JP2005289901A - Preparation method for 5alpha-pregnane derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for preparing a 5α-pregnane derivative used as an intermediate for preparing squalamine having a strong antimicrobial activity and a carcinostatic activity. <P>SOLUTION: A metal selected from among alkali metals and alkaline earth metals is reacted with (20S)-7α, 21-dihydroxy-20-methylpregna-1, 4-dien-3-one in the presence of an amine and/or ammonia to prepare (20S)-7α, 21-dihydroxy-20-methyl-5α-pregnan-3-one represented by formula II. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 5α-pregnane derivative useful as an intermediate for producing a biologically active compound such as squalamine.

  Formula (IV)

Is a compound that has been reported to have antibacterial activity as well as having strong antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, fungi, etc., and is attracting attention as a new antibiotic .

  Conventionally, squalamine has been extracted from shark liver, but its extraction efficiency is as low as 0.001 to 0.002% by weight, and various chemical synthesis methods have been studied. In particular, the formula (II)

(20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one represented by (see Patent Document 1 and Non-Patent Document 1) and Formula (V)

(20S) -21-tert-butyldimethylsilyloxy-7α-hydroxy-20-methyl-5α-pregna-3-one (see Patent Document 2) can be converted to squalamine in a relatively short process. It is known to be a useful synthetic intermediate.

  Conventionally, (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one is stereoselectively reduced to the α-form to give (20S) -7α, 21-dihydroxy-20. As a method for producing -methyl-5α-pregna-3-one, a method of birch reduction using 10 equivalents of metallic lithium in the presence of liquid ammonia (see Patent Document 1) has been developed.

As a method for producing (20S) -21-tert-butyldimethylsilyloxy-7α-hydroxy-20-methyl-5α-pregna-3-one, (20S) -7α, 21-dihydroxy-20-methylpregna -1,4-Dien-3-one is reduced by the above method to obtain (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one, followed by derivatization (patent Reference 2) was known.
International Publication No. 02/20552 Pamphlet WO03 / 51904 pamphlet “Organic Leters”, 2000, No. 2, p. 2921

  However, since the yield of the above method is only 65% even if it is high, it cannot be said that it is a preferable production method considering that the 5α-pregnane derivative is an expensive material, and it is still improved for industrial implementation. There was room for.

  That is, the object of the present invention is useful as a synthesis intermediate of squalamine by stereoselectively reducing (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one to the 5α form. An object of the present invention is to provide a method for producing (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one more efficiently.

  The purpose of the conventional reaction is to obtain a saturated ketone which is stereoselectively converted into a 5α form using an unsaturated ketone having double bonds at the 1,2-position and 4,5-position as a raw material compound. That is, the conventional reaction corresponds to a so-called partial reduction in which an unsaturated ketone is converted to a saturated ketone. However, it has been found that an overreaction is caused as a side reaction and an alcohol form is generated by reduction of the saturated ketone. In order to avoid this side reaction, it is very important to carry out the reaction using an equivalent amount of reducing agent necessary for partial reduction, but in practice, metallic lithium is used in a large excess. Yes.

As a result of studies by the present inventors, among the two double bonds contained in (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one in the reduction reaction, A new finding was obtained that the reduction reaction of the double bond at the 5-position proceeds significantly faster than the reduction reaction of the double bond at the 1,2-position.
Further, the raw material pregnane has a free primary hydroxyl group at the 21-position, but the reaction of the primary hydroxyl group with metallic lithium is fast, and it has been found that metal lithium is decomposed and the reducing ability is lost.
That is, since the conventional method aims to obtain a saturated ketone, excess lithium must be used for the above reason, and in this case, the primary hydroxyl group is a good proton in the reduction reaction. Since it also acts as a donor, it was thought that this resulted in by-product formation of alcohol due to overreaction as a side reaction.

  Therefore, as a result of intensive studies by the present inventors, the reduction of (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (II) is mainly performed as 4,5 as the first step. Reduction of the position is performed by reducing the equivalent of the reducing agent, and stereoselectively converts to the 5α form to give a corresponding mixture of 5α-saturated ketone and 5α-1-en-3-one. Next, as a second step, this problem can be solved by leading to the target 5α-saturated ketone by reducing the 1,2-position of the 5α-1-en-3-one form in the mixture. , By reducing the equivalent of the reducing agent used in the first step to suppress the by-product of the alcohol form due to the overreaction which is a side reaction, and found that the total yield is greatly improved, and the present invention is completed. It reached.

