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WO2018134842A1 - Procédé de préparation d'acide carbamique, d'ester de n,n'-[[1,1'-biphényl] -4,4'-diylbis]- 1 h-imidazole-5,2 diyi-(2s)-2,1-pyrrolidinédiyl[(1 s)-1-(1-méthyléthyl)-2-oxo-2,1-éthanediyl]]] bis-,c,c'-diméthyl et ses sels et polymorphes - Google Patents

Procédé de préparation d'acide carbamique, d'ester de n,n'-[[1,1'-biphényl] -4,4'-diylbis]- 1 h-imidazole-5,2 diyi-(2s)-2,1-pyrrolidinédiyl[(1 s)-1-(1-méthyléthyl)-2-oxo-2,1-éthanediyl]]] bis-,c,c'-diméthyl et ses sels et polymorphes Download PDF

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WO2018134842A1
WO2018134842A1 PCT/IN2018/000005 IN2018000005W WO2018134842A1 WO 2018134842 A1 WO2018134842 A1 WO 2018134842A1 IN 2018000005 W IN2018000005 W IN 2018000005W WO 2018134842 A1 WO2018134842 A1 WO 2018134842A1
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formula
compound
solvents
diyl
acid
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Srinivasan Thirumalai Rajan
Sajja Eswaraiah
Ghojala Venkat Reddy
Sagyam RAJESHWAR REDDY
Boge RAJESHAM
Porala SUBBANARASIMHULU
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a process for the preparation of carbamic acid, ⁇ , ⁇ '- [[1,1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [( 15)- 1 -( 1 -methyl ethyl)-2-oxo-2 ) I-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I).
  • the chemical structure of said compound is shown below:
  • the present invention also relates to crystalline forms of carbamic acid, ⁇ , ⁇ '-[[1 , ⁇ - biphenyl]-4,4'-diylbis[ lH-imidazole-5,2-diyl-(2S 2, 1 -pyrrolidinediyl[(l S 1 -( 1 -methyl ethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2) of formula (la) and process for their preparation thereof.
  • the present invention also relates to carbamic acid, N,N , -[[l s r-biphenyl]-4 ) 4'- diylbis[ 1 H-imidazole-5 ,2-diyl-(25 -2, 1 -pyrroIidinediyl[( 1S)-1-(1 -methylethyl) -2-oxo-2, 1 - ethanediyl]]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (lb) and process for its preparation thereof.
  • Daclatasvir dihydrochloride is a hepatitis C virus (HCV) NS5A inhibitor and indicated for the treatment of chronic HCV genotype 3 infections in combination with Sofosbuvir. Daclatasvir dihydrochloride is approved by United States Federal Drug Administration (US FDA) under the brand name of Daklinza® on July 24, 2015 to Bristol Myers Squibb (BMS).
  • US FDA United States Federal Drug Administration
  • step-b) Coupled with multiple of solvents like acetonitrile and toluene in step-b) (coupling stage) & step-c) (cyclization stage),
  • WO 2016/192691 Al discloses various solid salt forms of Daclatasvir with hydrochloric acid, hydrobromic acid, sulphuric acid, 2- naphthalenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid and fumaric acid and their process for preparation.
  • polymorphism refers to the ability of a substance to exist as two or more crystalline phases that have different spatial arrangements and/or conformations of molecules in their crystal lattices.
  • polymorphs refer to different crystalline forms of the same pure substance in which the molecules have different spatial arrangements of the molecules, atoms, and/or ions forming the crystal.
  • Different polymorphs may have different physical properties such as melting points, solubilities, X-ray diffraction patterns, etc.
  • the variation in solid forms may appreciably influence the pharmaceutical properties, such as bioavailability, handling properties, dissolution rate, and stability, and in turn such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorphic form. For these reasons, regulatory authorities require drug manufacturing companies to put efforts into identifying all polymorphic forms, e.g., crystalline, amorphous, solvates, stable dispersions with a pharmaceutically acceptable carriers, etc., of new drug substances.
  • the present invention provides crystalline forms and process for the preparation of compound of formula (I) which is efficient, industrially viable, cost effective, eco-friendly and avoids the disadvantages above noticed in the prior art process.
  • the first aspect of the present invention is to provide a process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(25)-2,l -pyrrolidine diyl ⁇ l ⁇ -l-Cl-methylethy ⁇ -oxo ⁇ .l-ethanediylJlJbis-.C ⁇ '-dimethyl ester of formula (I) or its salts.
  • the second aspect of the present invention is to provide carbamic acid, ⁇ , ⁇ '-[[1, ⁇ - biphenyl]-4,4'-diylbis[ 1H-imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidine diyl [( 1 S)-l -( 1 - methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester oxalic acid (1 :2) of formula (lb) and process for its preparation thereof.
  • the third aspect of the present invention is to provide a process for the purification of carbamic acid, N,N'-[[l,r-biphenyl]-4 5 4'-diylbisilH-i ⁇
  • the fourth aspect of the present invention is to provide crystalline form of carbamic acid, N-N'-KU'-bipheny ⁇ ⁇ diyl[(15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), hereinafter designated as "Form-S" and process for its preparation thereof.
  • the fifth aspect of the present invention is to provide crystalline form of carbamic acid, N'-ftl.l'-biphenylJ ⁇ '-diylbistlH-imidazole-S ⁇ -diyl ⁇ -pyrrolidine diyl[(15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), hereinafter designated as "Form-N" and process for its preparation thereof.
