PROCESS FOR THE PREPARATION OF HOMATROPINE AND ITS QUATERNARY SALTS THEREOF
FIELD OF THE INVENTION
[0001] The present invention relates generally to a novel process for the preparation of quaternary tropine derivatives. The invention is more especially concerned with a novel process for the preparation of Homatropine and its quaternary salts of the formula as given below:
(FORMULA REMOVED)
[0002] The aim of the present invention is to provide an improved industrial method of synthesis which enables the compounds of general formula mentioned above to be synthesised more easily, in a manner which is an improvement on the prior art.
BACKGROUND OF THE INVENTION
[0003] Homatropine is an anticholinergic medication that inhibits acetylchloine receptors and thus the parasympathetic nervous system. It is used in eye drops as a cydoplegic to temporarily paralyze accommodation and as a mydriatic to dialate the pupil.
[0004] Homatropine is less potent than atropine and has a shorter duration of action. It is available as the hydrobrimide or methylbromide salt.
[0005] Homatropine was first described by Ladenburg in Ann. 217, 82 (1883) and by Chemnitius in J. Prakt. Chem. 117,142 (1927).
[0006] Homatropine was synthesised by the condensation of tropine with mandeiic acid which was then quatemised to give quaternary salts like Homatropine [007] Hydrochloride, Homatropine Hydrobromide and Homatropine Methybromide.
[0008] The synthesis of Homatropine and its quaternary salte were described in the literature using various methods as given below:-
1) The document SU 370847 describes the synthesis of Homatropine by acylating tropine hydrochloride with PhCCXOCI in an organic solvent ( e.g. CHCI3) followed by the borohydride reduction of the resulting ester.
2) Singh, Tej; Handa, K. L; Rao, P. R. Reg. Res. Lab., Jammu, India. Research and Industry (1972), 17 (30, 92-3 describes the formation of Homatropine by esterificatkm of tropine with mandeloyi chloride followed by deacetylation.
3) The document SU 199149 discloses the reaction of tropine derivative with amygdalic acid in the presence of HCI.
4) The document DD 11056 discloses the formation of Homatropine by esterification of tropine in inert solvent preferably benzene or in chlorinated hydrocartx)n like chloroform with mandelic acid in the presence of sulphuric acid.
5) The document CH 75622 describes the reaction of tropine with mandelic add In the presence of aqueous hydrochloric acid.
6) The document US 5770738 describes the tropanyl methylbromide derivatives by condensation of scopine with CICPhaCOCI.
7) Anticholinergics may be used to advantage to treat a number of diseases. Particular mention may be made for example of the treatment of asthma or CORD (chronic obstructive pulmonary disease). Anticholinergics which have a scopine, tropenol or tropine basic structure are proposed for example by WO 02/03289 for the treatment of these diseases. Moreover, tiotropium bromide is particulariy disclosed in the prior art as a highly potent anticholinergic. Tiotropium bromide is known for example from EP 418 716 A1.
[0009] Ail these patents reported the advantage and disadvantages for the preparation of these quaternary salts in tenm of quality, yield and method of preparation. Efforte have been made to address the problems associated with all these processes reported in prior art and to develop a novel process for the preparation of Homatropine of good purity, high yield and easy to commercialise.
[0010] The above and other objects of the present invention will become apparent from the description hereinafter.
SUMMARY OF THE INVENTION
[0011] In accordance with the present invention, there is provided a process for the preparation of Homatropine, Homatropine Hydrobromide and Homatropine methylbromide. The steps involved in the process are as follows:-
(1) DL-Mandelic acid is esterified in the methanol in the presence of acid catalyst to give DL-Methyl mandelate which is used as such insitu or optionally isolated.
(2) DL-Methyl mandelate undergoes transesterification with Tropine in an organic solvent in the presence of alkali metal alkoxide to give Homatropine of fonnula of Fig. I
(FORMULA REMOVED)
(3) Homatropine of fonnula of Fig. I is then quatemised to give quartnery salts of
formula of figure II and formula of figure III.
(FORMULA REMOVED)
DETAILED DESCRIPTION OF THE INVENTION
[0012] Accordingly, this invention provides the process in which DL-Mandelic acid of formula of figure IV is reacted with methanol in the presence of sulphuric acid at reflux temperature.( 65° to 70*C)
(FORMULA REMOVED)
[0013] On completion of reaction, methanol is distilled off and the reaction mass is extracted in an organic solvent using the aqueous solution of inorganic base. The organic layer having product is washed successively with water and brine solution, dried over sodium sulphate. The organic layer is distilled of completely to give compound of formula of figure V which is used as such for next reaction or optionally isolated as low melting solid using antisolvent.
(FORMULA REMOVED)
[0014] The organic solvent used are halogenated aliphatic hydrocarbon such as methylene chloride, ethylene chloride , chloroform , aliphatic ester such as ethyl acetate, butyl acetate, aromatic hydrocarbon such as toluene , xylene or aliphatic ether such as diethyl ether , di-isopropyl ether. The most preferably used is methylene chloride. The aqueous solution of inorganic base used are of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal carbonate and bicarbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate. The most preferably used is potassium carbonate. The antisolvents used for isolation of compound of formula of fiqure V are heaxane, heptane, ether etc.
[0015] The compound of formula figure V is reacted with compound of fomiula figure VI in an organic solvent using alkali metal alkojdde at elevated temperature to give compound of formula having figure I.
(FORMULA REMOVED)
[0016] The organic solvent used for the reaction is aliphatic straight chain or branched chain C6 -C12 hydrocart)on such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarton such as methylene chloride , chloroform, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether. The preferably used is Heptane.
[0017] The alkali metal alkoxide used are sodium methoxide, sodium ethoxide, sodium -t-butaoxide, sodium isopropoxide. The preferably used is sodium methoxide.
[0018] On completion of reaction the organic solvent is either distilled off or drained from the reaction mass and the residue is dissolved in an organic solvent followed by washing with water. The organic solvent used for the dissolution is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarbon such as methylene chloride , chloroform, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether. The preferably used is methylene chloride.
[0019] The organic layer is then acidified with aqueous solution of mineral acid to extract the product in aqueous layer. The mineral acid used is Hydrochloric acid. Sulphuric acid, phosphoric acid, nitric add and preferably used is hydrochloric acid.
The aqueous layer having the compound of formula of figure I is washed with an organic solvent to remove the undesired impurities. The organic solvent used for the washing is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocartx)n such as methylene chloride , chlorofonnn, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether. The preferably used is methylene chloride.
[0020] The aqueous layer is then mixed with the organic solvent and the mixture is basified with a base to extract the compound of formula of figure I in organic layer. The organic solvent is completely distilled off. The antisolvent is added to the residue to provide compound of formula of figure I which is optionally purified.
[0021] The organic solvent used for extraction is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarbon such as methylene chloride , chlorofonn, etiiylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether. The preferably used is methylene chloride.
[0022] The base used for basification is the aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal carbonate and bicarbonate such as sodium cartbonate, sodium bicarbonate, potassium carbonate, liquor ammonia , organic base like triethyl amine, pyridine. The most preferably used is liquor ammonia.
[0023] The antisolvent used for tiie isolation is hexane, heptane, petroleum etiier, diethyl ether, di-isopropyl etiier, acetone, methanol, ethanol, isopropyl alcohol, water, 1,4-dioxane, toluene, xylene preferably used is petroleum ether and hexane and most preferably used is petroleum ether.
[0024] The compound of formula of figure I is dissolved in organic solvent to get a clear solution. The solution is optionally filtered to remove any undissolved impurity at elevated temperature. An anti solvent is then added to isolate the pure compound of formula of figure I at low temperature.
[0025] The organic solvent used for dissolution is aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocart)on such as methylene chloride , chloroform, ethylene dichioride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic alcohol such as methanol, ethanol, isopropyl alcohol, propanol, butyl alcohol, aliphatic ketone such as acetone, methylisobutyl ketone nethyl ethyl ketone and the preferably used is acetone.
[0026] The temperature used for dissolution is 10 -100 °C and preferably used is 55-60 °C.
[0027] The antisolvent used for the isolation Is hexane, heptane, petroleum ether, diethyl ether, di-isopropyl ether, acetone, methanol, ethanol, isopropyl alcohol, water, 1,4-dioxane, toluene, xylene preferably used is petroleum ether and hexane and most preferably used is Hexane.
[0028] The temperature of precipitation is -10 to +50 °C and preferably used is -10 to -5°C
[0029] The compound of formula of figure I is reacted with methyl bromide In solvents such as acetone, acetonitrile as per process mentioned in prior art to give compound of formula of figure II. The Methyl bromide used is either in the form of gas or a solution prepared by purging the gas in the solvent used for the reaction.
[0030] The compound of formula of figure I is reacted with Hydrogen bromide in solvents such as acetone, acetonitrile as per process mentioned in prior art to give compound of formula of figure III. The hydrogen bromide used is either in the form of gas or solution prepared by purging the gas in tiie solvent used for the reaction.
[0031] The compound of formula of figure II and compound of formula of figure III Is optionally purified by dissolving in organic solvent charcolised and pure compound is isolated using antisolvent
[0032] The organic solvent used for dissolution is aliphatic alcohol such as methanol, ethanol, isopropyl alcohol, propanol, butyl ateohol, and the preferabaly used is acetone.
[0033] The antisolvent used for isolation of pure compound is aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ketone such as acetone, methylisobutyl ketone nethyl ethyl ketone and the preferably used is acetone.
[0034] The invention is further illustrated by the process of the examples which do not limit the effective scope of the claims.
Example I: Preparation of Homatropine (Compound of fomiula having figure 1)
[0035] Charge DL-Methyl mandelate (Compound of fonnula having figure V ; 120 gms ; 0.723 mole) in Heptane (400 ml) at room temperature in a clean and dry flask. Add Tropine (Compound of fonnula having figure VI; 100 gms ; 0.71 mole) at the same temperature. Heat the reaction mass to reflux temperature. Add sodium methoxide (8 gms ; 0.148 mole) to the reaction mass in small lots while refluxing the reaction mass with azeotropically rerrraval of methanol. After the completion of reaction the solvent is distilled off and resklue is dissolved in methylene chloride and water. The layers are separated and organic layer is washed with water. The organic layer is then acidified with dilute Hydrochloric add and product is extracted into aqueous layer. The aqueous layer is then washed with methylene chloride. The aqueous layer having product is again mixed with methylene chloride and the reaction mass is basified with aqueous ammonia solution to extract back the product in methylene chloride. The layer is separated and organic layer is then washed successively with water, brine solution and dried on sodium sulphate. The solvent is distilled off and product is isolated by adding petroleum ether (300 ml). The product is dried at 40 - 45 °C to give Homatropine (compound of formula of figure I ; 120 gms). This product is optionally purified by dissolving in acetone (120 ml) by heating. The pure product is isolated by adding Hexane (120 ml). The product is dried at 40 -45 °C to give pure Homatropine (compound of formula having figure I; 110 gms ( 56 % ; HPLC purity 99 % ; Melting point 98-100 °C)
Example II: Preparation of Homatropine (Compound of fonnula having fiqure I) using insitu fomiation of DL-Methyl mandelate
[0036] Charge DL-Mandelic add (Compound of formula having figure IV ; 120 gms ; 0.79 mole) in methanol ( 300 ml) and heat to reflux temperature. Concentrated sulphuric add (24 ml) is added drop wise in 3-4 hours at 65-70 oC. The mixture is
further refluxed for 4 hours. On completion of reaction the reaction is cooled to 0 -10°Cand transferred in to methylene chloride. The reaction mass is basified using aqueous solution of potasium carbonate to extract the product in the organic layer. The organic layer is then washed successively with water, brine solution and dried over sodium sulphate. The solvent is then distilled off to give DL- methyl mandelate as an oil (120 gms). Heptane (400 mi) is added to this oil at room temperature. Add Tropine (Compound of fonnula having figure VI; 100 gms ; 0.71 mole) at the same temperature. Heat the reaction mass to reflux temperature. Add sodium methoxide (8 gms ; 0.148 mole) to the reaction mass in small lots while refiuxing the reaction mass with azeotrop'ically removal of methanol. After the completion of reaction the solvent is distilled off and residue is dissolved in methylene chloride and water. The layers are separated and organic layer is washed with water. The organic layer is then acidified with dilute Hydrochloric acid and product is extracted into aqueous layer. The aqueous layer is then washed with methylene chloride. The aqueous layer having product is again mixed with methylene chloride and the reaction mass is basified with aqueous ammonia solution to extract back the product in methylene chtoride. The layer is separated and organic layer is then washed successively with water, brine solution and dried on sodium sulphate. The solvent is distilled off and product is isolated by adding petroleum ether (300 ml). The product is dried at 40 - 45 °C to give Homatropine (compound of fomiula of firure I ; 130 gms). This product is optionally purified by dissolving in acetone (120 ml) by heating. The pure product is isolated by adding Hexane( 120 ml) . The product is dried at 40 - 45 °C to give pure Homatropine (compound of formula having figure I; 120 gms (61.5 %; HPLC purity 99.5 % ; Melting point 98-100 °C).
Example III: Preparation of Homatropine Methyl bromide (Compound of formula having figure 11)
[0037] Homatropine (compound of formula having figure I; 100 gms ;0.363 mole) is dissolved in acetone to get the clear solution. Methyl bromide solution in acetone (125 gm in 300 ml) is added at 30 - 35 °C and stinred for over night. The product precipitated out is filtered washed witii acetone and dried to give Homatropine methylbromide.
[0038] The product is purified by dissolving in methanol (375 ml) at room temperature. Activated cartran (1.25 gms) is added and stirred for 1 hour. The mass is filtered through hyflo and dear solution is concentrated. Acetone (800 ml) is added to the concentrated mass to give pure Homatropine methyl bromide which is dried at 55 -60 °C. The yield is 110 gms (82 %. HPLC purity: 99.5 %).
Example IV: Preparation of Homatropine Methyl bromide (Compound of formula having figure II)
[0039] Homatropine (compound of formula having figure I; 100 gms .0.363 mole) is dissolved in acetonitrile to get the dear solution. Methyt bromide solution in acetonitrile (125 gm in 300 ml) is added at 30 - 35 °C and stirred for over night. The product predpitated out is filtered washed with acetone and dried to give Homatropine methylbromide.
[0040] The product is purified as per process given in example III to give pure Homatropine methyl bromide which is dried at 55 - 60 °C. The yield is 100 gms (74.6 %, HPLC purity: 99.0 %).
Example V: Preparation of Homatropine Hydrobromide (Compound of formula having figure III)
[0041] Homatropine (compound of formula having figure I; 100 gms; 0.363 mole) is dissolved in acetone to get the dear solution. Hydrobromide solution in acetone (110 gm in 300 ml) is added at 30 - 35 °C and stirred for over night. The product precipitated out is filtered washed with acetone and dried to give Homatropine Hydrobromide (110 gms ;85.2 %, HPLC purity: 99 %).

We Claim:
1) A process for preparing the homatropine and its quaternary salts of fomnuia of figure I by reacting DL-methyl mandelate of fonnula of figure V with tropine of formula VI in an organic solvent using alkali metal alkoxide at elevated temperature, which is then quartinised to give its quaternary salts of homatropine of fonnula of figure II and figure III, as shown below:
(FORMULA REMOVED)
2) A process for preparing the homatropine and its quaternary salts of fomiula of figure I as claimed in claim 1, wherein the organic solvent used for the reaction is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarbon such as methylene chloride , chiorofomi, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether.
3) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 1, wherein the organic solvent is preferably heptane.
4) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 1, wherein the alkali metal alkoxide used are sodium methoxide, sodium ethoxide, sodium -t-butaoxide, sodium isopropoxide.
5) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 1, wherein the alkali metal alkoxide is preferably sodium methoxide.
6) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim I, wherein on completion of reaction the organic
solvent is either distilled off or drained from the reaction mass and the residue is dissolved in an organic solvent followed by washing with water.
7) A process for preparing the homatropine and its quaternary salts of formula of
figure I as claimed in daim 6, wherein the organic solvent used for the dissolution is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocartx)n such as toluene, xylene, aliphatic halogenated hydrocartx)n such as methylene chloride, chloroform, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-sopropyl ether.
8) A process for preparing the homati'opine and its quaternary salts of fonnula of figure I as claimed in daim 6, wherein the organic solvent used is preferably methylene chloride.
9) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 6, wherein the organic layer is then acidified with aqueous solution of mineral acid to extinct the product in aqueous layer.
10) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 9, wherein the mineral add used is Hydrochloric acid, sulphuric add, phosphoric add, nitiic add.
11) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 9, wherein the mineral add preferably used is hydrochloric add.
12) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 9, wherein the aqueous layer having the compound of formula of figure i is washed with an organic solvent to remove the undesired impurities.
13) A process for preparing the homatiropine and its quaternary salts of fonmula of figure I as daimed in daim 6, wherein the organic solvent used for the washing is aliphatic straight chain or branched chain C6 -C12 hydrocarbon such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocartxon such as methylene chloride , chloroform,
ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether.
14) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 13, wherein the organic solvent preferably used Is methylene chloride.
15) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 9, wherein the aqueous layer is then mixed with the organic solvent and the mixture is basified with a base to extract the compound of formula of figure I in organic layer.
16) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 15, wherein the organic solvent is completely distilled off and the antisolvent is added to the residue to provide compound of formula of figure I which is optionally purified .
17) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 16, wherein the organic solvent used for extraction is aliphatic straight chain or branched chain C6 -C12 hydrocarix)n such as Hexane, heptane, aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarbon such as methylene chloride , chloroform, ethylene dichloride. aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ether such as diethyl ether, di-isopropyl ether.
18) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 17, wherein the organic solvent preferably used Is methylene chloride.
19) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in claim 15, wherein the base used for basification is the aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal carisonate and bicarbonate such as sodium carbonate, sodium bicartonate, potassium carbonate, liquor ammonia organic base like triethyl amine, pyridine.
20) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 19, wherein the base most preferably used is liquor ammonia.
21) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 7, wherein the antisolvent used for the precipetation is hexane, heptane, petroleum ether, diethyl ether, di-isopropy! ether, acetone, methanol, ethanol, isopropyl alcohol, water, 1,4-dioxane, toluene, xylene.
22) A process for preparing the homatropine and its quaternary salts of formula of figure i as daimed in daim 21, wherein the antisolvent preferably used is petroleum ether and hexane.
23) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 22, wherein the antisolvent most preferably used is petroleum ether.
24) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 15, wherein the compound of formula of figure I is dissolved in organic solvent to get a clear solution.
25) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 24, wherein the dear solution is optionally filtered to remove any undissolved impurity at elevated temperature and an anti solvent is then added to predpitate out the pure compound of formula of figure I at low temperature.
26) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 24, wherein the organic solvent used for dissolution is aromatic hydrocarbon such as toluene, xylene, aliphatic halogenated hydrocarbon such as methylene chloride , chloroform, ethylene dichloride, aliphatic ester such as ethyl acetate, butyl acetate, aliphatic alcohol such as methanol, ethanol, isopropyl alcohol, propanol, butyl alcohol, aliphatic ketone such as acetone, methylisobutyl ketone nethyl ethyl ketone.
27) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in claim 26, wherein the organic solvent preferably used is acetone.
28) A process for preparing the homatropine and its quaternary salts of fomiula of figure I as claimed in daim 24, wherein the temperature used for dissolution is10-100°C.
29) A process for preparing the homatropine and its quaternary salts of fomiula of figure I as claimed in daim 28, wherein the temperature preferably used is 55-60 °C.
30) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 24, wherein the antisolvent used for the precipetation is hexane, heptane, petroleum ether, diethyl ether, di-isopropyl ether, acetone, methanol, ethanol, isopropyl alcohol, water, 1,4-dioxane, toluene, xylene.
31) A process for preparing the homatropine and its quaternary salts of formula of figure I as claimed in daim 30, wherein the antisolvent preferabaly used is petroleum ether and hexane.
32) A process for preparing the homatropine and its quaternary salts of fonnula of figure I as daimed in claim 31, wherein the antisolvent most preferably used is Hexane.
33) A process for preparing the homatropine and its quaternary salts of fonnula of figure I as daimed in claim 24, wherein the temperature of precipitation is -10-to+50 °C.
34) A process for preparing the homatropine and its quaternary salts of formula of figure I as daimed in daim 33, wherein the temperature preferably used is -10to-5°C.
35) A process for purification of the homatropine and its quaternary salts of formula of figure II and figure III as daimed in daim 1, wherein by dissolving in organic solvent, charcolised and pure compound is precipitated using antisolvent.
36) A process for purification of the homatropine and its quaternary salts of
fonnula of figure II and figure Hi as claimed in daim 35, wherein the organic
solvent used for dissolution is aliphatic alcohol such as methanol, ethanol,
isopropyl alcohol, propanol, butyl alcohol.
37) A process for purification of the homatropine and its quaternary salts of formula of figure II and fiquer III as claimed in daim 36, wherein the organic solvent preferably used is acetone.
38) A process for purification of the homatropine and its quaternary salts of formula of figure II and figure III as daimed in claim 35, wherein the antisolvent used for isolation of pure compound is aliphatic ester such as ethyl acetate, butyl acetate, aliphatic ketone such as acetone, methylisobutyl ketone nethyl ethyl ketone.
39) A process for purification of the homatropine and its quaternary salts of
formula of figure II and figure III as daimed in claim 38, wherein the
antisolvent used is preferably acetone.
40) A process for preparing the homatropine and its quaternary salts of formula of
figure i, figure II and figure III substantially as herein described.