PRIORITY

[0001] This application claims the benefit of Indian Provisional Applications 202021023049 filed on June 02, 2020, entitled “PROCESS FOR PREPARATION OF VERAPAMIL” the contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for the preparation of verapamil and salts thereof.

BACKGROUND OF THE INVENTION

[0003] Verapamil hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) indicated for the treatment of hypertension, to lower the blood pressure.

[0004] The chemical name of verapamil hydrochloride is (±)-benzeneacetonitrile, a-[3-[[2- (3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy -a-(l-methylethyl) monohydrochloride, depicted by the compound of formula I.

I

[0005] The verapamil hydrochloride obtained by processes known in the art was noted to have high content of a dimer impurity (A) and des methyl verapamil in pharmaceutically unacceptable content. Thus there was a need to prepare an economically viable process. The present invention provides a process for verapamil hydrochloride, a compound of formula I, which is cost effective, industrially feasible and provides verapamil hydrochloride free of unwanted impurities such as the dimer impurity A and des methyl verapamil.

SUMMARY OF THE INVENTION

[0006] In one embodiment, the present invention provides a process for the preparation of verapamil hydrochloride, a compound of formula I,

I the process comprising: a) treating verapamil, a compound of formula IA, with alkyl haloformate and/or sodium dihydrogen phosphate to obtain verapamil, wherein the level of one or more of the impurities des methyl verapamil and/or dimer impurity A is less than 1% w/w, as determined by HPLC; and b) treating the obtained verapamil with hydrochloric acid in a solvent to obtain verapamil hydrochloride, the compound of formula I.

DETAILED DESCRIPTION OF THE INVENTION [0007] In one embodiment, the present invention provides a process for the preparation of verapamil hydrochloride, a compound of formula I,

I the process comprising: a) treating verapamil, a compound of formula IA,

IA with alkyl haloformate and/or sodium dihydrogen phosphate to obtain verapamil, wherein the level of one or more of the impurities des methyl verapamil and/or dimer impurity A is less than 1% w/w, as determined by HPLC; and

A b) treating the obtained verapamil with hydrochloric acid in a solvent to obtain verapamil hydrochloride, the compound of formula I.

[0008] In one embodiment, in step a) reaction mixture comprising verapamil, desmethyl verapamil and dimer impurity A in an organic solvent is treated with sodium hydrogen phosphate.

[0009] The reaction mixture when treated with aqueous sodium di hydrogen phosphate, the dimer impurity A is removed. After removal of dimer impurity A, the reaction mixture is further treated with alkyl haloformate wherein the desmethyl impurity is converted into corresponding carbonate derivatives and are then separated from the reaction mixture - esme y verapam Desmethyl verapamil derivative

[0010] The desmethyl impurities may be either O-des methyl verapamil or N-desmethyl verapamil and may be represented by below structure:

[0011] In one embodiment, the alkyl haloformate is selected from the group consisting of Ci-Ce alkyl haloformate, wherein halo is chloro, bromo or iodo.

[0012] In one embodiment, the alkyl haloformate is selected from the group consisting of methyl chloroformate, ethyl chloroformate, propyl chloroformate, isopropyl chloroformate, and the like.

[0013] The solvent of the reaction mixture may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert- butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.

[0014] In one embodiment, in step a) it was surprisingly noted that the reaction mixture comprising verapamil, desmethyl verapamil and dimer impurity A, when treated with sodium dihydrogen phosphate removes the dimer impurity A; further treatment of reaction mixture with alkyl haloformate removes the des methyl impurity.

[0015] In one embodiment, in step a) the reaction mixture prior to treatment with sodium dihydrogen phosphate and alkyl haloformate, is having verapamil with a purity content less than 95% w/w; and the des methyl impurity and/or the dimer impurity A content more than 1 % w/w, as measured by HPLC.

[0016] In one embodiment, in step a) the reaction mixture prior to treatment with sodium dihydrogen phosphate and alkyl haloformate, is having verapamil with a purity content less than 95% w/w; and the des methyl impurity and/or the dimer impurity A content more than l%w/w, unknown impurity and/or single max impurity content is more than 1% w/w, as measured by HPLC.

[0017] In one embodiment, in step b) the verapamil obtained from step a) is treated with hydrochloric acid in an organic solvent.

[0018] In one embodiment, in step b) the verapamil obtained from step a) is treated with hydrochloric acid in non-aqueous organic solvent.

[0019] In one embodiment, the solvent used may be selected from the group consisting of C6-C12 aromatic hydrocarbon such as toluene, xylene, cyclohexane and the like; Ci-Ce alcohol such as methanol, ethanol, isopropyl alcohol, butyl alcohol, isobutyl alcohol and the like; C2-C6 aliphatic ether such as diethyl ether, tetrahydrofuran, methyl t-butyl ether, dioxane, tetrahydrofuran and the like; C2-C6 aliphatic ester such as ethyl acetate, isopropyl acetate, butyl acetate; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; dimethyl sulfoxide; dimethyl acetamide; or mixtures thereof.

[0020] In yet another embodiment, in step b) it was surprisingly noted that the yield of verapamil hydrochloride, obtained after treatment of reaction mixture comprising verapamil with sodium dihydrogen phosphate and alkyl haloformate is more than 90% with a purity of at least 96% w/w as measured by HPLC.

[0021] In one embodiment, verapamil or salt thereof may be purified by any method known in the art. The method, may involve any of the techniques, known in the art, including recrystallization, column chromatography, extraction, filtration, slurrying in solvent, precipitation from a solvent, and the like.

[0022] In one embodiment, verapamil or salt thereof may be purified by dissolving in a solvent system and recrystallizing.

[0023] In one embodiment, the present invention provides a process wherein verapamil HC1, the compound of formula I is purified by recrystallizing from a solvent or mixture thereof. [0024] In one embodiment, verapamil or salt thereof may be purified by dissolving in a solvent system and adding an anti-solvent.

[0025] In one embodiment, the solvent is selected from the group consisting of C6-C12 aromatic hydrocarbon, Ci-Ce alcohol such as ethanol, methanol, isopropanol, n-propanol and the like; C2-C6 aliphatic ester such as ethyl acetate, isopropyl acetate, butyl acetate and the like; C2-C6 aliphatic ether such as tetrahydrofuran, dioxane, methyl tert butyl ether and the like; and mixtures thereof. In one embodiment, the anti-solvent may be selected from the group consisting of toluene, xylene, ethyl acetate, methyl tert-butyl ether, isopropyl alcohol, n-butanol, isopropyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, di isopropyl ether, methylene dichloride, heptane, hexane, water and mixtures thereof and the like.

[0026] In one embodiment, the present invention provides a process for preparing verapamil hydrochloride the process comprising: a) treating verapamil, a compound of formula IA,

IA with alkyl haloformate and/or sodium dihydrogen phosphate to obtain verapamil, wherein the level of one or more of the impurities des methyl verapamil and/or dimer impurity A is less than 1% w/w, as determined by HPLC; and

A b) treating the obtained verapamil with hydrochloric acid in a solvent to obtain verapamil hydrochloride, the compound of formula I with purity greater than 96% as measure by HPLC and yield greater than 90%.

[0027] In one embodiment the present invention provides a process, wherein verapamil, the compound of formula IA,

IA is prepared by the process comprising the steps of: p) reacting a compound of formula V with l-bromo-3-chloropropane a compound of formula IV, Cl ^/ ' ^/N Br

V IV to obtain a compound of formula III; and

III q) reacting a compound of formula III with a compound of formula II,

III II in presence of a base and a solvent to obtain verapamil, the compound of formula IA. [0028] In one embodiment, the present invention provides a process, wherein reaction of the compound of formula V with l-bromo-3-chloropropane in step ‘p’, may be carried out in presence of a phase transfer catalyst.

[0029] In one embodiment, the phase transfer catalyst may be selected from the group consisting of tetra butyl ammonium bromide (TBAB), benzyltriethyl ammonium chloride (TEBA), cetyltrimethyl ammonium bromide, cetylpyridinium bromide, N-benzyl quininium chloride, tetra butyl ammonium chloride, tetra butyl ammonium hydroxide, tetra butyl ammonium iodide, tetraethyl ammonium chloride, benzyltributyl ammonium chloride, hexadecyltriethyl ammonium chloride, tetra methyl ammonium chloride, hexadecyltrimethyl ammonium chloride and octyltrimethyl ammonium chloride.

[0030] In one embodiment, the present invention provides a process, wherein the reaction of the compound of formula V with l-bromo-3-chloropropane in step ‘p’, may be carried out in presence of a solvent.

[0031] In one embodiment, the solvent may be selected from the group consisting of C6-C12 aromatic hydrocarbon, water, acetone, methylethylketone, methylisobutylketone, water, N, N-dimethylformamide, N, N-dimethylacetamide and mixtures thereof.

[0032] In one embodiment, the C6-C12 aromatic hydrocarbon solvent may be selected from the group consisting of toluene, xylene, and mixture thereof.

[0033] In one embodiment, the present invention provides a process, wherein the reaction of the compound of formula V with l-bromo-3-chloropropane in step ‘p’, may be carried out at a temperature of about 10°C to about 100°C.

[0034] In one embodiment, the reaction of a compound of formula V with l-bromo-3- chloropropane may be carried out in presence of a base.

[0035] In one embodiment, the reaction of the compound of formula V with l-bromo-3- chloropropane in step ‘p’, may be carried out at a temperature of about 10°C to about 80°C. [0036] In one embodiment, the reaction of the compound of formula V with l-bromo-3- chloropropane in step ‘p’, may be carried out at a temperature of about 10°C to about 60°C. [0037] In one embodiment, the reaction of the compound of formula V with l-bromo-3- chloropropane in step ‘p’, may be carried out at a temperature of about 10°C to about 40°C. [0038] In one embodiment, the reaction of the compound of formula V with l-bromo-3- chloropropane in step ‘p’, may be carried out at a temperature of about 10°C to about 20°C. [0039] In one embodiment, the base used in step ‘q’ may be selected from the group consisting of organic base, inorganic base, and mixture thereof.

[0040] In one embodiment, the organic base may be selected from the group consisting of amines such as trialkyl amine such as trie thy lamine, diisopropylethylamine (DIPEA); heterocyclic amine such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5- diazabicyclo[4.3.0]non-5 5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO) pyridine, pyrimidine, 4-(dimethylamino)pyridine (DMAP); cyclic aliphatic amine such as cyclohexyl amine, dicyclohexyl amine, piperidine, piperazine, trialkyl amine, heterocyclic amine, Ci-Ce aliphatic amine, C6-C12 aryl alkyl amines, C6-C12 aryl amines and the like; Ci-Ce aliphatic amine may be selected from the group consisting of methyl amine, propyl amine, n- butylamine and the like; C6-C12 aryl alkylamine may be selected from the group consisting of benzyl amine, phenyl ethyl amine, and the like; the C6-C12 aryl amine may be selected from the group consisting of aniline and the like.

[0041] In one embodiment, the organolithiums may be selected from the group consisting of methyl lithium, n-butyl lithium, t-butyl lithium and the like; tetraalkylammonium hydroxide may be selected from the group consisting of tetrabutylammonium hydroxide (TBAH), tetramethylammonium hydroxide and the like; the phosphonium hydroxide may be selected from the group consisting of tetra butyl phosphonium hydroxide and the like.

[0042] The inorganic base may be selected from the group consisting of metal alkoxides, metal carbonates, metal bicarbonates, metal hydroxides, metal amides, wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium, cesium and magnesium and the like.

[0043] In one embodiment, the present invention provides a process, wherein the reaction of the compound of formula III with the compound of formula II in step ‘q’ is carried out in situ.

[0044] In one embodiment, the reaction of a compound of formula III with the compound of formula II in step ‘q’ may be carried out using sodamide as a base.

[0045] In one embodiment, the compound of formula III may be isolated in step ‘a’ and reacted with the compound of formula II in step ‘q’.

[0046] In one embodiment, verapamil, the compound of formula IA may be converted to verapamil hydrochloride, the compound of formula I, without isolating the compound of formula IA.

[0047] In one embodiment, verapamil, the compound of formula IA may be isolated and further converted to verapamil hydrochloride, the compound of formula I.

[0048] In one embodiment, the present invention provides verapamil hydrochloride, the compound of formula of I,

I having a purity content of at least 99% as determined by HPLC.

[0049] In one embodiment, the present invention provides verapamil hydrochloride, the compound of formula of I,

I wherein the level of des methyl verapamil and dimer impurity A,

A is less than 5% w/w of the compound of formula I, as determined by HPLC.

[0050] In one embodiment, the present invention provides verapamil hydrochloride, the compound of formula of I, wherein the level of des methyl verapamil and dimer impurity A, is less than 2% w/w of the compound of formula I, as determined by HPLC.

[0051] In one embodiment, the present invention provides verapamil hydrochloride, the compound of formula of I, wherein the level of des methyl verapamil and dimer impurity A, is less than 1% w/w of the compound of formula I, as determined by HPLC.

[0052] In one embodiment, the present invention provides verapamil hydrochloride, the compound of formula of I, wherein the level of des methyl verapamil and dimer impurity A, is less than 0.15% w/w of the compound of formula I, as determined by HPLC.

[0053] In one embodiment, the present invention provides an oxalate salt of compound of formula III, a compound of formula ITT A.

IIIA

[0054] In one embodiment, the present invention provides a process wherein the compound of formula V may be prepared as depicted in scheme I.

(3 ,4-dimethoxyphenyl) 2-(3 ,4-dimethoxyphenyl) Reflux acetonitrile ethanamine

CH ₃ dimethoxyphenyl)

-N-[(Z)- phenylmethyliden sulphate e] ethanamine

Scheme I

[0055] In one embodiment, the 2-(3,4-Dimethoxyphenyl)acetonitrile reacts with Hydrogen in the presence of Raney Nickel and Aq. ammonia and isopropyl alcohol or methanol to form 2-(3,4-Dimethoxy phenyl)ethanamine. This reacts with benzaldehyde, dimethyl Sulphate in toluene followed by treatment with sodium hydroxide in water and hydrochloric acid to form 2-(3,4-Dimethoxy phenyl)-N-methylethanamine.

[0056] In one embodiment, the compound of formula II may be obtained by the below scheme

CN

"°y Paraformaldehyde^^ ~CN Isopropyl bromide Sodium cyanide Dimethyl sulfoxide

1,2-Dimethoxy benzene

II

[0057] The present invention provides verapamil hydrochloride as characterized and analysed by following techniques:

[0058] A] HPLC Method: High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting purity: Column: XBridge C18, 250 X 4.6mm, 5m; Column temperature: 30°C (±1°C);

Sample cooler temperature: 5°C ; Mobile Phase: Mobile phase A = Buffer: Acetonitrile (90:10, V/V); Buffer: 0.02M di-Potassium hydrogen phosphate and adjusted to pH 6.80 ±0.02with 10% ortho-phosphoric acid (v/v) in water ; Mobile phase B = Acetonitrile (100%); Diluent: (1) Water: Acetonitrile (70: 30, v/v) ;Diluent: (2) Water: Acetonitrile (90: 10, v/v); Flow Rate: 1.0 mL/minute ; Detection wavelength: UV 278 nm ; Injection Volume: 20 mL [0059] The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention.

EXAMPLES

[0061] Example 1: Preparation of 3-Chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]-N- methylpropan-1 -amine (III)

In a round bottom flask, sodium hydroxide (4 lg) was dissolved in water (30ml) and cooled to about 5°C to about 10°C followed by addition of 2-(3,4-dimethoxyphenyl)ethyl]-N- methylamine (V, lOOg) and tetrabutyl ammonium bromide (3.3g, TBAB). To this reaction mass, l-bromo-3-chloropropane (IV, 108.8g) was added over about 2h to about 3h and stirred for about 15h to about 18h at about 10°C to about 15°C. After completion of the reaction, toluene and water was added at about 10°C to about 15°C and stirred for about lOmin to about 15min. Cone hydrochloric acid (108g) was added to the reaction mass to bring pH to

1-2.This was stirred for about 20min to about 30min. The organic layer was separated. The aqueous layer was cooled to about 10°C to about 15°C, toluene was added followed by addition of 50% aq. sodium hydroxide solution to bring pH of reaction mass to 13-14. The toluene layer was separated, washed with water, 20% aqueous sodium chloride and distilled under vacuum at about 45°C to about 50°C to obtain oily mass (130g).

