WO2008119734A2 - Procédé de préparation de composés organiques - Google Patents

Procédé de préparation de composés organiques Download PDF

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WO2008119734A2
WO2008119734A2 PCT/EP2008/053641 EP2008053641W WO2008119734A2 WO 2008119734 A2 WO2008119734 A2 WO 2008119734A2 EP 2008053641 W EP2008053641 W EP 2008053641W WO 2008119734 A2 WO2008119734 A2 WO 2008119734A2
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optionally substituted
cycloalkyl
heterocyclyl
aryl
formula
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PCT/EP2008/053641
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WO2008119734A3 (fr
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Gregory Raymond Bebernitz
George Tien-San Lee
Prasad Koteswara Kapa
Xinglong Jiang
Herbert Franz Schuster
Louise Kirman
Joginder S. Bajwa
Guang-Pei Chen
Joseph Sclafani
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Novartis Ag
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel process for the preparation of (R)-3-Cycloalkyl-2-[4-(4- substitued amine-l-sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide and a composition obtainable by said chiral process.
  • X, Y and R are as defined below; in free form or in an appropriate acidic or basic salt form; are valuable glucokinase activators, which have been described in PCT Application No. PCT/US2006/038200, for example.
  • an object of the instant invention is the process for the preparation of a (i?)-3-Cycloalkyl-2- [4-(4-substitued amine- 1 -sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4-Z)]pyridin-2-yl)- propionamide, comprising:
  • step (d) reacting the acid chloride of step (c) with a compound of formula 6a in the presence of a base to form a compound of formula 7
  • step (f) reacting the compound formed in step (e) with or without isolation with a secondary amine
  • R is a C 3-6 cycloalkyl
  • Lg is a leaving group
  • Chiral auxiliary is any suitable chiral molecule that induces chirality
  • X is halogen, cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, aryl or heterocyclyl;
  • R 5 is hydrogen, (C 3 _i 2 )cycloalkyl, (C 6- io)aryl, (C 3- io)heterocyclyl or (d ⁇ alkyl optionally substituted by carboxy, (Ci -6 )alkoxy, (C ]-2 )alkoxy, (C ]-4 )alkoxy, (Ci -6 )alkylthio, (C 3-7 )cycloalkyl, (C 3- 7 )cycloalkoxy, (C 3-7 )cycloalkylthio, (C 6 -io)aryl, (C 6- io)aryloxy, (C 6- io)arylthio, (C 3- io)heterocyclyl or (C 3- 1 o)heterocyclyloxy ;
  • R 6 is either -(CR 7 R 8 ) m -W-R 9 in which
  • R 7 and Rg are, independently from each other, hydrogen, optionally substituted alkyl or cycloalkyl; or R 7 and R 8 combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered ring; m is zero or an integer from 1 to 5; W is -NRio- in which
  • Rio is hydrogen, optionally substituted alkyl or heterocyclyl; or Rio is -C(O)Rn, -C(O)ORn, or -C(O)NRi 2 Ri 3 in which
  • Ri i and Rn are, independently from each other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Ri 3 is hydrogen or lower alkyl; or
  • Ri 3 and R] 2 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or W is absent;
  • R 9 is hydrogen, optionally substituted Ci-C 7 alkyl, cycloalkyl, aryl or heterocyclyl; or R 9 and Ri 0 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or
  • R 6 and R 5 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring which may be optionally substituted, or may contain 1 to 3 other heteroatoms selected from oxygen, nitrogen and sulfur, or may be part of another ring, or
  • R 6 is free or esterified carboxy, tetrazolyl, cyano or -C(O)NRnRi 2 in which
  • Ri 1 and R i2 are, independently from each other, hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or
  • Ri 1 and R 12 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring.
  • Compound 1 may be reacted with (IR, 2R)-psuedoephedrine or any other suitable disposed chiral auxiliary (2) to form compound 3.
  • suitable chiral auxiliaries are (4R,5S )-(+)-4-methyl-5- phenyl-2-oxazolidinone, R (+)-diphenyl methyl-2-oxazolidinone, R (+)-isopropyl-2-oxazolidinone, R (+)-tert butyl-2-oxazolidinone, R (+)-phenyl-2-oxazolidinone or R (+)-benzyl-2-oxazolidinone; however, this list is not exhaustive or limiting.
  • This coupling to an amide bond may be performed as defined herein above, e.g., via conversion of the acid to the corresponding acid chloride or in the presence of a coupling agent such as EDCI, HOBt or PyBOP, or a mixture of coupling agent thereof.
