OA11347A

OA11347A - Method for preparing subsstituted 4-phenyl-4-cyanocyclohexanoic acids.

Info

Publication number: OA11347A
Application number: OA1200000100A
Authority: OA
Inventors: Kevin Webb; Wilford Mendelson; Jianhao Chen
Original assignee: Smithkline Beecham Corp
Priority date: 1997-10-10
Filing date: 2000-04-07
Publication date: 2003-12-17
Also published as: PL339759A1; DZ2619A1; WO1999018793A1; EP1043930A4; KR20010015709A; PE121599A1; SK4902000A3; EA200000406A1; UA67753C2; NO20001777L; JP2001519363A; HUP0003905A2; CA2305614A1; AU741832B2; NZ503759A; UY25524A1; PL191974B1; CN1275052A; BG104302A; BR9814064A

Abstract

This invention relates to a method of preparing a compound type where at least one of R' or R'' is a carboxyl group (I) by treating a compound of formula (II) with a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water.

Description

P50728 011347

Method for Preparing Substituted 4-Phenyî-4-cyanocyclohexanoic Acids

Scope of the Invention

This invention covers intermediates and a synthetic route for making 4-cyano-4- 5 (3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and its analogs. This acid andits named analogs are sélective for inhibiting the catalytic site in the phosphodiesteraseisoenzyme denominated IV (PDEIV hereafter) and as such the acids are useful intreating a number of diseases which can be moderated by affecting the PDE IV enzymeand its subtypes. 10 Area of the Invention

Bronchial asthma is a complex, multifactorial disease characterized byréversible narrowing of the airway and hyper-reactivity of the respiratory tract toextemal stimuli.

Identification of novel therapeutic agents for asthma is made diffîcult by the fact15 that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will hâve a substantialeffect on ail major components of chronic asthma. An alternative to the "mediatorapproach" is to regulate the activity of the cells responsible for the pathophysiology ofthe disease. 20 One such way is by elevating levels of cAMP (adenosine cyclic 3’,5- monophosphate). Cyclic AMP has been shown to be a second messenger mediating thebiologie responses to a wide range of hormones, neurotransmitters and drugs; [KrebsEndocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29,1973]. When the appropriate agonist binds to spécifie cell surface receptors, adenylate 25 cyclase is activated, which converts Mg+^-ATP to cAMP at an accelerated rate.

Cyclic AMP modulâtes the activity of most, if not ail, of the cells that contribute to the pathophysiology of extrinsic (allergie) asthma. As such, an élévation of cAMPwould produce bénéficiai effects including: 1) airway smooth muscle relaxation, 2)inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) 30 inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophageactivation. Hence, compounds that activate adenylate cyclase or inhibitphosphodiesterase should be effective in suppressing the inappropriate activation ofairway smooth muscle and a wide variety of inflammatory cells. The principal cellularmechanism for the inactivation of cAMP is hydrolysis of the 3-phosphodiester bond by 1

PS0728P 011347 one or more of a family of isozymes referred to as cyclic nucléotide phosphodiesterases(PDEs).

It has now been shown that a distinct cyclic nucléotide phosphodiesterase (PDE)isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and 5 inflammatory cells. [Torphy, "Phosphodiesterase Isozymes: Potential Targets forNovel Anti-asthmatic Agents" in New Drugs for Asthma, Bames, ed. IBC TechnicalServices Ltd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppresses degranulation of mastcells, basophils and neutrophils along with inhibiting the activation of monocytes and 10 neutrophils. Moreover, the bénéficiai effects of PDE IV inhibitors are markedlypotentiated when adenylate cyclase activity of target cells is elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would beeffective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin(activators of adenylate cyclase) are elevated. Such compounds would offer a unique 15 approach toward the pharmacotherapy of bronchial asthma and possess significanttherapeutic advantages over agents currently on the market.

The process and intermediates of this invention provide a means for makingcertain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids which are usefulfor treating asthma, and other diseases which can be moderated by affecting the PDE IV 20 enzyme and its subtypes. The final products of particular interest are fully described inU.S. patent 5,552,483 issues 03 September 1996. The information and représentationsdisclosed therein, in so far are that information and those représentations are necessaryto the understanding of this invention and in its practice, in total, are incorporatedherein by reference. 25 Summary of the Invention

This invention relates a method for making a compound of formula I

wherein 30 R! is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, - (CR4R5)nO(CR4R5)mR6, or -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; m is 0 to 2;n is 1 to 4;