HPLC purity: 93.85%; dimer impurity A: 2.49%, 2-(3, 4-dimethoxyphenyl) ethyl]-N- methylamine: 0.38%, single max impurity: 0.95%.

[0062] Example 2: Prepartion of 2-(3,4-dimethoxyphenyl)-5-[[2-(3, 4-dimethoxyphenyl) ethyl](methyl)amino]-2-(propan-2-yl)pentanenitrile (Verapamil, IA)

2-(3,4-dimethoxyphenyl)-3-methylbutanenitrile (II, 106.65g) was charged in toluene (200ml) and sodamide (24g) was added under nitrogen atmosphere at about 20°C to about 30°C and stirred at about 40°C to about 45°C. A solution of compound III (130g dissolved in 100ml toluene) was slowly added to the reaction mass, simltaneously increasing the temperature to about 60°C to about 65°C. The reaction mass was stirred at about 95°C to about 110°C for about 3h to about 5h. After completion of the reaction, reaction mass was cooled to about 20°C to about 30°C, methanol, water and toluene were added. The reaction mass was stirred for about 30min and layers were seperated. HPLC purity: 80.79%, dimer impurity: 0.9%, O-desmethyl impurity:0.39%, single max impurity: 8.12%. The organic layer was washed with water, 2% aquoeus sodium dihydrogen phosphate. The organic layer had purity:93.85%, dimer impurity: 0.01%, des methyl impurity :0.32%, single max impurity: 2.49% as measured by HLC. The organic layer was again washed with water, 20% aqueous sodium hydroxide solution was added to it and stirred for about lOmin at about 20°C to about 30°C. Methyl chloroformate was added to toluene layer and stirred for about 2h to about 3h at about 25°C to about 30°C. Water was added to the reaction mass and layers were separated. The organic layer was again washed with water and distilled under vacuum at about 50°C to about 55°C to obtain verapamil (IA, 208.5g). Yield:95.95%; HPLC purity 97.31%, dimer impurity A:ND, O-desmethyl verapamil: 0.26%, single max impurity: 0.92%.

[0063] Example 3: Preparation of 2-(3,4-dimethoxyphenyl)-5-[[2-(3,4- dimethoxyphenyl) ethyl](methyl)amino]-2-(propan-2-yl)pentanenitrile hydrochloride (Verapamil hydrochloride, I)

Verapamil (IA, 208.5g) was charged in toluene (800ml) and stirred for about lOmin to about 15min at about 20°C to about 30°C. Hydrochloric acid (12% w/w in ethylacetate, 168ml) was slowly added to the reaction mass, while maintaining the temperature at about 20°C to about 30°C. The reaction mass was stirred at about 20°C to about 25°C for about 4h. The reaction mas was filtered, solid was washed with toluene. The wet cake was dried under vaccum at about 45°C to about 55°C to obtain verapamil hydrochloride (I, 210g). Percentage Yield:93.20%, HPLC purity:98.63%; O-desmethyl verapamil: 0.12%; single max impurity: 0.24%.

[0064] Eample 4: Preparation of Verapamil hydrochloride (I)

Verapamil hydrochloride (I, 210g) was charged in ethyl acetate (525ml), methanol (63ml), heated to about 55°C to about 65°C and filtered through whatman paper. The reaction mass was heated to about 55°C to about 65°C and then slowly cooled to about 20°C to about 30°C and stirred for about 3h to about 4h, further cooled to about 0°C to about 5°C and stirred for about lh. The reaction mass was filtered and the solid was washed with ethylacetate. The wet cake was dried under vaccum at about 45°C to about 55°C for about 12h to about 15h to obtain verapmail hydrochoride (I, 184.8g). Percentage Yield:88.0%; HPLC purity :99.78%; O-desmethyl verapamil 0.05%; single max impurity: 0.05%.

[0065] Example 5: Preparation of Verapamil hydrochloride (I) In a round bottom flask, sodium hydroxide (40.97g) was dissolved in water (30ml) and cooled to about 5°C to about 10°C. The compound V (lOOg) and tetra butyl ammonium bromide (3.30g, TBAB) was added to the reaction mass under stirring l-bromo-3- chloropropane (108.8g) was added to the reaction mass over a time of about 2h to about 3h and stirred for about 15h to about 18h at about 10°C to about 15°C. After completion of the reaction, toluene, water was added to the reaction mass at about 10°C to about 15°C and stirred for about lOmin to about 15min. Cone hydrochloric acid (108g) was added to the reaction mass and stirred for about 20min to about 30min (pH of reaction mass was 1-2). The organic layer was separated. The aqueous layer was cooled to about 10°C to about 15°C, toluene was added followed by addition of 50% aq. sodium hydroxide solution to bring pH of reaction mass to 13-14. The organic layer was separated, washed with water, 20% aqueous sodium chloride and then distilled under vacuum at about 45°C to about 50°C to reduce volume to 100ml which contains compound of formula III. The compound II (106.6g) was charged in toluene (200ml) in another round bottom flask, sodamide (24g) was added to it under nitrogen atmosphere at about 20°C to about 30°C and reaction mixture was heated to about 40°C. The toluene layer containing compound III was added to the reaction mass, simltaneously increasing the temperature to about 60°C to about 65°C. The reaction mass was stirred at about 95°C to about 110°C for about 3h to about 5h. After completion of the reaction, reaction mass was cooled to about 20°C to about 30°C, methanol (8ml), water (300ml) and toluene (600ml) was added to it and stirred for about 30min. The layers were seperated, organic layer was washed with water. HPLC purity:92.31%; Stage A: 0.06%, dimer impurity A: 1.12%; O-desmethyl verapamil: 0.35%; Single max impurity: 1.72%

The organic layer was washed with water, 2% aqueous sodium dihydrogen phosphate and again with water. HPLC purity :93.67%; dimer impurity A:Not Detected; Stage A: Not Detected; O-desmethyl verapamil: 0.32%; single max impurity: 1.66% . 20% aqueous sodium hydroxide solution was added to the organic layer and stirred for about lOmin at about 20°C to about 30°C. Methyl chloroformate (8.80g) was added to the organic layer and stirred for about 2h to about 3h at about 25°C to about 30°C. Water was added to the reaction mass and layer were seperated. HPLC purity: 93.7%, O-desmethyl impurity:Not detected, single max impurity: 1.39%.

The organic layer was washed with water, hydrochloric acid (12% w/w in ethylacetate, 170 ml) was added slowly to it, while maintaining the reaction mass temperature at about 20°C to about 30°C. The reaction mass was stirred at about 20°C 25°C for about 4h, filtered, solid washed with toluene. The wet cake was dried under vaccum at about 45°C to about 55°C to obtain verapamil hydrochloride (I, 21 lg). Yield:84.4%, HPLC purity:97.89%. O-desmethyl impurity; ND, single max impurity: 0.65%.

[0066] Example 6: Preparation of Verapamil hydrochloride (I)

Verapamil hydrochloride (I, 21 lg) was charged in ethyl acetate (528ml), methanol (63ml), heated to about 55°C to about 65°C and filtered through whatman paper. The reaction mass was heated to about 55°C to about 65°C and then slowly cooled to about 20°C to about 30°C under stirring for about 3h to about 4h, further cooled to about 0°C to about 5°C and stirred for about lh. The reaction mass was filtered and the solid was washed with ethylacetate. The wet cake is dried under vaccum at about 45°C to about 55°C for about 12h to about 15h to obtain verapmail hydrochoride (I, 184.8g). Percentage Yield:88.0%; HPLC purity:97.83%. O-desmethyl verapamil ND , single max impurity: 0.06%.

