Description:The present invention relates to a synthesis of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate and also provided a purification of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate.

In one embodiment of the present invention provides, a synthesis of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate of formula (I), comprising the steps of:
a) reacting compound of formula (II) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in presence of solvent to obtain the crude compound of formula (I),

b) purifying the crude compound of formula (I) with 1,4-Dioxane.
According to an embodiment of the present invention, reacting compound of formula (II) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in presence of solvent, the reaction is carried out at 20 to 35°C for 1-4 hours, and followed by isolated with solvent to obtain the crude compound of formula (I), wherein dibromo impurity content is more than 3-5%. Crude compound of formula (I) is purified with 1,4-Dioxane, the reaction is carried out at 35 to 55°C and then cooled to 10 to 20°C to get pure compound of formula (I), wherein dibromo impurity content is less than 1.0%.

According to an embodiment of the present invention, wherein the solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, cyclohexanone, n-hexane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform, and/or mixtures thereof.

In yet another embodiment of the present invention provides a purification of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate compound of formula (I), comprising the steps of:
a) Crude compound of formula (I) was dissolved in 1,4-Dioxane,
b) heating the obtained suspension at suitable temperature,
c) cooling the obtained solution in step b), and
d) isolating the pure compound of formula (I).

According to an embodiment of the present invention, crude compound of formula (I) is purified with 1,4-Dioxane, the reaction is carried out at 35 to 55°C and then cooled to 10 to 20°C to get pure compound of formula (I), wherein dibromo impurity content is less than 1.0%.

According to an embodiment of the present invention provides, a compound of formula (I) has HPLC purity = 99.0%.
According to embodiment of the present invention, di bromo impurity compound of formula III,

According to embodiment advantages of the present invention, controlling di bromo impurity by using 1,4-Dioxane, thereby controlling the formation of di bromo impurity is less than 1.0%.

The following examples illustrate the present invention but should not be construed as limiting the scope of the invention.

EXAMPLES
Example-1:
Preparation of Butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (I).
Butyl 4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (100.0g, 0.2964 mol) and dichloromethane (700 mL) was added into RB flask. The reaction mixture was cooled to below 10°C and add portion wise DBDMH (44.07g, 0.1541 mol). The reaction mixture was allowing to room temperature (25-30°C) and stir for 1-2h. After completion of the reaction, the reaction mixture was distilled under vacuum to remove the traces off dichloromethane and finally isolated in methanol (500 ml) to give butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (113.0 g).

Yield: 91.5% (113 gm)
HPLC purity: ~95% and dibromo impurity: ~2-3%

Example-2:
Purification of Butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (I).
Take crude butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (100.0 g) and charged 1,4-dioxane (200 ml, 2vol) into RB flask and then reaction mass heat to 40-50°C, observed clear solution and then cool to 12-16°C. filter the solid and wash with 1,4-dioxane (15ml, 0, 15vol). The obtained product was dried at 50-60°C for 8-10 hrs to get pure Butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (95.0 g).

Yield: 95% (95 gm)
HPLC purity: =99% and Dibromo impurity: <1.0%.
, Claims:1. A synthesis of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate of formula (I), comprising the steps of:
a) reacting compound of formula (II) with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in presence of solvent to obtain the crude compound of formula (I),

b) purifying the crude compound of formula (I) with 1,4-Dioxane.

2. The process as claimed in claim 1, wherein the solvent is selected from tetrahydrofuran, toluene, water, acetone, acetonitrile, ethyl acetate, isopropyl alcohol, methanol, ethanol, dimethyl sulfoxide (DMSO), dimethylformamide (DMF), isopropyl acetate and n-butyl acetate, cyclohexanone, n-hexane, dichloromethane (MDC), dichloroethane, carbon tetrachloride and chloroform, and/or mixtures thereof.

3. A purification of butyl 1-bromo-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate compound of formula (I), comprising the steps of:

a) Crude compound of formula (I) was dissolved in 1,4-Dioxane,
b) heating the obtained suspension at suitable temperature,
c) cooling the obtained solution in step b), and
d) isolating the pure compound of formula (I).

4. The purification as claimed in claim 3, wherein the suitable temperature is carried out at 35-55°C.