WO2011005731A2 - Procédé de production d'antagoniste du récepteur cgrp - Google Patents

Procédé de production d'antagoniste du récepteur cgrp Download PDF

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WO2011005731A2
WO2011005731A2 PCT/US2010/041023 US2010041023W WO2011005731A2 WO 2011005731 A2 WO2011005731 A2 WO 2011005731A2 US 2010041023 W US2010041023 W US 2010041023W WO 2011005731 A2 WO2011005731 A2 WO 2011005731A2
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halo
substituted
unsubstituted
heterocycle
phenyl
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PCT/US2010/041023
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WO2011005731A3 (fr
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Kevin M. Belyk
Paul G. Bulger
Xin Linghu
Kevin M. Maloney
Mark Mclaughlin
Jun Pan
Bangping Xiang
Yingju Xu
Jingjun Yin
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Merck Sharp & Dohme Corp.
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Publication of WO2011005731A2 publication Critical patent/WO2011005731A2/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings

Definitions

  • This invention relates to a process for making 2-[(8i?)-8-(3,5-Difluorophenyl)-10- oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2i?)-2'-oxo-l,r,2',3-tetrahydrospiro[indene-2,3'- pyrrolo[2,3- ⁇ ]pyridin]-5-yl]acetamide, which is a CGRP receptor antagonist useful for the treatment of migraine.
  • This compound is described in U.S. Publication No. US-2007-0265225- Al, published on November 15, 2007, which is hereby incorporated by reference in its entirety.
  • CGRP Calcitonin Gene-Related Peptide
  • CGRP is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system.
  • CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation.
  • CGRP is expressed in alpha- and beta-forms that vary by one and three amino acids in the rat and human, respectively.
  • CGRP-alpha and CGRP-beta display similar biological properties.
  • CGRP When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase.
  • CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth muscle origin.
  • these receptors are divided into at least two subtypes, denoted CGRPl and CGRP2- Human ⁇ -CGRP-(8-37), a fragment of CGRP that lacks seven N-terminal amino acid residues, is a selective antagonist of CGRPl, whereas the linear analogue of CGRP, diacetoamido methyl cysteine CGRP ([Cys(ACM)2,7]CGRP), is a selective agonist of CGRP2- CGRP is a potent neuromodulator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache.
  • CGRP -mediated activation of the trigemino vascular system may play a key role in migraine pathogenesis. Additionally, CGRP activates receptors on the smooth muscle of intracranial vessels, leading to increased vasodilation, which is thought to contribute to headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9).
  • the middle meningeal artery the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP.
  • Trigeminal ganglion stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al., Ann. Neurol, 1988, 23, 193-196).
  • Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 1997, 17, 525-531).
  • Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J.
  • CGRP vascular effects of CGRP may be attenuated, prevented or reversed by a CGRP antagonist.
  • CGRP -mediated vasodilation of rat middle meningeal artery was shown to sensitize neurons of the trigeminal nucleus caudalis (Williamson et al, The CGRP Family:
  • CGRP Calcitonin Gene-Related Peptide
  • Amylin and Adrenomedullin
  • distention of dural blood vessels during migraine headache may sensitize trigeminal neurons.
  • Some of the associated symptoms of migraine, including extracranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et al, Ann. Neural 2000, 47, 614-624).
  • a CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization.
  • CGRP antagonists make them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans.
  • disorders include migraine and cluster headache (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al, Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al, Neurology, 2000, 14, 1335-1340); pain (Yu et al, Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al, Pain, 2000, 86, 163-175);
  • non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. ScL, 1992, 657, 397-404; Schini et al., Am. J. Physiol, 1994, 267, H2483-H2490; Zheng et al., J. Virol, 1993, 67, 5786-5791); shock, sepsis (Beer et al, Crit.
  • Urology 2001, 166, 1720-1723
  • allergic dermatitis Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143
  • psoriasis encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J.
  • the present invention describes an efficient and economical process for the preparation of 2-[(8i?)-8-(3, 5-Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2i?)-2'- oxo-1 , r,2',3-tetrahydrospiro[indene-2,3'-pyrrolo[2,3- ⁇ ]pyridin]-5-yl]acetamide using an asymmetric phase-transfer catalysis route.
  • the invention encompasses a novel process for making 2-[(8i?)-8-(3,5- Difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]-N-[(2i?)-2'-oxo-l,r,2',3- tetrahydrospiro[indene-2,3'-pyrrolo[2,3- ⁇ ]pyridin]-5-yl]acetamide, which is a CGRP receptor antagonist useful for the treatment of migraine, using an asymmetric phase-transfer catalysis route.
  • the invention also encompasses an efficient and practical synthesis of the (R)-acid intermediate, and generates the benzylic stereocenter in an enantioselective manner.
