WO2014081616A1 - Préparation de précurseurs d'antagonistes de leucotriène - Google Patents

Préparation de précurseurs d'antagonistes de leucotriène Download PDF

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WO2014081616A1
WO2014081616A1 PCT/US2013/070210 US2013070210W WO2014081616A1 WO 2014081616 A1 WO2014081616 A1 WO 2014081616A1 US 2013070210 W US2013070210 W US 2013070210W WO 2014081616 A1 WO2014081616 A1 WO 2014081616A1
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formula
palladium
compound
alkyl
aryl
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PCT/US2013/070210
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English (en)
Inventor
Jennifer E. ALBANEZE-WALKER
Yonggang Chen
Guy Humphrey
Shane William KRSKA
Ji QI
Lushi Tan
Tetsuji Itoh
Shigeru FUNANE
Tohru Yokozawa
Tohru Kobayashi
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Merck Sharp & Dohme Corp.
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Publication of WO2014081616A1 publication Critical patent/WO2014081616A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals

Definitions

  • the leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid.
  • the major leukotrienes are Leukotriene B4 (abbreviated LTB4), LTC4, LTD4, and LTE4.
  • LTB4 Leukotriene B4
  • LTC4, LTD4, and LTE4 The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and
  • Montelukast sodium is a known leukotriene antagonist.
  • WO2008131932 (Lonza) describes the preparation of chiral alcohol by asymmetric hydrogenation using H 2 in the presence of a platinum group complex catalyst comprising a chiral phosphine ligand.
  • the present invention also employs asymmetric hydrogenation to set the secondary alcohol stereocenter.
  • the hydrogenation set forth in the present invention is carried out on a ketone alcohol intermediate that already bears the pendant tertiary alcohol function of montelukast. In this way, the use of rare earth reagents is avoided.
  • the present invention utilizes newer generation asymmetric hydrogenation catalysts that impart higher catalytic activity and efficiency than those described in the aforementioned publication.
  • WO2010148209 (Dr. Reddy) describes the reduction of ketone alcohol to the diol using H 2 in the presence of ((R)-xyl-BINAP)(R,R)-DPEN)RuCl 2 .
  • the present invention also involves, in certain embodiments, the asymmetric hydrogenation of this ketone alcohol intermediate.
  • the above referenced publication employs a less efficient three step linear sequence of (i) a ketone protection step, (ii) a Grignard addition step, and (iii) a deprotection step, to install the tertiary alcohol functionality.
  • the present invention introduces this functional group in a convergent manner through a Heck coupling sequence with an aryl alcohol intermediate that already bears this functional group.
  • the present invention utilizes newer asymmetric hydrogenation catalysts that impart higher catalytic activity and efficiency than those described in the aforementioned publication.
  • WO2009042984 (Codexis) describes the reduction of the ketone alcohol to the diol using a ketoreductase enzymatic system.
  • the requisite ketone alcohol was actually generated from the diol product itself by oxidation, adding two additional, redundant steps to the original process for making montelukast, and retaining the requirement for a rare earth reagent in the overall process.
  • the present invention comprises a short, efficient, higher yielding route to the ketone alcohol intermediate that does not require the use of a rare earth reagent.
  • the present invention relates to an improved, more convergent, highly efficient and less waste-generating process for the preparation of a compound having formula (I)
  • the compound having formula (I) is the backbone diol precursor/intermediate used to produce montelukast sodium.
  • Montelukast sodium is a leukotriene antagonist and is a useful agent in the treatment of asthma as well as other conditions mediated by leukotrienes, such as inflammation and allergies, e.g. allergic rhinitis.
  • the present invention describes an improved and practical process for the synthesis of the backbone diol, a key intermediate, used for the synthesis of montelukast sodium, which gives improved yield and chemical purity.
  • This new process is a more convergent synthesis than the current process described in US Patent No. 5,614,632.