[0067] Example 7: Preparation of Verpamil hydrochloride (I)

The compound II (106.6g) was charged in toluene (200ml), sodamide (24g) was added to it under nitrogen atmosphere at about 20°C to about 30°C and heated to about 40°C. The compound III (130g) in toluene was added to the reaction mass, simultaneously incresasing the temperature to about 60°C to about 65°C. The reaction mass was stirred at about 95°C to about 110°C for about 3h to about 5h. After completion of the reaction, reaction mass was cooled to about 20°C to about 30°C, methanol (8ml), water (300ml) and toluene (600ml) was added to it and stirred for about 30min. The layers were separated and water (500ml) was charged in organic layer and cooled to about 15°C to about 20°C. Cone hydrochlorioc acid (65ml) was charged to the reaction mass (pH 2.0) and stirred for about 25min to about 30min at about 15°C to about 20°C. The organic layer was seperated and aqueous layer was washed with toluene. The pH of aqueous layer was readjusted to 1.0 using hydrochloric acid and stirred for about 6h to about 8h at about 20°C to about 25°C. The reaction mass was cooled to about 5°C to about 10°C and stirred for about 2h. The solid was filtered, washed with chilled water and dried in tray dryer at about 45°C to about 50°C for about 6h to about 8h to obtain verapamil hydrochloride (I, 170g). Percentage yield: 67.7%; HPLC purity: 99.47%. O-desmethyl verapamil: 0.29%; single max impurity: 0.10%.

[0068] Example 8: Preparation of Verapamil hydrochloride (I)

Verapamil hydrochloride (I, 170g) was charged in ethyl acetate (425ml) and methanol (51ml), heated to about 55°C to about 65°C and filtered through whatman paper. The reaction mass was heated to about 55°C to about 65°C and slowly cooled to about 20°C to about 30°C under stirring for about 3h to about 4h, further cooled to about 0°C to about 5°C and stirred for about lh. The reaction mass was filtered and the solid was washed with ethylacetate. The wet cake is dried under vaccum at about 45°C to about 55°C for about 12h to about 15h to obtain verapamil hydrochoride (I, 149.6g). Percentage Yield:90%; HPLC purity:99.84%; O- desmethyl verapamil:0.10%; single max impurity: 0.03%.

[0069] Example 9: Preparation of Verapamil (IA)

The compound II (106.65g) was charged in toluene (200ml), sodamide (24g) was added to it under nitrogen atmosphere at about 20°C to about 30°C and stirred at about 40°C to about 45°C. A solution of compound III (130g dissolved in 100ml toluene) was slowly added to the reaction mass, simltaneously increasing the temperature to about 60°C to about 65°C. The reaction mass was stirred at about 105°C to about 110°C for about 3h to about 5h. After completion of the reaction, reaction mass was cooled to about 15°C to about 25°C, methanol (8ml), water (650ml) was added to it and stirred for about 30min. The layers were seperated and aqueous layer was washed with toluene. Water was charged in toluene layer and cone hydrochloric acid (65ml) was added to it to attain pH of 2 and stirred for about 25min to about 30min at about 15°C to about 20°C. The layers were separated, the aqueous layer was washed with toluene. Toluene was charged in aqueous layer, cooled to 15-C to about 20°C. Aqeuous sodium hydroxide (30g in 600ml water) was added to the reation mass to attain pH of 11- 12 and stirred for about 15min to about 20min. The layers were separated, organic layer was washed with water and 2% aqueous sodium dihydrogen phosphate. The organic layer was again washed with water followed by 20% aqueous sodium chloride solution. Potassium carbonate (24.7g) was added to organic layer followed by mesyl chloride (20.58g) and stirred for about 4h to about 5h at about 25°C to about 30°C. Water was added to the reaction mass and layers were separated. The organic layer was washed with water and distilled under vacuum at about 50°C to about 55°C to obtain verapamil (IA, 204g). Yield:94%; HPLC purity:97.21%. O-desmethyl verapamihND; single max impurity: 0.80%.

