The method of obtaining pregnane

 

(57) Abstract:

The invention relates to the field of organic synthesis. Describes the synthesis of steroid drugs from the sterols of plant and animal origin. The method of obtaining pregnancv is that tsionirovanie derivatives of 17-ketosteroids is subjected to the protection of the 17-OH group and alkylation of 17 SP-group, followed by hydrolysis. As 17-ketosteroids use 3,17-diketonate General formula

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where R1or OH-group or atom N, R2Is H or Oh-group or instead of R1and R2double bond, R3- N or CH3group, R4Is h or Oh-group. Before alkylation protect 3-ketogroup with unsubstituted or 2-substituted, or 2,2-disubstituted propylenes. To protect the 17-OH group as a protective group used alkylvinyl ether. The method allows to increase the yield of the main product. 1 C.p. f-crystals.

The invention relates to the field of organic synthesis, namely the synthesis of steroid drugs from the sterols of plant and animal origin.

17-Ketosteroids are key intermediates in the synthesis of steroid drugs is tsya the most available and cheapest source of steroid raw materials.

There are several stereoselective methods of obtaining prignano, but the greatest interest of acetylene and tangerines methods.

Acetylene synthesis is the condensation of 17-ketosteroids with acetylindole alkali metal selectively on 17-ketogroup with subsequent transformation of the resulting 17-etinilnoy group in oxypregnanes or dixiecuties side chain (Y. Nitta et al. Bull. Chem. Soc. Ypn. 1985, 58 (3), 981 - 986; Tetrahedron Lett., 1980, v. 21, p. 2665 - 2666).

Langeronii synthesis as a method of introducing a side pregnanvy chain substituted 17-ketosteroids in recent years has gained more interest (GDR patent N 147669, 1997; US 4.500.461, 1985).

The closest to the invention is a method for prignano, namely, that tsionirovanie derivatives of 17-ketosteroids is subjected to the protection of the 17-OH group, the protection of 3-ketogroup and alkylation of 17 CN-group, followed by hydrolysis, leading to the formation of 17 - hydroxypregnenolone side chain (JP 62296, 1982, WITH 7 J 7/00).

In this way protection 3-ketogroup is the formation of 3,3-Atlanticists, therefore, used in the synthesis reaction of alkylation followed by alkylation at the 3 rd position that leads to is increasing the yield of the target product by reducing the probability of occurrence of adverse reactions.

The technical result is achieved in that in the method of obtaining prignano, namely, that tsionirovanie derivatives of 17-ketosteroids is subjected to the protection of the 17-OH group, the protection of 3-ketogroup and alkylation of 17 CN-group, followed by hydrolysis, as 17-ketosteroids use 3,17-diketonate General formula

< / BR>
where R1- or OH-group or H atom,

R2Is H or Oh-group or instead of R1and R2- double bond,

R3- H or CH3group,

R4Is H or Oh-group, a

protection 3-ketogroup performed using unsubstituted or 2-substituted, or 2,2-disubstituted propylenes.

In addition, to protect the 17-Oh group can be used alkylvinyl ether.

Protection4-3-ketogroup can be carried out by the formation of the enol-ether (methyl or ethyl), or Catala (as in the prototype), or enamine. The most preferred Cetelem was recognised atlantal [US 4500461] . However, the protection of 3-ketogroup is provided by the formation of five-membered 1,3-dioxolane cycle. Five-membered cycle is somewhat more intense than six-membered (J.March. Organic chemistry, T. 1, S. 192, Publishing house "Mir", M. 1987). In addition to tinselrown ether, requires rather stringent conditions (prolonged boiling in tetrahydrofuran (THF) or the use of high-boiling solvents (e.g., anisole) and accompanied by side reactions 1, 3-dioxolane ring with the formation of the product of the cleavage of C-O bonds 3-methyl-3-(acetoxy)-pregn-5-ene-17-ol-20-one with high yield (E. C. Popov, W. A. Andryushina, G. S. Grinenko, "Synthesis of derivatives of the banished", Chemistry of natural compounds (University), 1984, 3, S. 324 - 327).

The objectives set out in the proposed method applied protection4-3-ketogroup in the steroid molecule with the formation of 1, 3-dioxane, namely unsubstituted or 2-substituted, or 2,2-disubstituted propylenes, using, for example, 2,2-dimethyl-1,3-propane diol (neopentyl glycol).

The formation of 1,3-dioxane is more preferable as the protective group, as it flows easier with the formation of thermodynamically more favorable patterns: the output of the five-membered cyclic Catala is 84,2% [University N 4 (1984), S. 324], and the proposed method is 95 - 98%.

This proposed protection more sustainable in terms of conducting the alkylation reactions and allows to carry out these reactions in mild conditions using metallice at cachaca protection has a significant advantage in the yield of the target product: output of 17-hydroxyprogesterone with the use of 1,3-dioxolane protection is 88.5% [Ryakhovsky M. I. and other Chemical and pharmaceutical journal (HFG), 1987, 21 (4), S. 478 -481] , in the prototype, or 95.7%, and 1,3 - dioxane protection under the proposed method was 99.4%.

At the end of opinia the scheme for obtaining pregnane (17-hydroxyprogesterone) from Androstenedione (AD).

Examples get progesterone from HELL.

Example 1. Getting 17-hydroxy-17-Leandros-EN-3-one (II).

To a solution of 1.63 g of NaOH in 280 ml of methanol was added 100 g of Androstenedione (I). The suspension is heated to 40oC and add sequentially to 13.8 ml of water, and 47.8 ml acetonecyanohydrin. The reaction mass is maintained at a temperature of 35 - 6oC for one hour and slowly add (dropwise) 59 ml of water, then incubated at room temperature. Upon completion of the reaction, add slowly 217 ml of water and incubated for 2 hours at room temperature. The precipitate is filtered off, washed on the filter with a mixture of water and methanol (2:1, respectively) and water to a pH of 7.

Get 104,45 g of compound (II) with access to 95.5%, with a melting point 174 - 176oC.

Example 2. Getting 17-hydroxy-3,3(2,2-dimethylpropylene)-androst-5 EN-17-(carbonitrile (III).

Suspension 104,45 g of compound (II) in 522 ml of methylene chloride cooled to a temperature of 0...-5alpicola and 15,67 g of p-toluenesulfonic acid. The reaction mass is stirred for 8 hours. Upon completion of the reaction slowly add a solution of 68.3 g of sodium bicarbonate in 1.3 l of water. The suspension is cooled to a temperature of 0... +5oC and incubated for one hour. The precipitate is filtered off, washed with water to pH 7.

Get 130,52 g of chromatographically pure compound (III) with a yield of 98% with a melting point of 252oC (decomposition).

Example 3. Getting 17-hydroxyprogesterone (V).

To a suspension 130,52 g of compound (III) and 2, 61 g of p-toluenesulfonic acid in 1,175 l of tetrahydrofuran in a stream of dry nitrogen at room temperature add 130,52 ml of vinylethylene ether. The suspension is stirred to dissolve the precipitate and add 3, 26 ml of triethylamine (pH 8). The reaction mass is then cooled to a temperature of - 30oC and slowly added dropwise 784 ml of 1.4 M solution metallice in the air. The reaction mass is slowly heated to room temperature and stirred for 2 hours. Upon completion of the reaction, the reaction mixture is cooled to a temperature of 0... +5oC and added slowly dropwise a mixture of 260 ml of hydrochloric acid, 260 ml of water and 650 ml of methanol (pH 2). The reaction mass is stirred until the hydrolysis Catalinas group at C-3 and tx2">

After recrystallization from acetone with coal get 107,3 g of compound (V) with a yield of 99.4%, with a melting point 234oC.

Example 4. Getting 17-hydroxy-3,3(2,2-dimethylpropylene)-pregn-5-ene-20-it (VI).

The methylation reaction of compound (III) (20 g) is carried out in the conditions of example 3. Upon completion of the reaction the reaction mass is then cooled to a temperature of 0... +5oC, slowly add dropwise a mixture of 0.6 ml of hydrochloric acid and 0.6 ml of water, then diluted with 180 ml of water and stirred for one hour. The precipitate is filtered off.

After recrystallization from methylene chloride with coal get 20,64 g of chromatographically pure compound (V) with a yield of 99%.

Example 5. Getting 17-hydroxyprogesterone (V).

To a solution of 20 g of compound (Vl) in a mixture of 400 ml of ethanol and 100 ml of methylene chloride under stirring at room temperature, slowly add dropwise a mixture of 2.5 ml of hydrochloric acid and 2.5 ml of water (pH 2). Upon completion of the reaction the reaction mass is evaporated in vacuum to a volume of 300 ml To the residue under stirring at room temperature, add 600 ml of water. The suspension is cooled to a temperature of 0...+5oC and incubated for 2 hours. The precipitate is filtered off, washed on the filter ptx2">

1. The method of obtaining prignano, namely, that tsionirovanie derivatives of 17-ketosteroids is subjected to the protection of the 17-OH group, the protection of 3-ketogroup and alkylation of 17 CN-group, followed by hydrolysis, characterized in that as a 17-ketosteroids use 3,17-diketonate General formula

< / BR>
where R1- or OH-group or atom N;

R2Is h or Oh-group or instead of R1and R2- double bond;

R3- N or CH3-group;

R4Is h or Oh-group,

and protection 3-ketogroup performed using unsubstituted or 2-substituted, or 2,2-disubstituted propylenes.

2. The method according to p. 1, characterized in that to protect the 17-OH group as a protective group used alkylvinyl ether.

 

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--methylated steroids" target="_blank">

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where R-=0,-OH, and In the remains of

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and K=O, or group

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or

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where n=2,3;

R1-the remainder of the ether or of ester,

wavy lines indicate the mixture of isomers

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