  • the new two-step process includes: a novel one pot Heck-isomerization process to prepare the compound having formula V, followed by a highly efficient catalytic asymmetric hydrogenation to prepare the desired backbone diol compound having formula I.
  • This new process removes cerium chloride from the synthesis and replaces the stoichiometric chiral boron reduction with a catalytic asymmetric hydrogenation, thereby improving the overall process efficiency and generating less waste.
  • use of a highly active Ruthenium catalyst promotes the hydrogenation with a low catalyst loading.
  • the present invention provides a process for the preparation of a compound of formula (I)
  • R 1 is Br, I, phosphate or diazonium salt
  • X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R 2 ) 3 , -C(0)R 3 , -C(0)OR 4 , or 2- THP;
  • R 2 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;
  • R 3 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;
  • R 4 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;
  • the present invention provides a process for the preparation of a compound of formula (V)
  • X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R 2 ) 3 , -C(0)R 3 , -C(0)OR 4 , or 2-
  • R 2 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl
  • R 3 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl
  • R 4 is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;
  • R 1 is Br or I. In one aspect of the first embodiment, R 1 is Br.
  • the arylalcohol compound having formula (II) is: 2-(2-hromophenyl) propan-2-ol (IIA) or 2-(2-bromophenyl) tetrahydro- 2H-pyran (IIB).
  • X is ⁇ (IIA).
  • the metal catalyst is a transition metal catalyst.
  • the metal catalyst is a palladium catalyst.
  • a metal catalyst includes, but is not limited to, palladium(II) acetate, trans- diamminedichloropalladium(II), trans-diaminedibromopalladium(II), palladium(II) chloride, palladium(II) bromide, palladium(II) iodide, tetrakis(acetonitrile)palladium(II) tetrafluoroborate, bis(acetonitrile)dichloropalladium(II), bis(benzonitrile)palladium(II) chloride, tris(dibenzylideneacetone)dipalladium(0), allylpalladium chloride dimer, palladium(II) trifluoroacetate, palladium(II) acetylacetonate, sodium
  • the metal catalyst is trans-diaminedibromopalladium(II), (NH 3 ) 2 PdBr 2 .
  • the first base for the coupling step is selected from ⁇ , ⁇ -dicyclohexylmethylamine, N-ethyldicyclohexylamine, N,N- dimethylcyclohexylamine, dicyclohexylamine, Hunig's base, N,N-diethylbutylamine, tributylamine, 4,4'-trimethylenebis(l-methylpiperidine), 1,2,2,6,6-pentamethylpiperidine, 2,2,6,6-tetramethylpiperidine, l-ethyl-piperidine, morpholine, sodium bicarbonate, and sodium acetate.
  • the first base is N,N- dicyclohexylmethylamine.
  • the first solvent or a solvent mixture thereof for the coupling step is selected from DMF, DMAc, NMP, DMSO, t-Amyl OH, Propionitrile, CPME, n-BuOH, Toluene, Anisole, Diglyme or DMI, Anisole,
  • the solvent is DMF.
  • the solvent mixture is toluene/DMF.
  • the ligand for the coupling step is a phosphine ligand or a carbene ligand.
  • Representative phosphine ligands include, but are not limited to, the following:
  • R a , R b , R c , R d , R e are each independently selected from the group consisting of: hydrogen, amine, alkyloxy, halo, Ci-io alkyl, C 2- 6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein amine, Ci-io alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.
  • R , R y , R z are each independently selected from the group consisting of: CM O alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein Ci-io alkyl, C 2 . 6 alkenyl, C 2 . 6 alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.
  • the phosphine ligand is selected from:
  • the ligand is (o-tol) 3 P. In a further aspect, the ligand is omitted. In another aspect of the sixth embodiment of the invention, the ligand is a carbene ligand and the catalyst is a preformed carbene-palladium complex. Representative preformed carbene-palladium complexes include, but are not limited to, the following:
  • a preformed phosphine-palladium complex can be used as the catalyst.
