SU402209A1 - - Google Patents

Description

METHOD OF OBTAINING SUBSTITUTED STEROIDS

This invention relates to a method for producing substituted steroids with physiological activity. Based on the known reduction reaction with lithium aluminum hydride, the proposed 5 method for the preparation of substituted steroids of the general formula, 10 where RI is Ci-C3-alkyl; Zs are rings A and B with the following meanings: 20 volts per 25, where Rs is hydrogen or methyl; Cs - hydrogen or C2-C4-alka R4 - hydrogen, Ci-Cz-alkyl, Cs-Cy-cycloalkyl or C2-C4 alkanoyl, is that the compound of the general formula, LA-CHC-CH, -KR e RI and Zs have the above values; Rs is Ci-Cz-alkyl; Re and R are the same.

or equal C-C3 alkyls nln together with the nitrogen atom form a pyrrolidine or piperidine ring;

Y - a puleofugitive group, is treated with a complex metal hydride in an inert solvent, followed by a deprotection in Zs fragments and isolation of the target product by known methods.

The reaction is usually carried out at -80- (- (- 80) ° C), diethyl ether or tetrahydrofuran is used as an inert solvent, from complex metal hydrides, for example, lithium aluminum-hydride is used. The Y molset group is chlorine, bromine or iodine, it is bound to an ionic or covaleitic bond.

In order to protect the protective groups, in particular tetrahydropyranyl, the products are treated with acids in an organic solvent, for example, l-toluenesulfonic acid or 11N hydrate. hydrochloric acid in methanol, ethanol or benzene or in glacial acetic acid and water at room temperature.

Example 1. 17a-Propadienyl-3-methoxyestra-1, 3.5 (10) -triei-17p-ol.

17- (3-Dimethylamino-1-propynyl) -3-methoxyestra-1, 3.5 (10) -trigol-17 p-ol.

A mixture of 15.8 g of 17a-ethynyl-3-methoxyestra1, 3.5 (10) -triei-17p-ol, 15.0 ml of dimethylaminomethanol, 500 mg of cuprous chloride, 8.5 ml of glacial acetic acid and 125 ml of dioxane incubated for 5 hours at 70 ° C, ice water was added, the pH was adjusted to 10, extracted with ether and the foam was separated with -8.84 ° (, CHC1).

Methyl iodide 17- (3-dimethylamino-1-propynyl) -3-methoxyestra-1,3,5 (10) -triene-17 | 5-ol.

A mixture of 10.0 g of the obtained product, 290 ml of acetone and 87 ml of methyl iodide is incubated for 24 hours at 0 ° C and the crystals are filtered off with mp. 237-239 ° C.

17a-Propadienyl-3-methoxy-estra - 1,3,5 (10) trien-17p-ol.

11.25 ml of a 0.525 M solution of lithium aluminum ion hydride in tetrahydrofuran are added to a suspension of 3.006 g of the obtained crystals in 65 ml of anhydrous tetrahydrofuran at -75 ° C, stirred for 2 hours at -10 ° C until a plastic solution is formed, which is left overnight at room temperature The mixture is cooled to 0 ° C, a saturated aqueous solution of ammonium chloride is added and extracted with unsaturated ether. The output is quantitative, t. Il. 129.5-130.5 ° C; + 7.18 ° (, СНСЬ).

Example 2. Analogously to example 1, using 17a-ethinylestra-4-en-17p-ol; 3-cyclopentyloxy-17a-ethinylestra-1, 3.5 (10) -triene - 17 (3ol; 3-ethoxy-17a-ethynyl-13-ethylgon-1,3,5 (10) trien-17r-ol and 7a -ethynyl-4-ei-3p, G / rdiol, receive intermediate 17- {3-dimethylamino-1-propynyl) -estra-4-ei-17p-ol; 3-cyclopentyloxy-17a- (3-dimethylamino-1-propinyl) -estra-1,3,5 (10) -triene-17-ol; 3-ethoxy-G / a- (3-dimethylamino - 1 - ironinyl) - 13 ethylgone-1, 3.5 (10) -trien-17r-ol and 17cc- (3-dimethylamino-1-nroninyl) -estra-4 -en-3p, I / P-DIOL, their methyl iodides and target 17a-yropadienyl-estra-4-ene-17 (3-ol; 3-cyclopentyloxy-17a-pronadienyl-estra-1, 3.5 (10) -triene-17p- ol; 3-ethoxy-1 / p - propadienyl - 13 - ethylgon - 1,3,5 (10) Trie 11-17a-ol and 17a-proiadienestra-1-en-Zr, 1 / R-DIOL, t. pl. 80-82 ° C, respectively.

Example 3. 17a-1ropadienyl-3-methoxy-estra-2, 5 (10) -diene-17 (5-ol.

