WO2014081616A1 - Preparation of precursors for leukotriene antagonists - Google Patents

Abstract

The present invention relates to an improved 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.

Description

TITLE OF THE INVENTION

PREPARATION OF PRECURSORS FOR LEUKOTRIENE ANTAGONISTS

BACKGROUND OF THE INVENTION

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. 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

Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various disease states are also discussed in the book by Rokach.

Montelukast sodium is a known leukotriene antagonist. Processes for

synthesizing montelukast sodium have been described in the literature. The present invention is an alternative route to producing montelukast. US Patent No. 5,614,632 uses rare earth reagents such as cerium chloride in the process. Recently, growing concerns over the shortage of rare earth reagents such as cerium chloride have not only driven cerium chloride prices higher but also put the supply of montelukast sodium salt at risk. By obviating the need for large amounts of the rare earth reagent, the present invention eliminates the potential risk to the montelukast sodium supply and provides a more environmentally friendly process.

WO2008131932 (Lonza) describes the preparation of chiral alcohol by asymmetric hydrogenation using H₂ 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. However, 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. In addition, 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 H₂ in the presence of ((R)-xyl-BINAP)(R,R)-DPEN)RuCl₂. The present invention also involves, in certain embodiments, the asymmetric hydrogenation of this ketone alcohol intermediate. However, 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, on the other hand, introduces this functional group in a convergent manner through a Heck coupling sequence with an aryl alcohol intermediate that already bears this functional group. In addition, as mentioned previously, 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. However, in the Codexis application 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. In contrast, 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.

Accordingly, there exists a need for the present invention which sets forth an efficient synthesis of the precursors of montelukast sodium and provides improved overall yield. SUMMARY OF THE INVENTION

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. DETAILED DESCRIPTION OF THE INVENTION

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. In addition, 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)

(I)

which comprises: i) coupling an arylalcohol compound having formula (II)

wherein R¹ is Br, I, phosphate or diazonium salt;

X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R²)₃, -C(0)R³, -C(0)OR⁴, or 2- THP;

R² is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R³ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R⁴ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

with a compound having formula (IV)

in the presence of a metal catalyst, a first base, a first solvent, and, optionally, a ligand, to produce a mixture comprising a ketone compound having formula (V) and an enol compound having formula (VI)

(V);

OX

OH (VI);

and contacting the mixture of compounds of formula (V) and formula (VI) with a second base to isomerize the compound of formula (VI) to the compound of formula (V), and

reducing the compound of formula (V) in the presence of DIP-Cl or a ruthenium catalyst, hydrogen, a third base, and a second solvent;

so as to produce the compound of formula (I).

The present invention provides a process for the preparation of a compound of formula (V)

(V)

which comprises:

coupling an arylalcohol compound having formula (II)

(II), wherein R¹ is Br, I, phosphate or diazonium salt;

X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R²)₃, -C(0)R³, -C(0)OR⁴, or 2-

THP;

R² is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl; R³ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R⁴ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

with a compound having formula (IV)

in the presence of a metal catalyst, a first base, a first solvent, and, optionally, a ligand, to produce a mixture comprising a ketone compound having formula (V) and an enol compound having formula (VI)

and

contacting the mixture of compounds of formula (V) and formula (VI) with a second base to isomerize the compound of formula (VI) to the compound of formula (V);

so as to produce the compound of formula (V). In a first embodiment of the invention, R¹ is Br or I. In one aspect of the first embodiment, R¹ is Br.

In a second embodiment of the invention, the arylalcohol compound having formula (II) is: 2-(2-hromophenyl) propan-2-ol (IIA) or 2-(2-bromophenyl) tetrahydro- 2H-pyran (IIB).

IIA IIB In one aspect of the second embodiment, X is Η (IIA).

In a third embodiment of the invention, the metal catalyst is a transition metal catalyst. In one aspect of the third embodiment, 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

tetrachloropalladate(II), Di-mu-chlorobis[2'-(amino-N)[ 1 , 1 '-biphenyl]-2-yl-

C]dipalladium(II), sodium tetrachloropalladate (II), and palladium sulfate dihydrate. In another aspect, the metal catalyst is trans-diaminedibromopalladium(II), (NH₃)₂PdBr₂.