PS0728P 011347

Rô is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl,halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C741 polycycloalkyl, 5 tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group; 10 provided that: a) when Rô is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Rg is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,15 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then R6 is other than H in 20 -(CR4R5 )nO(CR4R5)mR6 ! X is YR2, halogen, nitro, NH2, or formyl amine;X2 is O or NR8; Y is O or S(O)m’; m’is 0, 1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, Cl-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted25 Cl-4 alkyl, -CH=CR8’R8’, cyclopropyl optionally substituted by Rs’, CN, ORs, CH2OR8, NR8R10, CH2NR8R10, CCZ^H, C(O)ORs, C(0)NR8Rio, or C^CRs’iR8 is hydrogen or C 1.4 alkyl optionally substituted by one to three fluorines;Rg’is Rs or fluorine;

RlO is OR8 or Ri 1; 30 Ri 1 is hydrogen, or Cj_4 alkyl optionally substituted by one to three fluorines; Z’ is O, NR9, NOR8, NCN, C(-CN)2, CRgCN, CR8NO2, CR8C(O)OR8, CR8C(O)NRsR8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRsR8; R’ and R" are independently hydrogen or -C(O)OX where X is hydrogen or an alkali métal ion; 35 which method comprises: a) combining a Lewis acid, which is an alkali métal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula H(a) or II(b),

PS0728P

H 011 347

R,X

CN R. '3

VZ y

R. '3 II(b) Π(η) where R,, R3, X2 and X are the same as for formula (I)

b) heating the combination to a température between about 60° and 100° C 5 for several hours, optionally under an inert atmosphère; c) forming a sait by adding a strong base; d) filtering off the amide-based solvent and water, and optionally 1) purifying further the sait, or 2) acidifying a second solution of the sait to obtain the acid. 10 Spécifie Ëmbodiments of the Invention

This process in volves the synthesis of certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids. It allows for converting a cyanoepoxide to itscorresponding acid via a lithium sait intermediate.

The compounds which are made by this process are PDE P/ inhibitors. They 15 are useful for treating a number of diseases as described in U.S. patent 5,552,438 issued3 September 1996.

The preferred compounds which can be made by this process are as follows:Preferred Ri substitutents for the compounds of ail named formulas are CH2- cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with 20 OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzylor Ci_2 alkyl unsubstituted or substituted by 1 or more fluorines,-(CH2)l-3C(O)O(CH2)0-2CH3, -(CH2)l-3O(CH2)0-2CH3, and -(CH2)2-4OH.

Preferred X groups for Formula (I), (Π) or (III) are those wherein X is YR2 andY is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. 25 Preferred R2 groups are a C1-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferablyfluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2moiety. Most preferred are the -CHF2 and -CH3 moieties.

P50728P 011347

Most preferred are those compounds wherein R} is -CH2-cyclopropyl,cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 isoxygen; and R2 is CF2H or methyl; and R3 is CN.

The lithium salts of these compound represent a sub-set of preferred5 compounds. In particular the lithium sait of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexanecarboxylic acid, i.e., lithium-4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexanecarboxylate represents a preferredembodiment. More particularly, the compound czi-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexanecarboxylate is most preferred. 10 A problem in preparing the acid from the acyl nitrile is that when the carboxylate is formed from the acyl nitrile, cyanide is generated. The carboxylate ismade by opening the epoxide with a Lewis acid, illustrated by an alkali halide, to getthe acyl nitrile which hydrolyzes to the acid in the presence of water. This lasthydrolysis step generates a cyanide ion. The challenge is one of removing this ion in a 15 cost-effective way. A feature of this invention is a means for effecting a more efficientremoval of the CN" ion generated when the cyanoepoxide is converted to thecarboxylate form and thence to the acid. It has been discovered that if the reaction is runwith an aprotic dipolar amide-based solvent using an aqueous solution of the alkalimétal sait to open the epoxide, the resulting carboxylate forms the alkali métal sait, and 20 when an aqueous solution of an inorganic hydroxide is added, the cyanate sait remainsin solution but the carboxylate sait précipitâtes out of solution. This permits removal ofessentially ail of the cyanate by filtering out the precipitate and discarding the solvent.And it avoids the extra step of having to oxidize the cyanate ion and the furtherpurification step of back-extracting into water to remove water-soluble components 25 from the product.

The preferred Lewis acids used in this invention are the alkali métal halides.Lithium and magnésium halides work best. Lithium bromide and magnésium bromideare most preferred. Lithium bromide is particularly preferred. It provides a source oflithium ions for forming the lithium cyanide sait, when used in excess relative to the 30 acyl nitrile. The advantage of this is that the lithium cyanide sait is highly soluble in the aqueous aprotic dipolar amide-based solvent, and thus effects more efficient and more complété removal of the cyanide ion from the acid sait when the amide-based

P50728P 011347 solvent is filtered off. Lithium cyanide is more soluble in the likes of DMF or N-methyl pyrrolidinone than is sodium cyanide, potassium cyanide or magnésiumcyanide. So it is more advantageous to use lithium as the cation of the Lewis acid, or touse lithium hydroxide or a similar lithium ion-containing strong base as the base in the5 salt-forming step of the process.