  • a coupling agent such as EDCI, HOBt or PyBOP, or a mixture of coupling agent thereof.
  • a resulting compound of formula 3 may then be treated with a base, such as sodium hydride, lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LHMDS), preferably LHMDS, followed by addition of an alkylating agent of the formula R-(CH 2 )-Lg wherein R has a meaning as defined herein above, and Lg represents a leaving group, such as chloride, bromide, iodide, mesylate, tosylate or triflate, preferably iodide or triflate, to afford a compound of the formula 5 above.
  • a base such as sodium hydride, lithium diisopropylamide (LDA) or lithium bis(trimethylsilyl)amide (LHMDS), preferably LHMDS
  • LHMDS lithium bis(trimethylsilyl)amide
  • the alkylation step is preferably conducted in a polar organic solvent, such as THF, DMF, N-methylpyrrolidone (NMP), l,3-dimethyl-3,4,5,6-tetrahydro-2(7H)-pyridone (DMPU) or l,3-dimethyl-3,4,5,6-tetrahydro- 2(7H)-pyrimidinone (DMTP), or in a mixture of solvents thereof.
  • a polar organic solvent such as THF, DMF, N-methylpyrrolidone (NMP), l,3-dimethyl-3,4,5,6-tetrahydro-2(7H)-pyridone (DMPU) or l,3-dimethyl-3,4,5,6-tetrahydro- 2(7H)-pyrimidinone (DMTP), or in a mixture of solvents thereof.
  • a polar organic solvent such as THF, DMF, N-methylpyrrolidone (NMP), l,3-
  • a resulting compound 5 may be readily hydro lyzed using a variety of aqueous acidic conditions such as glacial acetic acid, formic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof and preferably glacial acetic / 8 N sulfuric acid.
  • aqueous acidic conditions such as glacial acetic acid, formic acid, sulfuric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid or mixtures thereof and preferably glacial acetic / 8 N sulfuric acid.
  • auxiliary employed formula 5 may also be hydrolyzed, e.g., in the presence of an aqueous base such as sodium, lithium or potassium hydroxide and an organic solvent such as THF or lower alcohol, preferably, methanol or ethanol, to afford a carboxylic acid of formula 6 wherein R has meanings as defined herein above.
  • an aqueous base such as sodium, lithium or potassium hydroxide
  • an organic solvent such as THF or lower alcohol, preferably, methanol or ethanol
  • a peroxide such as hydrogen peroxide may facilitate this hydrolysis.
  • an activated derivative of a carboxylic acid e.g., those corresponding to carboxylic acids of formula 6, include acid chlorides, bromides and fluorides, mixed anhydrides, lower alkyl esters and activated esters thereof, and adducts formed with coupling agents, such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI), 1 -hydroxy benzotriazole (HOBt), O-( ⁇ ,2-dihydro-2-oxo-l-pyridyl)-N ) N,N ',N '-tetramethyluronium tetrafluoroborate, benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP) and the like.
  • coupling agents such as l-ethyl-3-(3-dimethylaminopropyl)carbodi
  • Mixed anhydrides are preferably such from pivalic acid, or lower alkyl hemiesters of carbonic acids, such as ethyl or isobutyl analogs.
  • Activated esters include, for example, succinimido, phthalimido or 4-nitrophenyl esters.
  • reaction of an activated derivative of a carboxylic acid, e.g., those corresponding to carboxylic acids of formula (6), with an amine, e.g., those of formula (6a) where X is defined herein, may be carried out in the presence of a base, such as pyridine, triethylamine (TEA), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM) in an inert organic solvent, such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran (THF), or a mixture of solvents thereof.
  • a base such as pyridine, triethylamine (TEA), diisopropylethylamine (DIEA) or N-methylmorpholine (NMM)
  • an inert organic solvent such as dichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran
  • Carboxylic acids of formula 6 may be converted to their activated derivatives using methods described herein or according to methods generally known in the art, e.g., a carboxylic acid of formula 6 may be treated with a chlorinating agent, such as thionyl chloride or oxalyl chloride, to afford a corresponding acid chloride thereof, or by the treatment of a coupling agent such as EDCI or HOBt, or a mixture of coupling agents thereof.
  • a chlorinating agent such as thionyl chloride or oxalyl chloride
  • Compound 7 containing R and X groups as defined herein may be treated with chlorosulfonic acid to afford the desired para substituted sulfonyl chloride along with minor amounts of regioisomers which are carried through to the next step.