  • Representative preformed phosphine-palladium complexes include, but are not limited to, the following: bis(tri-o-tolylphosphine)palladium(0), trans-Di ⁇ -acetato)bis[o- (di-o-tolylphosphino)benzyldipalladium(II), Dichlorobis(tri-o-tolylphosphine)
  • R x , R y , R z are each independently selected from the group consisting of: Ci-io alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein Q.io alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.
  • a phosphine ligand is used in conjunction with a metal catalyst in the coupling step, thereby forming one or more phosphine-palladium complexes in situ.
  • the phosphine-palladium complex formed in situ can be used as the catalyst.
  • the isomerization of the enol compound having formula VI to the desired ketone compound of formula V requires a second base. Accordingly, in a seventh embodiment of the invention, the second base is selected from:
  • the second base is DBU.
  • the coupling step includes wherein: the metal catalyst is (NH 3 ) 2 PdBr 2 , the ligand is (o-tol) 3 P, the first base is Cy 2 NMe, the second base is DBU, and the first solvent is DMF.
  • the compound of formula (V) is reduced with (i) one equivalent of a chiral reducing agent DIP-Cl, or (ii) in the presence of a catalytic amount of a ruthenium catalyst, hydrogen, a third base and a second solvent or solvent mixture, so as to thereby produce the compound of formula (I).
  • the chiral reducing agent is DIP-Cl used in stoichiometric quantities.
  • the ruthenium catalyst includes, but is not limited to, the following:
  • R a , R b , R c , R d , R e are each independently selected from the group consisting of: hydrogen, amine, alkyloxy, halo, Ci-io alkyl, C 2 . 6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein amine, Ci-io alkyl, C 2-6 alkenyl, C 2-6 alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.
  • the ruthenium catalyst includes RuCl[(/?)-daipena][(7?)-dmm- segphos] and Garphos catalyst.
  • the ruthenium catalyst is RuClt ⁇ -daipenaJf ⁇ -dmm-segphos].
  • the third base includes, but is not limited to, LiOH, K 2 C0 3 , K 3 P0 4 , KOtBu, KOH, KOEt, and KOMe.
  • the third base is KOtBu and the ruthenium catalyst is RuCl[(i?)-daipena][(i?)-dmm-segphos].
  • the asymmetric hydrogenation is carried out in a second solvent or solvent mixture thereof.
  • the second solvent includes, but is not limited to, the following: THF, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol.
  • the second solvent mixture includes, but is not limited to, the following: tetrahydrofuran/methanol, tetrahydrofuran/ethanol, tetrahydrofuran/isopropyl alcohol, tetrahydrofuran/l-butanol, toluene/ethanol, toluene/isopropyl alcohol, toluene/2-butanol.
  • the reaction temperature for the reaction may be in the range of about -20 °C to about 30 °C. In one aspect, the temperature range for the reaction is about -15 °C to about 20 °C.
  • hydrogenation reaction of the reduction step can be performed at a hydrogen pressure range of about 20 psi to about 1500 psi. In one aspect, the hydrogen pressure range is about 30 psi to about 1 10 psi. In another aspect, the hydrogen pressure is about 30 psi to about 40 psi.
  • the ratio of catalyst to compound of formula (V) is about 0.02mol% to about 2% mol%. In one aspect, the catalyst to compound of formula (V) ratio is about 0.03 mol% to about 0.1 mol%.
  • the ruthenium catalyst is RuCl[( ?)-daipena][(K)-dmm- segphos]
  • the third base is K(O'Bu)
  • the second solvent mixture is THF/EtOH, in the presence of 40 psi hydrogen gas.
  • the process further comprises preparing the crystalline form of the compound of formula (I) with a crystallizing solvent.
  • the crystallizing solvent is toluene:heptanes.
  • CyNMe 2 N,N-Dimethylcyclohexylamine
  • Hunig's base N, N-Diisopropylethylamine
  • BuNEt 2 N,N-Diethylbenzylamine
  • P 2 -Et 1 -Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2 ⁇ 5 ,4 ⁇ 5 -catenadi(phosphazene),
  • TBD l,5,7-Triazabicyclo[4.4.0]dec-5-ene
  • NMP N-Methylpyrrolidone
  • DIP-Cl B-Chlorodiisopinocampheylborane
  • alkyl is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms unless otherwise specified.
  • Ci-Cio as in “Ci-Cio alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear, branched, or cyclic arrangement.
  • Ci-Cio alkyl specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • alkoxy or “alkyloxy” represents an alkyl group as defined above, unless otherwise indicated, wherein said alkyl group is attached through an oxygen bridge.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 10 carbon atoms and at least 1 carbon to carbon double bond. Preferably 1 carbon to carbon double bond is present, and up to 4 non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkynyl refers to a hydrocarbon radical straight or branched, containing from 2 to 10 carbon atoms, unless otherwise specified, containing at least 1 carbon to carbon triple bond. Up to 3 carbon-carbon triple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • aryl is intended to mean any stable monocyclic or bicyclic carbon ring of up to 12 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 10 atoms in each ring, wherein at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • Heteroaryl groups within the scope of this definition include but are not limited to: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,
  • heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively. If the heteroaryl contains nitrogen atoms, it is understood that the corresponding N-oxides thereof are also encompassed by this definition.
  • heterocycle or “heterocyclyl” as used herein is intended to mean a 5- to 10-membered nonaromatic ring, unless otherwise specified, containing from 1 to 4 heteroatoms selected from the group consisting of O, N, S, SO, or S0 2 and includes bicyclic groups.
  • Heterocyclyl therefore includes, but is not limited to the following: piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, dihydropiperidinyl, tetrahydrothiophenyl and the like. If the heterocycle contains a nitrogen, it is understood that the corresponding N-oxides thereof are also emcompassed by this definition.
  • halo or halogen as used herein is intended to include chloro, fluoro, bromo and iodo.
  • alkoxy as used herein means an alkyl portion, where alkyl is as defined above, connected to the remainder of the molecule via an oxygen atom. Examples of alkoxy include methoxy, ethoxy and the like.
  • haloalkyl means an alkyl radical as defined above, unless otherwise specified, that is substituted with one to five, preferably one to three halogen. Representative examples include, but are not limited to trifluoromethyl, dichloroethyl, and the like.
  • the overall reaction sequence of the synthesis of the compound of formula (I) is illustrated below. The reaction sequence starting from known materials is illustrated in Schemes 1 to 3.
  • Arylalcohol (IIA) may be obtained from commercial sources, or may be prepared from methyl 2-bromobenzoate by addition of methyl Grignard reagent (Example 1).
  • Scheme 2 depicts the synthesis of the oxoalcohol compound having formula (VA).
  • the aryl alcohol (IIA) is coupled to the montelukast vinyl alcohol intermediate (IV) by an optimized Heck reaction to produce a mixture of the desired oxoalcohol product (VA) and the allylic alcohol isomer (VIA).
  • This Heck reaction is followed by an isomerization step, which converts allylic alcohol isomer (VIA) to the desired oxoalcohol product (VA).
  • the oxoalcohol product (VA) is directly isolated from the reaction mixture.
  • Scheme 3 depicts the synthesis of the montelukast backbone diol compound having formula (I).
  • the oxoalcohol compound (VA) is transformed to the montelukast backbone diol (I) by enantioselective reduction, by either DIP-Cl or catalytic
  • Diol intermediate (I) in excellent yield, chemical purity and optical purity.
  • Methylmagnesium bromide in toluene/THF (1.4 M, 1.24 L) was charged to a vessel under a nitrogen atmosphere. Methyl 2-bromobenzoate (164 g) was added. The reaction mixture was aged at 35-40 °C and assayed for completion. Ethanol (57.3 mL) was added. The mixture was aged at 45 °C for lh. A solution of pyridine-4-carboxaldehyde (8.09 g) in toluene (16 mL) was added. The mixture was aged at 45-50 °C. A vessel was charged with water (820 mL) and 37% hydrochloric acid (186 mL) and cooled to 0 °C.
  • reaction solution was added into the cold aqueous hydrochloric acid solution.
  • the mixture was aged at 20-25 °C, and the lower aqueous layer cut.
  • the organic layer washed with water and the lower aqueous layer cut.
  • the organic layer was concentrated under reduced pressure at 40-50 °C.
  • DMF (-200 mL) was added and concentration continued to afford -303 g solution of IIA as a slightly cloudy oil.
  • Quench solution preparation A flask was charged with Ammonium acetate (74.6 g), water (530 mL), solka flock (16.7g), ethylbenzene (60mL) and THF (20mL) and cooled to 5°C.
  • the batch was added into the quench solution. After quenching, the batch was warmed up and agitated at room temp. The batch was filtered, rinsed with
  • X is H (IIA) or THP (IIB)
  • Preparing vinyl alcohol IV solution In a 100 mL flask, vinyl alcohol IV (9.7g) was dissolved in Toluene (20.7 mL) and DMF (17.3 mL). To a 200 mL flask under Nitrogen was charged with the half volume of vinyl alcohol IV solution, bromo alcohol IIA (8.1 g), N.N-dicyclohexylmethylamine (Cy 2 NMe, 9.59 mL), Tri-o-tolylphosphine ((o-tol) 3 P, 110 mg) and Trans-diaminedibromopalladium(II) ((NH 3 ) 2 PdBr 2> 50 mg). The batch was heated to 100 °C. The rest of Vinyl alcohol IV solution was slowly charged via syringe pump. The batch was aged until completion. DMF (30 mL) was charged.
  • Oxoalcohol VA was isolated by crystallization using the procedure described in Method A.
  • catalyst solution In a separate reactor a catalyst solution was prepared by dissolving bis(acetonitrile)dichloropalladium(II) ((CH3CN) 2 PdCl 2; 3.24 mg) and tri-o- tolylphosphine ((o-tol) 3 P) in DMF (0.5 mL) in glovebox.
  • Reaction mixture was cooled down to room temperature and was charged with methanol (0.084 mL) and p- toluenesulfonic acid monohydrate (p-TSA, 163 mg). The mixture was agitated for at least 3 hours. Oxoalcohol VA was isolated by crystallization from DMF/water.
  • Oxoalcohol VA (19 g) was dissolved in THF (124 mL) at 20 °C under N 2 .
  • Base solution preparation In a separate reactor a base solution was prepared by charging potassium tert-butoxide (0.28 g) and ethanol (2.5 mL).
  • Catalyst solution preparation In a separate reactor under Nitrogen a catalyst solution was prepared by dissolving RuCl [(i?)-daipena][(/?)-dmm-Segphos] (Rucy-type, 25 mg) in THF (5 mL, 0.26 vol).
  • Backbone Diol was crystallized by slow addition of anti-solvent heptanes at 50 °C. The crystalline product was dried at room temperature under vacuum with nitrogen sweep to yield Backbone Diol I (17.8 g, 99.6 to 99.8% ee, 94% yield from the oxoalcohol VA).

Abstract

La présente invention concerne un procédé amélioré pour la préparation d'un composé ayant la formule (I). Le composé ayant la formule (I) est le précurseur/intermédiaire de diol de chaîne principale utilisé pour produire de sodium de montelukast. Le sodium de montelukast est un antagoniste de leucotriène et est un agent utile dans le traitement de l'asthme, ainsi que d'autres états à médiation par des leucotriènes, tels qu'une inflammation et des allergies, par exemple la rhinite allergique.
PCT/US2013/070210 2012-11-21 2013-11-15 Préparation de précurseurs d'antagonistes de leucotriène WO2014081616A1 (fr)

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