The method of receiving corticosteroids

 

(57) Abstract:

The invention relates to the field of organic synthesis. Describes the synthesis of steroid drugs, particularly corticosteroids General formula

< / BR>
where R1- or-OH-group or H, R2Is H or OH-group or F, or instead of R1, R2- double bond, R3- H, or CH3-group or F, R4Is H or OH-group, R5- or-CH3group or H atom, R6=H or AC, from sterols of plant and animal origin. 3,17-diketonate General formula

< / BR>
subjected to cyanidation, protection 17-- Oh groups with alkylvinyl ether, protection 3-ketogroup with unsubstituted or 2-substituted, or 2,2-disubstituted propylenes and alkylation of the 17-SP-group, followed by hydrolysis. The compound obtained is subjected to galoidirovaniya 21 provisions by direct iodination and subsequent replacement of iodine by hydroxy or acetoxy group. The method allows to increase the yield of the target product. 2 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-Ketov of sterols of plant and animal origin (sitosterol and cholesterol), which are currently the most available and cheapest source of steroid raw materials.

There are several ways to build dioxyaceton side chain of corticosteroids, which consists in the stereoselective construction of pregnanolone chain followed by the introduction of an oxygen function at C-21-carbon atom of the steroid molecule. Hydroxylation of the 21st provisions molecules 17 hydroxyprogesterone can be carried out by pre-iodination and subsequent substitution of the iodine atom at C-21 hydroxy - or acetoxy.

A method of obtaining corticosteroids, namely, that pregnan are galoidirovaniya C-21 position by indirect introduction of the iodine atom with subsequent substitution of the halogen on the hydroxy-group [Chemical-pharmaceutical journal, 1990, 11, S. 55-57. M. I. Ryakhovsky, E. C. Popov, W. A. Andryushina, G. S. Grinenko].

The technical result of the proposed method is to increase the yield of the target product by conducting building pregnanvy chain with sustainable protection4-3-ketogroup.

The technical result is achieved in that in the method of producing corticosteroids General formula I

< / BR>
DG communication,

R3- H, or F, or CH3group,

R4Is H or OH-group,

R5- or - CH3group or H atom,

R6- H or Ac,

namely, that pregnany General formula II

< / BR>
where R7and R8together ketogroup or unsubstituted,

2-monosubstituted or

2,2-disubstituted providential,

are galoidirovaniya C-21 position with subsequent substitution of the halogen by hydroxy or acetoxy group, to obtain pregnane as starting compounds are used 3,17 - diketonate General formula III

< / BR>
which is subjected to cyanidation, the protection of the 17-OH group, the protection of 3-ketogroup with unsubstituted or 2-substituted, or 2,2-disubstituted propylenes and alkylation of the 17-CN-group, followed by hydrolysis.

In addition, gorodilova can be done by direct iodination.

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

Tianidine method of introducing oxypregnanes side chain is hidrotsianova 17-ketosteroids education mostly 17-carbonitrile. Protection of 3-ketogroup and 17 HE - hydroxy-group, followed by methylation nitrile gruppy implement substantial trimethylchlorosilane or alkylvinyl esters, etc.

Protection 4-3-ketogroup can be carried out by the formation of the enol-ether, Catala or enamine. The most preferred Cetelem was recognised atlantal (US 4.500.461, 1985). However, this protection4-3-ketogroup is provided by reaction with ethylene glycol) and the formation of five-membered 1,3-dioxolane cycle. Five-membered cycle is more intense (transannular, picaresque voltage) than six-membered 1,3-dioxane loop formed at the protection of the above4-3-ketogroup interaction with 1,3-propane diol, where these stresses are absent (J. March. Organic chemistry, T. 1, S. 192, Ed. Mir, M., 1987).

In addition, it is known that the alkylation of the CN-group, 3,3-atelectasia 17-cyanhydrin Androstenedione Grignard reagent, where the hydroxyl at C-17 is secured, for example, trimethylsilyloxy ether, requires rather stringent conditions (prolonged boiling THF or the use of high-boiling solvents, such as anisole) and accompanied by a side reaction of 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 (anisole-quantitative [E. C. Popov, W. A. Andryushina, G. S. Grinenko "Since-793].

In the proposed method applied protection4-3 - ketogroup steroid molecule with the formation of the 1,3 - dioxane cycle using unsubstituted, 2-mono-and 2,2-disubstituted 1,3 - propandiol, for example, 2,2-dimethyl-1,3-propane diol (neopentylglycol).

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

In addition, the conditions of the alkylation reaction such protection is more stable and allows the reaction as in mild conditions using metallice as meteorologi agent, and under more severe conditions of the Grignard reaction. This comparative study of protection when carrying out methylation in the same conditions showed a significant benefit 1,3-dioxane protection under the proposed method in the yield of the target product: output of 17-hydroxyprogesterone with the use of 1,3-dioxolane protection and 88.5% [Ryakhovsky M. I. and others, HFG, 1987, 21 (4), S. 478-481], using a 1,3-dioxane protection under the proposed method was 99.4%.

the as calcium and catalytic amounts of salts of alkali and alkaline earth metals [L., Gatsenko, C. N. Petrov, HFG, 1972, T. 10, S. 27] . Subsequent reaction of nucleophilic substitution of an atom of iodine on the acetoxy group in an aprotic solvent receive 21-acetoxy - 17-hydroxy-derived high yield.

The scheme receiving corticosteroids

< / BR>
R7and R8together unsubstituted

2-monosubstituted or 2,2 - disubstituted propranolol

< / BR>
where IIA: R7and R8together keto-group;4< / BR>
IIb: R7and R8together propranolol, 5< / BR>
< / BR>
VII: R7and R8together keto-group;4< / BR>
VII: R7and R8together propranolol; 5< / BR>
< / BR>
Examples of the implementation of the proposed method (R1= R2= R3= R4= R5= H).

Example 1. Getting 17 - hydroxy - 17 Leandros - 4 EN-3-one [(IV), R1= R2= R3= R4= R5= H].

To a solution of 1.63 g of NaOH in 280 ml of methanol was added 100 g of Androstenedione (III). 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. . . 36oC for one hour and slowly add (dropwise) 59 ml of water, then incubated at room temperature. Upon completion of the reaction d on the filter with a mixture of water and methanol (2:1, respectively) and water to pH 7.

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

Example 2. Getting 17 - hydroxy - 3,3 (2,2 - dimethyl-Propylenediamine) - androst - 5 EN - 17 - carbonitrile (V) (R1= R2= R3= R4= R5=H).

Suspension 104,45 g of compound (IV) in 522 ml of methylene chloride cooled to a temperature of -0...-5oC in a stream of nitrogen consistently add 105 ml teeterboro ether orthomorphisms acid, 156,7 g of neopentyl glycol 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 (V) with a yield of 98% with a melting point of 252oC (decomposition).

Example 3. Getting 17 - hydroxyprogesterone (IIA).

To a suspension 130,52 g of compound (V) 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 tree the target 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 then diluted to 1.83 liters of water. At the end of the endurance (1 hour at room temperature the precipitate is filtered off. After recrystallization from acetone with coal get 107,3 g of compound (IIA) with a yield of 99.4%, with a melting point 234oC.

Example 4. Getting 17 - hydroxy -3,3 (2,2 - dimethylpropionic - pregn -5 EN - 20-she (IIB)

The methylation reaction of compound (V) (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 Il methylene chloride with coal get 20,64 g of chromatographically pure compound (IIB) with a yield of 99%.

Example 5. Getting 17 - hydroxyprogesterone (IIA).

K R is the temperature value added slowly 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 with water to pH 7.

Obtain 15.5 g of compound (IIA) with a yield of 98%, with a melting point 232-233oC.

Example 6. Getting 17 hydroxy-21-improvistion (VIIa).

To a solution of 10 g of 17-hydroxyprogesterone (IIA) in 100 ml of a mixture of methylene chloride and methanol (3:1) are added successively at room temperature 7.6 g of calcium oxide, 0.5 ml water, 10 g of iodine and a solution of 1.7 g of calcium chloride in 25 ml of methanol. The suspension is stirred at a temperature of 25oC for one hour. The reaction mass is diluted with 75 ml of methylene chloride and poured at a temperature of 0...5oC in a solution of 45 g of sodium bicarbonate in 540 ml of water. The precipitate is filtered off, washed on the filter with methylene chloride. The filtrate is transferred into a separating funnel, the organic layer is separated, the aqueous extracted with methylene chloride. The solvent is evaporated to small volume, the precipitate is filtered off. Get 13,45 g (98%) 17 - hydroxy-21-improvistion (VIIa) with so pl. 145oC, then cooled, precipitated precipitate is filtered off, washed on the filter with water. The residue is dissolved in methylene chloride, the solution lighten charcoal, evaporated to dryness. The residue is crystallized from acetone. Obtain 9.6 g (84%) 21 - acetoxy - 17-hydroxyprogesterone (I) so pl. 239-241oC.

1. The method of receiving corticosteroids General formula I

< / BR>
where R1- or IT is a group or atom N;

R2-N, or HE, or F, or instead of R1, R2- double bond; R3- N, or F, or CH3group; R4Is h or Oh-group; R5- or-CH3group or atom N; R6- H or AC,

namely, that pregnany General formula II

< / BR>
where R7and R8together keto-group, or unsubstituted, or 2-monosubstituted, or 2,2-disubstituted propranolol,

are galoidirovaniya C-21 position with subsequent substitution of the halogen by hydroxy or acetoxy group, characterized in that for obtaining pregnane as starting compounds are used 3,17 - diketonate General formula III

< / BR>
which is subjected to cyanidation, the protection of the 17-Oh group, the protection of 3-ketogroup with unsubstituted or 2-substituted the B. p. 1, characterized in that gorodilova carried out by direct iodination.

3. The method according to p. 1 or 2, characterized in that to protect the 17-Oh group using alkylvinyl ether.

 

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