Indian Patents. 278173:PROCESS FOR AND INTERMEDIATES OF LEUKOTRIENE ANTAGONISTS

Title of Invention	PROCESS FOR AND INTERMEDIATES OF LEUKOTRIENE ANTAGONISTS
Abstract	The present invention provides a novel method of producing Montelukast sodium and novel intermediates thereof.

Full Text	The present invention provides a novel method of producing Montelukast sodium and novel intermediates thereof. Background of the invention Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonist to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation. By way of example only, Montelukast sodium (structural formula VII, below), is an important leukortriene antagonist and useful in the treatment of asthmas and other related disorders. The organic solvent is preferably selected from one or more of dichloromethane, chloroform, acetonitriie or carbon tetrachloride. According to a third aspect of the invention, there is provided a method of synthesizing a compound of formula IV IV comprising converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate. Conversion into a formyl group may occur by any suitable means. According to one preferred embodiment, conversion is in the presence of one or more of hexamine or manganese dioxide and a suitable solvent. The solvent may be any suitable solvent, and preferably selected from one or more of acetic acid, aqueous acetic acid or water. According to a fourth aspect of the present invention, there is provided a method of synthesizing a compound of formula V comprising condensing alkyl 3-formylbenzoate with 7-Chloroquinaldine to give alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate. The condensation may be carried out in any suitable fashion. According to one preferred embodiment, it is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene. The condensation temperature may be any suitable temperature required for the reaction. Preferably it is maintained between 80-150° C and more particularly between 100-130° C. According to a fifth aspect of the invention, there is provided a method of synthesizing a compound of general formula VI Page 4 of21 VI comprising hydrolysing alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate to give 3-[((7-ChIoro-2-quinoIinyl)ethenyl)]benzoic acid. According to one preferred embodiment, hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide. In a still further preferred embodiment, the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylamine, oxalyl chloride or DMF and POCI3 to form the corresponding acid chloride. According to a sixth aspect of the invention, there is provided a method of synthesizing a compound of formula VII wherein R = halogen, hydroxyl or lower alkyl, and R' = Alkyl, aikenyl or aryl. In one preferred embodiment, the compound synthesized by this method has the following structural formula (VIP) and the method comprises: converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; reacting 3-methyIbenzoate to form alkyl 3-bromomethylbenzoate; converting alkyl 3-bromomethylbenzoate into alkyl 3- II R5 R2 is substituted lower alkyl carboxyl; R3 is hydrogen or lower alkyl; R4 is C1-C5 alkyl or alkenyl; and R5 is halogen, hydroxy or lower alkyl. In another preferred compound, R2 is COOR and R is hydrogen or lower alkyl, R3 is hydrogen, R4 is C2 alkenyl, and R5 is halogen. In a still further preferred compound, R2 is R3 is hydrogen, R4 is a 2 to 10 carbon-chain alkenyl group, R5 is halogen and R6 is halogen or hydroxyi. In another preferred compound, R4 comprises a 2 carbon alkenyl group; and R6 is hydroxyL Throughout this specification (including any claims which follow), unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. Detailed description of example embodiments: It is convenient to describe the invention herein in relation to particularly preferred embodiments relating to production of montelukast sodium. However, it is to be appreciated that other constructions and arrangements are also considered as falling within the scope of the invention. Various modifications, alterations, variations and or additions to the construction and arrangements described herein are also considered as falling within the ambit and scope of the present invention. Scheme II depicts the overall synthetic process of a preferred embodiment according to the present invention which relates to the synthesis of intermediates useful in synthesizing Montelukast. Example 1 Methyl 3-methyIbenzoate To a solution of m- toluic acid (136 g, 1 mol) in methanol (800 mL) was added dropwise concentrated sulphuric acid (10 mL) under stirring at room temperature and heated under reflux for 15 h. After completion of the reaction (monitored by TLC), about 80% methanol was distilled off. The reaction mixture was diluted with water (800 mL) and extracted with dichloromethane twice (2 X 200 mL) and the combined organic layer was washed with aqueous sodium bicarbonate (10%, 200 mL) solution followed by water. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by distillation. Colorless Liquid, 150 g (Quantitative yield) To a solution of Methyl 3-methyIbenzoate (150 g, 1 mol) and l,3-Dibromo-5,5-dimethyl hydantoin (DDH) (150 g, 0.52 mol) in dichloromethane (500 mL) was added AIBN (0.1 g, 0.0006 mol) at room temperature and heated under reflux for 10 h. AIBN in 0.1 g lots were added intermittently during reflux to complete the reaction. After completion of the reaction (monitored by TLC), the reaction mixture was poured into cold water (600 mL) and the organic layer was separated. The aqueous layer was extracted again with dichloromethane To a cooled solution of potassium ethyl malonate (46.1 g, 0.27 mol) in acetonitrile (400 mL) at 10-15°C under nitrogen was added triethylamine (41.8 g, 0.41 mol) followed by anhydrous MgCl2 (30.7g, 0.32 mol) under stirring. The Reaction mixture was allowed to warm to 20-25°C and stirring was contined for 2 hr. The slurry obtained was cooled to 0-5°C and added the acid chloride obtained above, quickly and the reaction mixture was kept overnight at 20-25°C. After completion of the reaction (monitored by TLC), acetonitrile was removed under vacuum, cooled to 10-15°C and acidified with (aq. HCI, 13 % , 270 mL) by maintaining the temperature below 25°C. The precipitate obtained was filtered and washed with water and dried under vacuum. Yellow solid, 44 g (90% yield)

