Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF IMIDAZOL-1-YLACETIC ACID

Abstract Present invention relates to an improved one-pot process for the preparation of imidazol-1-ylacetic acid of the formula I. The process comprises reacting imidazole with methyl chloroacetate in the presence or absence of a phase transfer catalyst and a base, in a dipolar aprotic solvent medium and hydrolyzing the ester formed with water and distilling of water to obtain imidazol-1-ylacetic acid. Imidazol-1-ylacetic acid is useful for the manufacture of zoledronic acid of formula-II,
Full Text FIELD OF INVENTION
The present invention relates to an improved process for the preparation of imidazol-1-ylacetic acid. Imidazol-1-ylacetic acid having the formula-I given below is an important intermediate used in the synthesis of zoledronic acid ((l-hydroxy-2-imidazole-l-yl-phosphonoethyl)-bisphosphonic acid) of the formula-II. Zoledronic acid has been shown to have direct effects on osteoclast maturation. It is widely used as a bone resorption inhibitor.

BACKGROUND OF INVENTION
Imidazol-1-ylacetic acid of the formula-I is reported for the first time in J. Chem. Soc, 1932, p1806-1812. The process of its preparation involves the following steps as shown in (Scheme-I). Aminoacetaldehyde diethylacetal is reacted with carbon disulfide in the presence of lead (II) acetate and sodium hydroxide to get acetalylthiocarbimide of the formula-III Treatment of this intermediate with 2-aminoethanol gave the imidazole derivative of the formula-IV. Oxidation of the intermediate compound of the formula-IV gave the required imidazol-1-ylacetic acid. Overall yield of the imidazol-1-ylacetic acid is 3.0%. Disadvantage in this process is poor yield of imidazol-1-ylacetic acid.


Starting from imidazole and trimethylsilyl chloroacetate a process for the preparation of imidazol-1-ylacetic acid is described in Chem. Ber. 1960, 93, 2804-09 (Scheme-II). According to this process imidazole and trimethylsilyl chloroacetate are heated in a molar proportion to get the corresponding trimethylsilyl ester of imidazol-1-ylacetic acid. Hydrolysis of this ester with water gave the required compound of the formula-I. Trimethylsilylchloro acetate required in the process was made from chloroacetic acid and hexamethyldisilazine.
*
Preparation of the compound of the formula-I is also reported in J. Org. Chem., 1994, 59, 6268-73. (Scheme-Ill) According to this process, imidazole is reacted with alkyl bromoacetate in the presence of potassium hydroxide and potassium carbonate under phase transfer catalysis conditions in methylene chloride and l,5-bis-(N,N-diethyl-ammonium)diethylether dichloride (BBDE CI) as catalyst. The corresponding alkyl


imidazol-1-ylacetates were isolated in 50-65% yield after column chromatographic purification. These esters were hydrolyzed to get the imidazol-1-ylacetic acid in quantitative yield.
The main drawback in this process is it requires costly bromo esters and uses costly and rare catalyst (BBDE CI). Also, the required esters were purified by column chromatography, which is not viable for commercial production.
A similar process for the preparation of methyl imidazol-1-ylacetate in 70-80% yield was described in Bioorg. Med. Chem. Lett., 1992, 2, 1717-22 using same BBDE CI catalyst. However, no experimental details or process for the preparation of methyl imidazol-1-ylacetate or its hydrolysis to get the imidazol-1-ylacetic acid are given in this communication.
A process for the preparation of ethyl imidazol-1-ylacetate is described in Bull. Soc. Chim. Fr., 1968, (6), 2438-46 (Scheme-IV). According to this process imidazole is reacted with ethyl iodoacetate in the presence of potassium metal to get the required compound of the formula-VII in 50% yield.

The main disadvantage in this process is availability of costly ethyl iodoacetate is limited and handling of potassium metal on commercial scale is limited due to its flammable nature.
Also, a process for the preparation of ethyl imidazol-1-ylacetate is described in Synthesis, 1981, 629-31 (Scheme-V).