17a-dimethylaminopropinyl-3-methoxy-estra2, 5 (10) -diene-17p-ol.

To a mixture of Grignard reagent (out of 1.50 g of magnesium and 4.68 g of ethyl bromide) and 70 ml of tetrahydrofuran, 5.3 g of dimethylaminopropine dissolved in 10 ml of tetrahydrofur} 1a were added dropwise after ethane was liberated at O- A solution of 1.716 g of 3-methoxy-espra-2, 5 (10) -diene-17p-one in 30 ml of tetrahydrofuran is added dropwise at 5 ° C, kept at 20-25 ° C for 4 hours, 100 ml of 2N is added. sodium hydroxide solution, concentrate at a temperature not exceeding 30 ° C to a total volume of 100 ml in vacuum and extract the concentrate with ether (5X25 ml) using a dry frit. After evaporation of the ether extracts and suctioning off the excess dimethylaminopropin, 17- (3-dimethylamino-1-nroninyl) 3-methoxyestra-2, 5 (10) -diene-17p-ol.

Methyl iodide 17- (3-dimethylamino-1-propinyl-3-methoxy-estra-2, 5 (10) -diene-17p-ol a.

3.5 g of methyl iodide is added to a solution of 2.0 g of an obtained product in 30 ml of acetone, incubated for 18 hours at 8 ° C, the crystals are filtered off and rinsed with anhydrous nonsteric ether.

17a-Propadienyl-3-methoxy-estra-2,5 (10) -diene-17p-ol.

9.3 ml of a 0.525 M solution of lithium aluminum hydride in tetrahydrofuran are added to a suspension of 2.5 g of the obtained crystals in 50 ml of tetrahydrofuran at -75 ° C, heated to -10 ° C, stirred until a clear solution is formed (min), kept for 12 hours at at room temperature, add 100 ml of aqueous 2N. a solution of sodium hydroxide containing 50 ml of di-greg-butyl cresol is concentrated in vacuo to a total volume of 100 ml, extracted (5X20 ml) with ether using a centrifuge, dried, the extracts over potassium carbonate and evaporated.

Example 4. 17a-Propadienyl-5 (10) en-17p-ol-3-one.

2.0 g of 17a-propadienyl-3-methoxyester2, 5 (10) -diene-17p-ol is dissolved in a mixture of 20 ml of glacial acetic acid and 2 ml of water, after 2 hours 200 ml of water are added and the product is extracted with ethyl acetate ( 5X HU ml). After evaporation of the extracts get the target product, so pl. 116-122 ° C.

Example 5. 17a-Propadienyl-4-en17P-OL-3-OH.

A solution of 5.5 g of 17a-propadienyl-3-methoxy-estra-2, 5 (10) -diene-17p-ol in a mixture of 50 ml of methanol and 1.5 ml of 11 n. hydrochloric acid is incubated for 30 minutes at 30 ° C, diluted with 100 ml of water, extracted with methylene chloride (5x15 ml), the extracts are evaporated, the residue is recrystallized from niclohexane and the pure desired product is obtained, mp. 135-137 ° C.

Example 6. Analogously to examples 3 and 4, using estrone-3-tetrahydrop crane sludge ether; 3-methoxy-13-ethyl-11a-2.5 (10) dip-17-one and 13-n-nropyl-3-tetrahydro-11-neyloxygon-2, 5 (10) -diene-17-one, get 17-apropylenyl-estra-1, 3, 5 (10) -trien-3.17r - diol; 13-ethyl-17a-propadienyl-4-ene-17p-ol-3on, t. Pl. 122-125 ° C and 17a-nropadienyl-13-npropyl-4-ene-17p-ol-3-one, respectively.

Example 7. As in Examples 3 and 4, using 3-methoxy-13-ethylgon-2,5 (10) -diene-17-oii, 13-ethyl-17a-propadienylgon-5 (10) en-17p-ol is obtained. -3-he.

Subject invention

The method of obtaining the substituted steroids of the general formula

R, OH

where RI is Ci-C3-alkyl; Zs - rings A and B

with the following values:

R2 (H

R.Oi

K, 0

in which Ra is hydrogen or methyl; Rs is hydrogen or C2-C4 alkanoyl;

R.-, - hydrogen. C-C3 alkyl, C3-Su-cycloalknl or Co-C4 alkanoyl,

about tl and h and y y and so that the compound of the general formula

HE

 upV

.-- CHC-CH, -U-R,

to.

where RI and Zs are as defined above;

Rs is Ci-Cz-alkyl;

Re and R are the same or different C-Csalkyls or together with the nitrogen atom form a pyrrolidine or piperidine ring;

Y is a nucleofugitive group, is reacted with a complex metal hydride in an inert solvent, translates the protected Zs structures of the reaction product into unprotected ones, followed by isolation of the target product by first methods.