In a fourth embodiment of the invention, the first base for the coupling step is selected from Ν,Ν-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. In one aspect of the fourth embodiment, the first base is N,N- dicyclohexylmethylamine.

In a fifth embodiment of the invention, 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,

Ethylbenzene, Diethoxyethane, and PhCl. In one aspect of the fifth embodiment, the solvent is DMF. In another aspect, the solvent mixture is toluene/DMF.

In a sixth embodiment of the invention, 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:

wherein 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, C₂.₆ alkenyl, C₂.₆ 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, C₂.₆ alkenyl, C₂.₆ alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.

In one aspect of the sixth embodiment, the phosphine ligand is selected from:

In another aspect of the sixth embodiment, the ligand is (o-tol)₃P. 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:

[(IPr)PdCI₂]₂ PEPPSI-IPr PEPPSI-SIPr

In another aspect, 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)

wherein

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.

In another aspect, 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:

TMG DBN DBU

In one aspect of the seventh embodiment, the second base is DBU.

In an eighth embodiment of the invention, the coupling step includes wherein: the metal catalyst is (NH₃)₂PdBr₂, the ligand is (o-tol)₃P, the first base is Cy₂NMe, the second base is DBU, and the first solvent is DMF.

In a ninth embodiment of the invention, 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).

In one aspect of the ninth embodiment, the chiral reducing agent is DIP-Cl used in stoichiometric quantities. In another aspect of the ninth embodiment, the ruthenium catalyst includes, but is not limited to, the following:

wherein Ar is defined as

wherein 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, C₂.₆ 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. In a further aspect, the ruthenium catalyst includes RuCl[(/?)-daipena][(7?)-dmm- segphos] and Garphos catalyst.

RuCI[(R)-daipena][(R)-dmm-segphos]

In a further aspect, the ruthenium catalyst is RuClt^-daipenaJf^-dmm-segphos].

In a tenth embodiment of the invention, the third base includes, but is not limited to, LiOH, K₂C0₃, K₃P0₄, KOtBu, KOH, KOEt, and KOMe.

In an eleventh embodiment of the invention, the third base is KOtBu and the ruthenium catalyst is RuCl[(i?)-daipena][(i?)-dmm-segphos]. In a twelfth embodiment of the invention, the asymmetric hydrogenation is carried out in a second solvent or solvent mixture thereof. In one aspect the second solvent includes, but is not limited to, the following: THF, methanol, ethanol, isopropyl alcohol, 1-butanol, 2-butanol. In another aspect 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. In another embodiment, 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.

In another embodiment, 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.

In another embodiment, 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%.

In another embodiment, 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.

In further embodiment, the process further comprises preparing the crystalline form of the compound of formula (I) with a crystallizing solvent. In one aspect of this embodiment, the crystallizing solvent is toluene:heptanes.

Definitions

Cy₂NMe = Dicyclohexylmethylamine

Cy₂NEt = Dicyclohexylethylamine

CyNMe₂ = N,N-Dimethylcyclohexylamine

Cy₂NH = Dicyclohexylamine

Hunig's base = N, N-Diisopropylethylamine

BuNEt₂ = N,N-Diethylbenzylamine

Bu₃N = Tributylamine

Bn₂NH = Dibenzylamine

CyNHMe = N-Methylcyclohexylamine DBN = l,5-Diazabicyclo[4.3.0]non-5-ene

P₂-Et = 1 -Ethyl-2,2,4,4,4-pentakis(dimethylamino)-2λ⁵,4λ⁵-catenadi(phosphazene),