  That is, the present invention relates to (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (I)

Is reacted with a metal selected from alkali metals and alkaline earth metals in the presence of amine and / or ammonia to give (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one ( II)

And (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III)

A first step to obtain a mixture of
(20S) -7α, 21-dihydroxy-20-methyl-5α-preg-1-en-3-one (III) in the mixture was converted to (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna. And a second step of reduction to -3-one (II), thereby solving the above-mentioned problems and achieving the object of the present invention.

  In the present invention, the metal is preferably an alkali metal.

  In the present invention, the alkali metal is preferably lithium.

  In the production method of the present invention, in the first step, first, the raw diene compound is reduced using a reducing agent having an equivalent amount smaller than that of the conventional method, and then in the first step, the product is not completely reduced in the product. Since the remaining compound having a double bond at the 1,2-position is further reduced, a two-step reduction treatment is performed, so that it is not necessary to use a large excess of reducing agent as in the conventional method. The yield of (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one, which is the target product, can be significantly improved by avoiding the formation of an alcohol form by overreaction.

  The present invention relates to (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (I)

(Hereinafter, also referred to as compound (I)) is reacted with a metal selected from alkali metals and alkaline earth metals in the presence of amine and / or ammonia to give (20S) -7α, 21- Dihydroxy-20-methyl-5α-pregna-3-one (II)

(Hereinafter also referred to as compound (II)) and (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III)

A first step of obtaining a mixture of (hereinafter sometimes referred to as compound (III));
(20S) -7α, 21-dihydroxy-20-methyl-5α-preg-1-en-3-one (III) in the mixture was converted to (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna. A second step of reduction to -3-one (II). Below, it demonstrates for every process.

(First step)
In the first step of producing a mixture of compound (II) and compound (III) from compound (I), a metal selected from alkali metals and alkaline earth metals is used as the reducing agent. As the alkali metal, lithium, sodium, potassium and the like are used, and as the alkaline earth metal, magnesium, calcium, strontium, barium and the like are used. Of these, alkali metals such as lithium, sodium, and potassium are preferable, and lithium is more preferable.

  The amount of the alkali metal or alkaline earth metal used is preferably in the range of 2 to 10 moles, more preferably in the range of 2 to 8 moles, and even more preferably to the compound (I). Is in the range of 2-6 mole times. If the amount of alkali metal or alkaline earth metal used is less than the above range, the reduction of double bonds may not proceed sufficiently and the yield may decrease. The side reaction may proceed.

  The reaction is carried out in the presence of ammonia or an amine. There are no particular limitations on the type of amine, for example, primary amines such as methylamine, ethylamine, isopropylamine, and butylamine; secondary amines such as dimethylamine, diethylamine, diisopropylamine, pyrrolidine, and piperidine; and tertiary amines such as triethylamine. Examples include linear, branched or cyclic amines having 1 to 6 carbon atoms such as tertiary amines, ethylenediamine, diaminopropane, N, N′-dimethylethylenediamine, and the like. preferable.

  The amount of ammonia or amine to be used is preferably in the range of 1 to 200 times by weight, more preferably 3 to 50 times by weight, relative to compound (I).

  Moreover, you may use a proton donor for reaction. The type of proton donor is not particularly limited, and examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid, and carbonic acid, or organic carboxylic acids such as formic acid, acetic acid, and benzoic acid, and ammonium salts or amine salts thereof; water; alcohols, and the like. However, the use of alcohol is preferred. Examples of the alcohol include primary alcohols such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol and 1-dodecanol; 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, Secondary alcohols such as cyclohexanol and 2-octanol; tertiary alcohols such as 2-methyl-2-propanol, tert-amyl alcohol, 2-methylhexanol and 1-methylcyclohexanol; ethylene glycol, 1,4- Examples thereof include linear, branched or cyclic alcohols having 1 to 12 carbon atoms such as polyhydric alcohols such as butanediol, 2,4-pentanediol and glycerin. A preferred alcohol type is a tertiary alcohol, more preferably 2-methyl-2-propanol.

  The amount of the proton donor to be used is preferably in the range of 2 to 20 mol times, more preferably in the range of 2 to 8 mol times with respect to the compound (I).

