Field of the Invention:

The present invention provides a process for the preparation of (1 S,3 S,7S, 1 OR, 11S, 12S, 16R)-7,11 -dihydroxy-8,8,10,12,16-pentamethyl-3-[( IE)-1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione represented by the following structural formula-1 and its intermediates. Formula-1 The present invention also provides a novel intermediate compound, which is useful for the preparation of compound of formula-1 and process for its preparation.

Background of the invention:

(lS,3S,7S,10R,llS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione, commonly known as Ixabepilone is an Epothilone B analog developed by Bristol-Myers Squibb as a chemotherapeutic medication for cancer.

US6605599B1 discloses the derivatives of Epothilones including aza derivatives. Ixabepilone and process for its preparation is first disclosed in US6605599B1. The disclosed process is schematically represented as follows.

The present inventors developed an improved process for the preparation of compound of formula-1.

Brief description of the invention:

The first aspect of the present invention is to provide a process for the preparation of (3S,6R,7S,8SJ2ZJ5S46E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4.

The second aspect of the present invention is to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxo heptadeca-12,16-dienoic acid compound of formula-3, which is a novel intermediate useful in the synthesis of compound of formula-1.

The third aspect of the present invention is to provide a process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3.

The fourth aspect of the present invention is to provide a process for the preparation of(lS,3S,7S,10R,HS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione compound of formula-1.

Detailed description of the invention:

The "suitable solvent" used in the present invention is selected from but not limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl cyclohexane, cycloheptane, pet ether, benzene, chlorobenzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl tert-butyl ether, di-tert-butyl ether, dimethoxy methane, dimethoxy ethane (monoglyme), diglyme, 1,4-dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, morpholine and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, iso-butyl acetate, tert-butyl acetate, diethyl carbonate and the like; "polar-aprotic solvents" such as dimethylacetamide (DMAc), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), hexamethyl phosphoramide (HMPA) and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbontetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol and the like; "polar solvents" such as water; acetic acid, formic acid or their mixtures.

The "suitable base" used in the present invention is selected from but not limited to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tertbutoxide, potassium tert.butoxide, lithium tertbutoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" such as methyl amine, ethyl amine, n-propyl amine, isopropyl amine, diisopropyl amine, diisopropylethyl amine (DIPEA), diisobutylamine, triethylamine, tert.butyl amine, di-tert-butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), l,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO), imidazole or their mixtures.

The first aspect of the present invention provides a process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2- methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 (commonly known as Epothilone-D) Formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid of formula-3, Formula-3 b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide compound of formula-4. Wherein, in step-a) the suitable azide is selected from alkali metal azides such as sodium azide, potassium azide, diphenylphosphoryl azide (DPPA), trialkylsilyl azides, tetrabutylammonium azide and the like; the suitable palladium catalyst is selected from Pd(PPh3)2Cl2) Pd(PPh3)4, Pd(OAc)2, Pd(OH)2, Pd2(dba)3, Pd(dppe)2Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, Pd(dcypp)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2 and the like;

In step-b) the suitable reducing agent is selected from trialkyl/aryl phosphines such as trimethylphosphine, triethylphosphine, trivinylphosphine, triphenyl phosphine and the like, Pt02, H2/Lindlar catalyst, trialkylsilanes, Pd/C, vitride, Raney Nickel; Fe, Zn in acidic medium such as HC1, acetic acid, NH4CI and the like;

In step-a) & step-b) the suitable solvent is selected from ether solvents, polar solvents, polar-aprotic solvents, ester solvents, hydrocarbon solvents, nitrile solvents, alcohol solvents, ketone solvents, chloro solvents, acetic acid, formic acid or their mixtures.

A preferred embodiment of the present invention provides a process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16- hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPli3)4 in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3,

b) reducing the compound of formula-3 with trimethylphosphine in a mixture of tetrahydrofuran and water to provide compound of formula-4.

The (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methyl thiazol-4-yl)prop-l-en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 utilized in the present invention can be obtained from any of the commercial sources available or it can be synthesized by any of the procedures known in the art.

The second aspect of the present invention provides (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid represented by the following structural formula.

The above azide compound is a very useful intermediate in the synthesis of compound of formula-1.

The third aspect of the present invention provides a process for the preparation of (3S,6R,7S,8S, 12Z, 15S, 16E> 15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3, comprising of reacting the (4S,7R,8S,9S, 16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl- 16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide compound of formula-3. Wherein, the suitable azide, the suitable palladium catalyst and the suitable solvent are same as defined in step-a) of the first aspect of the present invention.

A preferred embodiment of the present invention provides a process for the preparation of (3 S,6R,7S,8S, 12Z, 15S, 16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16- hexamethyH7-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3, comprising of reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPli3)4 in a mixture of tetrahydrofuran and water to provide compound of formula-3.