  • the sixth aspect of the present invention is to provide a process for the preparation of crystalline Form-M of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2- diyl-(2S 2, 1 -pyrrol idinediyl [( 15)- 1 -( 1 -methylethyl)-2-oxo-2, 1 -ethanediylJJJbis- C- dimethyl ester hydrochloride (1 :2) of formula (la).
  • Figure-1 Illustrates characteristic Powdered X-Ray Diffraction (PXRD) pattern of amorphous form of Daclatasvir oxalic acid (1 :2)
  • Figure-2 Illustrates the Infra-Red Spectra of amorphous form of Daclatasvir oxalic acid (1 :2)
  • Figure-3 Illustrates the PXRD pattern of crystalline Form-M of Daclatasvir hydrochloride (1 :2).
  • Figure-4 Illustrates the PXRD pattern of crystalline Form-M of Daclatasvir hydrochloride (1 :2)
  • FIG-5 Illustrates the Thermo Gravimetric Analysis (TGA) of crystalline Form-M of Daclatasvir hydrochloride (1 :2)
  • Figure-6 Illustrates the of pattern of solid state C-13 NMR crystalline Form-M of Daclatasvir hydrochloride (1 :2)
  • Figure-7 Illustrates the PXRD pattern of crystalline Form-S of Daclatasvir hydrochloride (1 :2)
  • Figure-8 Illustrates the solid state C-13 NMR spectrum of crystalline Form-S of Daclatasvir hydrochloride (1 :2)
  • Figure-9 Illustrates the PXRD pattern of crystalline Form-N of Daclatasvir hydrochloride (1 :2)
  • the present invention provides a process for the preparation of carbamic acid, ⁇ , ⁇ '- [[1,1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [( 15)-l -( 1 -methyl ethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I) and acid addition salts.
  • suitable solvent refers to the solvent selected from “alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and glycol solvents such as ethylene glycol, propylene glycol and the like; "chloro solvents” such as to methylene chloride, chloroform, ethylene dichloride and carbon tetra chloride; "ketone solvents” such as acetone, methyl ethyl ketone, methyl isobutyl ketone; “hydrocarbon solvents” such as to toluene, hexane, heptane and cyclohexane; “nitrile solvents” such as acetonitrile, propionitrile; "ester solvents” such as ethyl acetate, methyl acetate and isopropyl acetate, isobutyl acetate;
  • suitable base refers to the bases selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali metal phosphates such as potassium hydrogen phosphate, trisodium phosphate; organic bases such as sodium tertiary butoxide, potassium tertiary butoxide methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or their aqueous solution.
  • alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide
  • alkali metal carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, barium carbonate
  • suitable acid refers to the acid selected from inorganic acids like HCl, HBr, HI, H2SO ; organic acids like oxalic acid, succinic acid, formic acid, acetic acid, methane sulfonic acid (MsOH), p-toluene sulfonic acid (p-TsOH), trifluoro acetic acid (TFA). These acids can be used to prepare the acid addition salts of compound of formula (I) by the methods in the art or by the present invention.
  • the amine protecting group (PG) is selected from but not limited to tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz), 9-fluorenyImethyloxy carbonyl (Fmoc), benzyl (Bn), carbamate group, p-methoxyphenyl (PMP), p-methoxybenzyl (PMB), 3,4-dimethoxy benzyl (DMPM), trityl (Tr), alkyl/aryl sulfonyl such as methanesulfonyl, ethanesulfonyl, benzenesulfonyl, toluenesulfonyl and the like; acyl groups such as acetyl (Ac), trifluoroacetyl (TFA), benzoyl (Bz) group and the like.
  • the suitable amine protecting agent is selected such that it is capable of protecting the nitrogen atom with any of the above mentioned amine protecting groups.
  • Suitable amine protecting agent is selected from but not limited to di-tert.butyl dicarbonate (DIBOC), benzyl chloroformate, fiuorenylmethyloxy carbonyl chloride (FMOC chloride), trityl chloride, acetyl chloride, acetic anhydride, trifluoroacetic acid, trifluoroacetic anhydride, benzoyl halides, benzyl halides, alkyl/arylsulfonic acids/acid halides/anhydrides such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, p- toluenesulfonic anhydride and the like; alkyl trifluoroacetates such as
  • the suitable deprotecting agent is selected based on the protecting group employed.
  • the suitable deprotecting agent is selected from but not limited to acids such as hydrochloric acid (aqueous hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride, ethyl acetate.hydochloride, acetonitrile.hydrochloride), hydrobromic acid, sulfuric acid, nitric acid, aq.phosphoric acid, trifluoroacetic acid, methane sulfonic acid, p-toluenesulfonic acid and the like; acetyl chloride in combination with alcohols; bases such as alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates, cesium carbonate/imidazole, ammonia, cerium(IV) ammonium nitrate (CAN); organic bases such as methylamine, ethylamine, diethylamine, trie
  • suitable "coupling agent" used in the present invention refers to ⁇ , ⁇ '- dicyclohexylcarbodiimide (DCC), ⁇ , ⁇ '-diisopropylcarbodiimide (DIC), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), alkyl or aryl chloroformates such as ethyl chloroformate, benzylchloroformate, diphenyl phosphoroazidate (DPPA), thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride, 4- methyl-2-oxopentanoyl chloride (i-BuCOCOCI), benzotriazol-l-yl-oxytripyrrolidino phosphonium hexafluorophosphate (PyBOP), methane sulfonyl chloride and the like
  • the first aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(2S)-2,l-pyn-olidine diyl[(l-S)-l-(l -methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C , -dimethyl ester of formula (1) or its salts, comprising the steps of:
  • R represents W 201
  • X is selected from bromine, chlorine or iodine
  • step-a) (i) the suitable borylating agent is selected from bis(pinacolato)diboron or bis(neopentylglycolato)diboron; the catalyst is selected from PdCl 2 [P(t-Bu) 2 Ph] 2, Pd(dppf)Cl2 , Pd(PPh 3 ) 4 and the like; in step-a) (ii), the suitable catalyst is selected from Pd, Pd(OH) 2 , [jPdCh, Pd(0 2 CCH 3 ) 2s PdS0 , Pd 0 3 )2, Fe, Ni, copper sulfate, copper oxide, copper chloride and the like in presence of charcoal.
