) are in 520 ecm of Pioxane and 67.5 ecm of water dissolved, with 9.15 g of N-bromosuccinimide and 2.93 ecm of perchloric acid (70%) are added and the solution is left to stand at room temperature for 1 hour. After that it is in water poured in the precipitated 9ct-bromo-4,6-pregnadiene-3,20-dione-II / S, 17ct, 21-triol-21-acetate (III) filtered off, washed and dried.

Oxidation and elimination of H Br

10 g of bromohydrin (III) are dissolved in 100 ecm of absolute pyridine and a solution of 10 g of CrO ₃ in 100 ecm of absolute pyridine is added while cooling with ice.

Ac = lower acyl

The reaction mixture remains standing for 19 hours, is then poured into water, the precipitate is filtered off with suction, washed, dissolved in methanol, filtered and filtered again through silica gel. The solution is then concentrated and the residue consisting of 9a-bromo-4,6-pregnadiene-17a, 21-diol-3, ll, 20-trione-21-acetate is heated in 70 ecm of pyridine on the steam bath for 2 hours. The reaction mixture is then poured into water again, and the precipitate is filtered off, washed, dried and filtered through silica gel in ethyl acetate. On concentration, the 4,6,8 (9) -Pregnatriene-3, ll, 20-trione-17a, 21-diol-21-acetate (V) crystallizes out. Melting point 219 to 220 ° C. [a] i> + 886.6 ° (dioxane) -hnax 263 ηιμ, ε = 15350

375 ηιμ, ε = 9600.

By further recrystallization it is possible to obtain compound V in pure form with a melting point of 240 to 245 ⁰ C, as well as \ o \ d + 1128 ° and hnax 263ηιμ, Ε = 16800,

375ηιμ, Ε = 10200, to get.

. Saponification

1.8 g of 4,6,8 (9) -Pregnatrien-3, il, 20-trione-17 «, 21-diol-21-acetate (V) are dissolved in 52.24 ecm of methanol and together with 0.63 g of sodium hydrogen carbonate and 11 ecm of water for 7 minutes under a nitrogen atmosphere and refluxed. The reaction mixture is then poured into water and worked up as usual. The 4,6,8 (9) -Pregnatrien-3, ll ₎ 20-trione-17a, 21-diol (VI) crystallizes from acetone in coarse, coarse crystals with a melting point of 247 to 248 ° C; [ο] χ> = + 1197 ° (dioxane). Imax 261 ΐημ; E = 16,300,
276 πιμ; E = 10,200.

Claims (1)

Claim: Process for the production of Pregnatrien-trionen, characterized in that roan in a manner known per se is a 4,6-fregnadiei> 14 # 17a, 21-triol-3,20-diori-21-acylate treated with dehydrating agents, the 4,6,9 (II) -Pregnatriene-17a, 21-diol-3,20-dione-21-acylate thus produced, preferably by the action of an N-bromo-carboxamide into the 9a-bromine /? - hydroxyl derivative transferred, this by treatment with a mild oxidizing agent, preferably, by the action of chromic anhydride, in 9a-broro-4,6-pregnadicn-17a, 21-diol-S.II ^ O-trione-21-acylate converts and the latter by treatment with dehydrohalogenating agents, preferably by the action of a tertiary organic base in 4,6,8-pregnatriene-l 7a, 21-diol-3,11,20-trione-21-aylate transferred and, if appropriate, the latter compound by treatment methods which are customary per se converted into 4,6,8-pregnatrien-17a, 21-diol-3,11,20-trione with saponifying agents. Considered publications:
Journ. Amer. Chem. Soc, 79: 447 (1957). © 909 647/440 10.