In regards to the amide-based solvents, they are illustrated by the likes ofdimethylformamide (DMF), dimethylacetamide, and N-methyl pyrrolidinone. DMF ismost preferred. A second organic solvent can be used in addition to the amide-basedsolvent. For example acetonitrile has been used successfully in the reaction illustrated10 below. Normally water is added to the reaction pot, for two reasons: 1) as a means forgetting the Lewis acid into solution, and 2) for hydrolyzing the acyl nitrile in situ.Hence a further preferred embodiment of this invention is to use an aprotic dipolarsolvent which is water miscible. DMF, dimethylacetamide, and N-methylpyrrolidinone meet this standard. 15 The Lewis acid opens the epoxide to give an acyl nitrile. It is hydrolyzes to the acid in the presence of water and is usually not isolated. About 2 or more équivalentsof a strong base are then added to form two salts, a sait of the cyclohexanoic acid and asait of the cyanide group which is released in the hydrolysis of the acyl nitrile group.One can use any base strong enough to form these salts; formation of the cyanide sait is 20 the more critical of the two criteria for determining if a particular base is useful in thisstep. Inorganic hydroxides are preferred. For example one can use LiOH, NaOH, orKOH. One can also use ammonium salts, for example tétra-alkylammoniumhydroxides or NH4OH. Lithium hydroxide is preferred because the lithium cyanidesait is the most soluble of the alkali métal cyanide salts in the aqueous aprotic dipolar 25 amide-based solvent, and thus most effectively removes the cyanide ion contaminentfrom the desire carboxylic acid sait. A perferred practice of this invention is one in which the solvent(s) arecombined, lithium bromide is added, and then the epoxide. Once the reaction has goneto completion essentially, two or more équivalents of an aqueous solution of lithium 30 hydroxide are added, the cyclohexanoic acid sait is precipitated out of solution, and the solvent is removed by filtration. The lithium sait of the cyclohexanoic acid can be further purified if needs be to remove residual contaminants such as cyanide salts, or

P50728P 011347 converted to the acid by dissolving or suspending the sait in a solvent and acidifyingthat combination to obtain the free acid. A représentative schematic of the process is set out in Scheme I and Scheme Π.These graphical représentation uses spécifie examples to illustrate the generalmethodology used in this invention.

Scheme I SB 207499Route D1

H

Isovanillin

Step 5 1)

COOCH

Methylcyclohexane a

HjC

CfeCH,

CN SB 207219

Step 7

1) NaOMe

DioxaneCN COjCHj 2) NaHCqSB 206973 COOCH 1)N^CC^.HODioxane 2) Crystallize fromMethylcyclohexane/ SBEthyl acetate

CCfeLi 7

P50728P 011347

Referring to Scheme I, isovanillin (3-hydroxy-4-methoxybenzaldehyde) is areadily available starting material. It can be alkylated with an R,X moiety (X = Cl, Br,and I) as represented by cyclopentyl chloride. The reaction vessel is first flushed withan inert gas, for example nitrogen. An aprotic dipolar solvent such as DMF is then5 added to the vessel, then the isovanillin, then the R,X adduct, and some base. About 2équivalents of the R,X adduct versus the isovanillin are used. Likewise about 2équivalents of base are used, again relative to the isovanillin. The base can be anyinorganic base or a carbonate. Here it is illustrated by potassium carbonate. The vesselcontents are heated to about 125° C for about 90 to 120 minutes in which time the10 reaction will hâve gone to completion. The vessel contents are cooled to ambient température, filtered to remove the inorganic salts, and washed with an alcohol such asmethanol. This filtrate contains the aldéhyde, labeled 1-1.

The aldéhyde is then reduced to the alcohol using an inorganic reducing agent.To do this the filtrate from the foregoing reaction is treated with sodium borohydride15 and after workup affords the desired alcohol, 1-2 in 97% overall yield from isovanillin.This is achieved by cooling the filtrate to about 0° C after which a reducing agent, heresodium borohydride, is added. About 0.25 to 0.5 équivalents of this reducing agent isused. The température is keep at about 0° C during the addition of the reducing agentand for about 30 to 40 minutes thereafter. Then the température is allowed to rise to20 about room température after which about one-half an équivalent of HCl is added to thereaction vessel. The alcohol is then extracted into an organic solvent, toluene isillustrated, and washed with dilute sodium bicarbonate.