VIII IX
Scheme V According to this process, imidazole is reacted with ethyl diazoacetate to get 56% of the required compound of the formula-VIII along with regioisomers of the formula-EX as major impurities.
Keeping in view of the difficulties in the commercialization of the above-mentioned routes currently available for the preparation of the compound of the formula-I, we initiated R&D towards development of a simple and economically viable process for the preparation of compound of the formula-I.
Accordingly the main objective of the present invention is to provide an improved process for the preparation of compound of the formula-I which is simple and economical.
According to another objective of the present invention is to provide an improved process for the preparation of compound of the formula-I which involves readily and cheaply available raw materials.
Yet another objective of the present invention is to provide an improved process for the preparation of compound of the formula-I avoiding the usage of hazardous chemicals such as potassium metal, diazo esters, rare chemicals such as BBDE CI and making the process safe and environmentally friendly.
Still another objective of the present invention is to provide an improved process for the preparation of compound of the formula-I which is free from any regioisomers formation. During our sustained research & development program on developing an improved process for the preparation of compound of the formula-I we realized that methyl

chloroacetate is very cheap and readily available. We also found that imidazole reacts well with methyl chloroacetate if a dipolar aprotic solvent such as DMF, DMAc, DMSO, etc., is used in the reaction. The base required for neutralization of liberated HC1 and also to enhance the reactivity of imidazole is metal carbonate or bicarbonate.
Accordingly, the present invention provides an improved process for the preparation of imidazol-1-ylacetic acid of formula-I,
Which is useful in the manufacture of zoledronic acid of formula-II,

it
Which comprises:
(i) Reacting imidazole with methyl chloroacetate in the presence of a base with or without a catalyst and a solvent selected from dipolar aprotic solvent and a non-polar solvent at a temperature in the range of 20-100°C
(ii) Isolating the methyl imidazol-1-ylacetate formed from the reaction mass by solvent extraction
(iii) Distilling of the solvent and hydrolysing the crude methyl imidazoM-ylacetate at water reflux temperature
(iv) Distilling of the water and isolating the imidazol-1-ylacetic acid of the formula I by crystallization from a polar solvent.
The base used in the reaction is selected from metal carbonate such sodium or potassium carbonate, metal bicarbonate such as sodium or potassium bicarbonate, preferably potassium carbonate.

The non-polar solvent used in the reaction is selected from benzene, toluene, xylene, heptane, hexane, cyclohexane, ethyl acetate, THF, diisopropyl ether, methyl tert-butyl ether, etc., preferably toluene or ethyl acetate.
The dipolar aprotic solvent used in the reaction is selected from DMF, DMAc, DMSO, etc, preferably DMF. The amount of dipolar aprotic solvent used in the reaction can be in the range of 0.1-3.0 times (w/w) the weight of imidazole used in the reaction.
To make the process more economic dipolar aprotic solvent can be used at a very minimum level and as diluent a non-polar solvent such as benzene, toluene, cyclohexane, heptane, ethyl acetate, diisopropyl ether, etc., can be used in the reaction.
The reaction can be done with or without a cheap and readily available catalyst such as sodium or potassium iodide, tetra-n-butylammonium bromide, benzyl-triethylammonium bromide or chloride, tetrabutylammonium iodide, cetyl trimethylammonium bromide, tetramethylammonium bromide, etc., preferably potassium iodide or tetra-n-butylammonium bromide. The temperature of the reaction is between 20-100°C, preferably between 30-70°C.
The solvent used for crystallization of imidazol-1-ylacetic acid in step (iv) is selected from methanol, ethanol, isopropanol, n-butanol with/without water, preferably water or methanol.
The details of the process of the invention are provided in the Examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention

Example 1
Preparation of Imidazol-1-ylacetic acid
Into a 1-L, three-necked RB flask is charged lOOg of imidazole, 40ml of DMF, 400ml of toluene, 180g of potassium carbonate and lOg of tetrabutylammonium bromide. After stirring for 1Omin 240g of methyl chloroacetate was added slowly over a period of 1.5-2.0h at 25-30 °C. The reaction mass was kept under stirring at 25-30 °C for lh and slowly heated to 60-65 °C. After maintaining at same temperature for 2-3h reaction was found to be over by TLC. The reaction mass was cooled to 25-30 °C and added 200ml of ethyl acetate. The reaction mass was stirred for 20-30min and decanted the top organic layer. The residue was once again extracted with ethyl acetate (200ml). Finally water (200ml) was added to the reaction mass and stirred for 3 Omin. Inorganic salts were removed by filtration and the filtrate extracted with ethyl acetate (2 x 200ml). All ethyl acetate extractions were combined and distilled off under vacuum to get 220g of crude mass.
The crude mass was suspended in 500ml of water and refluxed for 4-5h. Reaction mass became a clear liquid. The reaction mass was treated with charcoal and distilled off water under vacuum keeping the temperature below 80 °C. The residue was cooled to 25-30 °C and added 250ml of methanol. The suspension was stirred for lh and filtered the mass. The wet cake was washed with 50ml of methanol and dried at 50-60C to get 150g of white crystalline solid of imidazol-1-ylacetic acid of the formula I. Melting point is 268-269 °C. Purity by HPLC is 99.2%.
Example 2
Preparation of Imidazol-l-ylacetic acid
Into a 100L, stainless steel reactor is charged 10kg of imidazole, 4L of DMF, 40L of toluene, 18kg of potassium carbonate, and 2kg of potassium iodide. After stirring for 10-20min 24kg of methyl chloroacetate was added slowly over a period of 1.5-2.0h at 25-30 °C. The reaction mass was kept under stirring at 25-30 °C for lh and slowly heated to 60-65 °C over a period of 60-90min. After maintaining at same temperature for 2.5-3.oh

reaction was found to be over by TLC. The reaction mass was cooled to 25-30 °C and added 20L of ethyl acetate. The reaction mass was stirred for 30-45min and decanted the top organic layer. The residue was once again extracted with ethyl acetate (20L). Finally water (20L) was added to the reaction mass and stirred for 30min. Inorganic salts were removed by filtration and the filtrate extracted with ethyl acetate (2 x 20L). All ethyl acetate extractions were combined and distilled off under vacuum to get 25kg of crude mass.
The crude mass was suspended in 50L of water and refluxed for 4-5h. Reaction mass became a clear liquid. The reaction mass was treated with charcoal and distilled off water under vacuum keeping the temperature below 80 °C. The residue was cooled to 25-30 °C and added 30L of methanol. The suspension was stirred for lh and filtered the mass. The wet cake was washed with 10L of methanol and dried at 50-60 °C to get 14kg of white crystalline solid of imidazol-1-y lace tic acid of the formula I. Melting point is 268-269 °C. Purity by HPLC is 99.4%.
Advantages of present invention
1. The process is simple and easily adaptable for commercial production of imidazol-1-ylacetic acid of purity of 99.4 %.
2. The process employs only cheap and readily available commercial raw materials such as methyl chloroacetate, tetrabutylammonium bromide, DMF, thereby making the process economical and simple.
3. The yield of imidazol-lyl-acetic acid is more than 75%.
4. The process is environmentally friendly.




Which comprises:
(i) Reacting imidazole with methyl chloroacetate in the presence of a base with or without a catalyst and a solvent selected from dipolar aprotic solvent and a non-polar solvent at a temperature in the range of 20-100°C
(ii) Isolating the methyl imidazol-1-ylacetate formed from the reaction mass by solvent extraction
(iii) Distilling of the solvent and hydrolyzing the crude methyl imidazol-1-ylacetate at water reflux temperature
(iv) Distilling of the water and isolating the imidazol-1-ylacetic acid by crystallization from a polar solvent.
2. An improved process as claimed in claim 1 wherein the base used in the reaction in step (i) is selected from carbonate or bicarbonate of sodium or potassium, preferably potassium carbonate.

