Process for synthesis of res metirom and its intermediates thereof
AssigneeRoyal Pharma
InventorNilesh Vipinchandra MEHTA
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Abstract
The present invention discloses a process for synthesis of Res metirom and its intermediates thereof. More particularly, the invention discloses process for synthesis of a key intermediate, 6-(4-amino, 2,6-dichlorophenoxy)4-isopropylpyridazin-3(2H)-one, of Res metirom via novel intermediate compounds of formula A. Wherein, R is selected from methyl, ethyl and propyl.
Claims18
A process for synthesis of 6-(4-amino, 2,6-dichlorophenoxy)4-isopropylpyridazin-3(2H)-one via an intermediate compound of formula A, the process comprising:
- a) reacting 4-(6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine with an acid anhydride of formula RC(═O)OC(═O)R, wherein R is a methyl, ethyl, or propyl, or an acid chloride of formula RCOCl, wherein R is methyl, ethyl or propyl, to obtain the intermediate compound of formula A;
- b) oxidizing the intermediate compound of formula A in the presence of NaOAc/AcOH to obtain a compound of formula B;
- and
- c) hydrolysing the compound of formula B in the presence of an alcohol and a mineral acid to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one.
An intermediate compound of formula A having the following structure:
- wherein R comprises a methyl, an ethyl or propyl group.
An intermediate compound of formula A1 having the following structure:
- wherein the intermediate compound of formula A1 is characterized by a m/z of 376.31.
A process for preparation of Res-metirom via an intermediate compound of formula A, the process comprising:
- a) reacting 4-(6-chloro-5-isopropylpyridazin-3-yloxy)-3,5-dichlorobenzenamine with an acid anhydride of formula RC(═O)OC(═O)R or an acid chloride of formula RCOCl, wherein R is methyl, ethyl or propyl, to obtain the intermediate compound of formula A;
- b) oxidizing the intermediate compound of formula A in the presence of NaOAc/AcOH to obtain an intermediate compound of formula B;
- c) hydrolysing the intermediate compound of formula B in the presence of an alcohol and a mineral acid to obtain 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one;
- d) reacting the 6-(4-amino-2,6-dichlorophenoxy)-4-isopropylpyridazin-3(2H)-one with N-cyanoacetyl urethane in the presence of sodium nitrite and sodium acetate to obtain (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester;
- and
- e) reacting the (2-cyano-2-{[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-hydrazono}-acetyl)-carbamic acid ethyl ester with sodium acetate or potassium acetate to obtain 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carbonitrile.
Dependencies are inferred from the claim text.