DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF AFATINIB DIMALEATE AND ITS INTERMEDIATES

INTRODUCTION
The present application relates to process for preparation of afatinib, its intermediates and its salts thereof.
The drug compound having the adopted name afatinib dimaleate, has a chemical name N-[4-[(3-chloro-4-fluorophenyl)amino]7-[[(3S)-tetrahydro-3-furanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-,(2E)-, (2Z)-2-butenedioate (1:2), and is represented by structure of formula I.

Formula I
Afatinib dimaleate is an anticancer protein kinase inhibitor indicated for treatment of non-small-cell lung cancer. Process for preparation of afatinib, afatinib dimaleate and intermediates useful in preparation of afatinib dimaleate are described in US Patent Nos. 7,019,012; 8,426,586 and 7,960,546.

SUMMARY OF THE INVENTION
The present application provides processes for preparation of afatinib, its intermediates and its acid addition salts thereof, specifically afatinib dimaleate salt.
In one aspect, the present application provides a process for preparation of formula VI or an acid addition salt thereof comprising
(a) hydrolyzing an alkyl ester of compound of formula VII using a hydrolase enzyme to form compound of formula VI,

(b) optionally, converting the compound of formula VI to its acid addition salt.
Where in R1 and R2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, substituted or unsubstituted aryl or heteroaryl, or R1 and R2 together with the nitrogen to which they are attached form a nitrogen containing heteroaryl or cycloheteroalkyl; R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
In another aspect, the present application provides a process for preparation of formula VI-A or an acid addition salt thereof comprising
(a) hydrolyzing an alkyl ester of compound of formula VII-A using a hydrolase enzyme to form compound of formula VI-A,

(b) optionally, converting the compound of formula VI-A to its acid addition salt.
Where in R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
In another aspect, the present application provides a process for preparation of afatinib or an acid addition salt thereof comprising
(a) hydrolyzing an alkyl ester of compound of formula VII-A using a hydrolase enzyme to form compound of formula VI-A,

(b) optionally, converting the compound of formula VI-A to its acid addition salt,
(c) reacting the compound of formula VI-A or its acid addition salt thereof with a compound of formula III to form afatinib of formula II

(d) optionally, converting afatinib of formula II to its acid addition salt.
In another aspect, the present application provides a process for preparation of afatinib dimaleate, comprising:
(a) providing a mixture of afatinib base and acetonitrile,
(b) adding a solution of maleic acid and acetonitrile into the mixture of step (a), and
(c) isolating afatinib dimaleate.
In another aspect, the present application provides afatinib or its acid addition salts having less than about 0.2% of its R-isomer.
In another aspect, the present application provides afatinib dimaleate having less than about 0.2% of its R-isomer.
The present application also encompasses the use of Afatinib dimaleate prepared by the process described herein for the preparation of a medicament, preferably for the treatment of cancer, particularly for the treatment of cancers mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases. The present invention further provides a pharmaceutical composition comprising Afatinib di-maleate of the present invention and at least one pharmaceutically acceptable excipient.
The present application also provides a method of treating cancer, comprising administering a therapeutically effective amount of Afatinib dimaleate of the present invention, or at least one of the above pharmaceutical compositions to a person suffering from cancer, particularly a person suffering from a cancer mediated by epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinases, e.g., solid tumors including but not limited to NSCLC, breast, head and neck cancer, and a variety of other cancers mediated by EGFR or HER2 tyrosine kinases.

DETAILED DESCRITPION
In one aspect, the present application provides a process for preparation of formula VI or an acid addition salt thereof comprising
(a) hydrolyzing of compound of formula VII using a hydrolase enzyme to form compound of formula VI,

