DE1146881B - Process for the preparation of esters of 17ª ‡ -low-alkyl-, 17ª ‡ -low-alkenyl- and 17ª ‡ -low-alkynyl derivatives of? -Oestren-17ª ‰ -ol-3-one - Google Patents

Description

GERMAN

PATENT OFFICE

S63611IVb / 12o

REGISTRATION DATE: JUNE 24, 1959

NOTICE
THE REGISTRATION
AND ISSUE OF
EDITORIAL: APRIL 11, 1963

The invention relates to a process for the preparation of 17 / S-acyloxy- / i ⁵ ' ¹⁰ ' -estren-3-ones which are substituted in the 17a-position by the radical of a lower aliphatic, saturated or unsaturated hydrocarbon; these compounds show a marked progestatic activity.

17a-ethynyl-zl ⁵ < ¹⁰ > -östren-17y9-ol-3-one and 17a-vinyl - d ⁵ ( ¹⁰ ) -östren-17 /? - ol-3-one are known compounds with marked progestatic activity. The novel 17-esters of these compounds which can be prepared according to the invention, however, show even greater progestatic effectiveness and furthermore have better solubility in solvents which are customarily used for the preparation of pharmaceutical injectables, such as, for. B. in vegetable oils, which facilitates the preparation of injection solutions.

The usual esterification procedures are for converting the above compounds into theirs 17-ester not suitable.

The novel process according to the invention for the preparation of the 17-esters of 17a-lower alkyl- (alkenyl, alkynyl) -J ⁵ < ¹⁰ > -estren-3-ones now takes place by adding the hydroxyl groups of certain precursors in their synthesis, namely the corresponding 17a -Lower-alkyl- (alkenyl, alkynyl) -3-alkoxy- ^ ² ' ⁵ ( ¹⁰ > -estradien-17 /? - ole (I), in a known manner by reaction with the anhydride or chloride of a carboxylic acid mixed with a tert. base such as pyridine or a mono- or Polymethylanalogen thereof, at elevated temperatures, preferably from 80 to 13O ⁰ C, are heated for 8 to 40 hours. the reaction mixture is then preferably poured into aqueous sodium carbonate, which contains an excess of alkali. in the resulting 17-alkyl (alkenyl, alkynyl) -17, S-acyloxy-3-alkoxy-zf. ^{2 5 <10>} -östradien (II) the Enoläthergruppen are then hydrolyzed by acid treatment under mild conditions, without any rearrangement of the To cause double bond. For this hydrolysis is preferred ise oxalic acid mixed with aqueous methanol for about 20 to 60 minutes, preferably 40 minutes, at a temperature around 25 ° C. The desired 17-esters of the corresponding 17a-lower-alkyl- (alkenyl, alkynyl) - / l ⁵ < ¹⁰ ) -estren-3-ones (III) are prepared.

The compounds of formula II are also prepared by adding the corresponding compound of Formula I in a mixture with the anhydride of a lower aliphatic acid, e.g. B. acetic anhydride, refluxed in the presence of calcium carbonate for 12 to 48 hours.

Process for the production of esters

from 17a-lower-alkyl-, na-lower-alkenyl- and 17a-lower alkynyl derivatives of

_z j5 (io) _östren-17 _j S-ol-3-ons

Applicant: Syntex S. A., Mexico (Mexico)

Representative: Dr. W. Schalk, Dipl.-Ing. P. Wirth,

Dipl.-Ing. G. E. M. Dannenberg and Dr. V. Schmied-Kowarzik, patent attorneys, Frankfurt / M., Große Eschenheimer Str. 39

Claimed Priority: Mexico June 25, 1958 (No. 51 374)

Francisco Alvarez and Carl Djerassi,

Mexico (Mexico), have been named as inventors

The following formulas illustrate the method according to the invention:

OH

RO

III

In the above equation, R 'stands for a low one Alkyl or lower oxyalkyl radical, R ″ for an aeyloxy group of a hydrocarbyl carboxylic acid with up to 12 carbon atoms and R for lower alkyl, lower alkenyl, or lower Alkynyl group, d. H. one with up to 5 carbon atoms.

309 549/339

The corresponding Ua-lower alkynyl compounds are used to prepare the 17a-lower alkenyl derivatives. then in a manner known per se with absorption of one molar equivalent Hydrogenated hydrogen.