  • the metal catalyst used in the step-a (ii) can be recovered by filtration after completion of the coupling reaction. The same recovered metal catalyst can be used in the coupling reaction of other batches of the compounds of formula (VIII).
  • the suitable base in step-a) (i) & (ii) selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal phosphates like dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate; organic bases like sodium acetate, potassium acetate, potassium propionate, sodium tertiary butoxide, potassium tertiary butoxide, methylamine, ethylamine, isopropylamine, diisopropyl ethylamine, triethylamine, ammonia or their aqueous solution.
  • the suitable solvent in step-a) (i) & (ii) is selected from alcohol solvents, glycol solvents, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents or mixtures.
  • step-a) (i) & (ii) optionally carried out in presence of phase transfer catalyst.
  • the another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[1 , -biphenyl]-4,4'-diylbis[lH-imidazole-5 s 2-diyl-(2S -2,l -pyrrolidine diyl[(lS)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, oxalic acid (1 :2) of formula (l
  • step-a) treating the compound of formula (I) with oxalic acid to provide the compound of formula (lb).
  • the suitable catalyst is selected from Pd, Pd(OH) 2 , fPdCl 2 , Pd(0 2 CCH 3 ) 2 , PdS0 4 ⁇ Pd (N0 3 ) 2) Fe, Ni, copper sulfate, copper oxide, copper chloride and the like in presence of charcoal.
  • the suitable base in step-a) selected from alkali metal hydroxides like sodium hydroxide, potassium hydroxide; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate; alkali metal phosphates like dipotassium hydrogen phosphate, tripotassium phosphate, trisodium phosphate.
  • the suitable solvent in step-a) is selected from alcohol solvents, glycol solvents, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents or mixtures.
  • Yet another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis(lH-imidazole-5,2-diyl-(25)-2,l -pyrrolidine diyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl] ]]bis-,C,C'-dimethyl ester, hydrochloric acid (1 :2) of
  • Formu a (la) comprising the steps of:
  • X represents bromine, chlorine or iodine
  • suitable metal catalyst, suitable base, suitable solvent are same as defined hereinbefore in previous aspects.
  • the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates and the like;
  • the suitable solvent is selected from chloro solvents, alcohol solvents, glycol solvents, ketone solvents, ester solvents, ether solvents, polar protic solvents, polar aprotic solvents, nitromethane or mixtures;
  • the suitable hydrochloric acid source is selected from hydrochloride, hydrochloride gas, SOCb/alcohol solvents, aqueous hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride, isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride and the like.
  • the preferred embodiment of the present invention provides a process " for the preparation of carbamic acid, N,N'-[[l,r-biphenyl]-4,4'-diylbis[lH-imidazoIe-5,2-diyl-(25)- 2, 1 -pyrrolidine diyl[(l S)- ⁇ -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-,C,C'-dimethyl ester hydrochloride (1 :2) of formula (la), comprising the steps of: a) self-condensing the two molecules of compound of formula (Villa) with each other (self-coupling) in presence of Pd(OH) 2 /C and dipotassium hydrogen phosphate
  • step-a) treating the product obtained in step-a) with oxalic acid to provide the compound of formula
  • step-b) treating the product obtained in step-b) with aqueous sodium hydroxide solution in presence of methylene chloride followed by treating the obtained compound with aqueous hydrochloric acid in methylene chloride to provide the compound of formula (la).
  • the another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[ 1 , 1 '-biphenyl]-4,4'-diylbis[ 1 H-imidazole-5,2-diyI-(2S)-2, 1 -pyrrolidine diyl[(15 -l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester of formula (I) or its salts, comprising the steps of:
  • X refers to chlorine, bromine, fluorine, iodine, methanesulfonyl group, ethanesulfonyl group,- benzenesulfonyl group, toluenesulfonyl group and the like;
  • PG refers to amine protecting group
  • Formula (VI) Formula (VI!) d) (i): treating the compound of formula (VIII) with the suitable borylating agent in presence of a catalyst, suitable base in a solvent to produce the compound of general formula (IX) followed by in-situ reacting with the compound of general formula (VIII) in presence of a suitable catalyst, base in a solvent.
  • step-d(i) or (ii) optionally, treating the compound of formula (I) obtained in step-d(i) or (ii) with oxalic acid to provide the compound of formula (lb),
  • step-f) optionally, treating the product obtained in step-f) with suitable base in presence of a suitable solvent followed by treating the obtained compound with suitable hydrochloric acid source in a suitable solvent to provide the compound of formula (la).
  • the suitable base is selected from alkylamine, dialkylamine or trialkylamine or alkali metal hydroxides, alkali metal carbonates
  • the solvent is selected from hydrocarbon solvents, ester solvents, ether solvents, nitrile solvents, alcohol solvents, polar aprotic solvents, chloro solvents and the like
  • the cyclization is carried out using ammonium acetate, ammonium hydroxide, acetamide or di(trimethylsilyl)amines in a suitable solvents such as hydrocarbon solvents, nitrile solvents, chloro solvents, alcohol solvents, ester solvents, ether solvents and the like.
  • step-b) deprotection is carried out by using suitable deprotecting agent such as non-aqueous acid solutions such as isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride and the like.
  • suitable coupling agent is selected from dicyclohexyl carbodiimide, diisopropylcarbodiimide, ethyl-(N,N'-dimethylaminopropyl)carbodiimide hydrochloride (EDC.
  • HC1 ⁇ , ⁇ '-carbonyldiimidazole (CDI), hydroxy benzotriazole (HOBt) or mixtures
  • suitable base is selected from organic or inorganic base
  • suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents and alcohol solvents or mixtures.
  • the suitable borylating agent is selected from bis(pinacolato)diboron or bis(neopentylglycolato)diboron;
  • the catalyst is selected from PdCl2[P(t-Bu) 2 Ph]2 , Pd(dppf)Cl 2, Pd(PPh3) and the like;
  • the base is selected from potassium acetate, potassium propionate, sodium alkoxides such as sodium methoxide, sodium ethoxide and the like;
  • the suitable solvent is selected from dimethoxyethane, 1 ,2-dichloroethane, hydrocarbon solvents, chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents and the like.
  • the self-coupling is carried out in presence of suitable catalyst, suitable base in a suitable solvent and optionally in presence of phase transfer catalyst.
  • the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates, alkali metal phosphates or aqueous mixtures;
  • the suitable hydrochloric acid source is selected from hydrochloride, aqueous hydrochloride, ethyl acetate hydrochloride, acetonitrile hydrochloride, isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, SOCl 2 / alcohol solvents and the like.
  • the preferred embodiment of the present invention provides a process for the preparation of carbamic acid, N J N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyI-(2S - 2,1 -pyrrolidine diyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C, -dimethyl ester of formula (I), comprising the steps of:
  • Formula (Via) Formula (VI I) d) self-condensing the two molecules of the compound of formula (Villa) with each other (self-coupling) in presence of Pd(OH) 2 /C in presence of dipotassium hydrogen phosphate (K 2 HP0 4 ) in ethylene glycol to provide the compound of formula (I).
  • step-e) treating the product obtained in step-e) with aqueous NaOH solution in presence of methylene chloride followed by treating the obtained compound with aqueous hydrochloric acid in methylene chloride to provide the hydrochloride salt compound of formula (la).
  • X refers to leaving group such as chlorine, bromine, fluorine, iodine, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, toluenesulfonyl group and the like;
  • PG refers to amine protecting group and 'R' refers to
  • the second aspect of the present invention provides carbamic acid, ⁇ , ⁇ '-[[1 , - biphenyl]-4,4'-diylbis[lH-imidazole- ⁇
  • Another aspect of the present invention provides a process for the preparation of Daclatasvir oxalic acid (1 :2) of formula (Ib), comprising:
  • step-a) adding the obtained compound in step-a) to oxalic acid or its solution to provide the Daclatasvir oxalic acid (1 :2).
  • Daclatasvir oxalic acid (1 :2) of formula (Ib) substantially characterized by the PXRD pattern as shown in Figure- 1 and also characterized by the IR Spectra as shown in Figure-2 and having IR characteristic peaks at 3840.11, 3410.86, 3142-83, 3033.73, 2966.38, 2878.26, 2722.51, 1925.23, 1718.91 , 1639.36, 1555.98, 1532.15, 1492.35, 1444.22, 1422.80, 1370.44, 1359.93, 1304.40, 1239.04, 1195.92, 1100.48, 1035.02, 1004.95, 970.29, 945.55, 920.45, 825.56, 779.40, 719.50, 628.76, 608.36, 561.21 , 523.92, 484.47 and 473.76 cm *1 .
  • the oxalic acid content in the compound of formula (Ib) is ranging between 17-24%. Preferably between 20-24%.
  • the another aspect of the present invention provides a process for the preparation of carbamic acid, N,N'-[[1 , 1 , -biphenyl]-4,4'-diylbis[ lH-imidazole-5,2-diyl-(25 -2, 1 - pyrrolidinediyl[(15)-l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-C ) C'-dimethyl ester, oxalic acid of formula (lb), comprising:
  • step a) isolating the compound of formula (lb).
  • the suitable solvent is selected from ketone solvents; ether solvents, ester solvents, nitrile solvents, chloro solvents, hydrocarbon solvents, polar protic solvents, polar aprotic solvents.
  • the oxalic acid solution is can be prepared by dissolving oxalic acid in suitable solvents like alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone and the like.
  • suitable solvents like alcohol solvents such as methanol, ethanol, isopropanol; ketone solvents such as acetone and the like.