(b) optionally, converting the compound of formula VI to its acid addition salt.
Where in R1 and R2 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, substituted or unsubstituted aryl or heteroaryl, or R1 and R2 together with the nitrogen to which they are attached form a nitrogen containing heteroaryl or cycloheteroalkyl; R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
The process involves enzymatic hydrolysis of compound of formula VII using a hydrolase enzyme such as lipase, esterase and protease enzyme and using a suitable solvent.
In one aspect, the compound of formula VII is methyl (E)-4-(dimethylamino)but-2-enoate and the hydrolase enzyme is Candida Antarctica Lipase B (CALB).
In another aspect, the compound of formula VII is methyl (E)-4-(piperidin-1-yl)but-2-enoate and the hydrolase enzyme is Candida Antarctica Lipase B (CALB).
The enzyme can be in the form of powder or in the form of liquid or in the form of immobilized.
The solvent used in the enzymatic hydrolysis is selected from methanol, ethanol, isopropanol, THF, acetonitrile, di-isopropyl ether, toluene and water. The enzyme used in the hydrolysis of compound of formula VII is from about 1 wt % to about 100 wt % to the compound of formula VII. The hydrolysis is carried out at about 0° C. to about 100° C.
After completion of the reaction the reaction mass may be neutralized with a suitable base and is extracted with a suitable solvent to get compound of formula VI.
Optionally, the compound of formula VI is treated with an appropriate acid to get an acid addition salt of compound of formula VI.
The compound of formula VI or an acid addition salt thereof prepared by the above process is used for the synthesis of afatinib or an acid addition salt thereof.
In another aspect, the present application provides a process for preparation of afatinib or an acid addition salt thereof comprising
(a) hydrolyzing an ester of compound of formula VII-A using a hydrolase enzyme to form compound of formula VI-A,

(b) optionally, converting the compound of formula VI-A to its acid addition salt,
(c) reacting the compound of formula VI-A or its acid addition salt thereof with a compound of formula III to form afatinib of formula II

(d) optionally, converting afatinib of formula II to its acid addition salt.
Where in R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
The compound of formula VI-A or an acid addition salt thereof is prepared by the process described above. The compound of formula VI-A or its salt is reacted with a compound of formula III in presence of an acid activating group and a suitable base to get afatinib or an acid addition salt thereof.
The suitable acid activating group used is selected from the group comprising of thionyl chloride, oxalyl chloride, carbonyl diimidazole, dicyclohexyl carbodiimide, 1-hydroxybenzotriazole, N-hydroxy succinimide, 1-hydroxy-7-azobenzotriazole and the like.
The suitable base used in the reaction is selected from the group comprising of an organic base such as diethylamine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, N-methylpyrrolidine, pyridine, 2,6-Lutidine and the like; inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate and the like or their mixtures thereof.
The suitable solvent used in the reaction is selected from the group comprising of halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride and the like; C1-C5 alcohols such as methanol, ethanol, isopropanol, tertiary butanol and the like; ether solvent such as diethyl ether, tertiary butyl methyl ether, tetrahydrofuran and the like; nitrile solvent such as acetonitrile, propionitrile and the like; ester solvent such as ethylacetate, isopropyl acetate and the like; amide solvent such as N,N-dimethyl formamide, N,N-dimethyl acetamide, N-methyl pyrrolidone and the like; sulfoxide solvent such as dimethylsulfoxide, dimethylsulfoxide and the like; and a mixture thereof.
The compound of formula VI-A, suitable base, suitable solvent and the acid activating reagent are reacted first, and then reacting the activated acid with the compound of formula III at a temperature of about 0° C. to about 100° C. for a period of 1 hour to about 20 hours. The compound of formula VI-A is used at the ratio of about 1.0 mole equivalents to about 5 mole equivalents to the compound of formula III.
After completion of the reaction, the reaction mass may be neutralized or may be basified using a suitable base. The organic solvent may be removed from the reaction mixture and residue is diluted with water and the compound of formula II may be isolated from the aqueous mass. The compound of formula II may be isolated as an acid addition salt by treating the compound of formula II with an appropriate acid.
The compound of formula III may be prepared by the processes known in the art or the compound of formula III may be prepared by the process described in this application.