3. An improved process as claimed in claim 1 & 2 wherein the catalyst when used in the reaction in step (i) is selected from sodium or potassium iodide, tetra-n-butyiammonium bromide, benzyltriethylammonium bromide, tetra-n-butylammonium iodide, cetyl trimethylammonium bromide, tetramethylammonium bromide, etc., preferably potassium iodide or tetra-n-butylammonium bromide.
4. An improved process as claimed in claims 1 to 3 wherein the dipolar solvent used in the reaction in step (i) is selected from N,N-dimethylformamide, N,N-dimethylacetamide, N-methyl-pyrrolidone, dimethyl sulfoxide, pyridine, preferably N,N-dimethylformamide.
5. An improved process as claimed in claims 1 to 4 wherein the non-polar solvent employed in the reaction in step (i) is selected from benzene, toluene, xylene, heptane, hexane, cyclohexane, ethyl acetate, THF, diisopropyl ether, methyl tert-butyl ether, preferably toluene or ethyl acetate.
6. An improved process as claimed in claims 1 to 5 wherein the reaction step (i) is effected at a temperature in the range of 30 to 70 °C.

7. An improved process as claimed in claims 1 to 6 wherein the solvent used for extraction in step (ii) is selected from ethyl acetate, methylene chloride, 1,2-dichloroethane, diisopropyl ether, tetrahydrofuran, methyl tert-butyl ether, preferably toluene or ethyl acetate.
8. An improved process as claimed in claims 1 to 7 wherein the solvent used for crystallization of imidazol-1-ylacetic acid in step (iv) is selected from methanol, ethanol, isopropanol, n-butanol with/without water, preferably water or methanol.
9. An improved process as claimed in claims 1 to 8 wherein the amount of dipolar aprotic solvent used in the reaction can be in the range of 0.1-3.0 times (w/w) the weight of imidazole used in the reaction.

10. An improved process for the preparation of imidazol-1-ylacetic acid of the formula I substantially as described in the Examples 1 & 2.
Dated this 30th day of November, 2004


Documents:

1080-che-2003-abstract.pdf

1080-che-2003-claims filed.pdf

1080-che-2003-claims granted.pdf

1080-che-2003-correspondnece-others.pdf

1080-che-2003-correspondnece-po.pdf

1080-che-2003-description(complete) filed.pdf

1080-che-2003-description(complete) granted.pdf

1080-che-2003-description(provisional).pdf

1080-che-2003-form 1.pdf

1080-che-2003-form 19.pdf

1080-che-2003-form 5.pdf

abs-1080-che-2003.jpg


Patent Number 202056
Indian Patent Application Number 1080/CHE/2003
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 26-Jun-2006
Date of Filing 31-Dec-2003
Name of Patentee NATCO PHARMA LTD
Applicant Address NATCO HOUSE ROAD NO 2, BANJARA HILLS HYDERABAD 500 033
Inventors:
# Inventor's Name Inventor's Address
1 PULLA REDDY MUDDASANI NATCO PHARMA LTD NATCO HOUSE ROAD NO 2, BANJARA HILLS HYDERABAD 500 033
2 USHA RANI VATTIKUTI NATCO PHARMA LTD NATCO HOUSE ROAD NO 2, BANJARA HILLS HYDERABAD 500 033
3 RADHA RANI KAGITHA NATCO PHARMA LTD NATCO HOUSE ROAD NO 2, BANJARA HILLS HYDERABAD 500 033
4 VENKAIAH CHOWDARY NANNAPANENI NATCO PHARMA LTD NATCO HOUSE ROAD NO 2, BANJARA HILLS HYDERABAD 500 033
PCT International Classification Number C07D403/12
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA