SK4902000A3 - Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids, intermediate and a mixture comprising the same - Google Patents

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

Technical field

The present invention includes intermediates and a synthetic process for preparing 4-cyano4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexanoic acid and analogs thereof. This acid and its analogs are selective in inhibiting the catalytic site in the phosphodiesterase isoenzyme called IV (hereinafter PDE IV) and are therefore useful in the treatment of many diseases that can be alleviated by the action of the PDE IV enzyme and its subtypes.

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airways and hyperactivity of the respiratory tract to external stimuli.

The identification of new therapeutic agents for asthma is more difficult due to the fact that many mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a significant effect on all major components of chronic asthma. An alternative to the mediator approach is to regulate the activity of the cells responsible for the pathophysiology of the disease.

One such method is to increase cAMP (cyclic adenosine 3 ', 5'-monophosphate) levels. Cyclic AMP has been shown to be the second mediator to mediate biological responses to a wide variety of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4 ^th International Congress Excerpta Medica, 17-29, 1973]. When a suitable agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg ⁺² -ATP to cAMP at an increased rate.

Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of external (allergic) asthma. An increase in cAMP per se would produce beneficial effects including; 1) Smooth muscle relaxation

2) inhibition of mast cell mediator release, 3) inhibition of neutrophil degranulation, 4) inhibition of baseophilic degranulation, and 5) inhibition of monocyte and macrophage activation. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing inappropriate activation of airway smooth muscle and a wide range of inflammatory cells. The major cellular mechanism for cAMP inactivation is the hydrolysis of the 3'phosphodiesteric linkage by one or more of a group of isoenzymes referred to as cyclic nucleotide phosphodiesterases (PDEs).

It has now been shown that a certain cyclic nucleotide phosphodiesterase (PDE) isoenzyme, PDE IV, is responsible for the degradation of cAMP in airway smooth muscle and inflammatory cells. [Torphy, Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research has shown that inhibition of this enzyme not only causes relaxation of airway smooth muscle, but also suppresses degranulation of mast cells, basophils and neutrophils, along with inhibition of monocyte and neutrophil activation. Furthermore, the beneficial effects of PDE IV inhibitors are greatly potentiated when the adenylate cyclase activity of the target cells is enhanced by the respective hormones or autocoids, as would be the case with in vivo. Thus, PDE IV inhibitors would be effective in asthmatic lungs where levels of prostaglandin E ₂ and prostacyclin (adenylate cyclase activators) are elevated. Such compounds would provide a unique approach to the pharmacotherapy of bronchial asthma and would be therapeutically considerably more advantageous than the agents currently available on the market.

The method and intermediates of the invention provide compositions for the preparation of certain 4-substituted-4- (3,4-disubstituted phenyl) cyclohexanoic acids which are useful in the treatment of asthma and other diseases that can be alleviated by the action of the PDE IV enzyme and its subtypes. The final products of particular interest are described in detail in U.S. Patent 5,552,483, issued September 3, 1996. The information and data provided therein, insofar as such information and data are necessary for an understanding of the invention and an overall embodiment of the invention, are incorporated herein by reference.

3. Summary of the Invention

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

where

R ¹ is - (CR ⁴ R ⁵ ) n C (O) O (CR ⁴ R ⁵ ) m R ⁶ , - (CR ⁴ R ⁵ ) n C (O) NR ⁴ (CR ⁴ R ⁵ ) m R ⁶ , - (CR ⁴ R ⁵ ) n O (CR ⁴ R ⁵ ) m R ⁶ or - (CR ⁴ R ⁵ ) _r R ⁶ , wherein the alkyl moieties may be optionally substituted by one or more halogen atoms;

m is 0 to 2;

n is 1 to 4;

r is 0 to 6;

R ⁴ and R ⁵ are independently selected from hydrogen or C 1-4 alkyl;

R ⁶ is hydrogen, methyl, hydroxyl, aryl, halogen-substituted aryl, aryloxyC 1-3 alkyl, halogen-substituted aryloxyC 1-3 alkyl, indanyl, indenyl, C 2 -upolycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C -6cykloalkyl ₃ or C ₄ cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;

provided that

a) when R ⁶ is hydroxyl, then m is 2; or

b) when R ⁶ is hydroxyl, then r is 2 to 6; or

c) when R ⁶ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R ⁶ 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 R ⁶ is other than H in - (CR ⁴ R ⁵ ) n O (CR ⁴ R ⁵ ) _m R ⁶ ;

-4X is YR ^2, halogen, nitro, NH 2, or formyl amine;

X ² is O or NR ⁸ ;

Y is O or S (O) _m ;

m 'is 0,1, or 2;

R ² is independently selected from -CH 3 or -CH 2 CH 3 optionally substituted with 1 or more halogens;

R ³ is hydrogen, halogen, C 1-4 alkyl, CH ₂ NHC (O) C (O) NH 2, halogen substituted

C 1-4 alkyl, -CH = CR ^8, R ⁸ ', cyclopropyl optionally substituted with R ⁸ ', CN, OR ⁸ , CH ₂ OR ⁸ ,

NR ⁸ R ¹⁰ , CH ₂ NR ⁸ R ¹⁰ , C (Z ') H, C (O) OR ⁸ , C (O) NR ⁸ R ¹⁰ ; or C = CR ⁸ ';

R ⁸ is hydrogen or C 1-4 alkyl optionally substituted with one or three fluorine atoms;

R ⁸ 'is R ⁸ or fluoro;

R ¹⁰ is OR ⁸ or R ¹¹ ;

R ¹¹ is hydrogen or C 1-4 alkyl optionally substituted by one or three fluorine atoms;

Z 'is O, NR ⁹ , NOR ⁸ , NCN, C (-CN) 2, CR ⁸ CN, CR ⁸ NO 2, CR ⁸ C (O) OR ⁸ , CR ⁸ C (O) NR ⁸ R ⁸ , C ( -CN) NO ₂ C (-CN) C (O) OR ⁹ or C (-CN) C (O) NR ⁸ R ⁸ ;

R 1 and R 2 are independently hydrogen or -C (O) OX, wherein X is hydrogen or a metal or ammonium cation;

which includes:

a) mixing a Group Ia or Group IIa metal halide with an aprotic dipolar amide solvent and water and a compound of Formula A or B;

wherein R ¹ , R ³ , X ² and X are the same as for formula I;

b) heating the mixture to a temperature of at least about 60 ° C for several hours, optionally under an inert atmosphere;

-5c) precipitating a compound of formula I by adding a strong base to said mixture;

d) removing the amide solvent and water from said precipitate and optionally

Further purification of the precipitate; or

2) acidifying the precipitate to give the free acid.

This method involves the synthesis of certain 4-substituted-4- (3,4-disubstituted phenyl) cyclohexanoic acids. This allows the conversion of the cyanoepoxide to its corresponding homologous acid using a salt of the intermediate group Ia or IIb.

The compounds produced by this method are PDE IV inhibitors. They are useful in the treatment of many diseases as described in U.S. Patent 5,552,438 issued September 3, 1996.

Preferred compounds that can be produced in this manner are as follows:

Preferred R ¹ substituents for compounds of all of the above formulas are CH 2 cyclopropyl, CH 2 -C 8 cycloalkyl, C 1-4 cycloalkyl unsubstituted or substituted by OHC 7-6 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-4 alkyl unsubstituted or substituted by one or more fluorine atoms, - (CH2) i-3C (O) O (CH2) 0-2CH3, - (CH2) i-30 (CH2) 0-2CH3, and - (CH2) 2-4OH.

Preferred X groups for compounds of formulas I or II are those wherein X is YR ² and Y is oxygen. A preferred X ² group for a compound of formula I is such that X ² is oxygen. Preferred R ² groups are C _{first 2} alkyl unsubstituted or substituted by one or more halogens. Halogen atoms are preferably fluorine or chlorine, more preferably fluorine. More preferred R ² groups are those when R ² is methyl or fluoro substituted alkyl, especially C 1-6 alkyl, such as a -CF 3, -CHF 2 or -CH 2 CHF 2 radical. Most preferred are -CHF 2 and -CH 3 residues.

Most preferred are those wherein R ¹ is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF ₂ H; X is YR ² ; Y is oxygen; X ² is oxygen; and R ² is CF 2 H or methyl; and R ³ is CN.

The lithium salt of these compounds represents a subset of preferred compounds. In particular, the 4-cyano-4- (3-cyclopenyloxy-4-methoxyphenyl) -1H-1-cyclohexanecarboxylic acid lithium salt, m.p. j., lithium 4-cyano-4- (3-cyclopenyloxy-4-methoxyphenyl) -1-cyclohexanecarboxylate represents a preferred embodiment. The most preferred compound is cis -lithium-4-cyano-4- (3-cyclopenyloxy-4-methoxyphenyl) -1 H -cyclohexanecarboxylate.

The carboxylate is produced by opening the epoxide with a metal halide of group Ia or IIa to form an acyl nitrile which hydrolyzes to an acid in the presence of water. A problem with the preparation of an acid from acylnitrile is that when the carboxylate is prepared from acylnitrile, hydrogen cyanide (HCN) is formed. The problem is to remove this HCN in an efficient manner. It is a characteristic of the present invention to provide a means for influencing more efficient HCN removal. It has been found that when the reaction proceeds in an aprotic dipolar amide solvent containing water, when a strong base is added, cyanide salts are formed and remain in the solvent, and the carboxylate salts that are formed at the same time precipitate from the solvent. This makes it possible to collect the precipitate and remove the solvent, and in this way remove most or substantially all of the cyanide salts from the alkanoic acid salt precipitate. This prevents another purification step, such as HCN oxidation, from being carried out.

The Group I or IIa metal halides used in this invention are some of the alkali metal and alkaline earth metal halides, i. lithium, sodium, potassium, rubidium, cesium or francium; and beryllium, magnesium, calcium, strontium, barium or radium. Preferred metals are lithium and magnesium. Halides include flouride, chloride, bromide and iodide. A preferred halide is bromide. Lithium and magnesium halides are preferred. Lithium bromide and magnesium bromide are most preferred. Lithium bromide is particularly preferred.

Preferred amide solvents are illustrated using typical solvents such as dimethylformamide (DMF), dimethylacetamide, and N-methylpyrrolidinone. DMF is most preferred. A second organic solvent may be used to add to the amide solvent. For example, acetonitrile has been used successfully in the reaction below. Normally, water is added to the reaction vessel when it hydrolyzes acylnitrile in situ to form the alkanoic acid. Therefore, another embodiment of the present invention is the use of an aprotic dipolar solvent that is miscible with water. DMF, dimethylacetamide, and N-methylpyrrolidinone comply with this standard. While it is necessary to have water in the reaction medium, the amount of water can vary considerably. The reaction proceeds even if only a small amount of water is present. Is a

Preferably having at least 0.1% by weight of water present in the reaction vessel, based on the liquid and solids present in the vessel. More preferably, the amount of water is at least about 1% by weight, and most preferably about 1 to 5% by weight of water. Although not all possible combinations of water and amide solvent systems have been tested, it is known that the reaction would also take place at 20% by weight of water. It is therefore believed that an even higher percentage of water may be used. Optimization of the organic solvent: water ratios can be achieved by one skilled in the art. The use of any amount of water in combination with an amide solvent is contemplated within the scope of this invention.

The reaction may be carried out at a temperature above about 60 ° C. Since there are many combinations of amide solvents and water that can be used, it is not reasonable to determine the exact upper temperature limit, as this will vary depending on the choice of solvent and the ratio of solvents selected.

The metal halides of Group Ia or IIa open the epoxide to give the acyl nitrile. It is hydrolyzed to acid in the presence of water. However, before the free acid is isolated, an insoluble carboxylate salt is formed by adding about two or more equivalents of the strong base to the reaction vessel. This base forms two salts, the cyclohexanoic acid salt and the HCN salt, which is released by hydrolysis of the acylnitrile group. The formed cyanide metal is soluble in the solvent and the alkanoic acid salt precipitates from the solvent. This allows the alkanoic acid salt to be separated from the cyanide salt by simply removing the solvent. The process of the invention may be carried out using less than two equivalents of base, but this may result in the loss of alkanoic acid as it would not precipitate out of the solvent, which would be disadvantageous from an economic point of view. And unreacted HCN could contaminate the alkanoic acid that precipitated from the solvent. Therefore, a preferred embodiment is the use of two or more equivalents of base.

The strong base of the invention is any base which will form a salt with a cyanide ion. Any base that is strong enough to form these salts can be used in an embodiment of the invention; the formation of the cyanide salt is the more critical criterion of the two determining criteria when the respective base is used in this step. Inorganic hydroxides are preferred. For example, LiOH, NaOH or KOH may be used. Ammonia salts such as tetraalkyl-8-ammonium hydroxides or NH ₄ OH may also be used. Lithium hydroxide is preferred because the lithium cyanide salt is highly soluble in aqueous aprotic dipolar amide solvent and thus causes more efficient and complete removal of the cyanide ion from the acid salt when the amide solvent is removed. Lithium cyanide is more soluble in DMF than sodium cyanide or potassium cyanide. Thus, it is preferable to make lithium a cation in a strong base in the salt formation step of the process.

A preferred embodiment of the process of the invention is where the solvent (s) is introduced into the reaction vessel, lithium bromide is added, followed by the epoxide. When the reaction is substantially complete, two or more equivalents of aqueous lithium hydroxide solution are added, the cyclohexanoic acid salt precipitates out of solution and is filtered to remove the solvent. The lithium salt of cyclohexanoic acid can be further purified to remove residual impurities such as cyanide salts, or it can be converted to an acid by dissolving or suspending the salt in a solvent and acidifying the material to give the free acid.

A representative process in the process of the invention is shown in Scheme I and Scheme II. These diagrams use specific examples to illustrate the general methodology used in the present invention.

Scheme I

isovanillin step 1

DMF

2) activated carbon

step 2

1) NaBH ₄ DMF / MeOH

2) HOAc / H ₂ O

step 3

1) horses. HCl Toluene

2) NaHCO ₃

-9krok4

1) NaCN DMF

2) Toluene / H ₂ O

step 5

1) <^ CO ₂ CH ₃ CH ₃ CN, BnMe ₃ N * OH · H ₂ O / CH ₃ OH

2) crystallization from methylcyclohexane

4) recrystallization from xylenes (optional) step 8

1) CICH _? CN MeO

THF / aqueous KOH C ₆ H ₅ CH ₂ N (C ₂ H 5) ₃ Cl

2) crystallization from THF / methylcyclohexane

3) washing the MeOH crystals i

CN

CN step 9_

1) LiBr / DMF H ₂ / CH ₃ CN

2) aqueous LiOH

3) washing the crystals with EtOAc

step 10

1) aqueous ethyl acetate HCl

2) crystallization from ethyl acetate / hexanes

CO ₂ H

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

Scheme II

isovanillin

step 3

1) horses. HCl

Toluene ^Me0

2) NaHCO ₃

step 4 phase transition conditions

step 5

1) <^ CO ₂ CH ₃ CH ₃ CN, BnMe ₃ N * OH H ₂ O / CH ₃ OH

2) cyclohexane / toluene

step 7

1) NaOMe, NaHCO ₃ Dioxane

2) horses. HCl

3) recrystallization from

4) xylenes (optionally) aqueous KOH

CN step 8

1) CICH 3 CN THF / aq. KOH C ₆ H _with CH ₂ N (C ₂ H 5) ₃ Cl

2) crystallization from THF / methylcyclohexane

3) washing the MeOH crystals

MeO

CN

-11 step 9

2) aqueous LiOH

3) Wash crystals with EtOAc ¹ ) LiBr / H ₂ O _MeQ dmf / ch ₃ cn

CO Li aqueous HCl ² ) crystallization from ethyl CN step 10

MeO

1) ethyl acetate / heptanes

ABOUT

ABOUT

CN / CO, H

The process illustrated in Scheme I is suggested in the present US patent application, which was registered as USSN 60/061613 (filed February 12, 1997) and also filed as PCT International Patent Application No. PCT / US98 / 02749, inter alia, US; was published as WO98 / 34584. That application is incorporated herein by reference, in particular as regards the process which covers steps 1 to 7.

The procedure in Scheme II is suggested in PCT International Patent Application No. PCT / EP98 / 05504 filed August 26, 1998, which, inter alia, designates US as a excluded application. A detailed description of this application is incorporated herein by reference. In addition, details of this second procedure are given below.

A general description of the procedure in Schemes I and II follows.

The mixture of cyclopentyl chloride, isovanillin and potassium carbonate in dimethylformamide was stirred at 125 ° C until formation of the cyclopentyloxy product was considered complete (approximately 2 hours). The mixture was cooled to 20-25 ° C, and the solid (potassium chloride and potassium bicarbonate) was washed with methanol before being separated by centrifugation. The dimethylformamide liquid and methanol wash are mixed for use in the next step.

A solution of the cyclopentyloxy compound in dimethylformamide and methanol is cooled to about 0 ° C and treated with sodium borohydride (about 1.5 hours). The temperature is kept below 5 ° C. Then the mixture is stirred at 0-10 ° C for 30 minutes and at 25-30 ° C until the reduction reaction is considered complete (approximately 1 hour). 50% acetic acid was added to remove excess borohydride and dimethylformamide and methanol was removed by distillation in vacuo. After cooling to 20

-12 to 25 ° C, the mixture was partitioned between water and toluene. The toluene phase containing the alcohol is washed with demineralized water and filtered for use in the next step.

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

The chloro compound solution is concentrated by distillation in vacuo. After cooling to approximately 20 ° C, demineralized water, tetrabutylammonium bromide and sodium cyanide are added. The mixture was then heated to 80 ° C and stirred at this temperature until the cyanidation reaction was considered complete (approximately 2 hours).

After cooling to less than 60 ° C, the mixture was partitioned between water and toluene. The toluene phase containing the cyano compound is washed at 30-25 ° C with demineralized water, distilled under vacuum to a minimum volume and acetonitrile is added thereto. The product solution in acetonitrile is used directly in the next step.

Solutions of methyl acrylate in acetonitrile and Triton B and acetonitrile are prepared. Approximately 16.6% of the methyl acrylate solution is added to the cyano compound solution at less than 25 ° C. Approximately 12.5% Triton B solution is then added, the mixture is stirred for several minutes, and then cooled to less than 25 ° C. This addition sequence is repeated three times, then the last 33% methyl acrylate solution and the last 50% Triton B solution are added in two portions. The reaction mixture is stirred at 20-25 ° C until the reaction is deemed complete (approximately 2-3 hours). Acetonitrile was removed by vacuum distillation to a minimum volume. The mixture was partitioned between cyclohexane / toluene and water at 50 ° C. The cyclohexane / toluene phase containing pimelate is allowed to stand for about 1 hour at about 0 ° C.

The product is isolated by centrifugation and washed with cold (less than 0 ° C) cyclohexane / toluene. Wet cake vacuum dried at max. 50 ° C provides the pimellate as a white to beige powder.

A 29% methanolic sodium methoxide solution is added in one portion to a solution of pimellate in dioxane. The mixture is heated to about 75 ° C (reflux) and maintained at this temperature until formation of 2-carbomethoxycyclohexan-1-one is considered complete (about 1 hour). Much of the methanol is distilled off and replaced

-13dioxánom. Sodium bicarbonate and demineralized water are added to the mixture which is heated to reflux (about 85-88 ° C) and maintained at this temperature until formation of cyclohexan-1-one is considered complete (about 10 hours).

Then, the mixture is cooled to less than 60 ° C and concentrated, and a hydrochloric acid solution is added to reduce the pH from more than 10 to 7.5.

A large portion of dioxane and methanol was removed by distillation in vacuo. The mixture was then partitioned between cyclohexane / toluene and water at about 70 ° C. The organic phase containing the ketone is washed twice with demineralized water at about 70 ° C.

The resulting solution was cooled to 10 ° C and allowed to stand for about 1 hour at 9-11 ° C. The product was isolated by filtration and washed with cold (10 ° C) cyclohexane / toluene. The wet cake is dried under vacuum at max. 50 ° C to give the ketone as a white powder.

Dicarbonitrile is prepared from the ketone by treating the ketone with chloroacetonitrile in the presence of an inorganic base and a catalytic amount of benzyltriethylammonium chloride (BTEAC). The ketone and a slight excess of chloroacetonitrile in a suitable solvent such as THF are placed in a mixture of a strong base (aqueous potassium hydroxide solution) and BTEAC and a water miscible solvent such as tetrahydrofuran at reduced temperature, about 0 ° C. The reaction is maintained at such a temperature for the duration of the reaction, usually about 1 hour. The product can be isolated or used as a crude oil.

The dicarbonitrile is converted to a cyclohexanecarboxylic acid using a Group Ia or IIa metal halide. The reaction is carried out by adding solvents; in this case DMF, acetonitrile and water and a metal halide of Groups 1a and 11a (preferably about 1.5 equivalents), LiBr is preferred; mixing the mixture with an inert gas; adding dicarbonitrile A or B; and heating the vessel and its components to about 100 ° C for several hours, 8 hours for example. The reaction mixture is diluted with DMF and optionally water. LiOH dissolved in water is added (about 50% molar excess is preferred). A suspension is formed. This was stirred at a slightly elevated temperature (40 to 80 ° C) for about one hour. The lithium salt is isolated by conventional means.

The acid is prepared, for example, by suspending the lithium salt in an organic solvent, such as ethyl acetate, and treating the suspension with an aqueous mineral

-14kyselinou. The organic solvent was separated, washed, and concentrated. The product is isolated by conventional means.

The following examples are provided to illustrate a specific embodiment of the invention, not to limit it. What is reserved for the inventors is set forth in the claims.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde

A mixture of cyclopentyl chloride (8.48 g, 0.08 mol), isovanillin (6.12 g, 0.04 mol) and potassium carbonate (1.1 g, 0.08 mol) in dimethylformamide (4.04 g) was stirred in a reactor (100 mL) at 120-125 ° C for 1.5 hours. A sample was taken to verify conversion. Result (GC): 0.5% isovanillin (required; £ 1%). The mixture was cooled to 20 ° C and filtered to remove the solid (potassium bicarbonate, potassium chloride). The wet cake was washed with methanol.

Example 2

Preparation of 3-cyclopentyloxy-4-methoxybenzyl alcohol

The dimethylformamide liquors and methanol wash of Example 1 were combined and transferred to a clean 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 mol) was added in small portions and the temperature was maintained at 4-9 ° C for 1 hour and 10 minutes. The mixture was stirred at 7.2 to 10 ° C for 30 minutes and then warmed to 25 ° C. The sample was taken after stirring for 110 minutes at 25-31 ° C and analyzed (GC) and the reaction was deemed complete. Then 50% acetic acid (1.8 g) was added to the reactor to destroy the remaining sodium borohydride. During this addition, the batch temperature was maintained at 24-25 ° C. Distillation in vacuo removed dimethylformamide and methanol (end of distillation; 58 ° C, 6 mbar). After cooling to 20-25 ° C, the mixture was partitioned between water (3.13 g) and toluene (28.07 g).

The toluene phase (containing the title compound) was washed with demineralized water (2.65 g).

Example 3

Preparation of 4-chloromethyl-2-cyclopentyloxy-1-methoxybenzene

The toluene solution of Example 2 was cooled to 20 ° C and concentrated hydrochloric acid (37.5%, 9.8 g) was added and the temperature was kept between 20-22.7 ° C. A sample was taken 40 minutes after completion of addition and analyzed (GC) and the reaction was deemed complete. The phases were separated and the lower, aqueous phase was removed. Sodium bicarbonate (1.2 g) was added to the reactor to neutralize the remaining hydrochloric acid. After stirring for 15 minutes, the mixture was cooled to 23 ° C and filtered to remove the solid (sodium bicarbonate, sodium chloride). A portion of the toluene (17.07 g) was removed by distillation under vacuum (end of distillation: 28 ^e C, 7 mbar).

Example 4

Preparation of 4-cyanomethyl-2-cyclopentyloxy-1-methoxybenzene

After cooling the solution of Example 3 to less than 25 ° C, tetrabutylammonium bromide (0.205 g, 0.63 mol), demineralized water (2.755 g) and sodium cyanide (1.976 g, 0.039 mol) were added, and the mixture was heated to 80 ° C. and then stirred at 78.1 to 80.4 ° C for 1 hour and 50 minutes. The sample was taken to verify conversion.

Toluene (5.841 g) and demineralized water (8.76 g) were added, the phases were separated (at about 54 ° C) and the lower, aqueous phase was removed. The toluene phase (containing the product) was washed with demineralized water (13.32 g). Toluene was removed by distillation under vacuum (end of distillation: 55 ° C, 1 mbar).

Example 5

Preparation of dimethyl 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) pimelate

The cyanomethyl compound prepared in Example 4 (9.05 g 85.4%, 7.73 g 100%, 0.0334 mol) was charged to the reactor (0.5 L) at room temperature. Then acetonitrile (28.56 g) and demineralized water (0.07 g) were added to the reactor. A solution was prepared from methyl acrylate (6.88 g, 0.029 mol) in acetonitrile (4.02 g) and methanolic Triton B (40.2%, 0.94 g, 2.269 mol Triton B) in acetonitrile (4.06 g) . At a temperature of 20 ° C, a first portion of an approximately 16.6% methyl acrylate solution (1.81 g) was added. Then a first portion of about 12.5% Triton B solution (0.63 g) was added. The batch temperature after addition was 31 ° C. A second portion of an approximately 16.6% methyl acrylate solution (1.82 g) was added at 28 ° C. Then a second portion of about 12.5% Triton B solution (0.63 g) was added. The batch temperature after the addition was 36 ° C. At 35 ° C, a third portion of an approximately 16.6% methyl acrylate solution (1.81 g) was added. Then a third portion of a 12.5% Triton B solution (0.62 g) was added. The batch temperature after addition was 32 C. At 32 ° C, a fourth portion of an approximately 16.6% methyl acrylate solution (1.81 g) was added. A fourth portion of a 12.5% Triton B solution (0.63 g) was then added. The batch temperature after the addition was 36 ° C. At 34 ° C, a fifth portion of an approximately 33.2% methyl acrylate solution (3.64 g) was added. Then a fifth portion of an approximately 25% Triton B solution (1.25 g) was added. The batch temperature after the addition was 38 ° C. Then the last portion of about 25% Triton B solution (1.25 g) was added. The batch temperature after the addition was 36 ° C. The reaction mixture was stirred at 20-25 ° C for 1.5 hours. Acetonitrile was removed by distillation under vacuum (end of distillation: 59 ° C, 20 mbar). The mixture was partitioned at about 50 ° C between cyclohexane / toluene (1145.9 / 254.6 g) and water (559.8 g). The cyclohexane / toluene phase (containing the product) was washed with demineralized water (559.8 g) at a temperature of about 50-52 ° C. The batch was cooled to 0 ° C for about 50 minutes to crystallize the title product. The batch was inoculated with pimellate and aged for 1 hour at 1 to 1 ° C. The pimelate was filtered and washed with cyclohexane / toluene (6.51 g / 1.44 g) and isolated by conventional means.

Example 6

Preparation of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one

The pimelate prepared in Example 5 (76.52 g, 1.8112 mol) was added to the reactor (100 mL). Dioxane (2214 g) and a 29.1% methanolic sodium methoxide solution were added

-17 (0.44 g, 24 mmol). The mixture was heated to reflux (77 ° C) and stirred at this temperature for 1 hour. The sample was taken to verify conversion. Distillation (16.82 g of distillate) removed methanol at a temperature below 97 ° C. The loss of dioxane during distillation was compensated by the addition of additional dioxane (121.6 g). Sodium bicarbonate (22.2 g, 26 mmol) and demineralized water (2.47 g) were then added. The mixture was heated to reflux (87 ° C) and stirred at 87 ° C for 10 hours. The sample was taken to verify conversion. The reactor contents were cooled to 78 ° C. Dioxane (0.13 g) and demineralized water (0.12 g) were added to simulate the wash. After cooling to less than 60 ° C, concentrated hydrochloric acid was added to adjust the pH to 7.5. Dioxane, methanol and a portion of water (27.73 g distilled) were removed by distillation under vacuum (end of distillation: 66 ° C, 305 mbar).

While stirring, cyclohexane (180 g) and toluene (65.5 g) were added to the reactor. The mixture was heated to 70 ° C and the phases were separated at 70 ° C and the lower, aqueous phase was removed. The organic phase containing the title ketone was washed in two portions of demineralized water (169.4 g total) at about 70 ° C. Cyclohexane (165 g) was added to the reactor to simulate washing. The batch was cooled to about 10 ° C for about 1 hour to crystallize the product. This was then aged for 6 hours at 9-11 ° C to complete the crystallization. The product feed was filtered and washed with cyclohexane / toluene (81.5 g / 28.2 g).

Example 7

Preparation of cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxaspiro [2,5] octane-2,6-dicarbonitrile

A 500 ml round bottom flask equipped with a suspended stirrer, internal thermometer and nitrogen inlet was purged with nitrogen. The flask was charged with 50% potassium hydroxide in water (22.0 g) and tetrahydrofuran (55 mL). While stirring at room temperature, benzyltriethylammonium chloride (0.81 g, 35 mmol, 0.05 equivalents) was added. The solution was then cooled to 0 ° C. A solution containing tetrahydrofuran (55 mL), 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (23.0 g, 73 mmol, 1 equivalent) and chloroacetonitrile (5.9 mL) was added via a pressure addition funnel. g, 78 mmol, 1.07 equiv) at room temperature. While you are

The contents of the 0 ° C flask were stirred, the solution was added via a pressure addition funnel over 15 minutes. The temperature was kept between 0-5 ° C and the mixture was stirred for 1 hour. The reaction mixture was warmed to 25 ° C, diluted with water (90 mL) and ethyl acetate (90 mL). The solution was stirred and allowed to settle for 30 minutes. The layers were separated, the organic layer was isolated and concentrated in vacuo by distillation to a residue. Methylcyclohexane / THF (5: 1) (54 mL) was added and the mixture was heated to 60 ° C, then cooled to 20 ° C over 90 minutes, the product began to crystallize at about 40 ° C. The suspension was then cooled to 0 ° C and held at 0-5 ° C for 2 hours. The product was filtered and washed with a mixture of methanol (46 mL) at 0 ° C. The product was dried to give the title product as a white crystalline solid.

Example 8

Preparation of cis -Lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1H-cyclohexanecarboxylate, 2

Dimethylformamide (200 mL), acetonitrile (200 mL), lithium bromide (32.4 g, 0.37 mol) were added to a 1 liter 3-neck round bottom flask equipped with a suspended stirrer, internal thermometer and reflux condenser connected to a caustic scrubber. water (5.6 g, 0.31 mol). The suspension was stirred until a solution was formed, followed by the addition of cis 6- [3- (cyclopentyloxy) -4-methoxyphenyl] -1-oxaspiro [2,5] octane-2,6-dicarbonitrile, 1 (90 g, 0.25 mol). The contents of the flask were heated to 90-95 ° C for 8-12 hours. The reaction mixture was cooled to 60 ° C and diluted with dimethylformamide (270 mL). Aqueous lithium hydroxide solution (21.65 g, 0.51 mol of lithium hydroxide monohydrate) was quickly added to the amber solution.

Dissolved in 112.5 ml of 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 dried to give compound 2 in 79.5% corresponding yield.

Example 9

Preparation of cis -4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1 H -cyclohexanecarboxylate, 3

CCfeLi

Ό ethyl acetate

3N aq. HCl

2) crystallization from ethyl acetate / heptane

CCfeH

To a 1 liter 3-neck round bottom flask equipped with a suspended stirrer and an internal thermometer was added cis-lithium 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1 H -cyclohexanecarboxylate, 2 (58.5) g, 0.167 mol) and ethyl acetate (500 mL). The light suspension was stirred at ambient temperature. This was followed by addition of 3N aqueous HCl (70 mL, 0.21 mol). The reaction mixture was stirred for 10 minutes and transferred to a separatory funnel. The organic layer was isolated and washed once with water (100 mL). The organic layer was stripped and filtered into a clean 1L 3-neck round bottom flask equipped with a distillation head and a suspended stirrer. The reaction mixture 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 (275 mL). The suspension was cooled to 5 ° C, held at this temperature for 2 hours, filtered and washed with cold (5 ° C) heptane (50 mL). The product was dried in a vacuum oven to give compound 3 at a constant weight of 50 g (85%).

Claims (2)

PATENT CLAIMS A process for producing a substituted 4-phenyl-4-cyanocyclohexanoic acid of the general formula I wherein R ¹ is - (CR ⁴ R ⁵⁾ n C (O) O (CR ⁴ R ⁵⁾ m R ^6, - (CR ⁴ R ⁵⁾ n C (O) NR ⁴ (CR ⁴ R ⁵⁾ m R ^6, - (CR ⁴ R ⁵ ) n O (CR ⁴ R ⁵ ) m R ⁶ or - (CR ⁴ R ⁵ ) r R ⁶ , wherein the alkyl moieties may be optionally substituted by one or more halogen atoms; m is 0 to 2; n is 1 to 4; r is 0 to 6; R ⁴ and R ⁵ are independently selected from hydrogen or C 1-2 alkyl; R ⁶ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi_3alkyl, halogen substituted aryloxy-3 alkyl, indanyl, indenyl, Cy.-upolycykloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C ₃ . ₆ cycloalkyl, or C _{4. 6} cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 or 3 methyl groups or one ethyl group; provided that a) when R ⁶ is hydroxyl, then m is 2; or b) when R ⁶ is hydroxyl, then r is 2 to 6; or c) when R ⁶ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R ⁶ 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 R ⁶ is other than H in - (CR ⁴ R ⁵ ) n O (CR ⁴ R ⁵ ) m R ⁶ ; X is YR ² , halogen, nitro, NH ₂ or formylamine; X ² is O or NR ⁸ ; Y is O or S (O) _m ; m 'is 0, 1, or 2; R ² is independently selected from -CH 3 or -CH 2 CH 3 optionally substituted with 1 or more halogen atoms; R ³ represents hydrogen, halogen, C 1-4 alkyl, CH 2 NHC (O) C (O) NH 2, halogen substituted C 1-4 alkyl, -CH = CR ^8, R ⁸ ', cyclopropyl optionally substituted with R ⁸ ', CN, OR ⁸ , CH ² OR ⁸ , NR ⁸ R ¹⁰ , CH ₂ NR ⁸ R ¹⁰ , C (Z ') H, C (O) OR ⁸ , C (O) NR ^b R ¹⁰ or C = CR ⁸ '; R ⁸ represents hydrogen or C 1-4 alkyl optionally substituted with one or three fluorine atoms; R ⁸ 'is R ⁸ or fluoro; R ¹⁰ is OR ⁸ or R ¹¹ ; R ¹¹ represents hydrogen or C 1-4 alkyl optionally substituted with one or three fluorine atoms; Z 'is O, NR ⁹ , NOR ⁸ , NCN, C (-CN) 2, CR ⁸ CN, CR ⁸ NO 2, CR ⁸ C (O) OR ⁸ , CR ⁸ C (O) -NR ⁸ R ⁸ , C (-CN) NO ₂ C (-CN) C (O) OR ⁹ or C (-CN) C (O) NR ⁸ R ⁸ ; R 1 and R 2 are independently hydrogen or -C (O) OX, wherein X is hydrogen or a metal or ammonium cation; characterized by comprising: a) mixing a Group Ia or Group IIa metal halide with an aprotic dipolar amide solvent and water and a compound of Formula IIa or IIb wherein R ¹ , R ³ , X ² and X are the same as for Formula I; -22b) heating the mixture to a temperature of at least about 60 ° C for several hours, optionally under an inert atmosphere; c) precipitating a compound of formula I by adding a strong base to said mixture; d) removing the amide solvent and water from said precipitate and optionally Further purification of the precipitate; or 2) acidifying the precipitate to give the free acid. The method of claim 1, wherein the product is a compound wherein R ¹ is -CH 2 -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF 2 H; X is YR ² ; Y is oxygen; X ² is oxygen; and R ² is CF 2 H or methyl; and R ³ is CN. Process according to claim 1 or 2, characterized in that the metal halide of group 1a or IIa is lithium or magnesium halide. Process according to any one of claims 1 to 3, characterized in that the metal halide of group 1a or IIa is lithium bromide or magnesium bromide. The process according to any one of claims 1 to 4, wherein the aprotic dipolar amide solvent is dimethylformamide, dimethylacetamide or N-methylpyrrolidinone. The process according to any one of claims 1 to 5, wherein the metal halide of group Ia or IIa is lithium bromide and the amide solvent is dimethylformamide. The process according to any one of claims 1 to 6, characterized in that the water is present in an amount of more than 0.1% by weight, based on the content of the reaction vessel. A process according to any one of claims 1 to 7, wherein the base is lithium hydroxide. -239. The method of any one of claims 1 to 8, wherein the compound of formula IIIa or IIb is cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl] 1-oxaspiro [2.5] octane-2, 6-dicarbonitrile. Intermediate cis -Lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-cyclohexanecarboxylate for the preparation of a compound of formula I by the process of any one of claims 1 to 9. 11. Compound cis -Lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1H-1-cyclohexanecarboxylate as an intermediate for the preparation of a compound of formula I. 12. A composition comprising substantially pure cis-lithium 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -1-cyclohexanecarboxylate.