[0070] Example 10: Preparation of Verapamil hydrochloride (I)

Verapamil (I A, 204g) was charged in ethyl acetate (2040ml) and stirred for about lOmin to about 15min at about 20°C to about 30°C. Hydrochloric acid (12% w/w in ethylacetate, 165ml) was slowly added to the reaction mass, while maintaining the temperature at about 20°C to about 30°C. The reaction mass was stirred at about 20°C to about 25°C and further cooled to about 0°C to about 5°C, stirred for about lh and filtered. The solid was dried under vaccum at about 45°C to about 55°C to obtain verapamil hydrochloride (I, 194g). Percentage Yield:95%; HPLC purity: 99.57%; O-desmethyl verapamil: ND, single max impurity:0.11%.

[0071] Example 11: Preparation of 3-Chloro-N-[2-(3,4-dimethoxyphenyl)ethyl]-N- methylpropan-1 -amine oxalate

In a round bottom flask, sodium hydroxide (41g) was dissolved in water (30ml) and cooled to about 5°C to about 10°C followed by addition of N-(3-chloropropyl)-N-[2-(3,4- dimethoxyphenyl) ethyl]-N-methylamine (V, lOOg) and tetrabutyl ammonium bromide (TBAB). To this reaction mass, l-bromo-3-chloropropane (108.8g) was added over about 2h to about 3h and stirred for about 15h to about 18h at about 10°C to about 15°C. After completion of the reaction, toluene (100ml) and water (500ml) was added at about 10°C to about 15°C and stirred for about lOmin to about 15min. The organic layer was separated and aqueous layer was washed with water and 20% aqueous sodium chloride to obtain compound III in toluene.

Oxalic acid (77.5g) was charged in acetone (200ml) and stirred for about 20min at about 20°C to about 30°C. To this solution, toluene layer containing compound III was charged and stirred for about 5h to about 6h at about 20°C to about 25 °C. The solid was filtered, washed with toluene and dried under vacuum at about 45°C to about 55°C for about 12h to about 15h to obtain oxalate salt of compound III (166.7g). Percentage yield: 90%, HPLC purity: 95.35%; dimer impurity: 2.92%; 2-(3,4-dimethoxyphenyl)ethyl]-N-methylamine: ND; single max impurity: 0.93%.

[0072] Example 12: Preparation of verapamil hydrochloride (I)

The oxalate salt of compoud III (166.7g) obtained in Ex 11 was charged in water (1660ml) and toluene (500 ml), stirred for about lOmin to about 15min at about 20°C to about 25°C. 10% aqeous sodium hydroxide (212ml) was added to the reaction mass to bring pH 13-14. The reaction mass was stirred for about 20min to about 30min, organic layer was seperated and washed with water followed by 20% aq. sodium chloride. The organic layer was distilled under reduced vaccum to reduce the volume to obtain compound III (water content 0.3%). The compound II (lOlg) was charged in toluene (200ml), sodamide (22.42g) was added to it under nitrogen atmosphere at about 20°C to about 30°C and heated to about 40°C. The toluene layer containing compound III was slowly added to the reaction mass, simultaneously increasing the temperature to about 60°C to about 65°C. The reaction mass was stirred for about 3h to about 5h at about 105°C to about 110°C. Progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to about 20°C to about 30°C. Methanol (8ml), water (300ml) and toluene (600ml) was added to the rection mass and stirred for about 30 min. The layers were seperated, organic layer was washed with water followed by 2% aquoues sodium dihydrogen phosphate. The organic layer was again washed with water, 20% aqueous sodium hydroxide was added to it and stirred for about lOmin at about 20°C to about 30°C. Methyl chloroformate (8.80g) was added to the organic layer and stirred for about 2h to about 3h at about 25°C to about 30°C. The organic layer was again washed with water, hydrochloric acid (12% w/w in ethylacetate, 170 ml) was slolwy added while maintaining the reaction mass temperature to about 20°C to about 30°C and stirred for about 4h. The reaction was then filtered, solid washed with toluene and dried under vaccum at about 45°C to about 55°C to obtain verapamil hydrochloride (I, 191.2g). Percentage Yield:84.6%; HPLC purity: 99.72%. O-desmethyl verapamil 0.02%, single max impurity: 0.09%.