The fourth aspect of the present invention provides a process for the preparation of (lS,3S,7S,10R,llS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione compound of formula-1. The said process comprising of the following steps:

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl- 16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (3S,6R,7S,8S,12Z,15S,16E)-15-aniino-3,7-dihydroxy-4,4,6,8,12,16-hexa methyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid of formula-4,

c) cyclization of compound of formula-4 by reacting it with a suitable peptide coupling agent in a suitable solvent optionally in presence of a suitable base to provide (4S,7R,8S,9SJ6S,Z)-4,8-dmydroxy-5,5J,9a3-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-1 -en-2-yl)azacyclohexadec-13-ene-2,6-dione compound of formula-5,

Formula-5 d) epoxidation of compound of formula-5 by reacting it with a suitable oxidizing agent in a suitable solvent to provide compound of formula-1.

Wherein, in step-a) the suitable azide, the suitable palladium catalyst and the suitable solvent are same as defined in step-a) of the first aspect of the present invention;

In step-b) the suitable reducing agent and the suitable solvent are same as defined in step-b) of the first aspect of the present invention;

In step-c) the suitable peptide coupling agent is selected from N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethylamino propyl)carbodiimide (EDC) or its hydrochloride salt, N,N-carbonyl diimidazole (CDI), substituted or unsubstituted alkyl or aryl haloformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, p-nitro phenylchloroformate, benzyl chloroformate and the like, diphenylphosphoryl azide (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), alkyl or aryl sulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride and the like optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxy benzotriazole (HOBt), 1-hydroxy-1H-1,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N,,N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxy succinimide (NHS), N-hydroxysulfosuccinimide (Sulfo-NHS) and the like; the suitable base is selected from organic or inorganic bases; the suitable solvent is selected from chloro solvents, polar-aprotic solvents, alcohol solvents, ether solvents, ester solvents, polar solvents, ketone solvents, nitrile solvents, hydrocarbon solvents, acetic acid, formic acid or mixtures thereof;

In step-d) the suitable oxidizing agent is selected from per acids such as perbenzoic acid, m-chloro perbenzoic acid, performic acid, peracetic acid, trifluoroperacetic acid and the like; sodium hypochlorite, hydrogen peroxide, oxone, dimethyl dioxirane (DMDO) and the like; the suitable solvent is selected from chloro solvents, ether solvents, hydrocarbon solvents, polar-aprotic solvents, polar solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, acetic acid, formic acid or their mixtures.

In the present invention, the epoxidation of (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)azacyclohexadec-13-ene-2,6-dione compound of formula-5 can be carried out optionally in presence of a suitable catalyst selected from 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), 4-methoxy TEMPO, 4-amino TEMPO, 4-acetamido TEMPO, 2-azaadamantane N-Oxyl (AZADO), 1-methyl-AZADO and the like.

A preferred embodiment of the present invention provides a process for the preparation of (lS,3S,7S,10R,HS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[(1E)-1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione compound of formula-1, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPh3)4 in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid of formula-3,

b) reducing the compound of formula-3 with trimethylphosphine in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4,

c) cyclization of compound of formula-4 by reacting it with l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride in presence of 1-hydroxybenzotriazole in a mixture of dimethylformamide and acetonitrile to provide (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)azacyclohexa dec-13-ene-2,6-dione compound of formula-5,

d) epoxidation of compound of formula-5 by reacting it with m-chloroperbenzoic acid in chloroform to provide compound of formula-1.

The present invention is schematically represented as follows: Scheme-I:

Examples:

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

Example-1: Preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid (Formula-3)

A mixture of tetrahydrofuran and water (15 ml; 10:1 ratio) was added to (4SJR,8S,9S46S,Z)-4,8-dmydroxy-5,5J,943-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl) prop-l-en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 (1 gm) at 25-30°C under nitrogen atmosphere. Purged the reaction mixture with nitrogen gas for 20 min. Pd(PPh3)4 (0.35 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Sodium azide (0.2 gm) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 45-50°C and stirred for 1 hr at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate were added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 10% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.0 gm.

Example-2: Preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid (Formula-4)

Tetrahydrofuran (25 ml) and water (5 ml) were added to (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxo heptadeca-12,16-dienoic acid compound of formula-3 (1 gm) at 25-30°C under nitrogen atmosphere. 1.0 M solution of trimethylphosphine in tetrahydrofuran (4.7 ml) was added to the reaction mixture at 25-3 0°C and stirred for 3 hrs at the same temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure and co-distilled with toluene to get the title compound. Yield: 0.95 gm.