  • a compound of formula 8 may be isolated as a stable compound or carried on without isolation.
  • a compound of formula 8 may then be treated with an amine of the formula , R 6 -NH-R 5 , or an acid addition salt thereof, wherein R 5 and R 6 have meanings as defined herein above, in the presence of a base, such as pyridine, TEA, DIEA or NMM, in an inert organic solvent, such as DCM, DMF or THF, or a mixture of solvents thereof, to afford a compound of the formula 10 wherein R, R 5 , Re and X have meanings as defined herein above.
  • the reaction is conducted at a temperature ranging from about -4 0 C to room temperature (RT), more preferably, the reaction temperature is about 0 0 C.
  • Amines of formula R 6 -NH-R 5 are known, or if they are novel they may be prepared using methods well known in the art or as described herein in the illustrative Examples. Regioisomers formed from the chlorosulfonylation reaction then lead to regioisomeric analogs of 10 are then readily separated at this stage by chromatography or recrystallization. Chromatography may be performed under normal or reverse phase conditions or in some instances by the use of chiral columns and conditions using solvents appropriate to the conditions and well known in the art.
  • Recrystallization may be effected in any number of solvents including alcohol solvents e.g., methanol, ethanol, isopropanol and the like as well as aprotic solvents e.g., ethyl acetate, acetone, methylene chloride, toluene and the like depending on the respective polarity of the compound.
  • alcohol solvents e.g., methanol, ethanol, isopropanol and the like
  • aprotic solvents e.g., ethyl acetate, acetone, methylene chloride, toluene and the like depending on the respective polarity of the compound.
  • Compound 6a is synthesized by the following scheme.
  • 6a The primary amino functionality of 6e may be protected as shown herein employing BOC anhydride or the like in the presence of a base, typically an amine base, e.g. DMAP, triethylamine or the like and in an aprotic organic solvent, e.g. tetrahydrofuran, dioxane or the like. Under these reaction conditions there is the possibility of forming a di-BOC material. Should this material be present the di-BOC compound may be converted to the desired mono BOC material using e.g. potassium carbonate in a suitable solvent.
  • BOC protecting group referred to herein, other amide, urethane and urea protecting agents as well as benzyl, imine acetal and others knowledgeable to those trained in the art would be acceptable.
  • Compound 6d may then be used in a coupling procedure using a substituted boronic acid or equivalent where X is defined herein, e.g. aryl, heteroaryl, optionally substituted alkyl and the like in addition to a palladium reagent affords 6b.
  • X is defined herein, e.g. aryl, heteroaryl, optionally substituted alkyl and the like in addition to a palladium reagent affords 6b.
  • substitution of X with amino groups is possible using Buchwald conditions, carbonylation affords esters and amides; nucleophilic displacement with thiols affords alkylthiol derivatives, which can be further oxidized to alkyl sulfoxides and sulfones.
  • the protecting group can be readily removed using acidic conditions, e.g. TFA or HCl in a suitable solvent followed by neutralization using ammonium hydroxide to afford 6a.
  • the compounds of formula I can exist in free form or in acid addition salt form. Salt forms may be recovered from the free form in a known manner and vice-versa. Acid addition salts may e.g. be those of pharmaceutically acceptable organic or inorganic acids.
  • the preferred acid addition salts are the hydrochlorides, salts of methanesulfonic, sulfuric, phosphoric, citric, lactic and acetic acid.
  • optionally substituted alkyl refers to unsubstituted or substituted alkyl groups, i.e., straight- or branched-chain hydrocarbon groups having 1-20 carbon atoms, preferably 1-10 carbon atoms.
  • exemplary unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, «-butyl, t- butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like.
  • Substituted alkyl groups include, but are not limited to, alkyl groups substituted by one or more of the following groups: halogen, hydroxy, alkanoyl, alkoxy, alkanoyloxy, thiol, alkylthio, alkylthiono, sulfonyl, sulfamoyl, carbamoyl, cyano, carboxy, acyl, aryl, alkenyl, alkynyl, aralkoxy, guanidino, optionally substituted amino, heterocyclyl including imidazolyl, fiiryl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyl and the like.
  • lower alkyl' 1 refers to those alkyl groups as described above having 1-7, preferably 2-4 carbon atoms.
  • halogen refers to fluorine, chlorine, bromine and iodine.
  • alkenyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon double bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkynyl refers to any of the above alkyl groups having at least two carbon atoms and further containing a carbon to carbon triple bond at the point of attachment. Groups having 2-4 carbon atoms are preferred.