Tetramethyl(tris(dimethylamino)phosphoranylidene)phosphorictriamid-Et-imin

TBD = l,5,7-Triazabicyclo[4.4.0]dec-5-ene

MTBD = 7-Methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene

DABCO = l,4-Diazabicyclo[2.2.2]octane

DBU = l,8-Diazabicyclo[5.4.0]undec-7-ene

TMG = 1, 1,3,3-Tetramethylguanidine

t-Amyl OH = 2-Methyl-2-butanol

nBuOH = 1-Butanol

CPME = Cyclopentyl methyl ether

DMAc = N,N-dimethylacetamide

DMF = dimethylformamide

DMSO = Dimethyl sulfoxide

DMI = l,3-Dimethyl-2-imidazolidinone

EtPh = Ethylbenzene

NMP = N-Methylpyrrolidone

NMR = nuclear magnetic resonance

PhCl = Chlorobenzene

THF = tetrahydrofuran

DIP-Cl = B-Chlorodiisopinocampheylborane

THP = tetrahydropyranyl

As used herein, "alkyl" is intended to include both branched and straight- chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms unless otherwise specified. For example, 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. For example, "Ci-Cio alkyl" specifically includes methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on. As used herein, the term "alkoxy" or "alkyloxy" represents an alkyl group as defined above, unless otherwise indicated, wherein said alkyl group is attached through an oxygen bridge.

As used herein, the term "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. Thus, "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.

As used herein, the term "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. Thus, "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.

As used herein, "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. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. In cases where the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring. As used herein, the term "heteroaryl", as used herein, 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,

benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydroindolyl, dihydroquinolinyl, methylenedioxybenzene, benzothiazolyl, benzothienyl, quinolinyl, isoquinolinyl, oxazolyl, and tetra-hydroquinoline. In cases where the 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.

The term "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 S0₂ 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.

As appreciated by those of skill in the art, "halo" or "halogen" as used herein is intended to include chloro, fluoro, bromo and iodo. The term "keto" means carbonyl (C=0). The term "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.

The term "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.

Overall Reaction Sequence

Oxoalcohol (VA) Allylic Alcohol (VIA) ^ (isomerization step) I

(reduction step)

Backbone Diol (I)

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 1

(III) (IV) Scheme 1 depicts the synthesis of the vinyl alcohol compound having formula (IV). Montelukast monoaldehyde (III) is transformed into the vinyl alcohol intermediate (IV) by addition of vinyl Grignard reagent.

Scheme 2

(VIA)

Scheme 2 depicts the synthesis of the oxoalcohol compound having formula (VA). In this scheme, 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

enantioselective hydrogenation, followed by isolation by crystallization to give the Diol intermediate (I) in excellent yield, chemical purity and optical purity.

The following examples are provided to more fully illustrate the present invention. The examples are not meant to limit in any manner the scope of the invention as defined in the claims.

EXAMPLE 1

2-(2-bromophenyl)propan-2-ol

(Compound IIA)

(IIA)

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. The 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. Ή NMR (500MHz, CDC1₃) δ 7.68 (dd, J= 8.0, 1.5 Hz, IH), 7.59 (dd, J= 8.0, 1.5 Hz, IH), 7.31 (m, IH), 7.11 (m, IH), 2.81 (s, IH), 1.76 (s, 6H) ¹³C NMR (125MHz, CDCI3) δ 146.0, 135.1, 128.5, 127.5, 127.2, 120.4, 73.5, 29.5.

EXAMPLE 2

(£)-l-(3-(2-(7-chloroquinoIin-2-yI)vinyl)phenyl)prop-2-en-l-oI

IV)

Monoaldehyde (III) Vinyl Alcohol (IV)

A flask was charged with monoaldehyde, (£)-3-(2-(7-chloroquinolin-2- yl)vinyl)benzaldehyde III, (94.7 g), ethylbenzene (500 mL) and THF (200 mL), and stirred. The mixture was cooled to -15°C. Vinyl magnesium chloride (1.6 M in THF, 232 mL) was slowly charged via additional funnel.

