Description:FORM 2
THE PATENTS ACT,
1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]

PROCESS FOR THE PREPARATION OF PIMOBENDAN AND ITS INTERMEDIATES

ZENFOLD SUSTAINABLE TECHNOLOGIES PRIVATE LIMITED an Indian company of 53 C, Praga Square, Bommasandra Industrial Area, Phase 1, Hosur Road, Bengaluru, Karnataka- 560099, India

The following specification particularly describes the invention & the manner in which it is to be performed.

Field of the invention

The disclosure generally relates to a synthetic process for preparing pimobendan and intermediates thereof.

Background of the invention
Pimobendan is a calcium sensitizer and a selective inhibitor of phosphodiesterase 3 (PDE3) with positive inotropic and vasodilator effects. It is used in the management of heart failure in dogs. It is marketed as Vetmedin Chewable Tablets and is indicated for the management of the signs of mild, moderate, or severe (modified New York Heart Association (NYHA) Class II, III, or IV) congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI) or dilated cardiomyopathy (DCM). VETMEDIN is indicated for use with concurrent therapy for congestive heart failure (e.g., furosemide, etc.) as appropriate on a case-by-case basis.

Pimobendan has been disclosed in U.S. Pat. No. 4,361,563. It is chemically (4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone) and the chemical structure is:

The process for preparation of pimobendan has been described in patents and applications, U.S. Pat. No. 4,361,563, European patent application EP2199291A1, and US patent publication no. 20110152283.

The US patent publication no. 20110152283 discloses various crystalline forms of pimobendan such as Form A, Form B, Form C and Form D.

The PCT patent publication no. 2011124638 discloses pimobendan methanol solvates and a process for the manufacture of a non-solvated crystalline pimobendan from pimobendan methanol solvates as intermediates.

The prior art process uses column chromatography for purification. A commercially available active substance preferably must contain a very low quantity of impurities which is preferable by many regulatory agencies across the globe. Further, it should be manufactured with the appropriate choice of intermediates and their solid forms in a manner that is reproducible, efficient, cost-effective and safe.

There is a need for a high-yielding large-scale production process for pimobendan which is safe, efficient and cost-effective. Further, there is a need for a process for the preparation of highly pure pimobendan.

Summary of the invention
The specification discloses a process for the preparation of pimobendan or pharmaceutically acceptable salt or hydrate or solvate thereof comprising:
(a) reacting 3,4-diamino benzoic acid with 4-methoxy benzaldehyde to get compound of Formula II
,
and
(b) reacting compound of Formula II with N,O-dimethylhydroxylamine or its hydrochloride salt to get compound of Formula III

or
reacting compound of Formula II with morpholine to get compound of Formula IIIA
.
The process further comprises converting compound of Formula III or compound of Formula IIIA
or

to compound of Formula IV
.
The process further comprises reacting compound of Formula IV

with glyoxylic acid to get compound of Formula V
.
The process further comprises reduction of compound of Formula V

to compound of Formula VI

wherein R is H or C1-4 alkyl.
The process further comprises reacting compound of Formula VI

wherein R is H or C1-4 alkyl,
with hydrazine hydrate to get pimobendan or hydrate or solvate thereof.

The specification also discloses a compound selected from the group consisting of
,
,
,
,
,

wherein R is H or C1-4 alkyl,
,
,
and
.
The specification also discloses a composition of pimobendan comprising substantially pure pimobendan and one or more impurities selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

In one embodiment the composition of pimobendan comprises at least about 95% w/w of pimobendan and not more than about 5% w/w of the one or more impurities.

Brief description of the drawing
Figure 1. Synthetic scheme for the preparation of pimobendan.

Detailed description
The disclosure is directed, in part, to processes for preparing pimobendan or pharmaceutically acceptable salt or hydrate or solvate thereof.

The processes for preparing pimobendan are suitable for manufacturing the drug substance at commercial scale, with good manufacturing practices. The processes described herein for manufacture of pimobendan active substance, provides pimobendan with a very low impurity profile. The manufacturing process provides improved manufacturability and lower cost of goods for obtaining a substantially pure pimobendan active substance suitable for commercial scale manufacturing.