  • alkylene refers to a straight-chain bridge of 2-6 carbon atoms connected by single bonds, e.g., -(CH 2 ) ⁇ -, wherein x is 2-6, which may be interrupted with one or more heteroatoms selected from O, OC(O)-, S, S(O), S(O) 2 or NR, wherein R may be hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl, sulfonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and the like.
  • the alkylene may further be substituted with one or more substituents selected from optionally substituted alkyl, cycloalkyl, aryl, heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy, alkoxycarbonyl and the like; and it may be part of another ring.
  • cycloalkyl refers to optionally substituted monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each of which may contain one or more carbon to carbon double bonds, or the cycloalkyl may be substituted by one or more substituents, such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy, alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and the like.
  • substituents such as alkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy
  • Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl and the like.
  • bicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6- dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like.
  • Exemplary tricyclic hydrocarbon groups include adamantyl and the like.
  • alkoxy refers to alkyl-O-.
  • alkanoyl refers to alkyl-C(O)-.
  • alkanoyloxy refers to alkyl-C(O)-O-.
  • alkylamino and “dialkylamino” refer to alkyl-NH- and (alkyl) 2 N-, respectively.
  • alkanoylamino refers to alkyl-C(O)-NH-.
  • alkylthio refers to alkyl-S-.
  • alkylthiono refers to alkyl-S(O)-.
  • alkylsulfonyl refers to alkyl-S(O) 2 -.
  • alkoxy carbonyl refers to alkyl-O-C(O)-.
  • alkoxycarbonyloxy refers to alkyl-O-C(O)O-.
  • carbamoyl refers to H 2 NC(O)-, alkyl-NHC(O)-, (alkyl) 2 NC(O)-, aryl-NHC(O)-, alkyl(aryl)-NC(O)-, heteroaryl-NHC(O)-, alkyl(heteroaryl)-NC(O)-, aralkyl-NHC(O)-, alkyl(aralkyl)- NC(O)- and the like.
  • sulfamoyl refers to H 2 NS(O) 2 -, alkyl-NHS(O) 2 -, (alkyl) 2 NS(O) 2 -, aryl-NHS(O) 2 -, alkyl(aryl)-NS(O) 2 -, ⁇ yI) 2 NS(O) 2 -, heteroaryl-NHS(O) 2 -, aralkyl-NHS(O) 2 -, heteroaralkyl-NHS(O) 2 - and the like.
  • sulfonamido refers to alkyl-S(O) 2 -NH-, aryl- S (O) 2 -NH-, aralkyl-S(O) 2 -NH-, heteroaryl- S(O) 2 -NH-, heteroaralkyl-S(O) 2 -NH-, alkyl-S(O) 2 -N(alkyl)-, aryl-S(O) 2 -N(alkyl)-, aralkyl-S(O) 2 - N(alkyl)-, heteroaryl-S(O) 2 -N(alkyl)-, heteroaralkyl-S(O) 2 -N(alkyl)- and the like.
  • sulfonyl refers to alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.
  • optionally substituted amino refers to an amino group which may optionally be substituted by substituents such as optionally substituted alkyl, acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl, heteroaralkoxycarbonyl, carbamoyl and the like.
  • aryl refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6-12 carbon atoms in the ring portion, such as phenyl, biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionally be substituted by 1-4 substituents, such as optionally substituted alkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio, arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono, sulfonyl, sulfonamido, heterocyclyl and the like.
  • monocyclic aryl refers to optionally substituted phenyl as described under aryl.
  • aralkyl refers to an aryl group bonded directly through an alkyl group, such as benzyl.
  • aralkanoyl refers to aralkyl-C(O)-.
  • aralkylthio refers to aralkyl-S-.
  • alkoxy refers to an aryl group bonded directly through an alkoxy group.
  • arylsulfonyl refers to aryl-S(O) 2 -.
  • arylthio refers to aryl-S-.
  • aroyl refers to aryl-C(O)-.
  • aroyloxy refers to aryl-C(O)-O-.
  • aroylamino refers to aryl-C(O)-NH-.
  • aryloxycarbonyl refers to aryl-O-C(O)-.
  • heterocyclyl refers to an optionally substituted, fully saturated or unsaturated, aromatic or nonaromatic cyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to 12-membered bicyclic or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom-containing ring.
  • Each ring of the heterocyclic group containing a heteroatom may have 1, 2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized.
  • the heterocyclic group may be attached at a heteroatom or a carbon atom.
  • Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl
  • bicyclic heterocyclic groups include indolyl, dihydroidolyl, benzothiazolyl, 4,5,6,7- tetrahydro-benzothiazolyl, benzoxazinyl, benzoxazolyl, benzothienyl, benzothiazinyl, thiazolo[5,4- b]pyridinyl, thiazolo[5,4-d]pyrimidinyl, oxazolo[5,4-b]pyridinyl, 6,7-dihydro-4H-thiopyrano[4,3- djthiazolyl, 6,7-dihydro-4H-pyrano[4,3-d]thiazolyl, 4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridinyl, 4,5,6,7-tetrahydro-pyrazolo[l,5-a]pyridinyl, 5,6,7,8-tetrahydro-
  • Exemplary tricyclic heterocyclic groups include carbazolyl, dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl, acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl, carbolinyl and the like.
  • heterocyclyl includes substituted heterocyclic groups.
  • Substituted heterocyclic groups refer to heterocyclic groups substituted with 1, 2 or 3 substituents selected from the group consisting of the following:
  • aryl optionally substituted with alkyl, cycloalkyl, alkoxy, hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.
  • heterocyclooxy denotes a heterocyclic group bonded through an oxygen bridge.
  • heteroaryl refers to an aromatic heterocycle, e.g., monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl, benziniidazolyl, benzofuryl and the like, optionally substituted by, e.g., lower alkyl, lower alkoxy or halo.
  • heteroarylsulfonyl refers to heteroaryl-S(O) 2 -.
  • heteroaroyl refers to heteroaryl-C(O)-.
  • heteroaryloxycarbonyl refers to heteroaryl-O-C(O)-.
  • heteroaroylamino refers to heteroaryl-C(O)NH-.
  • heteroaryl refers to a heteroaryl group bonded through an alkyl group.
  • heteroaralkanoyl refers to heteroaralkyl-C(O)-.
  • heteroaralkanoylamino refers to heteroaralkyl-C(O)NH-.
  • acyl refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl and the like.
  • acylamino refers to alkanoylamino, aroylamino, heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.
  • esterified carboxy refers to optionally substituted alkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclooxycarbonyl and the like.
  • X is halogen, cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio, alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino, aryl or heterocyclyl;
  • Y is NR 5 R 6
  • R 5 is hydrogen, (C 3 .i 2 )cycloalkyl, (C 6 -io)aryl, (C 3- io)heterocyclyl or (Ci -6 )alkyl optionally substituted by carboxy, (Ci -6 )alkoxy, (Ci -2 )alkoxy-(Ci -4 )alkoxy, (Ci ⁇ alkylthio, (C 3-7 )cycloalkyl, (C 3- 7 )cycloalkoxy, (C 3-7 )cycloalkylthio, (C 6 -io)aryl, (C 6- io)aryloxy, (C 6- io)arylthio, (C 3 _io)heterocyclyl or (C 3 . 1 o)heterocyclyloxy;
  • R 6 is either -(CR 7 Rg) 1n -W-R 9 in which
  • R 7 and R 8 are, independently from each other, hydrogen, optionally substituted alkyl or cycloalkyl; or R 7 and R 8 combined are alkylene which together with the carbon atom to which they are attached form a 3- to 7-membered ring; m is zero or an integer from 1 to 5; W is -NRio- in which
  • Rio is hydrogen, optionally substituted alkyl or heterocyclyl; or Rio is -C(O)Rn, -C(O)OR n , or -C(O)NR 12 Ri 3 in which
  • Rn and Ri 2 are, independently from each other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; Rn is hydrogen or lower alkyl; or
  • Rn and Ri 2 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or W is absent;
  • R 9 is hydrogen, optionally substituted Ci-C 7 alkyl, cycloalkyl, aryl or heterocyclyl; or R 9 and Rio combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; or
  • R 6 and R 5 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring which may be optionally substituted, or may contain 1 to 3 other hetero atoms selected from oxygen, nitrogen and sulfur, or may be part of another ring, or
  • R 6 is free or esterified carboxy, tetrazolyl, cyano or -C(O)NRnRi 2 in which
  • Ri 1 and Ri 2 are, independently from each other, hydrogen, optionally substituted alkyl, cycloalkyl, aryl or heterocyclyl; or Rn and Ri 2 combined are alkylene which together with the nitrogen atom to which they are attached form a 4- to 7-membered ring; in free form or in acid addition salt form.
  • Another group is one of above compounds of formula (I) wherein the substituent on the adamantyl is bonded on a bridgehead.
