JPS5919558B2 - Method for producing 3-substituted-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing 3-substituted-17α-1(3-hydroxypropyl)-17β-hydroxyandroster 3|5-dienes.

More specifically, the present invention provides 3-(3-oxo-7α-acetylthio-17β-hydroxyandrost 4-en-17α-yl)proviolactone (hereinafter abbreviated as spironolactone), which is useful as an anti-aldosterone diuretic and an antihypertensive agent.

) 3-substituted-17α-(3-hydroxypropyl)-17β-hydroxyandroster 3,
The present invention relates to a method for producing 5-diene. 3 obtained by the method of the present invention
-Substituted-17α-(3-hydroxypropyl)-17
Spironolactone can be produced by the method illustrated below using β=hydroxyandroster 3,5-diene as a raw material.

As a method for producing spironolactone, a method using 3β-hydroxyandrost-5-en-17-one as a starting material is known.

According to this method, 3β-hydroxyandrost-5-
En-17-one is ethynylated, reacted with carbon dioxide to form a propiolic acid derivative, and then hydrogenated to form an acrylic acid derivative. The acrylic acid derivative was further acid-treated to give 3-(3β,17β-dihydroxyandrost-5-en-17α-yl)acrylolactone, which was hydrogenated to give a saturated lactone, and then Otzpenauer monoxidized to give 3- (17β-hydroxyandrost-4
-en-3-one-17α-yl)propioclactone.

(J.A. Cella, E-A-BrOwnandR-
R-Burther; J・0rg. Chem. ,247
43 (1959)) Furthermore, the 6- and 7-positions of the obtained 3-(17β-hydroxyandrost-4-en-13-one-17α-yl)-propiolactone were dehydrogenated, and this and thioacetic acid were The reaction produces spironolactone.
(J.A. Cella and R.C. Tweit: J.
Org. Chem. ，? 1109 (1959)) The disadvantages of the above-mentioned method are the use of 3β-hydroxyandrost-5-ene-17-one as the starting material and the extremely large number of steps. In particular, 3β
-Hydroxyandrost-15-en-17-one is manufactured using diosgenin extracted from the roots of dioscorea (a type of mountain tuber) that grows wild in the mountains of Mexico through a complicated six-step process. Combined with the difficulty of cultivating wild potatoes, they are becoming extremely expensive.

On the other hand, in recent years, a method has been developed to produce androsta-1,4-diene-3,17-dione at low cost by microbial oxidation of steroids such as cholesterol obtained from wool grease and fish oil, which can be recovered in large quantities from wool washing wastewater. being developed.

The object of the present invention is to produce an important intermediate of spironolactone using inexpensive androsta-1,4-diene-3,17-dione instead of expensive 3β-hydroxyandrost-5-ene-17-one. The 3-substituted -17α-
An object of the present invention is to provide a simpler method for producing (3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene.

A method for producing 3-(17β-hydroxyandrost-4-en-3-one-17α-yne)propiolactone from androsta-1,4-diene-3,17-dione is already known. There is.

For example, in Japanese Patent Application Laid-Open No. 50-30861, androsta-1,4-diene-3,1
Reacting 7-dione 6 with 2-propyn-1-ol,
The resulting 17α-(3-hydroxypropynyl)-17
β-Hydroxyandrosta-1,4-dien-3-one 8 was hydrogenated in the presence of a complex catalyst to give 17α-(3-
Hydroxypropyl)-17β-hydroxyandrost-4-en-3-one C) was obtained, which was oxidized with chromic acid to give 3-(17β-hydroxyandrost-4-en-3-one-17α-yl). ) A method for producing pyropiolactone 9 is described. In addition, the same publication also states that from androst-4-ene-3,17-dione to 3-(17
β-Hydroxyandrost-4-ene-3-one-1
A method for the preparation of 7α-yl)propiolactone is described. According to it, Androst 14L-En1 3,17-
The dione is reacted with 2-propyn-1-ol to form 17α
-(3-Hydroxypropynyl)-17β-hydroxyandrost-4-en-3-one was obtained, which was further hydrogenated under pressure using tris(triphenylphosphine)rhodium chloride as a catalyst. Pino(ha)-17β-hydroxyandrost-4-en-3-one was obtained, which was oxidized with Johns reagent to give 3-
(17β-hydroxyandrost-4-en-3-one-17α-yl)propiolactone is obtained. The present inventors have developed a more economical method compared to these conventional methods.
As a result of intensive research on the production method of 7α-(3-hydroxypropyl)17β-hydroxyandrost-4-ene-3-one, we found that using dialkylborane with large steric hindrance,
Hydroboration of 3-monosubstituted 17α-allyl-17β-hydroxyandrost-3,5-diene yields 17α-(3-hydroxypropyl)-17β-hydroxyandrost-4-en-3-one in high yields. The present invention was achieved based on the discovery that the present invention can be obtained at a high rate. The gist of the present invention is the following general formula (1) (in the above formula, R1 and R2 and R3 and R4
are bonded together to form a ring, and -R1-R2- and -R3-R4- represent an alkylene group having 20 or less carbon atoms.

) using the following general formula 01) (in the above formula, Y usually represents an alkoxy group having 10 or less carbon atoms).

) 3-substituted-17α-allyl-17β-hydroxyandrosta-3,5-diene is hydroborated to form the following general formula (in the above formula, Y is As defined.

) 3-substituted-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3
, 5-diene.

3-substituted-17α-allyl-1, which is a raw material for the method of the present invention
7β-hydroxyandrosta-3,5-diene can be produced from androsta-1,4-diene-317-dione by the method shown in the reaction formula below. Androst-4-ene-3,17-dione old can be produced by hydrogenating androst-1,4-diene-3,17-dione (auto) in the presence of a suitable hydrogenation catalyst. .

As the hydrogenation catalyst, for example, a catalyst in which ruthenium or rhodium is supported on activated carbon, and a metal hydride of a complex compound such as tris(triphenylphosphine)rhodium chloride can be used. (C- DjelssiandJ・
Gutzwiller, J. Am. Chem. SOc.
, 884537 (1966)) Androst 1 4 -
From en-3,17-dione [F], 3-substituted-17
α-allyl-17β-hydroxyandrosta-3,
To produce 5-diene (), the carbonyl group at the 3-position of androst-4-ene-3,17-dione [F] is protected, and then an allylating reagent is reacted to form a 3-substituted androstane. The 17th position of -3,5-diene-17-one [F] is selectively allylated.

Methods for protecting the carbonyl group at position 3 include enamination,
Known methods such as enol etherification are applied.

For enamination, secondary amines such as dimethylamine, diethylamine, morpholine, piperidine, and pyrrolidine are used. For enol etherification, orthoesters such as orthoformate, orthoacetate, and orthopropionate, acetals such as dialkoxypropane, dialkoxybutane, and dialkoxycyclohexane, alcohols such as benzyl alcohol, and phenylmethane are used. Thiols such as thiol are used.

Among the above protection methods, enol etherification is simple and has a high yield, and following the protection of the carbonyl group at the 3-position,
The resulting 3-substituted-androsta-3,5-diene-17-one V) is allylated.

The simplest allylation method is a method using Grignard reagent.

In this method, the 3-substituted-androsta-3,5-dien-17-one [F] is converted into a Grignard reagent XMgCH
Reacts with 2CH=CH2 (X is Br or Cl). The Grignard reagent may be synthesized in advance or may be synthesized substantially within the reaction system. [Another allylation method is using the lithium compound LiCH2CH=CH2.

As in the case of the Grignard reagent, the lithium compound may be synthesized in advance or may be synthesized substantially within the reaction system. Next, the obtained 3-substituted-17α-allyl-17β-hydroxyandrosta-3,5-diene () is subjected to hydroboration.

It is known that the intracyclic double bonds and side chain double bonds of steroids are hydroborated.

Japanese Patent Publication No. 46-12121 discloses 17α-allyl-13
, 17β-dihydroxyandrost-5-ene G) to obtain 17α-(3-hydroxypropyl)-3,17β-dihydroxyandrost-5-ene I.

Also, M. Nussium et al., J. Org. Chem. ”
” 1120 is Cholest 1 4 - En 1 3 - On a
), cholestane-3β,
It is disclosed that 4α-diol (auto) can be obtained.

However, the above document discloses that 3-substituted-17α-allyl-17β-hydroxyandrosta-3,5-diene by hydroboration of the method of the present invention.
It goes without saying that this does not imply conversion to -(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene. That is, 3-substitution-
17α-allyl-17β-hydroxyandrosta-1
The above literature does not suggest that the double bond of the side chain undergoes selective hydroboration by hydroboration of 3,5-diene.

1 disclosed in the above-mentioned Japanese Patent Publication No. 46-12121
In the hydroboration of 7α-allyl-3,17β-dihydroxyandrost-5-ene, the double bond in the side chain undergoes hydroboration because the double bond in ring B is larger than that in ring A. This is because it is more inert.

Also, the above J. Org. Chem. Z? 1120 teaches that the double bond in the A ring undergoes hydroboration. Thus, the above document shows that the double bond of ring A can undergo hydroboration by the usual hydroboration of 3-monosubstituted-17α-allyl-17β-hydroxyandrosta-3,5-diene. However, by using a dialkylborane with large steric hindrance, the present inventors succeeded in suppressing only the side chain double bond of 3-monosubstituted-17α-allyl-17β-hydroxyandrosta-3,5-diene. It was found that hydroboration can be selectively performed.

The dialkylborane used in the method of the present invention is represented by the above general formula (1).

A specific dialkylborane is 9-borabicyclo(
3,3,1) nonane, 3,5-dimethylpolynandicyclohexylborane, diisopinocampheylborane, cyclohexylthexylborane, dicyamylborane, and the like. Hydroboration is performed, for example, as follows.

Sodium borohydride and cyclohexene are placed in dry tetrahydrofuran, and boron trifluoride ethyl etherate is added dropwise while maintaining the temperature at -10 to -5°C to produce synchlohexylborane.

Then, a steroid boron compound is produced by reacting a dry tetrahydrofuran solution of 3-monosubstituted-17α-allyl-17β-hydroxyandrosta-3,5-diene () with synchohexylborane at 0 to 40°C. All operations are performed in an inert gas atmosphere, and the solvents used are tetrahydrofuran and diglyme (
Dimethyl ether of diethylene glycol) is preferred. Also, in the process of synthesizing synchhexylborane, diethyl ether is not a suitable solvent because sodium borohydride is poorly soluble in diethyl ether;
Diethyl ether can be used satisfactorily as a solvent in the operation of reacting synchhexylborane once produced with a steroid. The method for synthesizing hydroboration reagents such as synchhexylborane does not necessarily require the above operations.

Synchronohexylborane can also be synthesized by dissolving cyclohexene in ether and absorbing and reacting diborane, and it is also possible to use lithium borohydride instead of sodium borohydride. be. In addition, sodium borohydride and zinc chloride are reacted in ethyl ether to produce Zn(BH2)2,
By sequentially adding cyclohexene and boron trifluoride ethyl etherate, synchlohexylborane can also be obtained in ether. Next, the obtained steroid boron compound is converted into 3-substituted-17α-(3-hydroxypropino(ha)-17β-hydroxyandrosta-3,5-diene).

This operation can be performed as follows.

The steroid boron compound dissolved in the organic solvent is not removed, and a dilute alkaline aqueous solution and aqueous hydrogen peroxide are sequentially or simultaneously added to this solution at an appropriate rate. After this, the generated 3-substituted-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene ([) is extracted and separated with an organic solvent such as tetrahydrofuran, and the solvent is distilled off to generate the Obtain crystals of product (1).These crystals may be recrystallized with a solvent such as methanol-ether and used as a pure product as a raw material for subsequent steps, but they may be used as raw materials for subsequent steps without recrystallization. It can also be used as a raw material.

It can also be used as a raw material for subsequent steps without extraction and separation. As described above, 3-monosubstituted-17α-(3-hydroxypropyl) obtained by the method of the present invention
-17β-hydroxyandrosta-3,5-diene is used as a raw material for spironolactone.
β-Hydroxyandrost-4-ene-3-one-1
7α-yl)propiolactone can be produced.

