WO2010035664A1 - Method for producing bisphosphonic acid derivative - Google Patents

Abstract

A method for producing a bisphosphonic acid derivative [I] or a salt thereof, which is characterized in that a reactive derivative of a carboxylic acid compound [II] is reacted with a phosphite ester [III], then reacted with a phosphite ester [V] and a silyl compound [VI], and then the resulting compound is treated with an acid.  (In the formulae, R represents a lower alkyl group, a lower alkyl group substituted by -NR6R7, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group or an optionally substituted phenyl group; R11, R12, R13, R21, R22 and R23 each represents a C1-18 alkyl group which may be substituted by a phenyl group; R3, R4 and R5 each represents an H, a lower alkyl group, an optionally substituted phenyl group, a halogen atom, a trifluoromethanesulfonyloxy, a methanesulfonyloxy or a p-toluenesulfonyloxy; and X represents a leaving group.)

Description

Production of bisphosphonic acid derivatives

The present invention relates to a method for producing a bisphosphonic acid derivative or a salt thereof useful as a therapeutic agent for osteoporosis.

Bisphosphonic acid derivatives such as alendronic acid, pamidronic acid, risedronic acid, zoledronic acid, etidronic acid and ibandronic acid or salts thereof are useful as therapeutic agents for osteoporosis.

As a method for producing a bisphosphonic acid derivative, the following production method is described in J. Org. Chem., 1995, 60, 8310-831. This document describes a method using methanesulfonic acid as a solvent.

In WO2007 / 010556, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a salt thereof is prepared by reacting 4-aminobutyric acid with phosphorous acid and PCl ₃ in sulfolane and hydrolyzing it. A method of manufacturing is disclosed.

US 2007/0066569 discloses a method for producing bisphosphonic acid or a salt thereof by reacting carboxylic acid with phosphorous acid and PCl _{3 in} the presence of anisole and hydrolyzing it.

In US2007 / 0,142,636 during cresol solvent, by reacting a carboxylic acid with phosphorous acid and PCl _3, by hydrolysis, bisphosphonic acid or a method of producing a salt thereof is disclosed.

The above-described conventional manufacturing method uses an expensive and special solvent for homogenizing the reaction system, and is not suitable for industrial production. Therefore, development of an economical manufacturing method that can be scaled up is desired.

The object of the present invention is to provide a novel process for producing a bisphosphonic acid derivative that can be reacted in a general-purpose solvent and is suitable for industrial production.

As a result of diligent studies to solve the above problems, the present inventor reacted a reactive derivative of carboxylic acid with a phosphite, further reacted a phosphite with a silyl compound, and treated the resulting compound with an acid treatment. As a result, it was found that a bisphosphonic acid derivative or a salt thereof could be produced, and the present invention was completed.

The present invention is as follows.
(1) General formula [II]:
R-COOH
Wherein R is a lower alkyl group, and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). Represents a lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group, or an optionally substituted phenyl group. ]
And a reactive derivative of the carboxylic acid compound represented by the general formula [III]:
P (OR ¹¹ ) (OR ¹² ) (OR ¹³ )
[Wherein R ¹¹ , R ¹² and R ¹³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
A phosphite represented by the general formula [V]:
P (OR ²¹ ) (OR ²² ) (OR ²³ )
[Wherein R ²¹ , R ²² and R ²³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
A phosphite represented by the general formula [VI]:
R ³ R ⁴ R ⁵ Si-X
[Wherein R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group or p- Toluenesulfonyloxy group, X represents a leaving group. ]
A compound represented by the general formula [I]:
R—C (PO ₃ H ₂ ) ₂ OH
[Wherein the symbols have the same meaning as described above. ]
The manufacturing method of the bisphosphonic acid derivative or its salt shown by these.
(2) General formula [VII]:
R—C (PO (OR ¹¹ ) (OR ¹² )) (PO (OR ²¹ ) (OR ²² )) OH
Wherein R is a lower alkyl group, and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). A lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group or an optionally substituted phenyl group, R ¹¹ and R ¹² may be the same or different and may be substituted with a phenyl group The preferred alkyl group having 1 to 18 carbon atoms, R ²¹ and R ²² are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ] The compound shown.
(3) R is (i) a C _1-8 alkyl group, (ii) a formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a C _1-8 alkyl group or C A C _1-8 alkyl group substituted with a group represented by ( _1-8 alkyl-carbonyl group), (iii) a pyridyl group-substituted C _1-8 alkyl group, (iv) an imidazolyl group-substituted C _1-8 alkyl Group or (v) a halogen atom, nitro, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, phenyl-C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 haloalkyl, C _1-8 selected _carbonyl, a _{C 1-8} alkoxycarbonyl and carbamoyl - haloalkoxy, _{amino, C 1-8} alkylamino, di _{C 1-8 alkylamino, C 1-8} alkyl - carbonyl amino, _{formyl, C 1-8} alkyl About 1 to about 5 substituents phenyl group which may be substituted with group (1) the procedure described.
(4) R is methyl, butyl, 3-aminopropyl, 3-acetylaminopropyl, 2-aminoethyl, 3-pyridylmethyl, 1-imidazolylmethyl, 2- (N-methyl-N-pentylamino) ethyl, 5 The process according to (1), which is aminopentyl or 2-dimethylaminoethyl.
(5) The process according to (1), wherein R ¹¹ , R ¹² and R ¹³ are the same or different and are a C _1-8 alkyl group.
(6) The process according to (1), wherein R ¹¹ , R ¹² and R ¹³ are the same or different and are methyl or ethyl.
(7) The process according to (1), wherein R ²¹ , R ²² and R ²³ are the same or different and are a C _1-8 alkyl group.
(8) The process according to (1), wherein R ²¹ , R ²² and R ²³ are the same or different and are methyl or ethyl.
(9) The process according to (1), wherein R ³ , R ⁴ and R ⁵ are the same or different and are a C _1-8 alkyl group.
(10) The process according to (1), wherein R ³ , R ⁴ and R ⁵ are methyl.
(11) The process according to (1), wherein X is a halogen atom.
(12) The reaction of the reactive derivative of the carboxylic acid compound represented by the general formula [II] and the phosphite represented by the general formula [III] is carried out in a solvent selected from halogenated hydrocarbons, toluene and tetrahydrofuran. The manufacturing method according to (1).
(13) The process according to (12), wherein the halogenated hydrocarbon is at least one selected from chloroform and dichloromethane.
(14) A product obtained by reacting a reactive derivative of the carboxylic acid compound represented by the general formula [II] with a phosphite represented by the general formula [III], and represented by the general formula [V] The process according to (1), wherein the reaction with the phosphite and the silyl compound represented by the general formula [VI] is carried out in a solvent selected from halogenated hydrocarbons, toluene and tetrahydrofuran.
(15) The process according to (14), wherein the halogenated hydrocarbon is at least one selected from chloroform and dichloromethane.
(16) The process according to (1), wherein an acid treatment is performed using an inorganic acid.
(17) The process according to (16), wherein the inorganic acid is hydrochloric acid.
(18) The process according to (1), wherein the reactive derivative is an acid halide, trifluoromethanesulfonic anhydride, methanesulfonic anhydride or p-toluenesulfonic anhydride.
(19) The process according to (1), wherein the reactive derivative is an acid halide.
(20) R is (i) a C _1-8 alkyl group, (ii) a formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and are a hydrogen atom, a C _1-8 alkyl group or C A C _1-8 alkyl group substituted with a group represented by ( _1-8 alkyl-carbonyl group), (iii) a pyridyl group-substituted C _1-8 alkyl group, (iv) an imidazolyl group-substituted C _1-8 alkyl Group or (v) a halogen atom, nitro, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, phenyl-C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 haloalkyl, C _1-8 selected _carbonyl, a _{C 1-8} alkoxycarbonyl and carbamoyl - haloalkoxy, _{amino, C 1-8} alkylamino, di _{C 1-8 alkylamino, C 1-8} alkyl - carbonyl amino, _{formyl, C 1-8} alkyl From 1 to 5 substituents in an optionally substituted phenyl group ^{that, R 11} and ^{R 12} are identical or different _{C 1-8} alkyl ^{group, R 21} and ^{R 22} are the same or different The compound according to (2), which is a C _1-8 alkyl group.
(21) R is methyl, butyl, 3-aminopropyl, 3-acetylaminopropyl, 2-aminoethyl, 3-pyridylmethyl, 1-imidazolylmethyl, 2- (N-methyl-N-pentylamino) ethyl, 5 -Aminopentyl or 2-dimethylaminoethyl, R ¹¹ and R ¹² are the same or different and are methyl or ethyl, and R ²¹ and R ²² are the same or different and are methyl or ethyl Compound.

Since the method of the present invention can be performed using a general-purpose solvent such as chloroform and dichloromethane, it is a production method that can be scaled up and is economically advantageous, and is suitable for industrial production.

Regarding the above general formula, the definitions of the symbols are as follows.
In this specification, unless otherwise specified, “lower” means 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms.

Examples of the lower alkyl group represented by R, R ³ , R ⁴ , R ⁵ , R ⁶ or R ⁷ include C _1-8 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, tert-pentyl, hexyl, 2-ethylbutyl and the like.

Examples of the lower alkylcarbonyl group represented by R ⁶ or R ⁷ include C _1-8 alkyl-carbonyl groups having 1 to 8 carbon atoms in the alkyl moiety, such as acetyl, propionyl, butyryl, isobutyryl, valeryl, Examples include isovaleryl and pivaloyl.

Substituted with a group represented by the formula: —NR ⁶ R ⁷ represented by R (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group) lower alkyl group "is intended to lower alkyl group as defined above is substituted with a group represented by the formula -NR ⁶ R ^7, C substituted with a group represented by the formula -NR ⁶ R ⁷ _{1- An 8} alkyl group is mentioned. Examples include aminomethyl, 2-aminoethyl, 3-aminopropyl, 5-aminopentyl, 2- (N-methyl-N-pentylamino) ethyl, 2-dimethylaminoethyl, 3-acetylaminopropyl, and the like.

The “pyridyl group-substituted lower alkyl group” represented by R is one in which the lower alkyl group defined above is substituted with a pyridyl group, and examples thereof include a pyridyl group-substituted C _1-8 alkyl group. For example, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl and the like can be mentioned. 3-Pyridylmethyl is preferable.

The “imidazolyl group-substituted lower alkyl group” represented by R is a group in which the above-defined lower alkyl group is substituted with an imidazolyl group, and includes an imidazolyl group-substituted C _1-8 alkyl group. Examples thereof include 1-imidazolylmethyl, 2-imidazolylmethyl, 4-imidazolylmethyl and the like. 1-imidazolylmethyl is preferable.

As the “optionally substituted phenyl group” represented by R, R ³ , R ⁴ or R ⁵ , a halogen atom (eg, bromine atom, chlorine atom, fluorine atom, iodine atom), nitro, cyano, hydroxy C _1-8 alkyl, C _1-8 alkoxy, phenyl-C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 haloalkyl, C _1-8 haloalkoxy, amino, C _1-8 alkylamino, di May be substituted with 1 to 5 substituents selected from C _1-8 alkylamino, C _1-8 alkyl-carbonylamino, formyl, C _1-8 alkyl-carbonyl, C _1-8 alkoxycarbonyl and carbamoyl A good phenyl group is mentioned. Preferably, it is phenyl.

Preferable examples of R include methyl, butyl, 3-aminopropyl, 3-acetylaminopropyl, 2-aminoethyl, 3-pyridylmethyl, 1-imidazolylmethyl, 2- (N-methyl-N-pentylamino) Examples include ethyl, 5-aminopentyl, 2-dimethylaminoethyl and the like.

Examples of the “alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group” represented by R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² and R ²³ include, for example, methyl, ethyl, propyl , Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, tert-pentyl, hexyl, 2-ethylbutyl, 2-ethylhexyl, octyl, nonyl, decyl , Benzyl, phenethyl, 1-phenylethyl, 3-phenylpropyl and the like.

R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² and R ²³ may be the same or different.
Preferable examples of R ¹¹ , R ¹² and R ¹³ include a lower alkyl group. More preferred is methyl or ethyl, and particularly preferred is methyl.
Preferable examples of R ²¹ , R ²² and R ²³ include a lower alkyl group. More preferred is methyl or ethyl, and particularly preferred is methyl.

Preferable examples of R ³ , R ⁴ and R ⁵ include a lower alkyl group. More preferred is methyl.

Examples of the “leaving group” include a halogen atom (eg, bromine atom, chlorine atom, iodine atom), trifluoromethanesulfonyloxy, methanesulfonyloxy, p-toluenesulfonyloxy and the like. A halogen atom is preferable, and a bromine atom is more preferable.

Preferred examples of the bisphosphonic acid derivative represented by the general formula [I] include etidronic acid (R is methyl), 1-hydroxybutylidene-1,1-bisphosphonic acid (R is butyl), and alendronic acid (R is 3-aminopropyl), pamidronic acid (R is 2-aminoethyl), risedronic acid (R is 3-pyridylmethyl), zoledronic acid (R is 1-imidazolylmethyl), ibandronic acid (R is 2- (N-methyl) -N-pentylamino) ethyl), neridronic acid (R is 5-aminopentyl), olpadronic acid (R is 2-dimethylaminoethyl), and the like.

Preferable examples of the carboxylic acid compound represented by the general formula [II] include acetic acid, pentanoic acid, 4-aminobutanoic acid, 4-acetylaminobutanoic acid, 3-aminopropanoic acid, (3-pyridyl) acetic acid, (1 -Imidazolyl) acetic acid, 3- (N-methyl-N-pentylamino) propanoic acid, 6-aminohexanoic acid, 3- (dimethylamino) propanoic acid and the like.

Examples of the reactive derivative of the carboxylic acid compound represented by the general formula [II] include acid halides (eg, acid chloride, acid bromide, acid iodide), trifluoromethanesulfonic anhydride, methanesulfonic anhydride, p-toluenesulfone. An acid anhydride etc. are mentioned. An acid halide is preferable, and an acid chloride is more preferable.

Preferable examples of the phosphite represented by the general formula [III] include trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tributyl phosphite, tribenzyl phosphite, tris phosphite ( 2-ethylhexyl) and the like. Trialkyl phosphite is preferred, and trimethyl phosphite or triethyl phosphite is more preferred.

Preferable examples of the phosphite represented by the general formula [V] include trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, tributyl phosphite, tribenzyl phosphite, tris phosphite ( 2-ethylhexyl) and the like. Trialkyl phosphite is preferred, and trimethyl phosphite or triethyl phosphite is more preferred.

Preferred examples of the silyl compound represented by the general formula [VI] include iodotrimethylsilane, bromotrimethylsilane, chlorotrimethylsilane, trimethylsilyl trifluoromethanesulfonate, and trimethylsilyl methanesulfonate. Preferred is bromotrimethylsilane.

Examples of the salt of the bisphosphonic acid derivative represented by the general formula [I] include alkali metal salts such as sodium salt (monosodium salt, disodium salt) and potassium salt (monopotassium salt, dipotassium salt). Preferably, it is a sodium salt (monosodium salt, disodium salt).

In the present invention, the bisphosphonic acid derivative represented by the general formula [I] or a salt thereof includes a solvate. Examples of solvates include hydrates and alcohol solvates (eg, methanol solvates and ethanol solvates).

Next, the production method of the present invention will be described in detail. The production method of the present invention is represented by the following reaction formula.

The production method of the present invention is considered to be via the following route.
General formula [II]:
R-COOH
Wherein R is a lower alkyl group, and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). Represents a lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group, or an optionally substituted phenyl group. ]
And a reactive derivative of the carboxylic acid compound represented by the general formula [III]:
P (OR ¹¹ ) (OR ¹² ) (OR ¹³ )
[Wherein R ¹¹ , R ¹² and R ¹³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
Is reacted with a phosphite represented by the general formula [IV]:
R-CO- (PO (OR ¹¹ ) (OR ¹² ))
[Wherein the symbols have the same meaning as described above. ]
And a compound represented by the general formula [V]:
P (OR ²¹ ) (OR ²² ) (OR ²³ )
[Wherein R ²¹ , R ²² and R ²³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
A phosphite represented by the general formula [VI]:
R ³ R ⁴ R ⁵ Si-X
[Wherein R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group or p- Toluenesulfonyloxy group, X represents a leaving group. ]
Is reacted with a silyl compound represented by the general formula [VII]:
R—C (PO (OR ¹¹ ) (OR ¹² )) (PO (OR ²¹ ) (OR ²² )) OH
[Wherein the symbols have the same meaning as described above. ]
And a compound represented by the general formula [I]: wherein the compound is treated with an acid.
R—C (PO ₃ H ₂ ) ₂ OH
[Wherein the symbols have the same meaning as described above. ]
The manufacturing method of the bisphosphonic acid derivative or its salt shown by these.

A reactive derivative of a carboxylic acid compound represented by the general formula [II] (hereinafter referred to as carboxylic acid compound [II]) and a phosphite represented by the general formula [III] (hereinafter referred to as phosphite [III]) Can be carried out in a solvent that does not inhibit the reaction.
Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane and chlorobenzene; toluene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, diethyl ether, diisopropyl ether and the like. Preferably, halogenated hydrocarbons such as chloroform and dichloromethane; or toluene and tetrahydrofuran are used.
The amount of the solvent to be used is generally 0.5 to 100 ml, preferably 5 to 10 ml, with respect to 1 g of the reactive derivative of carboxylic acid compound [II].

The amount of the phosphite [III] to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the reactive derivative of the carboxylic acid compound [II].
The reaction may be performed in the presence of a base. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine.
The amount of the base used is usually 0.5 to 10 mol, preferably 1 to 2 mol, relative to 1 mol of the reactive derivative of the carboxylic acid compound [II].
The reaction temperature is usually −50 ° C. to 150 ° C., preferably −20 ° C. to 40 ° C. The reaction time is usually 0.1 to 24 hours, preferably 1 to 5 hours.

The compound obtained by the above reaction is further converted into a phosphite ester represented by general formula [V] (hereinafter referred to as phosphite ester [V]) and a silyl compound represented by general formula [VI] (hereinafter referred to as silyl compound). [VI]).

The reaction can be performed by mixing the phosphite [V] and the silyl compound [VI] into the reaction mixture containing the compound obtained by the above reaction. Alternatively, the product is recovered by distilling off the solvent from the reaction mixture obtained by the above reaction, and this is dissolved or suspended in a suitable solvent to obtain the phosphite [V] and the silyl compound [VI]. You may mix.

The amount of the phosphite [V] to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the reactive derivative of the carboxylic acid compound [II].
The amount of silyl compound [VI] to be used is generally 1 to 10 mol, preferably 1 to 2 mol, per 1 mol of the reactive derivative of carboxylic acid compound [II].
Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane and chlorobenzene; toluene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, diethyl ether, diisopropyl ether and the like. Preferably, halogenated hydrocarbons such as chloroform and dichloromethane; or toluene and tetrahydrofuran are used.
The reaction temperature is usually −50 ° C. to 150 ° C., preferably −20 ° C. to 40 ° C. The reaction time is usually 0.1 to 24 hours, preferably 1 to 5 hours.

