CN1192025C - Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids - Google Patents

Abstract

The present invention relates to a method for preparing a compound of formula (I) wherein at least one of R' or R" is a carboxyl group, the method comprising treating the compound of formula (II) with a group I(a) or II(a) metal halide in the absence of a proton-dipolar amide solvent and water.

Description

Preparation method of substituted 4-phenyl-4-cyanocyclohexanecarboxylic acid

field of invention

The present invention relates to intermediates and synthetic routes for the preparation of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanecarboxylic acid and analogues thereof. The acid and its analogs selectively inhibit the catalytic site in phosphodiesterase isozyme IV (named) (hereinafter referred to as PDE IV), so the acid is used to treat a variety of diseases by affecting the PDE IV enzyme and its Subtype of disease in remission.

Background of the invention

Asthma is a complex multifactorial disease characterized by reversible narrowing of the airways and hyperresponsiveness of the airways to external stimuli.

The identification of new asthma treatments has been difficult because of the multiple mediators that play a role in the development of the disease. Therefore, it seems unlikely that abolishing the action of one mediator would have a significant effect on all major causes of bronchial asthma. Another meaning of "mediator access" is the modulation of cellular reactivity in response to disease pathophysiology.

One way is by increasing levels of cAMP (cyclic 3',5'-adenosine monophosphate). Cyclic AMP has been shown to be a second messenger that mediates biological responses to various hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When an appropriate antagonist binds to a specific cell surface receptor, adenylyl cyclase is activated and the conversion of Mg ⁺² -ATP to cAMP is accelerated.

Cyclic AMP regulates most, but not all, of the cellular activities that contribute to the pathophysiology of extrinsic (allergic) asthma. Increased cAMP levels will therefore have beneficial effects including: 1) relaxation of airway smooth muscle, 2) inhibition of release of mast cell mediators, 3) inhibition of neutrophil degranulation, 4) inhibition of basophil degranulation and 5) inhibition of monocyte degranulation. Activation of nuclear cells and macrophages. Thus, compounds that activate adenylyl cyclase or inhibit phosphodiesterase will effectively inhibit the inappropriate activation of airway smooth muscle and various inflammatory cells. The primary cellular mechanism for cAMP inactivation is hydrolysis of the 3'-phosphodiester bond by one or more isozymes of a family of cyclic nucleotide phosphodiesterases (PDEs).

A cyclic nucleotide phosphodiesterase (PDE) isoenzyme, PDE IV, has been shown to contribute to cAMP cleavage in airway smooth muscle and inflammatory cells. [Torphy, "Phosphodiesterase Isoenzymes: Potential Targets for New Anti-Asthma Drugs", New Drugs for Asthma, Barnes ed., IBC Technical Services Ltd., 1989]. Studies have shown that the inhibition of this enzyme not only relaxes the airway smooth muscle, but also inhibits the degranulation of mast cells, basophils and neutrophils, and also inhibits the activation of monocytes and neutrophils. Furthermore, in vivo, the beneficial effects of PDE IV inhibitors will be significantly enhanced when the nucleotide cyclase activity of target cells is increased by appropriate hormones or endocrine substances. Thus, PDE IV inhibitors would be effective in asthmatic lungs where levels of prostaglandin _E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds will provide a unique drug therapy approach for the treatment of bronchial asthma, and they have obvious therapeutic advantages compared with the drugs currently on the market.

The methods and intermediates of the present invention provide a means for the preparation of certain 4-substituted-4-(3,4-disubstituted phenyl)cyclohexanecarboxylic acids which are useful in the treatment of asthma and other diseases by affecting PDE IV enzymes and Its subtype alleviates the disease. End products of particular interest are fully described in US Patent 5,552,483, issued September 3,1996. All information and content disclosed therein that are necessary for the understanding and practice of the invention are incorporated herein by reference in their entirety.

