DESC:FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:

“A PROCESS FOR THE PREPARATION OF DICYCLOMINE OR SALT THEREOF”

2. APPLICANT(S):

a) NAME: Ami Lifesciences Private Limited

b) NATIONALITY: An Indian Company registered under The Companies Act, 1956

c) ADDRESS: 7th Floor, Lilleria 1038, Gotri Sevasi Road, New Alkapuri, Vadodara – 390 021, Gujarat, India.

3. PREAMBLE TO THE INVENTION:

COMPLETE:
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION:
The present invention relates to an improved, efficient, and industrially advantageous process for the preparation of pure Dicyclomine of Formula I or salt thereof.
The present invention also relates to a process for the preparation of Dicyclomine hydrochloride intermediate namely, 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
The present invention also relates to a process for the purification of Dicyclomine hydrochloride of Formula V.
BACKGROUND OF THE INVENTION:
Dicyclomine is chemically known as 2-(Diethylamino)ethyl 1-cyclohexylcyclohexane-1-carboxylate, having the structure of Formula I,

[Formula I]
Dicyclomine was developed by Allergan Sales LLC and was approved in the form of hydrochloride salt by USFDA on May 11, 1950, under the proprietary name Bentyl®. Dicyclomine hydrochloride is an antispasmodic and anticholinergic (antimuscarinic) agent indicated for the treatment of functional bowel/irritable bowel syndrome.
US patent number US 2474796 (herein after US ‘796) first discloses Dicyclomine and its hydrochloride salt. The US ‘796 also discloses process for the preparation of Dicyclomine hydrochloride which involves reduction of ß-diethylaminoethyl 1-phenylcyclohexanecarboxylate hydrochloride with Adam’s catalyst in presence of hydrogen and glacial acetic acid.
US ‘796 process suffers from the major drawback of requiring the use of Adam’s catalyst which is highly costly. Further, Adam’s catalyst becomes pyrophoric after exposure to hydrogen. Therefore, process as disclosed in US ‘796 is not an attractive option for large scale industrial production of Dicyclomine hydrochloride. Additionally, US ‘796 is also silent about purity and yield of obtained Dicyclomine hydrochloride API.
US patent number US 2694724 (herein after US ‘724) discloses process for the preparation of Dicyclomine hydrochloride comprising condensation of 1-chlorocyclohexyl cyclohexyl ketone with sodium 2-(diethylamino)ethanolate followed by work-up with ether, and treatment with methyl alcohol and anhydrous hydrogen chloride to obtain Dicyclomine hydrochloride.
US ‘724 process suffers from the major drawback of lower yield of Dicyclomine hydrochloride (38%). Further, US’724 process involves use of ether solvent during work-up which is commercially not viable. Also, US ‘724 process is silent about the purity of final Dicyclomine hydrochloride API. Therefore, process as disclosed in US ‘724 is not an attractive option for large scale industrial production of Dicyclomine hydrochloride.
Bulletin de la Societe Chimique de France (1952), 84-6 discloses process for the preparation of 1-chlorocyclohexyl cyclohexyl ketone by chlorination of dicyclohexyl ketone using sulfuryl chloride in absence of solvent.
Process disclosed in the above journal article suffers from the major drawback of lower yield of 1-chlorocyclohexyl cyclohexyl ketone. Therefore, process disclosed in the above journal article is not an attractive option for large scale industrial production of 1-chlorocyclohexyl cyclohexyl ketone.
Most of the prior art references suffers from disadvantages like use of costly reagents or catalysts, lower yield and are silent about purity of Dicyclomine hydrochloride. Therefore, there is an urgent need for the process for preparation of Dicyclomine hydrochloride which overcomes the drawbacks of prior arts processes.
The present inventors have developed an improved and cost-effective process for the preparation of Dicyclomine or salt thereof and its intermediate namely 1-chlorocyclohexyl cyclohexyl ketone, which offers advantages over the prior art processes in terms of higher yield, higher purity, simple work up process and industrially economical.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of pure Dicyclomine of Formula I or salt thereof.
Another object of the present invention is to provide a process for the preparation of Dicyclomine hydrochloride intermediate namely, 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
Further object of the present invention is to provide a process for the purification of Dicyclomine hydrochloride of Formula V.
Further object of the present invention is to provide highly pure Dicyclomine hydrochloride of Formula V, comprising:
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII.
SUMMARY OF INVENTION:
First aspect of the present invention is to provide a process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising the steps of:
a) reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III; and

