KR100560038B1 - Method for Preparing Substituted 4-Phenyl-4-cyanocyclohexanoic Acids - Google Patents

Abstract

The present invention is directed to treating a compound of formula (II) with a metal halide of group I (a) or group II (a), an aprotic dipolar amide-based solvent and water, wherein at least one R 'or R " It relates to a process for preparing compound (I).

<Formula I>

<Formula II>

Substituted 4-phenyl-4-cyanocyclohexanoic acid, metal halides of Group I (a) or II (a), aprotic dipolar amide-based solvents.

Description

Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acid {Method for Preparing Substituted 4-Phenyl-4-cyanocyclohexanoic Acids}

The present invention relates to intermediates and synthetic routes for preparing 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexanoic acid and its analogs. The acid and its homologues selectively inhibit the catalytic position in the phosphodiesterase isoenzyme named IV (hereinafter PDE IV), and such acid can be moderated by acting on the PDE IV enzyme and its subtypes. It is useful for treating diseases.

Bronchial asthma is a complex, multifactorial disease that is characterized by reversible narrowing of the airways and hypersensitivity of the circulatory system to external stimuli.

Identification of new therapeutic agents for asthma is difficult due to the fact that several mediators are involved in the development of the disease. Thus, eliminating the effects of a single mediator does not have a substantial effect on all major elements of chronic asthma. An alternative to the “media approach” is to limit the activity of cells involved in the pathogenesis of the disease.

One such method is to increase the level of cAMP (adenosine cyclic 3 ', 5'-monophosphate). Cyclic AMPs are second messengers that mediate biological responses to a wide range of hormones, neurotransmitters and drugs (Krebs' Endocrinology Proceedings of the 4th International Congress Excerpta Medica 17-29). When a suitable agonist binds to a receptor on a particular cell surface, adenylate cyclase is activated, which converts Mg ⁺² -ATP to cAMP at an accelerated rate.

Cyclic AMPs regulate the activity of most (but not all) cells involved in the physiology of foreign (allergic) asthma. Thus, an increase in cAMP may be associated with: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) inhibition of neutrophil degranulation, 4) inhibition of basophil degranulation, 5) inhibition of monocyte and macrophage activity Including beneficial effects will be obtained. Thus, compounds that activate adenylate cyclase or inhibit phosphodiesterase are effective in inhibiting inappropriate activity of airway smooth muscle and various inflammatory cells. The major cellular mechanism for inactivation of cAMP is the hydrolysis of 3'-phosphodiester bonds by one or more isoenzymes, referred to as cyclic nucleotide phosphodiesterases (PDEs).

Currently, PDE IV, a unique cyclic nucleotide phosphodiesterase (PDE) isozyme, has been shown to be responsible for the destruction of cAMP in airway smooth muscle and inflammatory cells (Torphy's Phhophodiesterase Isozymes: Potential Targets). for Novel Anti-asthmatic Agents], New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989). The study shows that inhibition of the enzyme inhibits degranulation of mast cells, basophils and neutrophils by inhibiting the activity of monocytes and neutrophils as well as airway smooth muscle relaxation. In addition, the beneficial effect of PDE IV inhibitors is markedly increased when the adenylate cyclase activity of the target cell is increased by a suitable hormone or autocoid, as in vivo. Thus, when the levels of prostaglandin E ₂ and prosaticycline (activators of adenylate cyclase) increase, PDE IV inhibitors are effective for asthmatic lungs. Such compounds provide a unique approach to pharmacotherapy of bronchial asthma and have significant therapeutic advantages over currently available agents.

The methods and intermediates of the invention make certain 4-substituted-4- (3,4-disubstituted phenyl) cyclohexanoic acid useful for treating asthma and other diseases that can be alleviated by PDE IV enzymes and subtypes thereof. It provides a means to. Particularly important end products are described in detail in US Pat. No. 5,552,483, issued September 3, 1996. The information and description set forth in this patent specification is incorporated herein by reference in its entirety, as long as such information and description are required for the understanding of the invention and its performance.