The anhydride or chloride used for esterification is derived from a straight and / or branched-chain and / or cyclic hydrocarbon carboxylic acid with up to 12 carbon atoms, wherein the acid can optionally be substituted with methoxy, halogen or other groups. At 17-esters were produced among others: acetate, propionate, butyrate, isobutyrate, tert-butyl acetate, hemisuccinate, Enanthate, caproate, benzoate, trimethylacetate, phenoxyacetate, cyclopentylpropionate, phenylpropionate and jS-chloropropionate.

The 17a-ethynyl and 17a-alkyl compounds of the formula I are known. Some of the 3-alkoxyzl ² ' ⁵ < ¹⁰ > -estradien-17 ^ -ols of the formula are hitherto unknown compounds.

The following examples illustrate the invention Procedure.

example 1

A mixture of 5 g of 17a-methyl-3-methoxy- _/ ] 2,5 (io) .estradien-17 ^ -ol, 50 ecm pyridine and 5 ecm acetic anhydride was heated on the steam bath for 8 hours and then poured into a solution of 10 Pour g of sodium carbonate into 200 ecm of ice water; the product was extracted with water, and the extract was washed with plenty of water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from acetone-hexane and yielded the 17a-methyl-3-methoxy- Δ ² · ^ ¹⁰ ^ - estradiene - Π β- ol-17-acetate.

A mixture of 3.5 g of the above compound, 300 ml of methanol and 5 g of oxalic acid dihydrate in 60 ml of water was heated to a temperature of 25 ° C. for 40 minutes with stirring. The reaction product was extracted with ether, and the extract was washed neutral with an aqueous sodium bicarbonate solution and then with water, dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization of the residue from ethyl acetate yielded the 17a-methyl-zl ⁵ < ¹⁰ >-estren-170-ol-3-one-17-acetate; p. 86 to 87 ° C; [a] _D + 169 °.

Example 2

According to the method of the previous example other low 3-alkoxy-z J ^{of 2} - ^{5 '10'} -östradien-17/5-Oie, which are substituted in Πα-position by the radical of a hydrocarbon, in their 17-esters, and then in the corresponding 17 / S-acyloxy-17a - lower - alkyl - (alkenyl, alkynyl) - ζί ⁵ < ¹⁰ > - estren-3-ones converted. The enol ether used was formed with some lower alkyl or oxyalkyl group, and the anhydride or chloride used was made from one of the carboxylic acids mentioned at the outset.

For example, 17a-ethynyl-3-methoxy-zl ² · ⁵ - ¹⁰ '-estradien-17 / J-ol was converted into its 17-propionate by reaction with propionic anhydride, and after subsequent hydrolysis of the enol ether group, the 17a-ethynyl-zl ⁵ < ¹⁰⁾ -estren-17β-ol-3-one-17-propionate, m.p. 130 to 132 ⁰ C; [a] _D + 100 °. Similarly, the 17a-ethyl-3-ethoxy <d ² was - ^5A0) -östradien-17j9-ol by reaction with isobutyric anhydride in his 17-isobutyrate, and then in the ^17-ethyl-5 zl ^(x ° '- Oestren-17/3-ol-3-one-17-isobutyrate; mp 95 to 98 ° C. In another experiment, 17a-propen (-l) yl-3-ethoxy- / 12.5 (10). estradiene-17/3-in oil-17-cyclopentylpropionate be converted, was in this case increased the esterification to about 40 hours or heated 8 hours to 135 ⁰ C, and the subsequent hydrolysis of the Enoläthergruppe afforded the 17a-propene (l) yl -17jS-cyclopentylpropionoxy - d ^{5 (} 10'-oestren-3-one; m.p. 80 to 82 ° C; [a] _D + 105 °.

