Title of Invention	"AN IMPROVED METHOD FOR THE PREPARATION OF 2-(2- CHLOROETHOXY) ACETIC ACID."
Abstract	An improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product.

Title of Invention

"AN IMPROVED METHOD FOR THE PREPARATION OF 2-(2- CHLOROETHOXY) ACETIC ACID."

Abstract

An improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product.

Full Text	This invention relates to an improved method for the preparation of 2-(2-chloroethoxy)acetic acid. 2-(2-Chloroethoxy)-acetic acid is an important key intermediate for the synthesis of cetirizine (antihistamine drug) and amlodepine (calcium channel antagonist drug). Hitherto the preparation of 2-(2-chloroethoxy)-acetic acid and/or its ester is known by a) Jones oxidation of 2-(2-chloroethoxy)ethanol, [Hiroshi, F., Toshiaki, S. Mitsuo, S., Yoshi, I and Takeshi, Y., EP 421823; CA: 115, 183355e (1991)]; b) base catalysed condensation of 2-chloroethanol with ethyl bromoacetate [Hiroshi, F., Kehkyusho, S., Jpn 04,112,852, CA: 117, 111151 (1992)]; c) acid catalysed condensation of ethylene chlorohydrin with paraformaldehyde and followed by CuCN reaction (Salami E.J., Leimu, R. and Kallio, H: Soumen Kemistilechti 17B, 17-19 (1944), CA: 40, 6492 (1946)]; d) reaction of ethylchloroacetate with ethylene oxide [Klamann, D., Weyerstahl, P. & Nerdel, F. Liebigs Ann. Chem.. 710, 59-70 (1967)]; and e) reaction of alcohol with 2-chloro-1,4-dioxene (Astle M.J., Welk, J.D.; J. Org. Chem.. 26, 4325-7 (1961)]. Prior art processes involves the use of large volume of solvent (acetone) and large amount chromium sludge, the use of expensive and fire prone base such as sodium hydride; high temperature and pressure. The main object of the present invention is to provide an improved process for the preparation of 2-(2-chloroethoxy)-acetic acid using cheaper and eco-friendly reagents i.e. nitric acid. As compared to the known processes, the inventors by their R&D work, developed an improved process for the preparation of 2-(2-chloroethoxy)-acetic acid from 2-(2-chloroethoxy)-ethanol by oxidation with cheaper and easily available reagent i.e. nitric acid. Accordingly, the present invention provides an improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product. In another embodiment in the present invention the organic solvent used for the extraction may be selected from dichloroethane, ethylacetate or methylisobutylketone. In a feature of the present invention 2-(2-chloroethoxy)-ethanol is prepared by the process i.e. chlorination of digol (diethylene glycol) [J. Org. Chem.; 40, 1207 (1975); ROM R088654 (1986) CA, 106, 66748 (1987) ROM RO 88443 (1988) CA: 105, 152534 (1988). The process of the present invention is described herein below with references to following examples which are illustrative and should not be construed to limit the scope of the present invention in any manners. Example 1. 2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (169 parts, 1.36 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (6.8 mole parts) at 25-30°C in one hour. The contents were further stirred at the same temperature for 12 hrs and then heated at 90°C for 1 hr. The excess of nitric acid was distilled off under reduced pressure (10-20 mm of mercury) at 80°C and the residue after cooling to room temperature was extracted with dichloroethane/ethylacetate (2 x 200 parts). The combined organic extract was washed with brine solution, dried over sodium sulphate, filtered and concentrated to give 2-(2-chloroethoxy)-acetic acid (176 parts, 1.27 mole parts, 93%). Example 2. 2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (87.5 parts, 0.70 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (450 parts, 7.14 mole parts) at 25-30°C in one hour. The contents were further stirred at the same temperature for 12 hrs and then heated at 90°C for 1 hr. After workup as described in example 1 gave 2-(2-chloroethoxy)-acetic acid (96 parts, 0.69 mole parts, 98%). Example 3. 2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (169 parts, 1.36 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (611 parts, 6.8 mole parts) at 80-85°C in 6 hours. The contents were further stirred at the same temperature for 2 hrs. The excess of nitric acid was distilled off under reduced pressure (10-20 mm of mercury) at 80°C and the residue after cooling to room temperature was extracted with dichloroethane/ethylacetate (2 x 200 parts). The combined organic extract was washed with brine solution, dried over sodium sulphate, filtered and concentrated to give 2-(2-chloroethoxy)-acetic acid (170 parts, 1.22 mole parts, 90%). WE CLAIM 1) An improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product. 2) An improved process as claimed in claim 1 wherein the organic solvent used for the extraction is selected from dichloroethane, ethylacetate or methylisobutylketone. 3) An improved process for the preparation of 2-(2-chloroethoxy)acetic acid as described hereinbefore with reference to examples.

