JPS5816000A - Preparation of acyloxysteroid - Google Patents

Abstract

PURPOSE:To obtain the titled compound inexpensively useful as an intermediate for preparing adrenal cortical hormone, by reacting a 17-halogeneacetyl-17- acyloxysteroid with an alkali metal salt of a lower fatty acid in a polar aprotic solvent, etc. CONSTITUTION:A 17-halogeneacetyl-17-acyloxysteroid(e.g., 17alpha-hydroxy-21-iodopregna-1,4-diene-3,20-dione 17-acetate, etc.) having a partial structure shown by the formulaI(X is halogen; Y is acyloxy) is reacted with an alkali metal salt (e.g., potassium acetate, etc.) of a lower fatty acid in a polar aprotic solvent (e.g., N-methyl-pyrrolidone, etc.) and/or in the presence of polyethylene glycol, to give the desired 17-acyloxyacetyl-17-acyloxysteroid. A compound shown by the formula II (dotted line is a single bond or double bond), etc. may be cited as the compound shown by the formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing acroxysteroids useful as intermediates for producing adrenocortical hormones such as hydrocortisone and prednisolone.

Recently, androst-zhen-ene-3,17-dione and androst-7,#-diene-3,17-dione have been produced in large quantities and at low cost by microorganisms such as Mycobacterium from cholesterol or sitosterol sterols. In recent years, steroid drugs such as estrone, testosterone, and spironolactone have been produced from these raw materials.

On the other hand, adrenal corticosteroids (corticoids), which account for the majority of steroid medicines, are still stigmasterol.
'Logsterone is produced from diosgenin/A-dehydropregnenolone as an intermediate raw material or by a long process using bile acids as raw material.

The present inventors discovered not only the above-mentioned androstoderene-3,17-dione, androsta-/,41C-diene-3,17-dione, which has become available in large quantities and at low cost in recent years, but also In recent years, it has come to be produced by fermentation.
lm-hydroxyandrostoderene-J,/7-
We began research to develop a more economical method for producing corticoids using A, DO, -II, and C'lambda Shear 3./7-dione produced by Dione Color as a raw material.

As a result, corcyloxysteroids can be produced by the reaction route shown in the formula below (in the formula, one dotted line represents a single bond or a double bond, X represents an iodine or bromine atom, and I represents an acyloxy group): can be produced, for example, according to the reaction route shown in the reaction formula below.

The present invention has a partial structural formula (I) (wherein or)-logen, and Y represents an acyloxy group. ), the present method relates to a method for producing 17-nologen acetyl/7-acyl having
- Particularly useful when applied to acyloxysteroids. This is because 17 represented by general formula (III)
This is because #-7 syloxyacetofk-17α-acetyl steroids are obtained and serve as a good intermediate for the production of hydrocortisone and glednisolone.

(In the formula, the dotted line represents a single bond or a double bond, and Y and Z represent acyloxy groups which may be different.) For example, 17g
, col-dihydroxypregna-1, #-diene-3,
20-dione/7. ．． 2/-diacetate), /7a, J
/-dihydroxypregn-≠-ene-3,20-dione/7,2/-diβ acetate can be easily converted to gredonisolone and I-hydrocortisone, respectively, by hydroxyl fermentation at the / and /Jj positions.

Conventionally, it is well known that a halogen compound is reacted with an alkali metal salt of a lower fatty acid to replace a halogen atom with an acyloxy group. Then, /7α-hydroxy-21-iodopregn-q-ene-3,20-dione is easily reacted with potassium acetate in total acetone solvent, /7a, Jl-dihydroxypregn-μ-ene-3
, 20-dionol-acetate is obtained quantitatively.

However, for example, in a compound having an acyloxy group at the 17-position, such as /7α-hydroxy-l-iodopregn-en-3,20-dione 17-acetate,
Conventionally known methods do not react at all. That is, it was found that steric hindrance caused by the acyloxy group at the 17th position significantly hinders this type of reaction.

As a result of intensive research aimed at solving all of these problems, the present inventors found that the use of a certain type of solvent greatly increases the reactivity of acyloxyacetone, resulting in 17-halogenacetyl-
The present invention was achieved by discovering that the halogen atom of 1-fuacyloxysteroid was substituted with an acyloxy group.

That is, the present invention combines a 17-halogenacetyl-1-fuacyloxysteroid having the partial structural formula (I) (wherein X represents a halogen atom and Y represents an acyloxy group) and an alkali metal salt of a lower fatty acid into a polar By reacting in the presence of an aprotic solvent and/or polyethylene glycols, 17-aziloxyacetyl 77
- Examples of acylnaoxysteroids characterized by the production of acyloxysteroids include:

β /7g-bromoacetyl-77#-acetoxyandrostoderen-3-one, /7a-ρ bromoacetyl-17--acetoxyandrosterl
, goudien-3-one, /7a-iodoacetyl-1
7--acetoxyandroster/, t-diene-3-
on, 17po-hydroxy-λ/-7'rompregn-keyen-3,20-dione 17-acetate, 77α
-Hydroxy-+21-iodopregunderen-3
．． co-O-dione/7-acetate, /7a-hydroxy-2/-iodopregna-/, 4C-diene-3, co-O
-Dione 17-acetate, 17g-human. Ya, /-J
/-Yaw1. A,,-oh 7, evening (,8-3.ko-
Examples include dione 17-acetate.

The solvent used in the present invention is a polar aprotic solvent such as dimethylsulfoxide, dimethylformamide, dimethylacetamide, M-methylpyrrolidone, etc. When these solvents are used, the halogen atoms are replaced with acyloxy groups. The reaction temperature is below iooo<0>C, usually about ao-to<0>C. If the reaction temperature is too high, 7
The acyloxy group at the 7-position is removed, resulting in 21-acyloxypregn-/A-ene-3,20-diones, such as 21-acetoxypregn-Hiro,/4-diene-3,2
0-dione, 2/-F lyacetoxypregna-t,a,tA-hoen-3.2Q
-Unfavorable because dione etc. are produced as by-products. Furthermore, since the target product, 17-acyloxyaceto-17-acyloxysteroids, also gives the above-mentioned by-products, a long reaction time is not preferred. Usually the conversion rate of raw materials is tO~2
It is preferable to stop at 7%, preferably in the range of 11 to 1. N-methylpyrrolidone and dimethylacetamide are preferable because they produce less by-products even at high conversion rates.

The second type is polyethylene glycols. Polyethylene glycol, polyethylene glycol monomethyl ether, polyethylene glycol dimethyl ether, etc. have a molecular weight of 200~/! 00. Preferably, those of 300 to too are used. Some of these polyethylene glycols are solid, and in that case, they can be used by mixing them with a suitable solvent such as N-methylpyrrolidone dimethylacetamide or dimethylformamide.
Even when the steroids are not dissolved, they can be used by mixing them with a suitable solvent that dissolves them. The reaction temperature is usually 1o
-to°C, preferably λo -so°C.

Examples of the alkali metal salts of lower fatty acids of the present invention include sodium formate, sodium acetate, potassium acetate, potassium propionate, etc., and potassium acetate is most preferred.

This will be explained in more detail by giving examples below.

Example 1 17m-human 0roxy λl-brompregna-/, 4
A-diene-3, co-O-dione 17-acetate 1.2
3g, potassium acetate 2. J/77, dimethylformamide JO- is stirred at 60°C for 7 # hours. Water-00m K
- If added, crystals will precipitate.

- When filtered and dried, /, j/1gr crystals are obtained.

When recrystallized λ times from octane-tetrahydrofuran, o
, r3zg/7e1@col-dihydroxypregna-
7,4L-diene-3,λO-dione/7,2/-diacetate is obtained.

NMR spectrum (apex,) ippm: o, to (s, 3H), z, 0A (8, J
H)2,/λ(S, JH),λ,ko2(El,jH)g,,r J (q%koH),t,/2(8,Hari t
, or<d, iH), 7. /J (d, /H) Example The reaction was carried out in exactly the same manner as in Example 1 except for the co-solvent and reaction temperature, and the reaction product 1 was analyzed by liquid chromatography.

Example 3 /7a-hydroxy-21-iodrugnar-/, goudien-3,λO-dione 17-acetate, 01gr
% potassium acetate, zzg, polyethylene glycol monomethyl ether (molecular weight 4'00) 21m, M-
The mixture of methylpyrrolidone/J- is stirred at 0° C. for 13 hours. The reaction solution is added dropwise to t-4 cool L of water. When the precipitated crystals were filtered and dried, 3.22 g of crude 17α1 was obtained.
．． 21-dihydroxypregna-/, $-diene-3,
λO-dione/7. J/-diacetate is obtained. According to analysis by liquid chromatography, the purity is to, t3
In %;l;b.

Applicant: Mitsubishi Chemical Industries, Ltd. Agent Patent Attorney Hase - 1 other person

Claims (2)

[Claims] (1) A 17-halogenacetyl-1-fuacyloxysteroid having the partial structural formula (I) (wherein, X represents a halogen atom and ! represents an acyloxy group) and an alkali metal salt of a lower fatty acid are combined into 1 reaction in the presence of a tonic solvent and/or polyethylene glycols, 17-aziloxyacetyl-17
- A method for producing an acyloxysteroid, which comprises producing an acyloxysteroid tube. (2) In claim 1, the 17-haloJgenacetyl-77-acyloxysteroid has the general formula (II) (wherein, the dotted line represents a single bond or a double bond, and ! represents an iodine or bromine atom. 17-aziloxyacetyl-77-acyloxysteroid is a steroid represented by the general formula (to) (in the formula, the 9 dotted line represents a single bond or a double bond, !, 2 represents an acyloxy group which may be different.