By subjecting the obtained compound to acid treatment, a bisphosphonic acid derivative represented by the general formula [I] (hereinafter referred to as bisphosphonic acid derivative [I]) or a salt thereof can be obtained. The acid treatment can be performed in the presence of water.
Acids used for the acid treatment include inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid and sulfuric acid; organic acids such as methanesulfonic acid; Lewis acids such as trimethylsilyl iodide, trimethylsilyl bromide, trimethylsilyl chloride, and sodium iodide Is mentioned. Preferably, it is hydrochloric acid.
The amount of the acid used is usually 1 to 100 ml, preferably 5 to 50 ml, based on 1 g of the reactive derivative of the carboxylic acid compound [II].
The reaction temperature is usually −20 ° C. to 200 ° C., preferably 50 ° C. to 150 ° C. The reaction time is usually 0.1 to 24 hours, preferably 1 to 5 hours.

When producing a bisphosphonic acid derivative [I] in which R is a lower alkyl group substituted with an amino group, the reactivity of the carboxylic acid compound [II] in which the amino group is protected with a lower alkylcarbonyl group (eg, acetyl) The reaction can be carried out using derivatives. By deprotection by acid treatment, a bisphosphonic acid derivative [I] in which R is a lower alkyl group substituted with an amino group can be obtained.

By reacting the obtained bisphosphonic acid derivative [I] with a base, a salt of the bisphosphonic acid derivative [I] can be obtained.
Suitable bases include, for example, alkali metal compounds such as sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate. These bases can be used as an aqueous solution or an alcohol solution (eg, methanol solution, ethanol solution). A sodium hydroxide aqueous solution is preferable.
The base may be used in an amount necessary to form the desired salt (eg, monosodium salt, disodium salt, monopotassium salt, dipotassium salt).

The obtained bisphosphonic acid derivative [I] or a salt thereof can be recovered by distilling off the solvent from the reaction mixture or by precipitating from the reaction mixture. The obtained product can be purified according to conventional methods such as recrystallization, crystallization, column chromatography, distillation and the like.

The reactive derivative of the carboxylic acid compound [II] can be produced from the carboxylic acid compound [II] according to a conventional method. For example, the acid halide of the carboxylic acid compound [II] can be obtained by reacting the carboxylic acid compound [II] with a halogenating agent such as oxalyl chloride or thionyl chloride. The halogenation can be carried out in a solvent that does not inhibit the reaction. Examples of the solvent include halogenated hydrocarbons such as chloroform, dichloromethane and chlorobenzene; toluene, tetrahydrofuran, dioxane, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, diethyl ether, diisopropyl ether and the like. A catalytic amount of N, N-dimethylformamide may be added to the reaction system. The reaction temperature is usually −50 ° C. to 200 ° C., preferably −20 ° C. to 120 ° C. The reaction time is usually 0.1 to 24 hours, preferably 1 to 5 hours. On the other hand, the trifluoromethanesulfonic anhydride, methanesulfonic anhydride or p-toluenesulfonic anhydride of the carboxylic acid compound [II] is obtained by converting the carboxylic acid compound [II] to trifluoromethanesulfonyl chloride, methanesulfonyl chloride or p-toluene. It can be obtained by reacting with a sulfonylating agent such as sulfonyl chloride in the presence of a base such as pyridine, lutidine or triethylamine. The sulfonylation can be carried out in a solvent that does not inhibit the reaction. Examples of the solvent include dichloromethane, tetrahydrofuran, toluene, ethyl acetate, diisopropyl ether, dioxane and the like. The reaction temperature is generally −78 ° C. to 150 ° C., preferably −10 ° C. to 50 ° C. The reaction time is usually 0.01 to 48 hours, preferably 0.1 to 5 hours.

General formula [VII] obtained in the reaction step of the production method of the present invention:
R—C (PO (OR ¹¹ ) (OR ¹² )) (PO (OR ²¹ ) (OR ²² )) OH
Wherein R is a lower alkyl group and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). A lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group or an optionally substituted phenyl group, R ¹¹ and R ¹² may be the same or different and may be substituted with a phenyl group The preferred alkyl group having 1 to 18 carbon atoms, R ²¹ and R ²² are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ] Is a novel compound.

EXAMPLES The present invention will be described more specifically with reference to examples below, but the present invention is not limited thereto.
In the following examples, “room temperature” refers to a temperature of 10 ° C. to 35 ° C.

