DESC:Field of the Invention:
The present invention relates to a process for the preparation of Neratinib intermediates. Neratinib is a tyrosine kinase inhibitor formula (I), having the chemical name (2E)-N-[4-[[3-Chloro-4-[(pyridin-2-yl)methoxy]phenyl]amino]-3-cyano-7-ethoxyquinolin-6-yl]-4-(dimethylamino)but-2-enamide.
Background of the Invention:
Neratinib is a tyrosine kinase inhibitor. Tyrosine kinase inhibitors are known to be useful in the treatment of cancers, including non-small cell lung cancer (NSCLC), breast cancer, polycystic kidney disease, colonic polyps, and stroke in mammals. Neratinib has the following chemical structure:

Formula 1
and its intermediates are known through PCT Publication Nos. WO 2005/028443, WO 2004/066919, WO2010/131921 &. WO 2005028421.
While developing the process for Neratinib inventors come across the process which is suitable for commercial synthesis, provide a product of higher purity and involved fewer steps.

Summary of the Invention:
In one aspect, the present invention provides a process for the preparation of intermediate compound of formula 2; intermediate compound of formula 3 and 3A which are useful in the synthesis of Neratinib.

In another aspect the present invention provides process for the preparation of intermediate compound of formula 2 as described in Scheme 1.

Scheme-1: Process for preparation of compound of formula 2:

Wherein R is alkyl group.
In another aspect the present invention provides process for the preparation of intermediate compound of formula 2 as described in Scheme 2.

Scheme-2: Process for preparation of intermediate of Formula-2:

Wherein R is alkyl group
In another aspect the present invention provides process for the preparation of intermediate compound of formula 2 as described in Scheme 3.

Scheme-3: Process for preparation of intermediate of Formula-2:

Wherein X is a halogen; R is alkyl group; LG is leaving group.
In another aspect the present invention provides process for the preparation of intermediate compound of formula 3 and 3A as described in Scheme 4.

Scheme-4: Process for preparation of intermediate of Formula-3 and 3A:

Wherein:-
Y is a halogen or OR1, and R1 is hydrogen or alkyl; LG is a leaving group and it can be a halogen or alkoxy; X is a halogen.
In another aspect, the present invention provides novel intermediate compounds of formula 7, formula 8, formula 10, formula 11, formula 13, formula 17, formula 18, formula 22 or solvates, pharmaceutically acceptable salts thereof and process for the preparation thereof.
In another aspect, the invention provides use of novel intermediate compounds of formula 7, formula 8, formula 10, formula 11, formula 13, formula 17, formula 18, formula 22 or solvates, pharmaceutically acceptable salts thereof in the preparation of Neratinib.

Detail Description of the Invention:
There is always a need for alternative preparative routes, which for example, use reagents, solvents that are less expensive, and/or easier to handle, consume smaller amounts of reagents and solvents, provide a higher yield of product, involve fewer steps, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity. More efficient methods of synthesis, particularly for the commercial scale synthesis, would be highly desirable. Major process improvements have been discovered in the present invention and have been developed to overcome the commercial manufacturing limitations.

The phrase "pharmaceutically acceptable salt" means a salt that is pharmaceutically acceptable. Examples of pharmaceutically acceptable salts include, but are not limited to: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as glycolic acid, pyruvic acid, lactic acid, malonic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, salicylic acid, muconic acid, and the like or (2) basic addition salts formed with the conjugate bases of any of the inorganic acids listed above, wherein the conjugate bases comprise a cationic component selected from among Na+, Mg2+, Ca2+, NHgR'''4-g+, in which R''' is a C1-3 alkyl and g is a number selected from among 0, 1, 2, 3, or 4. It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.
Each LG is a leaving group and it can be halogen or alkoxy group.
The halogen can be selected from chlorine, bromine, iodine or fluorine.
The term "alkyl" refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms.
The term "alkoxy" refers to an -O-alkyl group or an -O-cycloalkyl group, wherein "alkyl" refers to an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 10 carbon atoms and cycloalkyl cycloalkyl" refers to an unsubstituted or substituted carbocycle, in which the carbocycle contains 3 to 10 carbon atoms. Examples of -O-alkyl groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, t-butyloxy.
In one embodiment, the present invention provides a process for the preparation of intermediate compound of formula 2:

comprising the steps of :
i) reacting compound of formula 6 with alkyl acetate to give compound of formula 7:

ii) reducing compound of formula 7 in the presence of reducing agent; to obtain a compound of formula
8; and

iii) conversion of compound of formula 8 in presence of base to give compound of formula 2.

The reaction of Step-(i) can be performed in presence of organic base or inorganic base; organic base can be selected from but not limited to triethylamine, N,N-Diisopropylethylamine ; inorganic base can be selected from but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
The solvent for the reaction of step- (i) can be selected from but not limited to water; esters like ethyl acetate, isopropyl acetate; hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water, 1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reducing agent of step- (ii) selected from but not limited to metal borohydrides like sodium borohydride, lithium borohydride. Reaction of step-(ii) can also be performed using commonly available baker yeast.
The solvent for the reaction of step- (ii) can be selected from but not limited to water; esters like ethyl acetate, isopropyl acetate hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(iii) can be carried out by transforming the hydroxy group of compound 8 into a good leaving group (LG) by selectively installing a Hydroxy Protecting group. The hydroxy protecting group can be methyl, ethyl, isopropyl, tert-butyl, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate), tert-butyloxycarbonyl (BOC), Flourenylmethyloxycarbonyl (F-MOC), trityl, substituted Carboxybenzyl (CBZ) group, etc; Preferably, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate); and most preferably, methanesulfonyl (mesyl). Accordingly, the reagent used for the said transformation in compound 8 can be selected from but not limited to sulfonyl chlorides like methanesulfonyl chloride, p-toluenesulfonyl chloride, nitorbenzenesulfonyl chloride, trifluoromethanesulfonyl chloride; and most preferably, methanesulfonyl chloride.

The base used in step-(iii) can be selected from various organic or inorganic bases but not limited to tertiary and secondary amines such as triethylamin; N,N-diisopropylethylamine; sodium hydroxide; potassium carbonate; sodium carbonate; potassium hydroxide; potassium fluoride; tripotassium phospahte

The solvent for the reaction of step- (iii) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether; , esters like ethyl acetate, isopropyl acetate, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another embodiment, the present invention provides an alternative process for the preparation of intermediate compound of formula 2:

comprising the steps of :
i) reacting compound of formula 9 with trimethylsilylcyanide in presence of a base to give compound of formula 10;

ii) hydrolyzing compound of formula 10 in the presence of a acid to give compound of formula 11;

iii) alkylating compound of formula 11 in the presence of metal catalyst and a base to give compound of formula 12;

iv) esterify compound of formula 12 to give ester compound of formula 8;

v) conversion of compound of formula 8 in the presence of a base to give compound of formula 13;


vi) hydrolysis of compound of formula 13 and isolating compound of formula 2

The base used in Step-(i) can be selected from organic, inorganic bases; organic base can be selected from but not limited to Lithium bis(trimethyl)amide; tertiary and secondary amines such as triethylamine, N,N-Diisopropylethylamine; inorganic base can be selected from but not limited to lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium fluoride, tripotassium phosphate, preferably the alkali metal hydroxides, and most preferably lithium hydroxide monohydrate.
The solvent for the reaction of Step-(i) can be selected from one or more hydrocarbons such as toluene, xylene; chlorinated hydrocarbons like methylene chloride, ethylene chloride; , esters like ethyl acetate, isopropyl acetate; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, acetonitrile or mixtures thereof. Preferably ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane; and most preferably tetrahydrofuran (THF).
The acid used in reaction of step-(ii) can be selected from but not limited to hydrochloric acid.
The metal catalyst used in step-(iii) can be selected from but not limited to palladium-on-charcoal (Pd/C), platinum-on-charcoal (Pt/C), ruthenium-on-charcoal (Ru/C).
The base used in Step-(iii) can be organic, inorganic bases; organic base is selected from but not limited to Lithium bis(trimethyl)amide; tertiary and secondary amines such as triethylamine, N,N-Diisopropylethylamine; inorganic base is selected from but not limited to lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium fluoride, tripotassium phosphate, preferably tertiary and secondary amines such as triethylamine, N,N-Diisopropylethylamine; and most preferably triethylamine.
The solvent for the reaction of Step-(iii) can be selected from one or more hydrocarbons such as toluene, xylene; chlorinated hydrocarbons like methylene chloride, ethylene chloride; , esters like ethyl acetate isopropyl acetate; alcohols like methanol, ethanol, isopropanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,N-dimethylacetamide, N,N-dimethylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, acetonitrile or mixtures thereof. Preferably alcohols like methanol, ethanol, isopropanol; and most preferably methanol.
The reaction of step-(iv) wherein esterification can be done by alcohols selected from but not limited to methanol, ethanol, isopropanol, tert-butanol.
The solvent for the reaction of Step-(iv) can be selected from one or more hydrocarbons such as toluene, xylene; chlorinated hydrocarbons like methylene chloride, ethylene chloride; , esters like ethyl acetate isopropyl acetate; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether, dibutyl ether, tetrahydrofuran (THF), 1,4-dioxane or mixtures thereof. Preferably chlorinated hydrocarbons like methylene chloride, ethylene chloride; and most preferably methylene chloride.
The reaction of step-(v) can be carried out by transforming the hydroxy group of compound 8 into a good leaving group by selectively protecting hydroxy group. The hydroxy protecting group can be methyl, ethyl, isopropyl, tert-butyl, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate), tert-butyloxycarbonyl (BOC), Flourenylmethyloxycarbonyl (F-MOC), trityl, substituted Carboxybenzyl (CBZ) group, etc; Preferably, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate); and most preferably, methanesulfonyl (mesyl).
Accordingly, the reagent used for the said transformation in compound 8 can be selected from but not limited to sulfonyl chlorides like methanesulfonyl chloride, p-toluenesulfonyl chloride, nitorbenzenesulfonyl chloride, trifluoromethanesulfonyl chloride; and most preferably, methanesulfonyl chloride.
The base used in Step-(v) can be organic, inorganic bases; organic base is selected from but not limited to Lithium bis(trimethyl)amide; tertiary and secondary amines such as triethylamine, N,N-Diisopropylethylamine; inorganic base is selected from but not limited to lithium hydroxide monohydrate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium fluoride, tripotassium phosphate, preferably tertiary and secondary amines such as triethylamine, N,N-Diisopropylethylamine; and most preferably triethylamine.
The solvent for the reaction of step- (v) can be selected from one or more hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; , esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(vi) can be carried out in presence of base selected from various organic or inorganic bases but not limited to tertiary and secondary amines such as trimethylamine; N,N-diisopropylethylamine; sodium hydroxide; potassium hydroxide, potassium carbonate; sodium carbonate etc.,

The solvent for the reaction of step- (vi) can be selected from water, one or more hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; , esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol isopropyl alcohol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is water,isopropyl alcohol,methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another emdodiment, the present invention provides an alternative process for the preparation of intermediate compound of formula 2:

comprising the steps of:
i) reacting compound of formula 21 with benzylmethylamine to obtain a compound of formula 22

ii) reacting compound of formula 22 in presence of reducing agent to obtain a compound of formula 8.

iii) conversion of compound of formula 8 in presence of base to give compound of formula 13


iv) hydrolysis of compound of formula 12 and isolating compound of formula 2

The reaction of step-(i) is carried out by reacting compound of formula 21 with benzylmethylamine.
The reaction of Step-(i) can be performed in presence of organic base or inorganic base; organic base can be selected from but not limited to triethylamine, N,N-Diisopropylethylamine ; inorganic base can be selected from but not limited to sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
The solvent for the reaction of step- (i) can be selected from but not limited to water, hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is isopropyl alcohol, ethylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reducing agent used in step- (ii) can be selected from but not limited to metal catalyst such as palladium-on-charcoal (Pd/C), platinum-on-charcoal (Pt/C), ruthenium-on-charcoal (Ru/C).