As used herein, the term “substantially pure,” when used in reference to a compound, refers to composition where the composition contains more than 95% w/w, preferably more than 98% w/w, and more preferably more than 99% w/w of compound.

The term “pharmaceutically acceptable salt” of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Examples of some of the pharmaceutically acceptable salts which can be utilized are salts of the following acids: hydrochloric, sulphuric and phosphoric.

The term ‘C1-4 alkyl’ means straight or branched alkyl chain containing one to four carbon atoms for example methyl, ethyl or isopropyl.

In one embodiment, there is provided a composition of pimobendan comprising pimobendan and one or more impurities, wherein the composition comprises at least about 95% w/w of pimobendan and not more than about 5% w/w of the one or more impurities, and wherein the one or more impurities is selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

In another embodiment, there is provided a composition of pimobendan comprising pimobendan and one or more impurities, wherein the composition comprises at least about 97% w/w of pimobendan and not more than about 3% w/w of the one or more impurities, and wherein the one or more impurities is selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

In yet another embodiment, there is provided a composition of pimobendan comprising pimobendan and one or more impurities, wherein the composition comprises at least about 98% w/w of pimobendan and not more than about 2% w/w of the one or more impurities, and wherein the one or more impurities is selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

In a further embodiment, there is provided a composition of pimobendan comprising pimobendan and one or more impurities, wherein the composition comprises at least about 99% w/w of pimobendan and not more than about 1% w/w of the one or more impurities, and wherein the one or more impurities is selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

In one embodiment, there is provided a process for the preparation of pimobendan or pharmaceutically acceptable salt or hydrate or solvate thereof comprising:
(a) reacting 3,4-diamino benzoic acid with 4-methoxy benzaldehyde to get compound of Formula II
,
(b) reacting compound of Formula II with N,O-dimethylhydroxylamine or its hydrochloride salt to get compound of Formula III
,
(c) converting compound of Formula III to compound of Formula IV
,
(d) reacting compound of Formula IV with glyoxylic acid to get compound of Formula V
,
(e) reduction of compound of Formula V to compound of Formula VI

wherein R is H or C1-4 alkyl,
(f) reacting compound of Formula VI with hydrazine hydrate to get pimobendan or hydrate or solvate thereof.
(g) optionally, converting pimobendan or hydrate or solvate thereof to its pharmaceutically acceptable salt.

In an alternate embodiment, there is provided a process for the preparation of pimobendan or pharmaceutically acceptable salt or hydrate or solvate thereof comprising:
(a) reacting 3,4-diamino benzoic acid with 4-methoxy benzaldehyde to get compound of Formula II
,
(b) reacting compound of Formula II with morpholine to get compound of Formula IIIA
.
In one embodiment, there is provided a process for the preparation of compound of Formula II by reacting 3,4-diamino benzoic acid with 4-methoxy benzaldehyde. The reaction can be carried out in a suitable solvent for example mixture of alcohol and water. The alcohol can be selected from methanol, ethanol, propanol, isopropanol or n-butanol. The reaction can be preferably carried out in a mixture of ethanol and water. The reaction can be carried out using a suitable reagent for example sodium pyrosulphite (Na2S2O5). The reaction can be carried out at a suitable temperature for example 15°C to 150°C, preferably 50°C to 100°C, more preferably at 70°C to 80°C.

In another embodiment, there is provided a process for the preparation of compound of Formula III by reacting compound of Formula II with N,O-dimethylhydroxylamine or its hydrochloride salt. In an alternate aspect, there is provided a process for the preparation of compound of Formula IIIA by reacting compound of Formula II with morpholine. The reaction can be carried out in a suitable solvent for example dichloromethane, chlorobenzene, dichloroethane, mixture of water and dichloromethane. The reaction can be carried out using a suitable reagent for example 1-hydroxybenzotriazole (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl). The reaction can be carried out at a suitable temperature for example 0°C to 50°C, preferably 5°C to 25°C, more preferably 10°C to 15°C.

In another embodiment, a process for converting compound of Formula III or compound of Formula IIIA to compound of Formula IV is provided. In another aspect, a process for converting compound of Formula VII to compound of Formula VIII is provided. In another aspect, a process for converting compound of Formula IX to compound of Formula X is provided. The reaction can be carried out in a suitable solvent for example THF, diethyl ether, 2-methyl THF, MTBE. The reaction can be carried out using a suitable reagent for example alkyl magnesium halide (Grignard reagent) or alkyl lithium. The reaction can be carried out preferably using ethyl magnesium bromide. The reaction can be carried out at a suitable temperature for example -20°C to 50°C, preferably -10°C to 35°C.

In another embodiment, there is provided a process for the preparation of compound of Formula V by reacting compound of Formula IV with glyoxylic acid. The compound of formula V includes cis and trans isomers. Accordingly, the compound of formula V can be cis isomer, trans isomer or mixture of both. The reaction can be carried out in a suitable solvent for example dioxane, acetic acid, dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or mixtures thereof. The reaction can be carried out using a suitable acid for example sulfuric acid, Amberlyst 15, p-Toluenesulfonic acid (PTSA or pTsOH), tosylic acid (TsOH), hydrochloric acid or nitric acid. The reaction can be carried out at a suitable temperature for example 0°C to 110°C, preferably 50°C to 80°C.

In another embodiment, a process is provided for reduction of compound of Formula V to compound of Formula VI. The reaction can be carried out in a suitable solvent for example alcohol, ethyl acetate, methyl acetate. The alcohol can be selected from methanol, ethanol, propanol, isopropanol or n-butanol. The reaction can be carried out using a suitable reducing agent for example mixture of formic acid and activated zinc, mixture of ammonium format and zinc, mixture of acetic acid and zinc, mixture of ammonium format and Pd/C. The reaction can be carried out at a suitable temperature for example 0°C to 100°C, preferably 25°C to 60°C.

The compound of formula VI wherein R is C1-4 alkyl can also be prepared from the corresponding acid (compound of formula VI wherein R is H) by esterification methods known in the art.

In another embodiment, there is provided a process for the preparation of pimobendan or hydrate or solvate thereof by reacting compound of Formula VI with hydrazine hydrate. The reaction can be carried out in a suitable solvent for example alcohol. The alcohol can be selected from methanol, ethanol, propanol, isopropanol or n-butanol. The reaction can be carried out at a suitable temperature for example 25°C to 150°C, preferably 50°C to 100°C.

Pimobendan or hydrate or solvate thereof obtained according to the invention may be converted to its pharmaceutically acceptable salt by a process known to the person skilled in the art.

In one embodiment, a compound of formula VII is provided,
.
In one embodiment, a compound of formula VIII is provided,
.
In one embodiment, a compound of formula IX is provided,
.
In one embodiment, a compound of formula X is provided,
.
In one embodiment, there is provided a process for the preparation of compound of Formula VII by reacting Compound of Formula III with chloromethyl methyl ether in presence of sodium hydride in THF.

In another embodiment, there is provided a process for the preparation of compound of Formula IX by reacting Compound of Formula III with Boc anhydride in presence of 4-dimethylaminopyridine in acetonitrile.

The following examples illustrate specific embodiments; however, the full scope of the disclosure is not limited to the examples described below.

