JPH01156994A - Production of 21-acyloxy-20-keto-delta16-stroid - Google Patents

Abstract

PURPOSE:To economically obtain the title steroid useful for synthesizing anti- inflammatory adrenocortical steroids in high yield in a short process, by oxidizing a steroid having a specific partial structural formula and then isomerizing the resultant product. CONSTITUTION:(A) A steroid having a partial structural formula I is brought into contact with a platinum group compound catalyst in the presence of, e.g., oxygen, and oxidized to provide (B) a steroid having a partial structural formula II, which is then treated with an isomerization catalyst, such as metallic salt of a carboxylic acid, in an organic polar solvent (e.g., ethyl acetate), etc., to afford the aimed steroid having a partial structural formula III.

Description

Detailed Description of the Invention (Industrial Field of Application) The present invention provides 21-acyloxy-20-keto-delta 1
Regarding the new method for producing 6-steroids, more specifically, using 17α-ethynyl-17β-acyloxysteroids as a raw material, 20-acyloxy-17(20)
- A method for producing 21-acyloxy-20-keto-delta 16-steroids via methylene-21-al.

(Prior art) Conventionally, 21-acyloxy-20-keto-delta 16-
Steroids are known as key intermediates for the production of corticoids, which are important as pharmaceuticals.

Such 21-acyloxy-20-keto-delta 16-
Research on the synthesis of steroids has been actively conducted, for example, 21-acyloxy-20-keto-17α-
A method for producing 16-unsaturated steroids using hydroxysteroids as a raw material is known (US Pat. No. 38
No. 39369, No. 3493563, No. 36310
76 etc.). However, since this method uses the expensive corticoid itself as a raw material or "intermediate," there is a problem in industrially producing 21-acyloxy-20-keto-delta 16-steroid at a low cost.

(Problems to be Solved by the Invention) The present inventors have conducted intensive research to solve the above-mentioned problems, and as a result,
17α-ethynyl-17β-, which can be easily obtained from 17-kedosteroids that have recently become available at low cost.
Using acyloxysteroid as a raw material, it is oxidized to produce 20-acyloxy-17(20)methylene-
21- After making alsteroid, if isomerized, the desired 2
It was discovered that 1-acyloxy-20-keto-delta-steroids can be obtained economically and in high yield in a short process, and based on this knowledge, the present invention was completed.

(Means for Solving the Problems) Thus, according to the present invention, a steroid having a partial structural formula (I) is oxidized to a steroid having a partial structural formula (II), and then isomerized. A method for producing a 21-acyloxy-20-keto-delta 16-steroid having the partial structural formula (I) is provided.

(In the formula, R is a hydrocarbon residue, - is the steric configuration of the acyloxy group and formyl group bonded to the 20-position atom, EW, Z
The steroid used as a raw material in the present invention is a 17α-ethynyl-17β-acyloxysteroid having the above partial structural formula (I), which has the 17th position of the 17-ketosteroid. It can be obtained by acylating the 17β-hydroxyl group after subjecting it to 17α-ethynyl-17β-hydroxysteroid by a conventional method.
No. 8695, Journal Otsuogani, Kuchemistry, VoL 44. P 1582-1584゜1
979, etc.).

In the partial structural formula (I), R forming the acyloxy group moiety is not particularly limited as long as it is a hydrocarbon residue. Specific examples include alkyl groups such as methyl, ethyl, propyl, isobutyl, butyl, isobutyl, hexyl, octyl, and decyl; alkenyl groups such as allyl and brenyl; phenyl group,
Examples include aryl groups such as benzyl groups, and among them, alkyl groups having 5 or less carbon atoms are preferred.

17α-ethynyl-1 having such partial structural formula (I)
For example, 7β-acyloxysteroid is a steroid compound represented by the following structural formula.

In the present invention, the steroid skeleton may be a steroid in which the A ring has an aromatic nucleus, such as mestranol, or a 19-norsteroid, such as 19-norethisterone.

Furthermore, steroids having a carbonyl group at the 3-position may be protected in the acetal, enol, or enamine type. Furthermore, a hydroxyl group at the I-, 6-, 11-position, 11
Keto group at position 6-. Fluorine atom at 9-position, 1-. 6-.
A substituent such as a methyl group at the 16-position may be substituted.