  There are no particular restrictions on the timing when the proton donor is introduced into the reaction system. For example, a method in which compound (I) is introduced into the reaction system before reacting with an alkali metal or alkaline earth metal, or compound (I) is an alkali metal or The method can be selected from a method in which the reaction is performed with an alkaline earth metal and then charged into the reaction system.

  The reaction may be performed in the presence of a solvent. The type of the solvent is not particularly limited as long as it does not adversely affect the reaction. For example, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, cyclopropylmethyl ether, dimethoxyethane, 1,4-dioxane, etc. And hydrocarbons such as pentane, hexane, heptane, and octane. Of these, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, cyclopropylmethyl ether, dimethoxyethane, 1,4-dioxane are preferable, and tetrahydrofuran is more preferable.

  The amount of the solvent to be used is not particularly limited, but is preferably in the range of 1 to 200 times by weight, more preferably 3 to 50 times by weight with respect to compound (I).

  The reaction temperature is preferably in the range of −100 ° C. to 50 ° C., more preferably in the range of −50 ° C. to 20 ° C.

(Handling of mixture)
In the first step of producing a mixture of compound (II) and compound (III) from compound (I), contaminating compound (III) is converted into the target product by the subsequent second step. The obtained mixture is used in the second step as it is without performing a separation operation for separating the compound (II) and the compound (III).

(Second step)
The reduction method that can be applied in the second step is not particularly limited. For example, it is disclosed as a catalytic reduction using a transition metal catalyst, a reduction with a hydride reducing agent, and a method for producing compound (II) from compound (I). And a reduction method in which an alkali metal or alkaline earth metal is allowed to act. Of these, catalytic reduction using a transition metal catalyst is preferred. Hereinafter, although catalytic reduction is demonstrated, a 2nd process is not limited to this.

  Although there is no limitation in particular as a metal seed | species of the transition metal catalyst used for catalytic reduction, For example, ruthenium, rhodium, iridium, nickel, palladium, platinum etc. are mentioned. Of these, nickel, palladium and platinum are preferred, with palladium being most preferred.

  Transition metal catalyst forms include complex catalysts that dissolve in the reaction system (eg, tetrakistriphenylphosphine palladium, palladium acetate, etc.), heterogeneous catalysts that do not dissolve in the reaction system (eg, palladium carbon, palladium hydroxide, platinum oxide, Palladium black or the like may be used, but a heterogeneous catalyst in which the catalyst can be easily separated from the reaction system, particularly palladium carbon and palladium black are preferable.

  The amount of the transition metal catalyst used depends on the ratio of compound (II) or compound (III) mixed in the raw material mixture, but is 0.01 to 100% by weight, preferably 0.1 to 10%, based on the total weight of the mixture. % By weight.

  The kind of the reducing agent is not particularly limited, and examples thereof include molecular hydrogen, formic acid and salts thereof, and molecular hydrogen is preferable.

When molecular hydrogen is used as the reducing agent, the hydrogen partial pressure is preferably in the range of 1 × 10 ⁴ to 1 × 10 ⁷ Pa, more preferably in the range of 1 × 10 ⁵ to 1 × 10 ⁶ Pa. preferable.

  The reaction temperature is preferably in the range of 0 ° C to 150 ° C, more preferably in the range of 20 ° C to 100 ° C.

  The reaction is preferably performed in the presence of a solvent. The type of the solvent is not particularly limited as long as it does not adversely affect the reaction. For example, ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, cyclopropylmethyl ether, dimethoxyethane, 1,4-dioxane, etc. Hydrocarbons such as pentane, hexane, heptane and octane; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; esters such as methyl acetate, ethyl acetate, butyl acetate and methyl benzoate; methanol, ethanol Alcohols such as 1-propanol, 2-propanol, 1-butanol, 2-butanol and 1-octanol; amides such as N, N′-dimethylformamide and N-methylpyrrolidone; There may also be used in combination. From the economical viewpoint, it is preferable to use the same solvent as the reduction reaction with alkali metal or alkaline earth metal. Among these, tetrahydrofuran, diethyl ether, diisopropyl ether, methyl-tert-butyl ether, cyclopropyl methyl ether, Ethers such as dimethoxyethane and 1,4-dioxane are preferred, and tetrahydrofuran is more preferred.

  The amount of the solvent to be used is not particularly limited, but is preferably in the range of 1 to 200 times by weight, more preferably 3 to 50 times by weight with respect to compound (II).

