WO2015087351A2 - Procédé de préparation de (1s,3s,7s,10r,11s,12s,16r)-7,11-dihydroxy-8,8,10,12,16-pentaméthyl-3-[(1e)-1-méthyl-2-(2-méthyl-4-thiazolyl)éthényl]-17-oxa-4-azabicyclo[14.1.0]heptadécane-5,9-dione et de ses intermédiaires - Google Patents

Procédé de préparation de (1s,3s,7s,10r,11s,12s,16r)-7,11-dihydroxy-8,8,10,12,16-pentaméthyl-3-[(1e)-1-méthyl-2-(2-méthyl-4-thiazolyl)éthényl]-17-oxa-4-azabicyclo[14.1.0]heptadécane-5,9-dione et de ses intermédiaires Download PDF

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WO2015087351A2
WO2015087351A2 PCT/IN2014/000771 IN2014000771W WO2015087351A2 WO 2015087351 A2 WO2015087351 A2 WO 2015087351A2 IN 2014000771 W IN2014000771 W IN 2014000771W WO 2015087351 A2 WO2015087351 A2 WO 2015087351A2
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WO2015087351A3 (fr
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
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Msn Laboratories Private Limited
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Priority claimed from IN5704CH2013 external-priority patent/IN2013CH05704A/en
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Publication of WO2015087351A3 publication Critical patent/WO2015087351A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/28—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
    • C07F9/6539—Five-membered rings

Definitions

  • the present invention provides an improved process for the preparation of ( 1 S,3 S,7S, 1 OR, 11 S, 12S, 16R)-7, 11 -dihydroxy-8,8, 10, 12, 16-pentamethyl-3-[( 1 E)- 1 -methyl-2- (2-methyl-4-thia2iolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane-5,9-dione represented by the following structural formula I and intermediates thereof.
  • the present invention also provides novel intermediate compounds useful for the preparation of compound of formula I and its intermediates.
  • Epothilones are a new class of cancer drugs. Like taxanes, they prevent cancer cells from dividing by interfering with tubulin. But, Epothilones have better efficacy and milder adverse effects than taxanes.
  • Epothilones Early studies in cancer cell lines and in human cancer patients indicate superior efficacy of Epothilones to the taxanes. Their mechanism of action is similar, but their chemical structure is simpler. Due to their better water solubility, cremophors (solubilizing agents used for paclitaxel which can affect cardiac function and cause severe hypersensitivity) are not needed. Endotoxin-like properties known from paclitaxel, like activation of macrophages synthesizing inflammatory cytokines and nitric oxide, are not observed for Epothilone-B. Epothilones were originally identified as metabolites produced by the soil-dwelling myxobacterium Sorangium cellulosum.
  • the present inventors developed improved processes for the preparation of compound of formula I and its intermediates which produces the said compounds in higher yields and better purities.
  • the first aspect of the present invention is to provide an improved process for the preparation of compound of general formula A.
  • the second aspect of the present invention is to provide a novel process for the preparation of compound of general formula A-VII.
  • the third aspect of the present invention is to provide a process for the preparation of compound of general formula B-IV.
  • the fourth aspect of the present invention is to provide an improved process for the preparation of compound of general formula C.
  • the fifth aspect of the present invention is to provide an improved process for the preparation of compound of general formula AB-II.
  • the sixth aspect of the present invention is to provide an improved process for the preparation of compound of general formula AB-III.
  • the seventh aspect of the present invention is to provide an improved process for the preparation of compound of general formula AB-II.
  • the eighth aspect of the present invention is to provide an improved process for the preparation of compound of formula I.
  • the ninth aspect of the present invention is to provide novel intermediate compounds which are useful in the synthesis of compound of formula I and its intermediates.
  • the tenth aspect of the present invention is to provide an alternative process for the preparation of intermediate compound of general formula A- VII.
  • suitable solvent refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” such as dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; “ester solvents” such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n- butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents” such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidon
  • suitable base refers 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, cesium 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 tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; ammonia, alkali metal and alkaline earth metal salts of acetic
  • suitable protecting agent used in the present invention refers to a group of reagents independently selected such that they are capable of protecting the hydroxy groups of various compounds of the present invention with suitable O-protecting groups selected from but not limited to silyl protecting groups, 3,4-dihydro-2H-pyranyl (DHP), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), methyl, acetyl, benzyl, benzoyl, benzyloxycarbonyl (Cbz), trifluoroacetyl, pivaloyl, allyl, methoxymethyl (MOM), ethoxyethy (EE), methoxyethoxymethyl (MEM), p-methoxybenzyl (PMB), methylthiomethyl (MTM), triphenylmethyl (trityl), methoxytrityl (MMT), dimethoxytrityl (DMT), benzyloxymethyl (BOM), tert
  • DHP
  • the suitable protecting agent is selected from but not limited to trialkyl silyl halides such as trimethylsilyl chloride (TMSC1), triethylsilyl chloride (TESC1), triisopropylsilyl chloride (TIPSC1), tert-butyldimethylsilyl chloride (TBDMSC1), tert-butyldiphenylsilyl chloride (TBDPSC1) and the like; trialkyl silyl triflates such as trimethylsilyl triflate (TMSOTf), triethylsilyl triflate (TESOTf), triisopropylsilyl triflate (TIPSOTf), tert- butyldimethyl silyl triflate (TBDMSOTf or TBSOTf), tert-butyldiphenylsilyl triflate (TBDPSC1) and the like; N,0-bis(trimethylsilyl)acetamide (BSA), hexemethyldisilazane
  • the "suitable deprotecting agent” is selected from but not limited to acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, formic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid, camphor sulfonic acid and the like, bases such as alkali metal hydroxides, alkali metal carbonates, cesium carbonate/imidazole, alkali metal bicarbonates, ammonia, cerium ammonium nitrate (CAN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), hydrogenating agents such as Pd, Pd/C, Pd(OH) 2 /C (Pearlman's catalyst), palladium acetate, platinum oxide (Pt0 2 ), platinum black, sodium borohydride, BF 3 -etherate, Raney-Ni, triethylsilane, trimethylsilyl halides, copper(
  • the first aspect of the present invention provides an improved process for the preparation of compound of g
  • the said process comprises of the following steps; a) Reacting the (S)-2-hydroxysuccinic acid compound of " formula A-I
  • R 5 represents Ci-C 6 straight chain or branched chain alkyl or C 6 -Cio aryl groups
  • the suitable catalyst is selected from a Bronsted or a Lewis acid catalyst; preferable catalyst is p-toluenesulfonic acid;
  • the suitable reducing agent is selected from borane-dimethylsulfide, borane-tetrahydrofuran, (R)-2-methyl-CBS-oxazaborolidine and the like; the preferred catalyst is borane-dimethylsulfide;
  • step-c) and step-e) the suitable O-protecting agent is as defined above;
  • the suitable O-protecting group is selected from silyl based groups such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert.butyldimethylsilyl (TBS or TBD S), tri-iso-propylsilyloxymethyl (TOM), tert- butyldiphenylsilyl (TBDPS) and the like.
  • silyl based groups such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), tert.butyldimethylsilyl (TBS or TBD S), tri-iso-propylsilyloxymethyl (TOM), tert- butyldiphenylsilyl (TBDPS) and the like.
  • TMS trimethylsilyl
  • TES triethylsilyl
  • TIPS triisopropylsilyl
  • the suitable O-protecting agent is selected from tert- butyldimethylsilyl chloride (TBDMSC1), tert-butyldimethylsilyl inflate (TBDMSOTf or TBSOTf) and the O-protection step is carried out in presence of a suitable base selected form inorganic bases, organic bases, organolithium bases, organosilicon bases or their mixtures; in step-d) the suitable methyl metal is methyl lithium and the methyl metal derivative is selected from methyl magnesium halides such as methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide and the like;
  • the suitable base is selected from inorganic bases, organic bases, organolithium bases, organosilicon bases or any of their mixtures;
  • the suitable deprotecting agent is selected based on the type of O-protecting group employed.
  • the suitable O-protecting group is selected from silyl based groups such as defined above. Among those groups tert- butyldimethylsilyl is the preferable group.
  • the suitable deprotecting agent is selected from camphorsulfonic acid, tetra-n-butylammonium fluoride (TBAF), HF, HF- pyridine, HF-triethylamine, N-iodosuccinimde (NIS), combination of chlorotrimethylsilane and potassium fluoride dihydrate, acetic acid, trichloroacetic acid, BF -Et 2 0, CuCl 2 .2H 2 0 and the like;
  • camphorsulfonic acid tetra-n-butylammonium fluoride (TBAF), HF, HF- pyridine, HF-triethylamine, N-iodosuccinimde (NIS), combination of chlorotrimethylsilane and potassium fluoride dihydrate, acetic acid, trichloroacetic acid, BF -Et 2 0, CuCl 2 .2H 2 0 and the like;
  • the suitable oxidizing agent is selected form but not limited to Dess-Martin periodinane (DMP), oxalyl chloride-DMSO in presence of triethylamine in dichloromethane solvent (Swern oxidation), tetrapropylammonium perruthenate (TPAP) optionally in combination with N-methylmorpholine N-oxide (NMO) or molecular oxygen; Collins reagent (Cr0 -Py 2 ), pyridinium dichromate (PDC), pyridinium chlorochromate (PCC), Jones oxidation, sodium hypochlorite in presence of TEMPO, 2-iodoxybenzoic acid, N- chlorosuccinimide in combination with TEMPO and the like; the suitable base is selected form organic bases or inorganic bases or their mixtures;
  • DMP Dess-Martin periodinane
  • TPAP tetrapropylammonium perruthenate
  • NMO N-methylmorpholine N-oxide
  • the suitable base is selected from organosilicon bases, organolithium bases, organic bases, inorganic bases or their mixtures.
  • the suitable solvent is selected from hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvents or their mixtures.
  • a preferred embodiment of the present invention provides an improved process for the preparation of 4-((S,lE,5Z)-3-(tert-butyldimethylsilyloxy)-6-iodo-2-methylhepta-l,5- dienyl)-2-methylthiazole compound of formula Aa, comprising of;
  • a major disadvantage of ozonolysis process is that, the ozonide intermediates formed during the ozonolysis are highly explosive in nature which makes the process unsuitable for large-scale applications. Hence, the prior-known processes for the preparation of di-protected compound of general formula A- VII are not commercially viable.
  • the second aspect of the present invention provides a novel process for the preparation of compound of general formula A-VII, comprising of;
  • R' represents Ci-C 6 straight chain or branched chain alkyl or C6-C ]0 aryl groups
  • X' represents halogens such as CI, Br, I;
  • the suitable reducing agent is selected from sodium borohydride optionally in combination with BF 3 -etherate, sodium cyanoborohydride, lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminum hydride (vitride), lithium triethylborohydride (LiEt 3 BH), lithium tri-sec-butyl(hydrido)borate(l-) (L-selectride), diisobutylaluminium hydride (DIBAL) and the like;
  • step-b) the suitable O-protecting agent and the suitable conditions are same as defined in step-c) of the first aspect of the present invention.
  • the suitable reducing agent is diisobutylaluminium hydride (DIBAL);
  • the suitable halogenating agent is selected from but not limited to chlorine, bromine, iodine, phosphorous trichloride, phosphorous penta chloride, phosphorous tribromide, phosphorous penta bromide, phosphoryl chloride, N-chloro succinimide, N- bromo succinimide, N-iodo succinimide, oxalyl chloride, thionyl chloride, cyanuric chloride, sulfuryl chloride and the like;
  • the suitable base is selected from organic or inorganic bases; and the suitable catalyst is selected from tri alkyl/aryl phosphine, TMSC1, sulfuric acid, nitric acid and the like;
  • the suitable base is selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal amides and the like;
  • step-g) the oxidation is carried out by adopting Wacker oxidation process.
  • the said process involves applying oxygen gas pressure to the reaction mixture containing alkene in a suitable solvent or mixture of solvents in presence of a palladium catalyst such as palladium (II) chloride, palladium (II) acetate, palladium (II) sulfate, palladium (II) nitrate and the like; in this oxidation step chemical oxidants such as Cu (II), Fe (III), Mn0 2 , quinones such as p- benzoquinone, heteropolyacids, hydrogen peroxide are used for the regeneration of Pd(II) from Pd(0).
  • the preferable chemical oxidant is cuprous chloride (CuCl 2 ).
  • inorganic acids are sulfuric acid, nitric acid, perchloric acid (HCIO 4 ) and tetrafluoroboric acid (HBF 4 ).
  • the oxidation of compound of formula A-XVIII to compound of formula A- VII can also be carried out by using Jones reagent (Cr0 3 + H 2 S0 4 +H 2 0) in presence of mercury catalyst such as mercury acetate, mercury propionate and the like;
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • a preferred embodiment of the present invention provides a novel process for the preparation of (S)-3,5-bis(tert-butyldimethylsilyloxy)pentan-2-one compound of formula A- Vlla, comprising of;
  • the third aspect of the present invention provides a process for the preparation of co >mpound of general formula B-IV, comprising of;
  • P 3 represents O-protecting group
  • the suitable "peptide coupling agent” is selected from ⁇ , ⁇ '- dicyclohexyl carbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)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 phenylchloro formate, benzyl chloroformate and the like, diphenylphosphoryl azide (DPP A), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4- methyl-2
  • step-c) the suitable reducing agent is same as defined in step-a) of the second aspect of the present invention.
  • step-d) the suitable O-protecting agent and the suitable conditions are same as defined in step-c) of the first aspect of the present invention.
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • a preferred embodiment of the present invention provides a process for the preparation of (S)-tert-butyldimethyl(2-methylpent-4-enyloxy)silane compound of formula B-IVa, comprising of;
  • the fourth aspect of the present invention provides an improved process for the preparation of compound of general formula C, comprising of;
  • step-a) & step-c) the suitable O-protecting agent and the suitable conditions are same as defined in step-c) of the first aspect of the present invention
  • the suitable methylating agent is selected from dimethyl sulfate, methyl halides such as methyl bromide, methyl iodide, dimethyl carbonate, trimethyloxonium tetrafluoroborate (Me 3 O.BF 4 ), methyl alkyl/aryl sulfonates such as methyl methane sulfonate (MeOMs), methyl ethanesulfonate, methyl benzenesulfonate, methyl toluene sulfonate (MeOTs), methyl trifluoromethanesulfonate (MeOTf), tetramethylammonium salts such as tetramethylammonium halides, trimethylsilyldiazomethane (TMSD) and the like;
  • the suitable base is selected from inorganic bases, organic bases, organolithium bases, organosilicon bases or their mixtures;
  • step-d) the suitable reducing agent and the suitable solvent are same as defined in step-c) of the second aspect of the present invention.
  • the suitable base is selected form organic bases, inorganic bases, organolithium bases, organosilicon bases or their mixtures;
  • step-f) the oxidation of compound of general formula C-V is carried out by using the oxidizing agents as mentioned in step-h) of the first aspect of the present invention;
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • a preferred embodiment of the present invention provides an improved process for the preparation of (S)-5,7-bis(tert-butyldimethylsilyloxy)-4,4-dimethylheptan-3-one compound of formula Ca, comprisi
  • the fifth aspect of the present invention provides an improved process for the preparation of compound of general formula AB-II, comprising of;
  • the suitable Palladium catalyst is selected from Pd(PPh 3 ) 2 Cl 2> Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(OH) 2 , Pd 2 (dba) 3 , Pd(dppe) 2 Cl 2 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(dcypp)Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , PdCl 2 , palladium tetrakis-(triphenylarsine), Pd 2 (dba) 3 .CHCl 3 and the like;
  • the suitable base is selected form organic bases, inorganic bases, organosilicon bases, organolithium bases or their mixtures;
  • the suitable phase transfer catalyst may include any quaternary onium salt and their corresponding anions.
  • Suitable phase transfer catalyst include tetraalkylonium, tetraarylonium, tetraaralkylonium and any combination of these types of onium substituents. More specifically the phase transfer catalyst may include tetraaklylammonium halides such as tetrabutylammonium chloride or benzyltriethylammonium chloride.
  • the onium substituent may be ammonium, phosphonium, or arsonium.
  • Exemplary anions for these quartenary salts include, but are not limited to, halides, hydroxyl, cyano, phosphate, sulfate and the like.
  • the most preferable phase transfer catalyst is triphenylarsine.
  • the suitable reducing agent is same as defined in step-c) of the third aspect of the present invention.
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • a preferred embodiment of the present invention provides an improved process for the preparation of (2S,6Z,9S,10E)-9-(tert-butyldimethylsilyloxy)-2,6,10-trimethyl-l l-(2- methylthiazol-4-yl)undeca-6, -dien-l-ol compound of formula AB-IIa, comprising of;
  • the sixth aspect of the present invention provides an improved process for the preparation of compound of g
  • the suitable reducing agent is preferably diisobutylaluminium hydride (DIBAL) and the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • DIBAL diisobutylaluminium hydride
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • a preferred embodiment of the sixth aspect of the present invention provides an improved process for the preparation of (2S,6Z,9S, 10E)-9-(tert-butyldimethylsilyloxy)- 2,6,10-trimethyl-l l-(2-methylthiazol-4-yl)undeca-6,10-dienal compound of formula AB-IIIa,
  • Formula AB-IIIa comprising of reducing the (R)-3-((2S,6Z,9S,10E)-9-(tert-butyldimethylsilyloxy)-2,6, 10- trimethyl- 1 1 -(2-methylthiazol-4-yl)undeca-6, 10-dienoyl)-4-phenyloxazolidin-2-one compound of formula AB-Ia with diisobutylalurninium hydride in toluene to provide compound of formula AB-IIIa.
  • the seventh aspect of the present invention provides an improved process for the preparation of compound of general formula AB-II, comprising of;
  • P 3 represents O-protecting group
  • step-b) the suitable Palladium catalyst, the suitable base and the suitable phase transfer catalyst are same as defined in step-b) of the fifth aspect of the present invention;
  • step-c) the suitable deprotecting agent and the suitable conditions are same as defined in step-g) of the first aspect of the present invention;
  • the suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar solvents, nitrile solvents, polar aprotic solvents, ketone solvents or their mixtures.
  • the present inventors developed an improved process for the said coupling step by adopting coupling of compound of general formula A with borane compound of general formula B-VI and were able to get the product with enhance yields.
  • the present process is advantageous over the prior-art process and is commercially viable.
  • a preferred embodiment of the present invention provides an improved process for the preparation of (2S,6Z,9S,10E)-9-(tert-butyldimethylsilyloxy)-2,6,10-trimethyl-l l-(2- methylthiazol-4-yl)undeca-6, 10-dien- 1 -ol compound of formula AB-IIa, comprising of;
  • the eighth aspect of the present invention provides an improved process for the preparation of (1S,3S,7S,10R,11S,12S,16R)-7, 1 l-dihydroxy-8,8,10,12,16-pentamethyl-3- [(1 E)- 1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl]- 17-oxa-4-azabicyclo[ 14.1.0]heptadecane- 5,9-dione compound of formula I.
  • the said process comprises of the following steps;
  • the suitable azide source 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(PPh 3 ) 2 Cl 2> Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(OH) 2 , Pd 2 (dba) 3 , Pd(dppe) 2 Cl 2 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 .CH 2 Cl 2 , Pd(dcypp)Cl 2 , Pd(PhCN) 2 Cl 2 , Pd(CH 3 CN) 2 Cl 2 , PdCl 2
  • the suitable reducing agent is selected from trialkyl/aryl phosphines such as trimethylphosphine, triethylphosphine, trivinylphosphine, triphenylphosphine, Pt0 2 , H 2 /Lindlar catalyst, trialkylsilanes, Pd/C, Raney Nickel; Fe, Zn in acidic medium such as HC1, acetic acid, NH 4 C1 and the like;
  • step-c) the suitable peptide coupling agent, the suitable base and the suitable solvent are same as defined in step-a) of the third aspect of the present invention.
  • 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) and the like;
  • 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 and the like.
  • 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.
  • a preferred embodiment of the present invention provides an improved process for the preparation of (1 S,3S,7S,10R,1 1S,12S,16R)-7,1 l-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 I, comprising of;
  • the ninth aspect of the present invention provides novel intermediate compounds which are useful in the synthesis of compound of formula I and its intermediates.
  • the said novel intermediate compounds are represented by the below mentioned structural formulae;
  • 'X' represents halogens such as CI, Br, I; 'Pi'and ' ⁇ 2 ' are same or different and represents O-protecting groups.
  • the tenth aspect of the present invention provides an alternative process for the preparation of intermediate compound of general formula A- VII.
  • the said process comprises the steps of; a) Reducing the compound of general formula A-V with a suitable reducing agent in a suitable solvent to provide compound of general formula A-XIX,
  • the suitable reducing agent is diisobutyl aluminium hydride (DIBAL);
  • step-b) the suitable methyl metal and the suitable methyl metal derivative are same as defined in step-d) of the first aspect of the present invention
  • step-c) the suitable O-protecting agent and the suitable conditions are same as defined in step-c) of the first aspect of the present invention
  • the suitable oxidizing agent and the suitable solvent are same as defined in step-h) of the first aspect of the present invention; in step-a) to step-d) 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.
  • a preferred embodiment of the present invention provides a process for the preparation of (S) ⁇ 3,5-bis(tert-butyldimethylsilyloxy)pentan-2-one compound of formula A- Vlla, comprises the steps of;
  • 1,3-Dichloroacetone (169 gm) was slowly added to a mixture of thioacetamide (100 gm) and methanol (100 ml) at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 90 min at the same temperature. Ethyl acetate was added to the reaction mixture at 55- 60°C. Cooled the reaction mixture to 25-30°C and stirred for 40 min at the same temperature. Filtered the precipitated solid, washed with a mixture of methanol and ethyl acetate and dried the material for 20 min. The obtained solid was added to water (1000 ml) at 25-30°C. Slowly added aqueous sodium carbonate solution to the reaction mixture at 25-30°C.
  • Methyl tert.butyl ether was added to the reaction mixture and stirred for 30 min. Both the organic and aqueous layers were separated and the organic layer was washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure. Triethyl phosphite (245 ml) was added to the obtained compound at 25-30°C. Heated the reaction mixture to 125-130°C and stirred for 24 hrs at the same temperature. Reduced the temperature of the reaction mixture to 85-90°C and downward distilled the reaction mixture under reduced pressure. Cooled the reaction mixture to 25-30°C, water and cyclohexane were added and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
  • Example-2 Preparation of (S)-2-(2,2-dimethyl-5-oxo-l,3-dioxolan-4-yl)acetic acid (Formula A-II)
  • Aqueous ammonium chloride solution was slowly added to the reaction mixture at 0-5°C.
  • Methyl tert.butyl ether was added to the reaction mixture at 25-30°C and stirred for 20 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
  • Methyl magnesium chloride (1386 ml) was slowly added to the reaction mixture lot wise at -20°C to -15°C under nitrogen atmosphere and stirred for 5 hrs at the same temperature.
  • the obtained reaction mixture was slowly added to aqueous ammonium chloride solution at 0-5°C. Acidified the reaction mixture using aqueous acetic acid solution.
  • Methyl tert.butyl ether was added to the reaction mixture at 0-5°C and raised the temperature of the reaction mixture to 25-30°C. Filtered the reaction mixture, both the organic and aqueous layers were separated from the filtrate. Washed the organic layer with water followed by with aqueous sodium chloride solution and distilled off the solvent completely from the organic layer under reduced pressure.
  • Imidazole (66.1 gm) and triphenylphosphine (170 gm) were added to a pre-cooled mixture of (R)-3,5-bis(tert-butyldimethylsilyloxy)pentan-l-ol compound of formula A-XVIa (1 13 gm) and dichloromethane (1130 ml) at 0-5°C.
  • Iodine (164.5 gm) was added to the reaction mixture at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 hr at the same temperature. Quenched the reaction mixture with sodium thiosulfate solution.
  • Tetrahydrofuran (1300 ml) was added to diethyl (2-methylthiazol-4- yl)methylphosphonate compound of formula A- Vila (105 gm) under nitrogen atmosphere at 25-30°C. Cooled the reaction mixture to -70°C to -75°C. 1.6M n-butyl lithium (262 ml) solution was slowly added to the reaction mixture at -70°C to -75 °C and stirred for 1 hr at the same temperature.
  • Example-13 Preparation of (S,E)-3-(tert-butyIdimethylsilyIoxy)-4-methyl-5-(2- methylthiazoI-4-yI)pent-4-en-l-ol (Formula A-Xa) Methanol (1500 ml) and dichloromethane (1500 ml) were added to (S,E)-4-(3,5- bis(tert-butyldimethylsilyloxy)-2-methylpent-l-enyl)-2-methylthiazole compound of formula A-IXa (100 gm) at 25-30°C. Cooled the reaction mixture to -5°C to -10°C and stirred for 15 min at the same temperature.
  • D-camphor sulfonic acid 53 gm was slowly added to the reaction mixture at -5°C to -10°C and stirred for 30 min at the same temperature. Raised the temperature of the reaction mixture to 0-5°C and stirred for 5 hrs at the same temperature. 5% Aqueous sodium bicarbonate solution was added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was purified by column chromatography using 10% ethyl acetate in cyclohexane as eluent to get the pure title compound.
  • reaction mixture Cooled the reaction mixture to 0-5°C and 5% aqueous sodium bicarbonate solution followed by 5% aqueous sodium thiosulfate solution were slowly added to it. Raised the temperature of the reaction mixture to 25-30°C and stirred for 30 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. The obtained residue was purified ' by column chromatography using 5% ethyl acetate in cyclohexane as eluent to get pure title compound.
  • Example-15 Preparation of 4-((S,lE,5Z)-3-(tert-butyldimethyIsilyloxy)-6-iodo-2- methylhepta-l,5-dienyI)-2-methylthiazoIe (Formula Aa) Tetrahydrofuran ( 145 ml) was added to ethyl triphenyl phosphonium iodide (19.3 gm) under nitrogen atmosphere at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 10 min at the same temperature. 1.6M n-butyl lithium solution (48 ml) was added to the reaction mixture at -5°C to 0°C.
  • Example-16 Preparation of (S,E)-4-(3,5-bis(tert-butyldimethylsiIyloxy)-2-methylpent- l-enyl)-2-methylthiazole (Formula A-IXa)
  • Tetrahydrofuran (1300 ml) was added to diethyl (2-methylthiazol-4- yl)methylphosphonate compound of formula A- Villa (105 gm) at 25-30°C under nitrogen atmosphere. Cooled the reaction mixture to -25°C to -20°C and stirred for 20 min at the same temperature. Sodium bis(trimethylsilyl)amide (209 ml) was slowly added to the reaction mixture at -25°C to -20°C and stirred for 1 hr at the same temperature.
  • Triethylamine (53 ml) was added to the reaction mixture at -75°C to -70°C and stirred for 15 min at the same temperature. Raised the temperature of the reaction mixture to 0-5°C and stirred for 30 min at the same temperature. Water was added drop wise to the reaction mixture at 0-5°C and raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution followed by with water. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.
  • Tetrahydrofuran (490 ml) was added to ethyltriphenylphosphonium iodide (51.3 gm) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 10 min at the same temperature.
  • Sodium bis(trimethylsilyl)amide (62 ml) was added to the reaction mixture at 25-30°C and stirred for 30 min at the same temperature.
  • Aqueous ammonium chloride solution and methyl tert.butyl ether were added to the reaction mixture at -40°C to -35°C and raised the temperature of the reaction mixture to 25-30°C. Filtered the reaction mixture through hyflow bed and washed the hyflow bed with methyl tert.butyl ether. Both the organic and aqueous layers were separated from the filtrate and concentrated the organic layer under reduced pressure. Purified the obtained compound by column chromatography using 0-1% ethyl acetate in hexane to get the pure title compound.
  • Example-20 Preparation of (R)-4-phenyI-3-propionyIoxazolidin-2-one (Formula B-I) ( )-4-phenyloxazolidin-2-one (100 gm) and dimethylaminopyridine (10 gm) were added to a mixture of propionic acid (50 gm) and toluene (400 ml) at 25-30°C. Cooled the reaction mixture to 0-5°C, dicyclohexylcarbodiimide (151.5 gm) was slowly added and stirred the reaction mixture for 1 hr at the same temperature. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 14 hrs at the same temperature.
  • Aqueous ammonium chloride solution followed by methyl tert.butyl ether were added to the reaction mixture at 0-5°C. 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 washed the organic layer with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under reduced pressure and co- distilled with isopropyl alcohol. 300 ml of isopropyl alcohol was added to the obtained compound. Heated the reaction mixture to 60-65 °C and stirred for 15 min at the same temperature. Cooled the reaction mixture to 0-5°C. Petroleum ether (300 ml) was slowly added to the precipitated solid at 0-5 °C and stirred for 60 min at the same temperature. Filtered the solid, washed with petroleum ether and dried to get the title compound.
  • Example-24 Preparation of (R)-3,5-dihydroxypentanenitrile (Formula A-XIII) temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and washed the organic layer with aqueous sodium chloride solution. Dried the organic layer and distilled off the solvent completely under reduced pressure to get the title compound. Yield: 230.0 gm.
  • Example-31 Preparation of 4-((lE,3S,5Z,10S)-3,ll-bis(tert-butyIdimethylsilyloxy)- 2,6,10-trimethylundeca-l,5-dienyl)-2-methylthiazoIe (Formula AB-IVa)
  • Cesium carbonate (57 gm) was added to a solution of 4-((S,lE,5Z)-3-(tert- butyldimethylsilyloxy)-6-iodo-2-methylhepta-l ,5-dienyl)-2-methylthiazole compound of formula Aa (32.5 gm) in dimethylformamide (625 ml) at 25-30°C under nitrogen atmosphere and stirred the reaction mixture for 10 min at the same temperature. Triphenylarsine (2.7 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature.
  • Example-32 Preparation of (R)-3-((2S,6Z,9S,10E)-9-(tert-butyldimethylsilyloxy)- 2,6, 10-trimeth l- 11 -(2-methyIthiazol-4-yl)undeca-6, 10-dienoyl)-4-phenyloxazolidin- 2-one (Formula AB-Ia)
  • Pd(dppf)Cl2.CH 2 Cl2 (3.3 gm) was added to the reaction mixture at 25-30°C and stirred for 10 min at the same temperature. Water was added to the reaction mixture at 25-30°C and nitrogen gas was purged into the reaction mixture for 20 min and stirred for 4 hrs at the same temperature. The above obtained borane complex was added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Aqueous ammonium chloride solution and methyl tert-butyl ether were added to the reaction mixture at 0-5°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by column chromatography using 6% ethyl acetate in cyclohexane to get the pure title compound.
  • Example-37 Preparation of (7S,10R,llS,12S,19S,Z)-7-(tert-butyldimethylsilyloxy)- ll-hydroxy-2,2,3,3,8,8,1 ,12,16,21,21,22,22-tridecamethyH9-((E)-l-(2- methylthiazol-4-yl)prop-l-en-2-yl)-4,20-dioxa-3,21-disilatricos-16-en-9-one (Formula D-Ia)
  • 1.6M n-butyl lithium 23 ml was slowly added to a pre-cooled mixture of diisopropylamine (4.5 ml) and tetrahydrofuran (65 ml) at -10°C to -5°C under nitrogen atmosphere. Raised the temperature of the reaction mixture to 0-5°C and stirred for 45 min at the same temperature. Cooled the reaction mixture to -78°C and stirred for 15 min at the same temperature.
  • Example-38 Preparation of (7S,10R,llS,12S,19S,Z)-7,ll-bis(tert-butyldimethyl sUyloxy)-2,2,3,3,8,8,10,12,16,21,21,22,22-tridecamethyl-19-((E)-l-(2-methylthiazol-4- yl)prop-l-en-2-yl)-4,20-dioxa-3,21-disilatricos-16-en-9-one (Formula D-IIa)
  • Example-39 Preparation of (5S,8R,9S,10S,17S,Z)-9-(tert-butyldimethylsilyloxy)-5- (2-hydroxyethyl)-2,2,3,3,6,6,8,10,14,19,19,20,20-tridecamethyl-17-((E)-l-(2- methylthiazol-4-yl)prop- l-en-2-yl)-4, 18-dioxa-3, 19-disilahenicos- 14-en-7-one
  • D-Camphorsulfonic acid (1.8 gm) was slowly added to the reaction mixture at -10°C to -5°C and stirred for 30 min at the same temperature. Raised the temperature of the reaction mixture to -5°C to 0°C and stirred for 3 hrs at the same temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture at 0-5°C. 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 distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by flash column chromatography using 1*% ethyl acetate in cyclohexane to get the pure title compound.
  • Example-40 Preparation of (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris(tert- butyldimethylsilyloxy)-4,4,6,8, 12, 16-hexamethyl- 17-(2-methyIthiazol-4-yl)-5- oxoheptadeca-12,16-dienal (Formula D-IVa)
  • Example-41 Preparation of (3S,6R,7S,8S,12Z,15S,16E)-3,7,15-tris(tert- butyldimethylsilyloxy)-4,4,6,8,12,16-hexamethyl-17-(2»methylthiazol-4-yl)-5- oxoheptadeca-12,16-dienoic acid (Formula D-Va)
  • Example-42 Preparation of (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis(tert- butyldimethylsilyloxy)-15-hydroxy-4,4,6,8,12,16-hexamethyl-17-(2-methylthiazol-4- yl)-5-oxoheptadeca-12,16-dienoic acid (Formula D-VIa)
  • Triethylamine (3.4 ml) and 2,4,6-trichlorobenzoyl chloride (3.2 ml) were added to a pre-cooled mixture of (3S,6R,7S,8S,12Z,15S,16E)-3,7-bis(tert-butyldimethylsilyloxy)- 15-hydroxy-4,4,6,8, 12, 16-hexamethyl- 17-(2-methylthiazol-4-yl)-5-oxoheptadeca-l 2, 16- dienoic acid compound of formula D-VIa (3 gm) and tetrahydrofuran (50 ml) at ()-5°C under nitrogen atmosphere and stirred for 1 hr at the same temperature.
  • Trifluoroacetic acid (3.7 ml) was slowly added to a pre-cooled mixture of (4S,7R,8S,9S, 16S,Z)-4,8-bis(tert-butyldimethylsilyloxy)-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 D-VIIa (1.5 gm) and dichloromethane (15 ml) at 0-5°C under nitrogen atmosphere and stirred the reaction mixture for 45 min at the same temperature.
  • Example-45 Preparation of (3S,6R,7S,8S,12Z,15S,16E)-15-azido-3,7-dihydroxy- 4,4,6,8, 12, 16-hexamethyI- 17-(2-methylthiazol-4-yl) 5-oxoheptadeca- 12, 16-dicnoic acid
  • Formula E A mixture of tetrahydrofuran arid water (15 ml; 10:1 ratio) 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-l-en-2-yl)oxacyclohexadec-13-ene-2,6-dione compound of formula D (1 gm) at 25-30°C under nitrogen atmosphere.
  • Tetrahydrofuran (25 ml) and water (5 ml) were added to (3 S,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 E (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 25-30°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.
  • 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 F (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.
  • Example-48 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 (Ixabepilone)
  • 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 G (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.
  • Example-51 Preparation of (3S,6R,7S,8S)-ll-((2R,3S)-3-((S,E)-2-amino-3-methyI-4- (2-methylthiazol-4-yl)but-3-enyl)-2-methyloxiran-2-yl)-3,7-dihydroxy-4,4,6,8- tetramethyI-5-oxoundecanoic acid
  • Forma K A mixture of tetrahydroiuran and water (80 ml; 10:2 ratio) was added to (3S,6R,7S,8S)-l l-((2R,3S)-3-((S,E)-2-azido-3-methyl-4-(2-methylthiazol-4-yl)but-3- enyl)-2-methyloxiran-2-yl)-3,7-dihydroxy-4,4,6,8-tetramethyl-5-oxoundecanoic acid compound of formula J (4 gm
  • Trimethylphosphine solution (18.2 ml; 1M solution in tetrahydroiuran) was added to the reaction mixture at 25-30°C and stirred for 2 hrs at the same temperature. Distilled off the reaction mixture under reduced pressure and co-distilled with toluene. The obtained compound was purified by column chromatography using 30% methanol in ethyl acetate. Yield: 3.0 gm.
  • Example-52 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)ethenyI]-17-oxa- 4-azabicyclo[14.1.0]heptadecane-5,9-dione (Ixabepilone)

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Abstract

La présente invention concerne un procédé amélioré de préparation de (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12,16-pentaméthyl-3-[(1E)-1-méthyl-2-(2-méthyl-4-thiazolyl)éthényl]-17-oxa-4-azabicyclo[ 14.1.0]heptadécane-5,9-dione, représentée par la formule développée I suivante, et de ses intermédiaires. La présente invention concerne également de nouveaux composés intermédiaires utilisables en vue de la préparation du composé de formule I et de ses intermédiaires.
PCT/IN2014/000771 2013-12-11 2014-12-11 Procédé de préparation de (1s,3s,7s,10r,11s,12s,16r)-7,11-dihydroxy-8,8,10,12,16-pentaméthyl-3-[(1e)-1-méthyl-2-(2-méthyl-4-thiazolyl)éthényl]-17-oxa-4-azabicyclo[14.1.0]heptadécane-5,9-dione et de ses intermédiaires WO2015087351A2 (fr)

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IN2117CH2014 2014-04-28
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CN110922423A (zh) * 2019-10-16 2020-03-27 杭州励德生物科技有限公司 一种艾日布林中间体的合成方法
CN115552672A (zh) * 2020-04-01 2022-12-30 巴斯夫欧洲公司 在氧化还原液流电池中用作电解质的tempo衍生物的溶液

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US6365749B1 (en) * 1997-12-04 2002-04-02 Bristol-Myers Squibb Company Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs
WO2013164102A1 (fr) * 2012-04-30 2013-11-07 Xellia Pharmaceuticals Aps Procédé de préparation d'ixabépilone et intermédiaires utiles dans ledit procédé

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CN110922423A (zh) * 2019-10-16 2020-03-27 杭州励德生物科技有限公司 一种艾日布林中间体的合成方法
CN110922423B (zh) * 2019-10-16 2020-10-20 杭州励德生物科技有限公司 一种艾日布林中间体的合成方法
CN115552672A (zh) * 2020-04-01 2022-12-30 巴斯夫欧洲公司 在氧化还原液流电池中用作电解质的tempo衍生物的溶液

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