Example 1

Valeryl chloride (1) (903 mg, 7.5 mmol) was added dropwise at 8 ° C. to 10 ° C. to a stirred solution of trimethyl phosphite (930 mg, 7.5 mmol) in chloroform (5 ml). After stirring at room temperature for 1 hour, trimethyl phosphite (0.88 ml, 7.5 mmol) and bromotrimethylsilane (0.96 ml, 7.5 mmol) were added to the reaction mixture at 8 ° C. to 10 ° C. After stirring at room temperature for 1 hour, the solvent was distilled off. 6N hydrochloric acid (10 ml) was added to the residue. The reaction mixture was refluxed overnight. The solvent was distilled off to obtain Compound 2 (2.4 g, quantitative) as a pale yellow oil.
MS (ESI) m / z: 247 (M ⁺ -H); ¹ H-NMR (D ₂ O) δ: 1.93-2.08 (m, 2H), 1.50-1.55 (m, 2H), 1.28-1.40 (m , 2H), 0.85-0.93 (m, 3H).

Example 2

Concentrated sulfuric acid (1 drop) was added to a suspension of 4-aminobutanoic acid (GABA) (20.6 g, 0.2 mol) in acetic anhydride (20 ml). The mixture was stirred at 100 ° C. overnight. After cooling, diisopropyl ether was added to the reaction mixture. The resulting precipitate was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure at 60 ° C. to obtain compound 3 (24.9 g, yield 86%) as a colorless solid.
mp: 127-130 ° C; MS (ESI) m / z: 144 (M ⁺ -H); IR (Nujol) cm ^-1 : 1710, 1610, 1555; ¹ H-NMR (DMSO-d ₆ ) δ: 2.95 -3.05 (m, 2H), 2.15-2.25 (m, 2H), 1.75 (s, 3H), 1.55-1.65 (m, 2H); Anal.Calcd for C ₆ H ₁₁ NO ₃ : C, 49.65; H, 7.64; N, 9.65. Found: C, 49.58; H, 7.67; N, 9.63.

To a stirred suspension of compound 3 (20.0 g, 138 mmol) in dichloromethane (100 ml), oxalyl chloride (22.5 ml, 276 mmol) was added dropwise under ice cooling. After adding N, N-dimethylformamide (1 drop), the mixture was stirred at room temperature for 2 hours. The solvent was distilled off to obtain the acid chloride of Compound 3 as a colorless viscous oil. Trimethyl phosphite (17.1 g, 138 mmol) was added dropwise at −10 ° C. to 0 ° C. to a solution of the acid chloride of Compound 3 in chloroform (100 ml). After stirring at room temperature for 1 hour, trimethyl phosphite (17.1 g, 138 mmol) and bromotrimethylsilane (18 ml, 138 mmol) were added to the reaction mixture at −10 ° C. to 0 ° C. After stirring at room temperature for 1 hour, the solvent was distilled off. 6N hydrochloric acid (160 ml) was added to the residue. The reaction mixture was refluxed overnight. The solvent was distilled off to obtain an oil, which was taken up in water (100 ml). The pH was adjusted to 4.3 with aqueous sodium hydroxide. The resulting colorless precipitate was collected by filtration, washed with water and ethanol, and dried to give compound 5 (7.59 g, yield 20%, including impurities) as a colorless solid. After allowing the mother liquor to stand overnight, a light brown solid separated from the mother liquor. This solid was collected by filtration, washed with water and ethanol, and dried to obtain a light brown solid (24.77 g) containing Compound 5. Precipitation from the mother liquor and filtration were performed again to obtain a light brown solid (12.08 g) containing Compound 5. The solid containing compound 5 was dissolved in water. After stirring overnight and diluting with ethanol, the solid was collected by filtration, washed with water and ethanol, and dried to give compound 5 (26.84 g, 70% yield) as an almost colorless solid.
mp: 261-264 ° C (dec.); MS (ESI) m / z: 247 (M ⁺ -Na); ¹ H-NMR (D ₂ O) δ: 3.00-3.10 (m, 2H), 1.95-2.10 (m, 4H); IR (Nujol) cm ^-1 : 1649.

Example 3

To a stirred suspension of compound 3 (4.45 g, 30.7 mmol) in dichloromethane (30 ml), oxalyl chloride (5.3 ml, 62 mmol) was added dropwise under ice cooling. After adding N, N-dimethylformamide (1 drop), the mixture was stirred at room temperature for 2 hours. The solvent was distilled off to obtain the acid chloride of Compound 3 as a colorless viscous oil. Trimethyl phosphite (3.6 ml, 31 mmol) was added dropwise to a solution of the acid chloride of Compound 3 in chloroform (20 ml) under ice cooling. After stirring at room temperature for 1 hour, trimethyl phosphite (3.6 ml, 31 mmol) and bromotrimethylsilane (4 ml, 31 mmol) were added to the reaction mixture under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off. 6N hydrochloric acid (40 ml) was added to the residue. The reaction mixture was refluxed overnight. The solvent was distilled off to obtain an oil, and water was added thereto. The mixture was heated to 60 ° C to 90 ° C in a water bath, sonicated and diluted with ethanol. The resulting colorless precipitate was collected by filtration, washed with water and ethanol, and compound 6 (4.29 g, yield). 56%) was obtained as a colorless solid.
mp: 235-237 ° C (dec.); MS (ESI) m / z: 248 (M ⁺ ); ¹ H-NMR (D ₂ O) δ: 3.00-3.10 (m, 2H), 1.95-2.10 (m , 4H); IR (Nujol) cm ^-1 : 1630.