Summary of the invention

The present invention relates to the method for preparing compound of formula I,

in

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 moiety may be optionally substituted by one or more halogens;

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, halogen substituted aryl, aryloxy C _1-3 alkyl, halogen substituted aryloxy C _1-3 alkyl, 2,3-indanyl , indenyl, C _7-11 polycycloalkyl, tetrahydrofuran, furyl, tetrahydropyranyl, pyryl, tetrahydrothiophenyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C _3-6 Cycloalkyl or C _4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclyl moieties may be optionally substituted by 1 to 3 methyl groups or an ethyl group;

requirement is:

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-tetrahydrofuryl or 2-tetrahydrothiophenyl, then m is 1 or 2; or

d) when R ₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl or 2-tetrahydrothiophenyl, then r is 1 to 6; or

e) when n is 1 and m _is 0, then R in -(CR ₄ R ₅ ) _n O(CR ₄ R ₅ ) _m is not H;

X is YR ₂ , halogen, nitro, NH ₂ or formamide;

X ₂ is 0 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 by one 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' , optional Cyclopropyl substituted by 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 is hydrogen or C _1-4 alkyl optionally substituted by one to three fluorines;

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 to three fluorines;

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' and R" are independently selected from hydrogen or -C(O)OX, wherein X is hydrogen or a metal or ammonium cation;

The method includes:

a) mixing a Group I(a) or II(a) metal halide with an aprotic dipolar amide-based solvent and water and a compound of formula A or B,

In formulas A and B, R ₁ , R ₃ , X ₂ and X have the same meanings as in formula (I);

b) heating the mixture at at least 60° C. for several hours, this heating optionally being carried out under an inert atmosphere;

c) adding a strong base to the mixture to precipitate the mixture of formula (I);

d) removing amido solvent and water from said precipitate, and optionally

1) further purification of the precipitate, or

2) Acidify the precipitate to obtain free acid.

Invention specific plan

The method of the present invention involves the synthesis of certain 4-substituted-4-(3,4-disubstituted phenyl)cyclohexanecarboxylic acids. The cyanoepoxide is converted to the desired corresponding acid via a Group I(a) or II(b) salt intermediate.

The compound prepared by this method is a PDE IV inhibitor. They are used in the treatment of a variety of diseases described in US Patent 5,552,438, issued September 3,1996.

Preferred compounds that can be prepared using this method are the following:

Among the compounds of all named formulas, the preferred R ₁ substituents are CH ₂ -cyclopropyl, CH ₂ -C _5-6 cycloalkyl, unsubstituted or OH-substituted C _4-6 cycloalkyl, C _{7 -11} polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C _1-2 alkyl unsubstituted or substituted by one or more fluorine, -(CH ₂ ) _1-3 C(O)O(CH ₂ ) _0-2 CH ₃ , -(CH ₂ ) _1-3 O(CH ₂ ) _0-2 CH ₃ and -(CH ₂ ) _2-4 Oh.

In formula (I) or (II), preferred X groups are those wherein X is YR ₂ and Y is oxygen. In formula (I), preferred _X2 groups are those wherein _X2 is oxygen. Preferred R ₂ groups are C _1-2 alkyl unsubstituted or substituted with one or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R ₂ groups are methyl or fluorine substituted alkyl, especially C _1-2 alkyl, eg -CF ₃ , -CHF ₂ or -CH ₂ CHF ₂ . Most preferred are _-CHF2 and _-CH3 .

Most preferred are those compounds 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 ; R ₂ is CF ₂ H or methyl; and R ₃ is a compound of CN.

The lithium salts of these compounds represent a small class of preferred compounds. In particular the lithium salt of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-γ-1-cyclohexanecarboxylic acid, ie 4-cyano-4-(3- Lithium cyclopentyloxy-4-methoxyphenyl)-γ-1-cyclohexanecarboxylate represents a preferred variant. In particular, the compound lithium cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-γ-1-cyclohexanecarboxylate is most preferred.

Carboxylates are prepared by ring-opening the epoxide with a Group I(a) or II(a) metal halide to give the acylnitrile, which is hydrolyzed to the acid in the presence of water. One problem with the preparation of acids from acylnitriles is that hydrocyanic acid (HCN) is produced when the acylnitriles form carboxylates. It is desirable to remove the HCN by cost-effective means. The present invention is characterized by more efficient removal of HCN. The inventors have found that if the reaction is carried out in an aqueous aprotic dipolar amide-based solvent, when a strong base is added, a cyanide salt is formed and remains in solution with simultaneous formation of a carboxylate precipitate. By thus collecting the precipitate and removing the solvent, it is meant that most or substantially all of the cyanide salt is removed from the alkanoate precipitate. This avoids having to perform additional purification steps such as oxidation of HCN.

