JPS6115879B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 3,17-dihydroxypregn-5-
This invention relates to a method for producing en-20-yne. Specifically, the present invention relates to an improvement in the method for producing 3,17-dihydroxypregn-5-en-20-yne from androst-4-en-3,17-dione.

3β・17β-dihydroxypregn-5-en-20-yne (17α-ethynylandrost-5-
En-3,17-diol (hereinafter abbreviated as ETAD)
is useful, for example, as a raw material for producing spironolactone, a diuretic. Currently, ETAD is produced by ethynylation of 3β-hydroxyandrost-5-en-17-one (hereinafter abbreviated as DHA). However, due to the difficulty in obtaining diosgenin, which is a raw material for DHA, the future of the method for producing ETAD using DHA as a raw material is not bright.

It is also known that ETAD can be produced from androst-4-ene-3,17-dione (hereinafter abbreviated as 4AD), which is easily obtained by fermentation using sterols as a substrate. For example, journal
of American Chemical Society (J.
Am.Chem.Soc.) Vol. 81, p. 436 (1959, USA) describes the ethynylation of 4AD to form 17-hydroxypregn-4-ene-20-yn-3-one (17-
After acetylating the 3- and 17-positions, first reduce only the enol ester moiety at the 3-position, then remove the acetyl group at the 17-position. let me go
Obtained ETAD. However, the yield is only
It is 50%.

Furthermore, steroids having a 4-en-3-one type partial structure can be converted to 5-en-3-one type by treating with a strong base such as potassium t-butoxy or sodium amide and then contacting with an aqueous acetic acid solution. It has been reported that this will happen. [For example, Journal of Chemical Society (J.Chem.Soc.
) 2325 pages (1950, UK), Journal
of American Chemical Society Volume 85
See page 1538 (1963, USA) and Tetrahedron Letters, page 669 (1962, UK)] However, the yield is only about 80% at most. Moreover,
If a steroid having an ethynyl group such as ETN is similarly treated with a strong base, the ethynyl group at position 17 will be removed at a considerable rate. En-20-yn-3-one (17-ethynylandrost-5-en-3-one, hereinafter abbreviated as 5-ETN) cannot be produced in high yield.

In view of these circumstances, the present inventors conducted extensive research to develop a method for producing ETAD from 4AD with good yield, and arrived at the present invention.

That is, the gist of the present invention is to selectively ethynylate the carbonyl group at position 17 of 4AD by reacting 4AD with a metal acetylide in a reaction medium, and then reduce the pH of the reaction mixture with an alkali metal borohydride to a pH of 9 to 13. A method of manufacturing an ETAD is provided.

The present invention will be explained in detail below.

In the method of the present invention, 4AD is first reacted with a metal acetylide to selectively ethynylate the carbonyl group at position 17 of 4AD. Ethynylation is usually carried out in the presence of a hydrophilic organic solvent.

As the metal acetylide, alkali metal acetylides such as potassium acetylide, sodium acetylide, and lithium acetylide are used.

The hydrophilic organic solvent is preferably one that is stable during the subsequent reduction with an alkali metal borohydride, such as ether solvents such as tetrahydrofuran, dioxane, dimethoxyethane, diethoxyethane, and ethoxymethoxyethane, dimethyl sulfoxide, and dimethylformamide. and alcoholic solvents such as propanol, butanol and amyl alcohol, among which tetrahydrofuran and dioxane are preferred.

The reaction between 4AD and metal acetylide may be carried out by reacting 4AD with a metal acetylide produced in advance, or by reacting 4AD with an excess of a strong base and then blowing acetylene into the reaction mixture.

As the strong base, those that react with acetylene to produce metal acetylides are used, such as alkali metal alcoholates such as t-butoxypotassium and t-butoxysodium, and alkali metal amides such as sodium amide and potassium amide.

In this case, it is presumed that 4AD reacts with a portion of the strong base to form a carbanion, and the remaining strong base reacts with acetylene to form acetylide, which then reacts with the carbanion.

Among these methods, a method in which 4AD is reacted with a metal acetylide produced in advance is preferred in that the ethynylation reaction can proceed favorably.

The molar ratio of metal acetylide to 4AD is usually 1-100, preferably 2-20. If the amount of metal acetylide is too small, ethynylation of the carbonyl group at position 17 of 4AD will be incomplete. Furthermore, if the amount is too large, by-products such as diethinyl derivatives will increase, which is not preferable.

Although 4AD may be added to the reaction system as a solid, it is usually added as a solution in the above-mentioned solvent.

The temperature at which 4AD and metal acetylide are reacted is usually -50 to 50°C, preferably -30 to 30°C. Furthermore, if the reaction is carried out at a temperature below 20°C, products presumed to be intermediates may remain, reducing the yield. It is best to warm it up and hold it for 1 minute or more and 20 hours or less, preferably 5 minutes or more and 10 hours or less. In any case, if the reaction temperature is too low,
If the ethynylation of the carbonyl group at position 17 of 4AD becomes incomplete or the amount of intermediates produced increases, and if the reaction temperature is too high, the selectivity of the reaction will decrease, both of which are undesirable. Reaction time is 5 minutes to 20 minutes
The time is preferably 10 minutes to 10 hours.

When reacting 4AD with a metal acetylide, it is preferable to have acetylene present. That is, when 4AD is reacted with a metal acetylide, an alkali is liberated, but the liberated alkali tends to reduce the reaction yield. Therefore, it is preferable to convert the alkali into acetylide by converting the alkali into acetylide by having acetylene present in an amount equivalent to or more than the liberated alkali.

The amount of the hydrophilic organic solvent used is usually 5 to 500 ml, preferably 8 to 500 ml, per 1 g of metal acetylide.
It is 300ml. If the amount of solvent is too small, acetylide and product salts will precipitate, increasing the viscosity of the system and making the reaction difficult; if it is too large, the reaction rate will decrease, making it difficult for the reaction to proceed sufficiently. Neither is preferable because it may become difficult.

Further, among the hydrophilic organic solvents, the amount of the alcoholic solvent used is usually 20 or less, preferably 5 or less in molar ratio to the metal acetylide. If the amount of alcohol-based solvent is too large,
This is not preferred because it causes a decrease in the conversion rate of the ethynylation reaction and the rate of isomerization of double bonds to 5-ETN.

The reaction between 4AD and a metal acetylide can be carried out by a continuous method or a patch method.

When the reaction of 4AD and metal acetylide is carried out in a batch method, the addition time of 4AD to the reaction system is usually 20 minutes.
time, preferably from 5 minutes to 5 hours. If the addition time is too long, by-products such as diethynyl derivatives will increase, and if it is too short, dimers in which steroids are bonded to both sides of the ethynyl group will increase, both of which are unfavorable.

In the method of the present invention, 4AD is
After selectively ethynylating the carbonyl group at position 17 of 4AD by reacting with a metal acetylide, the pH of the reaction mixture is adjusted to 9-13, preferably 10-12. To bring the pH within this range, for example, there are two methods: diluting the reaction with water and reacting with an acid. When reacting with water alone, a large excess of water is required, which is impractical, so acids, especially weak acids, are used. It is preferable to use

Such weak acids are acids with a PKa of 2 or less,
Preferred weak acids include lower carboxylic acids such as acetic acid and oxalic acid, organic acids such as phenol, carbonic acid, boric acid, phosphoric acid, potassium dihydrogen phosphate,
Examples include inorganic acids such as sodium dihydrogen phosphate and acidic salts of inorganic acids, and in this specification, strong acids also refer to these acidic salts. Two or more of these weak acids may be used in combination, or they may be used as a mixed solution with a neutral salt, that is, a buffer solution.
The amount of weak acid may be sufficient as long as it can maintain the pH of the reaction mixture within the above range, and is usually at least 0.5 times the mole of the base such as metal acetylide used for ethynylation, or 100 times the amount of the weak acid.
It is not more than twice the molar amount, preferably 1.2 to 50 times the molar amount.

The reaction mixture of ethynylation is reacted with a weak acid to obtain PH
Those with a value of 9 to 13 are directly subjected to the next reaction with an alkali metal borohydride. Therefore, the reactant with the weak acid preferably contains enough water to dissolve the alkali metal borohydride added in the next step. Although it depends on the type of reaction medium for ethynylation, usually
Preferably, an aqueous weak acid solution containing 0.005 to 10 volumes of water, especially 0.01 to 5 volumes of water, is reacted with the reaction mixture.

The ethynylation reaction mixture may be reacted with a weak acid to a pH of 9 to 13 in one step, or once to a pH of 1 to 9.
and then adjust the pH to 9-13. PH is 1
If less than 13 or more than 13, the reaction product 5-
ETN readily isomerizes to ETN. At this stage
What becomes ETN will hardly become ETAD even if it is reduced in the next process.

In the present invention, the reduction of 5-ETN with an alkali metal borohydride is carried out at a pH of 9 to 13, where isomerization of 5-ETN does not occur and the reduction efficiency of the alkali metal borohydride is high. If the pH is less than 9, the alkali metal borohydride decomposes quickly and there is a lot of loss, and at the same time, a large amount of hydrogen is released at once, which is dangerous.

The temperature when reacting the reaction mixture with a weak acid is usually above the freezing point of the reaction medium and below 50°C, preferably 0°C.
~40℃. If the temperature is too high, by-products will increase and the yield of 5-ETN will decrease, and if the temperature is too low, the water used will turn into ice, causing operational difficulties and hazards. I also don't like it.

After adjusting the pH of the reaction mixture in this manner, the produced 5-ETN is reduced with an alkali metal borohydride.

The amount of alkali metal borohydride used is 5-
Usually 1 to 100 equivalents, preferably 1.2 to ETN
~50 equivalents. If the amount of alkali metal borohydride is too small, the reduction of 5-ETN will be insufficient, and if it is too large, no particular effect will be seen, which is not preferable.

The lower the temperature during reduction, the more the 3-position hydroxyl group becomes β-
This is desirable because it tends to improve coordination selectivity, but since it is a mixed solvent of water and a hydrophilic organic solvent, it is usually above the freezing point of the mixed solvent and below 70°C.
Preferably it is 0 to 50°C.

The reaction time for reduction varies depending on various other conditions, but is usually 1 minute to 100 hours, preferably 5 hours.
It takes about 20 minutes to 20 hours.

After the reaction is completed, the excess alkali metal borohydride is decomposed by contacting with an acid according to a conventional method, and then the solvent is distilled off and the solvent is distilled off, followed by filtration or extraction. ETAD can be separated by different methods. These may be used appropriately depending on the intended use of the product.

The produced ETAD can also be purified by a combination of well-known methods such as filtration and recrystallization, chromatography, and the like.

According to the method of the present invention, the desired ETAD can be produced with a simple operation and a high yield.

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

Example 1 Acetylene is absorbed into 16.7 g of potassium t-butoxy and 170 ml of tetrahydrofuran (hereinafter abbreviated as THF) with sufficient stirring to produce acetylide. While cooling this liquid to 10-15℃,
A solution of 16.15 g of 4AD in THF (150 ml) is added over 1-1.5 hours. After stirring for 1.5 hours at 10-15℃, 30℃
1 hour later, cooled again to 15℃, and
It is added to an aqueous monobasic potassium phosphate solution (KH ₂ PO ₄ 30.42 g KH ₂ PO ₄ /t-Buok = 1.5 times the mole, water 300 ml) at 20° C. while stirring over 15 minutes. The pH at this time was 7. To this, 29 g of tripotassium phosphate was added and stirred for 45 minutes. At this time
The pH was 11. This includes sodium borohydride.
1.8g was added and stirred at 15°C for 30 minutes. An aqueous potassium monophosphate solution (15 g of KH ₂ PO ₄ , 500 ml of water) was added to stop the reduction reaction. The pH at this time is 8
It was hot. After stirring for 30 minutes, THF was distilled off under reduced pressure, and the precipitated crude ETAD was collected by filtration. This one is 3α・
It contained 6% of 17β-dihydroxypregn-5-en-20-yne (hereinafter abbreviated as α-ETAD), and the consistent yield of ETAD from 4AD was 84 mol%.

Comparative Example 1 Acetylene is absorbed into 2.1 g of t-butoxypotassium and 30 ml of THF with sufficient stirring to generate acetylide. While cooling this solution,
A solution of 2.0 g of 4AD in THF (18 ml) is added over 1-1.5 hours. After stirring at 10-15°C for 1.5 hours, the temperature was raised to 30°C, and after 1 hour, it was cooled again to 15°C, and then heated to 20°C.
Potassium monophosphate aqueous solution (KH ₂ PO ₄ 3g,
(30 ml of water) over 15 minutes while stirring. After stirring at 15°C for 1 hour, the pH was 6. Add 0.55g of sodium borohydride to this and heat at 15℃.
Stirred for 1.5 hours. A 16% aqueous hydrochloric acid solution was added to adjust the pH to 1 to stop the reduction reaction. THF was distilled off under reduced pressure, and the precipitated crude ETAD was collected by filtration. The consistent yield of ETAD and the content of α-ETAD were the same as in Example 1.

Note that when the amount of sodium borohydride was reduced from the above amount, it was found that the reduction was insufficient.

These results show that about three times as much sodium borohydride as in Example 1 is required.

Example 2 Potassium t-butoxy 6.45g THF (97ml)
Ethynylation of 4AD was carried out in the same manner as in Example 1 using the solution and a solution of 5.49 g of 4AD in THF (56 ml). After ethynylation, monobasic potassium phosphate at 20℃
A solution of 11.76 g in water (136 ml) was added and stirred for 30 minutes. The pH at this time was 7. When 20 ml of 10% (by weight) sodium hydroxide aqueous solution was added to this and stirred for 15 minutes, the pH became 11. 0.618 g of sodium borohydride was added to this and stirred for 1 hour. 3.7 ml of 98 (weight)% sulfuric acid was added to adjust the pH to 1 to 2, and the mixture was stirred at 40°C for 1 hour to stop the reduction reaction.
Then, 5% (by weight) aqueous sodium hydrogen carbonate solution
50 ml and 210 ml of water were added to neutralize, THF was distilled off under reduced pressure, and the precipitated crude ETAD was collected by filtration. This product contains 6% α-ETAD, and the consistent yield of ETAD is 82
It was mol%.

Example 3 Acetylene is absorbed into 10 g of potassium t-butoxy and 150 ml of THF with thorough stirring to produce acetylide. Cool this liquid to 10-15℃
While maintaining the temperature at 15℃, add 90ml of THF solution containing 10g of 4AD.
Add at 30 minutes.

After stirring at 10-15°C for 1.5 hours, the temperature was raised to 30°C.
After 1 hour, the reaction solution was cooled again to 15°C and heated to 15°C.
250 ml aqueous acetic acid solution (containing 10 ml acetic acid) at °C
Add to the solution under stirring. The pH at this time was 5.

After adjusting the pH of this solution to 11 with tripotassium phosphate,
g of sodium borohydride was added and the mixture was reduced at 20°C for 2 hours. After treatment according to Example 1,
Got ETAD. ETAD was obtained from 4AD in 82.7% yield with 7.3% α-ETAD.

Example 4 Crude ETAD was obtained in the same manner as in Example 3, except that acetic acid was replaced with equimolar boric acid.

Yield 83.4 with 6.3% α-ETAD from 4AD
ETAD was obtained in %.

Claims (1)

[Scope of Claims] 1. Androst-4-ene-3.
The carbonyl group at position 17 of androst-4-ene-3.17-dione is selectively ethynylated by reacting 17-dione with a metal acetylide, and then the pH of the reaction mixture is adjusted to 9 to 13 to form an alkali metal borohydride. 1. A method for producing 3,17-dihydroxypregn-5-en-20-yne, which comprises reducing the 3,17-dihydroxypregn-5-en-20-yne. 2. In the method for producing 3,17-dihydroxypregn-5-en-20-yne according to claim 1, a hydrophilic organic A method characterized by using a solvent. 3. 3,17-dihydroxypregn-5-ene-20- according to claim 1 or 2
A method for producing phosphorus, which is characterized by using an excessive amount of metal acetylide. 4 3,17-dihydroxypregn-5- according to any one of claims 1 to 3
In the method for producing ene-20-yne, the reaction mixture is
A method characterized by setting the temperature to 50°C or less when adjusting the pH to 9 to 13. 5 3,17-dihydroxypregn-5- according to any one of claims 1 to 4
A method for producing en-20-yne, which comprises reacting the reaction mixture with an aqueous weak acid solution to adjust the pH to 9 to 13. 6 3,17-dihydroxypregn-5- according to any one of claims 1 to 5
A method for producing en-20-yne, characterized in that the temperature during reduction with an alkali metal borohydride is 70°C or less. 7 3,17-dihydroxypregn-5- according to any one of claims 1 to 6
In the method for producing en-20-yne, the amount of alkali metal borohydride is changed to androst-4-ene-
PH of reaction mixture of ethynylated 3,17-dione
A method characterized in that the amount is at least equivalent to 100 times equivalent to 17-hydroxypregn-5-en-20-yn-3-one produced when is set to 9 to 13.