DESC:Field of the invention
The present invention relates to the Process for the preparation of Apixaban and novel intermediates useful in the synthesis of Apixaban (I)

(I)

Background of the invention

Apixaban (BMS-562247-01, tradename Eliquis) is an anticoagulant for the prevention of venous thromboembolism and venous thromboembolic events. It is a direct factor Xa inhibitor.

US6967208B2 discloses a series of coagulation factor Xa inhibitors 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5-dihydropyrazolo[5,4-c]pyridine-3-carboxamide (also known as Apixaban). US7396932 discloses process for the preparation of Apixaban by condensing compound of formula II and compound of formula III in the presence of base.

II III

The published methodology involves diazotization species of compound of formula II and 1,3-dipolar addition of compound of formula II with compound of formula III to achieve Apixaban. A safer approach which is free form diazotization species and simple in operation is still needed.
The present invention addresses these issues and provides novel process for making Apixaban. The present invention also provides novel intermediates for the synthesis of Apixaban.

Object of the invention:

Accordingly, it is an object of the present invention to provide novel process for the preparation of Apixaban comprising a step of reacting compound of formula IV with compound of formula X or salt thereof in the presence or absence of base and aprotic solvent to obtain compound of formula V.

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-C6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
alternatively N Rb Rc is a 3-8 membered ring consisting of: carbon atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br, I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R3 is selected from ester, amide, nitrile, carboxylic acid.
R2 is selected from halogen, mesylate, tosylate, O-SO2-Ph, ORa, where in Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.

Another object of the present invention to provide process for the preparation of compound of formula V where in
R1 is preferably selected from NRbRc
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R2 is preferably selected from halogen, tosylate and mesylate;
R3 is preferably selected from ester, carboxylic acid.

Base that used for the preparation of compound of formula V is selected from the group comprising of organic base such as pyridine, dimethyl amine and trimethyl amine and Inorganic base such as KOH, NaOH, K2CO3, Na2CO3, CaCO3, NH4 and the like.

Aprotic solvent may be selected from the group consisting of chlorinated and ether solvent.
Chlorinated solvent is selected from methyl chloride, dichloride methane, and chloroform; ether solvent is selected from tetrahydrofuran, dimethyl ether, polyethylene glycol, dioxin, diethyl ether.

Further object of the present invention is to provide a novel process for the preparation of Apixaban comprising a step of reacting compound of formula V with compound of formula VI or salt thereof in the presence of aq. alcoholic solvent to obtain compound of formula VII.

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-C6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
Alternatively, N Rb Rc is a 3-8 membered ring consisting of: C atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R is selected from halogen, ORa, mesylate, tosylate, O-SO2-Ph.
R3 is selected from from ester, amide, nitrile, carboxylic acid.
R is selected from ORa where in Ra is alkyl.

Further object of present invention is to provide process for the preparation of compound of formula VII where in,
R1 is preferably selected from NRbRc
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R2 is preferably selected from halogen, tosylate and mesylate;
R3 is preferably selected from ester, carboxylic acid.

Aq alcoholic solvent that used in the preparation of compound of formula VII is mixture of alcohol and water. Alcoholic solvent is selected from the group consisting of C1 to C8 carbon. The preferred one is ethanol, methanol and isopropyl alcohol.

Yet another object of the present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein R3 is ester or carboxylic acid is reacted with ammonia.

Further object of present invention is to provide a novel compound of formula V and its use in the synthesis of Apixaban

V

Wherein R1 is selected from ORa , NRbRC, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
alternatively N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd.
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R3 is selected from ester, amide, nitrile, carboxylic acid.

Further object of present invention is to provide comopound of formula V where in
R1 is preferably selected from NRbRc
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R3 is preferably selected from ester, carboxylic acid.

Detailed description of the invention:

An embodiment of the present invention provides a process for the preparation of Apixaba comprising a step of reacting compound of formula IV with a compound of formula X in the presence or absence of base and aprotic solvent to obtain compound of formula V

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
alternatively N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd.
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R3 is selected from ester, amide, nitrile, carboxylic acid
R2 is selected from halogen, mesylate, tosylate, O-SO2-Ph, ORa.

Another embodiment of present invention is to provide process for the preparation of compound of formula V where in
R1 is preferably selected from NRbRc
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R2 is preferably selected from halogen, tosylate and mesylate;
R3 is preferably selected from ester, carboxylic acid.

Base that used for the preparation of compound of formula V is selected from the group comprising of organic base such as pyridine, dimethyll amine and trimethyl amine and Inorganic base such as KOH, NaOH, K2CO3, Na2CO3, CaCO3, NH4 and the like. More Preferabal inorganic base is K2CO3 and organic base is pyridine

The quantity of base used in this step may range from about 1 to about 3 molar equivalents, per mole of compound (IV).

Aprotic solvent may be selected from the group consisting of chlorinated and ether solvent.
Chlorinated solvent is selected from methyl chloride, dichloride methane, and chloroform; ether solovent is selected from tetrahydrofuran, dimethyl ether, polyethylene glycol, dioxin, diethyl ether.
The amount of solvent that preferably used in this step may range from about 5 to 30 volumes to compound of formula (IV).

The residue obtain after the completion of reaction is treated with 5 to 30 % HCl and solid is filtered off to obtain compound of formula V

Further embodiment of present invention is to provide Process for the preparation of Apixaban comprising a step of reacting compound of formula V with a compound of formula VI or salt thereof in the presence of aq. alcoholic solvent.

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
Alternatively, N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R is halogen, ORa, mesylate, tosylate, O-SO2-Ph
R3 is selected from ester, amide, nitrile, carboxylic acid.

Aq alcoholic solvent that used in the preparation of compound of formula VII is mixture of alcohol and water. Alcoholic solvent is selected from the group consisting of C1 to C8 carbon. The preferred one is ethanol, methanol and isopropyl alcohol.

The amount of solvent that preferably used in this step may range from about 5 to 30 volumes to compound of formula (V).

The salt of compound of formula VI is hydrochloride, hydrobromide or hydroiodide salt.

Yet another object of the present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein R3 is ester or carboxylic acid is reacted with ammonia.

Further embodiment of present invention is to provide a process for the synthesis of Apixaban (I) from the compound of formula VII wherein the compound of formula VII is treated with ammonia when R3 is ester or carboxylic acid.

One of the embodiments of present invention provides novel compound of formula V.

V
And its use in the synthesis of Apixaban

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
Alternatively N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd.
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R3 is selected from ester, amide, nitrile, carboxylic acid

Further embodiment of present invention provides compound of formula V where in
R1 is preferably selected from NRbRc
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R3 is preferably selected from ester, carboxylic acid.

The embodiments of present invention are shown schematically as below.

Scheme I

Scheme II

The process described in the present invention is illustrated in the following examples which should not be construed to limit the scope of the invention in any way.

Examples
Example 1
Preparation of ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate.
5,6-Dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone (100 gm) is stirred with Ethyl oxalyl chloride (42.24 gm) in dichloromethane (800 ml) in the presence of Pyridine (26.7 gm) at 25-30°C for 3 hrs. After the reaction completion dichloromethane is distilled completely and Ethyl acetate (100 ml) is added. To this 10 % HCl solution (500 ml) is added and stirred for 1 hr. The solid is filtered and dried. Yield 90%

Example 2
Preparation of Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate.
Ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate (100 gm) is stirred with 4-Methoxy phenyl hydrazine hydrochloride (49.72 gm) in aqueous Isopropyl alcohol (2000ml) at 50-55°C for 1 hr. After the reaction completion Isopropyl alcohol is distilled completely and the product is crystallized from mixture of Ethyl acetate and ethanol (1300 ml). The solid is filtered and dried. Yield 90%

Example 3
Preparation of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.
Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (100 gm) is heated with Ethylene glycol-NH3 (5-6 % w/w) (1000 ml) in pressure reactor at 115-120°C for 1.5 hrs. After the completion of reaction it is cooled to 35-40°Cand the product is precipitated by addition of water (600 ml). The solid is filtered and dried.
Yield 75%.

Example 4
Preparation of {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetic acid.
5,6-Dihydro-3-(4-morpholinyl)-1-[4-(2-oxo-1-piperidinyl)phenyl]-2(1H)-pyridinone (100 gm) is stirred with sodium monoethyl oxalate (45.3 gm) in Ethanol (800 ml. After the reaction completion ethanol is distilled completely and Ethyl acetate (100 ml) is added. To this 10 % HCl solution (500 ml) is added and stirred for 1 hr. The solid is filtered and dried.