EXAMPLES
Example 1
Preparation of 2-(4-methoxyphenyl)-1H-1,3-benzodiazole-5-carboxylic acid (compound of Formula II)
3,4-Diamino benzoic acid (100g) and p-methoxy benzaldehyde (89.5g) were charged into a 4-neck 2L round bottom flask (RBF) containing ethanol:water (1:1) (500mL). The reaction mixture was cooled to 15-25 °C. Then sodium pyrosulphite (Na2S2O5) (150g) was charged at 15-25 °C. The reaction mixture was heated to 70-80 °C ¬and stirred for 16 h. The reaction mass was filtered and the solid was washed with ethanol:water (1:1) (200 mL). The wet material was charged into a 2 L RBF followed by water (700 ml) and the reaction mixture was stirred for 2 h at 25-35 °C. The solid was filtered and washed with water (200 mL). The wet material was dried under vacuum at 50-55 °C for 8 h to obtain 165g of compound of Formula II. Yield: 93.5%. Isolated as beige crystalline powder. m/z (ESI): 269.15 [M+H]+, 266.9 [M-H]+; 1H NMR (400 MHz, DMSO-d6) δH: 3.86 (s, 3H, -OCH3), 7.14 (d, 2H, J = 8.4 Hz, Ar-H), 7.63 (d, 1H, J = 8 Hz, Ar-H), 7.83 (d, 1H, J=8.8, Ar-H), 8.14-8.47 (m, 3H, Ar-H), 12.75 (broad s, 1H, -NH), 13.13 (broad s, 1H, -OH).

Example 2
Preparation of N-methoxy-2-(4-methoxyphenyl)-N-methyl-1H-1,3-benzodiazole-5- carboxamide (compound of Formula III)
Dichloromethane (250mL) and compound of Formula II (50 g) were charged into a 3-neck 1L round bottom flask at 25-35 °C. The reaction mixture was stirred for 10 min and N,O-dimethylhyrdoxylamine hydrochloride (22.0g), 1-hydroxybenzotriazole (HOBT) (30.26g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (43g) were charged. The reaction mixture was cooled to 10 °C and triethylamine (56.5g) was added dropwise into reaction mass. The reaction mixture was stirred for 16 h at 25-35 °C. The reaction mixture was quenched with water (250 mL) and the organic layer was separated. The reaction mass was cooled to 10-15 °C and conc. HCl (15 mL) was added slowly. The mixture was stirred for 1 h at 25-35 °C. The solid was filtered and washed with water (100 mL). The wet material was added into round bottom flask containing dichloromethane (250 mL). The reaction mass was cooled to 10-20 °C and 10% sodium carbonate solution (500 mL) was added. The reaction mass was stirred to get a clear solution. The organic layer was separated and washed with water (100 mL). The solvent was distilled out completely to obtain 51.6 g of compound of Formula III. Yield: 89 %. Isolated as pale brown crystalline powder. m/z (ESI): 312.2 [M+H], 309.95 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 3.30 (s, 3H, -NCH3), 3.57 (s, 3H, -NOCH3), 3.85 (s, 3H, Ar-OCH3), 7.13 (d, 2H, J = 8.8 Hz, Ar-H), 7.46-7.88 (broad m, 3H, Ar-H), 8.14-8.47 (d, 2H, J = 9.2 Hz, Ar-H), 12.98 (broad s, 1H, -NH).

Example 3
Preparation of 1-[2-(4-methoxyphenyl)-1H-1,3-benzodiazol-5-yl]propan-1-one (compound of Formula IV)
Compound of Formula III (25g) and dry THF (250 mL) were charged into 4-neck 2L RBF at 25-35 °C. The reaction mixture stirred for 10 min and cooled to -10 °C. Ethyl magnesium bromide in diethyl ether (3.0 M) (54 mL) solution was slowly added to the reaction mass maintaining the temperature at 0 °C. The reaction mass was stirred at 25-35 °C for 3 h. The reaction mass was cooled to 0 °C and quenched with 20% aqueous ammonium chloride solution (250 mL). Ethyl acetate was added, the organic layer was separated and washed with 5% aqueous sodium bicarbonate solution (125 mL). The solvent was distilled out completely under vacuum at below 45 °C. Dichloromethane (50 mL) was added to the crude mass, heated to 40 °C and stirred for 15 min. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with dichloromethane (25 mL). The wet material was dried under vacuum at 55 °C for 8 h to obtain 17.5 g of compound of Formula IV. Yield: 78%. Isolated as off-white crystalline powder. m/z (ESI): 281.2 [M+H], 278.95 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 1.11-1.15 (t, 3H, -CH3), 3.09-3.15 (q, 2H, -CH2), 3.86 (s, 3H, Ar-OCH3), 7.14 (d, 2H, J = 8.8 Hz, Ar-H), 7.58-7.85 (broad m, 2H, Ar-H), 8.10-8.30 (broad m, 3H, Ar-H), 13.07 (broad s, 1H, -NH).