The top organic layer containing the alcohol is then treated with excessconcentrated hydrochloric acid at ambient température to afford, after workup, the25 desired benzyl chloride 1-3. The chloride is isolated as a w/w solution in an ami desolvent, DMF is illustrated, and treated with about a 50% molar excess of sodiumcyanide at a mildly elevated température, here illustrated as 55° C. This affords thedesired nitrile 1-4. The nitrile is isolated as a w/w solution in an appropriate solventsuch as anhydrous acetonitrile and used directly in the next step. 30 The nitrile solution is charged with methyl acrylate. It is cooled to about -10° C, and slowly treated with a catalytic amount of Triton-B in the same solvent as used todissolve the nitrile. The methyl acrylate is added in a 3 to 4-fold excess. The reaction

P50728P 011347

is complété within 30 to 45 minutes after which the acrylate addition, the pimelateproduct, 1-5, is isolated as a w/w solution in toluene and treated with about 2équivalents of sodium methoxide at about 75° C to give the β-keto-ester product, 1-6 .The reaction solution is cooled and neutralized to pH 7 with minerai acid such as 6N 5 hydrochloric acid. The solution is charged with dimethyl sulfoxide, sodium chloride,water, and heated, for example to about 150° C, to effect the décarboxylation to give 1-7. The ketone, 1-7, is isolated from the solvent System as an off-white solid.

The dicarbonitrile is prepared from the ketone by treating the ketone withchloroacetonitrile in the presence of an inorganic base and a catalytic amount of 10 benzyltriéthylammonium chloride (BTEAC). The ketone and a slight excess of acetonitrile is charged into a mixture of strong base (aqueous potassium hydroxide) anda water miscible solvent such as tetrahydrofuran at reduced température, about 0° C orthereabouts. The reaction is maintained at about that température for the duration of thereaction, usually about 1 hour. The product can be isolated or used as a crude oil. 15 The dicarbonitrile is converted to the cyclohexanecarboxylic acid using a Lewis acid catalyst. This reaction is carried out by charging a vessel with solvents; in thisinstance exemplified by DMF, acetonitrile and water, and the Lewis acid (about 1.5équivalents), LiBr is illustrated; sweeping the vessel with an inert gas; adding thedicarbonitrile Ha or Ilb, or a mixture of Ha and Ilb ; and heating the vessel and its 20 contents to about 100° C for a number of hours, 8 hours being an example. Thereaction is then cooled and diluted with DMF and, optionally, water and LiOHdissolved in water is added (about a 50% molar excess is preferred). A suspension isformed. This is stirred at a slightly elevated temperature(40 to 80 C) for about an houror so. After cooling the reaction, the lithium sait is recovered by conventional means. 25 The acid is prepared by suspending the lithium sait in an organic solvent of the likes of ethyl acetate, and treating the suspension with aqueous minerai acid. Theorganic solvent is then recovered, washed, and concentrated. The product is isolated byconventional means..

This invention is illustrated by chemistries starting with the cyclohexan-l-one 30 compound prepared in Step 7. This ketone is a known compound. It can be found in U.S. patent 5,449,686 which gives one method for its préparation. That patent is incorporated herein by reference in full as illustrative of one method for making said

P50728P 011347 ketone. The chemistries illustrated in Scheme I are set out in a co-pending U.S.application which has been assigned USSN 60/061613 (fïled 12 February 1997) andalso filed as PCT application serial number PCT/US98/02749 designating inter alia theU.S.; it has been published as WO98/34584. That application is also incorporatedherein by reference, particularly as regards the chemistries underpinning steps 1-7.

Scheme II illustrâtes a second very similar set of conditions that can be used inthis invention. This scheme follows the same route as the one outlined in Scheme I;some of the conditions in certain steps are changed.

Scheme II 10 15

Isovanillin

Stage 3

Stage 2

1) NaBH4 MeQDMF/MeOH

2) HOAc/H2O

1) Conc. HCl Y

Toluene Me0^A^.

2) NaHCO3 H

^OH

Stage 4 oO Stage 5 Phase-transferM nconditions > A 1) A^co2ch3CH3CN, BnMe3N+OH H2O/CH3OH 2) Cyclohexane/toluene

Stage 7

MeO

TH F/methy Icyclohexane3) Wash crystals

with MeOH 1) Na^Oæ H2ODioxane 2) Conc. HCl 3) Cyclohexane/toluene 4) Recrystallize fromxylenes (optional) 10

P50728P

Stage 10

co2h

Stage 9 011347 1) Ethyl acetate with EtOAc COLi aq-HCl uu2li 2) Crystallize trom

Ethyl acetate/Heptanes

These chemistries are set out in PCT application number 5 PCT/98EP/_which inter alia désignâtes the U.S. as a selected State. The full disclosure of that application is incorporated herein by reference. In addition thedetails of this second set of chemistries are given below. A mixture of cyclopentyl chloride, isovanillin and potassium carbonate indimethylformamide is stirred at about 125°C until formation of the cyclopentyloxy 10 product is deemed to be complété (approximately 2 hours). The mixture is cooled to20-25°C, the solid (potassium chloride and potassium bicarbonate) is removed bycentrifugation and is washed with methanol before being discarded. Thedimethylformamide liquors and methanol wash are combined for use in the next step.

The solution of the cyclopentyloxy compound in dimethylformamide and 15 methanol is cooled to about 0°C and treated with sodium borohydride (approximately1.5 hours). The température is maintained below 5°C. After that the mixture is stirredat 0 to 10°C for 30 minutes and at 25-30°C until the réduction reaction is deemed to becomplété (approximately 1 hour). Acetic acid 50% is added to destroy the excessborohydride and the dimethylformamide and methanol are removed by distillation in 20 vacuo. After cooling to 20-25°C the mixture is partitioned between water and toluene.The toluene phase, containing the alcohol is washed with demineralised water, passedthrough a filter for use in the next step.

The solution of alcohol in toluene is treated with concentrated hydrochloric acid(min 36%) at 15 to 25°C. The organic phase, containing the chloro compound is 25 separated and treated with sodium bicarbonate to neutralize the HCI traces. The solid(sodium chloride, sodium bicarbonate) is removed by filtration.

The solution of the chloro compound is concentrated by distillation in vacuo.After cooling to about 20°C, demineralised water, tetrabutylammonium bromide andsodium cyanide are added. After that the mixture is heated to 80°C and stirred at this 30 température until the cyanidation reaction is deemed to be complété (approximately 2hours). 11

PS0728P 011347

After cooling to <60°C the mixture is partitioned between water and toluene.The toluene phase, containing the cyano compound is washed at 30 to 25°C withdemineralised water, distilled in vacuo to minimum volume and to this is addedacetonitrile. The product solution in acetonitrile is used directly in the next step. 5 Solutions of methyl acrylate in acetonitrile and Triton acetonitrile are prepared.

About 16.6% of the methyl acrylate solution is added to the cyano compound solutionat <25°C. About 12.5% of the Triton B solution is the added, the mixture is stirred forsome minutes and then cooled back to <25°C. This addition sequence is repeated threemore times, then the final 33% of the methyl acrylate solution and the final 50% of the 10 Triton B solution are added in two portions. The reaction mixture is stirred at 20 to25°C until the reaction is deemed to be complété (approximately 2-3 hours). Theacetonitrile is removed by vacuum distillation to minimum volume. The mixture ispartitioned between cyclohexane/toluene and water at 50°C. The cyclohexane/toluenephases, containing the pimelate is aged for about 1 hour at 1 to 1°C. 15 The product is isolated by centrifugation and washed with cold (<0°C) cyclohexane/toluene. The wet cake vacuum dried at max 50°C to give the pimelate asan off white to beige powder. A 29% methanolic solution of sodium methoxide is added in one lot to asolution of the pimelate in dioxane. The mixture is heated to about 75°C (reflux) and 20 maintained at this température until formation of the 2-carbomethoxycyclohexan-l-oneis deemed complété (approximately 1 hour). Much of the methanol is distilled out andreplaced with dioxane. Sodium bicarbonate and deminieralised water are added to the .the mixture is heated to reflux (about 85 to 88°C) and maintained at this températureuntil formation of the cyclohexan-l-one is deemed to be complété (approximately 10 25 hours).

After that the mixture is cooled to <60°C and concentrated hydrochloric acidsolution is added to reduce the pH from >10 to 7.5

Much of the dioxane and methanol is removed by distillation in vacuo. Afterthat the mixture is partitioned between cyclohexane/toluene and water at about 70°C. 30 The organic phase, containing the ketone is washed twice with demineralised water atabout 70°C.

The product solution is cooled to 10°C and aged for about 1 hour at 9 to 11°C.The product is isolated by filtration and washed with cold (10°C) cyclohexane/toluene.the wet cake is vacuum dried at max 50°C to give the ketone as an off white 35 powder.The ketone is then converted to the epoxide and thence to the lithium sait andthe acid in the same manner as described above under Scheme I. 12

P50728P 011347

The following examples are provided to illustrate spécifie embodiments of theinvention, not to limit it. What is reserved to the inventors is set forth in the daimsappended hereto.

Spécifie Examples 5 Example 1 Préparation of 3-cyclopentvloxy-4-methoxvbenzaldehyde A mixture of cyclopentyl chloride (8.48 g, 0.08 moles), isovanillin (6.12 g, 0.04moles) and potassium carbonate (1.1g, 0.08 moles) in dimethylformamide (4.04 g) wasstirred in the reactor (100 mL) at 120 to 125°C for 1.5 hours. A sample was taken toverify the batch conversion. Resuit (GC): 0.5 area % isovanillin (target: < 1.0 area %). 10 The mixture was cooled to 20°C and filtered to remove the solid (potassiumbicarbonate, potassium chloride). The wet cake was washed with methanol.

Example 2

Préparation of 3-Cyclopentvloxy-4-methoxybenzyl alcohol

The dimethylformamide liquors and methanol wash were combined and15 retransferred into the cleaned reactor. An additional amount of methanol (8.52 g) was added and the batch was cooled to 0°C. Sodium borohydride (0.49 g, 0.0129 moles)was added in small portions over 1 hour and 10 minutes maintaining the températurebetween 4 and 9°C. The batch was stirred at 7.2 to 10°C for 30 minutes and thenheated to 25°C. A sample was taken after 110 minutes stirring at 25 to 31°C and 20 analysed (GC) and the reaction was deemed to be complété. Acetic acid 50% (1.80 g)was charged to the reactor to quench any remaining sodium borohydride. The batchtempérature of 24 to 25 °C was maintained during this charge. The dimethylformamideand methanol were removed by distillation in vacuo (end of distillation: 58°C, 6 mbar).After cooling to 20 - 25°C the mixture was partitioned between water (3.13 g) and 25 toluene (28.07 g). The toluene phase (containing the captioned compound) was washedwith demineralised water (2.65 g).

Example 3

Préparation of 4-Chloromethvl-2-cyclopentyloxy-l-methoxvbenzene

The toluene solution from Example 2 was cooled to 20°C and concentrated 30 hydrochloric acid (37.5%; 9.80 g) was added keeping the température between 20 and22.7°C. A sample was taken 40 minutes after the addition was complété and analysed(GC) and the reaction was deemed to be complété. The phases were allowed to separateand the lower, aqueous phase discarded. Sodium bicarbonate (1.20 g) was charged tothe reactor to neutralize the remaining hydrochloric acid. After stirring for 15 minutes 35 the mixture was cooled to 23°C and filtered to remove the solid (sodium bicarbonate, sodium chloride). A part of the toluene (17.07 g) was removed by distillation in vacuo (end of distillation: 28°C, 7 mbar). 13

P50728P 011347

Example 4

Préparation of 4-Cyanomethyl-2-cyclopentvîoxy-1 -methoxvbenzeneAfter cooling to < 25°C tetrabutylammonium bromide (0.205 g, 0.63 mmoles), demineralised water (2.775 g) and sodium cyanide (1.976 g, 0.039 moles) were added, 5 the mixture was heated to 80°C and then stirred at 78.1 to 80.4°C for 1 hour and 50minutes. A sample was taken to verify the batch conversion.

Toluene (5.841 g) and demineralised water (8.76 g) were added, the phases wereallowed to separate (at about 54°C) and the lower, aqueous phase discarded. Thetoluene phase (containing the product) was washed with demineralised water (13.32 g). 10 The toluene was removed by distillation in vacuo (end of distillation: 55°C, 1 mbar).Example 5

Préparation of Dimethyl-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)pimelate

The cyanomethyl compound prepared in Example 4 (9.05 g at 85.4%; 7.73 g at 100%;0.0334 moles) was charged in the reactor (0.5 L) at room température. Acetonitrile 15 (28.56 g) and demineralised water (0.07 g) was charged to the reactor. Solutions of methyl acrylate (6.88 g,0.029 moles) in acetonitrile (4.02 g) and methanolic Triton B40.2% (0.94 g, 2.269 mmoles Triton B) in acetonitrile (4.06 g) were prepared. A firstportion, about 16.6% of the methyl acrylate solution (1.81 g) was added at 20°C. Afirst portion, about 12.5% of the Triton B solution (0.63 kg) was then added. The batch 20 température after the addition was 31°C. A second portion, about 16.6% of the methylacrylate solution (1.82 g) was added at 28°C. A second portion, about 12.5% of theTriton B solution (0.63 g) was then added. The batch température after the additionwas 36°C. A third portion, about 16.6% of the methyl acrylate solution (1.81 g) wasadded at 35°C. A third portion, about 12.5% of the Triton B solution (0.62 g) was then

25 added. The batch température after the addition was 32°C. A fourth portion, about16.6% of the methyl acrylate solution (1.81 g) was added at 32°C. A fourth portion,about 12.5% of the Triton B solution (0.63 g) was then added. The batch températureafter the addition was 36°C. A fifth portion, about 33.2% of the methyl acrylatesolution (3.64 g) was added at 34°C. A fifth portion, about 25% of the Triton B 30 solution (1.25 g) was then added. The batch température after the addition was 38°C.The last portion, about 25% of the Triton B solution (1.25 g) was then added. Thebatch température after the addition was 36°C. The reaction mixture was stirred for 1.5hours at 20 - 25°C. The acetonitrile was removed by distillation in vacuo (end ofdistillation: 59°C, 20 mbar). The mixture was partitioned at about 50°C between 35 cyclohexane/toluene (1145.9/254.6 g) and water (559.8 g). The cyclohexane/toluenephase (containing the product was washed with demineralised water (559.8 g) at 50 to52°C. To crystallize the captioned product, the batch was cooled over 50 minutes to0°C. The batch was then seeded with pimelate and aged for 1 hour at -1 to 1°C. Thepimelate was filtered and washed with cyclohexane/toluene (6.51 g/1.44 g) and 40 recovered by conventional means.

Example 6

Préparation of 4-Cvano-4-(3-cyclopentvloxy-4-methoxyphenvl)cyclohexan-l-one 14

PS0728P 011347

The pimelate made in Example 5 (765.2g, 1,8112 moles) was charged into thereactor (0.5 L). Dioxane (21.37g) and a 29.1% methanolie of sodium methoxide(4.37g, 0.024 moles) were added. The mixture was heated to reflux (77°C) and stirredat this température for 1 hour. A sample was taken to verify the batch conversion. The 5 methanol was removed by distillation (16.82g distillate) to a bottom température of97°C. the loss of dioxane during this distillation was compensated by adding of freshdioxane (12.16.4g). Sodium bicarbonate (2.22g, 0.026 moles) and demineralised water(24.72g) were added. The mixture was heated to reflux (87°C) and stirred at about to87°C for 10 hours. A sample was taken to verify the batch conversion. The content of 10 was cooled to 78°C. Dioxane (1.27g) and demineralised water (1.18g) were added tosimulate a flush. After cooling to <60°C concentrated hydrochloric acid (37%, 2.58g)was added to adjust the pH to 7.5. The dioxane, methanol and a part of water (27.73gdistilled) were removed by vacuum distillation (end of distillation: 66°C, 305 mbar).Under stirring cuclohexane (18.00), the phases were allowed to separate at 70°C and 15 lower, aqueous phase was discarded. The organic phase, containing the captionedketone was washed in two portions with demineralised water (16.94g total) at about70°C. Cyclohexane (1.65g) was added to reactor to simulate a flush. To crystallize theproduct, the batch was cooled to 10°C over 1 hour. Then it was aged for 6 hours at 9 to11°C to complété the crystallization. The product batch was filtered and washed with 20 cyclohexane/toluene (8.15g/2.72g).

Example 7

Préparation of cts-Lithium-4-cy ano-4-(3-cvclopentvloxv-4-methoxyphenyl)-r-1 - cyclohexanecarboxylate, 2.

To a 1.0 L, 3-neck round bottom flask equipped with an overhead stirrer,internai thermometer and a reflux condenser connect to a caustic scrubber was chargeddimethylformamide (200 mL), acetonitrile (200 mL), lithium bromide (32.4 g, 0.37mol) and water (5.6 g, 0.31 mol). The suspension was stirred until a solution was 30 évident, followed by the addition of cis-(+/-)-6-[3-(cyclopentyloxy)-4- methoxyphenyl)]-l-oxabicyclo[2.5]octane-2,6-dicarbonitrile (also called cü-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-l-oxaspiro[2.5]octane-2,6-dicarbonitrile,l, (90.0g, 0.25 mol). The contents of the flask were heated between 90 and 95 °C for 8 to 12hours. The reaction was cooled to 60 °C and diluted with dimethylformamide (270 15

P50728P 011347 mL). Το the amber solution (60 °C) was quickly added an aqueous solution of lithiumhydroxide (21.65 g, 0.51 mol of lithium hydroxide monohydrate dissolved in 112.5 mLof water). The suspension was stirred at 60 °C for 1 hour, cooled to 5 °C, and held at 5°C for 1 hour. The suspension was filtered, washed with ethyl acetate (100 mL) and air 5 dried to provide 2 in 79.5 % corr yield.

Example 8

Préparation of cis- -4-cvano-4-(3-cvclopentyloxy-4-methoxyphenyl)-r-l- cyclohexanecarboxylate. 3.

To a 1.0 L, 3-neck round bottom flask equipped with an overhead stirrer and aninternai thermometer was added cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexanecarboxylate, 2 (58.5 g, 0.167 mol) and ethyl acetate ( 15 500 mL). The light suspension was stirred at ambient température followed by the addition of 3N aqueous HCl (70 mL, 0.21 mol). The reaction was stirred for tenminutes and transferred to a separatory funnel. The organic layer was isolated andwashed once with water (100 mL). The organic layer was isolated and filtered into aclean 1.0 L, 3-neck round bottom flask equipped with a distillation head and an 20 overhead stirrer. The reaction was concentrated by distilling off ethyl acetate (200 mL).The contents of the flask were cooled to 60 °C followed by the addition of heptane (275mL). The suspension was cooled to 5 °C, held at 5 °C for 2 hours, filtered, and washedwith cold (5 °C) heptane (50 mL). The product was dried in a vacuum oven to constantweight to afford 50.0 g (85%) of 3. 16

Claims

P50728P (I) 10 10 15 15 25 25 30 30

y *1*2

FT R. '3 011347 Rl is -(CR4R5)nC(O)O(CR4R5)mR6, -(CR4R5)nC(O)NR4(CR4R5)mR6, -(CR4R5)nO(CR4R5)mR6, °r -(CR4R5)rR6 wherein the alkyl moieties may beoptionally substituted with one or more halogens; m is 0 to 2;n is 1 to 4;r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; Rô is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCl-3 alkyl,halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl,tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containingone or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when Rg is hydroxyl, then r is 2 to 6; or c) when Rô is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Rô is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6; e) when n is 1 and m is 0, then Rô is other than H in-(CR4R5)nO(CR4R5)mR6; X is YR2, halogen, nitro, NH2, or formyl amine; X2 is O or NR8; Y is O or S(O)m’;m’is 0, 1, or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by1 or more halogens; R3 is hydrogen, halogen, Cl-4 alkyl, CH2NHC(O)C(O)NH2, halo-substitutedC1-4 alkyl, -CH=CR8’R8\ cyclopropyl optionally substituted by Rs’, CN, OR8,CH2OR8, NRsRlO, CH2NR8RIO, C(Z0H, C(O)OR8, C(O)NRsRl0, or GeCR8’ 17 P50728P 011347 Rg is hydrogen or ¢4.4 alkyl optionally substituted by one to three fluorines; Rg’ is Rg or fluorine; Ræis OR8 or Ru; Rl 1 is hydrogen, or C 1.4 alkyl optionally substituted by one to three fluorines; 5 Z’ is O, NR9, NORg, NCN, C(-CN)2, CRgCN, CR8NO2, CRsC(O)OR8, CRsC(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRsR8; R’ and R" are independently hydrogen or -C(O)OX where X is hydrogen or analkali métal ion; which method comprises: 10 a) combining a Lewis acid, which is an alkali métal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or ü(b),

15 20 where R,, R3, X2 and X are the same as for formula (I) b) heating the combination to a température between about 60° and 100° Cfor several hours, optionally under an inert atmosphère; c) forming a sait by adding a strong base; d) filtering off the amide-based solvent and water, and optionally 1) purifying further the sait, or 2) acidifying a second solution of the sait to obtain the acid.
2. The process of claim 1 wherein the product is a compound wherein Ri is-CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Yis oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN.
3. The process of claim 1 or 2 wherein the Lewis acid is a lithium or magnésium halide.
4. The process of any one of daims 1-3 in which the Lewis acid is lithiumbromide.
5. The process of any one of daims 1-4 in which the aprotic dipolar amide-30 based solvent is dimethylformamide, dimethylacetamide, or N-methyl pyrrolidinone.
6. The process of any one of daims 1-5 in which the Lewis acid is lithiumbromide and the amide-based solvent is dimethylformamide.
7. The process of any one of daims 1-6 in which the strong base is lithiumhydroxide. 18 P50728P 011347
8. The process of any one of claim 1-7 wherein the compound of formula—\/— ---- l w.avjy-H-xn<,i.iivXypiieiiyiyj-i-OXa3piiOL^..jjOvi<uie- 2,6-dicarbonitrile.
9. A product of the process of any one of daims 1-8 which is cz‘j-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-l-cyclohexanecarboxylate.
10. A compound which is czs-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1 -cyclohexanecarboxylate. 19