WO2005095435A1

WO2005095435A1 - Method for producing pregnane derivative

Info

Publication number: WO2005095435A1
Application number: PCT/JP2005/006808
Authority: WO
Inventors: Takashi Sugioka; Kenichi Koyakumaru
Original assignee: Kuraray Co., Ltd.
Priority date: 2004-03-31
Filing date: 2005-03-31
Publication date: 2005-10-13

Abstract

A method for producing a pregnane derivative is characterized by the process wherein a pregnane derivative represented by the general formula (II) below is produced by silylating a compound represented by the formula (I) below using a silylating agent in the presence of a base and one or more solvents selected from hydrocarbons, ethers and esters, then the resulting reaction liquid is cooled so that the pregnane derivative represented by the general formula (II) below is precipitated as a solid in the reaction liquid, and then the thus-obtained precipitate is filtered out of the reaction liquid. (In the formula, R1, R2 and R3 independently represent an optionally substituted alkyl group or the like.)

Description

Specification

Method for producing predanane derivative

Technical field

The present invention relates to a method for producing a predanane derivative.

Background art

The predanane derivative obtained in the present invention is an intermediate for synthesizing various compounds such as biologically active compounds, for example, a synthetic intermediate of a vitamin D derivative (for example, JP-A-2000-351796) or squalamine. Useful as an intermediate for the synthesis of

(2OS) —7a, 21-dihydroxy-20_methylpredana-1,4_gen_3_one, which is a compound serving as a raw material of the predanane derivative obtained in the present invention, is a compound of the formula: Fermented to obtain (2 OS) — 7 α-hydroxypredaner 1,4 _ gen-13 -one _ 20-carbaldehyde, which can be obtained by reduction with a reducing agent such as sodium borohydride (J Ρ—Β—252505049 or WO 02/20552).

Also, (20S) -7a, 21-dihydroxy-1-20-methylpredaner 1,41-gen_3_one has a primary hydroxyl group at the 21-position. Silyl etherification is known as a protection method for protecting a group.

In the case of performing silyl etherification, a method of reacting a compound having a hydroxyl group with a trisubstituted silyl halide is generally known. The reaction conditions include, for example, N, N— in the presence of a base such as imidazole. Generally, the reaction is carried out in a solvent such as dimethylformamide-methylene chloride (for example, J. Am. Chem. Soc., Vol. 94, p. 6190 (1972), Chemistry Letters, p. 41 ( 1987), Tetrahedron Letters, Vol. 22, p. 3455 (1981)).

As a method for silylating (20S) -7a, 21-dihydroxy-20-methylpredana-1,4,4-gen-3-one represented by the formula (I) to be described later, tertiary thioamide in the presence of imidazole is used. There is known a method of reacting monobutyldimethylsilyl chloride in a methylene chloride solvent, filtering the reaction solution to remove imidazole hydrochloride, concentrating the filtrate, and re-precipitating with diisopropyl ether. ing ("Synthetic Studies on Aliphatic and Alicyclic Biologically Active Substances", Nao Nakagawa, Ph.D., The University of Tokyo).

Disclosure of the invention

N, N-dimethylformamide is highly water-soluble and can be separated by diluting with a large amount of non-polar solvent and washing with water. There is a problem that wastewater containing amide is generated. In addition, the use of halogenated solvents such as methylene chloride has a problem that the burden on the environment in recent years is extremely large. Therefore, all solvents are difficult to use industrially, and there is a problem in selecting a solvent suitable for industrialization.

Also, the method described in “Synthetic Studies on Aliphatic and Alicyclic Bioactive Substances” (Nao Nakagawa, Ph.D. Dissertation, The University of Tokyo) shows that the yield of the predanane derivative represented by the formula (II) described later is 60%. %, And the melting point is 240 ° C, which is very different from the melting point of high-purity products (264 ° C to 265 ° C). Repurification may be required depending on the type of subsequent reaction. In particular, if the purification is carried out without using water, it is difficult to remove water-soluble impurities derived from the base and the like used in the reaction. In some cases.

The present invention has been made in order to solve the above-mentioned problems, and uses a predanane derivative useful as a synthetic intermediate such as vitamin D and squalamine in a small amount of a solvent having low toxicity to the environment to reduce waste. It is an object of the present invention to provide a method for producing a high-purity, simple, high-yield product that does not affect the conversion in the subsequent steps. As a result of the inventor's diligent studies, the problem was that (2 OS) -7α, 21-dihydroxy-l 20-methylpredaner 1,4-gen-13-one could be converted from hydrocarbons, ethers and esters. After completion of the reaction, the reaction product is cooled to precipitate the desired product from the reaction solution, which is collected by filtration. The present inventors have found that the problem can be solved by removing water-soluble impurities in the obtained precipitate by washing with water, and have completed the present invention. That is, the present invention provides a compound represented by the formula (I):

(2 OS)-7a, 21-dihydroxy-1 20-methylpredana-1 4- 1-gen-3-one (hereinafter abbreviated as predanane derivative (I)) is a base and a hydrocarbon, ether And silylation with a silylating agent (hereinafter abbreviated as silylating agent (III)) in the presence of one or more solvents selected from the group consisting of a compound of general formula (II)

(Wherein R ¹ R ² and R ³ each independently represent an alkyl group optionally having a substituent, an alkenyl group optionally having a substituent, Good alkynyl group, aralkyl group optionally having substituent (s), aryl group optionally having substituent group, alkoxyl group optionally having substituent group, and aryloxy group optionally having substituent (s) A predanane derivative represented by the following formula (hereinafter, abbreviated as predanane derivative (II)):

A method for producing a predanane derivative (II), comprising cooling the obtained reaction solution to precipitate the predanane derivative (II) as a solid in the reaction solution, and collecting the precipitate by filtration.

Further, a preferred embodiment is a method for producing a predanane derivative (II), wherein the precipitate is washed with water to remove water-soluble impurities.

According to the present invention, a small amount of a highly versatile and low-toxic solvent for the environment is used, and the reaction solution is filtered to remove salts produced as by-products with water, or water is added to the reaction solution and the solution is filtered as it is. By doing so, a high-purity predanane derivative (II) having a high yield and not affecting the subsequent conversion reaction can be obtained.

BEST MODE FOR CARRYING OUT THE INVENTION

In the predanane derivative (II) and the silylating agent (III), the alkyl group represented by R ¹ , R ² and R ³ is preferably an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, and a —Propyl group, isopropyl group, n-butyl group, 1-methylpropyl group, 2-methylpropyl group, n-pentyl group, 1-methylbutyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group and the like. These alkyl groups may have a substituent, and examples of such a substituent include halogen atoms such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group, and a propoxy group. And an alkoxyl group such as a butoxy group; an aralkyloxy group such as a benzyloxy group.

The alkenyl group represented by each of R ¹ , R ² and R ³ is preferably an alkenyl group having 3 to 6 carbon atoms, for example, 2-propyl group, 2-butenyl group, 3-butenyl group, and 1-alkenyl group. Methyl-2-propyl group, 2-methyl-2-propyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 1-methyl-2-buturyl group, 1-methyl-3-butyryl group , 2-methyl-2-butenyl, 2-methyl-3-butenyl, 3-methyl-2-butenyl, 3-methyl-3-butul, 1-ethyl-2-propenyl, 1-hexenyl And the like.

