FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Apixaban intermediate compound of Formula (I)

wherein R| is selected from halo, nitro, amino, N-protected amino, N-acyl optionally substituted with halo groups.
The present invention particularly relates to an improved process for the preparation of compound of Formula (I) without using any solvent.

wherein R] is selected from halo, nitro, amino, N-protected amino, N-acyl optionally substituted with halo groups.
BACKGROUND OF THE INVENTION
Apixaban is a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide. Its molecular formula is C25H25N504, which corresponds to a molecular weight of 459.5. Apixaban has the following structural formula:


Apixaban Apixaban was approved by FDA in 2012 which is marketed under the brand name ELIQUIS. Apixaban is generically disclosed in US 6,413,980 Bl. However, there is no specific process for Apixaban or its intermediates are provided.
Apixaban was specifically disclosed in US 6,967,208 B2, this patent also discloses process for preparing Apixaban and its intermediates. The process is shown in the scheme given below:
C
CN 101967145 B has discloses an alternate process for preparing Apixaban and its intermediates, wherein the process is shown in the scheme given below:

Apixaban
US 2017/0015663 Aldiscloses process for preparing Apixaban intermediate, which is shown in the scheme given below:


US '66?} further mentions that the chlorinalion of nitro intermediate is carried out in the presence of chlorinating agents such as thiony) chloride, phosphorous pen.tachIori.de, phosphorous trichloride which is carried out in non-halogenated solvents and mixtures thereof.
Due to the importance of Apixaban there needs to develop an improved process for the preparation of Apixaban key starring materials, wherein the process shall be cost effective, commercially and industrially feasible.
The present inventors have developed more simplified, cost effective, commercially feasible process for the preparation of .compound of Formula (1) an intermediate of Apixaban.
wherein R, is selected from halo, nitro, amino, N-protected amino, N-acyl optionally substituted with halo groups.

OBJECT OF THE INVENTION
The main object .of the invention is to provide a simple, cost effective,--improved and robust process for the preparation of compound of Formula (I), an intermediate of Apixaban.

wherein R| is selected from halo, nitro, amino, N-protected amino, N-acyl optionally substituted with halo groups.
'j Another, main objective of tl?.e present invention is to provide an improved process for the preparation of compound of Formula (I) without using any solvent.

wherein R| is selected from halo, nitro, amino. N-protected amino, N-acyl optionally substituted with halo groups.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of Formula (I)

wherein R\ is selected from halo, nitro, amino, N-protected amino, N-acyl optionally
substituted with halo groups, which comprises reacting compound of Formula II with a
chlorinating agent .^ ,- -, <,■«-*>> ■«-■


wherein the reaction is carried out in neat without using any solvent.
In a preferred aspect, the present invention provides an improved process for the preparation of compound of Formula (1A)

wherein R2 is selected from halo, amino, N-protected amino, N-acyl optionally substituted with halo groups, which comprises reacting compound of Formula (IIA)

wherein R2 is as defined above, with a chlorinating agent optionally in a solvent to give compound of Formula (IA), wherein the chlorinating agent is selected from thionyl chloride, sulfiiryl chloride, oxalyl chloride, carbonyl chloride,
In another preferred aspect, the present invention provides an improved process for the preparation of compound of Formula (IB)

which comprises reacting compound of Formula (IIB)


with a chlorinating agent optionally in .a- solvent to give compound of Formula (IB), wherein the chlorinating agent is selected from thiohyl chloride. Sulfur)-] chloride. In yet another preferred aspect, i.he present invention provides an improved process for the preparation of compound of Formula (IC)

which comprises reacting compound of Formula (IIC)

with a chlorinating agent to give compound of Formula (IB), wherein the reaction is ..„ carried out in neat without using any solvent.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of compound of Formula I, which is a key intermediate in the preparation of Apixaban.

wherein R[ is selected from halo, nitro, amino, N-protected amino, N-acyl optionally substituted with halo groups.

According to the present: invention R| in compound of Formula I is selected from halo such as bromo, chloro., fluoro and.lcdo, nitro, amino, N-protected amino or N-acetyl optionally substituted with halo groups, suitable amino protecting groups were selected from carbobenzyloxy (Cbz), tert-butyloxycarbonyl (BOC), p-methoxybenzyl carbonyl (Moz or MeOZ), 9-fluorenylmethyloxycarbonyl (FMOC), acetyl (Ac), benzoyl (Bz), benzyl (Bn), benzyl carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM). p-methoxyphenyl (PMP), tosyl (Ts), sulfonamides.
In a preferred embodiment. R| in compound of Formula I represents iodo which is prepared by chlorinating compound of Formula (IIB) with chlorinating agent optionally in the presence of a solvent.
In another preferred embodiment, R| in compound of Formula I represents nitro which is prepared by chlorinating compound of Formula (IIC) with a chlorinating agent, wherein the reaction is carried out in neat without using in solvent.
In another preferred embodiment R2 is selected from halo, amino, N-protected amino, N-acyl optionally substituted with halo groups. Preferably R2 is iodo or nitro.
In another preferred embodiment, the chlorinating agent used is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, carbonyl chloride, phosphorus trichloride,- phosphoryl chloride, phosphorus pentachloride, ZnCl2, A1C13, NCS (n-chlorosuccinimide), TMSC1 (Tiimethylsilyl chloride), CC14, triphosgene, NaOCl, HC1, cyanuric chloride, methanolic MCI, chlorine gas, l,3-dichloro-5,5-dimethylhydantoin.
In another preferred embodiment, solvent used in the present invention is selected from water, alcohol solvents such as methanol, ethanol, n-propanol. isopropanol, n-butanol and t-butanol, hydrocarbon solvents such as benzene, toluene, xylene, heptane, hexane and cyclohexane, ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone, esters solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, nitrile solvents such as acetonitrile, propionitrile, butyronitrile and