Specific examples of such 17α-ethynyl-17β-acyloxysteroids include, for example, 17α-ethynyl-1
7β-acyloxy-androst-4-en-3-one, 17α-ethynyl-17β-acyloxy-androst-1,4-dien-3-one, 17α-ethynyl-17β-acyloxy-androsta-4,9 (I1
) Dien-3-one, 17α-ethynyl-17β-acyloxy-androsta-1,4,9(I1)-trien-3-one, 17α-ethynyl-17β-acyloxy-3β-acetoxy-androsta-5- Examples include two.

In the present invention, first, the raw material having the partial structural formula (I) is oxidized to obtain a steroid having the partial structural formula (II). The oxidation reaction is carried out, for example, by bringing the raw material into contact with a platinum group compound catalyst in the presence of oxygen or peroxide.

When using oxygen as an oxidizing agent, the partial pressure of oxygen in the reaction system is usually 0.1 to 1 atm, and if necessary, the reaction may be carried out in a mixed gas atmosphere with an inert gas such as nitrogen. Can be done.

The peroxides used are peracetic acid, performic acid, perbenzoic acid,
Peracids such as methachloroperbenzoic acid, moseperphthalic acid, trifluoroperacetic acid, tart-butyl hydroperoxide, hydrogen peroxide, hydrogen peroxide solution, beloquinosulfuric acid,
Alkyl hydroperoxides such as cumene hydroperoxide, dialkyl oxides such as di-tert-butyl peroxide and dicumyl peroxide, diacyl peroxides such as benzoyl peroxide, di-p-chlorobenzoyl peroxide, diisopropyl percarbonate, and perbenzoic acid 7 ,, 7”-tert-shunter, peracid ester such as di-tert-methyl peracetate, sodium hypochlorite, sodium hypobromite, sodium hypoiodite, potassium hypochlorite, chlorite Sodium, sodium bromite, potassium iodite, potassium chlorite, sodium chlorate, sodium bromate, perchloric acid, sodium perchlorate, periodic acid, periodic acid), halogen acids such as IJium, etc. can be mentioned.

The amount of peroxide to be used is appropriately selected, but usually 1 to 10 mol of peroxide, preferably 1 mol per mol of raw material.
~5 mol.

The platinum group metal compound catalyst used is a salt or complex of palladium, ruthenium, platinum, rhodium, etc., and specific examples include palladium chloride, palladium bromide, palladium iodide, dichlorobis(acetonitrile), etc.
Palladium, dibromo bis(acetonitrile) radium, dichlorobis(benzonitrile) radium,
dibromobis(R-zonitrile)/4'radium, palladium(n) chloride sodium, palladium(II) chloride
Potassium, palladium (■) sodium bromide, palladium (II) bromide potassium bromide radium (II) lithium, palladium nitrate, radium sulfate, radium acetate, potassium hexachloroplatinate, rhodium chloride,
Examples include ruthenium chloride. Among the platinum group metals, palladium is preferred in terms of reactivity, and divalent palladium halide is particularly preferred.

The amount of the platinum group metal compound catalyst to be used is selected as appropriate, but is usually at a ratio such that the platinum group metal compound catalyst is 0.01 to 10 moles, preferably 0.1 to 5 moles, per 100 moles of the raw material. used in

In the reaction, a copper compound may be present as a cocatalyst, and specific examples include cupric chloride, cupric bromide, cupric acetate, cupric iodide, cupric formate, etc. Can be mentioned.

These promoters are usually used in a ratio such that the copper compound is 0.1 to 50 moles, preferably 0.1 to 5 moles per 100 moles of the raw material, and their use improves the activity of the reaction. be able to.

In the present invention, it is preferable to carry out the oxidation reaction in the presence of an acid in order to improve reactivity and yield.

Specific examples of such acids include formic acid, acetic acid,! low off 2
Examples include organic acids such as %/4radluenesulfonic acid and inorganic acids such as hydrochloric acid, hydrobromic acid, and hydrogen iodide. Among these, formic acid and hydrobromic acid are prized for their reactivity.

The amount of such acid to be used is appropriately selected, but it is usually 0.01 to 10 mol, preferably 0.0 mol per mol of the raw material.
The optimum amount of the acid used varies from 1 to 5 moles.