The alkynyl group represented by R ¹ , R ² and R ³ is preferably an alkynyl group having 3 to 6 carbon atoms, for example, 2-propynyl group, 2-buturyl group, 3-butynyl group, 2-pentulyl group, Examples thereof include a 3-pentul group, a 4-pentul group, a 1-methyl-3-butul group, a 2-methyl-13-butur group, and a 2-hexyl group. These alkenyl groups and alkynyl groups may have a substituent. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group and an ethoxy group. And an alkoxy group such as a propoxy group and a butoxy group; and an aralkyloxy group such as a benzyloxy group. The aralkyl group represented by R ¹ , R ² and R ³ is preferably an aralkyl group having an alkyl group having 1 to 6 carbon atoms as an alkyl moiety and having an aralkyl group having 6 to 10 carbon atoms as an aryl moiety. Examples thereof include a benzyl group, a 1-phenylethyl group, and a naphthylmethyl group. These aralkyl groups may have a substituent, and examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group, an n-propyl group, Alkyl groups such as isopropyl group, n-butyl group, isoptyl group, sec-butyl group and tert-butyl group; alkoxyl groups such as methoxy group, ethoxy group, propoxy group and butoxy group; aralkyloxy groups such as benzyloxy group And so on.

The aryl group represented by each of R ¹ , R ² and R ³ is preferably an aryl group having 6 to 10 carbon atoms, such as a phenyl group and a naphthyl group. These aryl groups may have a substituent. Examples of the substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methyl group, an ethyl group and a propyl group. Alkyl groups such as isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups; alkoxyl groups such as methoxy, ethoxy, propoxy and butoxy groups; Aryl group; aralkyloxy group such as benzyloxy group. Examples of the aryl group having a substituent include a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2,3-dimethylphenyl group, and a 2,4-dimethylinophenyl group. , 2,5-dimethynolephenyl group, 2,6-dimethynolephenyl group, 4-propynolephenyl group, 4-butylbutyl group, 2,3-dimethylnaphthyl group, 2,4-dimethylnaphthyl group, and the like.

The alkoxyl group represented by R ¹ , R ² and R ³ is preferably a linear, branched or cyclic alkoxyl group having 1 to 12 carbon atoms, such as methoxy, ethoxy, propoxy, Examples include an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a hexyloxy group, an octyloxy group, a dodecyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group. These alkoxyl groups may have a substituent. Examples of such a substituent include a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; a methoxy group, an ethoxy group, a propoxy group and a butoxy group. An alkoxyl group such as a group; an aralkyloxy group such as a benzyloxy group.

The aryloxy group represented by R ¹ , R ² and R ³ is preferably an aryloxy group having 6 to 10 carbon atoms, such as a phenyloxy group and a naphthyloxy group. These aryloxy groups may have a substituent, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkoxyl group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group. An aralkyloxy group such as a benzyloxy group.

Specific examples of the silylating agent (III) used in the present invention include trimethylsilyl chloride, trimethylsilyl bromide, ethyldimethylsilyl chloride, isopropyldimethylsilyl chloride, tert-butyldimethylsilyl chloride, tert-butyldimethylsilyl chloride, Trisubstituted silyl halides such as triethynolesilinochloride, tert-butyldiphenylnonylsilinochloride and triphenylsilyl chloride; trimethylsilyl trifluoride Methanesulfonate. Isopropyl dimethylsilyl trifluoromethanesulfonate, tert-butylinresinmethinolesylinoletrinorolenomethanshonolefonate, triethylsilyl trifluorene methanesnorefonate, tert-butynolefifenino Examples include trisubstituted silyltrifluoromethanesulfonates such as resilinoretreflenorolomethanesulfonate and triphenylsilyltrifluoromethanesulfonate, among which trisubstituted silyl halides are preferred. The amount of the silylating agent (III) to be used is preferably 0.8 to 5 mol, more preferably 0.9 to 3 mol, per 1 mol of the predanane derivative (I) from the viewpoints of production efficiency and economy. More preferred.

The silylation reaction of the present invention is carried out in the presence of one or more bases. Examples of such bases include nitrogen-containing compounds such as triethylamine, dimethylaminopyridine, acetylaminoviridine, imidazole, and 2,6-rutidine; metal hydrides such as sodium hydride and hydrogen hydride; sodium methoxide; Metal alkoxides such as methoxide, potassium methoxide, potassium ethoxide, and potassium tert-butoxide; and alkyllithiums such as methyllithium, n-butyllithium, s-butyllithium, and tert_butyllithium. More preferred. The total amount of the base used is preferably in the range of 1.0 to 5 mol per 1 mol of the silylating agent (III) from the viewpoint of production efficiency and economical viewpoint.