isobutyronitrile, ether solvents such as di-tert-butylether, dimethylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltertrbutylether, ethyl tert-butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran. 2-methoxyethanol and dimethoxyethane, Amide solvents such as formamide. DMF. DMAC, N-methyl-2-pynolidone, N-rnethyl formamide, 2-pyrrolidone, l-etl3er.yl-2-pyiTolid.one and/or mixtures thereof.
In yet another preferred embodiment, the present invention provides an improved
process for the preparation of compound of Formula (IB). ■.-.■.,...

which comprises reacting compound of Formula (IIB)

with a chlorinating agent optionally in a soivent to give compound of Formula (IB), „ . .wherein the chlorinating agent is selected from thionyl chloride, Sulfuryl chloride.
In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula (IB)

which comprises reacting compound of Formula (IIB)
_ v—y

with a chlorinating agent, wherein the reaction- is carried out in neat without using any solvent.
In yet another preferred embodiment, the present invention provides an improved process for .the preparation of compound ol'Formula (IB)

whicii comprises reacting compound of Formula (IIB)

with thionyi chloride in the absence of a solvent to give compound of Formula (IB).
.In yet another preferred embodiment, the present invention provides an improved process tor the preparation of compound of Formula (IB)

which comprises reacting compound of Formula (IIB)

with thionyi chloride in hydrocarbon solvent to give compound of Formula (IB).
In yet another preferred embodiment, the present invention provides an improved process for the preparation of compound of Formula (IC)
_ _ ,, T * T- r- T r-r- r- u -cr M M A T "I ft; »• Q, A > 1 \'-\ t 7 ' 1* 4''* 1 '~>


which comprises reacting compound of Formula (IIC)

with thio-iyl chloride to give compound of Formula (IB), wherein the reaction is carried out in neat without using any solvent.
The compounds of Formulae (TA). (IB). (IC) prepared according to the present invention are preferably used in the preparation of Apixaban. The intermediates of Formulae (IA), (IB), (IC) are converted to Apixaban using any of the process reported in US 6,967,208 B2, US 6,919,451 B2 and CN 101967145.
.• While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.
Examples:
Example 1: Preparation of compound of Formula (IB)
To thionyl chloride (250 ml) was slowly added compound of Formula (IIB) (25 gms) in a lot wise manner at 0.5°C. The temperautre of the reaction mas was raised to 80-85°C and maintained for 2-4 hrs. The reaction completion was monitored by TLC. Reaction mass was cooled to room temperature, followed by quenching with ice water at 0-5°C. Temperature was raised to RT, the.reaction mass was filtered and washed with water, obtained wet compound. Dissolving wet compound imMDOjOjOO ml) at reflux

condition, the reaction mass was filtered, followed by washing with 10% sodium bicarbonate solution (100 ml), The solvent was distilled completely followed by isolating the pure compound of FormuIa.(IB) in toluene. Yiled: 50%.Purity by HPLC: 915.4%.
Example 2: Preparation of compound of Formula (IB)
To the mixture of thionyl chloride (69.1 gm).and toluene (125 mi) was slowly added compound of Formula (IIB) (25 gms) in a lot wise manner at 0.5°C. The temperautre of the reaction mas was raised to 80-85°C and maintained for 2-4 hrs. The reaction completion was monitored by TLC. Reaction mass was cooled to room temperature, followed by quenching with ice water at 0-5°C. RM temperature was raised to.RT, the reaction mass was filtered and washed with water, obtained wet compound. pH was adjusted to 7-7.5 with 10% sodium carbonate, followed by isolating compound of Formula (IB). Yiled: 66% Purity by HPLC: 96%.
Example 3: Preparation of compound of Formula (IC)
. To thionyl chloride (250 ml) was slowly added compound of Formula (IIC) (25 gms) in a lot wise manner at 0.5°C. The temperautre of the reaction mas was raised to 80-85°C and maintained for 2-4 hrs. The reaction completion was monitored by TLC. Reaction mass was cooled to room temperature, followed by quenching with ice water at 0-5°C. Temperature was raised to RT, the reaction mass was filtered and washed with water, obtained wet compound. Dissolving wet compound in MDC (500 ml) at reflux condition, the reaction mass was filtered, following by washing with 10% sodium bicarbonate solution (100 ml). The solvent was distilled completely followed by isolating the pure compound of Formula (IC) in toluene.
Example 4: Preparation of compound of Formula (IC)
To the mixture of thionyl chloride (69.1 gm) and toluene (125 ml) was slowly added compound of Formula (IIC) (25 gms) in a lot wise manner at 0.5°C. The temperautre of the reaction mas was raised to 80-85°C and maintained for 2-4 hrs. The

reaction completion was monitored by TLC. Reaction mass was cooled to room temperature, followed by quenching with ice water at 0-5°C. Temperature was raised to RT. the reaction mass was filtered and washed with water, obtained wet compound. pH was adjusted to 7-7.5 with 10% sodium carbonate, followed by isolating compound of Formula (IC).