Example 4
Preparation of (2E)-4-[2-(4-methoxyphenyl)-1H-1,3-benzodiazol-5-yl]-3-methyl- 4-oxobut-2-enoic acid (compound of Formula V)
Compound of Formula IV (10 g) and 1,4-dioxane (50mL) were charge into 3-neck 100 mL round bottom flask at 25-35 °C. The reaction mixture was stirred for 10 min and 50% aqueous solution of glyoxylic acid (17 mL) and sulfuric acid (2.3 mL) were charged. The reaction mixture was stirred at 70 °C for 1 h. The reaction mass was cooled to 25-30 °C and quenched with water (100 mL). The solid was filtered and washed with water (5 mL). The wet material was dried under vacuum at 55 °C for 12 h to obtain 9.8 g of compound of Formula V. Yield: 82%. Isolated as light-yellow crystalline powder. m/z (ESI): 335 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 2.35 (d, 3H, -CH3), 3.89 (d, 3H, Ar-OCH3), 6.09 (d, 1H, C=CH), 7.22 (d, 2H, J = 7.6Hz, Ar-H), 8.07-8.21 (m, 3H, Ar-H), 8.10-8.30 (m, 3H, Ar-H).

Example 5
Preparation of 4-[2-(4-methoxyphenyl)-1H-1,3-benzodiazol-5-yl]-3-methyl-4-oxobutanoic acid (compound of Formula VI wherein R is H)
Compound of Formula V (4.0 g) and methanol (40 mL) were charged into a 3-neck 100mL RBF at 25-35 °C. The reaction mixture was stirred for 10 min and formic acid (2 mL) and activated zinc (2.33 g) were charged. The reaction mixture was stirred at 35-40 °C for 2 h. The reaction mass was cooled to 25-30 °C, filtered through celite bed and washed with methanol (2 mL). The solvent distilled out completely under vacuum at below 45 °C to obtain 3.6 g of compound of Formula VI. Yield: 90%. Isolated as pale-yellow crystalline powder. m/z (ESI): 337.1 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 1.16 (d, 3H, -CH3), 2.35 (dd, 1H -CH2), 2.75 (dd, 1H -CH2), 3.86 (s, 3H, Ar-OCH3), 3.97-4.038 (m, 1H, -CH), 7.14 (d, 2H, J = 8.8Hz, Ar-H), 7.64-7.86 (m, 2H, Ar-H), 8.12-8.18 (m, 3H, Ar-H).
Example 6
Preparation of 6-[2-(4-methoxyphenyl)-1H-1,3-benzodiazol-5-yl]-5-methyl-2,3,4,5- tetrahydropyridazin-3-one (Pimobendan)
Compound of Formula VI (2.0 g) and ethanol (20 mL) were charged into a 3-neck 100 mL round bottom flask at 25-35 °C. The reaction mixture was stirred for 10 min and 80% w/w aqueous hydrazine hydrate solution (6.0 mL) was charged. The reaction mixture was stir at 100 °C for 3 h. The solvent was completely distilled out under vacuum at below 50 °C. Dimethylformamide (20 mL) was added to the residual reaction mixture and was stirred at 40-50 °C for 15 min. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with water (50 mL). The wet material was dried under vacuum at 55 °C for 14 h to obtain 1.51 g of Pimobendan. Yield: 78%. Isolated as pale-yellow crystalline powder. m/z (ESI): 333.3 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 1.13 (d, 3H, J=7.2Hz, -CH3), 2.26 (d, 1H, J=16.8 Hz, -CH2), 2.72 (dd, 1H, J=6.8 Hz, -CH2), 3.50 (m, 1H, -CH), 3.85 (s, 3H, Ar-OCH3), 7.12 (d, 2H, J=8.4 Hz, Ar-H), 7.53-8.00 (broad m, 3H, Ar-H ), 8.12 (d, 2H, J=8.8 Hz, Ar-H), 10.90 (s, 1H, -NH), 12.86 (broad s, 1H, -NH benzimidazole). HPLC Purity: 99.8%.