  • the compounds of formula (I) exist in the form of optically active R isomer and the process of the present invention is capable of yielding compounds of formula (I) with a high (at least 95%) enantiomeric purity of the (R)-3-Cycloalkyl-2-[4-(4-substitued amine- l-sulfonyl)-phenyl]-N-(5- substituent-yl-thiazolo[5,4- ⁇ ]pyridin-2-yl)-propionamide.
  • a further object of the instant invention is a composition of (R)-3-Cycloalkyl-2-[4-(4- substitued amine- l-sulfonyl)-phenyl]-N-(5-substituent-yl-thiazolo[5,4- ⁇ ]pyridin-2-yl)-propionamide of formula (I), obtainable according to the process of claim 1, whereby 95% to 99,9% is (R)-3- Cycloalkyl-2- [4-(4-substitued amine- 1 -sulfonyl)-phenyl] -N-(5-substituent-yl-thiazolo [5,4-&]pyridin- 2-yl)-propionamide.
  • Preferred (R)-3-Cycloalkyl-2-[4-(4-substitued amine- 1 -sulfonyl)-phenyl]-N-(5-substituent-yl- thiazolo[5,4-&]pyridin-2-yl)-propionamides are those described as preferred compounds in the above process.
  • the mixture was heated to reflux to give a clear light solution which was filtered through a glass fiber filter.
  • the filtrate was heated to reflux using a Dean-Stark apparatus to distill off 300 mL of solvent (70 mL of water + 230 mL of ethyl acetate). Heating was stopped and the solution was allowed to cool to ambient temperature.
  • the product started crystallizing out at 67-70 0 C.
  • the batch was cooled to 0-5 0 C and held at 0-5 0 C for 30 min.
  • the white solids were filtered through a filter paper and the cake was washed with 2x250 mL of cold (0-5 0 C) ethyl acetate.
  • a nitrogen-flushed 3-L round bottomed flask was charged with 228 g (625.4 mmol, 1.0 equiv) of A4, 610 mL of glacial acetic acid and 610 niL of 8 N sulfuric acid and stirred.
  • the mixture was heated to reflux (105 0 C).
  • the batch was maintained at 105 0 C until completion of reaction (7.5 h).
  • the reaction mixture was cooled to 15 0 C over a period of 1 h.
  • the resulting black solid was filtered through a polypropylene filter paper and the cake washed with 2x500 mL of deionized water. The cake was pulled dry under house-vacuum for 30 min.
  • the black solid was transferred to a 2-L, 4-necked round bottomed flask and 8 g of charcoal and 750 mL of tert-butyl methyl ether was added. The mixture was stirred and heated to reflux (-65 0 C) for 20 min. The batch was cooled to 30-35 0 C and filtered through a pad of Celite ® over a filter paper. The cake was washed with 2x100 mL of tert-butyl methyl ether.
  • the cake was dried under vacuum until no more solvent came off the cake.
  • the solids were then transferred to a 1-L round bottom flask and 500 mL of 2 N HCl solution was added. The mixture was stirred for 5 min and transferred to a 2-L separating funnel. The mixture was extracted with 500 mL of tert-butyl methyl ether. The aqueous phase was reextracted with 250 mL of tert-butyl methyl ether. The combined organic phase was washed with 250 mL of deionized water and dried over anhydrous MgSO 4 .
  • reaction mixture was concentrated at 35 ⁇ 5 0 C (20 mbar.) to afford a yellow oil which was diluted with 269 g of hexane and flushed twice at 35 ⁇ 5 0 C (20 mbar) to give a straw- yellow oil (-104.5 g).
  • a 5-L 4-necked flask was charged with 81.6 g (0.44 mol, 1.01 equiv) of 5-chloro-thiazolo[5,4- &]pyridin-2yl-amine (A8), 0.8 g of N,N-dimethylaminopyridine, and 582 g of pyridine.
  • the mixture was stirred at 22 ⁇ 5 0 C for 15 min to give a homogenous mixture, and then the solution was cooled to 15 ⁇ 5 0 C.
  • the straw-yellow hazy contents were cooled to 10 ⁇ 5 0 C and 2.0 kg of 4 N hydrochloric acid solution were added slowly at 15 ⁇ 5 0 C over 30 min (pH >1) to give a straw- yellow suspension.
  • 1.628 kg of t- butyl methyl ether was then added and the mixture stirred at 20 ⁇ 5 0 C for 10 min.