[Formula III]
b) reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
Second aspect of the present invention is to provide a process for the preparation of 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
comprising reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
Third aspect of the present invention is to provide a process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
Fourth aspect of the present invention is to provide a process for the purification of Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising treating Dicyclomine hydrochloride of Formula V with mixture of water and ketone solvent.
Fifth aspect of the present invention is to provide highly pure Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising:
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII,

[Formula VII].
BRIEF DESCRIPTION OF DRAWINGS:
Figure-1: X-ray powder diffractogram (XRPD) of crystalline form of Dicyclomine hydrochloride of Formula V.

DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
The best methods and materials of performing the present invention are described here.
The present invention provides an efficient and industrially advantageous process for the preparation of Dicyclomine of Formula I or salt thereof.
According to first embodiment, the present invention provides a process for the preparation of Dicyclomine of Formula I or salt thereof.

[Formula I]
comprising the steps of:
a) reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III; and

[Formula III]
b) reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
In the first embodiment of step a), dicyclohexyl ketone of Formula II can be prepared by the process known in the prior-art.
In the first embodiment of step a), dicyclohexyl ketone of Formula II can be reacted with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
In the first embodiment of step a), chlorinating agent can be selected from the group consisting of phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2).
In the first embodiment of step a), molar equivalent of chlorinating agent with respect to compound of the Formula II can be 1.0 to 3.0, preferably 1.1 to 1.5.
In the first embodiment of step a), aromatic hydrocarbon solvent can be selected from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
In the first embodiment of step a), aromatic hydrocarbon solvent can be used in the proportion of 01 volume to 05 volumes with respect to compound of Formula II.
In the first embodiment of step a), chlorination reaction can be carried out at a temperature of 10oC to 70oC.
In the first embodiment of step a), chlorination reaction can be carried out for 7 hours to 11 hours.
In the first embodiment of step a), after completion of reaction, resulting mixture can be cooled to 10°C to 20°C and aromatic hydrocarbon solvent and water can be added to resulting mixture at 25°C to 35°C. Resulting mixture can be allowed to settle organic and aqueous layer. Resulting layers can be separated and organic layer can be washed with water followed by aqueous sodium bicarbonate. Resulting organic layer can be distilled completely under vacuum at not more than 70°C to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
Resulting 1-chlorocyclohexyl cyclohexyl ketone of Formula III may have purity greater than 96%, preferably greater than 98% by Gas chromatography (GC).
In the first embodiment of step b), 1-chlorocyclohexyl cyclohexyl ketone of Formula III can be reacted with sodium 2-(diethylamino)ethanolate of Formula IV in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
In the first embodiment of step b), sodium 2-(diethylamino)ethanolate of Formula IV can be prepared by reacting diethylethanolamine with sodium metal at a temperature of 20oC to 100oC for a period of 1 hour to 3 hours.
In the first embodiment of step b), molar equivalent of sodium 2-(diethylamino)ethanolate with respect to 1-chlorocyclohexyl cyclohexyl ketone of Formula III can be 1.1 to 2.0.
In the first embodiment of step b), diethylethanolamine can be used in the proportion of 0.5 volume to 04 volume with respect to 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
In the first embodiment of step b), reaction of 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV can be carried out at temperature 70°C to 110°C, preferably at a temperature of 80oC to 90oC.
In the first embodiment of step b), reaction of 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV can be carried out for a period of 1 hour to 2 hours.
In the first embodiment of step b), after completion of reaction, solvent can be distilled under vacuum. Aromatic hydrocarbon solvent and water can be added to the obtained distilled mass and resulting mixture can be allowed to separate organic and aqueous layer. Resulting organic layer can be washed with water, treated with neutral carbon, and filtered. Resulting filtrate can be distilled completely under vacuum at not more than 60°C to obtain oily mass of Dicyclomine of Formula I.
Resulting oily mass of Dicyclomine of Formula I can be purified by using ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone and then can be converted into Dicyclomine hydrochloride of Formula V by treatment with hydrochloric acid in presence of solvent selected from the group consisting of ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone; alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol.
In the first embodiment of step b), Dicyclomine hydrochloride of Formula V may have purity greater than 99% by High-performance liquid chromatography (HPLC).
In the first embodiment of step b), Dicyclomine hydrochloride of Formula V may contain i) less than 0.05% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.05% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII,

