FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)


A PROCESS FOR THE PREPARATION OF 3-[2-[4-(6-FLUORO-l,2-
BENZISOXAZOL-3-YL)-l-PIPERIDINYL]ETHYL]-6,7,8,9-TETRAHYDRO-2-
METHYL-4H-PYRIDO[l,2-a]PYRIMIDIN-4-ONE
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059, MAHARASHTRA, INDIA.
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

A PROCESS FOR THE PREPARATION OF 3-[2-[4-(6-FLUORO-l,2-
BENZISOXAZOL-3-YL)-l-PIPERIDINYL]ETHYL]-6,7,8,9-TETRAHYDRO-2-
METHYL-4H-PYRIDO[l,2-a]PYRIMIDIN-4-ONE
The present invention relates to a process for the preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one, commonly known as risperidone (INN name), compound of formula I. 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one is indicated for the treatment of psychotic disorders.

Formula-I
BACKGROUND OF THE INVENTION
Formula II Formula III Formula IV
United States patent number 4804663 (referred to herein as '663, Indian reference not available) exemplifies a process for the preparation of compound of formula I by N-alkylation of compound of formula II with compound of formula III (wherein X is halo) in DMF in the presence of sodium carbonate with catalytic amount of potassium iodide.

2

The crude risperidone is crystallized from a mixture of DMF and isopropanol; the overall yield of risperidone is only 46%, purity is not disclosed. Solvents like DMF, used in this prior art for the reaction, when utilized on large scale entail effluent disposal/treatment problems. The process of the present invention carries out N-alkylation in the presence of weakly nucleophilic to non-nucleophilic organic base, in an easy to recover/dispose organic solvent and does not employ any additional catalysts. The crude compound of formula I is purified to yield about 78% of the substantially pure compound of formula I.
Spanish patent 2074966 (Indian reference not available) describes a process for the preparation of compound of formula I by a method involving N-dialkyation of 3-(2-aminoethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidine-4-one (formula III, wherein X=NH2) with a compound of formula IV (wherein Y, Z stand for halo, or alkyl or aryl sulfonate). This patent does not disclose purity of compound of formula I. The process of the present invention prepares the compound of formula I using a different approach, wherein instead of 3-(2-aminoethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one, the piperidinyl compound of formula II is alkylated with pyrido[l,2-a]pyrimidine-4-one (formula III, wherein X is halo or acyloxy group).
PCT publication 0214286 (Indian reference not available) describes a process for the preparation of compound of formula I by N-alkylation of compound of formula II with III in the presence of an inorganic base in a solvent selected from the group of acetonitrile, isopropanol, ethyl methyl ketone and isobutanol. The yield as exemplified for the compound of formula I in this publication is 53-63%. The present invention carries out N-alkylation in the presence of weakly nucleophilic to non-nucleophilic organic base and yields around 78% compound of formula I.
All the above mentioned prior art carry out N-alkylation in the presence of an inorganic base in organic solvents. Inorganic bases used in these reactions are sparingly soluble in the organic solvent used as the medium for the reaction and consequently there would be problems of consistency and scalability of the reaction. The process of the present invention carries out N-alkylation in the presence of a weakly nucleophilic to non-
3

The crude risperidone is crystallized from a mixture of DMF and isopropanol; the overall yield of risperidone is only 46%, purity is not disclosed. Solvents like DMF, used in this prior art for the reaction, when utilized on large scale entail effluent disposal/treatment problems. The process of the present invention carries out N-alkylation in the presence of weakly nucleophilic to non-nucleophilic organic base, in an easy to recover/dispose organic solvent and does not employ any additional catalysts. The crude compound of formula I is purified to yield about 78% of the substantially pure compound of formula I.
Spanish patent 2074966 (Indian reference not available) describes a process for the preparation of compound of formula I by a method involving N-dialkyation of 3-(2-aminoethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidine-4-one (formula III, wherein X=NH2) with a compound of formula IV (wherein Y, Z stand for halo, or alkyl or aryl sulfonate). This patent does not disclose purity of compound of formula I. The process of the present invention prepares the compound of formula I using a different approach, wherein instead of 3-(2-aminoethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidine-4-one, the piperidinyl compound of formula II is alkylated with pyrido[l,2-a]pyrimidine-4-one (formula III, wherein X is halo or acyloxy group).
PCT publication 0214286 (Indian reference not available) describes a process for the preparation of compound of formula I by N-alkylation of compound of formula II with III in the presence of an inorganic base in a solvent selected from the group of acetonitrile, isopropanol, ethyl methyl ketone and isobutanol. The yield as exemplified for the compound of formula I in this publication is 53-63%. The present invention carries out N-alkylation in the presence of weakly nucleophilic to non-nucleophilic organic base and yields around 78% compound of formula I.
All the above mentioned prior art carry out N-alkylation in the presence of an inorganic base in organic solvents. Inorganic bases used in these reactions are sparingly soluble in the organic solvent used as the medium for the reaction and consequently there would be problems of consistency and scalability of the reaction. The process of the present invention carries out N-alkylation in the presence of a weakly nucleophilic to non-
3

nucleophilic organic base that is readily soluble in the organic solvent thereby eluding the problems mentioned.
PCT publication 0185731 (Indian reference - PCT/IN00/00053) describes a process for the preparation of compound of formula I by N-alkylation of compound of formula II with III, in the presence of an inorganic base in water. Further, the purity of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one, compound of formula I, by this invention is 99% which does not meet the standards of British Pharmacopoeia (not more than 0.3% total related impurities).The process of the present invention prepares substantially pure compound of formula I by N-alkylation of compound of formula II with III in the presence of weakly nucleophilic to non-nucleophilic organic base. The purity of the final product is greater than 99.7% and meets the purity specified by British Pharmacopoeia.
PCT publication 0185731 also describes and exemplifies preparation of compound of formula III by hydrogenation of compound of formula V in the presence of palladium/C in aqueous inorganic acidic medium.
Q : «. 0
X^ /\ >k../\ ••"' X
Formula III Formula V
However, this process is carried out at 100-120°C and under acidic conditions. The yield and purity reported for the compound of formula III in this publication are 83% and 99% respectively. The palladium catalyst used for the reaction is supported and belongs to the category of precious metal catalysts and hence is very expensive. Hydrogenations using palladium catalyst is known to cause dehalogenation of halo compounds. Thus the prior art method of hydrogenation may produce dehalogenated compounds as by-products (when X=halo in formula V). Besides, aqueous acidic conditions render usage of SS autoclaves incompatible for the hydrogenation reaction. The present invention uses hydrogenation catalysts like Raney metal type catalyst in an organic solvent. Also unlike
4

PCT publication 0185731, the present invention prepares compound of formula III under non-acidic conditions and non-aqueous conditions, conditions that are compatible for usage of SS autoclave for the hydrogenation. The Raney metal type catalysts, such as Raney nickel, are relatively inexpensive and have accelerated settling properties resulting in improved filtration from product due to its high density. In the process of the present invention dechlorination of compound of formula III when X is chloro is prevented as palladium based catalyst is not used. Unlike the hydrogenation reaction reported in prior art the process of the present invention carries out hydrogenation at ambient temperature thereby making the process less energy intensive. The process of the present invention results in high yield (>90%) and purity (>99.5%) of the hydrogenated product and is efficient and economical.
United States patent number 4804663 ('663) discloses preparation of compound of formula VIII by Friedel-Crafts acylation of l-acetyl-4-piperidinecarbonyl chloride with 1,3-difluorobenzene in the presence of aluminum chloride followed by hydrolysis of the intermediate N-acetyl derivative in an overall yield of 29.9%. This patent does not prepare compound of formula VIII by reacting compound of formula VI with an organometallic compound of formula VII.
°^Y


X
cr OR
VI

M(X1)

F O
VIII

United States patent number 4443451 (Indian reference not available) discloses preparation of compounds related to compound of formula VIII by the following steps (a) reacting l-benzyl-4-piperidinecarbonitrile with Grignard reagent generated from halobenzene derivatives to get N-benzyl-4-benzoylpiperidine derivative
5

(b) reaction of N-benzyl-4-benzoylpiperidine derivative with a chloroformate to get an N-(alkoxycarbonyl)-4-benzoylpiperidine and
(c) hydrolysis of the N-(alkoxycarbonyl)-4-benzoylpiperidine to get 4-benzoylpiperidine derivative
This patent however does not disclose the preparation of compound of formula VIII, nor is the process described similar to that of the present invention, which reacts compound of formula VI wherein Y is a halo group and R is selected from C1-C3 alkyl, aryl and aralkyl groups with an organometallic compound of formula VII.
OBJECT OF THE INVENTION
An object of the invention is to provide a simple process for the preparation of compound of formula I which is environment friendly and is commercially feasible.
Another object of the present invention is to provide a process for the preparation of substantially pure compound of formula I in higher yield.
SUMMARY OF THE INVENTION

Formula I
N-alkylation of compound of formula II or its acid addition salts, with compound of formula III,
Accordingly, the present invention provides a process for the preparation of compound of formula I comprising,
6


X.

o
^N

N'

Formula II

Formula III

wherein X is selected from halo and acyloxy group, in the presence of weakly nucleophilic to non-nucleophilic organic base in an organic solvent.
The present invention further provides a simple process for the preparation of compound of formula II by
(a) condensing compound of formula IX with haloformate YCOOR in the
presence of proton acceptor to yield l-(carbonyloxy)piperidine 4-carboxylic
acid ester, compound of formula X;

CU ^OR'
CU /Y

O^OR'
N
I
H O'T. ^OR CT ^OR
Formula IX Formula X Formula VI
wherein R is C1-C3 alkyl, aryl or aralkyl; Y is a halo radical; and R1 is alkyl or branched alkyl,.
(b) converting compound of formula X to compound of formula VI;
(c) reacting compound of formula VI with an organometallic compound of
formula VII, to prepare compound of formula XI;
M(X') F O

.N..OR
Y
o
Formula VII Formula XI
wherein M maybe magnesium or lithium; X1 is bromide, chloride or iodide;

7


(d) hydrolysis of compound of formula XI to yield compound of formula VIII; and
Formula VIII
(e) converting compound of formula VIII to compound of formula II.
DETAILED DESCRIPTION OF THE INVENTION
A convenient scalable process for the preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one of formula I has been developed in the present invention whereby substantially pure product of formula I can be synthesized in high yield.
Preparation of 3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-vl)-l-piperidinvnethvll-6,7,8,9 tetrahvdro-2-methvl-4H-pvridofl,2, -alpyrimidin-4-one, compound of formula I
According to the process of the present mvention 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one (formula I), is obtained by N-alkylation of compound of formula II or its acid addition salts, with compound of formula III. Said N-alkylation can conveniently be carried out in the presence of weakly nucleophilic to non-nucleophilic organic base in an inert solvent, preferably an organic solvent.
X in compound of formula III may be selected from halo and acyloxy groups. The halo group comprising chloro, bromo, & iodo, the acyloxy group may be selected from, trifluoroacetoxy, trichloroacetoxy and the like, chloro being the most preferred
The term weakly nucleophilic to non-nucleophilic organic base refers to an organic base which has the ability to protonate or scavenge protons, but does not itself participate in
8

nucleophilic substitution reactions such as N-alkylation with an alkylating agent to give an N-alkylated product or a quaternary salt. The inherent property of such bases for their weak or non-nucleophilicity is their relative inaccessibility of the lone pair on nitrogen by virtue of steric factors, electronic factors (such as conjugation of lone pair with 71 systems) or hydrogen bonding with neighboring hydroxyl groups present in the molecule. Use of such a base would not interfere or compete in the alkylation of compound of formula II with the compound of formula III to yield compound of formula I. The term weakly nucleophilic to non-nucleophilic organic base as referred to herein means an organic base that is relatively less nucleophilic than triethylamine. Preferred examples of weakly nucleophilic to non-nucleophilic organic base include hindered tertiary alkylamines having atleast one branched alkyl or cycloalkyl, or aryl or hetereoaryl substituent such as diisopropylethylamine or diisopropyl-3-pentanamine, ethyl dicyclohexylamine, N-isopropyl-N-ethylaniline; a hindered tertiary cyclic amine such as 1,2,2,6,6-tetramethylpiperidine; or a hindered heterocyclic aromatic base such as 2,6-dimethylpyridine (2,6-lutidine) or 2,4,6-trimethylpyridine (2,4,6-collidine) or the like; tertiary aromatic bases, whose lone pair is conjugated to the aromatic system, such as N,Nrdimethylaniline, N,N-diethyl aniline and the like More preferred examples of weakly/ non-nucleophilic organic base are tertiary, amines containing linear alkyls but having substituents capable of forming hydrogen bonds such as triethanolamine, hydroxyethylpiperidine, tripropanolamine, hydroxyethylmorpholine, diethanolethylamine and the like, the most preferred being triethanolamine.
According to another embodiment of the process of the present invention the organic solvent is selected from non-polar, polar, polar aprotic or polar protic.
In a preferred embodiment of the process of the present invention the organic solvent is a polar protic solvent selected from d to C4 alkanol. More preferably the alkanol is methanol.
The reaction is carried out at a temperature ranging from 0 to 100° C, preferably about 40
to80°C.
9

The product after N-alkylation may be isolated from the reaction mixture using methods known to those skilled in art such as distilling off the organic solvent to obtain thick slurry and adding water to it or by quenching the reaction mixture directly in water followed by using standard techniques.
The isolated product may be further purified by methods known to those skilled in this art. Methods such as chromatography, leaching, recrystallization etc. may be utilized, preferred method being recrystallization. Recrystallization may be carried out in solvent(s) or a mixture of solvents selected from non-polar, polar, polar aprotic or polar protic.
For instance, recrystallization of compound of formula I may be carried out by dissolving compound of formula I in an organic solvent with or without heating in the presence or absence of seed crystals and chilling/cooling to allow crystallization to occur. Compound of formula I is then filtered and dried using standard techniques known to those skilled in this art.
The compound of formula I on recrystallization is obtained in a substantially pure form.
As referred to herein substantially pure 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (formula I) in purity greater than 99.0% by HPLC.
Preferably the substantially pure 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (formula I) has purity greater than 99.5% by HPLC.
Most preferably, substantially pure 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a]pyrimidin-4-one (formula I) has a purity greater than 99.7% by HPLC.
10

Preparation of (2,4-difluorophenvl)(4-piperidinyI)methanone., compound of formula II
The compound of formula II used for the preparation of 3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one may be prepared by methods known to those skilled in this art.
In the present invention compound of formula II may be prepared by condensing compound of formula IX with haloformate YCOOR in the presence of a proton acceptor to yield l-(carbonyloxy)piperidine 4-alkylcarboxylic acid ester derivative, a compound of formula X;

O OR'
i
H Formula IX

0-^ ..OR"

0" OR Formula X

0^/Y

N
cr OR
Formula VI

wherein R is C1-C3 alkyl, aryl or aralkyl; R is alkyl or branched alkyl, preferably C1 to C3 alkyl; and Y is a halo radical selected from chloro, bromo and iodo, preferably chloro.
In the preferred embodiment of the present invention the haloformate YCOOR is ethyl chloroformate.
The proton acceptor may be selected from an inorganic and an organic base, more preferably an organic base, the most preferred being triethylamine.
11

The compound of formula X may be converted to compound of formula VI by methods known to those skilled in the art like reaction with thionyl chloride, oxalyl chloride and the like, preferably thionyl chloride.

Formula VII Formula XI Formula VIII
The compound of formula VI is then reacted with organometallic compound of formula VII in an inert organic solvent in an inert atmosphere to yield compound of formula XL The inert organic solvent may be selected from ethers, aromatic hydrocarbon and aliphatic hydrocarbon, or a halogenated hydrocarbon depending upon the organometallic compound being used. The solvent may. be used as such or in admixture, preferably ethers such as tetrahydrofuran or mixed solvent conhtaining tetrahydrofuran.
The M in the organometallic compound of formula VII maybe selected from lithium and magnesium (Grignard reagent), and when M is magnesium X1 is bromide, chloride or iodide. The organometallic compound of formula VII is prepared using standard reaction conditions used for their preparation, such as addition of metal (magnesium or lithium) or by metal exchange like treatment with n-butyllithium. For instance, the Grignard reagent is prepared by reacting l-bromo-2,4-difluorobenzene with activated magnesium in inert non-reactive solvents, such as tetrahydrofuran, in an inert atmosphere.
According to the process of the present invention organometallic reagent is prepared at a temperature of about -20 to 60°C, preferably 40 to 50° C in case of Grignard reaction.
12

The temperature at which the compound of formula VI is reacted with the organometallic reagent of compound of formula VII is in the range of about -20 to 20° C, preferably -10 to 10° C.
At the end of the reaction of activated compound of formula VI and organometallic reagent of compound of formula VII the reaction mass is worked up using standard techniques such as quenching with water or separating the organic phase and concentrating to yield compound of formula XL
Compound of formula XI is hydrolyzed to compound of formula VIE using standard techniques known to those skilled in this art like treatment with a mineral acid or a strong organic acid, preferably a mineral acid. The mineral acid may be selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid and the like, preferably sulfuric acid. The concentration of sulfuric acid that can be used may range from 20% to 100%, preferred being 35% to 70% and most preferred being 50 %.
According to the present invention hydrolysis Of compound of formula XI is carried out at temperatures ranging from about 50 to 200°C, preferably 75 to 150°C, most preferred being 90 to 120°C.
Compound of formula VUI may be converted to compound of formula II by a process known to those skilled in this art such as disclosed in United States Patent No. 4804663.
Stable addition salts of compound of formula II may be formed from acids; inorganic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric and nitric acid or organic acids such as oxalic acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
The salts of compound of formula II may be prepared by conventional processes such as, for example, by admixing equimolar amounts of the free base and the desired acid.
13

Preparation of 3-substituted ethvl-2-methyI-4H-pyrido[l,2-alpvrimidin-4-one, compound of formula III
The compound of formula III used for the preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l,2-a] pyrimidin-4-one, compound of formula I may be prepared by hydrogenation of 3-(substituted)ethyl-2-methyl-4H-pyrido[ 1,2-a]pyrimidin-4-one,compound of formula V,
O O

N
X^/\>k...^\ X.

N

^

- N — / -N
Formula III Formula V
wherein X is selected from halo and acyloxy, in the presence of a Raney metal type catalyst in an organic solvent.
X in compound of formula III and V may be selected from halo and acyloxy groups,
preferably a halo group; the halo group comprising chloro, bromo, fluoro & iodo,
preferably chloro.
Preferably, the hydrogenation is carried out in the presence of Raney metal type catalysts selected from the group comprising of Raney nickel, Raney cobalt and Raney copper, most preferred being Raney nickel.
According to process of the present invention the organic solvent is selected from the group comprising aliphatic, cyclic or aromatic hydrocarbons e.g. hexane, pentane, benzene, toluene, xylene, cyclohexane, cyclopentane and the like, alkanols e.g. methanol, ethanol, propanols and the like, esters e.g. methyl acetate, ethyl acetate and the like, ethers e.g. diethyl ether, dioxane, 1,2-dimethoxyethane ,tetrahydrofuran and the like, or an admixture of solvents, the preferred solvents are esters, most preferred being ethyl acetate.
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Hydrogenation may be carried out at a temperature ranging from about 0 to 100°C, preferably about 20°C to 80°C, the most preferred being about 20 to 30°C. The hydrogenation takes place at atmospheric to about 70psi, preferred being 40 to 60psi.
The product obtained can be isolated and purified by standard methods known to those skilled in art such as, distillation, extraction, chromatography, crystallization and the like preferably by crystallization. Crystallization may be carried out in solvents selected from water; alcohol e.g. methanol, ethanol, propanols and the like; aromatic hydrocarbon e.g. benzene, toluene xylene and the like; acyclic hydrocarbon eg., hexane, pentane and the like; cyclic hydrocarbon e.g. cyclohexane, cyclopentane and the like; halogenated hydrocarbon e.g. dichloromethane, 1,2-dichloroethane, chloroform and the like; ketone e.g. acetone, methyl ethyl ketone, cyclohexanone, 2-propanone, 4-methly-2 pentanone and the like; ester e.g. methyl acetate, ethyl acetate and the like; nitrile e.g. acetonitrile , propionitrile and the like; ether e.g. diethyl ether, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like; diethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N,N-dimethylacetamide, nitrobenzene, l-methyl-2-pyrrolodinone etc., preferred being hydrocarbon solvent, and the most preferred being cyclohexane.
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The invention is illustrated but not restricted by the description in the following examples. Examples Example 1
Preparation of 3-[244-(6-fluoro-l.,2-benzisoxazol-3-yl)-l-piperidinyl1ethvll-6,7,8,9-tetrahydro-2-methyl-4H-pyrido [1,2-al pyrimidin-4-one (Formula-I) A mixture of methanol (500ml), 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole (also referred to as 6-fluoro-3-(4-piperidinyl)-l,2-benisoxazole) hydrochloride salt of compound of formula II, lOOg (0.389mol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2-a]pyrimidin-4-one (formula III) 115.0g (0.507mol) triethanolamine 233.6g (1.565mol) is heated at 64-66° C for 5 hrs. Thereafter, the reaction mixture is concentrated to a thick slurry and treated with water (500ml) and sodium carbonate (60g). The resulting slurry is stirred for lhr., filtered, and washed with water (500ml). The wet cake is dissolved in a mixture containing water (500ml) and acetic acid (50ml). The aqueous solution is extracted with toluene. '(2x200ml), and the aqueous layer is charcolized, then basified with 12.5% w/v aqueous sodium carbonate to pH 9.5-10.0. The precipitated product is filtered and suck dried to give crude risperidone (144.0g, containing 2.5% water, crude yield 87.8% on dry basis with purity 99.46% when analyzed as per method in BP).
The crude material obtained as above is dissolved in dichloromethane (300ml), filtered (through Whatman filter paper) to remove any particles if present, and the filtrate is concentrated to dryness (this step is optional). The residue is recrystallized from a mixture containing dimethylformamide (300ml) and 2-propanol (300ml) by dissolution at 80-85° C and then gradually cooling to 10° C. The mixture is stirred at 10° C for lhr., filtered the product, and dried at 60-65° C to give risperidone (Yield 124.7g, 78.0%, purity 99.80%) which complies with the quality requirements as per BP.
Example 2
Preparation of 3-f2-f4-(6-fluoro-l,2-benzisoxazol-3-vl)-l-piperidinvllethyll-6,7,8,9-
tetrahydro-2-methvl-4H-pyrido[ 1,2-alpyrimidin-4-one ( Formula-I)
16

A mixture of methanol (50ml), 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride lOg (0.039mol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2-a]pyrimidin-4-one 11.48g (0.0506mol) and diisopropylethylamine 27.14ml (0.156mol) is heated at 65-70°C for 6 hrs. Thereafter, the reaction mixture is concentrated to a thick slurry and treated with water (50ml) and sodium carbonate (8.25g). The resulting slurry is stirred for lhr., filtered, and washed with water (50ml). The wet cake is dissolved in a mixture containing water (50ml) and acetic acid (5ml). The aqueous solution is extracted with toluene (2x 20ml), and the aqueous layer is charcoalized, then basified with 12.5% w/v aqueous sodium carbonate to pH 9.5-10.0. The precipitaited product is filtered and suck dried to give crude risperidone 12.23g, 76.5% yield with purity 99.08%. Recrystallization as per example 1 from a mixture of 2-propanol-dimethylformamide, 1:1 (50ml) gave 11.8g (overall yield 73.82%, purity 99.74%)
Example 3
Purification of 3-[2-[4-(6-fluoro-l, 2-benzisoxazol-3-vlM-piperidinyllethvl]-6,7,8,9-
tetrahvdro-2-methvl-4H-pvrido[l,2-al pyrimidin-4-one (Formula-I)
Example 1 was repeated on 40g scale. Crude yield was 57.0g (89.1%, purity 98.76%).
The product was purified by recrystallization from 2-propanol (300ml), and dried as
above, 52.61g(82.2%, overall).
Example 4
Purification of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-vn-l-piperidinyIlethyll-6,7,8,9-
tetrahydro-2-methvl-4H-pyrido [1,2-a| pyrimidin-4-one (Formula-I)
Example 1 was repeated on 50g scale. Crude yield was 84.Og containing 16.5% water (yield 87.7% on dry basis, purity 99.0%).
a) Purification of 5.0g of above from a mixture of 2-propanol-dimethylacetamide, 1:1 (17.5ml) by dissolution at 90° C, cooling to ambient temperature, then further to 10° C, filtration and drying gave pure risperidone. Recovery 88.7%, purity 99.81%.
b) Purification as in 4a) but from a mixture of 2-propanol-dimethylacetamide, 1:9 (15ml) gave pure risperidone, with recovery 91.1% and purity 99.75%.
17

c) Purification as in 4a) but 2-propanol-dimethylacetamide, 9:1 (22.5ml) gave pure risperidone, with recovery 88.7% and purity 99.71%.
Example 5
Purification of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-vl)-l-piperidinvllethvll-6,7.,8,9-
tetrahydro-2-methyl-4H-pyridof 1,2-al pyrimidin-4-one (Formula-I)
Example 1 was repeated on lOOg scale. Crude yield was 144.0g containing 2.5% water (yield 87.7% on dry basis, purity 99.49%).
a) Purification of lO.Og from a mixture of 2-propanol-dimethylformaide, 1:1 (45ml) by dissolution at 90° C, cooling to ambient temperature, then further to 10° C, filttration and drying gave pure risperidone. Recovery 92.4 %, purity 99.82%.
b) Purification as in 5a) but from a mixture of 2-propanol-dimethylformamide, 1:9 (30ml) gave pure risperidone, with recovery 89.8 % and purity 99.85%.
c) Purification as in 5a) but 2-propanol-dimethylformamicle, 9:1 (50ml) gave pure risperidone, with recovery 89.4% and purity 99.83%).
Example 6
Process for preparation of: 6Tfluoro-3-(4-piperidinyl)-l,2-benisoxazole)
hydrochloride (formula II)
(a) Preparation of carbamate (methyl piperidine-l-ethoxvcarbonvl-4-carboxylate) of
formula XI (R=Et. R'=Me)
To a mixture of methyl isonipecotate (200g, 1.396mol) and triethylamine (292ml, 2.094 mol) in toluene (1100ml) is added gradually ethyl chlorofoirmate (200ml, 2.093mol) while maintaining temperature between 30- 40° C. After further stirring for 30min. the reaction mixture is quenched by addition of water (600ml). The organic layer is separated and washed with water (2 x 600ml).
(b) Preparation of acid chloride (ethyl 4-chlorocarbonyl-piperidine-l-carboxvlate),
compound of formula VI (R=Et, Y-Cl)
To the organic layer containing the carbamate is added water (600ml), sodium hydroxide (112g, 2.80mol) and tertrabutylammonium hydrogensulfate (12g, 0.035mol) and the mixture stirred for 1 hr at ambient temperature. The aqueous layer containing product is
18

separated and acidified with cone. HC1 to pH<2, and the product is extracted into toluene (1200ml). The toluene layer is concentrated to about two thirds of the total volume at atmospheric pressure. Thionyl chloride (100ml) is added and stirred for 1 hr at ambient temperature. Thereafter the toluene is stripped off from the reaction mixture at below 75°C under reduced pressure to obtain a brownish colored liquid of ethyl 4-chlorocarbonyl-piperidine-1-carboxylate, compound of formula VI (R=Et, Y=C1), 287.26g (93.9% yield).
(c) Preparation of ethyl 4-(2,4-difluorobenzovl)piperidine-l-carboxvlate, compound of
formula XI (R=EO
A solution of l-bromo-2,4-difluorobenzene (150g, 0.777mol) in THF (300ml) is added to a suspension of activated magnesium (18.88g, 0.777mol) in THF (300ml) at 40 to 50°C during about 1.5 hr. and then stirred for further 1 hr to obtain the Grignard reagent. This is then added to a solution of the acid chloride (196g, 0.892mol) in THF (300ml) at -10 to 10°C during about 1.5 hr and then stirred for 30 min at 0 to 10°C in an inert atmosphere. The reaction mixture is quenched with water (600ml) and the THF layer containing the product is separated, and concentrated at 50-55° C under reduced pressure. The aqueous layer is extracted with toluene (750ml) and combined it with residue from the THF layer. The toluene solution is then washed successively with water (2x450ml), 5% sodium carbonate solution (450ml) and again with water (450ml). The solvent is then completely stripped off at 55-65°C under reduced pressure to yield a syrupy residue.
(d) Preparation of (2,4-difluorophenvl)(4-piperidinyl)methanone hydrochloride salt of
compound of formula VIII:
The syrupy residue of step (c) is heated with 50% w/w sulfuric acid (460ml) at 100 to 110°C for 4 hr. The reaction mass is cooled to ambient temperature and carefully diluted with water (460ml). After extraction once with toluene (460ml), the acidic aqueous layer is stirred with toluene (900ml) and basified carefully to pH 12-12.5 with 40%w/v NaOH solution. The toluene layer is then separated and acidified with a solution of-10% 2-propanol-dry HC1. After stirring for 15 min. the mixture is concentrated at atmospheric pressure (to about 500ml) and then gradually cooled to 10°C. The resulting slurry is filtered, the cake is washed with toluene (2x150ml) and then dried at 55-60°C. to obtain (2,4-difluorophenyl)(4-piperidinyl)methanone hydrochloride, salt of compound of
19

formula VIII, as a white to slight yellowish solid, 120g (overall yield from l-bromo-2,4-difluorobenzene is 60%).
(e) Compound of formula VIII is converted to compound of formula II using process of US 4804663 Example 1.
Example 7
Process for preparation of 3-(2-chloroethv0-2-methyl-6,7,8,9-tetrahvdro-pyridof 1,2-
alpvrimidin-4-one (Formula -III, X=CD
Charge 500 ml ethyl acetate, lOOg 3-(2-chloroethyl)-2-methyl-pyrido[l,2-a]pyrimidin-4-one followed by 10ml of Raney nickel to 1 lit autoclave for hydrogenation. Hydrogenate reaction mixture at ambient temperature under 3.5-4 kg/cm pressure till there is no more consumption of hydrogen. Filter the reaction mixture to remove Raney nickel and wash filtrate with water (50ml). Concentrate under reduced pressure at 50-60° C. Add 300ml cyclohexane to the residue and heat to reflux to form a clear solution. Gradually cool to ambient temperature and then to 10-15°C under stirring. Filter the crystallized product and wash it with cyclohexane (50ml). Yield 95g (93.3%), as white solid, purity 99.68%.
Comparative Example
Preparation of 3-[2-[4-(6-fluoro-l,2-benzisoxazol-3-vlM-piperidinyllethvll-6,7,8,9-tetrahvdro-2-methvl-4H-pvrido[l,2-a1pyrimidin-4-one (Formula-I)
A mixture of methanol (50ml), 6-fluoro-3-piperidin-4-yl-benzo[d]isoxazole hydrochloride lOg (0.039mol), 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-pyrido[l,2-a]pyrimidin-4-one 11.48g (0.0506mol) and triethylamine 21.8ml (0.156mol) is heated at 65-70°C for 6 hrs. Thereafter, the reaction mixture is concentrated to a thick slurry and treated with water (50ml) and sodium carbonate (8.25g). The resulting slurry is stirred for lhr., filtered, and washed with water (50ml). The wet cake is dissolved in a mixture containing water (50ml) and acetic acid (5ml). The aqueous solution is extracted with toluene (2x20ml), and the aqueous layer is charcoalized, then basified with 12.5% w/v aqueous sodium carbonate to pH 9.5-10.0.
The precipitated product is filtered and suck dried to give crude risperidone (11.14g on dry basis, crude yield 69.7%, with purity 99.62% when analyzed as per method in BP).
20

Recrystallization as per example 1 from a mixture of 2-propanol-dimethylformamide, 1:1 (50ml) gave l0.0g (overall yield 62.56%, purity 99.81%)

We claim :
1. A process for the preparation of compound of formula I comprising
O-N

Formula I
N-alkylation of compound of formula II or its acid addition salts, with compound of formula III


•H

X

0
*N

SN'

Formula II

Formula III

wherein X is selected from halo or acyloxy groups,
in the presence of weakly nucleophilic to non-nucleophilic organic base in an
organic solvent.
2 A process for the preparation of compound of formula I as claimed in claim 1 wherein X is chloro.
3 A process for the preparation of compound of formula I as claimed in claim 1 wherein X is trifluoroacetoxy.
4 A process for the preparation of compound of formula I as claimed in claim 1 wherein the base is triethanolamine.
5 A process for the preparation of compound of formula I as claimed in claim 1 wherein the organic solvent is methanol.
6 A process for the preparation of compound of formula I as claimed in claim 1 wherein N-alkylation temperature is about 40 to 80° C.

22

7 A process for the preparation of compound of formula I as claimed in claim 1 further comprising additionally purifying compound of formula I by recrystallization.
8 A process for the preparation of compound of formula I as claimed in claim 1 wherein the compound of formula I is obtained in a substantially pure form.
9 A process for the preparation of compound of formula I as claimed in claim 1 wherein the compound of formula II is prepared by
(a) condensing compound of formula IX with haloformate YCOOR in the presence of proton acceptor to yield l-(carbonyloxy)piperidine 4-carboxylic acid ester, compound of formula X;

OR'
°^Y

N
X
cr OR
CK^OR'

I H
0" ^OR
Formula IX Formula X Formula VI
wherein R is C1-C3 alkyl, aryl or aralkyl; Y is a*halo radical; and R1 is alkyl or branched branched alkyl,.
(b) converting compound of formula X to compound of formula VI;
(c) reacting compound of formula VI with an organometallic compound of formula VII, to prepare compound of formula XI;
M(X') F O


Formula VII Formula XI
wherein M maybe magnesium or lithium; X1 is bromide, chloride or iodide; (d) hydrolysis of compound of formula XI to yield compound of formula VIII; and

23

Formula VIII
(e) converting compound of formula VIII to compound of formula II.
10 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (a) the proton acceptor is triethylamine.
11 A process for the preparation of compound of formula I as claimed in claim 9 wherein the haloformate is ethyl chloroformate.
12 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (b) the compound of formula X is converted to compound of formula VI by reacting with thionyl chloride.
13 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (c) the M in organometallic compound of formula VII is magnesium, and X' is bromide.
14 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (c) orgarionietallic reagent of compound of formula VII is prepared at 40 to 50° C.
15 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (c) the reaction of compound of formula VI is carried out at -10 to 10° C.

16 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (d) the hydrolysis is carried out in the presence of 50% sulfuric acid.
17 A process for the preparation of compound of formula I as claimed in claim 9 wherein in step (d) the hydrolysis is carried out at 90 to 120° C.
18 A process for the preparation of compound of formula I as claimed in claim 1 wherein the compound of formula III is prepared by hydrogenation of compound of formula V,
24

o o

N

N

^

- N - ^ ,N
Formula III Formula V
wherein X is selected from halo and acyloxy groups,
in the presence of a Raney metal type catalyst in an organic solvent.
19 A process for the preparation of compound of formula I as claimed in claim 18 wherein X is chloro.
20 A process for the preparation of compound of formula I as claimed in claim 18 wherein the Raney metal type catalyst is Raney nickel.
21 A process for the preparation of compound of formula I as claimed in claim 18 wherein the organic solvent is ethyl acetate.
22 A process for the preparation of compound of formula I as claimed in claim 18 wherein the reaction is carried out at a temperature of about; 20 to 80° C.
23 A process for the preparation of compound of formula I as claimed in claim 18 wherein the hydrogenation is carried out at atmospheric to about 70 psi pressure.
24 A process for the preparation of compound of formula I as claimed in claim 1 wherein compound of formula II is prepared by a process as claimed in claim 9 and compound of formula III is prepared by a process as claimed in claim 18.
25 A process for the preparation of compound of formula I as claimed in claim 1 to 24 substantially as herein described and illustrated by examples 1 to 7.