  • the top organic layer was washed with 500 g of 2 N hydrochloric acid solution, 500 g of saturated sodium chloride solution, 500 g of saturated sodium bicarbonate solution followed by 500 g of saturated sodium chloride solution.
  • the organic phase was dried over 200 g of magnesium sulfate (anhydrous), filtered and the filter cake washed once with 148 g of methyl t-butyl ether.
  • the homogenous mixture was cooled to 5 ⁇ 5 0 C and added dropwise via a 1 -L addition funnel to a stirring mixture of 1.32 kg of methylene chloride, 3.0 kg of crushed ice, and 2.0 kg of water in a 12-L 4-necked flask Cool to 5 ⁇ 5 0 C over 1 h.
  • the 5-L flask and addition funnel were rinsed once with 396 g of methylene chloride.
  • the hazy mixture was warmed to 22 ⁇ 5 0 C to obtain two clear separated layers.
  • the organic layer was washed once with 1.5 kg of saturated sodium chloride solution and then dried with 200 g of sodium sulfate (anhydrous), the solids were filtered and washed Ix with 264 g of methylene chloride.
  • the filtrate was concentrated at 35 ⁇ 5 0 C (20 mbar) to a gummy solid, diluted at 30 ⁇ 5 0 C with 300 niL of t-butyl methyl ether and re-evaporated.
  • a flask was charged with 80.0 g (0.348 mol) of 5-Bromo-thiazolo[5,4-b]pyridin-2-ylAmine A2d, 1027 g of acetone, 50.8 g of triethylamine, 2.0 g of DMAP, and 100.4 g (0.46mol, 1.3 equiv) of di- tert-bxxty ⁇ di carbonate.
  • the mixture was stirred and heated to 50 0 C for 3 h.
  • the reaction mixture was cooled to 10 0 C, and 2000 g of water was added slowly while maintaining the reaction temperature at 10 ⁇ 5 0 C.
  • reaction mixture was stirred for 1 h and subsequently the solids were filtered off and the filter cake washed with 200 g of water. The solids were dried at 45 0 C for 16 h to give 90.4 g of (5-Bromo-thiazolo[5,4- ⁇ ]-2-carbamic tert-butyl ester A2c in 80% yield.
  • the aqueous solution was placed in a N 2 purged 1 L, 3-necked flask fitted with overhead stirring and the pH adjusted to 9.0 by adding 5.O g of ammonium hydroxide. The addition of base coincides with precipitation of solids. The resulting mixture was stirred for 15 min and the solids filtered and washed with two portions of 50 g of water. Air was pulled through the cake for 0.5 h and then the solids were placed in a vacuum oven with N 2 purge for 12 h at 50 0 C ⁇ 3 0 C to give 23.6 g (93.2%) of 5-[pridin-4-yl]-thazolo[5,4- ⁇ ] pyridine-2-ylamine A2.
  • the reaction mixture was concentrated at 30 ⁇ 5 0 C (20 mbar.) to a yellow oil and the residue flushed twice at 30 ⁇ 5 0 C (20 mbar) with a total amount of 34 g of hexane and reconcentrated to a straw- yellow oil (-13.1 g weight) of acid chloride.
  • a 1-L 4-necked flask was charged with 11.7 g (0.054 mol) of 5-pyridin-4-yl-thiazolo[5,4-b]pyridin- 2yl-amine A2, 0.2 g of N,N-dimeyhylaminopyridine, 8.2 g of triethylamine, and 168 g of N 5 N- dimethylformamide.
  • the mixture was heated at 45 ⁇ 5 0 C for 15 min to give a homogenous mixture and then cooled to 7 ⁇ 5 0 C.
  • the homogenous solution was cooled to -5 ⁇ 5 0 C, then the sulfonyl chloride from above was added portionwise at 10 ⁇ 5 0 C through a 1-L addition funnel at 5 ⁇ 5 0 C over 1 h.
  • the 5-L flask and addition funnel were rinsed once with 395 g of methylene chloride.
  • the contents were subsequently warmed to 22 ⁇ 5 0 C and stirred for 2 h.
  • Workup entailed addition of 4.333 kg of water into the mixture at 22 ⁇ 5 0 C to dissolve all 1-methylpiperazine salts.
  • the mixture was concentrated at 25 ⁇ 5 0 C (20 mbar) to a light tan suspension.