First, in order to remove the protecting group for the carbonyl group at the 3-position, the above product (l) is brought into contact with an acidic catalyst.

As the acid, in addition to mineral acids such as hydrochloric acid, sulfuric acid, and nitric acid, organic acids such as p-toluenesulfonic acid and acetic acid can be used. Other acidic resins can also be used. Next, the obtained 17α-(3-hydroxypropyl)-17β-
Hydroxyandrost-4-ene-3-one is oxidized to form a lactone ring.

For this purpose, oxidation with hexavalent chromium such as chromium trioxide is particularly suitable. Water, acetone, acetic acid, etc. are used as the oxidation solvent, but a two-component system or a three-component system selected from these may also be used.

When adding chromium trioxide, an appropriate amount of concentrated sulfuric acid is present. As described above, since the present oxidation reaction is carried out in the presence of sulfuric acid, the removal of the protecting group of the carbonyl group at the 3-position and the oxidation can be carried out simultaneously. Furthermore, as described above, an acid was added without isolating the 3-monosubstituted-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene to remove the protecting group of the carbonyl group at the 3-position. It is also possible to produce 3-(17β-hydroxyandrost-4-en-13-one-17α-yl)propiolactone by separating the mixture and oxidizing it by adding chromium trioxide and concentrated sulfuric acid. After the oxidation reaction is complete, a small amount of methanol is added to reduce the remaining chromium trioxide to make it insoluble.20 This is then removed by p-filtration, extracted and separated with an appropriate organic solvent, and then The solvent is removed under reduced pressure and the resulting residue is recrystallized from an organic solvent such as benzene to yield pure 3-(17β-hydroxyandrost-4-en-3-one-17α-yl)pro25piolactone. is obtained.

EXAMPLES The present invention will be specifically described below with reference to Examples, but the present invention is not limited to the following Examples unless it exceeds the gist thereof.

Example 30 (
A) Production of 3-ethoxy-17α-allyl-17β-hydroxyandrosta-8,5-diene Metal magnesium 1.759 and tetrahydrofuran 12TfL1 were charged in a four-necked flask, and under nitrogen atmosphere and stirring at room temperature, a dropping funnel was added. A solution consisting of 3.519 9 of 3-ethoxyandrosta-3,5-dien-17-one, 5.25 Tn of allyl bromide and 30 ml of tetrahydrofuran is added dropwise into a four-necked flask over a period of 2 hours.

60 after completion of 40 drops
Continue stirring for 1 hour and 30 minutes at °C. After the reaction is completed, excess metallic magnesium is separated from the reaction solution by decantation, and the excess Grignard reagent is decomposed using ice chips and a saturated ammonium chloride aqueous solution under ice cooling.

Thereafter, 50Tn1 of tetrahydrofuran was added, and tetrahydrofuran extraction was performed using a separatory funnel.

At this time, the aqueous layer is saturated with good salt. The organic layer is washed with an aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate overnight. After removal of the solvent, an oily product of 4.099% was obtained. A portion of this was purified using a silica gel column with benzene-tetrahydrofuran (85:
15) was developed with a mixed solvent to obtain crystals.

Melting point: 93.5-95°C, molecular weight by mass spectrometry: 3
56, the infrared absorption spectrum also shows that this is 3-ethoxy-
17α-allyl-17β-hydroxyandrosta-3
, 5-diene. 03-Ethoxy-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene Sodium borohydride 138Tf9 in a nitrogen stream in a four-bottle flask,
3.2 ml of tetrahydrofuran and 0 cyclohexene
．． 749 was charged and stirred to obtain a white slurry.

Next, while maintaining the bath temperature at -10 to 5°C, 0.699 g of boron trifluoride ethyl etherate was added dropwise over 15 minutes.
When stirring was continued for 30 minutes at 0° C. after the completion of the dropwise addition, the formation of crystals of synchhexylborane was observed. Then 0℃～1
Stirring was continued at 0°C for 1 hour and then at 20°C for 1 hour.

Then, a solution of 428 η of 3-ethoxy-17α-allyl-17β-hydroxyandrosta-3,5-diene dissolved in 3.5 ml of dry tetrahydrofuran was added dropwise at 10° C. over 15 minutes.

After the addition, stirring was continued at 10°C for 40 minutes, 20°C for 1 hour, and 40°C for 20 minutes, then 1.4TfL1 of a 3N caustic soda aqueous solution was added dropwise under cooling, followed by 30% peroxidation at 5°C or below. Hydrogen water was added dropwise. After the dropwise addition was completed, stirring was continued for 25 minutes at 20°C and further for 30 minutes at 40°C. After the reaction is complete, perform tetrahydrofuran extraction using 30 WLI of tetrahydrofuran (the aqueous layer is saturated with good salt).
Two drops of pyridine were added to the organic layer. Furthermore, this tetrahydrofuran layer was washed three times with saturated negative brine, and then dried over magnesium sulfate overnight.

After drying, the solvent was distilled off to obtain 1.08 g of white crude crystals. The white crude crystals were recrystallized using a mixed solvent of methanol and diethyl ether.
After obtaining crystal 44-19, the recrystallized mother liquor was subjected to preparative thin layer chromatography.

Developed on a silica gel plate using a mixed solvent of benzene-tetrahydrofuran (4:1), and extracted 113% from the mother liquor.
~ was recovered.

Combining this and the first and second crystals above, 3731RIy
crystals were isolated. This substance has a melting point of 159-161℃
, molecular weight 374 according to mass spectra, 3-ethoxy-17α-(3-hydroxypropyl)-17β-hydroxyandrosta-3,5-
It was confirmed that it was Jien. C3-(17β-hydroxyandrost-4-ene-13-one-17
α-yl)propiolactone 3-ethoxy-17α-(
To a solution of 824 g of 3-hydroxypropyl)-17β-hydroxyandrosta-3,5-diene dissolved in 10" of tetrahydrofuran, 2 g of a 4% aqueous hydrochloric acid solution was added, and the mixture was stirred at room temperature for 40 minutes.

After the reaction, 10" of a saturated aqueous solution of potassium carbonate was added, and after stirring well, the tetrahydrofuran layer was separated. This tetrahydrofuran layer was washed three times with a saturated aqueous solution of common salt, and then dried using anhydrous magnesium sulfate.

After removing anhydrous magnesium sulfate by filtration, the organic layer was removed under reduced pressure to obtain viscous material 721.

When this is recrystallized using benzene, the melting point is 163.3 ~
Crystals at 164.8°C were obtained. The crystals were dissolved in 90 g of acetone and cooled to 0.degree. While thoroughly stirring the contents, 0.74 g of a solution prepared by diluting 27 g of chromium trioxide and 25 mj of concentrated sulfuric acid to 100 g with water was added dropwise over 10 minutes. After the dropwise addition, stirring was continued for another 30 minutes, and then methanol was added five times to reduce remaining unreacted hexavalent chromium and stop the reaction.

The green trivalent chromium compound precipitated in the reaction solution was removed by phosphorus filtration, the slurry was concentrated, acetone was removed, and benzene was added to dissolve the concentrate. This was washed with a 3% aqueous potassium carbonate solution, and the benzene layer was separated. Benzene was removed from this benzene layer to obtain a white solid, which was further purified by thin layer chromatography, and NMR and infrared spectra showed that it was 3-(17β-hydroxyandrost-4-ene-1). It was confirmed to be 3-one-17α-yl)propiolactone.

Claims (1)

[Claims] 1 The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the above formula, R_1 and R_2 and R_3 and R_4 are respectively combined to form a ring, and - R_1-R_2- and -R_3-R_4- represent an alkylene group having 20 or less carbon atoms. ) Using the dialkylborane represented by, the following general formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) (In the above formula, Y represents an alkoxy group.) The following general formula is characterized in that 3-substituted-17α-allyl-17β-hydroxyandroster-3,5-diene is used as a hydroboration. (III)▲
There are mathematical formulas, chemical formulas, tables, etc.▼ (In the above formula, Y is as defined in the above general formula (II). 3-substituted-17α-(3-hydroxypropyl)-17β-hydroxy represented by A method for producing androsta-3,5-diene.