# US 10,370,365 B2 · Process for the preparation of Canagliflozin

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- Number: US 10,370,365 B2
- Document ID: US10370365B2
- Status: Granted
- Kind: B2
- Application number: 15/244,766
- Filed: 2016-08-23
- Published: 2017-03-16
- Granted: 2019-08-06
- Earliest claimed: 2015-09-16
- Assignees: Optimus Drugs (P) Limited
- Applicants: Optimus Drugs (P) Limited
- Inventors: Srinivas Reddy Desi Reddy; Dnyandev Ragho Rane; Venkata Srinivasa Rao Velivela
- Web page: https://patentgrep.com/patent/US10370365B2

## CPC

- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 333/16: by oxygen atoms
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07H 7/04: Carbocyclic radicals
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The present invention provides a novel process for the preparation of Canagliflozin (I) and its hydrates thereof by employing novel intermediates. The present invention is also provides commercially and industrial applicable process.

## Claims

### Claim 1

A process for the preparation of canagliflozin comprising:
a) reacting (5-bromo-2-methylphenyl) [5-(4-fluorophenyl) thiophen-2-yl] methanone with a tri alkyl orthoformate or tri alkyl orthoaceatate, optionally in the presence of acid, to produce 2-[(5-bromo-2-methylphenyl)(dimethoxy)methyl]-5-(4-fluorophenyl)thiophene;
b) (i) reacting 2-[(5-bromo-2-methylphenyl)(dimethoxy)methyl]-5-(4-fluorophenyl)thiophene with magnesium and iodine at about 25° C. to about 30° C. to form a Grignard reagent, and (ii) condensing the resulting Grignard reagent with 2,3,5,6 tetrakis-O-trimethylsilyl-D-glucanolactone to produce dimethoxy-[5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(2-hydroxy-3,4,5-trimethylsilyloxy-6-trimethylsilyloxymethyl-tetrahydro-pyran-2-yl)-phenyl]-methane;
c) deprotecting dimethoxy-[5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(2-hydroxy-3,4,5-trimethylsilyloxy-6-trimethylsilyloxymethyl-tetrahydro-pyran-2-yl)-phenyl]-methane in the presence of an acid and an alcohol solvent to produce [5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-phenyl]-methanone; and
d) reducing [5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(3,4,5-trihydroxy-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-2-yl)-phenyl]methanone with a trialkyl silane and a Lewis acid, wherein the Lewis acid is selected from boron trichloride, boron tribromide, diborane, boron trifluoride, and complexes thereof, to produce canagliflozin.

### Claim 2 (depends on 1)

The process according to claim 1, wherein in step a) the tri alkyl orthoformate is selected from trimethyl orthoformate and triethyl orthoformate, the tri alkyl orthoaceatate is triethyl ortho acetate, and the acid is selected from hydrochloric acid, sulfuric acid, methane sulfonic acid, and p-toluene sulfonic acid.

### Claim 3 (depends on 1)

The process according to claim 1, wherein in step c) the dimethoxy-[5-(4-fluorophenyl)-thiophen-2-yl]-[2-methyl-5-(2-hydroxy-3,4,5-trimethylsilyloxy-6-trimethylsilyloxymethyl-tetrahydro-pyran-2-yl)-phenyl]-methane is deprotected by reaction with a deprotecting agent in an alcohol solvent, where the deprotecting agent is selected from trifluoro acetic acid, hydrochloric acid, sulfuric acid, and methane sulfonic acid, and the alcohol solvent is selected from methanol, ethanol, propanol, and isopropyl alcohol.

### Claim 4 (depends on 1)

The process according to claim 1, wherein in step d) the trialkyl silane is selected from trimethyl silane, triethyl silane, and tri isopropyl silane.

### Claim 5 (depends on 1)

The process according to claim 1, wherein step d) is performed in a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, water, methanol, toluene, n-hexane, and any combination of any of the foregoing.

### Claim 6 (depends on 1)

The process according to claim 1, wherein the Lewis acid in step d) is boron trifluoride diethyl etherate.