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1. (WO2014203045) A NOVEL, GREEN AND COST EFFECTIVE PROCESS FOR SYNTHESIS OF TERT-BUTYL (3R,5S)-6-OXO-3,5-DIHYDROXY-3,5-O-ISOPROPYLIDENE-HEXANOATE
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CLAIMS

1) A process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0- isopropylidene-hexanoate of compound [I]


from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

a) reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 80% de in aqueous micellar aggregate at 0-5°C;

b) converting compound [VIII] to compound [XII] through reaction of 2,2- dimethoxy propane in presence of D-10-camphor sulfonic acid in acetone;

c) converting compound [XII] to optically pure compound [XI] in presence of tetra ft-butyl ammonium acetate in presence of polar aprotic solvent at 95°C and crystallization from n-heptane.

d) converting compound [XI] to compound [II] in presence of base in methanol as solvent.

e) converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

2) The process for synthesis of compound [I] as claimed in claim 1, wherein said micellar aggregate used is obtained from anionic surfactant selected from a group comprising sodium lauryl sulfate, sodium dioctyl sulfosuccinate and sodium dihexyl sulfosuccinate.

3) The process for synthesis of compound [I] as claimed in claim 1, wherein said polar organic solvent used is dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone (NMP); preferably NMP.

4) The process for synthesis of compound [I] as claimed in claim 1, wherein said base used is sodium carbonate, potassium carbonate, lithium carbonate; preferably potassium carbonate.

5) The process for synthesis of compound [I] as claimed in claim 1, wherein said copper salt used is selected from a group comprising CuCl, CuBr, CuCI2, CuSO4, Cu(OTf) and Cu(OTf)2; preferably CuCl.

6) The process for synthesis of compound [I] as claimed in claim 1, wherein said Diimine ligands used is selected from a group comprising pyridine, phenanthroline, bipyridine, DABCO and pybox; preferably bipyridine.

7) The process for synthesis of compound [I] as claimed in claim 1, wherein said organic solvent used is selected from a group comprising dichlorome thane, acetonitrile, mixture of dichloromethane/acetonitrile.

8) A process for synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-O- isopropylidene-hexanoate of compound [I]


from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

d) reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 30 % de in aqueous micellar aggregate at 0-5°C;

e) converting diastereomeric excess compound [VIII] to diastereomeric excess compound [XII] through reaction of 2,2-dimethoxy propane in presence of D- 10-camphor sulfonic acid in acetone;

f) converting compound [XII] to optically pure compound [IX] through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 20 °C, followed by separation of compound [IX] through selective extraction with n-hexane from crude product

[IX]·

9) A process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-0- isopropylidene-hexanoate of compound [I]


from (S)-tert-butyl 6-chloro-5-hydroxy-3-oxohexanoate [VI]


Comprising steps of:

f. reducing compound [VI] with sodium borohydride to yield compound [VIII] having at least 30 % de in aqueous micellar aggregate at 0-5°C; g. converting compound [VIII] to optically pure compound [IX] through selective ketal formation with 2,2-dimethoxy propane in presence of D-10-camphor sulfonic acid in dichloromethane, followed by separation of compound [IX] through selective extraction with n- hexane from crude product [IX] ;

h. converting compound [IX] to optically pure compound [XI] in presence of tetra n-butyl ammonium acetate in presence of polar aprotic solvent at 95°C and crystallization from n-heptane; i. converting compound [XI] to compound [II] in presence of base in methanol as solvent;

j. converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

10) The process for synthesis of compound [I] as claimed in claim 8 or 9, wherein said micellar aggregate used is obtained either from cationic surfactant selected from a group comprising benzalkonium chloride and cetyl tri-methyl ammonium bromide or amphoteric surfactant such as lecithin.

11) The process for synthesis of compound [I] as claimed in claim 9, wherein said polar organic solvent used is dimethylformamide, dimethylsulfoxide, N- methylpyrrolidone (NMP); preferably NMP.

12) The process for synthesis of compound [I] as claimed in claim 9, wherein said base used is sodium carbonate, potassium carbonate, lithium carbonate; preferably potassium carbonate.

13) The process for synthesis of compound [I] as claimed in claim 9, wherein said copper salt used is selected from a group comprising CuCl, CuBr, CuCI2, CuSO4,

Cu(OTf) and Cu(OTf)2; preferably CuCl.

14) The process for synthesis of compound [I] as claimed in claim 9, wherein said diimine ligands used is selected from a group comprising pyridine, phenanthroline, bipyridyl, bipyridine, DABCO and pybox; preferably bipyridyl. 15) The process for synthesis of compound [I] as claimed in claim 9, wherein said organic solvent used is selected from a group comprising dichlorome thane, acetonitrile, mixture of dichloromethane/acetonitrile.

16) A process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O- isopropylidene-hexanoate of compound [I]

from 4-chloro-3-((alkylsilyl)oxy)butanal [V]


Comprising steps of:

e) reacting compound [V] with Reformatsky reagent of compound [IV] in a solvent to obtain compound [VII] ;

f) treating compound [VII] with tetra-butyl ammonium fluoride in THF to obtain compound [VIII] ;

g) converting diastereomeric excess compound [VIII] to diastereomeric excess compound [XII] through reaction of 2,2-dimethoxy propane in presence of D- 10-camphor sulfonic acid in acetone.

h) Converting compound [XII] to optically pure compound [IX] having at least 98% de through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 25°C, followed by separation of compound [IX] through selective extraction with n-hexane from crude product [IX] .

17) A process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O- isopropylidene-hexanoate of compound [I]

from 4-chloro-3-((alkylsilyl)oxy)butanal [V]


Comprising steps of:

g. reacting compound [V] with Reformatsky reagent of compound [IV] in a solvent to obtain compound [VII] ;

h. treating compound [VII] with tetra-butyl ammonium fluoride in THF to obtain compound [VIII] ;

i. converting compound [VIII] to compound [IX] having at least 98% de through selective ketal formation with 2,2-dimethoxy propane in presence of D-10-camphor sulfonic acid in dichloromethane, followed by separation of compound [IX] through selective extraction with n- hexane from crude product [IX] ;

j. converting optically pure Compound [IX] to compound [XI] in presence of tetra n-butyl ammonium acetate in presence of polar aprotic solvent at 95 °C;

k. converting compound [XI] to compound [II] in presence of base in methanol as solvent;

1. Compound [II] was converted to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

18) The process for synthesis of compound [I] as claimed in claims 16 or 17, wherein said reaction is carried out in organic solvent is chosen from THF, 2-methylfuran; preferably THF.

19) The process for synthesis of compound [I] as claimed in claims 17, wherein said reaction is carried out in organic solvent is chosen from dimethylformamide, dimethyl sulfoxide, NMP; preferably NMP.

20) The process for synthesis of compound [I] as claimed in claims 17, wherein said reaction is carried out in presence of a base and base is chosen from sodium carbonate, potassium carbonate, lithium carbonate; preferably potassium carbonate.

21) The process for synthesis of compound [I] as claimed in claims 17, wherein said silyl protection group is chosen from a group comprising trimethyl silyl, tert-butyl dimethyl silyl group.

22) The process for synthesis of compound [I] as claimed in claims 17, wherein said copper salt used is selected from a group comprising CuCl, CuBr, CuCI2, CuSO4, Cu(OTf) and Cu(OTf)2; preferably CuCl.

23) The process for synthesis of compound [I] as claimed in claims 17, wherein said diimine ligands used are selected from a group comprising pyridine, phenanthroline, bipyridyl, bipyridine, DABCO and pybox; preferably bipyridyl.

24) The process for synthesis of compound [I] as claimed in claims 17, wherein said organic solvent used is selected from a group comprising dichlorome thane, acetonitrile or mixture of dichloromethane/acetonitrile.

25) The process for synthesis of compound [I] as claimed in claims 17, wherein said Reformatsky reagent of compound [IV] is selected from a group comprising reaction of zinc dust with ethyl bromoacetate, ethyl iodoacetate, teri-butyl bromoacetate and teri-butyl iodoacetate.

26) A process for synthesis of tert-butyl (3R,55)-6-oxo-3,5-dihydroxy-3,5-0- isopropylidene-hexanoate of compound [I]


from diasteromeric excess teri-butyl 2-((4R,65)-6-(acetoxymethyl)-2,2-dimethyl- l,3-dioxan-4-yl)acetate [XIII]

Comprising steps of:

d) Converting compound [XIII] to optically pure compound [XI] having at least 98 % de through selective hydrolysis of undesired isomer in biphasic mixture of 2 N aqueous hydrochloric acid and dichloromethane at 25°C, followed by separation of compound [XI] ;

e) Converting compound [XI] to compound [II] in presence of a base in methanol as solvent;

f) Converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

27) The process for synthesis of compound [I] as claimed in claims 26, wherein said reaction is carried out in presence of a base and base is chosen from sodium carbonate, potassium carbonate, lithium carbonate; preferably potassium carbonate.

28) The process for synthesis of compound [I] as claimed in claim 26, wherein said copper salt used is selected from a group comprising CuCl, CuBr, CuCl2, CuSO4, Cu(OTf) and Cu(OTf)2; preferably CuCl.

29) The process for synthesis of compound [I] as claimed in claim 26, wherein said diimine ligands used is obtained from is selected from a group comprising pyridine, phenanthroline, bipyridyl, bipyridine, DABCO and pybox; preferably bipyridyl.

30) The process for synthesis of compound [I] as claimed in claim 26, wherein said organic solvent used is selected from a group comprising dichloromethane or acetonitrile or mixture of dichloromethane/acetonitrile.

31) A process for synthesis of tert-butyl (3R,5S)-6-oxo-3,5-dihydroxy-3,5-O- isopropylidene-hexanoate of compound [I]


from diasteromeric excess tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl- 1,3-dioxan-4-yl)acetate [II]


Comprising of step:

b) Converting compound [II] to optically pure compound [I] in presence of Cu(Salt)/diimine ligands/TEMPO/O2 as oxidization system in organic solvent at 30-50°C.

32) The process for synthesis of compound [I] as claimed in claim 31, wherein said copper salt used is selected from a group comprising CuCl, CuBr, CuCl2, CuSO4, Cu(OTf) and Cu(OTf)2; preferably CuCl.

33) The process for synthesis of compound [I] as claimed in claim 23, wherein said diimine ligands used is obtained from is selected from group comprising pyridine, phenanthroline, bipyridyl, bipyridine, DABCO and pybox; preferably bipyridyl

34) The process for synthesis of compound [I] as claimed in claim 23, wherein said organic solvent used is selected from a group comprising dichlorome thane, acetonitrile or mixture of dichloromethane/acetonitrile.