WO2005066188A1

WO2005066188A1 - A process for the preparation of 2-(imidazol-1-yl)-1-hydroxyethane-1, 1-diphosphonic acid

Info

Publication number: WO2005066188A1
Application number: PCT/IN2004/000320
Authority: WO
Inventors: Vijaykumar Muljibhai Patel; Trinadha Rao Chitturi; Rajamannar Thennati
Original assignee: Sun Pharmaceutical Industries Ltd
Current assignee: Sun Pharmaceutical Industries Ltd
Priority date: 2003-10-17
Filing date: 2004-10-18
Publication date: 2005-07-21
Anticipated expiration: 2006-04-17

Abstract

The present invention provides a process for preparation of 2-(imidazol-1-yl)-1-hydroxyethane-1,1-diphosphonic acid, compound of formula (1), said process comprising (a) reacting imidazole with chloroacetyl chloride and benzyl alcohol in homogenous system in one pot to obtain benzyl 1-imidazolylacetate, compound of formula (3); (b) debenzylating benzyl 1-imidazolylacetate, a compound of formula (3) to imidazole 1-ylacetic acid, compound of formula (2) and (c) converting compound of formula (2) to compound of formula (1).

Description

A PROCESS FOR THE PREPARATION OF 2-(IMIDAZOL-l-YL)-l- HYDROXYETHANE-l.l-DIPHOSPHONIC ACID

The present invention relates to a process for the preparation of 2~(imidazol-l-yl)-l- hydroxyethane- 1 , 1 -diphosphonic acid, compound of formula 1, commonly known as zoledronic acid (INN Name) used as medicament for treatment of diseases associated with impairment of calcium metabolism.

Formula 1

BACKGROUND OF THE INVENTION

United States Patent No. 4,939,130 (Assigned to: Ciba-Geigy Corporation) discloses the preparation of zoledronic acid, compound of formula 1, from imidazol-1-ylacetic acid, compound of formula 2, o Formula 2 by two methods viz.

(a) Compound of formula 2 or its acid chloride is treated with suitable triphosphite of formula P(OR)₃ to give an intermediate compound which is reacted with a diphosphite of formula HPO(OR)₂ to give the diphosphonate, which on hydrolysis gives zoledronic acid, compound of formula 1.

(b) Compound of formula 2 is treated with phosphorous acid and phosphorus trihalide in halogenated hydrocarbons followed by hydrolysis to give zoledronic acid, compound of fomiula 1. This patented process however does not disclose the process for preparing imidazol-1 - ylacetic acid, compound of formula 2, the starting raw material for synthesis of zoledronic acid. Birkofer et.al in Chemische Berichte 1960, 93, 2804-9 reports the synthesis of imidazol- 1 -ylacetic acid by hydrolysis of trimethylsilyl 1-imidazoleacetate. This process uses silylating agents which are expensive.

Prior art methods (a) Zaderenko et.al in J. Org. Chem. 1994, 59, 6268-73 and (b) PCT publication 9955670 prepare different alkyl or alkylaryl esters of imidazol-1 -ylacetic acid. Further method (b) describes hydrolysis of the ester of imidazol-1 -ylacetic acid to imidazol-1 -ylacetic acid, compound of formula 2, by heating in water. The preparation of the ester involves treating imidazole with the required haloacetates in presence of potassium hydroxide and potassium carbonate in methylene dichloride and facilitator like l,5-bis[(N-benzyl-N,N-diethylammonio)ethyl]ether dichloride (BBDED). The method reported in prior art for synthesis of esters has several disadvantages, (i) It requires usage of haloacetates, which are relatively expensive, (ii) Additional base is used in the reaction which is inorganic that makes the reaction mixture heterogeneous and requires use of facilitator to facilitate the reaction, (iii) The yields of most of the esters obtained by this method are low. Method (a) prepares benzyl esters of imidazol-1 -yl acetic acid in low yield. Method (b) discloses preparation of methyl and malonyl esters of imidazol-1 - ylacetic acid in 70-80% and 49% yield respectively. Hydrolysis of these compounds will further reduce the overall yield of imidazol-1 -ylacetic acid, compound of fomiula 2. The process of the present invention prepares the benzyl ester of imidazol-1 -ylacetic acid, compound of fomiula 3, in greater than 80% yield. All the above mentioned prior art references prepare the haloacetate or trimethylsilyl haloacetate separately and then treat it with imidazole. The process of the present invention prepares the compound of formula 3, by directly reacting imidazole with benzyl alcohol and chloroacetyl chloride in one pot. It does not need a separate unit operation for preparation of the haloacetatae.

Surprisingly the benzyl ester of imidazol-1 -ylacetic acid, compound of formula 3, may be prepared in high yields, in one pot in a homogenous system by a novel method without the use of expensive haloacetates. The benzyl 1-imidazolylacetate, compound of fomiula 3, is then converted to imidazol-1 -ylacetic acid, compound of fomiula 2, by catalytic hydrogenolysis or by acid hydrolysis which is further converted to compound of fomiula 1.

