FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13) TITLE OF THE INVENTION
"An Efficient Process for Synthesis of Fluoro-substituted Aryl Carbonyl Piperidinyl Compounds"
Emcure Pharmaceuticals Limited.,
an Indian Company, registered under the Indian Company's Act 1957
and having its Registered Office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
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 a process for preparation of benzisoxazole piperidinyl compounds used as antipsychotics for the treatment of schizophrenia. Particularly, the present invention relates to the preparation of 4-(2,4-difluorobenzoyl)-piperidine, a key intermediate in the preparation of antipsychotic agents, by controlling the level of associated impurities and obtaining the intermediate having the desired purity.
Background of the invention:
Benzisoxazole piperidinyl compounds such as Iloperidone, which are used to treat psychiatric conditions, belong to the class of atypical antipsychotic drugs that exhibit their efficacy through a combination of dopamine type 2 (D2) and serotonin type 2 (5-HT2A) antagonisms.
Iloperidone of formula (I) is a monoamine neurotransmitter antagonist which exhibits its therapeutic efficacy by blocking the sites of noradrenalin (012c), dopamine (D2A and D3), and serotonin (5-HT1A and 5-HT6) receptors. It is considered as an 'atypical' antipsychotic that is less likely to cause movement disorders in patients when compared to conventional methods of psychotic treatment. Iloperidone acts on both dopamine and serotonin receptors and unlike most other atypical antipsychotics, displays a superior side effect profile with respect to dizziness, somnolence, and hypotension which are the most common adverse reactions.


The synthesis of antipsychotic agents such as iloperidone, paliperidone, risperidone involves a key intermediate, 4-(2,4-difluorobenzoyl)-piperidine of formula (II).

US 4,355,037 discloses 3-(4-piperidyl)-l,2-benzisoxazole compounds and a process for their preparation. The method comprises reaction of piperidine-4-carboxylic acid with formic acid and acetic anhydride to give l-formylpiperidine-4-carboxylic acid which is then converted to its acid chloride by treatment with thionyl chloride. Friedel-Craft acylation of 1,3-difiuorobenzene with the acid chloride in presence of a Lewis acid like A1C13 yields 4-(2,4-difluorobenzoyl)-l-formyl piperidine which is isolated with a yield of only 32% by triturating the obtained oil with pentane or petroleum ether. Subsequent oximation and cyclization of the N-alkanoyl piperidine oxime in presence of sodium hydride yields the benzisoxazole, which, on deprotection of the alkanoyl group leads to Iloperidone.
Use of anhydrous aluminium chloride in the process, in almost stoichiometric quantities with respect to dihalobenzene and waste disposal of the Lewis acid poses environmental problems due to the formation of aluminium hydroxide in the form of sludge during work up, which cannot be removed easily. Further, there is a likelihood of formation of impurity such as (IIIa), when 1,3-difluorobenzene is employed for coupling with piperidine-4-carboxylic acid. The presence of impurity (IIIa) thereby affects the yield and purity of the compound of formula (II) which needs to be purified subsequently,


WO 2009075857 discloses a method for the preparation of the compound of formula (II) comprising protection of 4-piperidinyl carboxylic acid of formula (IV) with a suitable protecting group such as tert-butoxycarbonyl followed by treatment with Weinreb amine N,0-dimethylhydroxylamine hydrochloride in a suitable organic solvent such as dichloromethane to provide a Weinreb amide of formula (VI). Compound (VI) when treated with 2,4-difluorobromobenzene was found to provide a compound of formula (II), which however was found to be contaminated with the associated impurity of formula (IIIb). The dimeric impurity of formula (IIIb) which was probably formed by a competing Wurtz reaction had to be curbed for obtaining compound of formula (II) having the desired purity and with the associated impurity conforming to regulatory limits. The dimeric impurity was difficult to remove by employing conventional purification methods, which thereby resulted in the final product having a lower purity. The removal of the dimer impurity (IIIb) was possible only by utilizing purification techniques such as column chromatography.


Thus, there was a need for obtaining a compound of formula (II) by a simple method and which would not result in the formation of the dimeric impurity above regulatory limits.
Object of the invention:
An objective of the present invention is to prepare 4-(2,4-difluorobenzoyl)-piperidine (II), a key intermediate in the preparation of benzisoxazole piperidinyl compounds, having the desired purity and with associated impurities conforming to regulatory limits.
Another object of the invention is to provide a process for preparation of fluoro-substituted aryl carbonyl piperidine derivative which does not utilize hazardous chemicals like aluminium chloride as a reagent.
Summary of the Invention:
An aspect of the invention relates to a process for the preparation of 4~(2,4-difluorobenzoyI)-piperidine (II) comprising refluxing a mixture of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-1-carboxylate of formula (VI) with magnesium in 2-methyl tetrahydrofuran, adding 2,4-difiuorobromobenzene (VII) -dissolved in 2-methyl tetrahydrofuran and isolating the compound of formula (II) as its hydrochloride salt (IIa).
Another aspect of the invention relates to a process for the preparation of fluoro-substituted aryl carbonyl piperidine derivative (II) wherein the isolation of the hydrochloride salt (Ha) is achieved by treating the reaction mixture with hydrochloric acid in ethyl acetate to obtain compound of formula (IIa) having the desired purity and with impurity level conforming to regulatory specification.
The objectives of the present invention will become fully apparent from the detailed description.

Detailed Description of the invention:
While carrying out extensive research on the synthesis of 4-(2,4-difluorobenzoyl)-piperidine hydrochloride of formula (Ha), the present inventors tried out various experimental conditions for the Grignard coupling of 2,4-difluorobromobenzene (VII) with piperidinyl carboxylic acid derivatives. However, the desired reaction was accompanied by formation of biaryl impurity such as 2,2',4,4'-tetrafluorobiphenyl of formula (IIIb) in substantial quantities, thereby affecting the purity of 4-(2,4-difluorobenzoyl)-piperidine, which eventually had to be purified thereby resulting in reduced yield.
Initially, the inventors had carried out this reaction by addition of 2,4-difluoromagnesium bromobenzene dissolved in a solvent such as tetrahydrofuran to the amide of formula (VI) dissolved in the same solvent. It was found that the impurity of formula (IIIb) was formed probably by a self exchange Wurtz reaction.
The inventors have found out that formation of impurities depended on mole ratio
of the reacting species, nature of the solvent and also on the sequence of addition of
the reactants, which can be inferred from Table I.
Table 1: Effect of mole ratio of the reactants per mole of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-l-carboxylate of formula (VI) and solvent on yield and formation of impurity (IIIb).

No. Mole equivalent of 2,4-difluorobromo benzene Mole
equivalent of magnesium
metal Solvent %Yield of desired Product (ID- Impurity (IIIb) formation (%)
1. 1.0 1.0 THF Nil 70
2. 1.0 1.5 THF Nil 70
3. 1.2 2.0 THF Nil 65
4. 1.5 2.0 THF Nil 62
5. 1.0 1.5 2-MTHF 30 40
6. 1.2 2.0 2-MTHF 44 <12.5
7. 2.0 2.5 2-MTHF 60 <2.5
8. 2.0 2.0 2-MTHF 50 3.4
THF: tetrahydrofuran; 2-MTHF: 2-methyl tetrahyd rofuran

It would be evident from Table-1 that the type of solvent and the mole equivalent of the reagents per mole of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-l-carboxylate of formula (VI) play an important part in reducing the level of impurity (IIIb) in the reaction. The compound of formula (II) when isolated in the form of its hydrochloride salt (IIa) was found to contain the impurity of formula (IIIb) below detectable limits, thereby providing the compound of formula (Ila) having the desired purity and with impurity level conforming to regulatory specification. It was further found that the impurity of formula (IIIb) could be removed to below detectable limits, if the level of the said impurity was less than 20% during the reaction.
The methodology can be schematically described as follows:

Scheme I: Method embodied in the present invention for preparation of 4-(2,4 difluorobenzoyl) piperidine
In an embodiment, l-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (V) was treated with N,0-dimethyl hydroxyl amine hydrochloride in an organic solvent such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane and in presence of isobutyl chloroformate and a base selected from the group comprising N-methyl morpholine, or Hunig's base to provide corresponding Weinreb amide of formula (VI).

The reaction was carried out in the temperature range of 25°C to 40°C and was monitored by HPLC.
In a further embodiment, the compound of formula (VI) was reacted with 2,4 difluorobromobenzene (VII) in an organic solvent such as 2-methyl tetrahydrofuran in presence of magnesium to yield l-(tert-butoxycarbonyl)-4-(2,4-difluorobenzoyl) piperidine which was then treated with an acid selected from the group of organic or inorganic acids in an organic solvent to yield compound of formula (11a).
Several solvents such as tetrahydrofuran, 2-methyl tetrahydrofuran, 1,2-dimethoxyethane were tried out but it was found that utilization of 2-methyltetrahydrofuran provided compound of formula (II) and (Ha) which had lower level of impurity.
Further, the level of impurities was found to depend, on the mole equivalent of 2,4 difluorobromobenzene and magnesium turnings, which were employed for the Grignard reaction.
The reaction was carried out in the temperature range of 55°C to 80°C and was monitored by HPLC.
After completion of reaction, an acid selected from inorganic acids such as hydrochloric acid or from the group of organic acids like methane sulfonic acid, trifluoroacetic acid, or mixtures thereof but preferably hydrochloric acid was added to the reaction mixture and stirred in the temperature range of 25°C to 45 °C.
The compound, 4-(2,4-difluorobenzoyl)-piperidine hydrochloride (IIa) obtained by concentrating the organic layer was substantially pure and could be directly used for further reactions leading to Iloperidone, paliperidone or risperidone.

Optionally, the compound of formula (IIa) was isolated by adding ethyl acetate containing 7-8% of hydrochloric acid. The mixture was stirred and the compound was allowed to separate out
Iloperidone of formula (I) was obtained by treating 4-(2,4-difiuorobenzoyl)-piperidine of formula (II) with hydroxylamine hydrochloride and aqueous ammonium acetate solution to yield the corresponding oxime, which was then treated with potassium hydroxide to yield 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazole. The corresponding hydrochloride salt was treated with 4-(3-chloropropoxy)-3-methoxyacetophenone to yield Iloperidone (I).
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not to be construed limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
Example 1:
Preparation of tert-butyl-4-(methoxy (methyl)carbamoyl) piperidine-1-
carboxylate (VI).
l-(tert-butoxycarbonyl)-piperidine-4-carboxylic acid (l00.0g. 0.436mol) and N-methyl morpholine (123.4g, 1.22 moles) were added to 2-methyl tetrahydrofuran (800ml) under nitrogen atmosphere at 25-30 °C and cooled to 0-5 °C. Isobutyl chloroformate (74.5g, 0.55moles) was added under nitrogen atmosphere over a period of 30-45 minutes at 0-5°C and stirred for additional 30-45 minutes. N,0-dimethyl hydroxyl amine hydrochloride (57.5g, 0.59mol) was added gradually at

10-15°C and the reaction mixture was stirred at 25-35°C for 4-5 hours and monitored by HPLC. After completion of reaction, water (600 ml) was added and 2-methyl tetrahydrofuran layer was separated. The organic layer was washed with 5% hydrochloric acid (200 ml) and concentrated to give tert-butyl-4-(methoxy (rnethyl)carbamoyl) piperidine-1-carboxylate (VI). Yield: 117.0 g; % Yield: 98.98%. Purity: > 99.0%
Example 2
Preparation of 4-(2,4-difluorobenzoyl)-Piperidine hydrochloride (Qa)
Magnesium turnings (21.6g, 0.90moles) were added to a solution of tert-butyl-4-(methoxy(methyl)carbamoyl)piperidine-1 -carboxylate (100gms;036moles) in 2-methyl tetrahydrofuran (800ml) under inert atmosphere and the reaction mixture was heated to 65-70°C. 2,4-Difluorobromobenzene (141.2 g,0.73 moles) dissolved in 2-methyl tetrahydrofuran (300ml) was added drop wise over a period of 45-60 minutes. The reaction mass was maintained under stirring for 2-3 hours at 65-70°C. After completion of reaction 10% aqueous acetic acid (60ml) was added drop wise over a period of 30 min at 10-15°C. The organic layer was separated and concentrated under reduced pressure and the residue obtained was treated with 7.5% hydrochloric acid in ethyl acetate (50ml), at ambient temperature and stirred for 15-30 minutes, to separate out 4-(2,4-difluorobenzoyl)-piperidine hydrochloride, which was then filtered and dried. Yield: 59.2 g, % Yield: 64%. Purity: > 99.5% % impurity of formula (IIIb) : < 0.10%
MS(CI): calcd. For C12H13F2NO HC1 (M+H)/z: 226.24, found: (M+H)/z: 226.2; 1H NMR (400 MHz, CDC13): d = 1.71-1.78 (m, 2H), 1.94-1.97 (m, 2H), 2.93-3.02 (m, 2H), 3.25-3.28 (m, 2H), 3.43-3.46 (m, 1H), 7.25-7.95 (m, 3H), 8.87 (br s, 1H), 9.09

(br s, 1H for HC1); l3C NMR (100 MHz, CDC13): 5 = 23.89, 40.12, 44.21, 105.63, 112.83, 121.67, 133.13, 160.35, 162.91, 164.1, 166.5, 198.86. Anal for C12H13F2NO HCI. Calcd; C, 55.12; H, 5.35; N, 5.35. Found: C, 55.2; H, 5.33; N, 5.31.
Example 3
Preparation of 6-fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe hydrochloride
Tert-butyl-4-(methoxy(methyl)carbamoyl) piperidine-1-carboxylate (10kg, 36moles), and magnesium (1.72 Kg, 72 moles) were mixed at room temperature in 2-methyltetrahydrofuran (80 Lit.) under inert atmosphere and then heated to 65-70°C. 2,4-difluorobromobenzene (14.12 Kg, 73mol) in 2-methyltetrahydrofuran (421itres) was added drop wise over a period of 45-60 minutes. The reaction mass was maintained under stirring for 2-3 hours at 65-70°C. After completion of reaction, 10% aqueous acetic acid (60 litres) was added drop wise over a period of 30 min at 10-15°C. The organic layer was separated and aqueous layer was extracted with 2-methyltetrahydrofuran, combined organic layer was then concentrated under vacuum to give a syrupy residue, which was then dissolved in methanol (20 Lit.) followed by addition of hydroxylamine hydrochloride (3.7Kg, 53moles) and 26.6% aqueous ammonium acetate solution (30 Lit.). The reaction mass was then heated to 85-90°C for 4-6 hours. After completion of reaction water (120 litres) was added at 25-30°C, the precipitated oxime was filtered and again charged to a 7.83% aqueous KOH solution (48 litres) and heated to 80-85°C for 2-4 h. After completion of reaction, the product was extracted in ethyl acetate (2 x l0litres), the organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was stirred in methanol (20 litres) and aqueous hydrochloric acid (8 litres) was added at ambient temperature and stirred for 2-4 hours to separate out 6-fluoro-3-(4-piperidmyl)-l,2-benzisoxazole hydrochloride which was filtered and dried at reduced pressure. Yield: 5.33Kg, %Yield: 57%. Purity: > 99.5% % impurity of formula (IIIb) < 0.10%.

Example 4
Preparation of Iloperidone
6-Fluoro-3-(4-piperidinyl)-l,2-benzisoxazoIe hydrochloride (5 Kg, 19.4 mol), 4-(3-chloropropoxy)-3-methoxyacetophenone (4.74Kg, 19.5mol), potassium carbonate (5.38Kg, 38.9mol) and sodium iodide (0.05Kg) were mixed together in propylene glycol (SOL) heated to 85- 90°C for 10-15h under nitrogen, after 15h of heating reaction mixture was cooled to 25-30°C and stirred for 30-45 minutes and filtered, the solid was washed with adequate amount of water and wet cake was again refluxed with Methanol (40L) for 30-45min, the reaction mixture was cooled to 25-30°C and filtered, the solid was washed with Methanol and dried to give greater than 99.8% pure Iloperidone Yield: 5Kg, %Yield: 60.24%. % impurity of formula (IIIb) < 0.10%.
MS (CI) calculated for C24H27FN2O4 (M+H)/z 427.49, found (M+H)/z: 427.4. White solid mp: 118-120°C. 'H NMR (400 MHz, CDC13): S = 2.05-2.21 (m, 8H), 2.56-2.61 (m, 5H), 3.07 (br d, 3H), 3.92 (s, 3H), 4.17 (t, 2H), 6.92 (d, 1H), 7.03 (t, 1H), 7.22 (m, 1H), 7.57 (m, 2H), 7.69 (m, 1H). Anal for C24H27FN2O4 Calcd: C, 67.59; H, 6.38; N, 6.57. Found: C, 67.57; H, 6.35; N, 6.53.

Claims:
1. A process for the preparation of 4-(2,4-difluorobenzoyl)-piperidine of formula (II) comprising refiuxing a mixture of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-l-carboxylate of formula (VI) with magnesium in 2-methyl tetrahydrofuran; adding 2,4-difluorobromobenzene dissolved in 2-methyl tetrahydrofuran and isolating the compound of formula (Ha).
2. The process as claimed in claim 1, wherein the amount of magnesium employed is in the range from 2.40 moles to 2.70 moles per mole of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-l-carboxylate of formula (VI).
3. The process as claimed in claim 1, wherein the amount of 2,4-difluorobromobenzene employed is in the range from about 1.80 moles and 2.20 moles per mole of tert-butyl-4-methoxy(methyl)-carbamoyl)piperidine-l-carboxylate of formula (VI),
4. The process as claimed in claim 1, wherein 4-(2,4-difluorobenzoyl)-piperidine hydrochloride (IIa) is isolated by quenching the reaction mixture with an aqueous solution of an organic acid or an inorganic acid, separating and concentrating the organic layer, adding gaseous hydrochloric acid dissolved in ethyl acetate and filtering the compound of formula (Ha).
5. The process as claimed in claim 4, wherein the organic acid is selected from the group comprising methane sulfonic acid, trifluoroacetic acid, and mixtures thereof.
6. The process as claimed in claim 4 wherein the inorganic acid is selected from the
group comprising hydrochloric acid and sulphuric acid.