Examples of the solvent used in the silylation reaction of the present invention include hydrocarbons such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane, petroleum ether, benzene, toluene, xylene, and mesitylene; tetrahydrofuran, Ethers such as ethynoleate, diisopropinoleate and dimethoxetane; esters such as methyl acetate, ethyl acetate, isopropyl acetate, methyl benzoate and ethyl benzoate, and mixtures thereof. Further, among these, the solubility of the predanane derivative (II) at 20 ° C. is preferably 5 g / 10 Om 1 or less from the viewpoint of simplicity of the post-treatment. Such solvents such as toluene and xylene , Mesitylene, getyl ether, diisopropyl ether. The amount of the solvent used is not particularly limited, but is preferably from 1 to 100 times the mass of the predanane derivative (I) from the viewpoints of production efficiency and economy.

The reaction temperature and reaction time vary depending on the predanane derivative (I), the type and amount of the base, the type and amount of the silylating agent (III), and the type and amount of the solvent, but an industrially advantageous reaction rate and It can be chosen accordingly to achieve selectivity.

By cooling the reaction solution thus obtained, the predanane derivative (II) is precipitated as a solid from the reaction solution and collected by filtration, but is used in the reaction for the purpose of improving the product recovery rate. It is also possible to add a poor solvent in which the solubility of the predanane derivative (II) is lower than the solvent used. Such a solvent can be selected from the solvents described above.

At this time, water is added to the obtained reaction solution, and the mixture is filtered to obtain a crude product. The product is washed with the same solvent or water used for the reaction, or the reaction solution is filtered and the crude product obtained is washed with water, and if necessary, further washed with the same solvent used for the reaction. It is also possible to wash. This makes it possible to remove water-soluble impurities such as salts contained in the crude product by-produced in the silylation reaction.

The temperature at which the predanane derivative (II) is filtered depends on the solubility of the predanane derivative (II) in the solvent used, the solubility of water-soluble impurities in water, and the stability of the product predanane derivative (II). Differently, it can be selected as appropriate, but in general, when water is present, it is preferably in the range of 0 ° C to 60 ° C, and when water is not present, it is preferably 20 ° C It is preferably in the range of C to 60 ° C, and in any case, more preferably in the range of 0 ° C to 40 ° C.

The temperature at which the predanane derivative (II) is washed with water depends on the solubility of water-soluble impurities in water and the stability of the predanane derivative (II), and can be selected as appropriate. It is preferably in the range of 60 ° C, more preferably in the range of 0 ° C to 40 ° C.

Example

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

Reference example 1

(Production example of crude material)

Under a nitrogen atmosphere, a crude (20 S) -7α-hydroxy-3-oxoxopregna-1,4-gen-1-20-carbotas aldehyde 22.0 g (weight in terms of pure matter) was placed in a flask with a capacity of 5 O Oml in a nitrogen atmosphere. _{20. 0 g, 54. 8 mm 0} 1), Etanoru 200 meters l was added, the mixture was cooled in ice with constant stirring. To this solution, 0.61 g (16. lmmo 1) of sodium borohydride was added in several portions, and after the addition was completed, the mixture was stirred for 1 hour under ice cooling. The reaction solution was neutralized by adding 3% hydrochloric acid, and after adding 20 Om1 of water, ethanol was distilled off under reduced pressure. The crude crystals precipitated in the residue were collected by filtration and washed with water. Toluene is added to the obtained crude crystals, and the mixture is heated. After water in the crude crystals is removed by azeotropic distillation with toluene, the toluene is distilled off under reduced pressure to give crude (20). S) -7α, 2 1-Dihydroxy-1 20-methylpredana 1,4-Gen-1 3-one 21.12 g (purity determined by HP LC: 89.1%, yield 93%) ) Was obtained.

Example 1

Under a nitrogen atmosphere, a crude (2 OS) obtained in Reference Example 1 in a flask having a capacity of 30 Om1 and obtained in Reference Example 1-la, 21 1 -dihydroxy-1 20 -methylpredana-1, 4-gen-1 3-one 9.885 g (Equivalent weight: 8.798 g, 25.5 mmo 1), 2.60 g (38.3 mmo 1) of imidazole and 100 ml of toluene were added and dissolved with stirring. Heated until the internal temperature reached 60 ° C. A solution of 5.00 g (33.2 mmo 1) of tert-butyldimethinolechlorosilane in 2 ml of Tonolene was added to this solution to maintain the internal temperature at 60 ° C to 65 ° C. And the mixture was further stirred for 5 hours after completion of the addition. After cooling the reaction mixture to room temperature, 5 Oml of water was added and the mixture was stirred for 30 minutes. This was filtered, and the residue was washed twice with 30 mL of toluene and then twice with 30 mL of water. The chloride ion concentration of the crystals before and after washing with water was measured to be 3000 ppm and 50 ppm, respectively. The solid was dried under reduced pressure to give (2 OS) -21-t-butyldimethylsilyloxy-17α-hydroxy-20-methylpredana-1,4-4-gen-3-one-10.53 g (90% yield, purity determined by HP LC: 99.6%, melting point: 264-265 ° C).

Example 2

The reaction and post-treatment were carried out in the same manner as in Example 1 except that toluene was replaced with diisopropyl ether in Example 1, and (2 OS) -21-t-butyldimethylsilyloxy_7α-hydroxyl There were obtained 0.53 g of 20-methylpredana-1,4-dien-3-one (90% yield, purity determined by HP LC: 99.2%). Reference example 2

In order to confirm the effect of residual chlorine on the reaction of the next process, the residual chlorine content was different (2 OS) — 21 1-tert-butinoresimetinolecinolenoleoxy-17α-hydroxy 20-methylpregnator Using 1, 4 _ gen _ 3-one, perform perch reduction with metallic lithium in liquid ammonia (Amount of metallic lithium used: 1 mol of raw material On the other hand, the conversion rate of the raw material was measured. The results are shown below.

Raw material lot. No. Chloride ion content (% by mass) Conversion (%)

[1] 0.15 9 0

[2] 0.01> 9 9 Melting point, purity and yield of the products obtained in Examples 1 and 2 and "Synthetic studies on aliphatic and alicyclic bioactive substances" (Nao Nakagawa, Tokyo As is clear from comparison of the melting point and the yield of the product obtained by the method of the University doctoral dissertation, in Examples 1 and 2, the product could be obtained in high yield and high purity. Was.

Industrial applicability

INDUSTRIAL APPLICABILITY The method for producing a predanane derivative of the present invention is useful as a method for using a small amount of a solvent having low toxicity to the environment, and as a method for obtaining a predanane derivative with low waste, high efficiency and high purity. This application is based on a patent application No. 2004-10864 filed in Japan on March 31, 2004, the contents of which are incorporated in full herein.

Claims

The scope of the claims

Formula (I)

(2 OS)-7a, 21 1-Dihydroxy-1-20-methylpredaner 14-1-Gen-3-one is used as a base and one or more solvents selected from hydrocarbons, ethers and esters. In the presence, the compound is converted to a compound of general formula (II)

(Wherein R ^] , R ² and R ³ each independently represent an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a group which has a substituent. Alkynyl group, aralkyl group optionally having substituent (s), aryl group optionally having substituent (s), alkoxyl group optionally having substituent (s) and optionally having substituent (s) A predanane derivative represented by the formula: is produced, and the resulting reaction solution is cooled to precipitate the predanane derivative represented by the general formula (II) as a solid in the reaction solution. A process for producing a predanane derivative represented by the general formula (II), characterized by filtering.

2. The method for producing a predanane derivative according to claim 1, wherein the precipitate is washed with water to remove water-soluble impurities.