  • the term "isolating” refers to the removal of solvent by filtration, distillation, distillation and co-distillation or decantation from the reaction mixture or suitable techniques which may be used for the removal of solvent include filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
  • ATFD agitated thin film drying
  • the preferred aspect of the present invention provides a process for the preparation of amorphous form of carbamic acid, N,N'-[[l, -biphenyI]-4,4'-diylbis[lH-imidazole-5,2-diyl- (2S)-2, 1 -pyrrol idinediyl[( IS)- 1 -(1 ⁇
  • step-a) combining the reaction mixture obtained in step-a) with oxalic acid in isopropanol; c) stirring the resulting reaction mixture;
  • the term "isolating" refers to filtration, distillation, precipitation by cooling he reaction mixture, solvent and anti-solvent technique by using the suitable solvents such as alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents.
  • suitable solvents such as alcohol solvents, chloro solvents, ester solvents, ketone solvents, nitrile solvents.
  • the suitable anti-solvent is selected from ether solvents such as 1 ,4-dioxane, tetrahydrofuran, diethyl ether; nitrile solvents, ester solvents, hydrocarbon solvents.
  • ether solvents such as 1 ,4-dioxane, tetrahydrofuran, diethyl ether; nitrile solvents, ester solvents, hydrocarbon solvents.
  • Another embodiment of the present invention provides an alternate process for the preparation of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:
  • the suitable catalyst is selected from palladium- tetrakis(triphenylphosphine) (Pd(PPh3) ), dichlorobis(triphenylphosphine)palladium(II) (Pd(PPh 3 ) 2 Cl 2 ), dichlorobis(tricycIohexylphosphine)palladium(II) (Pd(PCy 3 ) 2 Cl 2 ), [1,2- bis(diphenylphosphino)ethaneJdichloropalladium(II) (Pd(dppe)Cl 2 ), [1 ,1 '-bis
  • the suitable base is selected from alkali metal hydroxides or alkali metal carbonates, alkali metal bicarbonates or aqueous mixtures; chloro solvents, polar protic solvents, polar aprotic solvents, ester solvents, ether solvents, nitrile solvents and the like.
  • Another aspect of the present invention provides a process for the preparation of amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:
  • step-a) adding the obtained compound in step-a) to oxalic acid in isopropanol;
  • the preferred embodiment of the present invention provides a process for the preparation of amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising: a) self-condensing of methyl ((iS)-l-((5)-2-(5-(4-bromophenyl)-lH-imidazol-2- yl)pyrTolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate with each other in presence of Pd(OH) 2 / C, dipotassium hydrogen phosphate in ethylene glycol to provide the compound of formula (I);
  • the third aspect of the present invention provides a process for the purification of Daclatasvir oxalic acid (1 :2) of formula (lb), comprising:
  • step-g) filtering and washing the product obtained in step-g) to provide pure amorphous form of Daclatasvir oxalic acid (1 :2)
  • Another embodiment of the present invention provides the use of Daclatasvir oxalic acid (1 :2) of formula (lb) in the preparation of highly pure Daclatasvir hydrochloride (1 :2) of formula (la).
  • the fourth aspect of the present invention provides crystalline Form-S of carbamic acid, N,N'-[[1 , 1 *-biphenyl]-4,4'-diylbis[ 1H-imidazole-5 ,2-diyl-(2S)-2, 1 -pyrrolidinediyl [(15)- l-il-methylethyl ⁇ -oxo ⁇ .l-ethanediylJJJbis-.CC'-dimethyl ester, hydrochloride (1 :2).
  • Crystalline Form-S of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 8.2, 9.5, 15.2 ⁇ 0.2 degrees of two-theta. Crystalline Form-S of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 8.5, 10.5, 11.0, 13.1, 13.5, 14.8, 16.5, 17.1 , 17.8, 18.3, 21.0, 21.2, 21.5, 22.2, 22.5, 23.1, 23.6, 24.1 , 24.6, 25.3, 25.8, 26.5, 26.6, 27.8, 28.2, 28.6, 28.9, 29.4, 29.9, 30.5, 31.2, 32.1 , 33.5, 35.4, 36.0, 40.3, 42.1 ⁇ 0.2 degrees of two-theta.
  • PXRD Powder X-Ray Diffraction
  • Another embodiment of the present invention provides crystalline Form-S of compound of formula-la having particle size distribution of D90 less than 100 ⁇ . Prefarebly less than 50 ⁇ .
  • step-a) stirring the reaction mixture obtained in step-a) at a suitable temperature
  • step-a) isolating the crystalline Form-S of formula (la).
  • the suitable solvent is selected from ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, alcoholic solvents, polar solvents, water and/or mixtures and the suitable temperature is 25°C to reflux temperature of the solvent used.
  • the suitable temperature is ranging from 40°C to 100°C.
  • step-c) the term "isolating” refers to removing of the solvent by known techniques such as filtration, using a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
  • a rotational distillation device such as a Buchi Rotavapor, spray drying, agitated thin film drying (“ATFD”), freeze drying (lyophilization), and the like or any other suitable technique.