Fomiula 3 Formula 2

OBJECTS OF THE INVENTION:

The object of the present invention is to provide a simple and cost-effective process for the preparation of compound of fomiula 1.

Another object of the present invention is to prepare compound of fomiula 3 by a novel process in high yields by simple, convenient and commercially viable method from readily available and cheap reagents.

The compound of fomiula 3 can be used as an intermediate for the preparation of imidazole derivatives such as compound of fomiula 1.

SUMMARY OF INVENTION : The present invention provides a process for preparation of 2-(imidazol-l-yl)- 1- hydroxyethane- 1,1 -diphosphonic acid, compound of formula 1, said process comprising

Formula 1

(a) reacting imidazole with chloroacetyl chloride and benzyl alcohol in a homogenous system in one pot to obtain benzyl 1- imidazolylacetate, compound of formula 3;

Formula 3 (b) debenzylating benzyl 1-imidazolylacetate, compound of formula 3, to imidazol-1 - ylacetic acid, compound of formula 2, and

Formula 2 (c) converting compound of fomiula 2 to compound of fomiula 1.

The present invention also provides a process for preparing benzyl 1-imidazolylacetate, compound of formula 3, said process comprising

Formula 3 reacting imidazole with chloroacetyl chloride and benzyl alcohol in a homogenous system in one pot.

DETAILED DESCRIPTION OF THE INVENTION We have now developed a high yielding commercially viable process for the preparation of 2-(imidazol-l-yl)-l-hydroxyethane- 1,1 -diphosphonic acid, compound of fomiula 1. According to the process of the present invention 2-(imidazol-l-yl)-l-hydroxyethane-l,l- diphosphonic acid, compound of fomiula 1, may be prepared from compound of foπnula 3

Foπnula 1

Fomiula 2

This process prepares compound of formula 3 from cheap and readily available raw materials in a single pot. The compound of fomiula 3 is then debenzylated to compound of formula 2 which is then converted to compound of foπnula 1.

According to one embodiment of the process of the present invention the compound of foπnula 3, benzyl 1-imidazolylacetate, is prepared by reaction of imidazole with chloroacetyl chloride and benzyl alcohol in an organic solvent.

The process of the present invention prepares compound of fomiula 3, benzyl- 1- imidazolyl acetate, in one pot starting from chloroacetyl chloride, benzyl alcohol and imidazole. Imidazole is present in molar excess over chloroacetyl chloride and acts as reactant as well as base. The molar ratio of chloroacetyl chloride: imidazole may be selected in the range from 1 :2 to about 1 :6, preferably 1 :3.

Accordingly the process of the present invention is carried out in absence of additional base. The use of excess of imidazole avoids use of an additional inorganic base such as hydroxides, carbonates of alkali and alkaline earth metal salts such as potassium hydroxide &/or potassium carbonate and the like, or an organic base like tertiary alkylamines, such as triethylamine, diisopropylethylamine etc.

The reaction mixture of the present invention is homogenous, as imidazole is soluble in organic solvent, and a separate additional base is not used in the reaction. Accordingly the process of the present invention obviates the requirement of a facilitator such as a phase transfer catalyst.

The organic solvent may be selected from non-polar solvents like linear or cyclic aliphatic or aromatic hydrocarbons such as n-hexane, n-heptane, cyclohexane, methylcyclohexane, toluene, ethylbenzene, xylene and the like; aliphatic or aromatic halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, tetrachloroethane, trichloroethane, chlorobenzene, dichlorobenzene and the like; ethereal solvents, such as diethylether, di-isopropylether, dioxane, tetrahydrofuran and the like; esters such as ethyl acetate, tert-butyl acetate and the like; or inert polar aprotic solvents such as acetonitrile, sulfolane and the like.

The reaction may be carried out at temperature ranging from 30 to 100°C, preferably 40 to 70°C. The compound of formula 3 is thus prepared in high yields by simple, convenient and commercially viable method from readily available, and cheap reagents with reduced number of unit operations.

According to another embodiment of the process of the present invention the compound of fomiula 2, imidazol-1 -ylacetic acid, is obtained by debenzylating benzyl 1- imidazolyl acetate, compound of formula 3. The debenzylation may be carried by catalytic hydrogenolysis or by acidic hydrolysis.

Accordingly the debenzylation by catalytic hydrogenolysis may be performed in presence of metal catalysts like palladium, platinum, ruthenium or rhodium and the like. For instance the catalytic hydrogenolysis may be carried out in a solvent at atmospheric pressure or at higher pressures, at temperature between 5 and 100°C. The solvent maybe selected from a polar protic solvent such as methanol, ethanol, isopropanol, acetic acid and the like; or in aromatic hydrocarbons such as toluene, or esters such as ethyl acetate, tert-butyl acetate and the like

Alternatively, debenzylation may be perfoπned by acidic hydrolysis with a mineral or organic acid, wherein mineral acid may be selected from hydrochloric, sulfuric, hydrobromic and the like; and the organic acid may be selected from acetic, oxalic, para- toluenesulfonic, methaesulfonic and the like.

Acidic hydrolysis may be earned out by at temperature of about 20 -100 °C for 2-6 hours preferably at about 40 to 70°C.

The compound of fomiula 2, imidazol-1 -ylacetic acid is then converted to 2-(imidazol-l- yl)-l-hydroxyethane- 1,1 -diphosphonic acid, compound of fomiula 1 using standard methods known to those skilled in the art such as United States Patent No. 4,939,130. Preferably a process disclosed in our copending Indian Patent Application No. 837/MUM/2003 may be used.

The invention is illustrated but not restricted by the description in the following examples Examples

Example 1 Synthesis of benzyl 1-imidazolyl acetate (compound of formula 3) Chloroacetyl chloride (300g, 2.65mol) was charged slowly at 10-20° C to a stirred mixture containing imidazole (630g, 9.29mol), benzyl alcohol (300ml, 2.92mol) and acetonitrile (900ml). Temperature was raised to 50-55° C and stirred for 12 hours. Acetonitrile was distilled out under vacuum at 55-60° C and finally degassed for lhour at 55-60° C. Water was added to the residue and the product extracted into ethyl acetate. The ethyl acetate extract was washed successively with 10% sodium bicarbonate solution and water and then concentrated and degassed to get 467g of crude benzyl 1-imidazolylacetate compound of formula 3.

Example 2

Preparation of imidazol-1 -ylacetic acid (compound of fomiula 2)

A solution of the crude benzyl 1-imidazolyl acetate, compound of formula 3 (450g, 2. OS mol) as obtained in example 1, in 2-propanol (2.251tr) was hydrogenated in an autoclave with 50% wet 5.0% w/w palladium-carbon (22.5g) at 2.0kg pressure at ambient temperature for 2 hours. The reaction mixture was filtered and the cake containing product and palladium charcoal was washed with 2-propanol. The cake was then stiπed for 30 minutes with water and filtered. The aqueous filtrate was concentrated and degassed by co-distillation with 2-propanol. The residue obtained was suspended and stirred in methanol (300ml), filtered and dried to obtain imidazol-1 -ylacetic acid, compound of fomiula 2, 185g (purity > 99.0%). Example 3

Preparation of imidazol-1 -ylacetic acid (compound of fomiula 2)

A solution of the crude benzyl- 1-imidazolyl acetate, compound of fomiula 3 (25g) as obtained in example 1, in 10%o HCl (50ml) was heated to 65° C for 4 hours. The reaction mixture was washed with toluene (50ml). The aqueous layer was concentrated and degassed by co-distillation with toluene. The residue obtained was suspended in acetone, stured, filtered and dried to obtain imidazol-1 -ylacetic acid, compound of formula 2.

Example 4

Preparation of zoledronic acid (compound of fonriula 1)

A suspension of imidazol-1 -ylacetic acid, compound of formula 2 (50g, 0.396mol) and phosphorous acid (48.7g, 0.594mol) in sulfolane (180ml) was heated to 75° C for 30 min. The mixture was cooled to 35-40° C and phosphorous trichloride (117ml, 1.346mol) was gradually introduced while maintaining the temperature between 35-45° C. The mixture was heated to 63-67° C for 3 hours, whereby white solid results. It was then cooled to 0- 5° C and quenched by slow addition of water (500ml) at 0-5° C over a period of 1 hour. The resulting clear solution was heated at 100° C for 3 hours, cooled to ambient temperature and charcoalized. Acetone was added to the charcoalized solution. The mixture was then stirred for 4 hours at 20-25° C and the crystallized product was filtered, washed sequentially with chilled water, acetone and dried to obtain zoledronic acid.

Claims

WE CLAIM:

1. A process for preparing 2-(imidazol-l-yl)-l-hydroxyethane- 1,1 -diphosphonic acid, compound of fomiula 1, said process comprising

Foπnula 1

(a) reacting imidazole with chloroacetyl chloride and benzyl alcohol in a homogenous system in one pot to obtain benzyl 1-imidazolylacetate, compound of fomiula 3;

Formula 3

(b) debenzylating the benzyl 1-imidazolylacetate, compound of foπnula 3, to imidazol-1 -ylacetic acid, compound of foπnula 2; and

Fomiula 2 (c) converting compound of formula 2 to compound of formula 1.

2. A process as claimed in claim 1 step (a) wherein molar proportion of chloroacetyl chloride: imidazole is in the range of about 1 :2 to 1 :6.

3. A process as claimed in claim 1 step (a) wherein the reaction is carried out in absence of additional base.

4. A process as claimed in claim 1 step (a) wherein the reaction is carried out in absence of facilitator.

5. A process as claimed in claiml step (b) wherein debenzylation is carried out by catalytic hydrogenation or acidic hydrolysis.

6. A process for preparing benzyl 1-imidazolylacetate, compound of formula 3, said process comprising

Foπnula 3 reacting imidazole with chloroacetyl chloride and benzyl alcohol in a homogenous system in one pot.

7. A process as claimed in claim 6 wherein molar proportion of chloroacetyl chloride: imidazole is in the range of about 1 :2 to 1 : 6. process for the preparation of compound of formula 1 as claimed in claims 1 to substantially as herein described and illustrated by examples 1 to 4.