The solvent for the reaction of step- (ii) can be selected from but not limited to water, hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is formaldehyde, methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(iii) can be carried out by transforming the hydroxy group of compound 8 into a good leaving group by selectively installing a Hydroxy Protecting group. The hydroxy protecting group can be methyl, ethyl, isopropyl, tert-butyl, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate), tert-butyloxycarbonyl (BOC), Flourenylmethyloxycarbonyl (F-MOC), trityl, substituted Carboxybenzyl (CBZ) group, etc; Preferably, methanesulfonyl (mesyl), p-toluenesulfonyl (tosyl), nitrobenzenesulfonyl (nosyl), trifluoromethanesulfonyl (triflate); and most preferably, methanesulfonyl (mesyl). Accordingly, the reagent used for the said transformation in compound 8 can be selected from but not limited to sulfonyl chlorides like methanesulfonyl chloride, p-toluenesulfonyl chloride, nitorbenzenesulfonyl chloride, trifluoromethanesulfonyl chloride; and most preferably, methanesulfonyl chloride.
The base used in step- (iii) can be selected from various organic or inorganic bases but not limited to tertiary and secondary amines such as triethylamin; N,N-diisopropylethylamine; sodium hydroxide; potassium carbonate; sodium carbonate; potassium hydroxide; potassium fluoride; tripotassium phospahte

The solvent for the reaction of step- (iii) can be selected from one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(iv) can be carried out in presence of base selected from various organic or inorganic bases but not limited to tertiary and secondary amines such as trimethylamine; N,N-diisopropylethylamine; sodium hydroxide; potassium hydroxide, potassium carbonate; sodium carbonate etc.,

The solvent for the reaction of step- (iv) can be selected from water,one or more hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol isopropyl alcohol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is water,isopropyl alcohol,methylene dichloride, tetrahydrofuran, and acetonitrile or mixtures thereof.

In another embodiment, the present invention provides a process for the preparation of intermediate compound of formula 3:

comprising the steps of:
i) reacting compound of formula16 with acetonitrile in presence of a base to obtain compound of formula 17;

wherein LG is leaving group.
ii) reacting compound of formula 17 with dimethylacetamide to obtain compound of formula 18;

iii) cyclizing of compound 18 in presence of base to obtain compound of formula 19;

iv) halogenating compound of formula 19 to obtain compound of formula 20; and

v) reducing the compound of formula 20 and isolating compound of formula 3

vi) optionally acetyl protecting the compound of formula 3 to obtain compound
of formula 3A

The base used in Step-(i) can be selected from organic, inorganic bases; organic base can be selected from but not limited to Lithium diisopropylamide (LDA); Lithium bis(trimethylsilyl)amide; tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic base can be selected from but not limited to, sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
The solvent for the reaction of step- (i) can be selected from but not limited to water, hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water, 1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The solvent for the reaction of step- (ii) can be selected from but not limited to water, hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The base used in Step-(iii) can be organic, inorganic bases; organic base is selected from but not limited to Lithium bis(trimethylsilyl)amide; tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic base is selected from but not limited to, sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).
The solvent for the reaction of step- (iii) can be selected from but not limited to water, hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol, ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reaction of step-(iv) can be carried out by using any halogenating agent selected from but not limited to potassium tri chloride, thionyl chloride.
The solvent for the reaction of step- (iv) can be selected from but not limited to one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The reducing agent of step-(v) selected from but not limited to metals like iron; metal borohydrides like sodium borohydride, lithium borohydride.
The base used in step-(v) can be selected from organic, inorganic bases; organic base can be selected from but not limited to Lithium bis(trimethylsilyl)amide; tertiary and secondary amines such triethylamine, N,N-Diisopropylethylamine ; inorganic base can be selected from but not limited to, sodium hydroxide, Potassium carbonate (K2CO3), sodium carbonate (Na2CO3), potassium hydroxide (KOH); potassium fluoride, tripotassium phosphate (K3PO4).

The solvent for the reaction of step- (v) can be selected from but not limited to one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The solvent for the reaction of step- (vi) can be selected from but not limited to one or more of hydrocarbons like toluene, xylene; chlorinated hydrocarbons like methylene dichloride, ethylene dichloride and chlorobenzene; esters like ethyl acetate, isopropyl acetate; alcohols like methanol,ethanol; ethers like diethyl ether, diisopropyl ether, t-butyl methyl ether, 1,2-dimethoxy ether (DME), dibutyl ether, tetrahydrofuran, 1,4-dioxane; polar aprotic solvents like N,N-dimethylformamide, N,Ndimethyl acetamide, N-methylpyrrolidone, pyridine, dimethylsulfoxide, sulfolane, formamide, acetamide, propanamide, pyridine and acetonitrile or mixtures thereof. In particular, the solvent is methylene dichloride, 1, 2-dimethoxy ether (DME), dimethylformamide, water,1,4-dioxane, tetrahydrofuran, and acetonitrile or mixtures thereof.

The Neratinib can be obtained by coupling the compound of formula 2 and formula 3 by any known methods in the literature.
Examples:
Example 1
Preparation of ethyl glycinate hydrochloride (5’)

To a suspension of glycine (100.0 g, 1.33 mol) in ethanol (1000 mL) was added dropwise SOCl2 at 0 °C. After the addition was complete, the mixture was heated to reflux and stirred for 6 h. The reaction mixture was cooled to 25 °C, resultant suspension was filtered and the filter cake was washed with hexane and then dried under vacuum to provide ethyl glycinate hydrochloride (130.0 g, 70%)) as a white solid. 1H NMR (DMSO-d6) d 8.57 (brs, 3H), 4.18 (q, 2H), 3.74 (s, 2H), 1.22 (t, 3H); MS: 104.2 [M+H].
Example 2
Preparation of ethyl dimethylglycinate (6’)

Ethyl 2-aminoacetate hydrochloride (130.0 g, 0.28 mol), Formaldehyde (190 mL, 37% aqueous solution), and water (190 mL) were mixed in ethanol (2400 mL). To this mixture 10wt. % Pd on C (25.0 g, 50% wet) was added and reaction mass stirred for 2 h under hydrogen gas atmosphere (40 psi). Reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The concentrated mass was dissolved in water (400 mL) and NaHCO3 (80.0 g) was added. Reaction mass was extracted with EtOAc (2 x 450 mL), organic layer was concentrated to provide ethyl dimethylglycinate (106.0 g) as white solid. 1H NMR (400 MHz, CDCl3): 4.17 (q, 2H), 3.13 (s, 2H), 2.32 (s, 6H), 1.25 (t, 3H); MS: 132.1[M+H]+.
Example 3
Preparation of tert-butyl 4-(dimethyl amino)-3-oxobutanoate (7’)

To a solution of t-butyl acetate (233.8 mL, 1.77 mol) in THF (1300 mL), lithium hexamethyldisilazide (1.0 M in THF) (1616 mL, 1.61 mol) was added slowly at -10 °C through cannula and stirred for 30 minutes. To this reaction mass, a solution of ester 6’ (106.0 gm, 0.81 mol) was added slowly and continued to stir at – 10 °C for 1 hour. Reaction mixture was allowed to reach ambient temperature and then stirred for 12 h. The reaction mass was quenched with aqueous solution of ammonium chloride (91.55.0 g) and stirred for 30 min. Reaction mass was extracted with EtOAc (2 x 1500 mL) and the combined ethyl acetate layer was concentrated to provide tert-butyl 4-(dimethylamino)-3-oxobutanoate (139.0 g, 85%) as oily mass. 1H NMR (400 MHz, CDCl3): 3.38 (s, 2H), 3.21 (s, 2H), 2.28 (s, 6H), 1.45 (s, 9H); MS: 202.3 [M+H]+.
Example 4
Preparation of tert-butyl 4-(dimethylamino)-3-hydroxybutanoate (8’)

Sodium borohydride (28.9 g, 0.0.76 mol) was added portion wise to a stirred solution of tert-butyl 4-(dimethylamino)-3-oxobutanoate (139.0 g, 0.69 mol) in methanol (700 mL) at 0 to 5°C. The reaction was stirred for 30 minutes and then quenched with aqueous solution of ammonium chloride (36.99 g). The resulting mixture was extracted with EtOAc (3 x 750 mL), the organic phases were combined, and concentrated under reduced pressure to give tert-butyl 4-(dimethylamino)-3-hydroxybutanoate (122.0 g, 88%) as oily mass. 1H NMR (400 MHz, CDCl3): 5.42 (brs 1H), 4.11 (m, 1H), 2.54 (m, 2H), 2.40 (s, 6H), 1.46 (s, 9H); MS: 204.3 [M+H]+.
Example 5
Preparation of 4-(dimethylamino)but-2-enoic acid hydrochloride (2)

To a stirred solution of tert-butyl 4-(dimethylamino)-3-hydroxybutanoate (122.0 g, 0.60 mol) and triethyl amine (167.3 mL, 1.2 mol) in DCM (700 mL), methanesulfonyl chloride (51.16 mL) was added slowly at 0 to 5°C and then stirred overnight at ambient temperature. Reaction mass washed with water and then concentrated under reduced pressure to give tert-butyl (E)-4-(dimethylamino) but-2-enoate (78.0 g, 70%) as oily mass. This oily mass was stirred in 1200 mL EtOAc-HCl solution (1.2 molar) for 3 hours at ambient temperature to get a white slurry mass. Solid was filtered, washed with EtOAc (30 mL) and then dried to give 4-(dimethylamino)but-2-enoic acid hydrochloride salt as white solid (68 g). 1H NMR (400 MHz, DMSO-d6): 12.79 (brs, 1H), 11.28 (brs, 1H), 6.8 (m, 1H), 6.18 (d, 1H), 3.88 (d, 2H), 2.76 (s, 6H); 13C NMR (100.6 MHz, DMSO-d6): 165.95, 135.67, 129.39, 56.22, 41.69; MS: (130.1) [M+H]+.
Example 6
Preparation of 4-(1,3-dioxoisoindolin-2-yl)-3-((trimethylsilyl)oxy)butanenitrile (10).

To a solution of epoxyphthalimide (9) (25.0 g, 0.12 mol) in THF (50 mL), LiOH.H2O (3.1 g, 0.07 mol) was added and stirred at ambient temperature for 15-20 min. TMSCN (12.5 g, 0.12 mol) was added to the resultant suspension under ambient temperature and stirred further for 10 min then reaction mass stirred at 75-80oC for overnight. After completion of reaction, reaction mass was cooled to ambient temperature, DM water (100 mL) was added and extracted with EtOAc (150 mL). Organic layer was separated and evaporated under reduced pressure to provide 4-(1,3-dioxoisoindolin-2-yl)-3-((trimethylsilyl) oxy)butanenitrile (10) as a dark solid (34.0 g, 92% yield). 1H NMR: 7.84-7.86 (m, 2H), 7.73-7.75 (m, 2H), 4.26-4.28 (m, 1H), 3.73-3.89 (m, 2H), 0.04-0.12 (m, 9H), 2.51-2.64 (m, 2H); 13C NMR: 168.6, 168.1, 134.1, 133.8, 131.7, 131.6, 123.6, 123.4, 117.2, 66.3, 43.1, 24.0, 0.0, -0.1, -0.6; MS: 303.3 [M+H]+
Example 7
Preparation of 4-amino-3-hydroxybutanoic acid hydrochloride (11).

Solution of 4-(1, 3-dioxoisoindolin-2-yl)-3-((trimethylsilyl)oxy)butanenitrile (10) (34.0 g, 0.11 mol) in conc. HCl (200 mL) was stirred at 75-80 oC for 16 h. After completion of reaction, reaction mass was washed with DCM (200 mL). Aqueous layer was separated and concentrated under reduced pressure to provide 4-amino-3-hydroxybutanoic acid hydrochloride (11) (16.2 g, 93% yield). 1H NMR: 7.87 (brs, 1H), 3.60-3.68 (m, 1H), 3.14 (brs, 1H), 2.81-2.99 (m, 2H), 2.51-2.66 (m, 2H), 1.40 (brs, 2H); 13C NMR: 174.1, 72.8, 46.9, 40.7; MS: 120.2 [M+H]+
Example 8
Preparation of 4-(dimethylamino)-3-hydroxybutanoic acid (12).

To a solution of 4-amino-3-hydroxybutanoic acid hydrochloride (11) (16.0 g, 0.05 mol) in methanol (100 mL) and DM water (30 mL), formaldehyde (16 mL) and Pd/C (50% wet) (1.6 g) were added and stirred at ambient temperature under H2 atmosphere (40 psi). After completion of reaction, the catalyst was filtered through celite and the filtrate was concentrated under reduced pressure to provide 4-(dimethylamino)-3-hydroxybutanoic acid hydrochloride (13) as a white solid (7.6 g, 93% yield). IR: 3401, 2494, 1645, 1582 cm-1; 1H NMR: 11.32 (brs, 1H), 3.77-3.79 (m, 1H), 3.19-3.20 (m, 2H), 2.51-2.52 (m, 2H), 1.24-1.28 (m, 6H); 13C NMR: 174.3, 66.9, 63.2, 45.9, 39.7; MS: 148.2 [M+H]+
Example 9
Preparation of methyl 4-(dimethylamino)-3-hydroxybutanoate (8’’).

To a solution of 4-(dimethylamino)-3-hydroxybutanoic acid (12) (7.6 g, 0.05 mol) in methanol (70 mL), SOCl2 (8.0 ml) was added at 5-10 oC slowly. The reaction mass was stirred at 5-10 oC for 30-45 min and then at ambient temperature for 16 h. After completion of reaction, reaction mass concentrated under reduced pressure to give residue, that was dissolved in water (80 mL), solution basified with NaHCO3 (5.0 g, 0.06 mol) and reaction mass extracted with DCM (2 x 80 mL). Organic layers were mixed, washed with brine and concentrated under reduced pressure to provide methyl 4-(dimethylamino)-3-hydroxybutanoate (8”) (7.5 g, 91% yield).
IR: 3401, 2982, 1644, 1472 cm-1; 1H NMR: 3.85-3.87 (m, 1H), 3.52-3.56 (m, 2H), 3.05-3.12 (m, 3H), 2.61-2.66 (m, 2H), 1.36-1.43 (m, 6H); 13C NMR: 174.9, 67.0, 65.4, 52.3, 48.2, 39.6; MS: 162.1 [M+H]+
Example 10
Preparation of methyl 4-(dimethylamino) but-2-enoate (13’)

To a solution of methyl 4-(dimethylamino)-3-hydroxybutanoate (8”) (7.5 g, 0.046) in DCM (70 mL), Et3N (13.8 mL, 0.1 mol) was added and cooled to 5-10 oC. Methanesulfonyl chloride (4.2 mL, 0.055 mol)) was added to it slowly and stirred at ambient temperature. After completion of reaction, reaction mass was washed with DM water (100 mL). Organic layer was separated and then concentrated under reduced pressure to give methyl 4-(dimethylamino)but-2-enoate (13’) ( 5.3 g, 80%). IR: 2933, 1622, 1446, 1314 cm-1; 1H NMR: 7.52-7.54 (m, 1H), 5.42 (m, 1H), 3.67-3.69 (m, 3H), 2.86-2.97 (m, 6H), 3.10-3.17 (m, 1H); 13C NMR: 168.6, 134.3, 123.5, 66.5, 52.6, 47.8; MS: 144.1 [M+H]+
Example 11
Preparation of tert-butyl (E)-4-(dimethylamino)but-2-enoate Hydrochloride (2)

To a stirred solution of methyl 4-(dimethylamino)but-2-enoate (13’) (5.3 g, 0.037 mol) was dissolved in aq. 2M HCl (50 mL) and was refluxed for 6 h. Reaction mixture was cooled to ambient temperature and concentrated under reduced pressure to provide residue. It was crystalized with IPA (50 mL) to give (E)-4-(dimethylamino)but-2-enoic acid hydrochloride salt (2) as white solid (3.58 g, 75%). 1H NMR (400 MHz, DMSO-d6): 12.80 (brs, 1H), 11.25 (brs, 1H), 6.8 (m, 1H), 6.2 (d, 1H), 3.84 (d, 2H), 2.8 (s, 6H); 13C NMR (100.6 MHz, DMSO-d6): 165.97, 135.61, 129.39, 56.29, 41.72; MS: (130.1) [M+H]+.
Example 12
Preparation of ethyl 4-(benzyl(methyl)amino)-3-hydroxybutanoate

21’ 22
A solution of the ethyl 4-chloro-3-hydroxybutanoate (21’) (50.0 g, 0.3 mol), benzylmethylamine (38.7 ml, 0.3 mol), NaHCO3 (25.2 g, 0.3 mol) in IPA (250 ml) was stirred under nitrogen at 90 °C for 24 hours. The resulting mixture was concentrated in vacuo, diluted with EtOAc, washed with water, brine and then concentrated under reduced pressure to give ethyl 4-(benzyl(methyl)amino)-3-hydroxybutanoate (67.2 g, 91%). 1H NMR (CDCl3): 7.35 (m, 5H), 4.19 (m, 1H), 3.67 (d, 1H), 3.50 (d, 1H), 2.44 (m, 3H), 1.30 (t, 3H); MS: 252.15 [M+H]+
Example 13
Preparation of ethyl 4-(dimethylamino)-3-hydroxybutanoate

22 8a

To a solution of ethyl 4-(benzyl(methyl)amino)-3-hydroxybutanoate (22) (50.0 g, 0.198 mol) in ethanol (500 ml), Pd/C (50% wet) (10.0 g) were added and stirred at ambient temperature under H2 atmosphere (50 psi). After completion of debenzylation, 37% formaldehyde (2.5 ml, 0.25 mol) was added and stirred under H2 atmosphere for 2 h at ambient temperature. The catalyst was filtered through celite and the filtrate was concentrated under reduced pressure to provide ethyl 4-(dimethylamino)-3-hydroxybutanoate (8a) as an oil (25.1 g, 72% yield). 1H NMR (CDCl3): 4.05 (q, 2H), 3.59 (m, 1H), 2.50 (s, 6H), 1.19 (t, 3H); MS: 176.12 [M+H]+
Example 14
Preparation of ethyl 4-(dimethylamino) but-2-enoate.

8a 13’
To a solution of ethyl 4-(dimethylamino)-3-hydroxybutanoate (8a;25.0 g, 0.142 mol) in DCM (250 mL), Et3N (39.5 ml, 0.284 mol) was added and cooled to 0-5 oC. Methanesulfonyl chloride (12.08 ml, 0.156 mol)) was added to it slowly and stirred at ambient temperature. After completion of reaction, reaction mass was washed with DM water (200 ml). Organic layer was separated and then concentrated under reduced pressure to give ethyl 4-(dimethylamino)but-2-enoate (13’; 16.6 g, 74%). 1H NMR (CDCl3): 6.97 (m, 1H), 6.0 (d, 1H), 4.22 (q, 2H), 3.1 (m, 2H), 2.29 (s, 6H), 1.30 (t, 3H); MS: 158.2 [M+H]+.
Example 15
Preparation of ethyl 2,4-diethoxybenzoate (15’)

To a solution of compound 2,4-dihydroxybenzoic acid (14’) (100.0 g, 0.549 mol) in DMSO (400 mL), K2CO3(227.4 g, 1.64 mol) and then EtBr (239.5 g, 2.19 mol) was added at 20 °C. Reaction mixture was stirred at 40 °C for 5 h, it was cooled to rt and diluted with EtOAc (500 mL). Residue obtained was filtered out, filtrate was washed with water (2 x 500 mL) and then concentrated under reduced pressure to give ethyl 2,4-diethoxybenzoate (15’) (122.9 g, 94%) as colorless oil. 1H NMR (CDCl3) d 7.84 (d, 1H), 6.49 (m, 2H), 4.33 (q, 2H), 4.08 (m, 2H), 1.43 (m, 9H); MS: 239.2 [M+H]+.
Example 16
Preparation of ethyl 2,4-diethoxy-5-nitrobenzoate (16’)

A solution of ethyl 2,4-diethoxybenzoate (15’) (122.0 g, 0.512 mol) in conc. H2SO4 (700 ml) cooled at 0 °C, solution of potassium nitrate (62.1 g, 0.615 mol) was added, and then stirring was continued at the same temperature for 2 hours. Reaction mixture was poured into ice cold H2O (5.0 L), solid obtained was filtered out to give ethyl 2,4-diethoxy-5-nitrobenzoate (16’) (94.29 g, 65%) as yellowish solid. ). 1H NMR (DMSO-d6): 8.3 (s, 1H), 6.8 (s, 1H), 4.3-4.2 (m, 6H), 1.40-1.35 (m, 6H), 1.33-1.25 (m, 6H); MS: 284.3 [M+H]+.

Example 17
Preparation of 3-(2,4-diethoxy-5-nitrophenyl)-3-oxopropanenitrile (17’)

To a stirred solution of acetonitrile (43.6 mL, 0.830 mol) in THF (500 mL), lithium di-isopropyl amide (0.697 mol) was added at -20 °C and then ethyl 2,4-diethoxy-5-nitrobenzoate (94.0 g, 0.332 mol) in THF (300 mL) was added at the same temperature. Stirring was continued for 16 h at ambient temperature, quenched with 0.5 N HCl (500 mL) and extracted with EtOAc (500 mL). Organic layer was concentrated to give 3-(2,4-diethoxy-5-nitrophenyl)-3-oxopropanenitrile (83.4 g, 91%) as yellowish solid. 1H NMR (DMSO-d6): 8.3 (s, 1H), 6.8 (s, 1H), 4.50-4.30 (m, 4H), 2.49 (m, 2H), 1.46-1.23 (m, 6H); MS: 279.3 [M+H]+.
Example 18
Preparation of 2-(2,4-diethoxy-5-nitrobenzoyl)-3-methoxyacrylonitrile (18’)

A solution of 2-(2,4-diethoxy-5-nitrobenzoyl)-3-methoxyacrylonitrile (17’) (83.0 g, 0.298 mol) in DMF. dimethylacetamide (166 mL) was stirred at ambient temperature for 4 h. Reaction mixture was poured in water (1.6 L) and extracted with EtOAc (2 x 1 L). Organic layer was concentrated to give 2-(2,4-diethoxy-5-nitrobenzoyl)-3-methoxyacrylonitrile (69.6 g, 70%) as solid. 1H NMR (DMSO-d6): 7.81-7.78 (d ,1H), 6.8 (s,1H), 4.31-4.21 (m, 4H), 3.33 (s, 6H), 1.39-1.26 (m, 6H); MS: 334.2 [M+H]+.
Example 19
Preparation of 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (19’)

To a solution of compound 2-(2,4-diethoxy-5-nitrobenzoyl)-3-methoxyacrylonitrile (18’) (69.0 g, 0.207 mol),K2CO3 (0.21 mole), in EtOH (690 mL), aq. NH3 (35 mL) was added and stirred at 80 °C for 6 h. It was concentrated to give 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (19) (42.9 g, 80%) as yellowish solid. 1H NMR (DMSO-d6): 7.84-7.73 (t, 2H), 6.81(s, 1H), 4.30-4.17 (m, 4H), 1.37-1.28 (m, 6H); MS: 260.1 [M+H]+.
Example 20
Preparation of 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (20A)

A stirred mixture of 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile (42.0 g, 0.162 mol) and 1,2-dimethoxyethane was heated to 80-85 °C. To this was added 27 mL of phosphorus oxychloride over 15-20 minutes. The mixture was stirred at 80-85 °C for 3-4 hours. The mixture was cooled, filtered over a celite pad and washed with 1,2- dimethoxymethane. The filtrates were diluted with EtOAc (200 mL), and washed with potassium carbonate solution. EtOAc layer was concentrated to give 4-chloro-7-ethoxy-6-nitroquinoline-3-carbonitrile (35.0 g, 78%). 1H NMR (DMSO-d6): 8.50-8.47 (d, 2H), 7.19 (s, 1H), 4.27-4.21 (q, 2H), 1.40-1.23 (m, 6H); MS: 278.1 [M+H]+.
Example 21
Preparation of N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (3A)

A mixture of 6-amino-4-chloro-7-ethoxyquinoline-3-carbonitrile (35.0 g, 0.126 mol), iron (35.4 g, 0.631 mol), acetic acid (37.9 g, 0.635 mol), and sodium acetate (10.3 g, 0.126 mol) in 350 mL of methanol were refluxed for 3 h. The hot reaction mixture was filtered, and the solvents were evaporated under reduced pressure. The residue was partitioned between saturated NaHCO3 and EtOAc. The organic layer was separated and concentrated to give residue which was dissolved in acetonitrile (350 ml), K2CO3 and acetyl chloride was added at 0 °C. It was stirred at ambient temperature and then washed with NaHCO3 solution to give N-(4-chloro-3-cyano-7-ethoxyquinolin-6-yl)acetamide (27.0 g 74%). 1H NMR (DMSO-d6): 9.54 (s, 1H), 9.17 (s, 1H), 9.01 (s, 1H), 7.60 (s, 1H), 4.40 (q, 2H), 2.25 (s, 3H), 1.50 (t, 3H); MS: 290.1 [M+H]+.
Example 22
Preparation of ethyl 4-ethoxy-2-fluorobenzoate (15”)

14” 15”
To a solution of compound 2-fluoro-4-hydroxybenzoic acid (13.0 g, 0.083 mol) in DMSO (130 mL), K2CO3(34.5 g, 0.249 mol) and diethylsulphate (32.0 mL g, 0.249 mol) was added and stirred for 5 h at 25 °C. After completion of starting material, it was diluted with EtOAc (300 mL). Residue obtained was filtered out, filtrate was washed with water (2 x 300 mL) and then concentrated under reduced pressure to give ethyl ethyl 4-ethoxy-2-fluorobenzoate (17.0 g, 96%) as colorless oil. 1H NMR (CDCl3) d 7.90 (t, 1H), 6.71 (dd, 1H), 6.62 (dd, 1H), 4.37 (q, 2H), 4.09 (q, 2H), 1.45 (t, 3H), 1.40 (t, 3H); MS: 213.2 [M+H]+.
Example 23
Preparation of ethyl 4-ethoxy-2-fluoro-5-nitrobenzoate

15” 16”
A solution of ethyl 4-ethoxy-2-fluorobenzoate (17.0 g, 0.080 mol) in conc. H2SO4 (51.0 mL) cooled at 0 °C, potassium nitrate (8.09 g, 0.080 mol) was added, and then stirring was continued at the same temperature for 1 h. Reaction mixture was poured into ice cold H2O (200 ml), residue obtained after filtration was crystalized to give ethyl 4-ethoxy-2-fluoro-5-nitrobenzoate (11.33 g, 55%) as yellowish solid. 1H NMR (CDCl3): 8.57 (d, 1H), 6.81 (d, 1H), 4.41 (q, 2H), 4.24 (q, 2H), 1.54 (t, 3H), 1.41 (t, 3H); MS: 258.2 [M+H]+.
Example 24
Preparation of 3-(4-ethoxy-2-fluoro-5-nitrophenyl)-3-oxopropanenitrile

16” 17”
To a stirred solution of acetonitrile (5.6 mL, 0.107 mol) in THF (100 mL), LiHMDS (0.697 mol) was added at -30 to -20 °C, stirred for 30 min and then ethyl 4-ethoxy-2-fluoro-5-nitrobenzoate (11.0 g, 0.042 mol) in THF (30 mL) was added at the same temperature. Stirring was continued for 5 h at ambient temperature, quenched with 0.5 N HCl (50 mL) and extracted with EtOAc (200 mL). Organic layer was concentrated to give 3-(4-ethoxy-2-fluoro-5-nitrophenyl)-3-oxopropanenitrile (9.70 g, 90%) as yellowish solid. 1H NMR (CDCl3): 8.57 (d, 1H), 6.88 (d, 1H), 4.30 (q, 2H), 4.08 (s, 2H), 1.57 (t, 3H); MS: 253.2 [M+H]+.
Example 25
Preparation of 3-(dimethylamino)-2-(4-ethoxy-2-fluoro-5-nitrobenzoyl)acrylonitrile (4)

17” 18”

A solution of 3-(4-ethoxy-2-fluoro-5-nitrophenyl)-3-oxopropanenitrile (9.0 g, 0.035 mol) in THF (50 mL) and DMF.DMA (12.7 mL, 0.107 mol) was stirred at ambient temperature for 4 h. Reaction mixture was poured in water (200 mL) and extracted with EtOAc (2 x 200 mL). Organic layer was concentrated to give 3-(dimethylamino)-2-(4-ethoxy-2-fluoro-5-nitrobenzoyl)acrylonitrile (7.45 g, 68%) as solid. 1H NMR (CDCl3): 8.16 (d, 1H), 7.97 (s, 1H), 6.82 (d, 1H), 4.22 (q, 2H), 3.51 (s, 3H), 3.36 (s, 3H), 1.53 (t, 3H); MS: 307.2 [M+H]+.
Example 26
Preparation of 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile

18” 19
To a solution of compound (E)-3-(dimethylamino)-2-(4-ethoxy-2-fluoro-5-nitrobenzoyl)acrylonitrile (7.0 g, 0.022 mol), in 4 M NH3/MeOH (70 mL), K2CO3 (6.0 g, 0.044) was added and stirred at 80 °C for 6 h. It was concentrated to give 7-ethoxy-6-nitro-4-oxo-1,4-dihydroquinoline-3-carbonitrile ( 4.48 g, 76%) as yellowish solid. 1H NMR (DMSO-d6): 7.84-7.73 (t, 2H), 6.81(s, 1H), 4.30-4.17 (m, 4H), 1.37-1.28 (m, 6H); MS: 260.1 [M+H]+.
,CLAIMS:1. A process for the preparation of compound of formula 3

wherein X is a halogen; comprising:
i) reacting compound of formula 16 with acetonitrile in presence of a base to obtain compound of formula 17:

wherein LG is leaving group;
ii) reacting compound of formula 17 with dimethylacetamide to obtain compound of formula 18;

iii) cyclizing of compound 18 in presence of base to obtain compound of formula 19;

iv) halogenating compound of formula 19 to obtain compound of formula 20; and

v) reducing the compound of formula 20 and isolating compound of formula 3

vi) optionally acetyl protecting the compound of formula 3 to obtain compound of formula 3A

2. The process according to claim 1 wherein the base for step (i) and step (iii) can be selected from lithium diisopropylamide, trimethylamine or sodium hydroxide.
3. The process according to claim 1, wherein the step (v) can be performed in the presence reducing agent selected from iron; sodium borohydride or lithium borohydride.
4. A process for the preparation of compound of formula 2

comprising:
i) reacting compound of formula 6 with alkyl acetate to give compound of formula 7:

wherein R is alkyl group;
ii) reducing compound of formula 7 in the presence of reducing agent; to obtain a compound of
formula 8; and

iii) converting compound of formula 8 to compound of formula 2.

5. The process according to claim 4, wherein the reaction of step (i) and (iii) can be carried out in the presence of a base selected from trimethylamine, sodium hydroxide or potassium hydroxide.
6. The process according to claim 4, wherein the step (ii) can be performed in presence of reducing agent selected from sodium borohydride or lithium borohydride.
7. A process for preparation of compound of formula 2

comprising:
i) reacting compound of formula 9 with trimethylsilylcyanide in presence of a base to give compound of
formula 10;

ii) hydrolyzing compound of formula 10 in the presence of a acid to give compound of formula 11;

iii) alkylating compound of formula 11 in the presence of a metal catalyst and a base to give compound of formula 12;

iv) esterify compound of formula 12 to give ester compound of formula 8;

wherein R is alkyl group
v) converting compound of formula 8 to compound of formula 13 in the presence of base;


vi) hydrolysis of compound of formula 13 and isolating compound of formula 2

8.The process according to claim 7, wherein the catalyst used for step-(iii) can be selected from to palladium-on-charcoal (Pd/C), platinum-on-charcoal (Pt/C) or ruthenium-on-charcoal (Ru/C).
9. The process according to claim 7, wherein step-(iv) can be performed in the presence of alcohol selected from methanol, ethanol or isopropanol.
10. The process according to claim 7, wherein the step-(vi) can be performed in presence of base selected from lithium hydroxide; potassium carbonate or sodium hydroxide.
11. A process for preparation of compound of formula 2

comprising:
i) reacting compound of formula 21 with benzylmethylamine in the presence of base to obtain a compound of formula 22:

wherein X is a halogen; R is alkyl group;
ii) reacting compound of formula 22 in the presence of reducing agent to obtain a compound of formula 8;

iii) converting compound of formula 8 to compound of formula 13 in the presence of base;

iv) hydrolysis of compound of formula 12 and isolating compound of formula 2

12. The process according to claim 11, wherein the base used in step-(i) and step-(iii) can be selected from trimethylamine, sodium hydroxide or potassium hydroxide.
13. The process according to claim 11, wherein the reducing agent used for step-(ii) can be selected from palladium-on-charcoal (Pd/C), platinum-on-charcoal (Pt/C) or ruthenium-on-charcoal (Ru/C).
14. The process according to claim 11, wherein step (iv) can be performed in the presence base selected from lithium hydroxide, potassium carbonate or sodium hydroxide.

15. Intermediate compounds of formula 7, 8, 10, 11,13,17,18, 22:

;

;
;
;
;


wherein R is alkyl group; LG is leaving group.