FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 200J
COMPLETE SPECIFICATION

(See section 10 and rule13)
1. TITLE OFTHE INVENTION:

"PROCESS FOR THE PREPARATION OF HOMATROP1NE"

2. APPLICANT:
(a) NAME; INDOCO REMEDIES LIMITED

(b)NATIONALITY: Indian Company incorporated under the Companies Act, 1956
(c) ADDRESS: Indoco House, 166 C.S.T. Road, Santacruz (East), Mumbai - 400 098, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specificarton particularly describes the invention and the manner in which it is to be formed.

FIELD OF INVENTION:
The present invention relates to a process for preparation of the compound endo-(±)-α-hydroxybenzeneacelic acid 8-methyl-8-azabicyclo[3.2.1]oct-3-yl ester known as Homatropine of Formula I and its pharmaceuticallyacceptable salt.

BACKGROUND AND PRIOR ART:
The compound endo-(±-)-a-Hydroxybenzeneacetic acid 8-methyl-azabicyclo [3.2.1] oct-3-yl ester of Formula I is commonly known as Homatropine. The hydrobromide salt of Homatropine has parasympatholytic properties and is used in ophthalmology as a cycloplegic refraction, uveitis and mydriatic lens opacities. Homatropine is commercially marketed as its hydrobromide or methyl bromide sail.
The compound Homatropine was fist time disclosed in the Journal Ann.217. 82 (1883) by Ladenburg and in .1. Prakt. Chem. 117, 142 (1927) by Chemnitius. wherein tropine is reacted with mandelic acid to get Homatropine of Formula 1. which is then converted to its pharmaceutically acceptable salts of Homatropine hydrobromide. Homatropine hydrochloride. Homatropine sulfate and Homatropine salicylate.
Another patent SU370847 describes the preparation of Homatropine, wherein tropine hydrochloride is reacted with phenylglyoxylic acid chloride to get tropine phenylglyoxylate hydrochloride which is subjected to reduction with sodium borohydride to yield Homatropine of Formula I.
The drawback of the above invention is use of unstable phenyl glyoxylic acid chloride and formation of benzoyl chloride during the preparation of phenyl glyoxylic acid chloride which reduces the yield of Flomatropine.

Another patent application CN101643473 describes the preparation of Homatropine. wherein tropine is reacted with 2-formyloxy-2-phenylacetyl chloride in presence of triethyl amine to give tropine-2-formyloxy-2-pheny! acetate, which on hydrolysis with sulfuric acid yields Homatropine of Formula I. The reaction of Homatropine with 48% hydrobromic acid results in Homatropine hydrobromide.
The drawback of the above invention is the use of protected hydroxy! mandelic acid which requires protection and deprotection steps increasing the number of steps for the synthesis of Homatropine. Preparation of 2-formyloxy-2-phenylacety) chloride requires the use of hazardous thionyl chloride.
Yet another patent application 499/DEL/2009 describes the preparation of Homatropine. wherein mandelic acid is first reacted with methanol in presence of sulfuric acid to get methyl mandelate. which is then reacted with tropine in presence of base to get Homatropine of Formula I. The compound Homatropine is then reacted with hydrobromic acid in acetone to isolate Homatropine hydrobromide. The reaction sequence can be represented as in scheme I below;

The drawback of the above invention is lower yield and formation of unwanted dirtier impurity of Formula III during the reaction;


Thus it becomes necessary to develop a process which avoids the use of hazardous chemicals; having reduced number of steps to obtain Homatropine of Formula I., substantially free from impurities and with good yield.
The present inventors have now come out with an improved process which involves the use of ester of phenyl glyoxalic acid as reactant which ameliorates the drawbacks in prior art and avoids the formation of impurities during the reaction.
The advantage of the present invention lies in the use of the ester of the phenyl glyoxalic acid which reduces the protection and deprotection steps, which is mandatory for the compounds-having free hydroxyl group, to avoid the formation of dimer impurity. The ester compound also prevents the use of toxic chemicals such as thionyl chloride and the formation of corrosive benzoyl chloride as side product. The use of ester of the phenyl glyoxalic acid makes the reaction cleaner, environment friendly and produces alcohol as side product which can be easily removed from the reaction mixture and makes the reaction smooth for industrial scale production.
OBJECT OF THE INVENTION:
The object of the present invention is to prepare Homatropine of Formula ! with a rigid and efficient process with good yield.
Another object of the present invention is to prepare Homatropine of Formula 1 devoid of dimer impurity.
Another object of the present invention is to prepare pharmaceutically acceptable salt. Homatropine hydrobromide.

Another object of the present invention is to prepare pharmaceutically acceptable salt. Homatropine methyl bromide.
SUMMARRY OF THE INVENTION:
Accordingly, the present invention provides a process for the preparation of endo-(±)-α-hydroxybenzeneacetic acid 8-methyl-8-azabicyclo [3.2.1]oct-3-yl ester [Homatropine] of Formula I and its pharmaceutics lly acceptable salt

Formula I comprising the steps of:
a. reacting tropine of Formula II;

Formula II with an ester of phenyl glyoxalic acid of Formula III:

Formula III wherein R is C1 — C4 linear or branched alky! group: in presence of base and an organic solvent to obtain the compound tropine phenyl glyoxalate of Formula fV or its acid addition salt:

Formula IV
b. reducing the compound of Formula IV or its acid addition salt in presence of
reducing agent and solvent to isolate crude compound homatropine of Formula I.
and
c. purifying the crude homatropine followed by reacting with the compound R'X.
wherein X is chloride or bromide ion and R1 is independently hydrogen or a
methyl group to isolate pharmaceutically acceptable salt of Homatropine of
Formula ).
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a process for the preparation of endo-(±)-α-hydroxybenzeneacetic acid 8-methyl-8-azabicyclo [3.2.1]ocl-3-y| ester [Homatropine] of Formula I.

Formula I In one of the embodiments of the present invention, tropine of Formula II is reacted with the ester of phenyl glyoxalic acid of Formula III.

Formula III wherein R is C1 — C4 linear or branched alkyl group;

in presence of a base and an organic solvenl to isolate the compound tropine phenyl glyoxalate of Formula iV or its acid addition salt.
The base used for the reaction is organic or inorganic base selected from sodium methoxide, sodium ethoxide. sodium tert-butoxide. potassium tert- buloxide. sodium carbonate, potassium carbonate, sodium acetate. DMAP and pyridine. The preferred base used for the reaction is selected from sodium carbonate and potassium carbonate, wherein the most preferred base used for the reaction is potassium carbonate.
The organic solvent used for the reaction is aliphatic or aromatic hydrocarbon selected from hexane. heptane, cyclohexane, toluene, xylene and chlorobenzene. The most preferred solvent used for the reaction is Toluene.The reaction is carried out at reflux temperature of the solvent used with or without the removal of the corresponding alcohol formed during the reaction. After the completion of the reaction, the reaction mixture is cooled to 20 - 30°C and quenched with water. The organic layer containing the product is separated and washed with fresh water. The isolation of the product is done either directly or by making acid addition salt of the product.
Accordingly, the organic layer is concentrated under reduced pressure to directly get crude residual mass of tropine phenyl glyoxalate of Formula IV, Charged methanol to the residual mass and stirred at -5°C to 5°C and filtered the solid product of tropine phenyl glyoxalate of Formula IV.
In another process variant of the present invention, when isolation is carried out by making the acid addition salt of the product, the organic layer is separated and washed with water and dried over anhydrous sodium sulphate. The organic layer was cooled to 0°C and passed dry hydrochloric acid gas into the organic layer by maintaining temperature between 0°C to 10°C to adjust the pH of the reaction mass to 3. The temperature of the reaction mass was raised to 20°C and maintained for 2 hours at temperature of 20°C to 30°C. The solid mass separated was filtered to isolate the hydrochloride salt of the compound tropine phenyl glyoxalate of Formula IV.

In another embodiment: of the nresenl invention, the compound tropine phenyl glyoxalate of Formula IV or its acid addition salt on reaction with a reducing agent in presence of solvent results in the compound Homatropine of Formula I.
The solvent used for the reduction reaction is selected from C1 - C4 linear or branched alcohols; hydrocarbons or mixture thereof. The C1 - C4 linear or branched alcohol used is selected from methanol, ethanol. propanol. isopropanol, butanol. sec. butanol and tert. Butanol whereas the hydrocarbon solvents used are selected from tetrahydrofuran, hexane. heptane, cyclohexane. toluene, xylene and chlorobenzene. The preferred solvent used for the reduction reaction is C1 - C4 linear alcohol selected from methanol ethanol. propanol and butanol, whereas the most preferred solvent used for the reduction reaction is methanol.
The reducing agent used for the reduction reaction of the tropine phenyl glyoxalate or its acid addition salt is sodium borohydride. The reducing agent is charged slowly to control exothermictty of the reaction.
The reduction reaction of tropine phenyl glyoxalate or its acid addition salt is carried out at the temperature in the range of -10°C to 25°C. The preferred temperature of the reduction reaction is -5°C to 15°C. whereas the most preferred temperature for the reduction reaction is 0°C to 5°C. After complete addition of sodium borohydride the reaction mass is maintained for 1 to 2 hour. The completion of the reaction is checked and the solvent is distilled out completely under vacuum to obtain the residual mass of the compound Crude Homatropine of Formula I.
In another embodiment of the present invention the crude Homatropine of Formula 1 was purified to get the compound pure Homatropine of Formula I. To the above residual mass of crude Homatropine charged toluene and stirred. Distilled out 50% of the charged quantity of toluene under reduced pressure and quenched the reaction mass with water. Cooled the reaction solution to 10°C and adjusted the pH of the solution to 3 using a mineral acid selected from the group consisting of dilute hydrochloric acid, dilute sulfuric acid or dilute nitric acid. The dilution of the acid may be in the range of 1:1. The preferable dilute acid used is 1:1 hydrochloric acid solution. The diluent used to make 1:1

acid solution is water. Stirred and separated the organic layer and washed the aqueous layer with toluene. The aqueous layer is made alkaline by charging a base selected from the group consisting of sodium hydroxide, potassium hydroxide or. ammonium hydroxide. One preferable base according to the process of the invention is ammonium hydroxide. Accordingly, charged liquor ammonia solution to the aqueous layer to get the pH of the solution in the range of 9.5 - 1 1. Extracted the aqueous layer with chlorinated solvent selected from the group of dichloromethane. dichloroethane. and chlorobenzene. The preferred chlorinated solvent used is dichloromethane. The organic layer is separated and dried over anhydrous sodium sulphate. The dried organic layer was concentrated under reduced pressure below 6G°C to isolate pure Homatropine of Formula 1.
The compound Homatropine of Formula 1 is reacted with the compound R'X. wherein X is chloride or bromide ion and R1 is independently hydrogen or a methyl group, as per the process reported in the prior art to isolate corresponding pharmaceutical!}' accepted salt of compound Homatropine of Formula I.
The reaction sequence of the present invention can be represented as per scheme 2 below:


The present invention is further illustrated in detail with reference to the following examples. It is desired that the examples be considered in all respects as illustrative only and non restrictive to the invention.
EXAMPLES:
Example 1: Preparation of Tropine phenyl glyoxaiate:
Charged tropine (10 g). methyl phenyl glyoxaiate (16.30 g) and potassium carbonate (19.6 g) in toluene (100 ml). The temperature of the reaction mixture was raised to 100 -110°C under nitrogen atmosphere. Maintained the reaction at 100 -1 10°C for 3 hours and distilled out toluene (50 ml) using Dean Stark assembly. Charged fresh toluene (50 ml) and maintained the reaction mixture at 100 -110°C temperature for another 2-3 hr. After the reaction completion, the reaction mass was cooled to 25-30°C and quenched in water (50 ml). The organic layer was separated, washed with brine solution and then concentrated under reduced pressure to get crude residual mass of the compound tropine phenyl glyoxaiate as oil. The product was purified by adding methanol to the above residue; stirred under cooling at 0 - 5°C and filtered the solid compound of tropine phenyl glyoxaiate. Yield = 13.55 g
Example 2: Preparation of Homatropine:
Charged tropine phenyl glyoxaiate (13 g) in mixture of solvent methanol (20 ml) and dichloromethane (70 ml). Cooled the reaction mixture to 0 - 5°C and charged in lot wise sodium borohydride (1.80 g) maintaining the temperature at 0 - 5°C. After complete addition of sodium borohydride. maintained the reaction mixture at 0 - 5°C for 3-4 hours. After completion of the reaction quenched the reaction mixture with water (50 ml) and extracted with additional dichloromethane (65ml). Separated the organic layer washed with water and dried over anhydrous sodium sulphate. Concentrated the organic-layer under reduced pressure to get the compound Homatropine of Formula I. Yield:11.50 g

Example 3: Preparation of Homatropine Hydrobromide:
Charged Homatropine (11 g) in isopropyl alcohol (45 ml) and stirred to dissolve. Raised the temperature of the reaction mixture to 50°C and charcoalised. Filtered the solution and adjusted the pH of the solution to 3 to 4 using hydrobromic acid solution (5 ml, 0.45 vol.). Cooled the reaction mixture to 0 - 5°C and maintained for 1-2 hour. The solid compound obtained was filtered and washed with Isopropyl alcohol (10 ml) to get Homatropine hydrobromide. Yield: 11.7g
Example 4: Preparation of Tropine phenyl glyoxalate hydrochloride.
Charged tropine (10 g). methyl phenyl glyoxalate (29-05 g) and potassium carbonate (14.68 g) in toluene (130 ml). The temperature of the reaction mixture was raised to 110-115°C under nitrogen atmosphere. Maintained the reaction at 110 - I !5°C for 3 hrs and distilled out toluene (90 ml) using Dean Stark assembly. Charged fresh toluene {90 ml) and maintained at 110 - 1!5°C till completion of the reaction. After the reaction completion, the reaction mass was cooled to 25 - 30°C and quenched in water (50 ml). Separated the organic layer and aqueous layer was extracted with toluene (20 ml). Combined toluene layers were washed with water (2 x 50 ml). Further, washed with brine solution (30 ml). Charcoalisd the organic layer, filtered and dried over anhydrous sodium sulphate. Concentrated the toluene layer to about 140 ml and adjusted pH upto 3 by purging hydrochloric acid gas by maintaining temperature at 5 -10°C. Maintained reaction mass for 2 hour al 20 - 25°C and filtered the separated solid. Leached wet solid mass in 50 ml toluene at 25 -30°C and filtered the solid compound of tropine phenyl glyoxalate hydrochloride. Wet weight = 144gms.
Example 5: Preparation of Homatropine hydrobromide:
Charged tropine phenyl glyoxalate hydrochloride (14 g) in methanol (110 ml). Cooled the reaction mixture to 0 to - 5°C and charged in lot wise sodium borohydride (2.81 g) maintaining the temperature at 0 to - 5°C. After complete addition of sodium borohydride.. maintained the reaction mixture at 0 - 5°C for 1 hr. After reaction completion distilled out reaction mass. Charged toluene (77 ml) to degassed mass and distilled out toluene (about 30 ml).Charged water (77 ml) and adjusted pH 1 - 3 with

aqueous1: 1 hydrochloric acid (15.4 ml) at 10°C. Separated the aqueous layer and washed with toluene (46 ml). Adjusted the pH of aqueous layer with liquor ammonia to 9.5 -11, Extracted aqueous layer with dichloromethane (185 ml). Combined the organic layers washed with purified water (2x31 ml) and dried over anhydrous sodium sulphate. Concentrated the organic layer under reduced pressure to get the residual mass of compound Homatropine of Formula I.
Charged acetone (80 ml) to the residual mass and heated to 40-45°C to get a clear solution. Charcoalisd at 40-45°C. Filtered the solution and adjusted the pH of the solution upto 3 using hydrobromic acid solution (17 ml in 30 ml acetone). Maintained the reaction mass for 5-6 hours at 20 - 25°C. The solid compound obtained was filtered and washed with acetone (10 ml) to get homatropine hydrobromide. Yield: 7.6 g

We Claim:
1. A process for the preparation of endo-(±)-a-hydroxybenzeneacetic acid 8-methyl-8-azabicyclo[3.2. l]oct-3-yl ester [Homatropine] of Formula I and its pharmaceutically acceptable salt

Formula I comprising the steps of;
a. reacting the compound tropine of Formula II:

Formula If with an ester of phenyl glyoxalic acid of Formula MI:

Formula 111 wherein R is C1 - C4 linear or branched alkyl group: in presence of base and an organic solvent to obtain the compound tropine phenyl glyoxalate of Formula IV or its acid addition salt;

Formula IV b. reducing the compound of Formula IV or its acid addition salt in presence of reducing agent and solvent to isolate compound homatropine of Formula I:

c. purifying the compound homatropine to isolate pure homatropine compound
of Formula I: and
d. reacting pure homatropine with compound R1x, wherein X is chloride or
bromide ion and R1 is independently hydrogen or a methyl group in presence
of solvent to isolate pharmaceutically acceptable salt of Homatropine of
Formula i.
2. The process as claimed in claim 1(a). wherein the organic solvent used is aliphatic or aromatic hydrocarbon selected from the group consisting of hexane. heptane. cyclohexane. toluene, xylene and chlorobenzene.
3. The process as claimed in claim 1(a). wherein the base used is selected from the group consisting of sodium methoxide. sodium ethoxide. sodium tert-butoxide. potassium tert- butoxide. sodium carbonate, potassium carbonate, sodium acetate. DMAP and pyridine.
4. The process as claimed in claim 1(b). wherein the reducing agent used is sodium borohydride.
5. The process as claimed in claim 1(b). wherein the solvent used for reduction reaction is C1 - C4 linear or branched alcohol selected from the group consisting of methanol, ethanol. propanol. isopropanol. butanol. sec. butanol and tert. Butanol.
6. The process as claimed in claim 1(b). wherein the reduction reaction is carried out at temperature of-10°C to 25°C.
7. The process as claimed in claim !(c), wherein the purification of homatropine comprises the steps of;
a. dissolving the crude homatropine in toluene followed by charging water.
b. adjusting the pH of the solution in the range of 1 - 3 with mineral acid
selected from the group consisting of dilute hydrochloric acid, dilute
sulfuric acid or dilute nitric acid.

c. separating the organic layer and making the aqueous layer alkaline by
adding base selected from the group consisting of sodium hydroxide.
potassium hydroxide or ammonium hydroxide,
d. extracting the aqueous layer in chlorinated solvent and
e. separating the organic layer followed by concentrating under reduced
pressure to gel pure homatropine.
8. The process as claimed in claim 7(d). wherein the chlorinated solvent is selected from the group of dichloromethane, dichloroethane. and chlorobenzene.
9. The process as claimed in claim 1(d), wherein the pharmaceutical!)' acceptable salt is homatropine hydrobromide.