Further, a diluent may be present during the reaction, and specific examples thereof include nitriles such as water, niacetonitrile, zolobionitrile, benzonitrile, dimethylformamide, diethylformamide, dimethylacetamide, N- Amides such as methylpyrrolidone; Ethers such as tetrahydro-7rane, dioxane, diptyl ether, ethylene glycol dimethyl ether; Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone; ethyl acetate, propyl acetate, methyl propionate. Esters such as methanol, ethanol, clopanol, t@rt-tutanol, diethylene glycol monoethyl ether, etc. Sulfoxides such as dimethyl sulfoxide, diethyl sulfoxide, etc. Organic solvents such as benzene, toluene, xylene, etc. , or a mixed solvent of these and water, among which nitriles, amides, and ethers are particularly preferred.

These diluents are generally used in such a proportion that the concentration of the raw material is 1 to 50% by weight, and their use can improve reaction activity and catalyst stability.

The reaction temperature is usually 0°C or higher, preferably 20 to 100°C, and the reaction time is usually 5 minutes to 30 hours.

After the reaction is completed, if necessary, the target product is separated from the reaction solution by conventional methods such as solvent extraction, distillation, recrystallization, column chromatography, etc. to obtain the partial structural formula (I
20-acyloxy-17(20)-methylene-21-flusteroids with I) can be obtained in high purity, but especially! -f! It is also possible to proceed to the next step without manufacturing.

20-acyloxy-17(20)- thus obtained
Methylene-21-fluosteroid has an acyloxy group bonded to carbon position 20 and a polmyl group with a configuration of 8.
For example, the 7-syloxy group at the 20th position of the steroid shown in the structural formula below is a mixture of the 17β-position acyloxy group of the starting material 17α-ethynyl-17β-acyloxysteroid. It is.

For example, 17α-ethynyl-17β-acetoxysteroid yields 20-acetoxy-17(20)-methylene-21-alsteroid, and 17α-ethynyl-
20-inbutyryloxy-17(20)-methylene-21-al-steroid is obtained from 17β-benzotyryloxysteroid.

Also, 17-. 20-. The substituent and structure of the moiety removed from the 21-position are not particularly changed by this reaction, and a steroid retaining each partial structure is obtained.

In the present invention, next, 20-acyloxy-17(20)-methylene-21- having partial structural formula (II)
By isomerizing the flusteroid 0, the desired 21-acyloxy-20-keto-delta 16-steroid having the partial structural formula (I[l)] can be obtained.

Although the method of isomerization is not particularly limited, it may be carried out, for example, by treating the steroid having partial structural formula (II) with an isomerization catalyst in a polar organic solvent.

Examples of organic polar solvents include pyridine, N-methylpyrrolidone, dimethylsulfoxide, dimethylformamide, dimethylacetamide, acetonitrile, dimethoxyethane, tetrahydrol, methanol, ethanol, propyl, tsrt-sitanol, ethyl acetate, and acetic acid. Examples include propyl, among which dimethylformamide and ethyl acetate are preferred.

Specific examples of isomerization catalysts include metal salts of carboxylic acids and carbonates (for example, JP-A-48-86854), and strong non-nucleophilic bases.

Specific examples of carginic acid constituting the carcinic acid metal salt include lower aliphatic carbs with carbon atoms of about 5 or more, such as acetic acid, propionic acid, and butyric acid. acid, benzoic acid, p-
Aromatic carboxylic acids such as toluic acid are exemplified, and their salts include sodium salts, potassium salts, magnesium salts,
Examples include calcium salts and zinc salts. Among these, potassium acetate and zinc acetate are preferred.

A non-nucleophilic strong base has strong basicity to the extent that it pulls out hydrogen atoms bonded to carbon atoms without attacking positively charged carbon atoms. Specific examples thereof include, for example: , 1,5-diazobicyclo(:4.3.0)-non-5-ene, 1,8-diazobicyclo(5t4eO)
-undec-7-ene, 1,4-diazobicycloC2,
2,2:l-octane, tetrabutylammonium fluoride, tart-butoxypotassium, and the like.