  • the preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of carbamic acid, N ? N'-[[l,r-biphenyl]-4,4 -diylbis[lH- imidazoIe-5,2-diyl-(25 2, 1 -pyrrol idinediyl[( 15)- 1 -(1 -methyl ethyl) -2 -oxo-2, 1 -ethanediyl]]] bis-,C,C- dimethyl ester, hydrochloride (1 :2) of formula (la), comprising the following steps of:
  • the another preferred embodiment of the present invention provides a process for the preparation of crystalline form-S of carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[l-/ - imidazole-5,2-diyl-(2S)-2, 1 -pyrrolidinediyl[( 15)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]] bis-,C,C- dimethyl ester, hydrochloride (1 :2) of formula (la), comprising the following steps of:
  • step-d) dissolving the product obtained in step-d) in isobutyl acetate at 25-30°C; f) cooling the reaction mixture to-15°C to -20°C;
  • the fifth aspect of the present invention provides crystalline Form-N of carbamic acid, N,N'-[[1 , 1 '-biphenyl].4,4'-diylbis[lH-imida2ole-5,2-diyl-(2S)-2, 1 -pyrrol id inediyl [( 15)- l-(l-methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2).
  • Crystalline Form-N of the present invention is characterized by its Powder X-Ray Diffraction (PXRD) pattern having peaks at about 19.6, 24.1 ⁇ 0.2 degrees of two-theta. Crystalline Form-N of the present invention further characterized by its X-Ray powder diffraction pattern having additional peaks at about 8.3, 9.8, 12.8, 13.6, 16.1, 18.8, 19.6, 22.2, 23.4, 24.1, 25.1, 26.2 and 29.6 ⁇ 0.2 degrees of two-theta. The crystalline Form-N of the present invention is further characterized by the PXRD pattern as illustrated in figure-9.
  • PXRD Powder X-Ray Diffraction
  • Crystalline Form-N of the present invention is partially isobutyl acetate solvate form.
  • the sixth aspect of the present invention provides a process for the preparation of crystalline Form-M of Daclatasvir, hydrochloride (1 :2) of formula (la), comprising: a) adding carbamic acid, N,N'-[[l, -biphenyl]-4,4'-diylbis[lH-imidazole-5,2-diyl-(25 - 2, 1 -pyrrolidinediyI[( 1 S)- 1 -(1 -methylethyl)-2-oxo-2, 1 -ethanediylJjjbis-.C ⁇ '-dimethyl ester, oxalic acid (1 :2) of formula (lb) to a suitable solvent;
  • step-a) and step-f) isolating the crystalline Form-M of Daclatasvir, hydrochloride (1:2) wherein, in step-a) and step-f), the suitable solvent is selected from alcohol solvents, glycol solvents, chloro solvents, hydrocarbon solvents, ether solvents, ester solvents or mixtures, in step-b), the suitable base is selected from NaOH, KOH, Na2C0 3 , NaHC0 3 , sodium alkoxides, potassium alkoxides or their aqueous solutions or mixtures thereof,
  • step-e distillating off the solvent from the organic layer is carried out partially or completely under reduced pressure.
  • the acidification is carried out using hydrochloric acid source either in aqueous condition such as aqueous hydrochloride or non-aqueous condition such as isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, acetonitrile hydrochloride, acetone hydrochloride, or hydrochloric acid gas, or SOC ⁇ /suitable alcohol solvent.
  • aqueous condition such as aqueous hydrochloride or non-aqueous condition such as isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride, acetonitrile hydrochloride, acetone hydrochloride, or hydrochloric acid gas, or SOC ⁇ /suitable alcohol solvent.
  • the another aspect of the present invention provides crystalline Form-M of carbamic acid, N,N [l,l'-biphenyI]-4,4'-diylbis ⁇ [(15)- l-(l -methylethyl)-2-oxo-2,l-ethanediyl]]]bis-,C,C , -dimethyl ester, hydrochloride (1 :2) of formula (la) is hemihydrate.
  • Another embodiment of the present invention provides crystalline Form-M of carbamic acid, HN'-ttl '-biphenylJ- '-diylbisflH-imidazole-S ⁇ -diyl ⁇ S) ⁇ ,!- pyrrolidinediyl [(15)-l -( 1 -methylethyl)-2-oxo-2, 1 -ethanediyl]]]bis-,C,C'-dimethyl ester, hydrochloride (1 :2) of formula (la) having water content about 1.1 to 1.5% in its crystal lattice.
  • Another embodiment of the present invention provides crystalline Form-M of carbamic acid, N,N * -[[ 1 , 1 '-biphenyrj- '-diylbis.1 H-imidazole-5 ,2-diyl-(25 -2, 1 - pyrrolidinediyl [(1S)-1 -(l-methylethy ⁇ -oxo ⁇ -ethanediyllJJbis-jC ⁇ '-dimethyl ester hydrochloride (1 :2) of formula (la) showing weight loss of about 1.17% and same illustrated by its thermo gravimetric analysis (TGA) in figure-5.
  • TGA thermo gravimetric analysis
  • FIG. 6 Another embodiment of the present invention provides solid state C-13 NMR spectrum of crystalline Form-M of formula (la) is illustrated in figure-6.
  • Another embodiment of the present invention provides crystalline Form-M of compound of formula (la) having particle size distribution of D90 less than 300 ⁇ . preferably less than 100 ⁇ . More prefarebly less than 15 ⁇ .
  • the crystalline Form-M, Form-S, Form-N of Daclatasvir hydrochloride (1 :2) of formula (la) and amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb) of the present invention can be further micromzed or milled to get desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that may be used for particle size reduction includes but not limited to single or multi-stage micronization using wet milling, cutting mills, pin cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills. Milling or micronization may be performed before drying or after drying of the product.
  • compositions comprising a therapeutically effective amount of crystalline Form-M, S, N of Daclatasvir hydrochloride (1 :2) of formula (la) or amorphous form of Daclatasvir oxalic acid (1 :2) of formula (lb) and one or more pharmaceutically acceptable carriers.
  • compositions containing crystalline Form-M, S, N of Daclatasvir hydrochloride (1 :2) or Daclatasvir oxalic acid (1 :2) of the present invention may be prepared by using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, and lubricants.
  • Various modes of administration of the pharmaceutical compositions of the invention can be selected depending on the therapeutic purpose, for example tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • the oral pharmaceutical composition may contain one or more additional excipients such as diluents, binders, disintegrants and lubricants.
  • diluents include lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, microcrystalline cellulose, magnesium stearate and mixtures thereof.
  • binders are selected from L-hydroxy propyl cellulose, povidone, hydroxypropyl methyl cellulose, hydroxylethyl cellulose and pre- gelatinized starch.
  • Exemplary disintegrants are selected from croscarmellose sodium, cros-povidone, sodium starch glycolate and low substituted hydroxylpropyl cellulose.
  • Exemplary lubricants are selected from sodium stearyl fumarate, magnesium stearate, zinc stearate, calcium stearate, stearic acid, talc, glyceryl behenate and colloidal silicon dioxide.
  • a specific lubricant is selected from magnesium stearate, zinc stearate, calcium stearate and colloidal silicon dioxide.
  • Apparatus A liquid chromatographic system equipped with variable wavelength UV detector; Column; Kromasil 100-5-C18, 250*4.6 mm, 5 ⁇ (or) equivalent; Column temperature: 40°C; Wave length: 210 run; Injection volume: 5 ⁇ ; Elution: Gradient; Diluent: acetonitrile: milli- Q-water (1 : 1 v/v); Buffer: weigh accurately about 1.74 gm of dipotassium dihydrogen phosphate and added into 1000 mL of Milli-Q-water and 2.0 ml of triethylamine was added to above 1000 mL of milli-Q-water solution and adjust pH to 3.5 with orthbphosphoric acid (85%), mix well. Filter this solution through 0.22 ⁇ Nylon membrane filter paper; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile: Buffer (60:40 v/v).
  • Ammonium acetate (277.3 gms) was added to the above obtained organic layer at 25- 30°C Heated the reaction mixture to 90-95°C and stirred for 16 hrs at same temperature. Ethyl acetate (300 ml) and water (700 ml) were added to the reaction mixture and stirred for 15 min. Separated the both organic and aqueous layers. Washed the organic layer with aqueous sodium bicarbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure and then co-distilled with cyclohexane.
  • Example-3 Preparation of methyl((S)-l-((S)-2-(5-(4-bromophenyl)-lH-imidazoI-2-yl) pyrrolidin-l-yl)-3-methyI-l-oxobutan-2-yl)carbamate
  • reaction mixture Cooled the reaction mixture to 0- 5°C and added (5 -5-(4-bromophenyl)-2-(pyrrolidin-2-yl)-lH-imidazole dihydrochloride (50 gms) and stirred for 15 min at same temperature. Triethylamine (37.9 ml) was added to the reaction mixture at 0-5 °C and raised the temperature of reaction mixture to 15-20°C and stirred for 14 hrs at same temperature. Cooled the reaction mixture to 0-5°C and washed with aqueous sodium hydroxide solution and separating the aqueous layer and organic layers. Washed the organic layer with sodium chloride solution.
  • Example-4 Preparation of methyl ((S)-3-methyl-l-oxo-l-((S)-2-(5-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-lH-imidazol-2-yl)pyrr01idin-l-yl)butan-2- yl)carbamate
  • Example-5 Preparation of dimethyl ((25,2'5)-((25, 2'S)-2,2'-(5,5'-([l,l , -biphenyl]-4,4'- diyl)bis(lH-imidazole-5,2-diyI))bis(pyrroIidine-2 ⁇
  • Example-6 Preparation of carbamic acid, N ⁇ '-Hl. -biphenylJ ⁇ '-diylbisflH- imidazole-5,2-d ⁇ yl-(2S)-2 -p r ⁇ Ol ⁇ dinedi l[(lS)- (l--nethyleth l)-2-oxo-2,l-ethanedi yl]]]bis-,C,C-dimethyl ester, oxalic acid (1:2)
  • ExampIe-7 Preparation of pure dimethyl ((2S,2'5)-((2S, Z'SJ ⁇ '-i ⁇ S'-ffl '-biphen l]- 4,4 , -diyl)bis(lH-imidazole-5,2-diyI))bis(pyrroHdine-2,l-diyl))bis(3-methyl-l-oxobutane- 2,l-diyl))dicarbamate oxalic acid (1 :2)
  • Example-8 Preparation of carbamic acid, N,N'-[[l,l'-biphenyl]-4,4'-diylbis[lH- imidazole-S ⁇ -diyl- ⁇ S ⁇ U-p r olidinediylt ⁇
  • Ethylene glycol (1250 ml) was added to methyl((S)-l-((S>2-(5-(4-bromophenyl)-lH- imidazol-2-yl)pyrrolidin-l-yl)-3-methyl-l-oxobutan-2-yl)carbamate (50 gms) under nitrogen atmosphere at 25-30°C.
  • Potassium hydrogen phosphate 32.94 gms
  • 20% Pd(OH) 2 /C (12.5 gms, 50% wet) in 50 ml of water were added at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 90-95°C and stirred for 12 hrs at same temperature.