Example 7
Preparation of N-methoxy-1-(methoxymethyl)-2-(4-methoxyphenyl)-N-methyl-1H-benzimidazole-5-carboxamide (compound of Formula VII)
Compound of Formula III (10g) and THF (100mL) were charged into 4-neck 500mL RBF at 25-35o C and then sodium hydride (1.4g) was added. The reaction mass was stirred for 30min and cooled to 0-5°C. Chloromethyl methyl ether (2.55 g) was added slowly at 0-5°C. The reaction mixture was heated to 20-30°C and stirred for 3h. The reaction mass was filtered and the solid was washed with THF:water (1:1). The wet material was dried under vacuum at 50-55°C for 8 h to obtain 8g of compound of Formula VII. Yield: 70% Isolated as light-yellow crystal. m/z (ESI): 356.4 [M+H] ; 1H NMR (400 MHz, DMSO-d6) δH: 3.32 (s, 3H, N-CH3), 3.38 (s, 3H, N-OCH3), 3.58 (s, 3H, Ar-OCH3), 3.88 (s, 3H, -OCH3), 5.64 (s, 2H, N-CH2), 7.21 (d, 2H, J = 8.8 Hz, Ar-H), 7.62 (d, 1H, J = 8 Hz, Ar-H), 7.79 (d, 1H, J=8.4, Ar-H), 7.94 (d, 2H, J = 8.8 Hz, Ar-H), 8.15 (s, 1H, Ar-H).

Example 8
Preparation of 1-[1-(methoxymethyl)-2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]propan-1-one (compound of Formula VIII)
Compound of Formula VII (10g) and dry THF (100 mL) were charged into 4-neck 500mL RBF at 25-35 °C. The reaction mixture was stirred for 10 min and cooled to -10 °C. Ethyl magnesium bromide in diethyl ether (3.0 M) (14 mL) solution was slowly added to the reaction mass maintaining the temperature at 0 °C. The reaction mass was stirred at 25-35 °C for 3 h. The reaction mass was cooled to 0 °C and quenched with 20% aqueous ammonium chloride solution (250 mL). Ethyl acetate was added and the organic layer was separated and washed with 5% aqueous sodium bicarbonate solution (125 mL). The solvent was distilled out completely under vacuum at below 45 °C. Dichloromethane (50 mL) was added to the crude mass, heated to 40 °C and stirred for 15 min. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with dichloromethane (25 mL). The wet material was dried under vacuum at 55 °C for 8 h to obtain 7.35 g of compound of Formula VIII. Yield: 80% Isolated as light-yellow crystal. m/z (ESI): 325.5 [M+H] ; 1H NMR (400 MHz, CDCl3) δH: 1.26-1.30 (t, 3H, -CH3), 3.08-3.14 (q, 2H, -CH2), 3.45-3.48 (d, 3H, N-OCH3), 3.89 (s, 3H, -OCH3), 5.48-5.51 (d, 2H, N-CH2), 7.06 (d, 2H, J = 8.8 Hz, Ar-H), 7.55 (d, 1H, J = 8.8 Hz, Ar-H), 7.81-8.04 (m, 3H, Ar-H), 8.21-8.43 (m, 1H, Ar-H).

Example 9
Preparation of tert‐butyl 5‐[methoxy(methyl)carbamoyl]‐2‐(4‐methoxyphenyl)‐1H‐1,3‐benzodiazole‐1‐carboxylate (compound of Formula IX)
Compound of Formula III (20g) and acetonitrile (200mL) were charged to 4-neck 1L RBF at 25-35°C and the reaction mixture was stirred for 10 minutes. 4-Dimethylaminopyridine (7.85g) was added lot wise and the reaction mixture was cooled to 0-5°C. Boc anhydride (17.6mL) was added dropwise into reaction mass and the reaction mixture was stirred for 3h at 25-35°C. Water and dichloromethane (200mL) were charged and the organic layer was separated. The organic layer was washed with 1% dilute hydrochloric acid solution followed by 5% sodium bicarbonate solution. The solvent was distilled out completely to obtain 25 g of compound of Formula IX. Yield: 94.5%. Isolated as light-yellow crystal. m/z (ESI): 412.5 [M+H] ; 1H NMR (400 MHz, DMSO-d6) δH: 1.39-1.42 (t, 9H, -tert CH3), 3.31-3.29 (q, 3H, -N-CH3), 3.56-3.57 (d, 3H, N-OCH3), 3.85 (s, 3H, -OCH3), 7.07 (d, 2H, J = 8.8 Hz, Ar-H), 7.64-7.79 (m, 3H, Ar-H), 7.97-8.02 (m, 1H, Ar-H), 8.28 (d, 1H, Ar-H).

Example 10
Preparation of tert‐butyl 2‐(4‐methoxyphenyl)‐5‐propanoyl‐1H‐1,3‐
benzodiazole‐1‐carboxylate (compound of Formula X)
Compound of Formula IX (5g) and dry THF (50 mL) were charged into 4-neck 250mL RBF at 25-35 °C. The reaction mixture stirred for 10 min and cooled to -10 °C. Ethyl magnesium bromide in diethyl ether (3.0 M) (6 mL) solution was slowly added to the reaction mass maintaining the temperature at 0 °C. The reaction mass was stirred at 25-35 °C for 3 h. The reaction mass was cooled to 0 °C and quenched with 20% aqueous ammonium chloride solution (50 mL). Ethyl acetate was added and the organic layer was separated and washed with 5% aqueous sodium bicarbonate solution (25 mL). The solvent was distilled out completely under vacuum at below 45 °C. Dichloromethane (50 mL) was added to the crude mass, heated to 40 °C and stirred for 15 min. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with dichloromethane (25 mL). The wet material was dried under vacuum at 55 °C for 8 h to obtain 3.7 g of compound of Formula X. Yield: 80%. Isolated as Off-white powder. m/z (ESI): 381 [M+H] ; 1H NMR (400 MHz, DMSO-d6) δH: 1.13 (q, 3H, J= 7.2Hz, 5.6Hz, -CH3), 1.42 (d, 9H, -tert CH3), 3.11-3.16 (m, 2H, -CH2), 3.85 (s, 3H, -OCH3), 7.07 (d, 2H, J = 8.8 Hz, Ar-H), 7.66-8.04 (m, 4H, Ar-H), 8.46 (d, 1H, Ar-H).

Example 11
Preparation of [2-(4-methoxyphenyl)-1H-1,3-benzimidazol-5-yl](morpholin-4-yl)methanone N-methoxy-2-(4-methoxyphenyl)-N-methyl-1H-1,3-benzodiazole-5-carboxamide (compound of Formula IIIA)
Dichloromethane (50mL) and compound of Formula II (10 g) were charged into a 3-neck 1L round bottom flask at 25-35 °C. The reaction mixture was stirred for 10 min and morpholine (4.88g), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (8.67g) were charged. The reaction mixture was cooled to 10 °C and triethylamine (5.6g) was added dropwise into reaction mass. The reaction mixture was stirred for 16 h at 25-35 °C. After completion of reaction, the organic layer distilled out completely. To the reaction mass ethyl acetate was added and stirred for 15 min at 40 °C. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with ethyl acetate (5 mL). The wet material was dried under vacuum at 55 °C for 8 h to obtain 8 g of compound of Formula IIIA. Yield : 63.6%. Isolated as pale brown crystalline powder. m/z (ESI): 338.3 [M+H] ; 1H NMR (400 MHz, DMSO-d6) δH: 3.54-3.70 (broad doublet, 8H, -morpholine), 3.85 (s, 3H, Ar-OCH3), 7.12 (d, 2H, J = 8.8 Hz, Ar-H), 7.23-7.26 (m, 2H, Ar-H) 7.53-7.66 (m, 2H, Ar-H), 8.14-8.47 (d, 2H, J = 8.4 Hz, Ar-H), 12.95 (s, 1H, -NH).