Full Text

This invention relates to an improved method for the preparation of 2-(2-chloroethoxy)acetic acid.
2-(2-Chloroethoxy)-acetic acid is an important key intermediate for the synthesis of cetirizine (antihistamine drug) and amlodepine (calcium channel antagonist drug).
Hitherto the preparation of 2-(2-chloroethoxy)-acetic acid and/or its ester is known by a) Jones oxidation of 2-(2-chloroethoxy)ethanol, [Hiroshi, F., Toshiaki, S. Mitsuo, S., Yoshi, I and Takeshi, Y., EP 421823; CA: 115, 183355e (1991)]; b) base catalysed condensation of 2-chloroethanol with ethyl bromoacetate [Hiroshi, F., Kehkyusho, S., Jpn 04,112,852, CA: 117, 111151 (1992)]; c) acid catalysed condensation of ethylene chlorohydrin with paraformaldehyde and followed by CuCN reaction (Salami E.J., Leimu, R. and Kallio, H: Soumen Kemistilechti 17B, 17-19 (1944), CA: 40, 6492 (1946)]; d) reaction of ethylchloroacetate with ethylene oxide [Klamann, D., Weyerstahl, P. & Nerdel, F. Liebigs Ann. Chem.. 710, 59-70 (1967)]; and e) reaction of alcohol with 2-chloro-1,4-dioxene (Astle M.J., Welk, J.D.; J. Org. Chem.. 26, 4325-7 (1961)].
Prior art processes involves the use of large volume of solvent (acetone) and large amount chromium sludge, the use of expensive and fire prone base such as sodium hydride; high temperature and pressure.
The main object of the present invention is to provide an improved process for the preparation of 2-(2-chloroethoxy)-acetic acid using cheaper and eco-friendly reagents i.e. nitric acid.
As compared to the known processes, the inventors by their R&D work, developed an improved process for the preparation of 2-(2-chloroethoxy)-acetic acid from 2-(2-chloroethoxy)-ethanol by oxidation with cheaper and easily available reagent i.e. nitric acid.
Accordingly, the present invention provides an improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product.
In another embodiment in the present invention the organic solvent used for the extraction may be selected from dichloroethane, ethylacetate or methylisobutylketone.
In a feature of the present invention 2-(2-chloroethoxy)-ethanol is prepared by the process i.e. chlorination of digol (diethylene glycol) [J. Org. Chem.; 40, 1207 (1975); ROM R088654 (1986) CA, 106, 66748 (1987) ROM RO 88443 (1988) CA: 105, 152534 (1988).
The process of the present invention is described herein below with references to following examples which are illustrative and should not be construed to limit the scope of the present invention in any manners.
Example 1.
2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (169 parts, 1.36 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (6.8 mole parts) at 25-30°C in one hour. The contents were further stirred at the same temperature for 12 hrs and then heated at 90°C for 1 hr. The excess of nitric acid was distilled off under reduced pressure (10-20 mm of mercury) at 80°C and the residue after cooling to room temperature was extracted with dichloroethane/ethylacetate (2 x 200 parts). The combined organic extract was washed with brine solution, dried over sodium sulphate, filtered and concentrated to give 2-(2-chloroethoxy)-acetic acid (176 parts, 1.27 mole parts, 93%).
Example 2.
2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (87.5 parts, 0.70 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (450 parts,
7.14 mole parts) at 25-30°C in one hour. The contents were further stirred at the same temperature for 12 hrs and then heated at 90°C for 1 hr. After workup as described in example 1 gave 2-(2-chloroethoxy)-acetic acid (96 parts, 0.69 mole parts, 98%).
Example 3.
2-(2-Chloroethoxy)-ethanol of 98% G.C. purity (169 parts, 1.36 mole parts) was added dropwise to vigorously stirred 70% nitric acid d=1.42 (611 parts, 6.8 mole parts) at 80-85°C in 6 hours. The contents were further stirred at the same temperature for 2 hrs. The excess of nitric acid was distilled off under reduced pressure (10-20 mm of mercury) at 80°C and the residue after cooling to room temperature was extracted with dichloroethane/ethylacetate (2 x 200 parts). The combined organic extract was washed with brine solution, dried over sodium sulphate, filtered and concentrated to give 2-(2-chloroethoxy)-acetic acid (170 parts, 1.22 mole parts, 90%).

WE CLAIM
1) An improved method for the preparation of 2-(2-chloroethoxy)acetic acid, which comprises reacting of 2-(2-chloroethoxy) ethanol with nitric acid for the period ranging between 2-12 hrs at temperature ranging from 10-90°C, distilling the nitric acid from reaction mixture under reduced pressure ranging between 10-20 mm at temperature ranging between 60-80°C and extracting with organic solvent such as herein described, separating the organic solvent, and removing the solvent to obtain the product.
2) An improved process as claimed in claim 1 wherein the organic solvent used for the extraction is selected from dichloroethane, ethylacetate or methylisobutylketone.
3) An improved process for the preparation of 2-(2-chloroethoxy)acetic acid as described hereinbefore with reference to examples.

Documents:

2942-del-1997-abstract.pdf

2942-del-1997-claims.pdf

2942-del-1997-complete specification [granted].pdf

2942-del-1997-correspondence-others.pdf

2942-del-1997-correspondence-po.pdf

2942-del-1997-description (complete).pdf

2942-del-1997-drawings.pdf

2942-del-1997-form-1.pdf

2942-del-1997-form-2.pdf

2942-del-1997-form-4.pdf

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Patent Number

232403

Indian Patent Application Number

2942/DEL/1997

PG Journal Number

13/2009

Publication Date

27-Mar-2009

Grant Date

17-Mar-2009

Date of Filing

14-Oct-1997

Name of Patentee

COUNCIL OF SCIENTIFIC AND INDUSTRIAL RESEARCH

Applicant Address

RAFI MAG, NEW DEHI-110001. INDIA

Inventors:

#	Inventor's Name	Inventor's Address
1	THOTTAPPILLIL RAVINDRANATHAN	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
2	VISHNU HARI DESHPANDEY	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
3	VIJAY BABURAO PATIL	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
4	ASHOK RAMCHANDRA MEHENDALE	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
5	RAJGOPAL JAGANATH LAHOTI	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
6	RAMESH ANNA JOSHI	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
7	ROHINI RAMESH JOSHI	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
8	UTTAM RAMRAO KALKOTE	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA
9	IYAKANNU SHIVAKUMAR	NATIONAL CHEMICAL LABORATORY, PUNE 411008, INDIA

PCT International Classification Number

A61K 31/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA