FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
COMPLETE SPECIFICATION
(SECTION 10)
IMPROVED ONE POT PROCESS FOR SYNTHESIS OF
BUSPIRONE BASE
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

IMPROVED ONE POT PROCESS FOR SYNTHESIS OF BUSPIRONE BASE
FIELD OF THE INVENTION
The present invention relates to an improved one pot process for the preparation of Buspirone base via condensation of l-(2-pyrimidinyl)-piperazine, 1,4-dibromobutane and 3,3-tetramethylene glutarimide having HPLC purity above 99.50%.
BACKGROUND OF THE INVENTION
Buspirone hydrochloride (marketed as BUSPAR as 5mg and 10 mg tablets, by Bristol-Myers Squibb) is very popular & widely used non-benzodiazepine anxiolytic and is chemically described as 8-[4-[4-(2-Pyrimidinyl)-l-piperazinyl] butyl]-8-azaspiro [4,5] decane-7,9-dione , having the Formula (I) , given below-

Synthesis of Buspirone and the pharmaceutically acceptable acid addition salts thereof were reported under US 3717634 (Y.H. Wu et al in 1973). The synthesis reported under this patent is as mentioned in the below SCHEME-I


According to said disclosed process, l-(2-pyriraidinyl) piperazine , 4-chioro butyronitrile and sodium carbonate were refluxed in n-butanol to form 4-(2-pyrimidinyl)-l-(3-cyanopropyI)piperazine (Formula -II); hydrogenation of this intermediate using W-6 Raney nickel catalyst to form l-(4-arninobutyI)-4-(2-pyrimidinyI) piperazine (Formula III); and reacting it with 8-oxaspiro [4,5]-decane-7,9-dione (Formula-IV) in pyridine to give buspirone base in moderate yield. The said process suffers from the disadvantages such as requirement of high vacuum distillation, handling of hazardous reagents such as Raney nickel or pyridine, and lower overall yield. Further during crystallization high losses occur and purification.using fractional distillation requires higher temperatures and low pressure, which leads to the decomposition of the product.
US 5473072 (Tibor Mezei et AL July 1995) relates to a process for synthesis of a buspirone base by catalytic hydrogenation of 8-[4-[4-(pyrimidine-2-yl)-piperazine-l-yl]-but-2-inyI]-8-aza-spiro[4,5]decane-7,9-dione of the Formula-VI, in the presence of Palladium or Raney Nickel catalyst in an inert organic solvent like methanol, ethanol, benzene and/or THF. However, the said process suffers from the disadvantages such as requirement of an autoclave and further the buspirone obtained is contaminated with various impurities, and it is extremely difficult to get a pure product. The said process is represent by SCHEME II


US 4351939 (Jack Simms, Sep., 1982) appears to cover a process for the preparation of azaspiroalkanedione compounds, wherein preparation of Busprione involves condensation of 1-(2-pyrimidinyl)piperazine with 1,4-dibromobutane, in presence of finely powdered sodium carbonate, in IPA as a solvent to give 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro [4,5] decane bromide; reacting it with 3,3-tetramethylene glutarimide (also called as 8-azaspiro [4,5]decane-7,9-dione) in n-butanol as a solvent & potassium carbonate as a base to get a crude solid; stirring it with acetic anhydride at about 45°C and evaporating to dryness and after work-up, buspirone base is obtained. The disadvantage of this process is low yield of the reaction, and handling of acetic anhydride, which is lachrymatory, and potentially hazardous material. The process according to US4351939 is represented by SCHEME III.
SCHEME-III


EP 0680961 (Melton, Jack, April, 1995) relates to the preparation of large-scale process for the azapirone synthesis. The said process involves the steps of preparation of potassium salt of 3,3 tetra methylene glutarimide using 3,3 tetramethylene glutarimide & potassium tertiary butoxide in toluene as a solvent at room temperature to give potassium 8-azaspiro[4.]decane-7,9-dione (Formula-VII); reacting it with 8-(2-pyrimidinyI)-8-aza-5-azoniaspiro[4,5]decane bromide in n-butyl acetate as solvent, followed by work up to give buspirone base in 95% yield. The disadvantages of this process are isolation of the product; longer vacuum drying of the product; use of hygroscopic and costlier base i.e. potassium tert-butoxide. The process according to EP0680961 can be represented by SCHEME IV.
SCHEME-IV


Thus rn view of the above cited prior art and mentioned drawbacks, there exist a need for the development of a simple, scalable, industrially safe, ecofriendly, cost effective, industrially advantageous, robust process for the preparation of Buspirone base, which will eliminate the disadvantages associated with the prior art reported processes.
OBJECT OF THE INVENTION
The object of the present invention is to provide an improved one pot process for the preparation of buspirone base, with good yields and high HPLC purity.
Another object of the present invention is to provide a simpler, cost effective, eco friendly and industrially safe process for the synthesis of buspirone base.
Still another object of the present invention is to provide an efficient, robust, and industrially scalable process for the synthesis of buspirone, which avoids the use of hygroscopic or hazardous reagents.
SUMMARY OF THE INVENTION

The present invention relates to an improved, one pot process for preparation of Buspirone base (of Formula-I)

Buspirone base (Formula-]),
comprising the step of condensation of l-(2-pyrimidinyl)-piperazine; 1,4-dibromobutane and 3,3-tetramethylene gJutarimide in presence of an inorganic base and in an organic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, one pot process for the preparation of Buspirone base of Formula (I), i.e. 8-[4-[4-(2-pyrimidinyl)-l-piperazinylj butyl]-8-azaspiro [4.5] decane-7,9-dione.
Further, it has been observed that the Buspirone base can be prepared in a single pot without the isolation of any intermediate and in the presence of single solvent
The process according to present invention, wherein the said process comprises the step of condensation of l-(2-pyrimidinyl)-piperazine; 1,4-dibromobutane and 3.3-tetramethylene glutarimide in presence of an inorganic base and in an organic solvent.
The process according to present invention, wherein the l-(2-pyrimidinyl)-piperazine is reacted with 1,4-dibromobutane to generate 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide in-situ; and 3,3-tetramethylene glutarimide is reacted

with the inorganic base to form an in-situ inorganic salt of 3,3-tetramethylene glutarimide.
The in-situ formation of 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide takes place generally at 80 - 130°C, preferably at 90 - 100°C, more preferably at 93 - 96°C; and for 18-20 hrs.
Further for the in-situ formation of the inorganic salt of 3,3-tetramethylene glutarimide reaction temperature is raised to 120 - 125°C; and the reaction is kept under reflux for 18 hrs.
The process according to the present invention, wherein the in-situ formed 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide and inorganic salt of 3,3-tetramethylene glutarimide are reacted to form Buspirone base.
The said Buspirone base formation reaction takes place at 115 - 130°C, preferably at 120 - 125°C, more preferably at 123 - 125°C.
The process according to present invention, wherein the organic solvent used is an organic ester solvent and it comprises of n-propyl acetate, n-butyl acetate, n-pentyl acetate, n-hexyl acetate; preferably the said solvent is n-butyl acetate.
The process according to the present invention, wherein the said inorganic base comprises of potassium carbonate or cesium carbonate; preferably it is anhydrous potassium carbonate or anhydrous cesium carbonate; most preferably it is anhydrous potassium carbonate.
The process according to the present invention, wherein the inorganic salt of 3,3-tetramethylene glutarimide generated is the potassium salt of 3,3-tetramethylene glutarimide.

The process according to the present invention wherein work-up of the process involves addition of water to the reaction mass containing Buspirone base; followed by layer separation. Aqueous layer was back extracted with n-butyl acetate; and both the organic layers were extracted with 8% hydrochloric acid. After layer separation, HC1 layer was then washed with methylene dichloride to selectively remove the impurities. It further involves pH adjustment with 30% sodium hydroxide to separate out Buspirone base as a solid, which was isolated via washing, and drying.
The Buspirone base thus obtained according to the process of the present invention can be purified via crystallization from an organic solvent. The said organic solvent used for the purification of Buspirone base is an alcohol; preferably it is iso-propyl alcohol. Thus. Buspirone base obtained according to the present invention is of purity of greater than 99%, preferably greater than 99.5% and with quantitative yield.
Thus, the present invention provide an improved one pot process for the preparation of Buspirone base, having HPLC purity above 99.50% with yield 90%, starting from l-(2-pyrimidinyl)-piperazine.
The Buspirone base thus obtained can be further converted into Buspirone Hydrochloride, using anhydrous Isopropanolic HC1. The crude hydrochloride salt upon crystallization from IPA gives pure Buspirone Hydrochloride, complying as per USP / EP specification. It also complies as per the limits of ICH guide lines for residual solvents.
The process according to present invention is represented according SCHEME V. SCHEME V:


Thus, the present invention with noteable features involves improved insitu one pot process, wherein the reaction which is carried out only in one solvent i. e in n-butyl acetate, and use of other solvents like IPA & Toluene is avoided. Further, it does not involve isolation & drying of any intermediates. Potassium tert. butoxide is replaced by freshly powdered, anhydrous Potassium carbonate. Total reaction time is reduced, and finally this cost effective, ecofriendly, robust and industrially safe process produces Buspirone base having HPLC purity 99.50%, with yield of reaction is 90 %.
In the following section, the embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.
EXAMPLE
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims Example 1
Preparation of 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl] butyl]-8-azaspiro [4.5] decane-7,9-dione ( i.e. buspirone base)

In a five liter, four neck RBF, provided with coil condenser, oil bath, nitrogen inlet tube and anhydrous Calcium chloride guard tube, was charged 1500 ml of n-Butyl acetate and stirred. 100 gms of 1-(2-pyrimidinyl) piperazine (0.6097 moles), at RT (28 ° C -35 °C) was charged, followed by additional 25 ml n-Butyl acetate. Further 158 gms of 1,4-dibromobutane (0.731 moles) was charged into the flask, followed by 25 ml of n-Butyl acetate. Reaction mass was heated to 45°C. Then 168 gms of freshly powdered anhydrous potassium carbonate, (1.127 moles) was added at 40-45 °C; followed by additional 50 ml of n-butyl acetate. Temperature was increased to 90 to 95 °C and the reaction mass was stirred for next 18-20 Hrs at 95-97°C. Progress of the reaction is monitored on both TLC and HPLC.
Second lot of 168 gms (1.127 moles) of freshly powdered potassium carbonate at 95°C was charged into the reaction mass, followed by 140 gms of 3,3-tetramethylene glutarimide (0.838 moles), & raised the temperature from 95°C to 120-125°C. The reaction mixture was kept under reflux for 18 hrs- 20 hours. . Progress of the reaction is monitored on TLC, and also on HPLC.
The reaction mass was cooled to 85° C - 90°C and 900 ml of water was added in the reaction mass, stirred for 15-20 min. Layer separation was carried out. Aqueous layer was back extracted with 80 ml of n-Butyl acetate. Both organic layers were combined and washed with 2 X 200 ml of process water; extracted with 400 ml of 8 % hydrochloric acid. Aqueous layer containing the product was separated. Organic layer was back extracted with 125 ml of 8 % hydrochloric acid. Combined aqueous layer was washed with 80 ml N-butyl acetate followed by 2 X 50 ml of Dichloromethane. Separated aqueous layer was washed with 2 X 80 ml of n-Butyl acetate pH of aqueous was adjusted to 9.5 to 9.7 with slow addition of 30% aq. sodium hydroxide solution at RT (25° C -35°C). Reaction mass was stirred for next 30 min at RT; and then chilled to 0-5 °C & stirred for 30 min. The slurry was filtered on Buckner funnel & suck dried well & washed the wet cake with 4 X 100 ml chilled water. Wet material was dried at 50 °C in vacuum oven till constant wt. Dry wt of buspirone base was 211 gms. KF-0.07%, HPLC purity = 99.46 %, at 210 nm (Yield of reaction = 89.88 %). Melting Point 105° C to 107 °C.

Purification
In one liter four necks RBF, 600 ml of IPA was charged and stirred. While stirring 205 gms of crude, dry buspirone base was added. Temperature was then raised to gentle reflux (About 82 ° C), and a clear solution was observed. Then 12 gms of activated carbon, suspended in 77 ml of IPA was charged into the flask and stirred at reflux temperature for half an hour. Charcoal was filtered off on a hyflo bed and the bed was washed with 100 ml of hot IPA. The filtrate was slowly cooled to RT under stirring. Then further cooled to 10 to 15 °C. and maintained for 30 minutes. Solid was filtered off on buchner, washed with 2 X 100 ml of chilled IPA. Wet product was dried in vacuum oven at 50 °C for six hours to get 193 gms of pure dry buspirone base. HPLC purity was 99.757%, KF was 0.05 %, LOD was 0.05%, Assay by HPLC was 100.3%, and Melting point was 106° C to107°C.
We Claim:

1. An improved one pot process for synthesis of Buspirone base (i.e. 8-[4-[4-(2-
pyrimidinyl)-I-piperazinyl] butyI]-8'azaspiro [4,5] decane-7,9-dione) of formula
(I),
comprising of condensation of l-(2-pyrimidinyl)-piperazine; 1,4-dibromobutane and 3,3-tetramethylene glutarimide in presence of an inorganic base and in an organic solvent.
2. An improved process according to Claim 1, wherein l-(2-pyrimidinyl)-piperazine reacted with 1,4-dibromobutane in presence of inorganic base and in organic solvent to form an in-situ 8-(2-pyrimidinyl)-8-aza-5-azoniaspiro[4,5]decane bromide.
3. An improved process according to Claim 2, wherein the said reaction takes place at 80 - 130°C; preferably at 90 - 100°C; more preferably at 93-96°C.
4. An improved process according to Claim 1, wherein 3,3-tetramethylene glutarimide reacted with the inorganic base to form an in-situ inorganic salt of 3,3-tetramethylene glutarimide.
5. An improved process according to Claims 1 - 4, wherein Buspirone base formed by reacting in-situ 8-(2-pyrimidinyl)- 8-aza-5-azoniaspiro[4,5]decane bromide with inorganic salt of 3, 3-tetramethylene glutarimide.

6. An improved process according to Claim 5, wherein the said reaction takes place at 115 - 130°C; preferably at 120 - 125°C; more preferably at 123 - 125°C.
7. An improved process according to Claim 1, wherein organic solvent comprises of n-propyl acetate, n-butyl acetate, n-pentyl acetate, n-hexyl acetate; preferably n-butyl acetate.
8. An improved process according to Claim 1, wherein inorganic base comprises of potassium carbonate, cesium carbonate; preferably anhydrous potassium carbonate.
9. An improved process according to Claim 4, wherein the said inorganic salt of 3,3-tetramethylene glutarimide is a potassium salt of 3,3-tetramethylene glutarimide.
10. An improved process according to Claim 5, wherein Buspirone base purified with an organic solvent, preferably alcoholic organic solvent, more preferably isopropyl alcohol.
11. An improved process according to Claim 10, wherein Buspirone base obtained with purity of greater than 99%, preferably greater than 99.5% and with quantitative yield.
12. An improved process according to any of the preceding claims substantially as herein described with reference to the example.