In one aspect, the compound of formula II is treated with maleic acid and is isolated as afatinib dimaleate.
In another aspect, the present application provides a process for preparation of afatinib dimaleate, comprising:
(a) providing a mixture of afatinib base and acetonitrile,
(b) adding a solution of maleic acid and acetonitrile into the mixture of step (a), and
(c) isolating afatinib dimaleate.
The step (a) of the process involves providing a mixture of afatinib base and acetonitrile solvent. The mixture may be stirred for about 10 minutes to about 10 hours.
The step (b) of the process involves addition of a solution of maleic acid and acetonitrile. The maleic acid solution is prepared by adding maleic acid into acetonitrile and dissolving the maleic acid in the acetonitrile solvent. The maleic acid solution is added to the mixture of step (a) at a temperature of about 10° C to about 70° C. After addition, the mixture may be stirred for about 10 minutes to about 10 hours at a temperature of about 10° C to about 70° C.
The step (c) involves isolation of afatinib dimaleate. The isolation can be by using the processes known in the art such filtration by gravity.
The resulting compound obtained in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 60°C, less than about 50°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the afatinib dimaleate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours
In another aspect, the present application provides the compound of formula II prepared by the process described in this application contains less than 0.2% of its R-isomer.
In one aspect, the present application provides the compound of formula II is treated with maleic acid and is isolated as afatinib dimaleate salt having less than 0.2% of afatinib R-isomer.
The present application further encompasses 1) a pharmaceutical composition comprising Afatinib di-maleate having less than 0.2% of (R)-isomer, as described above, and at least one pharmaceutically acceptable excipient; and 2) the use of Afatinib di-maleate having less than 0.2% of (R)-isomer, in the manufacture of a pharmaceutical composition, and 3) a method of treating a solid tumor such as NSCLC, breast, head and neck cancer, and a variety of other cancers, comprising administration of an effective amount of a pharmaceutical composition comprising Afatinib di-maleate having less than 0.2% of (R)-isomer described herein.
Although the exemplified procedures herein illustrate the practice of the present invention in some of its embodiments, the procedures should not be construed as limiting the scope of the invention. Modifications from consideration of the specification and examples within the ambit of current scientific knowledge will be apparent to one skilled in the art.
Definitions
The following definitions are used in connection with the present application unless the context indicates otherwise.
All percentages and ratios used herein are by weight of the total composition, unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise and all measurements are made at 25oC and normal pressure unless otherwise designated. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
Terms such as "about," "generally," "substantially," or the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure", it generally means, unless specified otherwise, that the material is 99% pure or more, as determined by methods conventional in art such as high performance liquid chromatography (HPLC) or optical methods. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities, and unreacted starting materials. In the case of stereoisomers, "pure" also means 99% of one enantiomer or diastereomer, as appropriate. "Substantially" pure means, the same as "pure except that the lower limit is about 98% pure or more and likewise, "essentially" pure means the same as "pure" except that the lower limit is about 95% pure.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES
Example 1: Preparation of Trans-4-(dimethylamino)but-2-enoic acid hydrochloride by enzymatic hydrolysis
Water (30 mL) and methyl (E)-4-(dimethylamino)but-2-enoate hydrochloride (20 gm) were charged into 500 mL round bottomed flask. The pH of the solution was adjusted to 7.5 by adding aqueous potassium carbonate (10 gm of potassium carbonate was dissolved in 10 mL of water). Immobilized Candida Antarctica Lipase B (2 gm) was charged into the flask at 25° C and pH of the reaction mass was maintained 7.5 by adding aqueous potassium carbonate. The reaction mass was stirred for 5 hours at 25° C. Reaction progress was monitored by TLC. After completion of the reaction the reaction mass was diluted with methanol and filtered through celite. The filtrate was concentrated under vacuum to remove methanol. Isopropanol (100 mL) was charged and the resultant solution was concentrated under vacuum to remove water and the resultant was diluted with 100 mL of isopropanol and pH was adjusted to 6.2 with IPA hydrochloric acid. The solution was filtered through hi-flow and the filtrate was concentrated under vacuum. The residue was added to IPA hydrochloric acid (30 mL) and resultant solution was cooled to 5° C. and stirred for 2 hours at 5° C. The precipitation was filtered and wet cake was washed with pre-cooled isopropanol and dried under vacuum at 40°C to get 11 gm of the title compound as white powder.

Example 2: Preparation of Trans-4-(dimethylamino)but-2-enoic acid hydrochloride by enzymatic hydrolysis
Water (75 mL) and methyl (E)-4-(dimethylamino)but-2-enoate hydrochloride (50 gm) were charged into 500 mL round bottomed flask. The pH of the solution was adjusted to 7.5 by adding aqueous potassium carbonate (25 gm of potassium carbonate was dissolved in 25 mL of water). Immobilized Candida Antarctica Lipase B ((4.5 gm) (2 gm of recovered enzyme and 2.5 gm of fresh enzyme)) was charged into the flask at 25° C and pH of the reaction mass was maintained 7.5 by adding aqueous potassium carbonate. The reaction mass was stirred for 8 hours at 25° C. Reaction progress was monitored by TLC. After completion of the reaction the reaction mass was filtered through Celite. The enzyme taken into water (25 mL) and stirred for 10 minutes and filtered through Celite. Both the filtrates were mixed and pH adjusted to 6.5 using isopropanolic HCl (8 mL). The reaction mass was chased with isopropanol (8 ? 250 mL). The reaction mass was cooled to 5°C and isopropanolic HCl (8 mL) was added and stirred for 10 minutes. The precipitation was filtered and wet cake was washed with isopropanol (50 mL) and suction dried under nitrogen atmosphere. The wet cake was taken in isopropanol (250 mL) and stirred for 2 hours at 30°C. The precipitation was filtered and wet cake was washed with isopropanol (50 mL) and suction dried under nitrogen atmosphere. The solid dried under vacuum at 65°C to get 34.5 gm of the title compound as white powder.
Purity: 98.5% by HPLC, Cis isomer: not detected.