The Group I(a) or II(a) metal halides used in the present invention are any alkali metal or alkaline earth metal, namely lithium, sodium, potassium, rubidium, cesium or francium; and beryllium, magnesium, calcium, strontium, barium or Radium halides. Preferred metals are lithium and magnesium. Halides include fluoride, chloride, bromide and iodide. The preferred halide is bromide. Halides of lithium and magnesium are preferred. Lithium bromide and magnesium bromide are most preferred. Lithium bromide is especially preferred.

As the amide-based solvent, dimethylformamide (DMF), dimethylacetamide, and N-methylpyrrolidone can be cited. DMF is most preferred. In addition to amide-based solvents, a second solvent can also be used. Acetonitrile, for example, was successfully used in the reaction described below. Water is usually added to the reaction tank to hydrolyze the acylnitrile in situ to give the alkanoic acid. Another preferred embodiment of the present invention is the use of water-miscible aprotic dipolar solvents. DMF, dimethylacetamide, and N-methylpyrrolidone meet this requirement. While water must be present in the reaction medium, the amount of water can vary widely. The reaction proceeds even when relatively small amounts of water are present. In the reaction vessel, water is preferably present at least 0.1% (w/w) of the total amount of any liquids and solids in the vessel. A more preferred amount of water is at least about 1% w/w, most preferably about 1-5% w/w. Although not all possible mixed solvent systems of water and amide-based solvents were tested, it is known that the reaction can be performed in the presence of 20% (w/w) water. Therefore, it is believed that higher percentages of water can be used. The optimum ratio of organic solvent to water is known to a practitioner in the art. The use of any amount of water in combination with the amide-based solvent is considered to be within the scope of this invention.

The reaction can be carried out at any temperature above about 60°C. Since a wide variety of solvent mixtures of amido solvents and water can be used, it is impractical to limit the temperature to a definite upper limit, since the temperature will vary with the chosen solvent and the ratio of the chosen solvent.

Group I(a) or II(a) metal halides ring open epoxides to give acylnitriles. Acylnitriles are hydrolyzed to acids in the presence of water. Insoluble carboxylate salts can be formed by adding about 2 equivalents or more of strong base to the reaction vessel, rather than isolating the free acid. The base forms two salts, one of cyclohexanecarboxylic acid and one of HCN, which is liberated upon hydrolysis of the acylnitrile group. The resulting metal cyanide dissolves in the solvent, while the salt of the alkanoic acid precipitates out of solution. This allows separation of the alkanoic acid from the cyanide salt by simple removal of the solvent. The present invention can be carried out using less than 2 equivalents of base, but this may result in a loss of alkanoic acid, so that part of the alkanoic acid does not precipitate out of solution, which is unfavorable from an economic point of view. Unreacted HCN may contaminate the alkanoic acids that precipitate out of solution. Therefore, it is preferred to use 2 or more equivalents of alkanoic acid.

A strong base according to the invention is any ion which can form a salt with a cyanide ion. Any base strong enough to form such salts can be used; the formation of cyanide salts is the more decisive of the two criteria for identifying whether a particular base is used in this step. Inorganic hydroxides are preferred. For example, lithium hydroxide, sodium hydroxide, and potassium hydroxide can be used. Ammonium salts such as tetraalkylammonium hydroxide or ammonium hydroxide may also be used. Lithium hydroxide is preferred because lithium cyanide salts are highly soluble in aqueous aprotic dipolar amide-based solvents, allowing more efficient and complete removal of the cyanide ion from the salt when the amide-based solvent is removed. Lithium cyanide is more soluble in DMF than sodium or potassium cyanide. Therefore, it is more advantageous to use lithium as the cation in the strong base in the salt-forming step.

The preferred version of the present invention is to load the solvent into the reaction vessel, add lithium bromide, and then add the epoxide. Once the reaction is substantially complete, two or more equivalents of lithium hydroxide in water are added, the cyclohexane carboxylate is filtered from the precipitate, and the solvent is discarded. If desired, the lithium salt of cyclohexanecarboxylic acid can be further purified from residual impurities such as cyanide salts, or converted to the free acid by dissolving or suspending the salt in a solvent and acidifying it.

Representative reaction schemes for this approach are shown in Figures I and II. The Figures illustrate the general methodology of the invention using specific example representations.

Figure I

Figure II illustrates a second, very similar condition applicable to the present invention. The flow of this figure is the same as that outlined in Figure 1, but some conditions of some steps are changed.

The chemical reactions depicted in Figure 1 are described in co-pending U.S. application No. USSN 60/061613 (February 12, 1997) and Specially Designated U.S. Application No. PCT/US98/02749, published as WO 98/ 34584 PCT applications. These applications are incorporated herein by reference, especially as they relate to the chemistry of steps 1-7.

The chemical reaction of Figure II is described in PCT Application No. PCT/EP98/05504, filed August 26, 1998, which specifically designates the United States as the designated country. The entire disclosure of this application is incorporated herein by reference. The chemical reactions in Figure II are specifically described below.

A general description of the chemical reactions in Figures I and II follows:

A mixture of cyclopentyl chloride, vanillin, and potassium carbonate in dimethylformamide was stirred at about 125[deg.] C. until the cyclopentyloxy product was considered complete (about 2 hours). The mixture was cooled to 20-25°C, the solids (potassium chloride and potassium bicarbonate) were removed by centrifugation, washed with methanol and discarded. The dimethylformamide mother liquor and methanol washings were combined for the next step.

A solution of the cyclopentyloxy compound in dimethylformamide and methanol was cooled to about 0°C and treated with sodium borohydride (about 1.5 hours). Keep the temperature below 5°C. The mixture was stirred at 0-10°C for 30 minutes, then at 25-30°C until the reduction was considered complete (about 1 hour). Acetic acid 50% was added to consume excess borohydride, and dimethylformamide and methanol were removed by vacuum distillation. After cooling the mixture to 20-25°C, it was partitioned between water and toluene. The alcohol-containing toluene phase was washed with demineralized water and passed through a filter for the next reaction.

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

The chloride solution was concentrated by vacuum distillation. After cooling to about 20°C, demineralized water, tetrabutylammonium bromide and sodium cyanide were added. After the mixture was heated to 80° C., it was stirred at this temperature until the cyanation reaction was considered complete (approximately 2 hours).

After cooling the mixture to below 60°C, it was partitioned between water and toluene. At 30-25°C, the toluene phase containing cyano compounds was washed with demineralized water, vacuum distilled to a minimum volume, and acetonitrile was added thereto. The acetonitrile solution of this product was used directly in the next step.

A solution of methyl acrylate in acetonitrile and a solution of tetraalkylammonium hydroxide (TritonB) and acetonitrile were prepared. A 16.6% methyl acrylate solution was added to the cyano compound solution at below 25°C. A solution of about 12.5% tetraalkylammonium hydroxide was added and the mixture was stirred for a few minutes before cooling to below 25°C. Repeat this addition sequence for more than three times, and then add the last 33% methyl acrylate solution and the last 50% tetraalkylammonium hydroxide solution in two batches. The reaction mixture was stirred at 20-25 °C until the reaction was considered 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 was aged for about 1 hour at about 0°C.

The product was centrifuged and washed with cold (below 0°C) cyclohexane/toluene. The wet filter cake was vacuum dried at a maximum of 50°C to yield the pimelate as an off-white to beige powder.

29% sodium methoxide in methanol was added in one portion to the solution of pimelate in dioxane. The mixture was heated to about 75°C (reflux) and kept at this temperature until complete formation of 2-methoxycarbonylcyclohexane-1-one (about 1 hour). After distilling off most of the methanol, dioxane was used instead of methanol. Sodium bicarbonate and demineralized water were added to the mixture, heated to reflux (ca. 85-88°C) and the mixture was maintained at this temperature until complete formation of the cyclohexane-1-one (ca. 10 hours).

After cooling the mixture to below 60°C, concentrated hydrochloric acid solution was added to lower the pH from above 10 to 7.5.

Most of the dioxane and methanol were removed by vacuum distillation. Afterwards, the mixture was partitioned between cyclohexane/toluene and water at about 70°C. At about 70° C., the ketone-containing organic phase was washed twice with demineralized water.

The product solution was cooled to 10°C and aged at 9-11°C for about 1 hour. The product was isolated by filtration and washed with cold (10°C) cyclohexane/toluene, and the wet cake was vacuum dried at no more than 50°C to give the ketone as an off-white powder.

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

The dinitrile is converted to cyclohexanecarboxylic acid using a Group I(a) or II(a) metal halide. The reaction is carried out as follows: a solvent is added to a vessel, here exemplified by DMF, acetonitrile and water, and a Group I(a) or II(a) metal halide (preferably about 1.5 equivalents), such as LiBr; an inert gas is passed through the A container; add dinitrile A or B or a mixture of A and B; heat the container and its contents at about 100° C. for several hours, for example 8 hours. The reaction was diluted with DMF and optionally water. Aqueous lithium hydroxide solution is added (approximately 50% molar excess is preferred). A suspension formed. Stir at slightly elevated temperature (40-80° C.) for about 1 hour. Lithium salts are recovered by conventional means.

For example, the acid is prepared by suspending the lithium salt in an organic solvent, such as ethyl acetate, and treating the suspension with an aqueous solution of the mineral acid. The organic solvent was then removed, washed and concentrated. The product is isolated by conventional methods.

The following examples illustrate, but do not limit, specific embodiments of the invention. The inventors reserve the scope as set forth in the appended claims.

Example 1

Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde

At 120-125°C, cyclopentyl chloride (8.48g, 0.08mol), isovanillin (6.12g, 0.04mol) and potassium carbonate (1.1g, 0.08mol) in dimethylformamide (4.04g) The mixture in was stirred in a reactor (100ml) for 1.5 hours. Samples were taken to identify bulk transformations. Results (GC): 0.5 area% isovanillin (target: < 1.0 area%). The mixture was cooled to 20°C and filtered to remove solids (potassium bicarbonate, potassium chloride). The wet cake was washed with methanol.

Example 2

Preparation of 3-cyclopentyloxy-4-methoxybenzyl alcohol

The dimethylformamide mother liquor and the methanol washing solution obtained in Example 1 were combined and transferred to a clean reactor. Additional methanol (8.52 g) was added and the batch was cooled to 0°C. With the temperature maintained at 4-9°C, sodium borohydride (0.49 g, 0.0129 mol) was added in small portions over 1 hour and 10 minutes. The reaction was stirred at 7.2-10°C for 30 minutes, then heated to 25°C. After stirring at 25-31°C for 110 minutes, a sample was taken and analyzed (GC) and the reaction was considered complete. Acetic acid 50% (1.80 g) was added to the reactor to consume the remaining sodium borohydride. The temperature was maintained at 24-25°C during operation. Dimethylformamide and methanol were distilled off in vacuo (distillation end point: 58° C., 6 mbar). After cooling to 20-25°C, the mixture was partitioned between water (3.13g) and toluene (28.07g). 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%; 9.80 g) was added while maintaining the temperature at 20-22.7°C. A sample was taken and analyzed (GC) 40 minutes after the addition was complete and the reaction was considered complete. The phases were separated and the lower aqueous phase was discarded. Sodium bicarbonate (1.20 g) was added to the reactor to neutralize remaining hydrochloric acid. After stirring for 15 minutes, the mixture was cooled to 23°C and the solids (sodium bicarbonate, sodium chloride) were removed by filtration. Part of the toluene (17.07 g) was removed by vacuum distillation (distillation end point: 28° C., 7 mbar).

Example 4

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

The solution obtained in Example 3 was cooled to below 25°C, tetrabutylammonium bromide (0.205g, 0.63mol), demineralized water (2.775g) and sodium cyanide (1.976g, 0.039mol) were added, and the The mixture was heated to 80°C and then stirred at 78.1-80.4°C for 1 hour and 50 minutes. Samples were taken to confirm conversion of reactants.

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 discarded. The toluene phase (containing product) was washed with demineralized water (13.32 g). Toluene was removed by vacuum distillation (distillation end point: 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 of 85.4% purity; 7.73 g of 100% purity; 0.0334 mol) was added to the reactor (0.5 L) at room temperature. Acetonitrile (28.56 g) and demineralized water (0.07 g) were added to the reactor. Solutions of methyl acrylate (6.88 g, 0.029 mol) in acetonitrile (4.02 g) and methanolic Triton B (40.2%, 50.94 g, 2.269 mol Triton B) in acetonitrile (4.06 g) were prepared. At 20°C, a first batch of about 16.6% methyl acrylate solution (1.81 g) was added. Then a first batch of about 12.5% Triton B solution (0.63 kg) was added. The temperature after the addition was 31°C. At 28°C, a second batch of about 16.6% methyl acrylate solution (1.82 g) was added. A second batch of about 12.5% Triton B solution (0.63 g) was then added. The temperature of the reactant after the addition was 36°C. At 35°C, a third batch of about 16.6% methyl acrylate solution (1.81 g) was added. A third batch of approximately 12.5% Triton B solution (0.62 g) was then added. The temperature of the reactant after the addition was 32°C. At 32°C, a fourth batch of about 16.6% methyl acrylate solution (1.81 g) was added. Then about 12.5% Triton B solution (0.63 g) was added. The temperature of the reactant after the addition was 36°C. At 34°C, a fifth batch of about 33.2% methyl acrylate solution (3.64 g) was added. A fifth batch of approximately 25% Triton B solution (1.25 g) was then added. The temperature of the reactant after the addition was 38°C. A final batch of approximately 25% Triton B solution (1.25 g) was then added. The temperature of the reactant after the addition was 36°C. The reaction mixture was stirred at 20-25°C for 1.5 hours. The acetonitrile was removed by vacuum distillation (distillation end point: 59° C., 20 mbar). The mixture was then partitioned between cyclohexane/toluene (1145.9/254.6 g) and water (559.8 g). The cyclohexane/toluene phase (containing product) was washed with demineralized water (559.8 g) at 50-52°C. To crystallize the title product, the product solution was cooled to 0°C over 50 minutes. Then pimelate seed crystals were seeded and aged at -1-1°C for 1 hour. The pimelate was filtered off, washed with cyclohexane/toluene (6.51 g/1.44 g) and recovered by conventional means.

Example 6

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

Pimelate (76.52 g, 1.8112 mol) prepared in Example 5 was added to the reactor (100 ml). Dioxane (2214 g) and 29.1% sodium methoxide in methanol (0.44 g, 24 mmol) were added. The mixture was heated to reflux (77°C) and stirred at this temperature for 1 hour. Samples were taken to confirm conversion of reactants. Methanol (16.82 g distillate) was distilled off to a reactor bottom temperature of 97°C. Fresh dioxane (121.6 g) was added to replace dioxane lost during distillation. Sodium bicarbonate (22.2 g, 26. mmol) and demineralized water (2.47 g) were added. The mixture was heated to reflux (87°C) and stirred at about 87°C for 10 hours. Samples were taken to confirm conversion of reactants. The reaction was cooled to 78°C. Dioxane (0.13g) and demineralized water (0.12g) were added to bring the reaction to level. After cooling to below 60°C, concentrated hydrochloric acid (37%, 0.265 g) was added to adjust the pH to 7.5. Dioxane, methanol and part of the water (27.73 g distillate) were removed by vacuum distillation (distillation end point: 66° C., 305 mbar).

Cyclohexane (180.0 g) and toluene (65.5 g) were added to the reactor with stirring. The reaction was heated to 70°C and the phases were separated at 70°C or slightly lower, and the aqueous phase was discarded. At about 70° C., the organic phase containing the title ketone was washed with two portions of demineralized water (169.4 g in total). Cyclohexane (165.0 g) was added to the reactor to bring the reaction to level. To crystallize the product, the reaction was cooled to 10°C over 1 hour. It was then aged at 9-11°C for 6 hours to complete the crystallization. The product was filtered and washed with cyclohexane/toluene (81.5g/27.2g).

Example 7

cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-oxaspiro[2.5]octane- Preparation of 2,6-dinitrile

The 500ml garden bottom flask that the upper end is equipped with stirrer, inner thermometer is passed into nitrogen cleaning. A 50% aqueous potassium hydroxide solution (22.0 g) and tetrahydrofuran (55.0 ml) were added to the flask. With stirring at room temperature, benzyltriethylammonium chloride (0.81 g, 35 mmol, 0.05 equiv) was added. The solution was cooled to 0 °C. At room temperature, add tetrahydrofuran (55.0ml), 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-one (23.0 g, 73 mmol, 1.0 equiv) and chloroacetonitrile (5.9 g, 78 mmol, 1.07 equiv). The contents of the flask were stirred at 0°C and the solution in the isobaric addition funnel was added over 15 minutes. The reaction temperature was maintained at 0-5°C and stirred for 1 hour. The reaction was warmed to 25°C and diluted with water (90.0ml) and ethyl acetate (90.0ml). The solution was stirred and allowed to stand for 30 minutes. The layers were separated and the organic layer was separated and concentrated in vacuo to give a residue. Methylcyclohexane/THF (5:1) (54.0 ml) was added and the solution was heated to 60°C and then recooled to 20°C over 90 minutes; at about 40°C the product started to crystallize. The suspension was then cooled to 0°C and kept at 0-5°C for 2 hours. At 0°C, the product was filtered and washed with methanol mixture (46.0 ml). The product was dried to give the title product as a white crystalline solid.

Example 8

cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-

Preparation of lithium γ-1-cyclohexanecarboxylate, 2

Add dimethylformamide (200ml), acetonitrile (200ml), lithium bromide (32.4g.0.37 mol) and water (5.6 g, 0.31 mol). The suspension was stirred until a solution was obtained, after which cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-oxaspiro[2.5]octane-2,6-di Nitrile, 1 (90.0 g, 0.25 mol). The contents of the flask were heated at 90-95°C for 8-12 hours. The reaction was cooled to 60°C and diluted with dimethylformamide (270ml). Aqueous lithium hydroxide solution (21.65 g, 0.51 mol of lithium hydroxide monohydrate dissolved in 112.5 ml of water) was rapidly added to the amber solution (60°C). The suspension was stirred at 60°C for 1 hour, cooled to 5°C and kept at 5°C for 1 hour. The suspension was filtered, washed with ethyl acetate (100 ml) and air dried to afford 2 in 79.5% calibrated yield.

Example 9

cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-γ-1-cyclohexanecarboxylic acid, 3

preparation of

Add cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-γ-1-ring Lithium hexanecarboxylate, 2 (58.5g, 0.167mol) and ethyl acetate (500ml). The pale suspension was stirred at room temperature, then 3N aqueous hydrochloric acid (70 ml, 0.21 mol) was added. The reaction was stirred for 10 minutes before being transferred to a separatory funnel. The organic phase was separated and washed once with water (100ml). The organic layer was separated and filtered into a clean 1.0 L three necked round bottom flask fitted with a distillation head and a stirrer mounted on top. Ethyl acetate (200ml) was distilled off to concentrate the reaction. The concentrate in the flask was cooled to 60°C, then heptane (275ml) was added. The suspension was cooled to 5°C and kept at 5°C for 2 hours, filtered and washed with cold (5°C) heptane (50ml). The product was dried to constant weight in a vacuum oven to yield 50.0 g (85%) 3 .

Claims (7)

1, the method for preparing formula (I) compound,                

in R ₁ is -(CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moiety is optionally substituted by one or more halogens; r is 0 to 6; R ₄ and R ₅ are independently selected from hydrogen or C _1-2 alkyl; R ₆ is C _3-6 cycloalkyl or C _4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties can be optionally replaced by 1 to 3 methyl groups or one Ethyl substitution; X is YR ₂ , halogen, nitro, NH ₂ or formamide; _X2 is O; Y is O; R ₂ is independently selected from —CH ₃ or —CH ₂ CH ₃ optionally substituted with one 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 ', optionally Cyclopropyl substituted by 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 by one to three fluorines; 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 to three fluorines; 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' and R" are independently selected from hydrogen or -C(O)OX, wherein X is hydrogen or Li; The method includes: a) lithium bromide or magnesium bromide halide is mixed with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b),

In formula II(a) and II(b), R ₁ , R ₃ , X ₂ and X have the same meanings as in formula (I); b) heating the mixture at at least about 60°C for several hours, optionally under an inert atmosphere; c) adding a sufficient amount of LiOH to the mixture to precipitate a compound of formula (I) to form a compound of formula (I) in which X is Li in C(O)OX; d) removing the amide-based solvent and water from the precipitate, and optionally 1) further purifying the Li salt, or 2) Acidifying the Li hydrochloride to obtain the free acid. 2. The method of claim 1, wherein R ₁ in formula (I) is -CH ₂ -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF ₂ H; X is YR ₂ ; Y is Oxygen; _X2 is oxygen; and _R2 is _CF2H or methyl; and _R3 is CN. 3. The method of claim 2, wherein the protic dipolar amide-based solvent is dimethylformamide, dimethylacetamide or N-methylpyrrolidone. 4. The process of claim 3 wherein the halide is lithium bromide and the amide-based solvent is dimethylformamide. 5. The method of claim 4, wherein the water is present in an amount greater than 0.1% by weight of the contents of the reaction vessel. 6. The method of claim 5, wherein the compound of formula II(a) or II(b) is cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-1-oxa Spiro[2.5]octane-2,6-dicarbonitrile. 7. A compound which is lithium cis-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-γ-1-cyclohexanecarboxylate.