  • a N 2 purged 5-L 4-necked flask was charged with 320 g of crude LCZ960 A6, 4.0 kg of water and 2.64 kg of methylene chloride. The mixture was stirred with overhead mechanical stirrer for 5 min at 17 0 C ⁇ 3 °C. The pH was adjusted to 1.0 by addition of 60 g of 6 N HCl in water to give two homogeneous layers. The methylene chloride layer was separated and discarded. The aqueous layer containing the drug substance was extracted twice with a total of 2.64 kg of methylene chloride. The pH of the solution was adjusted to 9 by adding 10 g of a 1 :1 solution of ammonium hydroxide and water to give a precipitate.
  • a flask was charged with 7.2 g of the crude drug substance,60 mL of methanol and the mixture was heated to 50 0 C and maintained at this temperature for 4 h.
  • the reaction mixture was cooled to 20 0 C and the solids were filtered (filtration rate was slow) and washed with 20 mL of methanol.
  • the solids were dried at 45 0 C for 16 h to give 5.8 g of drug substance in 81% yield, (chemical purity >98%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)

Abstract

La présente invention porte sur un procédé de préparation d'un (R)-3-cycloalkyl-2-[4-(4-substituée amine-1-sulfonyl)-phényl]-N-(5-substituant-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide. Ce procédé comporte les opérations consistant à (a) prendre un composé chiral de formule 6 et former un chlorure d'acide in situ ; (b) faire réagir le chlorure d'acide de l'étape (a) avec un composé de formule 6a en présence d'une base afin de former un composé de formule 7 ; (c) faire réagir le composé de formule 7 avec de l'acide chlorosulfonique dans un solvant aprotique afin de former un composé de formule 8 in situ ; (d) faire réagir le composé formé à l'étape (c) sans isolement avec une amine secondaire ; (e) récupérer un composé de formule 10 sous forme libre ou sous forme de sel d'addition avec un acide.
PCT/EP2008/053641 2007-03-29 2008-03-27 Procédé de préparation de composés organiques WO2008119734A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010100144A1 (fr) * 2009-03-04 2010-09-10 Merck Serono S.A. Composés bicycliques fusionnés utilisés comme inhibiteurs de la pi3 kinase
US8946440B2 (en) 2008-04-28 2015-02-03 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
EP2878339A1 (fr) 2013-12-02 2015-06-03 Siena Biotech S.p.A. Antagonistes SIP3

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095418A1 (fr) * 2004-04-02 2005-10-13 Novartis Ag Derives de sulfonamide-thiazolpyridine en tant qu'activateurs de glucokinase utiles dans le traitement du diabete de type 2
WO2007041366A1 (fr) * 2005-09-30 2007-04-12 Novartis Ag Dérivés de sulfonamide en tant qu'agents activants de glycokinase pouvant être employés dans le traitement du diabète de type 2
WO2007041365A2 (fr) * 2005-09-30 2007-04-12 Novartis Ag Composes organiques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005095418A1 (fr) * 2004-04-02 2005-10-13 Novartis Ag Derives de sulfonamide-thiazolpyridine en tant qu'activateurs de glucokinase utiles dans le traitement du diabete de type 2
WO2007041366A1 (fr) * 2005-09-30 2007-04-12 Novartis Ag Dérivés de sulfonamide en tant qu'agents activants de glycokinase pouvant être employés dans le traitement du diabète de type 2
WO2007041365A2 (fr) * 2005-09-30 2007-04-12 Novartis Ag Composes organiques

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8946440B2 (en) 2008-04-28 2015-02-03 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
US9452977B2 (en) 2008-04-28 2016-09-27 Kyorin Pharmaceutical Co., Ltd. Cyclopentylacrylamide derivative
WO2010100144A1 (fr) * 2009-03-04 2010-09-10 Merck Serono S.A. Composés bicycliques fusionnés utilisés comme inhibiteurs de la pi3 kinase
EP2878339A1 (fr) 2013-12-02 2015-06-03 Siena Biotech S.p.A. Antagonistes SIP3
WO2015082357A1 (fr) 2013-12-02 2015-06-11 Siena Biotech S.P.A. Antagonistes de s1p3
US9951017B2 (en) 2013-12-02 2018-04-24 Teva Pharmaceutical Industries Limited S1P3 antagonists
EP3689864A1 (fr) 2013-12-02 2020-08-05 Teva Pharmaceutical Industries Limited Antagonistes du s1p3
EP3896068A1 (fr) 2013-12-02 2021-10-20 Teva Pharmaceutical Industries Limited Antagonistes du s1p3
US11472772B2 (en) 2013-12-02 2022-10-18 Teva Pharmaceutical Industries Limited S1P3 antagonists

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