Example 3: Preparation of Trans-4-(dimethylamino)but-2-enoic acid hydrochloride by enzymatic hydrolysis
Water (125 mL) and methyl (E)-4-(dimethylamino)but-2-enoate hydrochloride (100 gm) were charged into 1000 mL round bottomed flask. The pH of the solution was adjusted to 7.5 by adding aqueous potassium carbonate (50 gm of potassium carbonate was dissolved in 50 mL of water). Immobilized Candida Antarctica Lipase B (10 gm)) was charged into the flask at 25° C and pH of the reaction mass was maintained 7.5 by adding aqueous potassium carbonate. The reaction mass was stirred for 20 hours at 25° C. Reaction progress was monitored by TLC. After completion of the reaction the reaction mass was filtered through Celite and the enzyme was washed with water (25 mL). The filtrate pH was adjusted to 6.5 using isopropanolic HCl (15 mL). The reaction mass was chased with isopropanol (8 ? 300 mL). The reaction mass was cooled to 5°C and isopropanolic HCl (50 mL) was added and stirred for 10 minutes. The precipitation was filtered and wet cake was washed with isopropanol (100 mL) and suction dried under nitrogen atmosphere. The wet cake was taken into isopropanol (500 mL) and stirred for 8 hours at 30°C. The precipitation was filtered and wet cake was washed with isopropanol (100 mL) and suction dried under nitrogen atmosphere. The solid dried under vacuum at 65°C to get 70.2 gm of the title compound as white powder.
Purity: 99.97% by HPLC, Cis isomer: 0.01%.

Example 4: Preparation of Trans-4-(dimethylamino)but-2-enoic acid hydrochloride by enzymatic hydrolysis
Water (1.88 Ltr) and methyl (E)-4-(dimethylamino)but-2-enoate hydrochloride (1.5 Kg) were charged into 10 Ltr round bottomed flask. The pH of the solution was adjusted to 7.5 by adding aqueous potassium carbonate (0.750 Kg of potassium carbonate was dissolved in 750 mL of water). Candida Antarctica Lipase B (150 gm)) was charged into the flask at 25° C and pH of the reaction mass was maintained 7.5 by adding aqueous potassium carbonate. The reaction mass was stirred for 20 hours at 25° C. Reaction progress was monitored by TLC. After completion of the reaction the reaction mass was filtered through filter paper and the enzyme was washed with water (380 mL). The filtrate was taken into another flask and chased with isopropanol (7.5 Ltr ? 8) until to get moisture content below 1%. Isopropanolic HCl (3 Ltr) was charged into another flask and cooled to 5°C. The reaction mass was added to pre cooled Isopropanolic HCl and stirred for 1 hour at 5°C. The precipitation was filtered and wet cake was suction dried under nitrogen atmosphere. The wet cake was taken into MTBE (7.5 Ltr) and stirred for 2 hours at 30°C. The precipitation was filtered and wet cake was suction dried under nitrogen atmosphere. The solid dried under vacuum at 65°C for 6 hours to get 1.215 kg of the title compound as white powder.
Purity: 99.28% by HPLC, Cis isomer: Not detected

Example 5: Preparation of Trans-4-(dimethylamino)but-2-enoic acid hydrochloride by chemical hydrolysis
Potassium carbonate solution (prepared by dissolving 94 gm of potassium carbonate in 300 mL of water) and Methyl (E)-4-(dimethylamino)but-2-enoate hydrochloride (100.0g) were charged into a 1000 mL round bottom flask and the solution was stirred for 10 minutes. The free base was extracted into MTBE (300 mL ? 4). MTBE layer dried over anhydrous Na2SO4 and concentrated to dryness at 50 °C and the residue was diluted with 100 mL of water. Prepared sodium hydroxide solution (27g in 100 mL) and added slowly to above reaction mass at 0-5 °C. Maintained the reaction mass at 5°C for 1.5 hours. Reaction mass pH was adjusted to 8.5 using IPA HCl (165 mL). Reaction mass was chased with IPA (2 ? 800 mL) and then with (7 ? 500 mL), during the chasings maintained 6-8 volumes remained in the RBF. To the residue 500 mL of IPA was added at 28°C and moisture content was checked (water content is below 1.0% w/w). In another round bottom flask charged 160 mL of IPA.HCl and cooled to 0-10 C and added above reaction mass. Filtered at 5°C and wet cake was washed with 100 mL of IPA and 200 mL of MTBE under nitrogen atmosphere. Wet cake and MTBE 400 mL was charged in another RBF and stirred at 28°C for 1 hour. The suspension was filtered and the wet cake was washed with 100 mL of MTBE and suction dried under nitrogen atmosphere. Wet cake and methanol (200 mL) were charged in another RBF and stirred at 28°C for 3 hours and added 500 mL of MTBE and stirred for 1 hour and the suspension was filtered. Wet cake was washed with 100 mL of MTBE and suction dried under nitrogen atmosphere. The solid was dried under vacuum tray drier for 8 hours at 65°C to get 73.6 gm of the title compound as white powder.
Purity: 99.3% by HPLC, Cis impurity: Not detected.

Example 6: Preparation of (S)-N-(3-chloro-4-fluorophenyl)-6-nitro-7-((tetrahydrofuran-3-yl)oxy)quinazolin-4-amine (compound of formula IV)
Potassium tertiary butoxide (183.3 gm) and N,N-dimethylformamide (550 mL) were charged into 2000 mL round bottomed flask at 27°C. The mixture was cooled to 0°C and stirred for 15 minutes. (S)-3-Hydroxy tetrahydrofuran (34.02 gm) was added slowly over a period of 10 minutes and the resulted mixture was stirred for 30 minutes at 0°C. N-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine (100 gm) was added portion-wise over a period of 30 minutes and resulted mixture was stirred for 1 hour at 0°C. Reaction progress was monitored by HPLC. After completion of the reaction water (2000 mL) was added slowly and the resulted solution was stirred for 30 minutes at 27°C and pH of the mas was adjusted to 7.4 with 2N aqueous hydrochloric acid (300 mL). The resulted mixture was stirred for 1 hour at 28°C. The precipitation was filtered and solid was washed with water (800 mL) and the solid was dried under vacuum at 60°C to obtain 114 gm of light yellow colored solid. Purity: 98.28% by HPLC
The solid (110 gm), methanol (2000 mL) and acetonitrile (500 mL) were charged into a 5000 mL round bottomed flask at 27°C. The mixture was heated to 65°C and stirred for 2 hours at 65°C. The mixture was cooled to 27°C and stirred for 1 hour. The precipitation was filtered and the solid was washed with methanol (200 mL) and the solid was dried under vacuum at 60°C to obtain 97 gm of white solid.
Purity: 99.62%; Chiral purity: 99.83% (S-isomer), 0.17% (R-isomer).

Example 7: Preparation of (S)-N4-(3-chloro-4-fluorophenyl)-7-((tetrahydrofuran-3-yl)oxy)quinazoline-4,6-diamine (compound of formula III)
Compound of formula IV (500 gm), ethylacetate (10 Ltrs), Raney Nickel (100 gm) and water (100 mL) were charged into a clean 20 Ltrs autoclave and the autoclave was flushed with nitrogen gas and 7 Kg of hydrogen gas pressure was applied in the auto clave. The autoclave was heated to 33°C and maintained the temperature and hydrogen gas pressure for 5 hours. After completion of the reaction the hydrogen gas was removed and the reaction mixture was flushed with nitrogen gas. The reaction mixture was unloaded and filtered through a celite bed and the celite bed was washed with ethylacetate (1000 mL). The filtrate was concentrated under vacuum at 50°C up to 2 volumes. n-Heptane (5 Ltrs) was charged into the reaction mixture and the resulted mixture was concentrated under vacuum at 50°C up to 5 volumes and stirred for 30 minutes at 28°C. The precipitation was filtered and the solid was washed with n-heptane (1000 mL) and the solid was dried under vacuum at 50°C to obtain 400 gm of solid.
The solid (400 gm), acetonitrile (2765 mL) and water (2765 mL) were charged into a 10 Ltr round bottomed flask at 27°C. The mixture was heated to 82°C and maintained for 30 minutes. The mixture was cooled to 27°C and stirred for 2 hours. The precipitation was filtered and the solid was washed with a mixture of acetonitrile and water (100 mL of acetonitrile and 800 mL of water) and the solid was dried under vacuum at 60°C for 20 hours to obtain 329 gm of white solid.
Purity: 99.95%; Chiral purity: 99.98% (S-isomer); 0.02% (R-isomer).