  • Example-9 Preparation of crystalline Form-M of dimethyl ((2S,2'5)-((2S, 2'5)-2,2'-(5,5*- ([U'-biphenylM ⁇ '-diy bisil/Mm
  • Aqueous NaOH solution (10 gms of NaOH in 100 ml of water) was added to dimethyl ((25,2 , S)-((25, 2'S)-2,2 , -(5 3 5 , -([l,l , -biphenyl]-4,4 , -diyl)bis(lH-imidazole-5,2-diyl)) bis(pyrrolidine-2,l-diyl))bis(3-methyl-l -oxobutane-2,l-diyl))dicarbamate, oxalic acid (1 :2) (10 gms) in methylene chloride (100 ml) solution at 25-30°C and stirred for 15 min at same temperature. Separated the both aqueous and organic layers and partially distilled off the solvent from the organic layer to get the compound of formula (I).
  • Example-10 Preparation of crystalline Form-M of dimethyl ((2S,2'S)-((2S, 2'5)-2,2'- (5,5'-([i , -biphenyl]-4,4 ⁇ diyI)bis(l /-imidazole-5 -diyl))bis(pyrrolidine-2,l-diyl))bts(3- methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)
  • the PXRD pattern of the title compound was similar to the PXRD pattern illustrated in figure-3.
  • Example- 11 Preparation of crystalline Form-M of dimethyl ((2S,2'S)-((2S, 2 ⁇ S)-2,2'-
  • the PXRD pattern of the title compound was similar to the PXRD pattern illustrated in figure-3.
  • Example-12 Preparation of crystalline Form-M of dimethyl ((2S,2 , S)-((2S, 2'S)-2,2*- (5,5'-([ia ⁇ biphenyl].4,4 ⁇ diyl)bis(l ⁇ -imidazole-5,2-diyl))bis(pyrrolidine-2, ⁇
  • Example-13 Preparation of pure crystalline Form-M of dimethyl ((2S,2'5)-((2S, 2'5)- 2,2 , -(5,5'-([l,l'-biphenyl]-4,4 , -diyI)bis(lH-imidazole-5,2-diyl))bis(pyrrolidine-2,l- diyl))bis(3-methyl-l-oxobutane-2,l-diyl))dicarbamate, hydrochloride (1:2)
  • Example-14 Preparation of crystalline Form-S of carbamic acid, N,N'-[[l, -biphenyl]- 4,4 , -diy-bis[lH-imidazoIe-5,2-d-yH ⁇
  • Example-15 Preparation of crystalline Form-S of carbamic acid, N,N'-[[l,l'-biphenyl]- 4,4'-diylbis[lH-imidazole-5,2-diyl-(2S)-2,l-pyrrolidinediyl[(lS)-l-(l-methylethyl)-2-oxo- 2,l-ethanediyl]]]bis-,C,C'-dimethyI ester, hydrochloride (1:2)
  • Methylene chloride (280 ml) was added to Daclatasvir oxalic acid (1 :2) (70 gms) in water (350 ml) at 25-30°C and stirred for 20 min. Basified the reaction mixture with aqueous NaHCCb solution at 25 ⁇ 30°C. Separated both the organic and aqueous layers. Methylene chloride (210 ml) was added to the aqueous layer and separated the organic and aqueous layers. Combined the total organic layers and washed with water. Added charcoal to the organic layer and stirred for 40 min and filtered through highflow bed. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with isobutyl acetate.
  • D(10) is 0.79 ⁇
  • D(50) is 7.05 ⁇
  • D(90) is 87.05 ⁇ ⁇ .
  • Example-16 Preparation of crystalline Form-S of carbamic acid, N,N'-[[l,l'-biphenyl]-
  • Example-17 Preparation of crystalline Form-N of Daclatasvir hydrochloride (1:2).

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Abstract

La présente invention concerne le procédé de préparation d'acide carbamique, d'ester de N,N'-[[1,1'biphényl]- 4,4'-diylbis[ I H-imidazole-5,2-diyl-(2S)-2, 1-pyrrolidinédiyl[ (1S)-1-( 1-méthyléthyl)-2- oxo-2,1-éthanediyl]]]bis-,C,C'-diméthyl de formule (I), ses sels et ses polymorphes. La structure chimique du composé de formule (I) est présentée ci-dessous
PCT/IN2018/000005 2017-01-23 2018-01-22 Procédé de préparation d'acide carbamique, d'ester de n,n'-[[1,1'-biphényl] -4,4'-diylbis]- 1 h-imidazole-5,2 diyi-(2s)-2,1-pyrrolidinédiyl[(1 s)-1-(1-méthyléthyl)-2-oxo-2,1-éthanediyl]]] bis-,c,c'-diméthyl et ses sels et polymorphes Ceased WO2018134842A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN112213418A (zh) * 2020-09-17 2021-01-12 石家庄凯瑞德医药科技发展有限公司 索非布韦中有关物质的检测方法

Citations (1)

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CN106220617A (zh) * 2016-07-22 2016-12-14 上海众强药业有限公司 一种达卡他韦的合成新方法

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CN106220617A (zh) * 2016-07-22 2016-12-14 上海众强药业有限公司 一种达卡他韦的合成新方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112213418A (zh) * 2020-09-17 2021-01-12 石家庄凯瑞德医药科技发展有限公司 索非布韦中有关物质的检测方法
CN112213418B (zh) * 2020-09-17 2022-08-23 石家庄凯瑞德医药科技发展有限公司 索非布韦中有关物质的检测方法

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