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1. (WO2018162964) AN IMPROVED PROCESS FOR THE PREPARATION OF TETROFOSMIN OR ACID ADDITION SALT THEREOF
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We claim:

1. A process for the preparation of tetrofosmin or acid addition salt thereof, comprising the steps of:

a) reduction of diethylbenzylpho


Formula 8

by treating with a suitable reducing agent in the presence of a suitable solvent, optionally in the presence of catalyst, to provide benzyl phosphine of Formula

9;


Formula 9

b) coupling the benzyl phosphine of Formula 9 with vinyl ethyl ether of Formula 3

Formula 3

in the presence of suitable solvent and catalyst to provide benzylbis(2- ethoxyethyl)phosphane of Formula 4; proviso that said coupling step is not carried out under photolytic conditions;


Formula 4

c) coupling of benzylbis(2-ethoxyethyl)phosphane of Formula 4 with 1,2- dibromoethane of Formula 10,


optionally using a suitable solvent, to provide ethane- l,2-diylbis(benzylbis(2- ethoxyethyl)phosphonium)bromide of Formula 11 ;


d) converting the ethane- l,2-diylbis(benzylbis(2-ethoxyethyl) phosphonium) bromide of Formula 11 using a suitable base in the presence of suitable solvent into ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12:


Formula 12

e) deoxygenating ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12 using the suitable reagent in the presence of suitable solvent to obtain tetrofosmin, and;

f) optionally, converting tetrofosmin into acid addition salt thereof.

2. A process for the preparation of tetrofosmin or acid addition salt thereof comprising the steps of:

a) reduction of diethylbenzylphosphonate of Formula 8 by treating with lithium aluminium hydride in presence of solvent selected from ether, aliphatic or aromatic hydrocarbon and mixture thereof to provide benzyl phosphine of Formula 9;

b) coupling the benzyl phosphine of Formula 9 with vinyl ethyl ether of Formula 3 in the presence of radical initiator, optionally using solvent, to provide benzylbis(2-ethoxyethyl)phosphane of Formula 4; proviso that said coupling step is not carried out under photolytic conditions;

c) coupling of benzylbis(2-ethoxyethyl)phosphane of Formula 4 with 1,2- dibromoethane of Formula 10 using solvent selected from ester, ketone, nitrile, aliphatic or aromatic hydrocarbons, ethers, halogenated hydrocarbons and mixture thereof to provide ethane- l,2-diylbis(benzylbis(2- ethoxyethyl)phosphonium) bromide of Formula 11 ;

d) converting ethane- l,2-diylbis(benzylbis(2-ethoxyethyl)phosphonium) bromide of Formula 11 using aqu. sodium hydroxide in the presence of alcoholic solvent into ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12;

e) deoxygenating ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12 using hexachlorodisilane in the presence of aprotic solvent to obtain tetrofosmin, and;

f) optionally, converting tetrofosmin into acid addition salt thereof.

3. The process according to claim 1 and 2, wherein in step a) reducing agent used is selected from alkali or alkaline metal hydride such as sodium hydride, sodium borohydride, lithium aluminium hydride (LAH), vitride, diisobutyl aluminium hydride, lithium trialkoxy aluminium hydride; and solvent used is selected from ethers, aliphatic or aromatic hydrocarbons and mixture thereof, ethers are selected from the group comprising of diethyl ether, methyl tert- butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, aliphatic or aromatic hydrocarbons are selected from hexane, heptane, toluene, xylene, benzene and mixture thereof; wherein in step b) catalyst used is selected from radical initiator compounds such a-azo-isobutyronitrile (AIBN), l, l'-azobis(cyclohexanecarbonitrile) (ABCN), tert-amyl peroxybenzoate, 4,4- azobis(4-cyanovaleric acid), 2,2-bis(tert-butylperoxy)butane, l,l-bis(tert- butylperoxy)cyclohexane, 2,5-bis(tert-butylperoxy)-2,5-dimethylhexane, 2,5- bis(tert-butylperoxy)-2,5-dimethyl-3-hexyne, Bis(l-(tert-butyl peroxy)-l- methyl ethyl) benzene, l, l-bis(tert-butylperoxy)-3,3,5-trimethylcyclohexane, tert-butylhydro peroxide, tert-butyl peracetate, tert-butyl peroxide, tert-butyl peroxybenzoate, tert-butylperoxy isopropyl carbonate, cumene hydroperoxide, cyclohexanone peroxide, dicumyl peroxide, lauroyl peroxide, 2,4- pentanedione peroxide, peracetic acid, potassium persulfate benzoyl peroxide ((PhCOO)i), methyl ethyl ketone peroxide and acetone peroxide.

4. The process according to claim 1 and 2, wherein in step c) solvent used is selected from esters, ketone, nitrile, aliphatic or aromatic hydrocarbons, ethers and mixture thereof; and wherein in step d) solvent used is selected from water, alcohols, nitrile and mixture thereof; and base used is selected from organic or inorganic base, wherein inorganic base used is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate and mixture thereof.

5. The process according to claim 1 and 2, wherein in step e) reagent used for deoxygenating is selected from hexachlorodisilane, trichlorosilane, alkyl dichlorosilane; and solvent used is selected from aliphatic or aromatic hydrocarbons, chloro solvents and mixture thereof.

6. A process for the preparation of tetrofosmin or acid addition salt thereof, comprising the steps of:

a) reduction of diethylbenzylphosphonate of Formula 8 by treating with lithium aluminium hydride in presence of methyl tertiary butyl ether to provide benzyl phosphine of Formula 9;

b) coupling the benzyl phosphine of Formula 9 with vinyl ethyl ether of Formula 3 in the presence of a-azo-isobutyronitrile (AIBN) to provide benzylbis(2- ethoxyethyl)phosphane of Formula 4; proviso that said coupling step is not carried out under photolytic conditions;

c) coupling of benzylbis(2-ethoxyethyl)phosphane of Formula 4 with 1,2- dibromoethane of Formula 10 using acetonitrile as solvent to provide ethane- l,2-diylbis(benzylbis(2- ethoxyethyl)phosphonium) bromide of Formula 11;

d) converting ethane- l,2-diylbis(benzylbis(2- ethoxyethyl)phosphonium) bromide of Formula 11 using aq. sodium hydroxide in the presence of ethanol as solvent into ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12;

e) deoxygenating ethane- 1, 2-diylbis(bis(2-ethoxyethyl)phosphine oxide of Formula 12 using hexachlorodisilane in the presence of toluene as solvent to obtain tetrofosmin, and;

f) optionally, converting tetrofosmin into acid addition salt thereof.

7. A process for the preparation tetrofosmin or acid addition salt thereof comprising the steps of:

a) coupling of benzyl phosphine of Formula 9 with vinyl ethyl ether of Formula 3 to provide benzylbis(2-ethoxyethyl)phosphane of Formula 4; proviso that said coupling step is not carried out under photolytic conditions; and;

b) further converting the compound of Formula 4 into tetrofosmin or acid addition salt thereof.

8. A process for the preparation of tetrofosmin disulfosalicylate salt, comprising the steps of:

a) dissolving 5-sulfosalicylic acid in water;

b) contacting this reaction mixture with tetrofosmin or its solution thereof, and;

c) isolating tetrofosmin disulfosalicylate salt.

9. The process according to claim 8, wherein in step b) solvent used for the preparation of solution of tetrofosmin is selected from water, alcohol, nitrile and mixture thereof.

10. A process for the preparation of polymorphic form J of tetrofosmin disulfosalicylate salt comprising the steps of:

a) dissolving 5-sulfosalicylic acid in water;

b) contacting this reaction mixture with tetrofosmin, and;

c) isolating tetrofosmin disulfosalicylate salt.