[Formula VII].
In the first embodiment of step b), Dicyclomine hydrochloride of Formula V may be further purified by purification techniques known in the art such as crystallization or recrystallization.
According to second embodiment, present invention provides a process for the preparation of 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
comprising reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
In the second embodiment, dicyclohexyl ketone of Formula II can be prepared by the process known in the prior-art.
In the second embodiment, chlorinating agent can be selected from the group consisting of phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2).
In the second embodiment, molar equivalent of chlorinating agent with respect to compound of the Formula II can be 1.0 to 3.0, preferably 1.1 to 1.5.
In the second embodiment, aromatic hydrocarbon solvent can be selected from the group consisting of benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
In the second embodiment, aromatic hydrocarbon solvent can be used in the proportion of 01 volume to 05 volumes with respect to compound of Formula II.
In the second embodiment, chlorination reaction can be carried out at a temperature of 10°C to 70°C.
In the second embodiment, chlorination reaction can be carried out for 7 hours to 11 hours.
In the second embodiment, after completion of reaction, resulting mixture can be cooled to 10°C to 20°C and aromatic hydrocarbon solvent and water can be added to resulting mixture at 25°C to 35°C. Resulting mixture can be allowed to settle organic and aqueous layer. Resulting layers can be separated and organic layer can be washed with water followed by aqueous sodium bicarbonate. Resulting organic layer can be distilled completely under vacuum at not more than 70°C to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
The resulting 1-chlorocyclohexyl cyclohexyl ketone of Formula III may have purity greater than 96%, preferably greater than 98% by GC.
According to third embodiment, present invention provides a process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
In the third embodiment, 1-chlorocyclohexyl cyclohexyl ketone of Formula III can be reacted with sodium 2-(diethylamino)ethanolate of Formula IV in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
In the third embodiment, sodium 2-(diethylamino)ethanolate of Formula IV can be prepared by reacting diethylethanolamine with sodium metal at a temperature of 20oC to 100oC for a period of 1 hour to 3 hours.
In the third embodiment, molar equivalent of sodium 2-(diethylamino)ethanolate with respect to 1-chlorocyclohexyl cyclohexyl ketone of Formula III can be 1.1 to 2.0.
In the third embodiment, diethylethanolamine can be used in the proportion of 0.5 volume to 04 volume with respect to 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
In the third embodiment, reaction of 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV can be carried out at temperature 70°C to 110°C, preferably at a temperature of 80oC to 90oC.
In the third embodiment, reaction of 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV can be carried out for a period of 1 hour to 2 hours.
In the third embodiment, after completion of reaction, solvent can be distilled out under high vacuum. Aromatic hydrocarbon solvent and water can be added to the obtained distilled mass and resulting mixture can be allowed to separate organic and aqueous layer. Resulting organic layer can be washed with water, treated with neutral carbon, and filtered. Resulting filtrate can be distilled completely under vacuum at not more than 60°C to obtain oily mass of Dicyclomine of Formula I.
Resulting oily mass of Dicyclomine of Formula I can be purified by using ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone and then can be converted into Dicyclomine hydrochloride of Formula V by treatment with hydrochloric acid in presence of solvent selected from the group consisting of ketone such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone; alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol.
In the third embodiment, Dicyclomine hydrochloride of Formula V may have purity greater than 99% by HPLC.
In the third embodiment, Dicyclomine hydrochloride of Formula V may contain
i) less than 0.05% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.05% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII.

[Formula VII]
In the third embodiment, Dicyclomine hydrochloride of Formula V may be further purified by purification techniques known in the art such as crystallization or recrystallization.
According to fourth embodiment, present invention provides a process for the purification of Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising treating Dicyclomine hydrochloride of Formula V with mixture of water and ketone solvent.
In the fourth embodiment, ketone solvent can be selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone.
In the fourth embodiment, ketone solvent can be used in the proportion of 2.0 volume to 3.0 volume with respect to Dicyclomine hydrochloride of Formula V.
In the fourth embodiment, water can be used in the proportion of 0.3 volume to 0.5 volume with respect to Dicyclomine hydrochloride of Formula V.
In the fourth embodiment, Dicyclomine hydrochloride of Formula V can be treated with mixture of water and ketone solvent. Particularly Dicyclomine hydrochloride of Formula V can be treated with mixture of water and ketone solvent by methods such as slurry wash or by heating up to reflux temperature.
Resulting pure Dicyclomine hydrochloride of Formula V can be isolated by various methods reported in the prior art such as cooling, crystallization, evaporation, distillation, addition of anti-solvent or by using combination of these methods.
Resulting pure Dicyclomine hydrochloride of Formula V may have purity greater than 99.8%, preferably 99.9% by HPLC.
Resulting pure Dicyclomine hydrochloride of Formula V may contain
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII.

[Formula VII]
Resulting pure Dicyclomine hydrochloride of Formula V is in crystalline form.
The crystalline form of Dicyclomine hydrochloride of Formula V can be characterized by X-ray powder diffraction (XRPD) pattern as shown in Figure-1,
According to fifth embodiment, present invention provides highly pure Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising:
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII

[Formula VII].
In the fifth embodiment, highly pure Dicyclomine hydrochloride of Formula V may contain 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI and 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII below the level of detection.
In the fifth embodiment, identification and analysis of impurities can be done by HPLC or GC.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.

Example 01: Preparation of 1-chlorocyclohexyl cyclohexyl ketone of Formula III
To a stirred solution of toluene (1000 mL) and dicyclohexyl ketone (500 g), sulphuryl chloride (382 g) was added at temperature of 25°C to 35°C. Resulting mixture was heated to 50°C to 55°C and stirred at the same temperature for 10 hours. After completion of reaction, the resulting mixture was cooled to 10°C to 20°C and toluene and purified water were added to the mixture. Resulting mixture was stirred and allowed layers to separate.
The resulting organic layer was washed with purified water (2 x 250 mL), followed by washing with aqueous sodium bicarbonate solution (35 g in 500 mL) and purified water (250 mL). Resulting organic layer was distilled out completely under vacuum at 65°C to 70°C to obtain titled compound (584.5 g).
Purity by GC: 99.00 %

Example 02: Preparation of Dicyclomine hydrochloride of Formula V
Stirred mixture of Diethylamino ethanol (1280.7 g) and sodium metal (75.38 g) was heated to temperature of 80°C to 90°C. Resulting mixture was stirred for 2 hours at the same temperature to obtain solution containing sodium diethlyaminoethanolate.
To the resulting solution was added 1-chlorocyclohexyl cyclohexyl ketone of Formula III (500 g) and diethyl aminoethanol (220 g) at temperature of 80°C to 90°C. The resulting mixture was maintained at the same temperature for 1 hour. After competition of reaction, resulting mixture was distilled at a temperature up to 90°C under vacuum to obtain a residue.
The resulting residue was cooled to temperature of 20°C to 25°C and toluene (1500 mL) and purified water (1750 mL) were added. Resulting mixture was stirred and allowed layers to separate. The resulting organic layer was washed with purified water (2x1000 mL), distilled completely under vacuum at not more than 60°C to obtain residue. To the resulting residue, acetone (250 mL) was added, and solvent was distilled completely under vacuum at not more than 50°C to obtain residue. To the resulting residue, acetone (2500 mL) was added, and the resulting solution was filtered and washed with acetone. Resulting filtrate was cooled to temperature of 0°C to 5°C and hydrochloric acid solution was added to adjust the pH to not more than 3.0. The resulting mixture was stirred at 0°C to 5°C for 1 hour, filtered, washed with acetone, and dried in Air Tray Drier at 55°C to 60°C for 8 hours to obtain titled compound (515.2 g).
Purity by HPLC: 99.36 %
1,1’-bi(cyclohexane)-1-carboxylic acid: Not detected
2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate: 0.04%
Example 03: Preparation of pure Dicyclomine hydrochloride of Formula V
To a stirred mixture of acetone (1170 mL) and purified water (180 mL) Dicyclomine hydrochloride of Formula V (450 g) was added and resulting mixture was heated to 45°C to 50°C. The resulting mixture was stirred at the same temperature to get a clear solution and activated carbon (22.5 g) was added. The resulting mixture was maintained at the same temperature for 15 minutes to 30 minutes and filtered through Hyflo bed followed by washing with acetone (450 mL). Resulting filtrate was heated to 45°C to 50°C and acetone (450 mL) was added. The resulting mixture was gradually cooled to -5°C to 0°C, filtered, washed with acetone (450 mL) and dried in Vacuum Tray Drier at 40°C to 45°C for 8 hours to obtain titled compound (372 g).
Purity by HPLC: 99.91 % and Purity by GC: 99.94 %
1,1’-bi(cyclohexane)-1-carboxylic acid: Not detected.
2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate: 0.01%
Differential scanning calorimetry (DSC) exhibits Onset peak at 174.71°C and endotherm peak at 179.47°C.
Thermogravimetric analysis (TGA): 0.056 %
Dated this 29th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.
I /We claim:
1. A process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising the steps of:
a) reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III; and

[Formula III]
b) reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
2. The process as claimed in claim 1, wherein chlorinating agent is phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2) and aromatic hydrocarbon solvent is benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
3. The process as claimed in claim 1, wherein in step a) is carried out at temperature of 10°C to 70°C.
4. A process for the preparation of 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
comprising reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
5. The process as claimed in claim 4, wherein in chlorinating agent is phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2) and aromatic hydrocarbon solvent is benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
6. The process as claimed in claim 4, wherein in step a) is carried out at a temperature of 10°C to 70°C.
7. A process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
8. A process for the purification of Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising treating Dicyclomine hydrochloride of Formula V with mixture of water and ketone solvent.
9. The process as claimed in claim 6, wherein ketone solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone
10. A highly pure Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising:
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII,

[Formula VII].

Dated this 29th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

.

ABSTRACT

“A PROCESS FOR THE PREPARATION OF DICYCLOMINE OR SALT THEREOF”
The present invention relates to an improved, and efficient process for the preparation of pure Dicyclomine of Formula I or salt thereof.

[Formula I]
The present invention also relates to a process for the preparation of Dicyclomine hydrochloride intermediate 1-chlorocyclohexyl cyclohexyl ketone of Formula III.

[Formula III]
The present invention also relates to a process for the purification of Dicyclomine hydrochloride of Formula V.

[Formula V]
Dated this 29th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 1 of 1

Figure 01
Dated this 29th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.
,CLAIMS:I /We claim:
1. A process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising the steps of:
a) reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III; and

[Formula III]
b) reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
2. The process as claimed in claim 1, wherein chlorinating agent is phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2) and aromatic hydrocarbon solvent is benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
3. The process as claimed in claim 1, wherein in step a) is carried out at temperature of 10°C to 70°C.
4. A process for the preparation of 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
comprising reacting dicyclohexyl ketone of Formula II,

[Formula II]
with chlorinating agent in presence of aromatic hydrocarbon solvent to obtain 1-chlorocyclohexyl cyclohexyl ketone of Formula III.
5. The process as claimed in claim 4, wherein in chlorinating agent is phosphorus trichloride (PCl3), phosphorus pentachloride (PCl5), phosphorous oxychloride (POCl3), thionyl chloride (SOCl2) or sulphuryl chloride (SO2Cl2) and aromatic hydrocarbon solvent is benzene, toluene, o-xylene, m-xylene, p-xylene, mixture(s) of xylene, or mixture thereof.
6. The process as claimed in claim 4, wherein in step a) is carried out at a temperature of 10°C to 70°C.
7. A process for the preparation of Dicyclomine of Formula I or salt thereof,

[Formula I]
comprising reacting 1-chlorocyclohexyl cyclohexyl ketone of Formula III,

[Formula III]
with sodium 2-(diethylamino)ethanolate of Formula IV,

[Formula IV]
in presence of diethylethanolamine to obtain Dicyclomine of Formula I or salt thereof.
8. A process for the purification of Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising treating Dicyclomine hydrochloride of Formula V with mixture of water and ketone solvent.
9. The process as claimed in claim 6, wherein ketone solvent is acetone, methyl ethyl ketone, methyl isobutyl ketone, or ethyl isobutyl ketone
10. A highly pure Dicyclomine hydrochloride of Formula V,

[Formula V]
comprising:
i) less than 0.02% of 1,1’-bi(cyclohexane)-1-carboxylic acid of Formula VI; and

[Formula VI]
ii) less than 0.02% of 2-(diethylamino)ethyl 1,1’-bi(cyclohexan)-1’-ene-1-carboxylate of Formula VII,

[Formula VII].

Dated this 29th day of March 2025

Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.