Example-3: Preparation of (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl- 16-((E)-l-(2-methylthiazol-4-yl)prop-l-en-2-yl)azacycIohexadec-13-ene-2,6-dione (Formula-5) N,N-dimethylformamide (10 ml) was added to (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4 (0.95 gm) at 25-30°C under nitrogen atmosphere and stirred for 10 min at the same temperature. Acetonitrile (95 ml) was added to the reaction mixture at 25-30°C and cooled to 0-5°C. 1-hydroxybenzotriazole (0.25 gm) and l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (0.9 gm) were added to the reaction mixture at 0-5 °C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 25-30°C and stirred for 12 hrs at the same temperature. Water and ethyl acetate were added to the reaction mixture at 25-3 0°C and stirred for 10 min at the same temperature. Both the organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 5% aqueous sodium bicarbonate solution followed by 5% aqueous sodium chloride solution. Distilled off the solvent completely form the organic layer under reduced pressure. The obtained residue was purified by column chromatography using 60% ethyl acetate in cyclohexane as eluent. Yield: 0.43 gm.

Example-4: Preparation of (lS,3S,7S,10R,HS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16- pentamethyl-3-[(lE)-l-methyl-2-(2-methyl-4-thiazoIyl)ethenyl]-17-oxa-4-azabicyclo [14.1.0]heptadecane-5,9-dione(Formula-l) Chloroform (45 ml) was added to (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)azacyclohexadec-13 -ene-2,6-dione compound of formula-5 (0.43 gm) at 25-30°C under nitrogen atmosphere and stirred for 10 min at the same temperature. Cooled the reaction mixture to -15°C to -20°C and m-chloro perbenzoic acid (0.23 gm) was added and stirred for 4 hrs at the same temperature. Dichloromethane and 7% aqueous sodium bicarbonate solution were added to the reaction mixture. Raised the temperature of the reaction mixture to 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and the organic layer was washed with 7% aqueous sodium bicarbonate solution, 25% aqueous sodium sulfite solution followed by 5% aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was purified by preparative HPLC to get the tile compound. Yield: 0.31 gm.

We Claim:

1. A process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione of formula-2

Formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide compound of formula-4.

2. A process according to claim 1, wherein, in step-a) the suitable azide is selected from alkali metal azides such as sodium azide, potassium azide; diphenylphosphoryl azide (DPPA), trialkylsilyl azides, tetrabutylammonium azide; the suitable palladium catalyst is selected from Pd(PPh3)2Cl2) Pd(PPh3)4, Pd(OAc)2, Pd(OH)2, Pd2(dba)3, Pd(dppe)2Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, Pd(dcypp)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2;

In step-b) the suitable reducing agent is selected from trialkyl/aryl phosphines such as trimethylphosphine, triethylphosphine, trivinylphosphine, triphenylphosphine, Pt02, H2/Lindlar catalyst, trialkylsilanes, Pd/C, Raney Nickel; Fe, Zn in acidic medium such as HC1, acetic acid, NH4CI;

In step-a) & step-b) the suitable solvent is selected from ether solvents, polar solvents, polar-aprotic solvents, ester solvents, hydrocarbon solvents, nitrile solvents, alcohol solvents, ketone solvents, chloro solvents, acetic acid or their mixtures.

3. A process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy- 4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5 -oxoheptadeca-12,16-dienoic acid compound of formula-4, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l- (2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPh3)4 in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7- dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca- 12,16-dienoic acid of formula-3,

b) reducing the compound of formula-3 with trimethylphosphine in a mixture of tetrahydrofuran and water to provide compound of formula-4.

4. A process for. the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy- 4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3, comprising of reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13 -pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexa dec-13-ene-2,6-dione compound of formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide compound of formula-3.

5. A process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3, comprising of reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexa dec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPli3)4 in a mixture of tetrahydrofuran and water to provide compound of formula-3.

6. A process for the preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methyl thiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4, comprising of reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide compound of formula-4.

7. A process for the preparation of (lS,3S,7S,10R,HS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[( 1E)-1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione compound of formula-1, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-l-en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with a suitable azide in a suitable solvent optionally in presence of a suitable palladium catalyst to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3,

b) reducing the compound of formula-3 with a suitable reducing agent in a suitable solvent to provide (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-4,

c) cyclization of compound of formula-4 by reacting it with a suitable peptide coupling agent in a suitable solvent optionally in presence of a suitable base to provide (4S,7R,8S,9S, 16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methyl thiazol-4-yl)prop-l-en-2-yl)azacyclohexadec-13-ene-2,6-dioneof formula-5, I rormulao d) epoxidation of compound of formula-5 by reacting it with a suitable oxidizing agent in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula-1.

8. A process according to claim 7, wherein, in step-a) the suitable azide is selected from alkali metal azides such as sodium azide, potassium azide, diphenylphosphoryl azide (DPPA), trialkylsilyl azide, tetrabutylammonium azide; the suitable palladium catalyst is selected from Pd(PPh3)2Cl2; Pd(PPh3)4, Pd(OAc)2, Pd(OH)2, Pd2(dba)3, Pd(dppe)2Cl2, Pd(dppf)Cl2, Pd(dppf)Cl2.CH2Cl2, Pd(dcypp)Cl2, Pd(PhCN)2Cl2, Pd(CH3CN)2Cl2;

in step-b) the suitable reducing agent is selected from trialkyl/aryl phosphines such as trimethylphosphine, triethylphosphine, trivinylphosphine, triphenyl phosphine, Pt02, H2/Lindlar catalyst, trialkylsilanes, Pd/C, Raney Nickel; Fe, Zn in acidic medium such as HC1, acetic acid, NH4CI;

in step-c) the suitable peptide coupling agent is selected from N,N'-dicyclohexyl carbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), l-ethyl-3-(3-dimethyl aminopropyl)carbodiimide (EDC) or its hydrochloride salt, N,N-carbonyldiimidazole (CDI), substituted or unsubstituted alkyl or aryl haloformates such as methyl chloroformate, ethyl chloroformate, isobutyl chloroformate, phenyl chloroformate, p-nitro phenylchloroformate, benzyl chloroformate, diphenylphosphoryl azide (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4-methyl-2-oxopentanoyl chloride (i-BuCOCOCl), benzotriazol-1-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), alkyl or aryl sulfonyl halides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride optionally in combination with l-hydroxy-7-azatriazole (HOAt), 1-hydroxybenzotriazole (HOBt), l-hydroxy-lH-l,2,3-triazole-4-carboxylate (HOCt), 0-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU), N-hydroxy succinamide (NHS), N-hydroxysulfosuccinimide (Sulfo-NHS); the suitable base is selected from organic or inorganic bases;

in step-d) the suitable oxidizing agent is selected from peracids such as perbenzoic acid, m-chloro perbenzoic acid, performic acid, peracetic acid, trifluoroperacetic acid, sodium hypochlorite, hydrogen peroxide, oxone, dimethyl dioxirane (DMDO); the suitable catalyst is selected from 2,2,6,6-tetramethyl-piperidin-l-yl)oxyl (TEMPO), 4-methoxy TEMPO, 4-amino TEMPO, 4-acetamido TEMPO, 2-azaadamantane N-Oxyl (AZADO), 1-methyl-AZADO;

in step-a) to step-d) the suitable solvent is selected from chloro solvents, ether solvents, hydrocarbon solvents, polar-aprotic solvents, polar solvents, ester solvents, alcohol solvents, ketone solvents, nitrile solvents, acetic acid or their mixtures.

9. A process for the preparation of (lS,3S,7S,10R,HS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[(l E)-1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione compound of formula-1, comprising of;

a) Reacting the (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-l-(2-methylthiazol-4-yl)prop-1 -en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula-2 with sodium azide in presence of Pd(PPh3)4 in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca-12,16-dienoic acid compound of formula-3,

b) reducing the compound of formula-3 with trimethylphosphine in a mixture of tetrahydrofuran and water to provide (3S,6R,7S,8S,12Z,15S,16E)-15-amino-3,7-dihydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4-yl)-5-oxoheptadeca- 12,16-dienoic acid compound of formula-4,

c) cyclization of compound of formula-4 by reacting it with l-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride in presence of 1-hydroxybenzotriazole in a mixture of dimethylformamide and acetonitrile to provide (4S,7R,8S,9S,16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl) azacyclohexa dec-13-ene-2,6-dione compound of formula-5,

d) epoxidation of compound of formula-5 by reacting it with m-chloro perbenzoic acid in chloroform to provide compound of formula-1.

10. A process for the preparation of (lS,3S,7S,10R,llS,12S,16R)-7,ll-dihydroxy-8,8,10,12,16-pentamethyl-3-[( 1E)-1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione compound of formula-1, comprising of epoxidation of (4S,7R,8S,9S, 16S,Z)-4,8-dihydroxy-5,5,7,9,13-pentamethyl-16-((E)-1 -(2-methylthiazol-4-yl)prop-1 -en-2-yl)azacyclohexadec-13 -ene-2,6-dione compound of formula-5 with a suitable oxidizing agent selected from sodium hypochlorite, hydrogen peroxide, oxone, peracids such as perbenzoic acid, m-chloro perbenzoic acid, performic acid, peracetic acid, trifluoroperacetic acid in a suitable solvent optionally in presence of a suitable catalyst to provide compound of formula-1.