  • the invention encompasses a process for synthesizing a compound of Formula I
  • Step 1 reacting a compound of Formula A
  • Rl is selected from Cl-ioalkyl, C2-10 a lkenyl, C2-10 a lkynyl, C3-6cycloalkyl and aryl,
  • R2 is hydrogen or a first protecting group
  • R3 is selected from hydrogen, acyl, silyl or a metal, with a compound of Formula B
  • Xi is selected from the group consisting of: N(R)2, NO2, N3, halogen and OR, wherein each R is independently selected from hydrogen, acyl, Ri-S(O)2, Ci_6alkoxy, aryl, benzyl and Ci-galkyl, optionally substituted with halogen, aryl, silyl or oxo, wherein Ri is Cl-6alkyl or aryl,
  • Yl is a first leaving group
  • Zi is a second leaving group in a first organic solvent with a first inorganic base, optionally in an aqueous solvent, to yield a compound of Formula C
  • Step 2 reacting a compound of Formula C with the catalyst of Formula D,
  • R4 is selected from ethyl and vinyl
  • R5 is selected from hydrogen and methoxy
  • Ar is selected from aryl or heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 5 substituents independently selected from Cl-4alkyl, aryl, Cl-4alkoxy, hydroxy, CN, acyl, NR2, NO2, halogen and CF3, and if the compound of Formula C was isolated the step 1 above, in a second organic solvent with a second inorganic base, optionally in an aqueous solvent, to yield a compound of Formula
  • Step 3 deprotecting the compound of Formula E to yield a compound of Formula F
  • Step 4 - generating the free aniline compound of Formula G from the compound of Formula F
  • Step 5 and coupling a compound of Formula G with a compound of Formula H
  • first protecting group means a group introduced into the compound of Formula A at the indicated position in order to obtain chemoselectivity in the subsequent chemical reaction.
  • First protecting group includes alkyl, unsubstituted or substituted with halogen, aryl, silyl, oxygen and the like.
  • the term also includes acyl, sulfonyl, aryl and the like.
  • first leaving group and second leaving group means a group with the ability to detach itself from the molecule.
  • first leaving group and second leaving group include OR and halogen, where R is selected from hydrogen, alkyl
  • first organic solvent and “second organic solvent” include any common organic solvent, such as toluene, dichloromethane, DMF, MeCN, DMAc, NMP, MTBE, CPME, diethyl ether, THF, DME, 2-Me THF, xylene (all isomers), ethyl benzene, substituted benzenes, and the like.
  • first organic solvent and “second organic solvent” are independent of each other, for example, the first organic solvent can be toluene and the "second organic solvent” can be DMF.
  • first inorganic base and second inorganic base includes for example MetOH, Met2CO3, Met3PO4, wherein Met is selected from Li, Na and K.
  • first inorganic base and second inorganic base are independent of each other.
  • Ar includes benzene, substituted benzenes (substitutions include one of more of alkyl, aryl, alkoxy, hydroxy, CN, acyl, NR2, NO2, halogen, CF3), polycyclic aromatics including naphthalene, anthracene or heteroaromatics including pyridine, substituted pyridines, and the like.
  • deprotection can be carried out under acidic conditions, for example using acids including but not limited to HCl, MeSO ⁇ H, H2SO4 and the like, hydrogenation conditions or basic conditions as appropriate.
  • the free aniline can be generated by transition metal (such as Pd and Cu) catalyzed C-N bond formation reaction with HN(R)2, NH3, NH4X (X is OH or halogen), benzophenone imine, or any other ammonia surrogate followed by deprotection.
  • transition metal such as Pd and Cu
  • X is OH or halogen
  • benzophenone imine or any other ammonia surrogate followed by deprotection.
  • steps 3 and 4 can also be reversed as appropriate.
  • the invention includes both step 3 followed by step 4 or step 4 followed by step 3.
  • step 4 is followed by step 3, the free aniline is generated, followed by deprotection to yield the compound of Formula G
  • conditions for an amide bond formation between an acid and an amine/aniline include for example reacting the compounds of Formulas G and H with an amide coupling reagent and optionally an additive and a first base in a third organic solvent.
  • Amide coupling reagents include for example EDC, S0C12, (COC1)2, DCC, T3P, DPPA, HOSu, and the like.
  • Additives include HOBT, HOAt, HATU, HOBO, and the like.
  • first base includes amines having formula N(R)3 wherein R is hydrogen, alkyl, aryl, and the like.
  • Third organic solvent means for example DMF, MeCN, NMP, DMAc, THF, 2-Me THF, CPME, EtOAc, IPAc, DMSO, and the like.
  • the invention encompasses the process of Steps 1 to 5 above, wherein
  • Rl is methyl
  • R2 is t-butyl
  • R3 is hydrogen
  • Xl is N(R)2, wherein each R is benzyl
  • Yl is OH
  • R4 is vinyl
  • R5 is hydrogen
  • Ar is 3,5-bis(trifluoromethyl)phenyl.
