Claims:WE CLAIM:
1. An improved process for the preparation of Neratinib maleate of Formula (I), comprising the steps of:

Formula I

a) reacting the (E)-4-(dimethylamino)-2-butenoic acid hydrochloride of formula (IV),

Formula IV

with oxalyl chloride in the presence of DMF catalyst in chlorinated solvent to produce (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of formula (IVa);

Formula IVa

b) reacting the compound of Formula (IVa) with 4-[4-(2-pyridylmethoxy)-3- chloro]amino-6-amino- 3-cyano-7-ethoxy-quinoline of Formula (III)

Formula III
in presence of suitable solvent to produce Neratinib base of formula (Ia).

Formula Ia
c) purifying Neratinib base of formula Ia in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula II.

Formula II
d) treating the Neratinib DMSO solvate of formula II with maleic acid in suitable solvent to produce Neratinib maleate of formula-I.

2. The process as claimed in claim 1, wherein the chlorinated solvent used in step-(a) is selected from dichloromethane, chloroform or mixture thereof. wherein suitable solvent used in step-(b) is selected from N-methyl-2-pyrrolidinone, dimethyl acetamide or mixture thereof.

3. The process as claimed in claim 1, wherein the suitable solvent used in step-(d) is selected from the keto solvent and alcohol solvents, water or mixture thereof.

4. A process for the preparation of crystalline Form-I of Neratinib maleate, comprising steps of:
a) treating the Neratinib DMSO solvate with maleic acid in aqueous keto solvent;
b) triturating the wet produt of step-(a) in alcoholic solvent.

5. The process as claimed in claim 4, wherein aqueous keto solvent used in step-(a) is selected from acetone, ethyl methyl ketone, methyl iso butyl ketone and methyl amyl ketone or mixture thereof; and the alcohol solvent used in step-b) is selected from methanol, propanol, isopropanol, ethanol or mixture thereof.

6. Neratinib DMSO solvate of formula (II), which is used in the preparation of Neratinib maleate of formula (I).

7. A crystalline form of Neratinib DMSO solvate of formula (II) is characterised by:
a) its powder X-ray diffractogram having peaks at 4.09, 5.76, 5.96, 8.47, 11.90, 12.23, 16.32 , 16.63, 16.96, and 17.89 ±0.2° degrees of two-theta;
b) having the endotherm at 173°C±5°C in its differential scanning calorimetric (DSC) thermogram;
c) absorption peaks at 3316.80, 3287.14, 2945.72, 2770.40, 2209.92, 1672.89, 1624.60, 1544.59, 1504.46, 1459.34, 1435.63, 1397.46, 1288.98, 1222.73 and 1033.03 cm-1 in its infrared spectrum.

8. A process for the preparation of crystalline form of Neratinib DMSO solvate, comprising the steps of:
a) reacting the (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of Formula (IVa),

Formula IVa

with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quino- line of Formula (III),

Formula III
in the presence of suitable solvent to produce Neratinib base of formula (Ia).

Formula Ia
b) purifying Neratinib base of formula Ia in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).


Formula II

wherein, the Neratinib DMSO solvate of formula II having purity >99.5% by HPLC.

9. The process as claimed in claim 8, wherein the suitable solvent used in step-(a) is selected from N-methyl-2-pyrrolidinone, dimethyl acetamide or mixture thereof.

10. The process as claimed in claim 1, wherein the HPLC purity of Neratinib Maleate of formula I is >99.5%.
, Description:FIELD OF THE INVENTION
The present invention relates to an improved process for preparation of Neratinib maleate Formula (I) and intermediate thereof.

Formula I

BACKGROUND OF THE INVENTION
Neratinib Maleate is chemically known as (E)-N-{4-[3-chloro-4-(pyridin-2-yl methoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl}-4-(dimethylamino)but-2-enamide maleate. It is a kinase inhibitor indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Neratinib Maleate was approved in 2017 by USFDA. It is marketed in the form of oral tablets under the brand name Nerlynx® by Puma Biotechnology.
US Patent No. 6288082 discloses Neratinib generically.
US Patent No. 7399865 discloses Neratinib and its pharmaceutically acceptable salts.
US 7399865 discloses a process for the preparation of Neratinib base of Formula (Ia) by reaction of (E)-4-(dimethylamino)-2-butenoic acid hydrochloride of formula (IV) with oxalyl chloride in the presence of N,N-dimethylformamide as a catalyst in tetrahydrofuran followed by reaction with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy- quinoline of Formula (III) in the presence of N-methyl-2-pyrrolidinone and Aq. NaOH in acetonitrile and THF solvent mixture to produce Neratinib base of Formula (Ia).
The synthetic procedure is illustrated in Scheme-I as below:

Scheme-I

The process disclosed in US 7399865 suffers from the following disadvantages outlined below:
1) Acid chloride (Formula IVa) is found less stable in tetrahydrofuran and it is
deteriorating with progress of reaction with time.
2) It is observed that about 25% of amine compound (Formula III) left unreacted when the reaction is conducted for about 8 hours in tetrahydrofuran during monitoring.
3) Purification of crude Neratinib base in acetonitrile / tetrahydrofuran solvents resulted about 98% purity only and limit for specified impurities (Not more than 0.15%) and unspecified impurities (Not more than 0.10%) is not accomplished.
US 20060270669 discloses a process for the preparation of Neratinib maleate (I) by treating with maleic acid in 5% water/n-propanol mixture at about the temperature of 50-60oC followed by recrystallized from 7.5% water/n-propanol mixture to produce Neratinib maleate (I).

The synthetic procedure is illustrated in Scheme-II as below:
Scheme-II
The process disclosed in US 20060270669 suffers from the following disadvantages outlined below:
1) Neratinb maleate has relatively more solubility in aqueous propanol.
2) Recrystallization of maleic acid in 7.5% aqueous propanol resulted low yield (67% only).
3) Lengthy reaction duration (12-15 h) is observed.
4) Residual solvent content is observed 3000-8000PPM and it required high drying temperature conditions to achieve the limit.
US 20060270668 discloses a process for the preparation of Neratinib maleate (I) by treating with maleic acid in 10% water/n-propanol mixture at about the temperature of 40-50oC followed by recrystallized from 10% water/n-propanol mixture to produce Neratinib maleate (I).
The synthetic procedure is illustrated in Scheme-III as below:
Scheme-III
The process disclosed in US 20060270668 suffers from the following disadvantages outlined below:
1) Neratinib maleate has relatively more solubility in aqueous propanol.
2) Recrystallization of maleic acid in 7.5% aqueous propanol resulted low yield (67% only) and it can be reduced further in 10% aqueous propanol.

CN 105949176 A discloses a method for purifying Neratinib, characterized in that the method comprises the following steps:
1) the crude Neratinib is mixed with dimethyl sulfoxide and tetrahydrofuran, and stirred;
2) heating to 50-90 ° C and stirring to obtain a suspension;
3) cooling the suspension to 20-30°C and maintaining agitation at this temperature;
4) Filtration, washing the filter cake with water, and drying to obtain a product.

The process disclosed in CN 105949176 A suffers from the following disadvantages outlined below:
1) Purification is described twice, (i) tetrahydrofuran and acetonitrile solvents and (ii) DMSO/THF.
2) Two purifications can result low yield.

Hence, there exists a need to have simple, easy to handle and cost effective process for the preparation of Neratinib maleate of Formula (I) and intermediate thereof with high chemical purity and higher yield.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide a simple and cost effective process for the preparation of Neratinib maleate of Formula (I) and intermediate thereof with high purity and good yield on a commercial scale.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Neratinib maleate of Formula (I), comprising the steps of:

Formula I

a) reacting the (E)-4-(dimethylamino)-2-butenoic acid hydrochloride of formula (IV),

Formula IV

with oxalyl chloride in the presence of DMF catalyst in chlorinated solvent to produce (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of formula (IVa)

Formula IVa

b) reacting the compound of Formula (IVa) with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quinoline of Formula (III)

Formula III
in the presence of suitable solvent to produce Neratinib base of formula Ia.