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

ethylbenzene/THF and phase cut. The organic phase was washed with water. Solvent was removed under reduced pressure at ~50°C. The batch was concentrated and slowly cooled to room temp and agitated for 15h. The crystalline product was collected by filtration, rinsed with ethylbenzene and dried under vacuum with nitrogen sweep to yield vinyl alcohol IV (94.94 g, 91% yield from the monoaldehyde III, (£)-3-(2-(7-chloroquinolin-2-yl)vinyl)benzaldehyde). Ή

NMR (500MHz, CDC1₃) δ 8.10 (d, J= 8.5 Hz, IH), 8.08 (d, J= 2.0 Hz, IH), 7.71 (od, J= 16.2 Hz IH), 7.70 (d, J= 8.6 Hz, IH), 7.68 (m, IH), 7.64 (d, J= 8.5 Hz, IH), 7.55 (m, IH), 7.45 (dd, J= 8.6, 2.0 Hz, IH), 7.40 (t, J= 7.5 Hz, IH), 7.38 (od, J= 16.2 Hz, IH), 7.36 (om, IH), 6.09 (ddd, J= 17.1, 10.4, 5.9 Hz, IH), 5.41 (dt, J= 17.1, 1.3 Hz IH), 5.28 (brm, IH), 5.25 (m, IH) 2.23 (s, IH). ¹³C NMR (125MHz, CDC1₃) δ 156.8, 148.6, 143.2, 140.1, 136.6, 136.1, 135.6, 135.0, 129.0, 128.8, 128.6, 128.2, 127.1, 126.85, 126.79, 125.7, 125.1, 1 19.6, 115.5, 75.2.

EXAMPLE 3

(£ -l-(3-(2-(7-chloroquino!in-2-yl)vinyl)phenyl)-3-(2-(2-hydroxypropan-2- yI)phenyl)propan-l-one

(Compound VA)

X is H (IIA) or THP (IIB)

(VI)

Reaction Procedures: Method A

A flask under Nitrogen was charged with vinyl alcohol IV (97 g), bromo alcohol IIA (81g ), DMF (380 mL) and N,N-dicyclohexylmethylamine (Cy₂NMe, 96.5 mL). To the reaction mixture was charged tri-o-tolylphosphine ((o-tol)₃P, 506 mg) and trans- diaminedibromopalladium(II) ((NH₃)₂PdBr_2> 454 mg). The batch was heated to -100 °C and aged until completion. To the batch was charged 1, 8-diazabicyclo[5.4.0]undec-7- ene (DBU, 68.3 mL). The mixture was heated to 120 °C and aged for at least 6h.

The batch was cooled to 45°C, aq. Glycolic acid (56.8 mL, 70 wt %,) was slowly charged. Oxoalcohol VA was crystallized by slow addition of anti-solvent DI water at 55°C. The crystalline product was dried at room temperature under vacuum with nitrogen sweep to yield oxoalcohol VA (110.7 g, 82% corrected yield from the vinyl alcohol IV. M.p. =Ή NMR (500MHz, CDC1₃) δ 8.25 (m, 1H), 8.11 (d, J= 8.5 Hz, 1H), 8.08 (d, J= 1.5 Hz, 1H), 7.94 (m, 1H), 7.80 (m, 1H), 7.75 (d, J- 17.5 Hz, 1H), 7.72 (d, J= 5.0 Hz, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.49 (m, 1H), 7.46 (dd, J= 8.6, 2.0 Hz 1H), 7.43 (om, 1H), 7.42 (d, J= 16.3 Hz, 1H), 7.29 (dd, J= 7.6, 1.7 Hz, 1H), 7.24 (m, 1H), 7.19 (m, 1H), 3.49-3.42 (om, 4H), 2.47 (s, 1H), 1.73 (s, 6H). ¹³C NMR (125MHz, CDC1₃) δ 199.7, 156.4, 148.6, 145.6, 139.8, 137.4, 136.8, 136.2, 135.6, 134.0, 131.6, 131.5, 129.6, 129.1, 128.7, 128.24, 128.21, 127.28, 127.26, 126.8, 126.0, 125.75, 125.69, 119.8, 73.8, 42.0, 32.2, 28.5. LC-MS (ESI+) m/z calculated C₂₉H₂₇C1N0₂ for 456.2 found 456.5 (M+H).

Method B

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 (Cy₂NMe, 9.59 mL), Tri-o-tolylphosphine ((o-tol)₃P, 110 mg) and Trans-diaminedibromopalladium(II) ((NH₃)₂PdBr_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.

Toluene was removed under heating and reduced pressure, to the original reaction volume. The batch was charged with 1, 8-diazabicyclo[5.4.0]undec-7-ene (DBU, 6.82 mL). The mixture was heated to 120 °C and aged for 6 hours. Oxoalcohol VA was isolated by crystallization as the procedure described in Method A.

Method C

A flask under Nitrogen was charged with vinyl alcohol IV (97.2 g), bromo alcohol

IIA (81 g), DMF (380 mL), N,N-dicyclohexylmethyl amine (Cy₂NMe, 96.5 mL) and trans-diaminedibromopalladium(II) ((NH₃)₂PdBr_2>454 mg). The batch was heated to -120 °C and aged until completion. To the batch was charged 1, 8- diazabicyclo[5.4.0]undec-7-ene (DBU, 68.3 mL). The batch was heated to 120 °C and agitated for 6h.

Oxoalcohol VA was isolated by crystallization using the procedure described in Method A.

Method D (Coupling with Bromoalcohol THP ether IIB)

Preparing catalyst solution: In a separate reactor a catalyst solution was prepared by dissolving bis(acetonitrile)dichloropalladium(II) ((CH3CN)₂PdCl_2; 3.24 mg) and tri-o- tolylphosphine ((o-tol)₃P) in DMF (0.5 mL) in glovebox.

To a 4 mL reactor under Nitrogen was charged with vinyl alcohol IV (84 mg), bromo alcohol THP ether IIB (0.104 g), DMF (0.3 mL), N,N-dicyclohexylmethyl amine (Cy₂NMe, 0.073 g, 0.375 mmol) and catalyst solution (0.05 mL). The mixture was heated to 85 °C and agitated for at least 14 hours. Reaction mixture was cooled down to 45 °C and was charged with l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.057 g). The mixture was heated to 120 °C and agitated for at least 5 hours. 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.

EXAMPLE 4 (S,£)-l-(3-(2-(7-chIoroquinolin-2-yI)vinyl)phenyl)-3-(2-(2-hydroxypropan-2- yl)phenyl)propan-l-ol

(Compound I)

Oxoalcohol VA Backbone Diol I

Oxoalcohol VA (19 g) was dissolved in THF (124 mL) at 20 °C under N₂.

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).

An autoclave was charged with the solution of oxoalcohol VA (19 g) in THF

(124 mL). The mixture was cooled to -5 °C under nitrogen. Potassium tert-butoxide (1.0 M in THF, 2.5 mL) was charged. The catalyst solution was added. Autoclave was purged with hydrogen and pressurized to 40 psig. The reaction mixture was agitated until reaction was completed. To the batch was charged with Toluene (76 mL) and heated to 40 °C. Organic layer was washed with water and 1 wt% aq. NaCl solution. THF was removed under reduced pressure at 50 °C. Toluene (190 mL) was charged. The batch was concentrated to ~135 mL total. The batch temperature was adjusted to 48- 52 °C. 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). Ή NMR (500MHz, CDC1₃) δ 8.08 (d, J= 8.5 Hz, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.71 (m, 1H), 7.69 (d, J= 8.0 Hz, 1H), 7.64 (m, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.52 (m, 1H), 7.44 (dd, J= 8.5, 2.0 Hz, 1H), 7.39-7.35 (m, 3H), 7.32 (m, 1H), 7.27 (dd, J= 7.5, 1.5 Hz, IH), 7.23 (m, IH), 7.16 (m, IH), 4.74 (m, IH) 3.19 (m, 2H), 2.15 (m, IH), 1.71 (s, 3H), 1.68 (s, 3H). ¹³C NMR (125MHz, CDC1₃) δ 156.9, 148.7, 145.4, 145.0, 140.2, 136.4, 136.1, 135.5, 135.1, 131.5, 128.8, 128.63, 128.57, 128.2, 127.3, 127.1, 126.41, 126.36, 125.6 , 125.5, 124.6, 119.6, 74.2, 73.1, 42.0. 32.08, 32.06, 29.7.

Claims

WHAT IS CLAIMED IS:

1. A process for the preparation of a compound of formula (I)

which comprises: i) coupling an arylalcohol compound having formula (II)

(Π), wherein R¹ is Br, I, phosphate or diazonium salt;

X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R²)₃, -C(0)R³, -C(0)OR⁴, or 2-

THP;

R² is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R³ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R⁴ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

with a compound having formula (IV)

in the presence of a metal catalyst, a first base, a first solvent, and, optionally, a ligand, to produce a mixture comprising a ketone compound having formula (V) and an enol compound having formula (VI)

contacting the mixture of compounds of formula (V) and formula (VI) with a second base to isomerize the compound of formula (VI) to the compound of formula (V), and

(ii) reducing the compound of formula (V) in the presence of DIP-Cl or a ruthenium catalyst, hydrogen, a third base, and a second solvent;

so as to thereby produce a compound of formula (I).

2. The process of claim 1, wherein the aryl bromoalcohol compound having formula (II) is 2-(2-bromophenyl) propan-2-ol or 2-(2-bromophenyl) tetrahydro-2H- pyran.

3. The process of claim 1, wherein the metal catalyst is selected from 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, Di-mu-chlorobis[2'-(amino-N)[l, l'- biphenyl]-2-yl-C]dipalladium(II), sodium tetrachloropalladate(II), and palladium sulfate dihydrate.

4. The process of claim 1 , wherein first solvent or mixture thereof is selected from DMF, DMAc, NMP, DMSO, t-Amyl ΟΗ, Propionitrile, CPME, n-BuOH, Toluene, Anisole, Diglyme or DMI, Anisole, Ethylbenzene, Diethoxyethane, and PhCl.

5. The process of claim 1, wherein the first base is selected from N,N- dicyclohexylmethylamine, N-ethyldicyclohexylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, Hunig's base, Ν,Ν-diethylbutylamine, tributylamine, 4,4'- trimethylenebis( 1 -methylpiperidine), 1 ,2,2,6,6-pentamethylpiperidine, 2,2,6,6- tetramethylpiperidine, 1-ethyl-piperidine, morpholine, sodium^' bicarbonate, and sodium acetate.

6. The process of claim 1, wherein the ligand is a phosphine ligand or a carbene ligand.

7. The process of claim 3, wherein the metal catalyst is a preformed Palladium-phosphine complex catalyst selected from: bis(tri-o- tolylphosphine)palladium(O), trans-Di^-acetato)bis[o-(di-o- tolylphosphino)benzyldipalladium(II), Dichlorobis(tri-o-tolylphosphine) palladium(II), and

wherein R , R^y, R^z are each independently selected from the group consisting of: CMO alkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein CJ.JO 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.

8. The process of claim 3, wherein the metal catalyst is a preformed

Palladium-carbene complex catalyst selected from:

[<iPr)Pdcy₂ PEPPSi-IPr PEPPSI-SIPr

9. The process of claim 1, wherein the second base is selected from TMG,

DBN, DBU, MTBD, TBD, Cs₂C0₃ and P₂-Et.

10. The process of claim 1, wherein the chiral reducing agent is DIP-Cl.

1 1. The process of claim 1, wherein the ruthenium catalyst is selected from:

herein Ar is defined as

wherein R^a, R^b, R^c, R^d, R^e, are each independently selected from the group consisting of: hydrogen, amine, alkyloxy, halo, CMO alkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein amine, CMO 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.

12. The process of claim 11, wherein the ruthenium catalyst is RuCl[(7?)- daipena] [( ?)-dmm-segphos] .

13. The process of claim 1, wherein the third base is selected from LiOH, K₂C0₃, K3PO4, KOtBu, KOH, KOEt, and KOMe.

14. The process of claim 1, wherein the second solvent is selected from THF, methanol, ethanol, isopropyl alcohol, 1-butanol, and 2-butanol.

15. The process of claim 14, wherein the second solvent is a mixture selected from tetrahydrofuran/methanol, tetrahydrofuran/ethanol, tetrahydrofuran/isopropyl alcohol, tetrahydrofuran/l-butanol, toluene/ethanol, toluene/isopropyl alcohol, and toluene/2-butanol.

16. The process of claim 1 , further comprising the crystallization of the compound of formula (I) with a crystallizing solvent.

17. The process of claim 16, wherein the crystallizing solvent is

toluene:heptanes.

18. A process for the preparation of a compound of formula (V)

(V)

which comprises: coupling an arylalcohol compound having formula (II)

(II), wherein R¹ is Br, I, phosphate or diazonium salt;

X is H, alkyl, aryl, alkenyl, alkynyl, benzyl, -Si(R²)₃, -C(0)R³, -C(0)OR⁴, or 2-

THP;

R² is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R³ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

R⁴ is independently selected from the group consisting of alkyl, aryl, alkenyl, alkynyl, and benzyl;

with a compound having formula (IV)

in the presence of a metal catalyst, a first base, a first solvent, and, optionally, a ligand, to produce a mixture comprising a ketone compound having formula (V) and an enol compound having formula (VI)

(VI);

and

contacting the mixture of compounds of formula (V) and formula (VI) with a second base to isomerize the compound of formula (VI) to the compound of formula (V);

so as to produce the compound of formula (V).

19. The process of claim 18, wherein the aryl bromoalcohol compound having formula (II) is 2-(2-bromophenyl) propan-2-ol or 2-(2-bromophenyl) tetrahydro-2H- pyran.

20. The process of claim 18, wherein the metal catalyst is selected from 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, Di-mu-chlorobis[2'-(amino-N)[l,r- biphenyl]-2-yl-C]dipalladium(II), sodium tetrachloropalladate(II), and palladium sulfate dihydrate.

21. The process of claim 18, wherein first solvent or mixture thereof is selected from DMF, DMAc, NMP, DMSO, t-Amyl ΟΗ, Propionitrile, CPME, n-BuOH, Toluene, Anisole, Diglyme or DMI, Anisole, Ethylbenzene, Diethoxyethane, and PhCl.

22. The process of claim 18, wherein the first base is selected from N,N- dicyclohexylmethylamine, N-ethyldicyclohexylamine, N,N-dimethylcyclohexylamine, dicyclohexylamine, Hunig's base, Ν,Ν-diethylbutylamine, tributylamine, 4,4'- trimethylenebis(l-methylpiperidine), 1,2,2,6,6-pentamethylpiperidine, 2,2,6,6- tetramethylpiperidine, 1-ethyl-piperidine, morpholine, sodium bicarbonate, and sodium acetate.

23. The process of claim 18, wherein the ligand is a phosphine ligand or a carbene ligand.

24. The process of claim 20, wherein the metal catalyst is a preformed Palladium-phosphine complex catalyst selected from: bis(tri-o- tolylphosphine)palladium(O), trans-Di^-acetato)bis[o-(di-o- tolylphosphino)benzyldipalladium(II), Dichlorobis(tri-o-tolylphosphine) palladium(II), and

wherein R^X, R^Y, R^Z are each independently selected from the group consisting of: CMO alkyl, C_2-6 alkenyl, C_2-6 alkynyl, aryl, heteroaryl, heteroaryl, heterocyclyl, wherein Cj.io alkyl, C_2-6 alkenyl, C₂.₆ alkynyl, aryl, heteroaryl, heteroaryl, and heterocyclyl, are each optionally substituted with one or more halo, alkyl or haloalkyl substituents.

25. The process of claim 20, wherein the metal catalyst is a preformed Palladium-carbene complex catalyst selected from:

[(IPr)PdCI₂]₂ PEPPSI-IPr PEPPSI-SIPr

26. The process of claim 18, wherein the second base is selected from TMG, DBN, DBU, MTBD, TBD, Cs₂C0₃ and P₂-Et.