The amount of the isomerization catalyst to be used for the steroid having the partial structural formula (II) is appropriately selected depending on the type of the steroid, and in the case of a strong base, it is usually 0.01 to 1 mole.

The reaction temperature varies depending on the isomerization catalyst and polar organic solvent.
It is carried out at a temperature of 0 to 150°C, preferably 30 to 100°C, and is usually completed in 1 to 12 hours.

When a strong non-nucleophilic base is used as an isomerization catalyst, it may be preferable because the reaction proceeds even with a simple process as described above, and it can be recovered by simple operations such as extraction. .

After the reaction is complete, the target product is separated from the reaction solution using conventional methods such as solvent extraction, recrystallization, column chromatography, etc. to obtain highly pure 21-acyloxy-20-
Keto-delta 16-steroids can be obtained.

The 21-acyloxy-20-keto-delta 16-steroid thus obtained is, for example, a steroid compound represented by the following structural formula.

The 7-syloxy group at the 21-position is obtained by rearranging the acyl group at the 20-position of the intermediate 20-acyloxy-17(20)-methylene-21-al-steroid to the 21-position. For example, from 20-acetoxy-17(20)-methylene-21-al-steroid, 21-acetoxy-
20-keto-16-steroids are obtained, and 20-isobutyryloxy-17(20)-methylene-21-al-steroids give 21-inbutyryloxy-20
- Keto-delta 16-steroids are obtained.

Also in this reaction, 17-. 20-. The substituent and structure of the moiety removed from the 21-position are not particularly changed, and a steroid retaining each partial structure can be obtained.

These 21-acyloxy-20-keto-delta 16
- Steroids are useful in the synthesis of many anti-inflammatory corticosteroids.

(Effects of the Invention) Thus, according to the present invention, 17α-ethynyl-17β-acyloxysteroid, which can be easily produced from inexpensive 17-ketosteroids, is used as a raw material to produce 20-acyloxy-17(20)-methyloxysteroid through an oxidation reaction. Ren-21
- By isomerizing the resulting alsteroid, 21-acyloxy-20-keto-delta 16-steroid can be produced in a short process, economically, and in high yield.

(Example) The present invention will be described in more detail with reference to Examples below.

Example 1 (I) 1 mmol of 17α-ethynyl-17β-isobutyryloxy-androsta-4,9(I1)-dien-3-one (4) in the reactor, 06 radium bromide/4
0.05 mmol of 48% hydrogen bromide solution, 0.01 mmol of 48% aqueous hydrogen bromide, and 5rILl of ethylene glycol dimethyl ether were added, and the mixture was stirred at 60° C. in the atmosphere for 2 hours.

After the reaction was completed, the reaction product was cooled with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to yield 20-isobutyryloxy-3-! Kisogregner 4.9 (I1), 17 (20)-) diene-
21-Al (B) was obtained in a yield of 90%.

(2) 20-isobutyryloxy-3-oxo-pregna-4,9 (I1) was then obtained in the reactor.

17 (20)-) diene-21-al(B)1 mi
15 mmol of potassium acetate, and 51 nl of dimethylformamide were added, and the mixture was heated and stirred at 60° C. for 8 hours under a nitrogen atmosphere. After the reaction was completed, the reaction product was cooled with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. When the residue was purified by silica gel chromatography, it was found that 21-inbutyryloxy-
Brebner-4,9(I1),16-)diene-3,20
-dione (C) was obtained in a yield of 90-.

Example 2 (I) An experiment was carried out in the same manner as in Example 1 (I) except that the steroid compounds shown in Table 1 were used as raw materials and the reaction was carried out for a predetermined period of time, and the reaction intermediate was produced in the yield shown in Table 1. I got it.

(2) Next, using each reaction intermediate obtained, the first
Example 1 (2) except that the reaction was carried out for the predetermined time shown in the table.
), the desired product was obtained in the yield shown in Table 1.

Example 3 1 mmol of 17α-ethynyl-17β-isobutyryloxy-androsta-4,9(I1)-dien-3-one, 0.05 mmol of radium bromide, 48
0.01 mmol of % hydrogen bromide water and 5 ml of dimethylformamide were added, and the mixture was stirred at 60° C. in the atmosphere for 2 hours. After the oxidation reaction was completed, without performing any isolation operation, the inside of the reactor was made into a nitrogen atmosphere, and 1.5 mmol of potassium acetate was added.
The mixture was heated at 60° C. for 9 hours. After the reaction was completed, the reaction product was cooled with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to yield 21-inbutyryloxy-Brebner-4 #9 (I1).