Example 12
Alternate preparation of 1-[2-(4-methoxyphenyl)-1H-1,3-benzodiazol-5-yl]propan-1-one (compound of Formula IV)
Compound of Formula IIIA (5g) and dry THF (50 mL) were charged into 4-neck 250mL RBF at 25-35 °C. The reaction mixture stirred for 10 min and cooled to -10 °C. Ethyl magnesium bromide in diethyl ether (3.0 M) (12.4 mL) solution was slowly added to the reaction mass maintaining the temperature at 0 °C. The reaction mass was stirred at 25-35 °C for 3 h. The reaction mass was cooled to 0 °C and quenched with 20% aqueous ammonium chloride solution (50 mL). Ethyl acetate was added, the organic layer was separated and washed with 5% aqueous sodium bicarbonate solution (25 mL). The solvent was distilled out completely under vacuum at below 45 °C. Dichloromethane (25 mL) was added to the crude mass, heated to 40 °C and stirred for 15 min. The reaction mass was cooled to 20-30 °C and stirred for 30 min. The solid was filtered and washed with dichloromethane (5 mL). The wet material was dried under vacuum at 55 °C for 8 h to obtain 2.8 g of compound of Formula IV. Yield: 67.4%. Isolated as off-white crystalline powder. m/z (ESI): 281.2 [M+H], 278.95 [M-H]; 1H NMR (400 MHz, DMSO-d6) δH: 1.11-1.15 (t, 3H, -CH3), 3.09-3.15 (q, 2H, -CH2), 3.86 (s, 3H, Ar-OCH3), 7.14 (d, 2H, J = 8.8 Hz, Ar-H), 7.58-7.85 (broad m, 2H, Ar-H), 8.10-8.30 (broad m, 3H, Ar-H), 13.07 (broad s, 1H, -NH).
, Claims:We claim:

1. A process for the preparation of pimobendan or pharmaceutically acceptable salt or hydrate or solvate thereof comprising:

(a) reacting 3,4-diamino benzoic acid with 4-methoxy benzaldehyde to get compound of Formula II
,
and
(b) reacting compound of Formula II with N,O-dimethylhydroxylamine or its hydrochloride salt to get compound of Formula III

or
reacting compound of Formula II with morpholine to get compound of Formula IIIA
.
2. The process according to claim 1 wherein the step (a) is carried out in presence of sodium pyrosulphite.

3. The process according to claim 1 wherein the process further comprises converting compound of Formula III or compound of Formula IIIA
or

to compound of Formula IV
.
4. The process according to claim 3 wherein the reaction is carried out in presence of alkyl magnesium halide or alkyl lithium.

5. The process according to claim 3 wherein the process further comprises reacting compound of Formula IV

with glyoxylic acid to get compound of Formula V
.

6. The process according to claim 5 wherein the process further comprises reduction of compound of Formula V

to compound of Formula VI

wherein R is H or C1-4 alkyl.

7. The process according to claim 6 wherein the process further comprises reacting compound of Formula VI

wherein R is H or C1-4 alkyl,
with hydrazine hydrate to get pimobendan or hydrate or solvate thereof and optionally, converting pimobendan or hydrate or solvate thereof to its pharmaceutically acceptable salt.

8. A compound selected from the group consisting of
,
,
,
,
,

wherein R is H or C1-4 alkyl,
,
,
and
.

9. A composition of pimobendan comprising substantially pure pimobendan and one or more impurities selected from the group consisting of compound of Formula II, III, IIIA, IV, V, VI, VII, VIII, IX and X.

10. The composition according to claim 9 wherein the composition comprises at least about 95% w/w of pimobendan and not more than about 5% w/w of the one or more impurities.