Example 8: Preparation of Afatinib base ((S,E)-N-(4-((3-chloro-4-fluorophenyl) amino)-7-((tetrahydrofuran-3-yl)oxy)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide (compound of formula II))
Trans-4-(dimethylamino)but-2-enoic acid hydrochloride (8.8 gm), acetonitrile (100 mL) and N,N-dimethylformamide (0.5 mL) were charged under nitrogen atmosphere into 500 mL round bottomed flask at 27°C. The reaction mass was cooled to 0°C. Oxalyl chloride (7.4 gm) was added slowly at 0°C and the temperature of the reaction mas was raised to 28°C and stirred for 2 hours. The reaction mass was cooled to 0°C and a solution of compound of formula III (10 gm of compound of formula III was dissolved in 100 mL of acetonitrile and 60 mL of NMP) was added. Temperature of the reaction mass was raised to 28°C and stirred for 2 hours. After completion of the reaction the reaction mass was cooled to 0°C and saturated lithium hydroxide solution (50 mL) was added slowly and acetonitrile was distilled out completely under vacuum. The crude was taken into another 1000 mL round bottom flask and water (500 mL) was slowly added the mixture was stirred for 12 hours at 28°C. The precipitation was filtered and washed with water (100 mL) and the solid was dried under vacuum at 50°C to yield 11 gm of white solid. Purity: 95.05% by HPLC.
Afatinib base ((compound of formula II), 11 gm) and acetonitrile (132 mL) were charged into 500 mL round bottom flask and the mixture was heated to 85°C and stirred until clear solution formed. Water (275 mL) was added at 85°C and stirred for 30 minutes. The suspension was cooled to 30°C and stirred for 1 hour. The precipitation was filtered and washed with water (110 mL) and the solid was dried under vacuum at 50°C to yield 7.2 gm of white solid. Purity: 99.75% by HPLC; Chiral purity: 99.93% (S-isomer); 0.07% (R-isomer).

Example 9: Preparation of Afatinib dimaleate
Afatinib base (2 gm) and acetonitrile (30 mL) were charged into 100 mL round bottom flask and then maleic acid solution (1.02 gm of maleic acid in 30 mL of acetonitrile) added at 30°C. The mass was stirred for 2 hours at 30°C. The precipitation was filtered and washed with acetonitrile (10 mL) and the solid was dried under vacuum at 50°C to yield 2.6 gm of white solid. Purity: 99.87% by HPLC.
,CLAIMS:CLAIMS
We claim:
1. A process for preparation of formula VI-A or an acid addition salt thereof, comprising:
(a) hydrolyzing an alkyl ester of compound of formula VII-A using a hydrolase enzyme to form compound of formula VI-A,

(b) optionally, converting the compound of formula VI-A to its acid addition salt.
where in R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
2. The process according to claim 2, wherein R is methyl.
3. The process according to claim 2, wherein the hydrolase enzyme is Candida Antarctica Lipase B.
4. A process for preparation of afatinib or an acid addition salt thereof comprising
(a) hydrolyzing an alkyl ester of compound of formula VII-A using a hydrolase enzyme to form compound of formula VI-A,

(b) optionally, converting the compound of formula VI-A to its acid addition salt,
(c) reacting the compound of formula VI-A or its acid addition salt thereof with a compound of formula III to form afatinib of formula II

optionally, converting afatinib of formula II to its acid addition salt.
where in R is alkyl, alkenyl, cycloalkyl, cycloalkenyl or aralkyl.
5. The process according to claim 4, wherein the hydrolase enzyme is Candida Antarctica Lipase B.
6. The process according to claim 4, wherein the afatinib acid addition salt is afatinib dimaleate.
7. Afatinib or its acid addition salts having less than about 0.2% of its R-isomer.
8. Afatinib dimaleate having less than about 0.2% of its R-isomer.
9. A process for preparation of afatinib dimaleate, comprising:
(a) providing a mixture of afatinib base and acetonitrile,
(b) adding a solution of maleic acid and acetonitrile into the mixture of step (a), and
(c) isolating afatinib dimaleate having less than about 0.2% of its R-isomer.
10. A pharmaceutical composition comprising Afatinib di-maleate having less than about 0.2% of its (R)-isomer and at least one pharmaceutically acceptable excipient.