  • the invention encompasses the process of the invention wherein in Step 1, the first inorganic base is KOH in an aqueous solvent and the compound of Formula C is not isolated, in Step 3, deprotection of the compound of Formula E is carried out under acidic conditions, in Step 4, the free aniline compound of Formula G is generated by hydrogenation of the compound of Formula F, and in Step 5, the compound of Formula G is coupled with a compound of Formula H by reacting the compounds of Formulas G and H with an amide coupling reagent and optionally an additive and a first base in a third organic solvent.
  • the invention encompasses the process of Steps 1 to 5 above further comprising making the compound of Formula A by reacting a compound of Formula J
  • R7 is OR8, wherein R8 is selected from Cl-ioalkyl and aryl, to yield a compound of Formula K
  • each R9 is independently Ci_ioalkyl, and M ⁇ -RlO or (2) M ⁇ -N(R9)2 to yield a compound of Formula L
  • RlO is Ci-ioalkyl
  • X4 is selected from OH, halogen and ORl 1 wherein Rl 1 is selected from Cl-l()alkyl, acyl and RU-S(0)2, wherein RU is Cl-6alkyl or aryl, to yield a compound of Formula A.
  • the "third leaving group” may be, for example, halogen, cyano and ORl 4, wherein Rl 4 is alkyl and aryl.
  • fourth organic solvent means, for example, an ethereal solvent such as THF, 2-Me THF, MTBE, CPME, and the like.
  • Ml is a metal, for example Li, Na or K.
  • RlO includes methyl, n-butyl, n-hexyl and the like.
  • fourth leaving group includes for example halogen, cyano, ORl5, wherein Rl 5 is alkyl or aryl.
  • alkyl is intended to mean linear, branched and cyclic structures having no carbon-to-carbon double or triple bonds.
  • Cl-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that Cl- galkyl specifically includes, but is not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl.
  • Cycloalkyl is an alkyl, part or all of which forms a ring of three or more atoms.
  • Cycloalkyl include mono-, bi- or tri-cyclic structures, including bridged structures such as adamantanyl.
  • Co or C()alkyl is defined to identify the presence of a direct covalent bond.
  • alkenyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond.
  • C2- galkenyl for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like.
  • alkynyl means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond.
  • C2-6 a lkynyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C2-6 a lkynyl specifically includes 2-hexynyl and 2-pentynyl.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl.
  • heteroaryl represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to six heteroatoms selected from the group consisting of N, O, S, P and Si, and wherein the nitrogen, sulfur and phosphorus heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole,
  • benzisothiazole benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof.
  • alkoxy as in C1-C6 alkoxy, is intended to refer to include alkoxy groups of from 1 to 6 carbon atoms of a straight, branched and cyclic configuration. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • acyl means an organic radical derived from an organic acid by the removal of the hydroxyl group, e.g., R-C(O)-. Examples include acetyl and benzoyl.
  • metal means for example Li, Na and K.
  • sil means (R ⁇ )3Si-, wherein R ⁇ is for example alkyl or aryl.
  • TMS trimethylsilyl
  • TDPS te/t-butyldiphenylsilyl
  • TIPS triisopropylsilyl
  • each Rl 2 is independently selected from the group consisting of:
  • phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • each Rl3 is independently selected from (1) -Ci-galkyl, which is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halo, (2) halo, (3) -ORa, and (4) -CN,
  • R a is independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,
  • R c are independently selected from:
  • Ci-galkyl which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6 or 7
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • Cl-6alkyl which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from:
  • heterocycle selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,
  • Step 1 reacting a compound of Formula O
  • Rl is selected from Ci_ioalkyl, C2-10 a lkenyl, C2-10 a lkynyl, C3_6cycloalkyl and aryl,
  • R2 is hydrogen or a first protecting group
  • R3 is selected from hydrogen, acyl, silyl or a metal, with a compound of Formula P
  • Xi is selected from the group consisting of: N(R)2, NO2, N3, halogen and OR, wherein each R is independently selected from hydrogen, acyl, Ri-S(O)2, Cl-6alkoxy, aryl, benzyl and Cl-6alkyl, optionally substituted with halogen, aryl, silyl or oxo, wherein Ri is Cl-6alkyl or aryl,
  • Yl is a first leaving group
  • Zi is a second leaving group, in a first organic solvent with a first inorganic base, optionally in an aqueous solvent, to yield a compound of Formula Q , and optionally isolating the compound of Formula Q;
  • Step 2 reacting a compound of Formula Q with the catalyst of Formula D,
  • R4 is selected from ethyl and vinyl
  • R5 is selected from hydrogen and methoxy
  • Ar is selected from aryl or heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 5 substituents independently selected from Ci_4alkyl, aryl, Ci_4alkoxy, hydroxy, CN, acyl, NR2,
  • Step 3 deprotecting the compound of Formula R to yield a compound of Formula S
  • Step 4 generating the free aniline compound of Formula N from the compound of Formula S
  • Xi is N(R)2, NO2, N3, reduction or hydrogenation of the compound of Formula S, or when Xi is halogen or OR, transition metal catalyzed C-N bond formation reaction with the compound of Formula S and an ammonia surrogate followed by deprotection,
  • the invention also encompasses a process of making the compound of Formula R according to Steps 1 and 2 described immediately above, wherein all variables are also defined as above.
  • the invention also encompasses a process for making a compound of Formula T
  • each Rl 2 is independently selected from the group consisting of:
  • phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, azetidinyl, piperazinyl, pyrrolidinyl, thienyl and morpholinyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • each Rl3 is independently selected from (1) -Cl-6alkyl, which is unsubstituted or substituted with 1, 2, 3, 4, 5 or 6 halo, (2) halo, (3) -ORa, and (4) -CN,
  • R a is independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,
  • R c are independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • Cl-6alkyl which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • Step 1 reacting a compound of Formula O
  • Rl is selected from Cl-l()alkyl, C2-10 a lkenyl, C2-10 a lkynyl, C3-6cycloalkyl and aryl,
  • R2 is hydrogen or a first protecting group
  • R3 is selected from hydrogen, acyl, silyl or a metal, with a compound of Formula P
  • Xi is selected from the group consisting of: N(R)2, NO2, N3, halogen and OR, wherein each R is independently selected from hydrogen, acyl, Ri-S(O)2, Cl-6alkoxy, aryl, benzyl and Cl-6alkyl, optionally substituted with halogen, aryl, silyl or oxo, wherein Ri is Ci-galkyl or aryl,
  • Yl is a first leaving group
  • Zi is a second leaving group, in a first organic solvent with a first inorganic base, optionally in an aqueous solvent, to yield a compound of Formula Q , and optionally isolating the compound of Formula Q;
  • Step 2 reacting a compound of Formula Q with the catalyst of Formula U,
  • R4 is selected from ethyl and vinyl
  • R5 is selected from hydrogen and methoxy
  • Ar is selected from aryl or heteroaryl, said aryl and heteroaryl optionally substituted with 1 to 5 substituents independently selected from Ci_4alkyl, aryl, Ci_4alkoxy, hydroxy, CN, acyl, NR2,
  • first leaving group second leaving group
  • first organic solvent first organic base
  • aqueous solvent second organic solvent
  • second inorganic base second organic solvent
  • the invention also encompasses the process for making the compound of Formula I described in steps 1 to 5 above, further comprising making the compound of Formula H by reacting a compound of Formula V
  • the piperazinone is formed by reacting the compound of Formula V with an amine nucelophile of Formula W, optionally in a fifth organic solvent, such as sulfolane, toluene, acetonitrile, cyclopentylmethyl ether, and tetrahydrofuran, to form the intermediate V
  • a fifth organic solvent such as sulfolane, toluene, acetonitrile, cyclopentylmethyl ether, and tetrahydrofuran
  • the intermediate is then hydrolyzed under acidic conditions by charging an acid such as HCl, HBr, or H 2 SO 4 , to form the intermediate of V"
  • the intermediate V" is then neutralized with a base such as LiOH, NaOH, or KOH to form the piperazinone of the compound of Formula X.
  • a base such as LiOH, NaOH, or KOH
  • the term "fifth leaving group” means any suitable leaving group such as bromide, chloride, sulfonate (including but not limited to mesylate and tosylate).
  • the "second base” can be for example LHMDS, NaHMDS, or KHMDS.
  • the ester is then hydro lyzed under basic condition by adding a hydroxide base such as LiOH, NaOH, or KOH.
  • the compound of Formula V is reacted with an amine nucleophile of Formula W in a fifth organic solvent.
  • the fifth organic solvent is selected from the group consisting of: sulfolane, toluene, acetonitrile, cyclopentylmethyl ether, or tetrahydrofuran. In a further embodiment, the fifth organic solvent is sulfolane.
  • Another embodiment of the invention encompasses the process immediately described above for making the compound of Formula H, further comprising making the compound of Formula V by reacting a compound of Formula Y
  • a chiral hydrogenation catalyst comprising a palladium pre-catalyst and a chiral ligand selected from the group consisting of: (5)-l-[(li?)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (SL- J002-2), (S)- 1 -[( lR)-2-(di- 1 -naphthylphosphine)ferrocenyl]ethyldi-tert-butylphosphine (SL- J216-2), (S)- 1 -[( li?)-2-(di-/? ⁇ r ⁇ -tolylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (SL-JO 12- 2), or (5)-l-[(li?)-2-(di-ortho-toly
  • the invention described above for making the acid fragment of Formual H represents an efficient, practical synthesis of this intemediate and generates the benzylic stereocenter in an enantioselective manner.
  • the acid fragment was previously synthesized in racemic form and resolved by chiral HPLC separation.
  • the synthesis of the racemic compound was low-yielding and suffered from issues arising from chemical instability of some of the intermediates.
  • This invention encompasses a process that is higher yielding, more cost efficient and with no need for chiral HPLC separation.
  • the invention also encompasses a process for making a compound of Formula
  • Rl 4 and Rl 5 are each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl, indolyl, indazolyl, benzimidazolyl, and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, imidazolyl, furanyl, tetrahydrofuranyl, thiazolyl and oxazolyl, wherein the phenyl or heterocycle is optionally fused to the ring, and which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperdinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • R a is independently selected from:
  • Ci-galkyl which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6 or 7
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl,
  • R c are independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • Cl-6alkyl which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is
  • Rl 7 is Cl-6alkyl, optionally in a fifth organic solvent, followed by hydrolysis under acidic conditions and subsequent neutralization to make the compound of Formula AA or AAl.
  • the terms "fifth organic solvent,” “hydrolysis under acidic conditions” and “subsequent neutralization” are defined as described above.
  • the compound of Formula BB or BBl is reacted with an amine nucleophile of Formula C in a fifth organic solvent.
  • the fifth organic solvent is selected from the group consisting of: sulfolane, toluene, acetonitrile, cyclopentylmethyl ether, and tetrahydrofuran. fin another embodiment, the fifth organic solvent is sulfolane.
  • the invention encompasses a process for making a compound of Formula DD or DDl
  • R.18 is selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl, indolyl, indazolyl, benzimidazolyl, and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • (d) -ORa (3) phenyl or heterocycle, wherein said heterocycle is selected from: pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, morpholinyl, thiazolyl and oxazolyl, which phenyl or heterocycle is unsubstituted or substituted with 1-5 substituents each independently selected from:
  • Ra is independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • R c are independently selected from:
  • Ci_6alkyl which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6 or 7
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • Cl-6alkyl which is unsubstituted or substituted with 1, 2, 3 or 4 substituents each independently selected from:
  • phenyl or heterocycle wherein said heterocycle is selected from pyridyl, pyrimidinyl, thienyl, pyridazinyl, piperidinyl, azetidinyl, furanyl, piperazinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and pyrazinyl, which phenyl or heterocycle is unsubstituted or substituted with 1 , 2 or 3 substituents each independently selected from:
  • a chiral hydrogenation catalyst corresponding to the desired chiral product DD or DDl in the presence of hydrogen
  • said chiral hydrogenation catalyst comprising a palladium pre-catalyst and the appropriate chiral ligand selected, in a methanol solvent to yield a compound of Formula DD or DDl.
  • a chiral hydrogenation catalyst comprising a palladium pre-catalyst and the appropriate chiral ligand selected, in a methanol solvent to yield a compound of Formula DD or DDl.
  • chiral product DD would be prepared using a chiral ligand selected from the group consisting of: (S)-l-[(li?)-2-(diphenylphosphino)ferrocenyl]ethyldi-tert- butylphosphine (SL-J002-2), (S)- 1 -[( li?)-2-(di- 1 -naphthylphosphine)ferrocenyl]ethyldi-tert- butylphosphine (SL-J216-2), (S)- 1 -[( li?)-2-(di-/? ⁇ ra-tolylphosphino)ferrocenyl]ethyldi-te/t- butylphosphine (SL-J012-2), or (5)-l-[(li?)-2-(di-ortho-tolylphosphino)ferrocenyl]ethyldi-tert
  • seeded can be readily prepared by taking out ca. 50OmL of the solution and stirred at rt with traces of seeds that form on simple evaporation on a spatula) to form a very thick slurry.
  • a 100-L, four-necked, round-bottomed flask was charged with the diester 3 in 38 L of THF from the previous step. While cooling with a dry ice-acetone bath (ca. -50 0 C), L1AIH4 (26 L) was added dropwise via an addition funnel keeping the internal temperature ⁇ 5 0C (ca. 1.5 h addition). The resulting reaction mixture was aged at -12 to 1 0 C for 3 h.
  • reaction mixture was warmed to room temperature and diluted with 36 L (ca. 6 vol.) of MTBE.
  • the reaction mixture was seeded to initiate crystallization and then diluted with an additional 18 L of MTBE and aged at room temperature for ca. 2 h (usually ⁇ 5% chloride in the mother liquor).
  • the crystals were collected by filtration, washed with 50 L of MTBE (to ensure the complete removal of HCl), and dried under vacuum with a nitrogen sweep to give 6.67 kg (95%) [6.27 kg (90% yield) corrected for 94 weight % (ca. 5% MTBE and ca. 1% MeCN by lH NMR)] of white crystals (LCAP >98.5%).
  • reaction temp rose to 83 0 C in a few minutes due to exotherm and an ice-water bath was immediately applied to cool the reaction (very minor refluxing of solvent observed). Reaction temp rose to 90 0 C and held at that temp for 10 min before dropping.
  • the mixture was transferred to a IOOL extractor for separation.
  • the aq layer (35 L) was cut, and the organic layer (50 L) was treated with HCl ( 2.0 N, -24 L ) to PH 0.45.
  • reaction was aged for 20min at the temp of -6 to -8°C.
  • Methyl Chloroformate (2.05L, 1.00 equiv.) was slowly added via addition funnel over 43 min (exothermic, internal temp was controlled ⁇ 14.2 0 C); 10 min after addition (when temp became steady), the reaction was aged for about 1.5 h at 15 to 20 0 C (@92%conversion based on the ratio of LCAP).
  • Another 0.04 eq. (82 ml) of Methyl chloroformate was added to get about 94% conversion (before addition, temp was about 15 0 C).
  • Step (3) After the above reaction completed, it was cooled to 0 0 C with dry ice-acetone bath and methyl chloro formate (2.66 L, 1.3 equiv.) was added via an addition funnel over 25 min (controlling temp below 13 0 C during addition. Reaction went from a dark solution to an orange slurry).
  • the organic layer was then transferred to a 100 L RB flask and concentrated to give 2OL of a slurry.
  • the product had begun to crystallize out and 60 L of n-heptane (6.7% loss in supernatant with only 30 L heptane) was charged via additional funnel in about 60 min.
  • the resulting pale yellow slurry was aged for ca. 2 h (overnight aging is fine too).
  • the product was collected by filtration, rinsed with 13 L of a solution of THF/heptane (1 :13) and then 10 L heptane.
  • the pale yellow product was dried under vacuum/N2. to give total 5.0 kg of the K-salt was obtained (>99% LCAP, 94%wt, 63%yield) and with 5.6% loss in the mother liquid.
  • KOH 15.966 kg of 88.5 wt% pellets
  • ice-bath cooling under nitrogen at such a rate as to maintain the internal temperature at ca. 30 0 C.
  • the water was drained from the ice-bath and the remaining KOH added rapidly, to achieve a maximum internal temperature of 37 0 C and complete dissolution of the KOH.
  • the mixture was then allowed to cool to 32 0 C, then placed in an ice bath. Once the temperature reached 28 0 C, KOH began to crystallize (slightly exothermic). 15 minutes after the onset of crystallization, PhMe (28 L) was added, and the stirring rate increased to maximum.
  • chloride 2 (2.367 kg, 93.5 wt%, remainder MTBE and MeCN) was added in two equal portions over 5 minutes (minor exotherm), rinsing with PhMe (1 L). After a further 15 minutes 0.50 eq. of oxindole (6.246 kg of a 0.11438 wt% solution in PhMe, 0.715 kg oxindole) was added in two portions over 2 minutes (exotherm from 11.9 to 14.0 0 C). After a further 15 minutes 0.45 eq. of oxindole (5.622 kg of a 0.11438 wt% solution in PhMe, 0.643 kg oxindole) was added in two portions over 2 minutes (exotherm from 13.3 to 14.6 ° C).
  • Catalyst 12 (0.171 kg) was added in one portion, rinsing with PhMe (1.1 L). The mixture was stirred at ca. 10 0 C for a further 16 h.
  • the solution was cooled to 38 0 C and diluted with MeOH (22 L, exothermic for the first 4L MeOH addition). The solution was further cooled to RT and subdivided to two equal halves for hydrogenation.
  • the first half of the above solution was charged to a hydrogenation vessel with 2 L MeOH rinse followed by 112 g of 10% Pd/C (wet) and a 2 L MeOH rinse. Applied 60 psi of H2 gas with slow agitation in the first 30 min when the temperature rose from 20 0 C to 27 0 C. The agitation was increased and the reaction was continued at RT until LC revealed ⁇ 0.1% of mono-debenzylation product vs. product 14. The second half of solution of A was hydrogenated under the same conditions. The two batches were combined and filtered through solka floe with MeOH rinse.
  • the filtrate was concentrated to 22 L, transferred to a IOOL extractor with IL MeOH and IL water rinse. Water (34 L) was added. The mixture was cooled back to 20 0 C and pH was adjusted to 1.5-2 with 9.6 L IO N NaOH. Toluene (24 L) was added and the mixture was stirred for 10 min and settled for 30 min. The top toluene layer was analyzed to confirm no product loss and then discarded. The aqueous layer was collected and transferred back to the IOOL RBF and further pH adjusted to 4 over 30min with a 2.8 L 5 N NaOH (crystals started to come out at pH 2.2 after -300 ml of the NaOH solution addition). A water bath was used to cool the very slight exothermic process.
  • the reaction mixture was diluted with EtOAc (27 L, 10 vol.) and water (27 L, 10 vol.), and the resulting aqueous layer (ca. 3% of compound of Formula I) was separated and extracted with 13.5 L of EtOAc (5 vol.).
  • EtOAc 8% NaHCO3 solution
  • water 27 L
  • EtOAc solution is then solvent-switched to EtOH (80 L) maintaining a volume of ca. 50 L (note, crystallization began during the solvent switch).
  • the tan slurry was diluted with 40 L of EtOH bringing the total vol. to ca. 90 L (15 vol. with respect to the compound of Formula I).
  • the slurry was heated to 55 0 C and then allowed to cool to room temperature and aged for 14 h.
  • the acid 15 can be made by following one of Examples 2 or 3:
  • starting material 1.5 %; bromoketone, 83.0 %; toluene, 7.9 %; and dibromoketone, 5.1 %.
  • the layers were allowed to settle, and the two lower aqueous layers were removed.
  • the iPAc layer was washed with degassed water (23 L), iPAc (7.8 kg) was added and the diluted solution was washed again with water (23 L).
  • the cloudy iPAc layer was then filtered through a ⁇ 5 cm layer of solka flok on a ⁇ 50 cm filter pot.
  • a 12-L, 4-necked round bottom flask is fitted with an overhead stirrer, thermocouple, reflux condenser, nitrogen inlet and vacuum inlet.
  • MeOH 4.18 L
  • DCM 1.39 L
  • This stirred solution is degassed with vacuum/nitrogen cycles and then [(p-cymene)RuCl2]2 (58.3 g) and (,S)-BINAP (122 g) are added.
  • the dark slurry is heated to 50 0 C and aged two hours while stirring under nitrogen. At end of reaction a homogeneous dark solution is achieved and the catalyst is used directly.
  • the hydrogenation vessel is charged with a solution of ketone MSA salt (2.50 kg) and methanesulfonic acid (153 g) in methanol (12.5 L). The solution is degassed and the prepared catalyst solution added to the vessel maintaining an inert atmosphere. The reaction is then hydrogenated at 80 0 C and 400 p.s.i. for 18 hours.
  • the mixture is concentrated and flushed with toluene to completely remove methanol. It is diluted with toluene to ⁇ 45 L and z-Pr2NEt (6.28 kg, 8.46 L, 48.6 mol) is added. The mixture is cooled to -35 0 C, SOCI2 (2.12 kg, 1.30 L, 17.8 mol) is added slowly while maintaining the batch at ⁇ -20 0 C. The mixture is aged at -20 0 C for Ih and quenched with water (20 L) after confirming the completion of the reaction.
  • Step 5 Oxidation to the sulfamate with NaIOzJ.
  • a solution of the phosphate buffer (pH 6.5) was made by dissolving NaH2PO4 (972 g, 8.1 mol) and Na2HPO4 (383 g, 2.70 mol) in water (11.5 L). Sulfmamate 6 solution in toluene (-20 L) was added and then ACN (10 L) was added. Solid Nal ⁇ 4 (4.85 kg) was added in portions while maintaining the batch at 15-25 0 C with ice-water cooling bath.
  • the mixture was aged at 20-25 0 C until complete conversion was achieved.
  • the reaction was then quenched with MeOH (0.5 L) and aged for 1 h.
  • the mixture was filtered through a Solka-Floc pad and the filter cake was rinsed with toluene (15 L).
  • the organic layer was separated, washed with water (15 L x 2), concentrated and flushed with ACN to minimum volume ( ⁇ 10 L).
  • Glycine ethyl ester free base TMG (1,1,3,3-tetramethyl guanidine, 3.55 kg, 3.88 L, 30.8 mol) was added to a slurry of glycine ethyl ester HCl salt (4.52 kg, 32.4 mol) in ACN (6.8 L) with dry-ice acetone bath to maintain the batch at ⁇ 10 0 C. The mixture was aged at 0 0 C for Ih then MTBE (34 L) was added. The mixture was aged for 2 h and then filtered. The filter cake was washed with MTBE (10 L) and the filtrate was concentrated to ⁇ 4-5 kg and kept cold ( ⁇ 0 0 C).
  • This process should be conducted under inert gas (N2) with exclusion of water/oxygen at all stages until aqueous workup (maintain exclusion of oxygen during workup).
  • N2 inert gas
  • a two-phase mixture of IM HCl (227mL, 1.0 equiv) and MTBE (400 mL) is prepared and cooled to 0-10 0 C.
  • the reaction mixture is transferred into the aqueous workup mixture, maintaining ⁇ 10 0 C.
  • the resulting two-phase mixture can be allowed to warm to 20 0 C for the phase cut.
  • This process should be conducted under inert gas (N2) with exclusion of water at all stages until aqueous workup.
  • N2 inert gas
  • the filtered 2-Me-THF solution was switched with heptane until the ratio of 2- Me-THF : heptane is approx 1 : 2 and the total volume is around 5 volumes (relative to starting hydroxyketone).
  • the slurry is cooled to 0 0 C and aged for 1 h before it is filtered.
  • the cake is rinsed with 2-Me-THF : heptane (1 : 2) mixture (1-2 bed volumes) then heptane.
  • Isolated off- white solid (116 g) is > 99 LCAP, > 99 wt% purity by NMR. Isolated yield is 86% (corrected) from 2.
  • the cyclic imine 3 (62 g) was suspended in anhydrous MeOH (solubility of sulfamate in MeOH is ⁇ 20 g/L at ambient temperature) and transferred to a hastalloy autoclave hydrogenation vessel under vacuum pressure (415 mL total MeOH used for the entire transfer process). The suspension was agitated at ambient temperature during the catalyst preparation process.
  • Hydrogenation catalyst prep (carried out inside a nitrogen-filled glovebox) :
  • the Pd(O Ac)2 (179 mg) and (5)-(-)-l-[(i?)-2-(diphenylphosphino)ferrocenyl]ethyldi-t- butylphosphine (SL-J002-2; 481 mg) were charged to a 40 ml vial equipped with stir bar.
  • the solids were dissolved in 20 mL dichloromethane and the resulting solution was agitated at ambient temperature for 1 h prior to transferring it to the lower stage of a stainless steel dual- reservoir catalyst bomb.
  • the upper stage was charged with anhydrous methanol (20 ml) inside the glovebox.
  • the bomb was sealed prior to removal from glovebox.
  • the catalyst solution in the lower stage of the catalyst bomb was charged under nitrogen to the hydrogenation vessel under vacuum pressure at ambient temperature.
  • the methanol in the upper stage was used to rinse the lower stage reservoir prior.
  • the rinse was then transferred to the hydrogenation vessel under vacuum pressure.
  • the batch was pressurized to 80 psi with hydrogen and the batch was warmed to ⁇ 40 0 C.
  • the batch was agitated under hydrogen pressure for a total of 16 h prior to sampling for HPLC analysis.

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  • Plural Heterocyclic Compounds (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention englobe un nouveau procédé de production de 2-[(8R)-8-(3,5-difluorophényl)-10-oxo-6,9-diazaspiro[4.5]déc-9-yl]-N-[(2R)-2'-oxo-1,1',2',3-tétrahydrospiro[indène-2,3'-pyrrolo[2,3-b]pyridin]-5-yl]acétamide, qui est un antagoniste du récepteur CGRP utile pour le traitement de la migraine, à l'aide d'une voie de catalyse par transfert de phase asymétrique. L'invention englobe également une synthèse efficace et pratique de l'intermédiaire acide (R), et génère les stéréocentes benzyliques d'une manière énantiosélective.
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WO2013138418A3 (fr) * 2012-03-14 2014-05-30 Merck Sharp & Dohme Corp. Procédé de production d'antagonistes du récepteur cgrp
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WO2013138413A1 (fr) * 2012-03-14 2013-09-19 Merck Sharp & Dohme Corp. Sels alcaloïdes bis-quaternaires de quinquina à titre de catalyseurs par transfert de phase asymétrique
AU2013232196C1 (en) * 2012-03-14 2017-03-16 Merck Sharp & Dohme Llc Process for making CGRP receptor antagonists
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RU2667909C2 (ru) * 2012-03-14 2018-09-25 Мерк Шарп И Доум Корп. Бисчетвертичные соли алкалоида хинного дерева в качестве асимметрических межфазных катализаторов
RU2672056C2 (ru) * 2012-03-14 2018-11-09 Мерк Шарп И Доум Корп. Способ получения антагонистов рецепторов cgrp
JP2019206586A (ja) * 2012-03-14 2019-12-05 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． Ｃｇｒｐ受容体アンタゴニストの製造方法
RU2712971C2 (ru) * 2014-12-23 2020-02-03 Галдерма Ресерч Энд Девелопмент Новые гетероциклические соединения и их применение в медицине и косметике
WO2016102882A1 (fr) 2014-12-23 2016-06-30 Galderma Research & Development Nouveaux composés hétérocycliques et leur utilisation en médecine ainsi qu'en cosmétique
EP3708566A1 (fr) 2014-12-23 2020-09-16 Galderma Research & Development Nouveaux composés hétérocycliques et leur utilisation en médecine ainsi qu'en cosmétique
US11400081B2 (en) 2017-05-17 2022-08-02 The University Of Sheffield Compounds

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