16-Doriene-3,20-dione was obtained in a yield of 83q6.

Example 4 An experiment was conducted in the same manner as in Example 1 except that zinc acetate was used instead of potassium acetate in Example 1 (2).
21-Imbutyryloxy-pregna-4,9(I1)
, 16-) diene-3,20-dione was obtained in a yield of 80.

Example 5 0.12 mmol of palladium ω) potassium bromide was added to a reactor, and 35% aqueous peroxide solution containing 9 mmol of hydrogen peroxide was added while stirring. Next, ethylene glycol dimethyl ether 5g was added, and 17α was added under a nitrogen stream.
-500ml of ethylene glycol dimethyl ether solution containing 3 mmol of 17β-inbutyryloxy-androsta-4,9(I1)-dien-3-one at 60°C.
The mixture was added dropwise over 10 minutes, and then reacted for 4 hours. After the reaction was completed, the reaction product was cooled with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give 20-inbutyryloxy-3-oxo-brebna-4,9(I1), 17(20)-triene-2
1-al was obtained with a yield of 74%.

Hereinafter, an experiment was conducted in the same manner as in Example 1 (2), and the results were as follows.
1), 16-) diene-3,20-dione was obtained in a yield of 90.

Reference Example 1 An experiment was carried out in the same manner as in Example 1 (I) except that a catalyst as shown in the second diagram was used instead of i4radium bromide and the reaction was carried out for a predetermined period of time, and 20-inbutyryloxy-3
-Oxo-pregna-4,9 (I1).

17(20)-)dien-21-al was obtained in the yield shown in Table 2.

Table 2 Experiment number Catalyst Reaction time Yield (hr) (a) Reference 1-1 Palladium chloride 12
40 Reference 1-2 Palladium Chloride (IO Sodium 10 60 Reference 1-3 Dichlorobis(acetonitrile) Palladium 12 60 Reference 1-4
Dichlorobis(benzonitrile) nogradium
12 70 Reference Example 2 10 mmol of formic acid was used in place of the 48% hydrogen bromide solution, and 0.05 ml of a copper compound such as No. 3 Coating was used as a cocatalyst.
An experiment was carried out in the same manner as in Example 1 (I) except that 20-isobutyryloxy-3-oxo-pregna-4 #9 (I1),
17(20)-trien-21-al was obtained in the yield shown in Table 3.

Reference Example 3 Instead of 48 thiobromide water, acid 1O as shown in Table 4 was used.
An experiment was carried out in the same manner as in Example 1 (I) except that mmol was used and the reaction was carried out for a predetermined time.
1), 17(20)-) diene-21-al was obtained in the yield shown in Table 4.

Reference Example 4 In place of ethylene glycol dimethyl ether, the fifth
An experiment was carried out in the same manner as in Example 1 (I), except that the solvent shown in Table 1 was used and the reaction was carried out for a predetermined period of time.
1) #17(20)-trien-21-al was obtained in the yield shown in Table 5.

Table 5 Reference Example 5 20-isobutyryloxy-3-oxo-pregna-4,9(I1), 17(20)-triene-2 in the reactor
1-al 0.26 mmol, dimethylformamide 2d
, the specified isomerization catalyst shown in Table 6 was charged, and the reaction was carried out under the specified conditions shown in Table 6 under a nitrogen atmosphere. After the reaction was completed, the same operation as in Example 1 (2) was carried out, and 2
1-impltyryloxygregner-4,9 (I1),
16-) Diene-3,20-noone was obtained in the yield shown in Table 6.

Claims (1)

[Claims] 1. Having a partial structural formula (III) characterized in that the steroid having the partial structural formula (I) is oxidized to produce a steroid having the partial structural formula (II), and then isomerized. 21
-Production method of acyloxy-20-keto-delta^1^6-steroid. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
(III) (In the formula, R is a hydrocarbon residue, ■ is an E-type configuration of the acyloxy group and formyl group bonded to the 20th carbon position, and Z
Indicates that either type is acceptable. )