In the same way, other compounds were made from the starting materials listed below:

Source material

End product

17a-propyn (-l) yl-3-methoxy-Zl ² ' ⁵ < ¹⁰ > -estradien-17β-ol 17a-propyn (-l) yl-3-methoxy-4 ² ' ⁵ < ¹⁰ > -estradien-17 / S-ol 17a-propyn (-l) yl-3-methoxy- / d ² . ⁵ ( ¹⁰ »-estradien-17 | 9-ol 17a-propen (-l) yl-3-methoxy-zl ² ' ⁵ < ¹⁰ > -estradien-17jS-ol 17a-propen (-l) yl-3-methoxy -zl ^{2. 5, <10>} -östradien-17.beta.-ol 17a-propene (-l) yl-3-methoxy-zl ^{2 '5 (10)} -östradien-17 (3-ol 17a-Butm (-l) yl -3-ethoxy-zl ^{second 5 <10>} -östradien-17 / S-ol

Example 3

The alkynyl group of a 17-ester of a 3-alkoxy-17a-alkynyl-zl ² ' ^{5 (10)} -estradien-17j8-ol or a 17a-alkynyl-zl ⁵ ( ¹⁰ ) -estren-17 ^ -ol- 17a-propyn (-l) yl- / d ⁵ <* °>-estren-170-ol-3-on-acetate;
M.p. 103 to 105 ° C; [a] _D + 141 °

17a-propin (-l) yl-, d ⁵ < ¹⁰ >-estren-17/5-ol-3-one-3-caproate; M.p. 73 to 75 ⁰ C; [from + 134 °

17a-propyn (-l) yl- / I ⁵ ( ^{1 ()} ) -estren-17 _j 8-ol-3-one benzoate; M.p. 109 to 111 ° C; [a] _D +132 ^o

17a-propene (-l) ^ yl ^{5 (10} '-estrene-17 ^ -ol-3-one-acetate;
M.p. 89 to 90 ⁰ C; [a] _D + 125 °

17a-propen (-l) yl-4 ⁵ ( ¹⁰⁾ -estren-17) S-ol-3-one-caproate;
M.p. 61 to 63 ° C; [a] _D + 116 °

17a-propen (-l) yl-zI ⁵ ( ^{1 (} "-estren-17 _j 8-ol-3-one-benzoate; mp 95 to 96 ° C; [a] _D + 109 °

17a-butyn (-l) yl- ^ ⁵ < ^lo >-estren-170-ol-3-one-enanthate;
Oil; [from + 100 °

3-ons converted to the corresponding alkenyl group; so were z. B. S-methoxy-na-propin - (- l) yl- / l ² - ⁵ ' ¹⁰ ' -estradien-17jS-ol-acetate into 3-methoxy-17a-propen (-l) yl- ^ ² - ⁵ < ¹⁰ '-estradien-17j3-ol-acetate

and 17a-ethynyl- / l ^{5 '10} > -estren-17 / S-ol-3-one-17-cyclopentylpropionate into the 17a-vinyl-zl ⁵ < ¹⁰ > -estren-17 / i-ol-3-one -17-cyclopentyl propionate converted. M.p. 105 to 107 ⁰ C; [a] _D + 104 °.

Example 4

5 g of 17a - ethynyl - 3 - methoxy - Δ ² - ^{5 (10)} - östradien- Πβ-ο \ were added to a suspension of 1 g of calcium carbonate in 140 cc of acetic anhydride, the mixture was heated under reflux for 24 hours and StickstoiFatmosphäre then concentrated to about 25 ecm under reduced pressure. The mixture was poured into 1200 ecm of ice water containing 62 g of anhydrous sodium carbonate, and the reaction product was extracted a few times with ethyl acetate. The extract was washed with water, dried over anhydrous sulfate, evaporated to dryness, the residue was recrystallized from acetone - hexane and so that

17-acetate obtained, which according to Example 1 in the 17a-ethynyl- / J ⁵ < ¹ ° »-estren-l 7 /? - ol-3-one-l 7-acetate, mp 138 to 14O ⁰ C; [a] _D + 102 °.

Claims (2)

PATENT CLAIMS: 1. Process for the preparation of esters of 17a-lower alkyl, 17a-lower alkenyl and 17a-lower alkynyl derivatives of <d ⁵ < ¹⁰ > -Östren- Πβ-οΙ-3-one with hydrocarbon carboxylic acids with up to 12 Carbon atoms, characterized in that a corresponding 3-alkylenol ether-17 (3-oxy compound is esterified by methods known per se and then the ether group is hydrolyzed under mild acidic conditions, the corresponding 17a-low alkenyl derivatives then being used to prepare the 17a-low-alkenyl derivatives Alkynyl derivatives are hydrogenated in a manner known per se. 2. The method according to claim 1, characterized in that the hydrolysis with oxalic acid is carried out at room temperature. © 309 549/339 4.63