Example 5
Preparation of ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate.
{5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetic acid (10 gm) was refluxed with Ethanolic HCl (100ml). After completion of the reaction ethanol is removed under reduced pressure. Ethyl acetate (15 ml) is added and the solid is filtered and dried.

Example 6
Preparation of ethyl {5-hydroxy-6-oxo-1-[4-(2-oxopiperidin-1-yl)phenyl]-1,2,3,6-tetrahydropyridin-4-yl}(oxo)acetate.
3-ethoxy-1-[4-(2-oxopiperidin-1-yl)phenyl]-5,6-dihydropyridin-2(1H)-one (50 gm) is stirred with Ethyl oxalyl chloride (20 gm) in dichloromethane (350 ml) in the presence of Pyridine (13.5 gm) at 25-30°C for 3 hrs. After the reaction completion dichloromethane is distilled completely and Ethyl acetate (50ml) is added. To this 10 % HCl solution (250 ml) is added and stirred for 1 hr. The solid is filtered and dried.

,CLAIMS:
1. Process for the preparation of Apixaban comprising a step of reacting compound of formula IV with a compound of formula X in the presence or absence of base and aprotic solvent to obtain compound of formula V

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
alternatively N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R3 is selected from ester, amide, nitrile, carboxylic acid.
R2 is selected from halogen, mesylate, tosylate, O-SO2-Ph, O-CO-CO-ORx.
Rx is selected from alkyl, substituted alkyl and cyclo alkyl.

2. Process for the preparation of Apixaban comprising a step of reacting compound of formula V with a compound of formula VI or salt there of in the presence of aq. alcoholic solvent.

Wherein R1 is selected from ORa , NRbRC, Cl, Br, I, SRa
Ra is H, C1-C6 alkyl, aryl, aryl substituted with alkyl group.
Rb and Rc are selected from C1-6, alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl and benzyl.
Alternatively, N Rb Rc is a 3-8 membered ring consisting of: carboan atoms, N and 0-1 O atoms
Y is selected from phenyl, pyridyl or pyrimidyl.
Z is selected from Cl, Br , I, CN, NO2, NH2 or 5-10 membered heterocycle ring containing from 1-4 heteroatoms selected from the group consisting of N,O and S subistituted with 0-2 Rd
Rd at each occurance, is selected from H, =O, CHO, Cl, Br, I, CH3, CH2-CH3, CH2-CH2-CH3, CH2-CH2-CH2-CH3, CH (CH3)2, CH2- CH (CH3)2, CN, NO2.
R is halogen, ORa, mesylate, tosylate, O-SO2-Ph.
R3 is selected from ester, amide, nitrile, carboxylic acid.

3. Compound of fromula V

V
And its use in the synthesis of Apixaban

R1 is preferably selected from NRbRc and ORa
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
ORa is preferabally selected from H and 0-6 alkyl
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R3 is preferably selected from ester and carboxylic acid.

4. A process as claimed in claim 1 or claim 2 where in R1 is preferably selected from NRbRc and ORa;
NRbRc is preferably selected from morpholino, pyrolidino, pipieridino;
ORa is preferably selected from H and 0-6 alkyl;
Y is preferably selected from phenyl;
Z is preferably selected from pyridine 2-one;
R2 is preferably selected from halogen, tosylate and mesylate;
R3 is preferably selected from ester, carboxylic acid;
R is preferably selected from ORa.

5. A process as claimed in claim 1 where in base is selected from the group comprising of organic base such as pyridine, dimethyll amine and trimethyl amine and Inorganic base such as KOH, NaOH, K2CO3, Na2CO3, CaCO3, NH4 and the like.

6. A process as claimed in claim 5 where in organic base is pyridine and inorganic base is K2CO3.

7. A process as claimed in claim 2 where in alcoholic solvent is selected from the group consisting of C1 to C8 carbon.

8. A process as claimed in claim 7 where in alcoholic solvent is ethanol, methanol and isopropyl alcohol.

9. A process according to claim 2 or 4 where in R3 is ester or carboxylic acid treated with ammonia to obtain apixaban of formula (I)