Example 4

Oxalyl chloride (2.6 ml, 30 mmol) was added dropwise to a suspension of compound 7 (2.02 g, 14.7 mmol) in dichloromethane (15 ml) with stirring under ice cooling. After adding N, N-dimethylformamide (1 drop), the mixture was stirred at room temperature for 3 hours. The solvent was distilled off to give compound 8 as a pale yellow and partially purple solid. To a suspension of compound 8 in chloroform (15 ml), trimethyl phosphite (1.8 ml, 15 mmol) and triethylamine (2.1 ml, 15 mmol) were added dropwise under ice cooling. After stirring at room temperature for 1 hour, trimethyl phosphite (1.8 ml, 15 mmol) and bromotrimethylsilane (2 ml, 15 mmol) were added to the reaction mixture containing Compound 9 under ice cooling. After stirring at room temperature for 1 hour, the solvent was distilled off to obtain Compound 10 as a brown oil.
MS (APCI) m / z: 340 (M + + H).

Concentrated hydrochloric acid (20 ml) was added to compound 10. After refluxing overnight, the solvent was distilled off to obtain a brown oil, to which ethanol and water were added. The resulting brown precipitate was collected by filtration and dried to obtain a crude product of compound 11 (1.135 g) as a brown amorphous solid. The crude product of Compound 11 (940 mg) was crystallized from water, and the crystals were collected by filtration, washed with cold water and ethanol, and dried to give Compound 11 (505 mg) as a black gray solid. To compound 11 (490 mg) was added 1N aqueous sodium hydroxide solution (1.7 ml). The above aqueous solution was added dropwise to acetone while stirring. The resulting pale brown precipitate was collected by filtration, washed with acetone, and dried to give Compound 12 (554 mg, 14% yield from Compound 7) as a pale brown solid.
MS (ESI) m / z: 282 (M ⁺ -H); ¹ H-NMR (D ₂ O) δ: 8.70-8.75 (m, 1H), 8.45-8.60 (m, 2H), 7.80-7.90 (m , 1H), 3.40-3.50 (m, 2H); Anal.Calcd for C ₇ H ₁₀ NO ₇ P ₂ Na1.6H ₂ O0.2NaOH: C, 24.59; H, 3.95; N, 4.10; Na, 8.07 ; P, 18.12. Found: C, 24.39; H, 3.68; N, 3.92; Na, 7.98; P, 15.40; IR (Nujol) cm ^-1 : 1660.

ADVANTAGE OF THE INVENTION According to this invention, the manufacturing method of a bisphosphonic acid derivative or its salt useful as an osteoporosis therapeutic agent is provided. Since the reaction of the present invention can be carried out using a general-purpose solvent such as chloroform and dichloromethane, it can be scaled up and is economically advantageous, and is suitable for industrial production.
In addition, the compound represented by the general formula [VII] is useful as an intermediate of a bisphosphonic acid derivative or a salt thereof.

This application is based on Japanese Patent Application No. 2008-244171 filed in Japan, the contents of which are incorporated in full herein.

Claims (21)

General formula [II]:
R-COOH
Wherein R is a lower alkyl group, and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). Represents a lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group, or an optionally substituted phenyl group. ]
And a reactive derivative of the carboxylic acid compound represented by the general formula [III]:
P (OR ¹¹ ) (OR ¹² ) (OR ¹³ )
[Wherein R ¹¹ , R ¹² and R ¹³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
A phosphite represented by the general formula [V]:
P (OR ²¹ ) (OR ²² ) (OR ²³ )
[Wherein R ²¹ , R ²² and R ²³ are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ]
A phosphite represented by the general formula [VI]:
R ³ R ⁴ R ⁵ Si-X
[Wherein R ³ , R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group, an optionally substituted phenyl group, a halogen atom, a trifluoromethanesulfonyloxy group, a methanesulfonyloxy group or p- Toluenesulfonyloxy group, X represents a leaving group. ]
A compound represented by the general formula [I]:
R—C (PO ₃ H ₂ ) ₂ OH
[Wherein the symbols have the same meaning as described above. ]
The manufacturing method of the bisphosphonic acid derivative or its salt shown by these. Formula [VII]:
R—C (PO (OR ¹¹ ) (OR ¹² )) (PO (OR ²¹ ) (OR ²² )) OH
Wherein R is a lower alkyl group, and a group represented by the formula —NR ⁶ R ⁷ (wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a lower alkyl group or a lower alkylcarbonyl group). A lower alkyl group substituted with, a pyridyl group-substituted lower alkyl group, an imidazolyl group-substituted lower alkyl group or an optionally substituted phenyl group, R ¹¹ and R ¹² may be the same or different and may be substituted with a phenyl group The preferred alkyl group having 1 to 18 carbon atoms, R ²¹ and R ²² are the same or different and each represents an alkyl group having 1 to 18 carbon atoms which may be substituted with a phenyl group. ] The compound shown. R is (i) a C _1-8 alkyl group, (ii) a formula —NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-8 alkyl group or a C _1-8 A C _1-8 alkyl group substituted with a group represented by (C) represents an alkyl-carbonyl group, (iii) a pyridyl group-substituted C _1-8 alkyl group, (iv) an imidazolyl group-substituted C _1-8 alkyl group, or ( v) halogen atom, nitro, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, phenyl-C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 haloalkyl, C _1-8 haloalkoxy, a 1 chosen _carbonyl, a _{C 1-8} alkoxycarbonyl and carbamoyl - _{amino, C 1-8} alkylamino, di _{C 1-8 alkylamino, C 1-8} alkyl - carbonyl amino, _{formyl, C 1-8} alkyl Process according to claim 1, which is a 5 substituents phenyl group which may be substituted with group and. R is methyl, butyl, 3-aminopropyl, 3-acetylaminopropyl, 2-aminoethyl, 3-pyridylmethyl, 1-imidazolylmethyl, 2- (N-methyl-N-pentylamino) ethyl, 5-aminopentyl Or the process according to claim 1, which is 2-dimethylaminoethyl. The process according to claim 1, wherein R ¹¹ , R ¹² and R ¹³ are the same or different and each is a C _1-8 alkyl group. The process according to claim 1, wherein R ¹¹ , R ¹² and R ¹³ are the same or different and are methyl or ethyl. The process according to claim 1, wherein R ²¹ , R ²² and R ²³ are the same or different and each is a C _1-8 alkyl group. The process according to claim 1, wherein R ²¹ , R ²² and R ²³ are the same or different and are methyl or ethyl. The process according to claim 1, wherein R ³ , R ⁴ and R ⁵ are the same or different and each is a C _1-8 alkyl group. The process according to claim 1, wherein R ³ , R ⁴ and R ⁵ are methyl. The process according to claim 1, wherein X is a halogen atom. The reaction of the reactive derivative of the carboxylic acid compound represented by the general formula [II] and the phosphite represented by the general formula [III] is carried out in a solvent selected from halogenated hydrocarbons, toluene and tetrahydrofuran. Item 1. The production method according to Item 1. The process according to claim 12, wherein the halogenated hydrocarbon is at least one selected from chloroform and dichloromethane. A product obtained by reacting a reactive derivative of the carboxylic acid compound represented by the general formula [II] with a phosphite represented by the general formula [III], and phosphorous acid represented by the general formula [V] The process according to claim 1, wherein the reaction with the ester and the silyl compound represented by the general formula [VI] is carried out in a solvent selected from a halogenated hydrocarbon, toluene and tetrahydrofuran. The process according to claim 14, wherein the halogenated hydrocarbon is at least one selected from chloroform and dichloromethane. The process according to claim 1, wherein the acid treatment is performed using an inorganic acid. The process according to claim 16, wherein the inorganic acid is hydrochloric acid. The process according to claim 1, wherein the reactive derivative is an acid halide, trifluoromethanesulfonic anhydride, methanesulfonic anhydride or p-toluenesulfonic anhydride. The process according to claim 1, wherein the reactive derivative is an acid halide. R is (i) a C _1-8 alkyl group, (ii) a formula —NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are the same or different and each represents a hydrogen atom, a C _1-8 alkyl group or a C _1-8 A C _1-8 alkyl group substituted with a group represented by the following _formula : (iii) a pyridyl group-substituted C _1-8 alkyl group, (iv) an imidazolyl group-substituted C _1-8 alkyl group or ( v) halogen atom, nitro, cyano, hydroxy, C _1-8 alkyl, C _1-8 alkoxy, phenyl-C _1-8 alkoxy, C _1-8 alkylthio, C _1-8 haloalkyl, C _1-8 haloalkoxy, a 1 chosen _carbonyl, a _{C 1-8} alkoxycarbonyl and carbamoyl - _{amino, C 1-8} alkylamino, di _{C 1-8 alkylamino, C 1-8} alkyl - carbonyl amino, _{formyl, C 1-8} alkyl A and 5 substituents phenyl group which may be substituted with a ^{group, R 11} and ^{R 12} are the same or different is a _{C 1-8} alkyl ^{group, R 21} and ^{R 22} are the same or different C The compound according to claim 2, which is a _1-8 alkyl group. R is methyl, butyl, 3-aminopropyl, 3-acetylaminopropyl, 2-aminoethyl, 3-pyridylmethyl, 1-imidazolylmethyl, 2- (N-methyl-N-pentylamino) ethyl, 5-aminopentyl Or 2-dimethylaminoethyl, R ¹¹ and R ¹² are the same or different and are methyl or ethyl, and R ²¹ and R ²² are the same or different and are methyl or ethyl.