Formula Ia
c) purifying Neratinib base of formula (Ia) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).

Formula II
d) treating the Neratinib DMSO solvate of formula (II) with maleic acid in suitable solvent to produce Neratinib maleate (I).
The present invention further provides a process for the preparation of crystalline form-I of Neratinib maleate, comprising steps of:
a) treating the Neratinib DMSO solvate with maleic acid in aqueous keto solvent;
b) Triturating the wet product of step-(a) in alcoholic solvent.
The present invention relates to Neratinib DMSO solvate of formula (II), which is used in the preparation of Neratinib maleate of formula (I).
The present invention further provides crystalline form of Neratinib DMSO solvate of formula (II) is characterised by powder X-ray diffraction (PXRD) containing 2T peaks (±0.2°) at 4.09, 5.76, 5.96, 8.47, 11.90, 12.23, 16.32 , 16.63, 16.96, and 17.89.
The present invention further provides a process for the preparation of crystalline form of Neratinib DMSO solvate, comprising the steps of:
a) reacting the (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of Formula (IVa),

Formula IVa

with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quino- line of Formula (III),

Formula III

in the presence of suitable solvent to produce Neratinib base of formula (Ia).

Formula Ia
b) Purifying Neratinib base of formula (I) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).

Formula II

BRIEF DESCRIPTION OF THE DRAWINGS
Figure-1: Illustrates the characteristic PXRD pattern of crystalline Form of Neratinib DMSO solvate.
Figure-2: Illustrates the DSC thermogram of crystalline Form of Neratinib DMSO solvate.
Figure-3: Illustrates the TGA of crystalline Form of Neratinib DMSO solvate.
Figure-4: Illustrates the IR of crystalline Form of Neratinib DMSO solvate.
Figure-5: Illustrates the characteristic PXRD pattern of crystalline Form-I of Neratinib Maleate salt.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of Neratinib maleate of Formula (I), comprising the steps of:
a) reacting the (E)-4-(dimethylamino)-2-butenoic acid hydrochloride of formula (IV), with oxalyl chloride in the presence of DMF catalyst in chlorinated solvent to produce (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of formula (IVa);
b) reacting the compound of Formula (IVa) with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quinoline of Formula (III) in the presence of suitable solvent to produce Neratinib base of formula (Ia).

c) purifying Neratinib base of formula (I) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).
d) treating the Neratinib DMSO solvate of formula (II) with maleic acid in suitable solvent to produce Neratinib maleate (I).
The chlorinated solvent used in step a) is selected from dichloromethane, chloroform or mixture thereof preferably dichloromethane.

In step (a) of the present invention, the reaction may be performed usually from 5°C to 10oC for 4 hours to 5 hours, preferably 5°C for 4 hours to 5 hours. The obtained compound of formula (IVa) may be used in the next reaction directly or optionally after further purification.
In step (b) of the present invention, suitable solvent is selected from N-methyl-2-pyrrolidinone, dimethyl acetamide or mixture thereof, preferably N-methyl-2-pyrrolidinone.

In step (b) of the present invention, reacting the compound of Formula (IVa) with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quinoline of Formula (III) in the presence of N-methyl-2-pyrrolidinone solvent to produce Neratinib base of formula (Ia).

In step (b) of the present invention, the reaction may be performed usually from 0°C to 10°C for 2 hours, preferably 5°C
In step (c) of the present invention, the purifying Neratinib base of formula (I) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).
In step (c) of the present invention, the reaction may be performed usually from 70°C to 75°C for 30 min to 20-30°C for 3-4 hours
In step (c) of the present invention, the HPLC purity of Neratinib DMSO solvate of formula (II) obtained after purification process is >99.5%.
In step (d) of the present invention, treating the Neratinib DMSO solvate of formula (II) with maleic acid in suitable solvent to produce Neratinib maleate of formula (I).
In step (d) of the present invention, suitable solvent is selected from water, keto solvents and alcohol solvents or mixture thereof preferably aqueous acetone.

In step (d) of the present invention, the reaction may be performed usually from 20-30°C for 3-4 hours, preferably 25°C.

In step (d) of the present invention, the HPLC purity of Neratinib maleate of formula (I) obtained after purification process is >99.5%.

The present invention further provides crystalline Form-I of Neratinib maleate, comprising steps of:
a) Treating the Neratinib DMSO solvate with maleic acid in aqueous keto solvent;
b) triturating the wet product of step-(a) in alcoholic solvent.
The keto solvent used in step a) is selected from acetone, ethyl methyl ketone, methyl iso butyl ketone and methyl amyl ketone or mixture thereof preferably acetone.
In step (a) of the present invention, the reaction may be performed usually from 20°C to 30oC for 3-4 hours, preferably 25°C for 3-4 hours.

The alcohol solvent used in step b) is selected from methanol, ethanol, propanol, isopropanol, tert-butylalcohol, isoamylalcohol, 2-methoxyethanol or mixture thereof preferably methanol.

In step (b) of the present invention, the reaction may be performed usually from 20°C to 30oC for 1 hour to 1½ hours, preferably 25°C for 1 hour to 1½ hours.

Crystalline Form-I of Neratinib maleate obtained in above process is characterised by powder X-ray diffraction (PXRD) containing 2T peaks (±0.2°) at 6.06, 7.29, 8.13, 8.65, 10.1, 12.15, 12.51 , 13.56, 14.55, 15.64, 16.16, 17.29, 18.56, 19.88, 20.21, 20.50, 21.16, 22.19, 22.7, 23.8, 24.5, 25.3, 25.8, 26.4, 27.3, 26.46, and 29.25 and same has been illustrated in figure- 5
The present invention relates to Neratinib DMSO solvate of formula (II), which is used in the preparation of Neratinib maleate of formula (I).
The present invention further provides crystalline form of Neratinib DMSO solvate of formula (II) is characterised by powder X-ray diffraction (PXRD) containing 2T peaks (±0.2°) at 4.09, 5.76, 5.96, 8.47, 11.90, 12.23, 16.32 , 16.63, 16.96, and 17.89 and same has been illustrated in figure-1.
Further, Neratinib DMSO solvate of formula (II) is characterized by its differential scanning calorimetric (DSC) thermogram which is showing first endotherm at about 173±5°C, and the second endotherm at about 140±5°C and the same has been illustrated in figure- 2.
The Neratinib DMSO solvate of formula (II) is further characterized by its thermo gravimetric analysis (TGA) thermogram which is showing weight loss of 0.03194% and same has been illustrated in figure-3.
The Neratinib DMSO solvate of formula (II) is further characterized by its Infrared spectrum (IR) absorption peaks at 3316.80, 3287.14, 2945.72, 2770.40, 2209.92, 1672.89, 1624.60, 1544.59, 1504.46, 1459.34, 1435.63, 1397.46, 1288.98, 1222.73 and 1033.03 cm-1 and same has been illustrated in figure-4.
The present invention further provides a process for the preparation of crystalline form of Neratinib DMSO solvate, comprising the steps of:
a) reacting the (E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of Formula (IVa) with 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quino- line of Formula (III), in the presence of suitable solvent to produce Neratinib base of formula (Ia).
b) purifying Neratinib base of formula (I) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).
In step (a) of the present invention, suitable solvent is selected from N-methyl-2-pyrrolidinone, dimethyl acetamide or mixture thereof, preferably N-methyl-2-pyrrolidinone.

In step (a) of the present invention, the reaction may be performed usually from 0°C to 10°C for 2 hours, preferably 5°C
In step (b) of the present invention, the purifying Neratinib base of formula (I) in-situ from DMSO and THF solvent mixture to produce Neratinib DMSO solvate of formula (II).
In step (b) of the present invention, the reaction may be performed usually from 70°C to 75°C for 30 min. to 20-30°C for 3-4 hours.
In step (b) of the present invention, the HPLC purity of Neratinib DMSO solvate of formula (II) obtained after purification process is >99.5%.

Advantages of present invention:
1) Developed acid to acid chloride conversion in dichloromethane solvent resulting in stable acid chloride formation (Formula-IVa) affording not detected level or <0.5% of amine compound (Formula-III) which has practical applicability in commercial scale.
2) Developed the process adopting single purification process in DMSO/THF solvents (1.5:1.0, 12 Vol.) resulting about 77.5% yield and >99.5% purity with specified impurity level of not more than 0.15% and unspecified impurity level of not more than 0.10%.
3) Developed preparation of maleate salt in aqueous acetone solvent in 3-4 hours with 89% yield and >99.5% purity with specified impurity level of not more than 0.15% and unspecified impurity level of not more than 0.10%.
4) Developed the process to achieve residual solvent content limit <300 PPM in the pharma.
The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.
Example-1: Preparation of ((E)-4-(dimethylamino)-2-butenoic acid chloride hydrochloride of Formula (IVa)
(E)-4-(dimethylamino)but-2-enoic acid (Formula-IV, 81.72g, 2.0 m. eq.) was added to methylene chloride (500 mL) at 20-30°C followed by catalytic amount of dimethyl formamide (3.3g) under nitrogen atmosphere. Thereafter, cooled the suspension to 0-5°C added oxalyl chloride (51.22g, 1.8 m. eq.) at 0-10°C and maintained the reaction mass for 4-5h. The progress of reaction was monitored by HPLC and cooled the reaction mass to 0-5°C after completion of reaction.
Example-2: Preparation of (E)-N-[4-[3-chloro-4-(2-pyridylmethoxy)-anilino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-but-2-enamide of Formula (Ia).
A solution of 4-[4-(2-pyridylmethoxy)-3-chloro]amino-6-amino-3-cyano-7-ethoxy-quino- line of Formula-III (100 g, 1.0 m. eq.) in N-methyl pyrrolidinone solvent was added to the above acid chloride of Formula-IVa reaction mass and stirred the reaction mass for about 2h. The progress of the reaction was monitored by HPLC to achieve unreacted amine content of Formula-III <2.0%. After completion of reaction, the thick suspension of hydrochloride salt of coupled product is quenched with DM water at 0-10°C. The MDC layer was separated and added tetrahydrofuran to the aqueous layer and adjusted pH to 9-10 with 20%w/v aqueous sodium hydroxide solution. The crystallized product was filtered to achieve wet crude product.
Example-3: Purification of Neratinib base (DMSO solvate of formula (II)):
The crude wet product obtained above was purified from mixture of dimethyl sulfoxide and tetrahydrofuran to afford (E)-N-[4-[3-chloro-4-(2-pyridylmethoxy)-anilino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-but-2-enamide DMSO solvate of Formula-II: 110g (77.5% as Neratinib base, HPLC purity >99.5%) as a light cream to yellow colored crystalline solid.
Yield: 77.5%; Purity: >99.5%
Example-4: Preparation of (E)-N-[4-[3-Chloro-4-(2-pyridylmethoxy) anilino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)but-2-enamide Maleate of Formula (I).
Neratinb base (75.0 g) was added to 5.0% v/v particle free aqueous acetone (528 mL) at 20-30°C in a multi-neck round bottom flask. Added particle free Maleic acid solution to the above suspension and heated the reaction mass to 45-50°C for about 30 min. The reaction mass was gradually cooled to 20-30°C and stirred for about 4h. The precipitated product was filtered and triturated with methanol to afford (E)-N-[4-[3-chloro-4-(2-pyridylmethoxy)-anilino]-3-cyano-7-ethoxy-6-quinolyl]-4-(dimethylamino)-but-2-enamide maleate of Formula-I: 69g (87% based on Neratinib base input on 100% assay, HPLC purity >99.5%).
Yield: 89%; Purity: >99.5%