(Isolation and purification)
The method for isolating and purifying the compound (II) produced after the second step is not particularly limited, but after the extraction, etc., the organic compound is post-treated, isolated and purified, such as by recrystallization or silica gel chromatography. A method generally used for the above can be adopted.

(material)
Although the manufacturing method of (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (I) used as a raw material is not particularly limited, for example, (20S) -7α, 21-Dihydroxy-20-methylpregna-1,4-dien-3-one (I) performs a conversion reaction using microorganisms on 3α, 7α-dihydroxy-5S-cholanic acid and / or its salt ( No. 2525049) to 7α-hydroxy-3-oxo-pregna-1,4-diene-20α-carbaldehyde, followed by reduction of position 20 with sodium borohydride (WO 02 / 20552 pamphlet).

  EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

(First step)
(20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) and (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one Synthesis of Mixture of (III) A 3 L three-necked flask was cooled to −40 ° C. under a nitrogen atmosphere, and ammonia (1000 ml), tetrahydrofuran (250 ml), (20S) -7α, 21-dihydroxy-20-methylpregna- 1,4-Dien-3-one (I) (50.00 g, 145.1 mmol) was added. Next, lithium metal (3.0 g, 432.2 mmol) was slowly added while maintaining the temperature at −50 to −40 ° C., and the mixture was further stirred at −40 ° C. for 4 hours after the addition was completed. After ammonium chloride (28.0 g, 518.6 mmol) was added to the reaction solution, the reaction solution was stirred while gradually warming to room temperature to remove ammonia. 3N Hydrochloric acid (250 ml) was added to the obtained reaction mixture, ethyl acetate (400 ml) and tetrahydrofuran (400 ml) were added, and the organic layer and the aqueous layer were separated. The aqueous layer was extracted with ethyl acetate (250 ml) and tetrahydrofuran (250 ml), and the combined organic layer was dried over magnesium sulfate and concentrated. When the obtained crude product was analyzed by HPLC, (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) (20.8 g, yield 41.3%) And (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (22.5 g, 45% yield) (III).

(Second step)
Synthesis of (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) (catalytic reduction)
Under a nitrogen atmosphere, (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) (20.8 g, 60.0 mmol) obtained in the first step was placed in a 2 L three-necked flask. ) And (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III) (22.5 g, 64.9 mmol), tetrahydrofuran (1250 ml), 10% Pd After adding / C (1.32 g), the mixture was replaced with a hydrogen atmosphere and reacted at room temperature for 16 hours under normal pressure. After confirming disappearance of (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III) by HPLC analysis, the reaction was carried out by replacing the catalyst with a nitrogen atmosphere and filtering off the catalyst. The liquid was concentrated. The obtained crude product was purified by silica gel chromatography to obtain (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (40.4 g) (II) having the following physical properties. {Yield 93% (contained (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) and (20S) -7α, 21-dihydroxy-20-methyl- Based on the sum of 5α-pregna-1-en-3-one (III))}.
¹ H-NMR spectrum (270 MHz, CDCl ₃ , TMS, ppm) δ:
710 (s, 3H), 1.01 (s, 3H), 1.04 (d, 3H, J = 6.9 Hz), 1.0-2.5 (m, 22H), 3.34 (dd, 1H, J = 6.9, 10.9 Hz), 3.61 (dd, 1H, J = 3.0, 10.9 Hz), 3.84-3.85 (brs, 1H).

  The production method of the 5α-pregnane derivative of the present invention is as follows. (20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (I) has 1,2- and 4,5-positions. This is useful as a method for producing (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) in a high yield by reducing the carbon-carbon double bond.

Claims (3)

(20S) -7α, 21-dihydroxy-20-methylpregna-1,4-dien-3-one (I)

And (20S)-, wherein a metal selected from an alkali metal and an alkaline earth metal is reacted in the presence of an amine and / or ammonia to remove a hydroxyl-protecting group as necessary. 7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II)

And (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III)

A first step to obtain a mixture of
(20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-1-en-3-one (III) in the mixture was converted to (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna. A second step of reduction to -3-one (II) (20S) -7α, 21-dihydroxy-20-methyl-5α-pregna-3-one (II) 3-oxopregnane derivative Manufacturing method.   The manufacturing method according to claim 1, wherein the metal is an alkali metal.   The production method according to claim 2, wherein the alkali metal is lithium.