Full Text

The present invention provides a novel method of producing Montelukast sodium and novel intermediates thereof.
Background of the invention
Leukotrienes are autocrine and paracrine eicosanoid lipid mediators derived from arachidonic acid by 5-lipoxygenase. It has been found that antagonist to leukotrienes can perform valuable functions in the treatment or amelioration of certain disease states, particularly those associated with inflammation.
By way of example only, Montelukast sodium (structural formula VII, below), is an important leukortriene antagonist and useful in the treatment of asthmas and other related disorders.

The organic solvent is preferably selected from one or more of dichloromethane, chloroform, acetonitriie or carbon tetrachloride.
According to a third aspect of the invention, there is provided a method of synthesizing a compound of formula IV

IV
comprising converting alkyl 3-bromomethylbenzoate into alkyl 3-formylbenzoate. Conversion into a formyl group may occur by any suitable means. According to one preferred embodiment, conversion is in the presence of one or more of hexamine or manganese dioxide and a suitable solvent. The solvent may be any suitable solvent, and preferably selected from one or more of acetic acid, aqueous acetic acid or water.
According to a fourth aspect of the present invention, there is provided a method of synthesizing a compound of formula V

comprising condensing alkyl 3-formylbenzoate with 7-Chloroquinaldine to give alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate. The condensation may be carried out in any suitable fashion. According to one preferred embodiment, it is carried out in the presence of a mixture selected from one or more of: (a) acetic anhydride, (b) acetic anhydride and toluene, (c) acetic anhydride and pyridine, (d) acetic anhydride and triethylamine or (e) acetic anhydride, pyridine and toluene. The condensation temperature may be any suitable temperature required for the reaction. Preferably it is maintained between 80-150° C and more particularly between 100-130° C.
According to a fifth aspect of the invention, there is provided a method of synthesizing a compound of general formula VI
Page 4 of21

VI
comprising hydrolysing alkyl 3-[((7-Chloro-2-quinolinyl)ethenyl)]benzoate to give 3-[((7-ChIoro-2-quinoIinyl)ethenyl)]benzoic acid. According to one preferred embodiment, hydrolysis of the ester is carried out in the presence of one or more of aqueous sodium hydroxide, methanolic sodium hydroxide, sodium ethoxide, sodium methoxide or sodium tertiary amyloxide. In a still further preferred embodiment, the acid is treated with one or more of the thionyl chloride, thionyl chloride and triethylamine, oxalyl chloride or DMF and POCI3 to form the corresponding acid chloride.
According to a sixth aspect of the invention, there is provided a method of synthesizing a compound of formula VII

wherein R = halogen, hydroxyl or lower alkyl, and R' = Alkyl, aikenyl or aryl. In one preferred embodiment, the compound synthesized by this method has the following structural formula (VIP) and the method comprises:

converting 3-methylbenzoic acid into alkyl 3-methylbenzoate; reacting 3-methyIbenzoate to form alkyl 3-bromomethylbenzoate; converting alkyl 3-bromomethylbenzoate into alkyl 3-

II
R5
R2 is substituted lower alkyl carboxyl; R3 is hydrogen or lower alkyl; R4 is C1-C5 alkyl or alkenyl; and R5 is halogen, hydroxy or lower alkyl. In another preferred compound, R2 is COOR and R is hydrogen or lower alkyl, R3 is hydrogen, R4 is C2 alkenyl, and R5 is halogen. In a still further preferred compound, R2 is

R3 is hydrogen, R4 is a 2 to 10 carbon-chain alkenyl group, R5 is halogen and R6 is halogen or hydroxyi. In another preferred compound, R4 comprises a 2 carbon alkenyl group; and R6 is hydroxyL
Throughout this specification (including any claims which follow), unless the context requires otherwise, the word 'comprise', and variations such as 'comprises' and 'comprising', will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
Detailed description of example embodiments:
It is convenient to describe the invention herein in relation to particularly preferred embodiments relating to production of montelukast sodium. However, it is to be appreciated that other constructions and arrangements are also considered as falling within the scope of the invention. Various modifications, alterations, variations and or additions to the construction and arrangements described herein are also considered as falling within the ambit and scope of the present invention.
Scheme II depicts the overall synthetic process of a preferred embodiment according to the present invention which relates to the synthesis of intermediates useful in synthesizing Montelukast.

Example 1
Methyl 3-methyIbenzoate

To a solution of m- toluic acid (136 g, 1 mol) in methanol (800 mL) was added dropwise concentrated sulphuric acid (10 mL) under stirring at room temperature and heated under reflux for 15 h. After completion of the reaction (monitored by TLC), about 80% methanol was distilled off. The reaction mixture was diluted with water (800 mL) and extracted with dichloromethane twice (2 X 200 mL) and the combined organic layer was washed with aqueous sodium bicarbonate (10%, 200 mL) solution followed by water. The organic layer was dried over anhydrous sodium sulphate and the solvent was removed by distillation.
Colorless Liquid, 150 g (Quantitative yield)

To a solution of Methyl 3-methyIbenzoate (150 g, 1 mol) and l,3-Dibromo-5,5-dimethyl hydantoin (DDH) (150 g, 0.52 mol) in dichloromethane (500 mL) was added AIBN (0.1 g, 0.0006 mol) at room temperature and heated under reflux for 10 h. AIBN in 0.1 g lots were added intermittently during reflux to complete the reaction. After completion of the reaction (monitored by TLC), the reaction mixture was poured into cold water (600 mL) and the organic layer was separated. The aqueous layer was extracted again with dichloromethane

To a cooled solution of potassium ethyl malonate (46.1 g, 0.27 mol) in acetonitrile (400 mL) at 10-15°C under nitrogen was added triethylamine (41.8 g, 0.41 mol) followed by anhydrous MgCl2 (30.7g, 0.32 mol) under stirring. The Reaction mixture was allowed to warm to 20-25°C and stirring was contined for 2 hr. The slurry obtained was cooled to 0-5°C and added the acid chloride obtained above, quickly and the reaction mixture was kept overnight at 20-25°C. After completion of the reaction (monitored by TLC), acetonitrile was removed under vacuum, cooled to 10-15°C and acidified with (aq. HCI, 13 % , 270 mL) by maintaining the temperature below 25°C. The precipitate obtained was filtered and washed with water and dried under vacuum.
Yellow solid, 44 g (90% yield)

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Patent Number

278173

Indian Patent Application Number

1710/CHE/2006

PG Journal Number

53/2016

Publication Date

23-Dec-2016

Grant Date

15-Dec-2016

Date of Filing

19-Sep-2006

Name of Patentee

LAURUS LABS PRIVATE LIMITED

Applicant Address

2nd Floor, Serene Chambers, Road No: 7, Banjara Hills, Hyderabad- 500034, Telangana State, India

Inventors:

#	Inventor's Name	Inventor's Address
1	GOTTUMUKKALA VENKATA SUBBARAJU OF LAKSHMI SURYA	A-16 NALANDA NAGAR TIRUPATI 517502 Andra pradesh.
2	CHAVA, SATYANARAYANA	PLOT NO. 40, PARK VIEW ENCLACE, MANO VIKAS NAGAR, HASMATHPET ROAD, SECUNDERABAD 500009, AP, INDIA
3	CASUKHEL SOMESWARA RAO	PLOT NO. 94, FLAT NO. 301, ROAD NO. 13A, BANJARA HILLS, HYDERABAD 500034, AP, INDIA

PCT International Classification Number

C07K14/715

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA