WO2013105100A1 - Procédés de préparation de 5-chloro-n-( {(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl méthyl)-2-thiophène-carboxamide et de ses intermédiaires - Google Patents

Procédés de préparation de 5-chloro-n-( {(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl méthyl)-2-thiophène-carboxamide et de ses intermédiaires Download PDF

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WO2013105100A1
WO2013105100A1 PCT/IN2012/000025 IN2012000025W WO2013105100A1 WO 2013105100 A1 WO2013105100 A1 WO 2013105100A1 IN 2012000025 W IN2012000025 W IN 2012000025W WO 2013105100 A1 WO2013105100 A1 WO 2013105100A1
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unsub
formula
compound
halogen atom
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PCT/IN2012/000025
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Dodda Mohan Rao
Buthukuri Venkat Reddy
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Symed Labs Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to processes for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)-2-thiophene- carboxamide and intermediates thereof.
  • Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is approved in US and Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto®.as 10 mg tablets in Europe and US.
  • Rivaroxaban is chemically described as 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is represented by the structural formula I shown below:
  • the novel processes for the preparation of rivaroxaban from novel intermediate compounds of present invention proceeds with good yields while achieving a good chemical and optical purity.
  • the new process comprises preparation of an alcohol precursor of rivaroxaban by novel methods and activation of an alcohol precursor, amination with some specific amines, which may be removed.
  • the herewith proposed processes of the present invention are particularly advantageous in its practical industrial application since it is much more cost effective. No chromatography is required and final rivaroxaban is obtained with high purity.
  • rivaroxaban can be produced safely and simply with high yields and purities.
  • the present invention relates to processes for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3-[4-(3 -oxo-4-morphol inyl)phenyl]- 1 ,3 -oxazol idin-5 -y 1 ⁇ methyl)-2-thiophene- carboxamide and intermediates thereof.
  • the present invention relates to a process for the preparation of 4- ⁇ 4- [5(S)-(aminomethyl)-2-oxo-l,3-oxazol ⁇ din-3-yl]phenyl ⁇ mo ⁇ holin-3-one compound of formula (II) or a salt thereof ,
  • the reaction step is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol.
  • amine source which may be dissolved in solvent like water or alcohol.
  • solvent like water or alcohol.
  • ammonium hydroxide for example ammonium hydroxide.
  • HL inorganic acids such as HC1, HI and the like; organic acids such as methane sulfonic acid, p -toluene sulfonic acid and the like which can form salt with the amine compound of formula II.
  • the present invention relates to an alternate process for the preparation of 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one compound of formula (II) or a salt thereof
  • the present invention relates to an alternate process for the
  • the present invention provides a process for the preparation of substituted oxazolidinone-phenyl-morpholinone compound of formula (IV)
  • Rl is -OR2,-CX3 or NR 4
  • R 2 ⁇ C _i. 2 _alk l-Straight-cham ⁇ with 1 -3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;
  • R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring;
  • X halogen atom
  • R 7 C M 2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;
  • R10, Rl 1, 12 independently selected from the group consisting of C i_i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • the present invention provides substituted oxazolidinone phenyl morpholinone compound of formula VI.
  • R 8 C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl staright or branched chain;
  • R9 C 2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy
  • R10, Rl 1 , 12 independently selected from the group consisting of C i.i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • the present invention provides a compound of formula VII.
  • the present invention provides a process for the synthesis of compound of formula VII. — . -
  • R7 is same as defined above and X is a halogen atom
  • the present invention relates to an alternate process for the preparation of substituted oxazolidinone phenyl morpholinone compound of formula VI
  • R6 is same as defined above;
  • R2,R3,R4,X same as defined for compound of formula VIII;
  • R 8 C H2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain;
  • R9 C 1-12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);
  • R10, Rl 1, 12 independently selected from the group consisting of C i-i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl; to provide the compound of formula VI.
  • the present invention provides compound of formula IX
  • Rl is -OR2,-CX3 or NR4R3
  • R2 C 1- i2 alkyl straight chain or branched chain, optionally substituted with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;
  • R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring;
  • X halogen atom
  • R C i-i 2 alkyl straight or branched chain, optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl straight or branched chain;
  • R9 C i-i 2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C i-i 2 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);
  • R10, Rl 1, 12 independently selected from the group consisting of C ].i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl.
  • the present invention relates to a process for the preparation of compound of formula IX OCOR,
  • R 5 , R 6 is same as defined above;
  • R14 -OR 15 , NR 3 R 4 , CX 3 or X, where R 3 , R 4 together form a single ring group with the 'N' to which they are bonded or a heteroaryl ring;
  • R15 C ⁇ . 2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;
  • X halogen atom;
  • the present invention provides a compound of formula XI
  • R C 1 -12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- i o alkenyl straight or branched chain;
  • R9 C 1.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1 -12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-Fluorenyl methyloxy (Fmoc);
  • R10, Rl 1 , 12 independently selected from the group consisting of C i- i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • the present invention provides the compound of
  • halogen atom halogen atom
  • R9 C alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);
  • R10, Rl 1, R12 independently selected from the group consisting of C i-i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen-atom-(-s-)rSub-orunsub aryl, sub or unsub arylalkyl;
  • the present invention relates to a process for the preparation of compound 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyI]-l ,3-oxazolidin-5- yl ⁇ methyl)-2-thiophene-carboxamide of formula I
  • R13 is sub or unsub. benzyl, C 3 . 10 alkenyl straight or branched chain;
  • the present invention provides a compound of formula III
  • Rn is C 3 . 10 alkenyl straight or branched chain
  • Fig. 1 -4 are schematic representations of the processes of present invention.
  • the present invention provides the processes for the preparation of 5-chloro-N-( ⁇ (5S)-2-oxo- 3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl ⁇ methyl)-2-thiophene-carboxamide and intermediates thereof.
  • the present invention provides a process for the preparation of 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-o azolidin-3-yl]phenyl ⁇ mo holin-3-one compound of formula (II) or a salt thereof ,
  • the reaction is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol.
  • amine source which may be dissolved in solvent like water or alcohol.
  • solvent like water or alcohol.
  • ammonium hydroxide for example ammonium hydroxide.
  • the solvents as defined herein in this reaction step is selected from alcohols such as methanol, ethanol, isopropanol and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like;_Jialogenated— solvents— suclr ⁇ as ⁇ dichloromethane, ethylene dichloride and the like; esters such as ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF) and the like; or a mixture thereof.
  • tetrahydrofuran or isopropyl alcohol or a mixture thereof Preferably tetrahydrofuran or isopropyl alcohol or a mixture thereof.
  • the reaction can be carried out at a temperature range from about 30°C to about 150°C or the boiling point of the solvent(s) used, preferably at boiling point of the solvent (s) used.
  • the time period required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 8 hour to about 36 hours, preferably from about 12 to 24 hours.
  • HL inorganic acids such as HC1, HI and the like; organic acids such as methane sulfonic acid, p -toluene sulfonic acid and the like which can form salt with the amine compound of formula II.
  • thermodynamic properties of intermediate compound of formula II it would be beneficial to improve the thermodynamic properties of intermediate compound of formula II by providing other salt forms, which have consistent physical and chemical properties.
  • the present invention seeks to provide these and other benefits, which will become apparent as the description progresses.
  • salt formation provides a means of altering the physicochemical characteristics without modifying its chemical structure.
  • a salt form can have a dramatic influence on the properties of the compound.
  • the selection of a suitable salt is partially dictated by yield, rate and quantity of the crystalline structure.
  • hygroscopicity, stability, solubility and the process profile of the salt form are important considerations.
  • the present invention provides various inorganic and organic salt forms of compound of formula II.
  • the acid addition salts are selected from organic salts such as mesylate, para toluene sulfonate, fumarate, succinate, citrate, maleate, acetate, formate, oxalate and like; Inorganic acid salts such as HC1, hydrobromide, hydroiodide, hydrogen sulfate, phosphoric acid salt and like.
  • the salt of compound of formula II are obtained by forming a solution of compound formula II by dissolving in a solvent or mixture of solvents or their aqueous mixtures.
  • the solvents that can be used include, but are not limited to ; Ci -C 6 aliphatic alcohols selected form the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, and tertiary butyl alcohol and the like; C3-Ci 0 aliphatic ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and the like; C 2 -C 5 aliphatic nitriles such as acetonitrile, propionitrile and the like; C3-C10 aliphatic esters such as ethyl acetate, isopropyl acetate and the like: or mixtures thereof in various proportions or their aqueous mixtures.
  • Ci -C 6 aliphatic alcohols selected form the group consisting of methanol, ethanol, n-propanol, isopropanol
  • the compound of formula II and the acid must be combined in the solvent to form the solution.
  • the conditions are such that the entire compound of formula II (and all of the acid) is dissolved in the solvent.
  • the contacting or combining of the compound of formula II -containing solvent with the acid is advantageously performed at an ambient or higher than ambient temperature, including the reflux temperature of the solvent.
  • the acid can be added, e.g., substantially at the same time as the base, before the base, etc.
  • the isolation of the salt in crystalline or amorphous form can be accomplished in various ways.
  • the precipitation can occur spontaneously upon contacting of the compound of formula II with the acid in the organic solvent.
  • Precipitating of the acid addition salt of compound of formula II can also be induced by seeding the solution, cooling the solution, stirring at the same temperatures for longer time period evaporating at least part of the solvent, adding an antisolvent, and by combining one or more of these techniques. Careful control of precipitation temperature and seeding may be used to improve the reproducibility of the production process and the particle size distribution and form of the product.
  • the antisolvents include, but are not limited to, hydrocarbon solvents such as n-hexane, n- heptane, cyclohexane, petroleum ether, toluene and the like or mixtures thereof in various proportions without limitation.
  • hydrocarbon solvents such as n-hexane, n- heptane, cyclohexane, petroleum ether, toluene and the like or mixtures thereof in various proportions without limitation.
  • n-hexane n-hexane.
  • volume of solvent and antisolvent used to precipitate the solid can range from about 5 volumes to about 100 volumes with reference to starting compound taken. Preferably, from about 40 volumes to about 60 volumes with reference to starting compound are taken.
  • the present invention provides an alternate process for the preparation of 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one compound of formula (II) or a salt thereof
  • the suitable metal azides that can be used in the step (a) is selected from the group consisting of sodium azide, potassium" azide, lithium azide or a mixture thereof ; preferably sodium azide is being used.
  • the solvents that can be used in step (a) is selected from nitriles such as acetonitrile and the like; ketones such as acetone and the like; esters such as ethyl acetate, isopropyL
  • ⁇ , ⁇ -dimethylformamide DMF
  • DMSO dimethyl sulfoxide
  • ⁇ , ⁇ -dimethylformamide DMF
  • the reaction step (a) is carried out at a temperature from about 30°C to about boiling point of the solvent(s) used, preferably at from about 70 °C to about 90°C.
  • the time required for the reaction to complete may also vary widely, depending on 20 various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
  • the suitable reducing agents that can be used in the step (b) is selected from metal catalysts such as zinc, nickel, platinum, palladium and the like combined with hydrogen 25 source.
  • the said hydrogen source is preferably one or more selected from hydrogen gas, hydrazine hydrate, ammonium formate, formic acid and formic acid azotrope.
  • hydrogen gas Preferably hydrogen gas.
  • the metal catalyst may be provided on an inert support such as carbon, activated 30 carbon or alumina.
  • Other reducing agents such as triphenyl phosphine, metal borohydrides such as zinc borohydride, sodium borohydride and the like; trimethyl silyl iodide and the like; preferably triphenyl phosphine or catalytic reduction is being used.
  • the other reducing agents which can convert azides into amines known in the literature are also contemplated within this invention.
  • the solvents that can be used in step (b) is selected from the group consisting of alcohols such as methanol, ethanol and the like; esters such as ethyl acetate, isopropyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; hydrocarbons such as toluene and the like; nitriles such as acetonitrile and the like; halogenated solvents such as dichloromethane, chloroform and the like; or a mixture thereof.
  • alcohols such as methanol, ethanol and the like
  • esters such as ethyl acetate, isopropyl acetate and the like
  • ethers such as tetrahydrofuran (THF) and the like
  • hydrocarbons such as toluene and the like
  • nitriles such as acetonitrile and the like
  • halogenated solvents such as dichloromethane, chloroform and
  • the reaction step (b) is usually carried out at a temperature range from about 30°C to about boiling point of the solvent(s) used, preferably at about 30°C.
  • the time required for the reaction step (b) to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected_under_the-preferred-conditions ⁇ discussed above, a period of from about 1 hour to about 15 hours, preferably from about 1 hour to 5 hours.
  • the present invention provides an alternate process for the preparation of 4- ⁇ 4-[5(S)-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholin-3-one compound of formula (II) or a salt thereof
  • the suitable sub. or unsubstituted dibenzylamine used in the step (a) is selected from the group consisting of dibenzylamine , 4,4' -dimethyl dibenzylamine,
  • the solvents that can be_used_in-step-faVis-selected-from ⁇ the group consisting of alcohols such as methanol, ethanol, and the like; halogenated solvents such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; hydrocarbon solvents such as toluene, xylene and the like; ketones such as acetone and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or mixture thereof.
  • acetonitrile or DMF Preferably acetonitrile or DMF.
  • the reaction step a) is carried out in the presence of a base
  • the base that can used is selected from organic bases such as triethyl amine, pyridine and the like; inorganic bases alkali and alkaline earth metal carbonates such as sodium carbonate and the like; bicarbonates such as sodium bicarbonate and the like ; or mixture thereof.
  • the reaction can be carried out at a temperature range from about 30°C to about the boiling point of the solvent(s) used, preferably from about 50°C to about boiling point of the solvent (s) used.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
  • the reaction step (b) can be carried out using suitable reducing agents reported for debenzylation in the literature.
  • the preferable reducing agents are metal catalyst and a hydrogen source, wherein the said metal catalyst is preferably palladium on carbon and or platinum on carbon; more preferably, palladium - carbon.
  • the said hydrogen source is preferably one or more selected from the group consisting of hydrogen, hydrazine hydrate, ammonium formate, formic acid and formic acid azotrope, most preferably hydrogen.
  • the solvents that can be used in step (b) is selected from alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; ketones such as acetone and the like; hydrocarbons such as toluene and the like or a mixture thereof.
  • alcohols such as methanol, ethanol and the like
  • esters such as ethyl acetate and the like
  • ethers such as tetrahydrofuran (THF) and the like
  • ketones such as acetone and the like
  • hydrocarbons such as toluene and the like or a mixture thereof.
  • methanol or ethyl acetate Preferably methanol or ethyl acetate.
  • the reaction step (b) is usually carried out at a temperature range from about 0°C to about 50°C, more preferably at about 30°C.
  • the reaction step (b) is carried out in pjOs ⁇ nm-Of-hydrogen-pressure-range-from-about " 1 to 50 atmospheres, preferably at 1-5 atmospheres.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 6 hours.
  • the leaving group for L in the compound of formula IV can be halogen atom (F, CI, Br, I) or sulfonyloxy group like methanesulfonyloxy, p-toluenesulfonyloxy,
  • Rl is -OR2,-CX3 or NR 4 R 3
  • R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring;
  • X halogen atom
  • R 8 C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s),
  • sub/unsub aryl sub/unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkenyl straight or branched chain;
  • R9 C 1-12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1-12 alkoxy straight or branched chain optionally sub. with 1 -3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy;
  • the suitable bases that can be used in step a) is selected from base having an alkoxide group with C i -7 ; C i -4 alkyl carbanion such as methyl, sec-butyl, butyl or tert-butyl; a conjugate base of a carbamate; lithium diisopropyl amide, lithium amide, n-butyl lithium and the like or mixture thereof.
  • a base does not contain a lithium cation (bases for ex. Sodium, potassium or tetra alkyl ammonium salt)
  • lithium salt such as lithium chloride, lithium bromide, lithium iodide, lithium acetate, lithium tetraflouroborate and other lithium inorganic salts can be used to form the lithium cation and base in situ.
  • reaction step a) is carried out using a nucleophile.
  • nucleophile is not critical.
  • An example of a nucleophile is an alkoxide group, linear or branched, having C i -7 atoms.
  • Preferred nucleophile is methoxide or ethoxide or isopropoxide or isobutoxide or 2-ethoxyethyl, 2-(N,N-dimethylamino) ethoxide or 2,2,2- trichloroethoxide or 2,2,2-trifluoroethoxide.
  • alkoxide salts such as lithium, sodium or potassium methoxide, ethoxide or isopropoxide can be used or the alkoxide formed insitu by reacting a_base-as-referred-above with a corresponding alcohol such as methanol, ethanol or isopropanol.
  • a lithium alkoxide is used as a nucleophile and a base
  • the lithium cation, the base and the nucleophile required may be from the same chemical substance and atleast two equivalents of such chemical substance are needed for reaction.
  • the solvents that can be used in step a) should be neutral but are not limited to alcohols such as tert-amyl alcohol, tert-butyl alcohol and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF), 2-methyl THF and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), N,N-dimethylacetamide (DMA), acetonitrile and the like; halogenated solvents such as dichloromethane, chloroform and the like; Preferably, ⁇ , ⁇ -dimethylformamide (DMF) or THF or mixture thereof is being used.
  • alcohols such as tert-amyl alcohol, tert-butyl alcohol and the like
  • hydrocarbon solvents such as toluene and the like
  • ethers such as tetrahydrofuran (THF), 2-methyl THF and the like
  • the reaction step a) can be carried out at a temperature range from about -78°C to the boiling point of the solvent(s) used, preferably from about 0°C to about 30°C.
  • the time required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 8 hour to about 20 hours.
  • the deprotection reaction step (b) can be carried out by using any deprotecting agent reported in the art and capable of disassociating the desired protecting group. The use of suitable deprotecting reagents depends upon the protecting group present.
  • the suitable deprotection reagents used is selected from the group consisting of trimethyl silyl chloride; trimethyl silyl iodide; inorganic acids such as HC1, HBr, sulfuric acid, phosphoric acid and the like; alkali or alkaline earth metal alkoxides such as sodium
  • methoxide, magnesium methoxide and the like metal carbonates such as potassium carbonate, and the like
  • metal carbonates such as potassium carbonate, and the like
  • hydrazine hydrate catalysts comprising of zinc, nickel, platinum, palladium and the like combined with hydrogen source.
  • Alkali hydroxides such as potassium hydroxide and the like.
  • the solvents that can be used in step (b) is selected from the group consisting of water, acetic acid, alcohols such as methanol, ethanol, and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate,
  • ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; aprotic polar solvents such as N,N-dimethylformamide (DMF), acetonitrile and the like; or mixture thereof.
  • THF tetrahydrofuran
  • DMF N,N-dimethylformamide
  • acetonitrile or mixture thereof.
  • the reaction step (b) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably at about 30°C.
  • the time required for the reaction step (b) to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed. However, the reaction is effected under the preferred conditions discussed above, a period of from about 1 hour to about 15 hours, preferably from about 2 hour to 10 hours.
  • reaction step (c) can be carried out by reacting the compound of formula V obtained in step (b) with a suitable reagent such as R-S0 2 C1
  • R C 1 -4 alkyl straight or branched chain, sub or unsub. aryl, sub or unsub arylalkyl.
  • the reaction step c) is carried out in the presence of a base.
  • the base that can be used is selected from the group consisting of organic bases such as tri (C i -6 alkyl) amines like triethyl amine and the like;pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like or mixture thereof; preferably triethyl amine.
  • the solvents that can be used in step (c) include but are not limited to nitriles such as acetonitrile and the like; ketones such as acetone and the like; ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like; ester such as ethyl acetate and the like; halogenated solvents such as dichloromethane, chloroform and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF) and the like; or mixture thereof; Preferably dichloromethane.
  • nitriles such as acetonitrile and the like
  • ketones such as acetone and the like
  • ethers such as tetrahydrofuran (THF), 1,4-dioxane and the like
  • ester such as ethyl acetate and the like
  • halogenated solvents such as dichloromethane, chloroform and the like
  • the reaction step (c) can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 30°C.
  • the duration of time for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.
  • the compound of formula IVd can be converted into the compound of formula IVe
  • R is same as defined above and X is a halogen atom (F, CI, Br, I )
  • the reaction is carried out by reacting the compound of formula IVd with metal halides selected from lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, potassium bromide and potassium iodide in the presence of an organic solvent selected from ketones such as acetone and the like; ether such as tetrahydrofuran (THF) and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), acetonitrile and the like; or a mixture thereof; Preferably acetone is being used.
  • metal halides selected from lithium chloride, lithium bromide, lithium iodide, sodium bromide, sodium iodide, potassium bromide and potassium iodide in the presence of an organic solvent selected from ketones such as acetone and the like; ether such as tetrahydrofuran (THF) and the like; aprotic polar solvents such as ⁇ , ⁇ -di
  • W halogen atom or sulfonyloxy group
  • R 8 C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl straight or branched chain;
  • R9 C alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy;
  • R10, Rl 1, 12 are independently selected from the group consisting of C M 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • i)R 8 C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- i 0 alkenyl staright or branched chain;
  • R9 C .n alkyl straight or branched chain, optionally sub.with 1 -3 halogen atom(s), C i_i2 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);
  • R10, Rl 1, 12 independently selected from the group consisting of C 1-12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • the present invention provides a process for the synthesis of compound of formula VII.
  • R7 is same as defined above and X is a halogen atom
  • the above reaction step can be optionally carried out in the presence of a solvent selected from halogenated solvents such as dichloromethane, ethylene dichloride and the like; esters such as ethyl acetate and the like; ethers such as tetrahydrofuran (THF) and the like; hydrocarbon solvents such as toluene, xylene and the like; polar aprotic solvents such as acetonitrile, ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide, and the like or a mixture thereof, preferably dichloromethane is being used.
  • halogenated solvents such as dichloromethane, ethylene dichloride and the like
  • esters such as ethyl acetate and the like
  • ethers such as tetrahydrofuran (THF) and the like
  • hydrocarbon solvents such as toluene, xylene and the like
  • polar aprotic solvents such as
  • the reaction step is generally carried out without the use of a base and optionally performed using a base which can be selected from organic bases such as tri (C i -6 alkyl) amines like triethyl amine and the like; pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.
  • organic bases such as tri (C i -6 alkyl) amines like triethyl amine and the like
  • pyridine and collidine and the like inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.
  • the reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 0°C to about 30°C.
  • the time period required for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.
  • R6 is same as defined above.
  • W halogen atom or sulfonyloxy group
  • Rl -OR2, NR3,R4 or CX3; Where R2, R3, R4, X are same as defined for compound VIII;
  • R C 1.12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3.10 alkeny! straight or branched chain;
  • R9 C 1.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9- fluoroenylthethyloxy (Fmoc);
  • R10, Rl 1, 12 independently selected from the group consisting of C 1.12 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metai carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; preferably potassium carbonate.
  • inorganic bases such as alkali or alkaline earth metai carbonates such as sodium carbonate, potassium carbonate
  • bicarbonates such as sodium bicarbonate and the like
  • metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like
  • amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; preferably
  • the suitable organic solvents that can be used include but are not limited to alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; nitriles such as acetonitrile and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF) and the like; or mixture thereof.
  • acetonitrile or DMF is being used.
  • the reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably from about 50°C to the boiling point of the solvent(s) used.
  • the duration of time for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 12 hours.
  • Rl is -OR2,-CX3 or NR4R3
  • R3and R4 together form a single ring group with the 'N'to which they are bonded or a heteroaryl ring;
  • X halogen atom;
  • R 8 C 1-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl straight or branched chain;
  • R9 C j.12 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyi, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);
  • R10, Rl l, 12 independently selected from the group consisting of C i.i 2 alkyl straight or branched chain optionally sub. with 1-3 halogen atom (s), sub or unsub aryl, sub or unsub arylalkyl;
  • Rl is same as defined above;
  • X halogen atom
  • the above reaction step is carried out in the presence of a solvent selected from ethers such as tetrahydrofuran (THF) and the like; halogenated solvents such as dichloromethane, ethylene dichloride and the like; hydrocarbon solvents such as toluene, xylene and the like; polar aprotic solvents such as acetonitrile, ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide, and the like or a mixture thereof, preferably dichloromethane is being used.
  • ethers such as tetrahydrofuran (THF) and the like
  • halogenated solvents such as dichloromethane, ethylene dichloride and the like
  • hydrocarbon solvents such as toluene, xylene and the like
  • polar aprotic solvents such as acetonitrile, ⁇ , ⁇ -dimethyl formamide (DMF), dimethyl sulfoxide, and the like or a mixture
  • the reaction step is generally carried out without the use of a base and optionally performed using a base which can be selected from organic bases such as tri (C i -6 alkyl) amines like triethyl amine and the like;pyridine and collidine and the like; inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.
  • organic bases such as tri (C i -6 alkyl) amines like triethyl amine and the like
  • pyridine and collidine and the like inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; or a mixture thereof; preferably triethyl amine.
  • the reaction step can be performed at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably at about 0°C to about 30°C.
  • the time period required for the reaction to complete may also vary widely, typically a period of from about 30 minutes to about 24 hours, preferably from about 30 minutes to about 5 hours.
  • R 8 C i-i 2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl staright or branched chain;
  • R9 C i .i 2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy, 9-fluoroenylmethyloxy (Fmoc);
  • R 15 Ci-12 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub or unsub aryl, sub or unsub arylalkyl;
  • X halogen atom;
  • the suitable organic solvents that can be used in step (a) include but are not limited to alcohols such as methanol, ethanol and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or a mixture thereof.
  • ethanol or aqueous ethanol is being used.
  • reaction step (a) can be carried in the presence of catalyst selected from inorganic salts such as zinc chloride, ferric chloride, sodium iodide, lithium chloride, lithium bromide, stannic chloride and the like; ⁇ -cyclodextrin.
  • catalyst selected from inorganic salts such as zinc chloride, ferric chloride, sodium iodide, lithium chloride, lithium bromide, stannic chloride and the like; ⁇ -cyclodextrin.
  • the amount of catalyst employed can be in the range from about 0.01 mole to about 1 mole on the 1 mole of compound of formula Ila taken.
  • the reaction step (a) is carried out in the presence of a base
  • the suitable bases that can be used is selected from the group consisting_piLinorganic-bases-sueh-as-aIkalr or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, collidine, diisopropylethyl amine, pyridine and the like or a mixture thereof; preferably collidine.
  • the reaction step a) can be carried out at a temperature range from about 30°C to the boiling point of the solvent(s) used, preferably at boiling point of the solvent used.
  • the time period required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 12 hour to about 64 hours, preferably from about 8 hours to about 24 hours.
  • the carbonylation step (b) is being carried out in the presence of suitable carbonylating agent selected from the group consisting of phosgene or phosgene equivalent such as diphosgene, triphosgene and like; carbon monoxide equivalents such as N,N- carbonyldiimidazole (CDI), diethyl carbonate and the like; mixture thereof.
  • suitable carbonylating agent selected from the group consisting of phosgene or phosgene equivalent such as diphosgene, triphosgene and like; carbon monoxide equivalents such as N,N- carbonyldiimidazole (CDI), diethyl carbonate and the like; mixture thereof.
  • phosgene or phosgene equivalent such as diphosgene, triphosgene and like
  • carbon monoxide equivalents such as N,N- carbonyldiimidazole (CDI), diethyl carbonate and the like
  • CDI N,N- carbonyldiimidazole
  • the suitable solvents that can be used in step (b) is selected from the group consisting of alcohols such as methanol, ethanol and the like; hydrocarbons such as toluene and the like; halogenated solvent such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; ethers such as tetrahydrofuran (THF), 2-methyl THF and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), N,N-dimethyIacetamide (DMA) and the like; or mixture thereof.
  • dichloromethane is being used.
  • the reaction step (b) can be performed at any suitable temperature, specifically at a range from about 20°C to the boiling temperature of the solvent(s) used. Preferably from about 30 °C to about 35°C.
  • the time period for the reaction to complete may vary widely, depending upon various factors, typically a period of from about 30 minutes to about 48 hours, preferably from about 2 hours to about 24 hours is being used.
  • the suitable organic solvents that can be used in step (c) include but are not limited to alcohols such as methanol, ethanol and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; ethers such as tetrahydrofuran (THF) and the like; halogenated solvent such as dichloromethane, chloroform and the like; nitriles such as acetonitrile and the like; ketones such as acetone and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF) and the like; or a mixture thereof.
  • methanol or acetonitrile is being used.
  • the reaction step (c) is carried out in the presence of base
  • the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof; preferably diisopropylethyl amine.
  • inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; amines such as triethyl amine, diisopropylethyl amine,
  • the reaction step (c) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably from about 0° C to about 30°C.
  • the time period required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 10 hours.
  • the reaction step (d) is being carried out by reacting the compound of formula XIa with a suitable base
  • the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; n-butyl lithium, lithium diisopropyl amide and the like or mixture thereof; preferably sodium methoxide or lithium tert-butoxide or a mixture thereof.
  • inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; metal alkoxides such as sodium methoxide, lithium tert-butoxide and the like; n-butyl lithium, lithium diisopropyl amide
  • reaction step (d) is carried out using a nucleophile
  • nucleophile is not critical.
  • An example of a nucleophile is methoxide or
  • the suitable solvents that can be used in step (d) is selected from the group consisting of alcohols such as methanol, ethanol and the like; ethers such as tetrahydrofuran (THF), 2- rriethyl THF and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), acetonitrile and the like; or a mixture thereof.
  • alcohols such as methanol, ethanol and the like
  • ethers such as tetrahydrofuran (THF), 2- rriethyl THF and the like
  • aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), acetonitrile and the like
  • DMF ⁇ , ⁇ -dimethylformamide
  • the reaction step (d) can be performed at any suitable temperature, specifically at a range from about 25°C to the boiling temperature of the solvent(s) used. Preferably at boiling point of the solvent(s) used.
  • the duration of time for the reaction step (d) to complete may also vary widely, depending upon various factors, typically a period of'from about 30 minutes to about 48 hours, preferably from about 2 hours to about 24 hours is being used.
  • reaction steps (c) and (d) can be carried out in a single pot.
  • R hydroxyl protecting group
  • R C i.i 2 alkyl straight or branched chain, optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryl alkyl, sub /unsub trityl, tetrahydropyranyl, C 3- io alkenyl straight or branched chain;
  • R9 C i.i 2 alkyl straight or branched chain, optionally sub.with 1-3 halogen atom(s), C 1.12 alkoxy straight or branched chain optionally sub. with 1-3 halogen atom(s), sub/unsub aryl , sub /unsub aryloxy, sub /unsub arylalkyl, sub/unsub arylalkoxy; 9-fluorenylmethyloxy (Fmoc);
  • Ri 3 is sub or unsub. benzyl, C -i 0 alkenyl straight or branched chain;
  • the reaction step (a) is carried out in the presence of base
  • the suitable bases that can be used is selected from the group consisting of inorganic bases such as alkali or alkaline earth metal carbonates such as sodium carbonate, bicarbonates such as sodium bicarbonate and the like; hydroxides sodium hydroxide and the like; amines such as triethyl amine, diisopropylethyl amine, pyridine and the like or mixture thereof;
  • the reaction step (a) is carried out in the presence of a solvent
  • the suitable organic solvents that can be used in step (c) include but are not limited to esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene and the like; nitriles such as acetonitrile and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like; or a mixture thereof, preferably N,N- dimethyl
  • the reaction step (a) can be carried out at a temperature range from about 50°C to about 150 °C, preferably from about 70°C to 150 °C.
  • the time period required for the reaction to complete may also vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 10 hours.
  • reaction step (b) is carried out by reacting the compound of formula III with the compound of formula IXa or with a corresponding_c ⁇ rbonyLhalides-preferably--carbonyl "
  • the suitable bases that can be used in step (b) is selected from the group consisting of inorganic bases such as alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like; amines such as triethyl amine, N,N-diethylamine, pyridine and the like or mixture thereof; Preferably triethylamine or sodium bicarbonate.
  • inorganic bases such as alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like
  • amines such as triethyl amine, N,N-diethylamine, pyridine and the like or mixture thereof; Preferably triethylamine or sodium bicarbonate.
  • the suitable activating or coupling agents used in step (b) is selected from the group consisting of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimide. HC1, ⁇ , ⁇ '- dicyclohexylcarbodiimide, 1-hydroxybenzotriazole monohydrate and the like.
  • the solvents that can be used in step (b) include but are not limited to water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, chloroform and the like; hydrocarbon solvents such as toluene and the like; ethers such as diethyl ether, tetrahydrofuran (THF) and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide (DMA), acetonitrile, pyridine, hexamethyl phosphoric triamide and the like; or mixture thereof.
  • DMF N,N- dimethylformamide
  • DMA ⁇ , ⁇ -dimethylacetamide
  • acetonitrile pyridine, hexamethyl phosphoric triamide and the like
  • the reaction step (b) can be carried out at a temperature range from about 0°C to the boiling point of the solvent(s) used, preferably from
  • the time period required for the reaction to complete may vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 4 hours.
  • the suitable deprotecting agent used in step (c) is selected depends upon protecting group present.
  • the suitable deprotecting reagents that can be used in step (c) is selected from the group consisting of p-toluene sulfonic acid, N-bromosuccinimide, triflouro acetic acid; hydrogenation catalysts like palladium on carbon, platinum oxide combined with hydrogen source and the like; inorganic acids such as HCl, HBr, sulfuric acid, phosphoric acid and the like or mixture thereof.
  • the suitable solvents that can be used in step (c) is selected from the group consisting of water, alcohols such as methanol, ethanol and the like; halogenated solvents such as dichloromethane, chloroform and the like; esters such as ethyl acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; aprotic polar solvents such as N,N- dimethylformamide (DMF), acetonitrile and the like; or mixture thereof.
  • methanol or toluene is being used.
  • the reaction step (c) can be carried out at a temperature range from about 0°C to about boiling point of the solvent(s) used, preferably from about 30°C to about 50°C.
  • the time period required for the reaction step (c) to complete may vary widely, depending on various factors, notably the reaction temperature, the nature of the reagent and the solvents employed, a period of from about 1 hour to about 24 hours, preferably from about 2 hour to about 4 hours.
  • process steps of present invention can be carried out by one pot synthesis independently.
  • novel processes of present invention for the preparation of rivaroxaban from novel intermediate compounds proceeds with high yields while achieving a good chemical and optical purity.
  • the novel process comprises preparation of alcohol precursor of rivaroxaban (I) by novel methods and the activation of an alcohol precursor, amination with some specific amines, which may be removed, and the submission of the compound obtained to an acetylation reaction and to a dealkylation reaction.
  • the process of the present invention is advantageous since it avoids some of the drawbacks of the previously reported processes. Indeed, when phthalimide is used instead of the amines of the present invention, while being an expensive reactive, there are difficulties due to the obtention of side-products difficult to be isolated from the desired product.
  • the deprotection reaction of phthalimide compounds can be carried out with hydrazine or using basic conditions. As known in the art, the use of hydrazine involves several process difficulties and the basic conditions require high temperatures which may not be compatible with rivaroxaban.
  • the compounds of formula (VI), (VII), (IX), (XI) and (XIa) obtained according to the processes of the present invention are novel and useful as intermediates in the synthesis of active oxazolidinone derivatives like rivaroxaban (I), which were identified, characterized and confirmed by the characterization data like C 13 NMR, 1 H 1 NMR, MASS, IR.
  • the rivaroxaban (I) obtained following the processes of the present invention is of high purity with respect to the R-enantiomer and other impurities, without the need of tedious complicated purification steps such as chromatography. This is due to the abstention of pure intermediates, in particular the intermediate compounds of formula (II), (IV) and (VI) of the processes of the present invention.
  • Intermediates of formula (II),(IV) and (VI) can be purified by crystallization or by formation of salts.
  • rivaroxaban (I) can be produced safely and simply in high yield.
  • Rivaroxaban (I) is a compound with a low solubility in most solvents. This fact represents a drawback for the purification of the same.
  • the inventors have further found that rivaroxaban may be obtained at high yields and purity levels if once synthesized it is recrystallized from a solvent of the group consisting of ketones, a mixture of (Ci-C 4 )-alcohol/water, a mixture of (C2-Cg)-ethers and (Ci-C4)-alcohols.
  • a preferred solvents are a mixture of (Ci-C 4 )-alcohol with water or ketones alone or a mixture with water.
  • the starting amine compound of formula (Ila) is commercially available and can be prepared by any of the methods known in the art.
  • the intermediate compounds of formula II or a salt thereof obtained by the process of present invention can be further converted to the oxazolidinone derivatives like rivaroxaban (I) by the processes reported in the literature for example US 7,585,860.
  • the reaction mixture was diluted by adding 20ml of saturated ammonium chloride solution and tetrahydrofuran (THF) was evaporated under reduced pressure.
  • the aqeous phase was extracted with dichloromethane (5 X 20 ml).
  • the combined organic phases were dried over anhydrous magnesium sulphate.
  • the solvent was distilled completely at about 30°C under vacuum.
  • the crude obtained was suspended in 10 ml of ethyl acetate followed by heating to about reflux for about 30 min.
  • the reaction suspension was cooled to about 30°C.
  • the solid separated was filtered and the solid was washed with 2 ml of ethyl acetate to afford the title compound as light brownish solid. Yield : 2.0 gms, (% Yield: 74.8%).
  • Step-I Preparation of 4-[4- ⁇ (R)-2,3-dihydroxy-prop lamino ⁇ phen l]mo holin-3-one
  • Step-II Preparation of 4-(4-((R)-5-hydroxymethyl)-2-oxo-oxazolidin-3- yl) henyl)morpholin-3-one:
  • Step II Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3- yl)phenyl)morpholin-3-one:
  • the reaction mixture was quenched with 20ml of saturated NH 4 C1 solution and water (20 ml).
  • the reaction mass was extracted with dichloromethane (20ml x 4).
  • the organic phases were combined and dried over anhydrous MgS0 4 and concentrated under vacuum.
  • the crude obtained was purified by column chromatography (n-hexane-ethyl acetate (80:20) as a eluant) to yield title compound as an off-white solid.
  • Step III Preparation of 4-(4(R)-5-hydroxymethyl)-2-oxo-oxazolidin-3- I)phenyl)morpholin-3-one:
  • Step-II Preparation of 4-(4-((R)-5-(Benzyloxy methyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one:
  • Step-IV Preparation of 4-(4-((R)-5-(benzyloxyrnethyl)-2-oxo-oxazolidin-3-yl)phenyl)- morpholin-3-one:
  • Step-III Preparation of 4-(4-((R)-5-(hydroxymethyl)-2-oxo-oxazolidin-3-yl)-phenyl)- orpholin-3-one:
  • Step-I Preparation of 4- ⁇ 4-[(5R)-5-(azidomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ - morpholin-3-one (Compound-IV a):
  • Step-I Preparation of 4- ⁇ 4-[(5S)-5-((dibenzylamino)methyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl ⁇ morpholin-3-one (Compound-IVb):
  • Step-II Preparation of 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl ⁇ morpholin-3-one:
  • Step-Ill Preparation of Rivaroxaban (I): To a solution of 5- ⁇ 1 ⁇ 1 ⁇ - ⁇ -[ ⁇ (58)-2- ⁇ -3-[4-(3- ⁇ -4- ⁇ > ⁇ ) ⁇ 1 ⁇ > ⁇ ]-1,3- oxazolidin-5-yl ⁇ methyl]-N'-benzyl-2-thiophene carboxamide (Prepared in Step-II) (5.0 g) in ethanol ( 100 ml) was added 10 % Pd-C( l.Og) and the mixture was hydrogenated at 50-55°C under a hydrogen pressure of 4-5 kgs for about 18 hrs. Filtered the catalyst and concentrated the filtrate and the crude obtained was re-crystallized from acetone to yield the title compound as white crystalline solid. Yield: 2.25g (% Yield: 54.3%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne des procédés de préparation de dérivés d'oxazolidinone. Plus particulièrement, la présente invention concerne des procédés de préparation de 5-chloro-N-( {(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl méthyl)-2-thiophène-carboxamide et de ses intermédiaires, où L est un groupe partant comme un atome d'halogène (F, CI, Br, I) ou -OS02R où R = alkyle C'-4 à chaîne droite ou à chaîne ramifiée, aryle substitué ou non substitué,arylalkyle substitué ou non substitué; avec un réactif approprié pour donner le composé de formule (II). L'étape de réaction est effectuée en faisant réagir le composé de formule (IV) avec une source d'amine qui peut être dissoute dans un solvant comme de l'eau ou de l'alcool, par exemple de l'hydroxyde d'ammonium.
PCT/IN2012/000025 2012-01-09 2012-01-09 Procédés de préparation de 5-chloro-n-( {(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phényl]-1,3-oxazolidin-5-yl méthyl)-2-thiophène-carboxamide et de ses intermédiaires WO2013105100A1 (fr)

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104262335A (zh) * 2014-09-30 2015-01-07 常州市勇毅生物药业有限公司 一种利伐沙班的制备方法
CN104447726A (zh) * 2013-09-18 2015-03-25 深圳翰宇药业股份有限公司 一种利伐沙班的制备方法
CN105566310A (zh) * 2014-10-15 2016-05-11 常州诺贝朗生物医药科技有限公司 一种利伐沙班中间体的制备方法
CN106008492A (zh) * 2016-08-12 2016-10-12 杭州和泽医药科技有限公司 一种利伐沙班的合成方法
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN107970967A (zh) * 2017-11-21 2018-05-01 江苏扬农化工集团有限公司 一种用于催化加氢制备氯代芳胺催化剂的制备方法
CN114555582A (zh) * 2019-10-18 2022-05-27 Fmc公司 用于制备5-溴-2-(3-氯-吡啶-2-基)-2h-吡唑-3-甲酸的方法
CN114641471A (zh) * 2019-10-18 2022-06-17 Fmc公司 用于制备5-溴-2-(3-氯-吡啶-2-基)-2h-吡唑-3-甲酸的方法
CN115397961A (zh) * 2020-02-19 2022-11-25 科学与工业研究委员会 将不同取代呋喃的醛选择性还原为甲基的不含金属催化剂和氢气的方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032472A1 (en) * 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
US20090137535A1 (en) * 2007-08-14 2009-05-28 Masse Craig E Substituted oxazolidinone derivatives
US20100273798A1 (en) * 2009-04-28 2010-10-28 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
WO2011080341A1 (fr) * 2010-01-04 2011-07-07 Enantia, S.L. Procédé de préparation de rivaroxaban et ses intermédiaires
US20110288294A1 (en) * 2010-05-21 2011-11-24 Michael Nonnenmacher Preparation process for an inhibitor of a blood clotting factor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070032472A1 (en) * 2004-04-19 2007-02-08 Symed Labs Limited Novel process for the preparation of linezolid and related compounds
US20090137535A1 (en) * 2007-08-14 2009-05-28 Masse Craig E Substituted oxazolidinone derivatives
US20100273798A1 (en) * 2009-04-28 2010-10-28 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof
WO2011080341A1 (fr) * 2010-01-04 2011-07-07 Enantia, S.L. Procédé de préparation de rivaroxaban et ses intermédiaires
US20110288294A1 (en) * 2010-05-21 2011-11-24 Michael Nonnenmacher Preparation process for an inhibitor of a blood clotting factor

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104447726A (zh) * 2013-09-18 2015-03-25 深圳翰宇药业股份有限公司 一种利伐沙班的制备方法
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN104262335A (zh) * 2014-09-30 2015-01-07 常州市勇毅生物药业有限公司 一种利伐沙班的制备方法
CN105566310A (zh) * 2014-10-15 2016-05-11 常州诺贝朗生物医药科技有限公司 一种利伐沙班中间体的制备方法
CN106008492A (zh) * 2016-08-12 2016-10-12 杭州和泽医药科技有限公司 一种利伐沙班的合成方法
CN107970967A (zh) * 2017-11-21 2018-05-01 江苏扬农化工集团有限公司 一种用于催化加氢制备氯代芳胺催化剂的制备方法
CN107970967B (zh) * 2017-11-21 2020-07-14 江苏扬农化工集团有限公司 一种用于催化加氢制备氯代芳胺催化剂的制备方法
CN114555582A (zh) * 2019-10-18 2022-05-27 Fmc公司 用于制备5-溴-2-(3-氯-吡啶-2-基)-2h-吡唑-3-甲酸的方法
CN114641471A (zh) * 2019-10-18 2022-06-17 Fmc公司 用于制备5-溴-2-(3-氯-吡啶-2-基)-2h-吡唑-3-甲酸的方法
CN115397961A (zh) * 2020-02-19 2022-11-25 科学与工业研究委员会 将不同取代呋喃的醛选择性还原为甲基的不含金属催化剂和氢气的方法

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