Summary of the Invention

The present invention

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

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

c) adding a strong base to the formulation to precipitate a compound of formula (I)

d) amide-based solvents and water are removed from the precipitate, optionally

1) further purifying the precipitate,

2) acidifying the precipitate to obtain a free acid

It relates to a process for the preparation of a compound of formula (I) comprising:

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 moiety is 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, halosubstituted aryl, aryloxyC _1-3 alkyl, halosubstituted aryloxyC _1-3 alkyl, indanyl, indenyl, C _7-11 polycycloalkyl , Tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C _3-6 cycloalkyl, or one or two unsaturated bonds Containing C _4-6 cycloalkyl, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by one to three methyl groups or one ethyl group,

only,

a) when R ₆ is hydroxyl, m is 2, or

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

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

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

e) when n is 1 and m is 0, 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 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 one or more halogens,

R ₃ is optionally hydrogen, halogen, C _1-4 alkyl, CH ₂ NHC (O) C (O) NH ₂ , halosubstituted C _1-4 alkyl, —CH = CR _{8 ′} R _{8 ′} , R _{8 ′} Substituted cyclopropyl, 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 fluorine,

R _{8 '} is R ₈ or fluorine,

R ₁₀ is OR ₈ or R ₁₁ ,

R ₁₁ is hydrogen or C _1-4 alkyl optionally substituted by one to three fluorine,

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 hydrogen or —C (O) OX where X is hydrogen or a metal or ammonium cation.

Wherein R ₁ , R ₃ , X ₂ and X are the same as in formula (I).

The method relates to the synthesis of certain 4-substituted-4- (3,4-disubstituted phenyl) cyclohexanoic acids. The invention converts cyanoepoxides to their corresponding homologized acids through the use of intermediates of salts of groups I (a) or II (b).

The compound produced by this method is a PDE IV inhibitor. They are useful for treating many diseases as described in US Pat. No. 5,552,438, issued September 3, 1996.

Preferred compounds which can be prepared by the process are as follows.

Preferred R ₁ substituents for all compounds of the above formulas are OHC _7-11 polycycloalkyl, (3- or 4-cyclopentyl), phenyl, tetrahydrofuran-3-yl, benzyl or 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, or CH ₂ -cyclopropyl, CH ₂ -C _5-6 cycloalkyl, C _4-6 cycloalkyl unsubstituted or substituted with unsubstituted C _1-2 alkyl.

Preferred X groups of formula (I) or (II) are YR ₂ and Y is oxygen. Preferred X ₂ groups of formula (I) are oxygen. Preferred R ₂ groups are C _1-2 alkyl unsubstituted or substituted by one or more halogens. Halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R ₂ groups are alkyl substituted with methyl or fluorine, in particular C _1-2 alkyl, such as —CF ₃ , —CHF ₂ or —CH ₂ CHF ₂ residues. Most preferred are -CHF ₂ and -CH ₃ residues.

Most preferred is that 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 CN.

Lithium salts of these compounds represent subgroups of preferred compounds. In particular, the lithium salt of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylic acid, ie lithium-4-cyano-4- (3-cyclo Pentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate represents a preferred embodiment. More specifically, the compound cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate is most preferred.

Carboxylates are prepared by opening epoxides with metal halides of groups I (a) or II (a) to hydrolyze in the presence of water to obtain acyl nitriles that become acids. The problem with preparing acids from acyl nitriles is that hydrogen cyanide (HCN) is produced when the carboxylate is formed from acyl nitriles. Removing this HCN in a cost-effective way is challenging. A feature of the present invention is a means for removing HCN more efficiently. When the reaction is carried out in an aprotic bipolar amide-based solvent containing water, it is observed that when strong bases are added, cyanide salts are formed and remain in solution, and carboxylate salts are formed simultaneously and precipitate out of solution. It turns out. This allows the precipitate to be collected and the solvent removed, thereby removing most or essentially all of the cyanide salt from the alkanoic acid salt precipitate. This avoids performing additional purification steps such as oxidation of HCN.

Metal halides of Group I (a) or II (a) used in the present invention include alkali and alkaline earth metals, such as lithium, sodium, potassium, rubidium, cesium or francium, and beryllium, magnesium, calcium, strontium, Any halide of barium or radium. Preferred metals are lithium and magnesium. Halides include fluoride, chloride, bromide and iodide. Preferred halides are bromide. Lithium and magnesium halides are preferred. Most preferred are lithium bromide and magnesium bromide. Lithium bromide is particularly preferred.

As for the amide-based solvents, they are exemplified such as dimethylformamide (DMF), dimethylacetamide, N-methyl pyrrolidinone and the like. The second organic solvent can be used in addition to the amide-based solvent. For example, acetonitrile has been used successfully in the reactions illustrated below. Generally water is added to the reaction vessel and they hydrolyze the acyl nitrile in the reaction system to obtain alkanoic acid. Thus, more preferred embodiments of the present invention use an aprotic dipolar solvent miscible with water. DMF, dimethylacetamide and N-methyl pyrrolidinone meet this criterion. Although it is essential to include water in the reaction medium, the amount of water can vary widely. The reaction is carried out even in the presence of a small amount of water. In any case, it is preferred to be present at least 0.1% w / w in the container, calculated on the basis of both liquid and solids present in the container. More preferred amount of water is at least about 1% w / w, most preferably about 1-5% w / w. Although not all possible combinations of water and amide-based solvent systems have been tested, it is known that the reaction proceeds in 20% water (weight / weight). Therefore, it is recognized that higher% water can be used. The optimum ratio of organic solvent to water can be achieved by the skilled person. It is also within the scope of the present invention to use any amount of water with an amide-based solvent.

The reaction may be carried out at any temperature of about 60 ° C. or higher. Since numerous combinations of amide-based solvents and water can be used, it is not practical to set an exact upper limit of temperature that varies based on solvent selection and the proportion of solvent selected.

Metal halides of groups I (a) or II (a) open the epoxide to obtain acyl nitrile. Acyl nitrile is hydrolyzed to an acid in the presence of water. However, rather than being isolated as free acid, at least about 2 equivalents of strong bases are added to the reaction vessel to form insoluble salts of carboxylates. This base forms two salts: salts of cyclohexanoic acid and salts of HCN released during hydrolysis of the acyl nitrile groups. Metal cyanide is found to be dissolved in the solvent and salts of alkanoic acid precipitate out of solution. This makes it possible to separate the salt of alkanoic acid from the cyanide salt by simply removing the solvent. The present invention can be carried out using up to 2 equivalents of base, but this can lead to the loss of alkanoic acid because it does not precipitate out of solution, which is not economically desirable. In addition, unreacted HCN can contaminate the alkanoic acid precipitated from solution. Therefore, it is preferable to use 2 equivalents or more of bases.

Strong bases for the purposes of the present invention are any base which forms salts with cyanide ions. Any strong base sufficient to form such salts may be used. The formation of cyanide salts is more important for both criteria for determination if a particular base is useful for this step. Inorganic hydroxides are preferred. For example, LiOH, NaOH or KOH can be used. It is also possible to use ammonium salts, for example tetra-alkylammonium hydroxide or NH ₄ OH. Lithium hydroxide is preferred because lithium cyanide salts are very soluble in aqueous aprotic dipolar amide-based solvents, and thus more efficient and more complete cyanide ions from the acid when the amide-based solvents are removed. Will be removed. Lithium cyanide is more soluble in DMF than sodium cyanide or potassium cyanide. Thus, it is advantageous to form lithium cations in strong bases in the salt-forming step of the process.

A preferred practice of the present invention is to add the solvent (s) to the reaction vessel, add lithium bromide and then add epoxide. When the reaction is basically terminated, two equivalents or more of an aqueous lithium hydroxide solution is added, the cyclohexanoic acid salt is precipitated from the solution, filtered off and the solvent is discarded. The lithium salt of cyclohexanoic acid can be further purified if necessary to remove contaminants, such as cyanide salts, or converted to acids by dissolving or suspending the salt in a solvent and acidifying the material to give the free acid.

Representative reactions of the process are shown in Schemes I and II. This schematic representation illustrates the general methodology used in the present invention using specific embodiments.

Scheme II illustrates a second very similar set of conditions that can be used in the present invention. This scheme follows the same route as outlined in Scheme I, with some conditions changing at certain stages.

The chemistry exemplified in Scheme I is assigned the application number USSN 60/061613 (filed Feb. 12, 1997) and is also PCT filed PCT / US98 / 02749 with the United States Designation and published as WO98 / 34584. It is described in detail in pending US applications. This application is incorporated herein in particular by reference to the chemistry which demonstrates steps 1-7.

The chemistry of Scheme II is described in detail in PCT Application No. PCT / EP98 / 05504, filed Aug. 26, 1998 and designating the United States as the country of choice. The entirety of this application is incorporated herein by reference. In addition to such a detailed description, a second end of chemical action is shown below.

The general description of the chemical reactions in Schemes I and II is as follows.

The mixture of cyclopentyl chloride, isovanillin and potassium carbonate in dimethylformamide was stirred at about 125 ° C. (approximately 2 hours) until the formation of the cyclopentyloxy product was considered complete. The mixture is cooled to 20-25 ° C. and centrifuged to remove solids (potassium chloride and potassium bicarbonate) and washed with methanol before discarding. The dimethylformamide solution and the methanol wash are combined and used in the next step.

The solution of cyclopentyloxy compound in dimethylformamide and methanol is cooled to about 0 ° C. and treated with sodium borohydride (approximately 1.5 hours). Keep the temperature below 5 ° C. The mixture is stirred at 0-10 ° C. for 30 minutes and then at 25-30 ° C. until the reduction reaction is considered complete (approximately 1 hour). Excess borohydride is decomposed by adding 50% acetic acid, and dimethylformamide and methanol are distilled off in vacuo. After cooling to 20-25 ° C., the mixture is partitioned between water and toluene. The toluene phase containing alcohol is washed with demineralized water and passed through a filter for use in the next step.

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

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

After cooling to below 60 ° C., the mixture is partitioned between water and toluene. The toluene phase containing the cyano compound is washed with demineralized water at 30 to 25 ° C., distilled to minimum volume in vacuo, and acetonitrile is added. The product solution in acetonitrile is used directly in the next step.

A solution of methyl acrylate and Triton B and acetonitrile in acetonitrile is prepared. About 16.6% of methyl acrylate solution is added to the cyano compound solution below 25 ° C. About 12.5% of Triton B solution is added and the mixture is stirred for a few minutes and then cooled back to below 25 ° C. After this addition process is repeated three or more times, finally, 33% methyl acrylate solution and finally 50% Triton B solution are added in two portions. The reaction mixture is stirred at 20-25 ° C. until the reaction is considered complete (approximately 2-3 hours). Acetonitrile is removed by vacuum distillation to the minimum volume. The mixture was partitioned between cyclohexane / toluene and water at 50 ° C. The cyclohexane / toluene phase containing pimelate is aged at about 0 ° C. for 1 hour.

The product is isolated by centrifugation and washed with cold (less than 0 ° C.) cyclohexane / toluene. The wet cake is vacuum dried at up to 50 ° C. to give the pimelate as an off-white or beige powder.

A 29% methanol solution of sodium methoxide is added to the pimelate solution in dioxane all at once. The mixture is heated to about 75 ° C. (reflux) and maintained at this temperature until the formation of 2-carbomethoxycyclohexan-1-one is considered complete (approximately 1 hour). Large amounts of methanol are distilled off and replaced with dioxane. Sodium bicarbonate and demineralized water are added to the mixture and heated to reflux (about 85-88 ° C.) and maintained at this temperature until the formation of cyclohexan-1-one is considered complete (approximately 10 hours).

The mixture is cooled to below 60 ° C. and concentrated hydrochloric acid solution is added to reduce the pH to 7.5-10 below.

Large amounts of dioxane and methanol are removed by distillation in vacuo. The mixture is 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 product solution is cooled to 10 ° C. and aged at 9-11 ° C. for about 1 hour. The product is isolated by filtration and washed with cold (10 ° C.) cyclohexane / toluene. The wet cake was dried in vacuo at up to 50 ° C. to obtain a ketone as off-white powder.

The ketone is treated with chloroacetonitrile in the presence of an inorganic base and a catalytic amount of benzyltriethylammonium chloride (BTEAC) to produce dicarbonitrile from the ketone. A mixture of strong base (aqueous potassium hydroxide) and water miscible with BTEAC and tetrahydrofuran was charged with ketone and a slight excess of chloroacetonitrile in a suitable solvent such as THF around reduced temperature. The reaction is maintained at this temperature, usually for a reaction time of about 1 hour. The product is isolated and used as crude oil.

Dicarbonitriles are converted to cyclohexanecarboxylic acids using metal halides of groups I (a) or II (a). This reaction is carried out by filling the container with a solvent, in this case for example DMF, acetonitrile and water, and a metal halide of group I (a) or II (a), for example LiBr (preferably about 1.5 equivalents) And washing the vessel with an inert gas, adding dicarbonitrile A or B, or a mixture of A and B, and heating the vessel to heat the contents at about 100 ° C. for several hours, for example eight hours. The reaction is diluted with DMF and optionally water. LiOH dissolved in water is added (a molar excess of about 50% is preferred). A suspension is formed. It is stirred for about 1 hour at a slightly elevated temperature (40 to 80 ° C). The lithium salt is recovered by conventional methods.

For example, the lithium salt is suspended in an organic solvent such as ethyl acetate and the suspension is treated with an aqueous inorganic acid to prepare an acid. The organic solvent is then recovered, washed and concentrated. The product is isolated in a conventional manner.

The following examples illustrate certain embodiments of the present invention and do not limit it. What is reserved to the inventor is indicated in the claims appended hereto.

<Example 1>

Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde

A mixture of cyclopentyl chloride (8.48 g, 0.08 mol), isovaniline (6.12 g, 0.04 mol) and potassium carbonate (1.1 g, 0.08 mol) in dimethylformamide (4.04 g) was added to the reactor (100 mL) 120 to 125 Stir for 1.5 hours at a temperature of ℃. Samples were taken to confirm batch conversion. Results (GC): 0.5 area% isovanillin (target: 1.0 area% or less). 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 liquid and the methanol washing liquid of Example 1 were combined and sent back to the washed reactor. 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 over 1 hour and held at a temperature of 4-9 ° C. for 10 minutes. The batch was stirred at 7.2-10 ° C. for 30 minutes and then heated to 25 ° C. Samples were stirred at 25-31 ° C. for 110 minutes, then taken and analyzed to regard the (GC) reaction as complete. 50% (1.80 g) of acetic acid was charged to the reactor and any remaining sodium borohydride was removed. A batch temperature of 24-25 ° C. was maintained during the filling process. Dimethylformamide and 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 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%, 9.80 g) was added to maintain the temperature at 20 to 22.7 ° C. Samples were taken 40 minutes after the addition was complete and analyzed to consider the (GC) reaction terminated. The phases were separated and the lower aqueous phase was discarded. Sodium bicarbonate (1.20 g) was charged to the reactor to neutralize remaining hydrochloric acid. After stirring for 15 minutes, the mixture was cooled to 23 ° C. and filtered to remove solids (sodium bicarbonate, sodium chloride). A portion of toluene (17.07 g) was removed by distillation in vacuo (end of distillation: 28 ° C., 7 mbar).

<Example 4>

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

After cooling the solution of Example 3 to below 25 ° C., tetra-butylammonium bromide (0.205 g, 0.63 mol), demineralized water (2.775 g) and sodium cyanide (1.976 g, 0.039 mol) were added and the mixture was added. After heating to 80 ° C., the mixture was stirred at 78.1 to 80.4 ° C. for 1 hour 50 minutes. Samples were taken to confirm batch conversion.

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

<Example 5>

Preparation 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 mol) was charged to a reactor (0.5 L) at room temperature. Acetonitrile (28.56 g) and demineralized water (0.07 g) were charged to the reactor. A solution of methyl acrylate (6.88 g, 0.029 mol) in acetonitrile (4.02 g) and methanolic triton B (40.2%, 0.94 g, 2.269 mmol of Triton B) in acetonitrile (4.06 g) were prepared. A first portion, about 16.6% of methyl acrylate solution (1.81 g) was added at 20 ° C. Then, a first portion, about 12.5% of Triton B solution (0.63 kg) was added. The batch temperature after addition was 31 ° C. A second portion, about 16.6% of methyl acrylate solution (1.82 g) was added at 28 ° C. Then, a second portion, about 12.5% of Triton B solution (0.63 g) was added. The batch temperature after addition was 36 ° C. A third portion, about 16.6% of methyl acrylate solution (1.81 g) was added at 35 ° C. Then, a third portion, about 12.5% of Triton B solution (0.62 g) was added. The batch temperature after addition was 32 ° C. A fourth portion, about 16.6% of methyl acrylate solution (1.81 g) was added at 32 ° C. Then, a fourth portion, about 12.5% of Triton B solution (0.63 g) was added. The batch temperature after addition was 36 ° C. A fifth portion, about 33.2% of methyl acrylate solution (3.64 g) was added at 34 ° C. Then, a fifth portion, about 25% of Triton B solution (1.25 g) was added. The batch temperature after addition was 38 ° C. A final portion, about 25% Triton B solution (1.25 g) was added. The batch temperature after addition was 36 ° C. The reaction mixture was stirred at 20-25 ° C. for 1.5 h. Acetonitrile was removed by distillation in vacuo (end of distillation: 59 ° C., 20 mbar). The mixture was partitioned between cyclohexane / toluene (1145.9 / 254.6 g) and water (559.8 g) at about 50 ° C. The cyclohexane / toluene phase (containing product) was washed with demineralized water (559.8 g) at 50-52 ° C. To crystallize the product, the batch was cooled at 0 ° C. over 50 minutes. The batch was then seeded with pimelate and aged at −1 to 1 ° C. for 1 hour. Fimelate was filtered off, washed with cyclohexane / toluene (6.51 g / 1.44 g) and recovered in the usual manner.

<Example 6>

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

The pimelate (76.52 g, 1.8112 mol) prepared in Example 5 was charged to the reactor (100 mL). Dioxane (2214 g) and 29.1% methanolate (0.44 g, 24 mmol) of sodium methoxide were added. The mixture was heated to reflux (77 ° C.) and stirred at this temperature for 1 hour. Samples were taken to confirm batch conversion. Methanol was distilled off to a bottom temperature of 97 ° C. (16.82 g of distillate). The loss of dioxane during this distillation is compensated by adding unreacted dioxane (121.6 g). 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 batch conversion. The contents of the reactor were cooled to 78 ° C. Dioxane (0.13 g) and demineralized water (0.12 g) were added to simulate flush. 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 some water (27.73 g distilled water) were removed by vacuum distillation (end of distillation: 66 ° C., 305 mbar).

While stirring, cyclohexane (180.0 g) and toluene (65.5 g) were charged to the reactor. The mixture was heated to 70 ° C. and the phases separated at 70 ° C. to discard the lower aqueous phase. The organic phase containing the title ketone was washed with two portions of demineralized water (169.4 g total) at about 70 ° C. Cyclohexane (165.0 g) was added to the reactor to simulate the flush. To crystallize the product, the batch was cooled to 10 ° C. over 1 hour. The crystallization was then terminated by aging at 9-11 ° C. for 6 hours. The product batch was filtered and washed with cyclohexane / toluene (81.5 g / 27.2 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 an overhead stirrer, thermometer and nitrogen inlet was washed with nitrogen. The flask was charged with 50% potassium hydroxide in water (22.0 g) and tetrahydrofuran (55.0 mL). Benzyltriethylammonium chloride (0.81 g, 35 mmol, 0.05 equiv) was added while stirring at room temperature. The solution was cooled to 0 ° C. Tetrahydrofuran (55.0 mL), 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (23.0 g, 73 mmol, 1.0 equiv) in a pressure-equalization addition funnel And a solution containing chloroacetonitrile (5.9 g, 78 mmol, 1.07 equiv) at room temperature. The flask contents were stirred at 0 ° C. and the solution in the pressure addition funnel was added over 15 minutes. The temperature was maintained at 0-5 ° C. and stirred for 1 hour. The reaction was warmed to 25 ° C. and diluted with water (90.0 mL) and ethyl acetate (90.0 mL). The solution was stirred and precipitated for 30 minutes. The layers were separated, the organic layer was isolated and concentrated in vacuo by vacuum distillation. Methylcyclohexane / THF (5: 1) (54.0 mL) was added and the solution was heated to 60 ° C., then cooled to 20 ° C. over 90 minutes, and the product started crystallizing at about 40 ° C. The suspension was then cooled to 0 ° C. and held at −0 to 5 ° C. for 2 hours. The product was filtered off and washed with methanol mixture (46.0 mL) at 0 ° C. The product was dried to give the title product as a white crystalline solid.

<Example 8>

Cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate, 2 .

1.0 L, 3-neck round bottom flask equipped with reflux condenser connected to overhead stirrer, thermometer and caustic gas scrubber, dimethylformamide (200 mL), acetonitrile (200 mL), lithium bromide (32.4 g, 0.37 mol) ) And water (5.6 g, 0.31 mol). The suspension is stirred until the solution is clear and then cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl)]-1-oxaspiro [2.5] octane-2,6-dicarbonitrile, 1 (90.0 g, 0.25 mol) was added. The contents of the flask were heated to 90-95 ° C. for 8-12 hours. The reaction was cooled to 60 ° C. and diluted with dimethylformamide (270 mL). To an amber solution (60 ° C.) was quickly added an aqueous lithium hydroxide solution (21.65 g of lithium hydroxide monohydrate dissolved in 112.5 mL of water, 0.51 mol). The suspension was stirred at 60 ° C. for 1 hour, cooled to 5 ° C. and maintained at 5 ° C. for 1 hour. The suspension was filtered, washed with ethyl acetate (100 mL) and air dried to give 2 in 79.5% yield.

Example 9

Cis-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate, 3

Cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarr in a 1.0 L, 3-necked round bottom flask equipped with an overhead stirrer and thermometer Voxylate, 2 (58.5 g, 0.167 mol) and ethyl acetate (500 mL) were added. The bright suspension was stirred at ambient temperature before 3N aqueous HCl (70 mL, 0.21 mol) was added. The reaction was stirred for 10 minutes and transferred to a separating funnel. The organic layer was isolated and washed once with water (100 mL). The organic layer was isolated and filtered into a clean 1.0 L, 3-neck round bottom flask equipped with a distillation head and an overhead stirrer. The reaction was concentrated by distillation with ethyl acetate (200 mL). After the contents of the flask were cooled to 60 ° C., heptane (275 mL) was added. The suspension was cooled to 5 ° C., then held at 5 ° C. for 2 hours, filtered and washed with cold (5 ° C.) heptane (50 mL). The product was dried to constant weight in a vacuum oven to give 50.0 g (85%) of 3 .

Claims (12)

a) combining a metal halide of Group I (a) or II (a) with an aprotic dipolar amide-based solvent and water together with a compound of Formula IIa or IIb, b) in a process comprising heating said blend under an inert atmosphere at a temperature of 90-95 [deg.] C. for 8-12 hours. c) sufficient LiOH is added to the formulation to form a compound of formula (I) wherein X in —C (O) OX is Li; d) amide-based solvents and water are removed from the precipitate, 1) further purification of the Li salt, 2) acidifying the Li salt to obtain a free acid Method for producing a compound of formula (I) comprising a. <Formula I>

Where R ₁ is — (CR ₄ R ₅ ) _r R ₆ , wherein the alkyl moiety is unsubstituted or may be 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 moiety is unsubstituted or substituted by one to three methyl groups or one ethyl group Can be used), X 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 , which is unsubstituted or substituted with one or more halogens, R ₃ is hydrogen, halogen, C _1-4 alkyl, CH ₂ NHC (O) C (O) NH ₂ , halosubstituted C _1-4 alkyl, —CH = CR _{8 ′} R _{8 ′} , unsubstituted or R _{8 "substituted} by _{cyclopropyl, 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 unsubstituted or substituted by one to three fluorine, R _{8 '} is R ₈ or fluorine, R ₁₀ is OR ₈ or R ₁₁ , R ₁₁ is hydrogen or C _1-4 alkyl unsubstituted or substituted by one to three fluorine, 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 hydrogen or —C (O) OX where X is hydrogen or Li.

Wherein R ₁ , R ₃ , X ₂ and X are the same as in formula (I). The method of claim 1, 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; R ₃ is CN Method of Preparation of the Compound. The method of claim 1 wherein the metal halide of Group I (a) or II (a) is lithium or magnesium halide. 4. The method of claim 3 wherein the metal halide of Group I (a) or II (a) is lithium bromide or magnesium bromide. 5. The process of claim 4 wherein the aprotic dipolar amide-based solvent is dimethylformamide, dimethylacetamide or N-methyl pyrrolidinone. The method of claim 2 wherein the metal halide of Group I (a) or II (a) is lithium bromide and the amide-based solvent is dimethylformamide. The method of claim 6 wherein the water is present in an amount of at least 0.1% by weight based on the weight of the contents of the reaction vessel. delete 8. A compound according to claim 7, wherein the compound of formula (IIa) or (IIb) is cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl)]-1-oxaspiro [2.5] octane-2,6-dicarbonitrile How to be. The product according to the method of claim 1, which is cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate. Cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate. delete