MXPA00003405A - Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids - 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

METHOD FOR PREPARING SUBSTITUTE 4-PHENYL-4-CYANOCYCLOHEXANIC ACIDS FIELD OF THE INVENTION The invention relates to intermediates and to a synthetic route for making 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -cyclohexanoic acid and its analogues. This acid and its analogues are selected to inhibit the catalytic site in the isoenzyme phosphodiesterase designated IV (PDE IV hereafter) and as such the acids are useful for treating a number of diseases that can be moderated by affecting the PDE IV enzyme and its subtypes .

BACKGROUND OF THE INVENTION Bronchial asthma is a complex, multifactorial disease characterized by the reversible narrowing of the respiratory tract and hyper-reactivity of the respiratory tract to external stimuli. The identification of novel therapeutic agents for asthma is difficult because multiple mediators are responsible for the development of the disease. In this way, it is unlikely that the elimination of the effects of a single mediator will have a substantial 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 way to do this is to raise the levels of cAMP (3 ', 5'-cyclic adenosine monophosphate). It has been discovered that cyclic AMP is a secondary messenger that mediates biological responses to a wide variety of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg + 2-ATP to cAMP at an accelerated rate. The cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. Thus, an elevation of cAMP will produce beneficial effects that include: 1) relaxation of the smooth muscle of the respiratory tract, 2) inhibition of the release of mediator of barley cell, 3) suppression of degranulation of neutrophils, 4) inhibition of degranulation of basophils , e 5) inhibition of monocyte and macrophage activation. Therefore, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of smooth muscle of the respiratory tract and a wide variety of inflammatory cells. The main cellular mechanism for the inactivation of cAMP is the hydrolysis of the 3'-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs). It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for the breakdown of cAMP in the smooth muscle of the respiratory tract and inflammatory cells. [Torphy, "Phosphod esterase Isozymes: Potential Targets for Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. The research indicates that the inhibition of this enzyme not only produces smooth muscle relaxation of the airways, but also suppresses the degranulation of mast cells, basophils and neutrophils together with the inhibition of activation of monocytes and neutrophils. In addition, the beneficial effects of PDE IV inhibitors are especially potential when the adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Therefore, PDE IV inhibitors will be effective in the asthmatic lung, where the levels of prostaglandin E2 and prostacyclin (adenylate cyclase activators) are high. These compounds offer a unique approach when it comes to pharmacotherapy of bronchial asthma and provide important therapeutic advantages over agents that are currently on the market. The process and intermediates of the invention provide a means to make certain 4-substituted-4- (3, 4-disubstituidophenyl) cyclohexanoics that are useful for treating asthma, and other diseases that can be moderated by affecting the PDE IV enzyme and its subtypes. The final products of particular interest are described fully in the U.S. Patent. No. 5,552,483 issued September 3, 1996. The information and graphic representations described herein, provided that the information and said representations are necessary for the understanding of the invention and its practice, are incorporated in their entirety as reference in the I presented.

BRIEF DESCRIPTION OF THE INVENTION The invention relates to a method for making a compound of formula I where Ri is - (CR4R5) nC (0) 0 (CR4R5) m 6, - (CPv4R5) nC (O) NR4 (CR4R5) mR6, - (CR4R5) nO (CR4R5) mR6, or - (CR R) rR6 wherein the alkyl portions may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C? -2 alkyl; R6 is hydrogen, methyl, hydroxyl, aryl, substituted halogen aryl, aryloxyC1.3alkyl, substituted aryloxyC1 -3 halogen alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl , tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C 3-6 cycloalkyl, or a C-6 cycloalkyl containing one or more unsaturated bonds, wherein the cycloalkyl and heterocyclic portions may be optionally substituted by 1 to 3 methyl groups or an ethyl group; with the proviso that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when Re is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when Re 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 R6 is different from H in -X is YR2, halogen, nitro, NH2, or formylamine; X2 is O or NR8; And it is O or S (O) m; m 'is 0, 1 or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC (O) C (O) NH2, C1-4 alkyl, substituted halogen, -Ch CRβ-R '. cyclopropyl optionally substituted by R8, CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C (Z ') H, C (O) OR8, C (O) NR8R? or, or C = CR8 >; Rβ is hydrogen or C1-4alkyl optionally substituted by one to three fluorines; R8 'is Rs or fluorine; R11 is hydrogen, or C1-4alkyl optionally substituted by one or three fluorines; Z 'is O, NR9, NOR8, NCN, C (-CN) 2, CR8CN, CR8NO2, CR8C (O) OR8, CR8C (O) NR8R8, C (-CN) NO2, C (-CN) C (O) OR9, or C (-CN) C (O) NR8R8; R 'and R "are independently hydrogen or -C (O) OX wherein X is hydrogen or metal or ammonium cation, which method comprises: a) combining a metal halogenide of group l (a) or group ll (a) , with a solvent based on dipolar aprotic amide and water and a compound of formula A or B, B wherein R1, R3, X2 and X are the same as for formula (I); b) heating the combination to a temperature of at least about 60 ° for several hours, optionally under an inert atmosphere; c) precipitating a compound of formula (I) by adding a strong base to said combination; d) removing the amide-based solvent and water from said precipitate, and optionally 1) further purifying the precipitate, or 2) acidifying the precipitate to obtain the free acid.

DETAILED DESCRIPTION OF THE INVENTION This process involves the synthesis of certain 4-substituted-4- (3,4-disubstituted-phenyl) -cyclohexane acids. It makes it possible to convert a cyanoepoxide to its corresponding homologous acid through the use of a salt intermediate of group l (a) or ll (b). The compounds that are made by this method are PDE IV inhibitors. They are useful for the treatment of various diseases as described in the U.S. Patent. DO NOT. 5,552,438 issued September 3, 1996. The preferred compounds that can be made by this process are the following: Preferred Ri substituents for the compounds of all the mentioned formulas are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, C4 cycloalkyl -6 unsubstituted or substituted by OH-polycycloalkyl of C7.11, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, alkyl or C2-2-benzyl substituted or unsubstituted by 1 or more fluorines, - (CH2) 1-3C (O) O (CH2) o-2CH3, - (CH2)? -3O (CH2) 0-2CH3, and - (CH2) 2-4OH. Preferred X groups for formula (I) or (II) are those wherein X is YR2 and Y is oxygen. The preferred group X2 for the formula (I) is that wherein X2 is oxygen. Preferred R2 groups are a C? -2 alquilo alkyl substituted or unsubstituted by one or more halogens. The halogen atoms are preferably fluorine or chlorine, very preferably fluorine. Preferred R2 groups are those in which R2 is methyl, or fluorosubstituted alkyls, specifically a C? -2 alkyl, such as a portion -CF3, -CHF2, or -CH2CHF2. Most preferred are the portions -CHF2 and -CH3. Most preferred are compounds wherein R ^ is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN. The lithium salt of this compound represents a subset of preferred compounds. In particular the lithium salt of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylic acid, ie 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) r-1 - lithium cyclohexanecarboxylate represents a preferred embodiment. Particularly preferred is the compound 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanedicarboxylate of c / s-lithium. The carboxylate is prepared by opening the epoxide with a metal halide group of group l (a) or ll (a) to obtain the acyl nitrile which is hydrolyzed to the acid in the presence of water. A problem in preparing the acid from acyl nitrile is that when the carboxylate is formed from the acyl nitrile, hydrogen cyanide (HCN) is generated. The challenge is to remove this HCN effectively in terms of costs. A feature of the invention is a means to effect a more efficient removal of HCN. It has been found that if the reaction is run in a solvent based on dipolar aprotic amide containing water, when a strong base is added a cyanide salt forms and remains in solution and the carboxylate salt formed at the same time precipitates out of solution. This makes it possible to collect the precipitate and remove the solvent, and by this means remove most or essentially all of the cyanide salt from the alkanoic acid salt precipitate. This avoids having to run an additional purification step, such as oxidizing the HCN. The metal halides of group l (a) or ll (a) used in the invention are any of the halides of the alkali metals and alkaline earth metals, ie, lithium, sodium, potassium, rubidium, cesium or francium; and beryllium, magnesium, calcium, strontium, barium or radium. The preferred metals are lithium and magnesium. Halides include fluorine, chlorine, bromine and iodine. The preferred halide is bromine. Lithium and magnesium halides are preferred. Most preferred are lithium and magnesium bromide. Lithium bromide is particularly preferred. With respect to the amide-based solvents, they are illustrated by the types of dimethylformamide (DMF), and dimethylacetamide and N-methylpyrrolidinone. The DMF is the most preferred. A second organic solvent can be used in addition to the amide based solvent. For example, acetonitrile has been used successfully in the reaction illustrated below. Water is usually added to the reaction vessel as it hydrolyzes the acyl nitrile in situ to give the alkanoic acid. Thus, a further preferred embodiment of the invention is to use an aprotic dipolar solvent that is water-soluble. DMF, dimethylacetamide, and N-methylpyrrolidinone meet this standard. Although it is essential to have water in the reaction medium, the amount of water can vary widely. The reaction is more uniform when there is a smaller amount of water. It is preferable to have at least 0.1% w / w (w / w) in the reaction vessel, calculated based on both liquids and solids, if any, present in the vessel. A more preferred amount of water is at least 1% w / w, and most preferably about 1-5% water w / w. Although not all systems of possible combinations of water and amide-based solvent have been tested, it is known that the reaction will be carried out with 20% water (w / w). Therefore, it is believed that it is even possible to use high percentages of water. The optimization of the organic solvent to water ratios can be achieved by the practicing expert. The use of any amount of water in combination with an amide-based solvent is considered within the scope of the invention. The reaction can run at any temperature above 60 ° C.

Since there are numerous combinations of solvent based on amide and water that can be used, it is not practical to establish an exact maximum limit to the temperature because it can vary depending on the selection of solvent and the ratio of the selected solvents. The metal halogenide of group l (a) or ll (a) opens the epoxide to give an acyl nitrile. It hydrolyzes with the acid in the presence of water. However, instead of isolating the free acid, an insoluble salt of the carboxylate is formed by adding about 2 or more equivalents of a strong base to the reaction vessel. This base forms two salts, a salt of the cyclohexane acid and a salt of HCN that is released in the hydrolysis of the acyl nitrile group. The metal cyanide that is produced is soluble in the solvent and the alkanoic acid salt precipitates out of the solution. This makes it possible to separate the alkanoic acid salt from the cyanide salt by simply removing the solvent. The invention can be practiced using less than 2 equivalents of base, however the foregoing could result in a loss of alkanoic acid because it will not precipitate out of the solution, which is inconvenient from an economic point of view. An unreacted HCN can contaminate the alkanoic acid that was precipitated out of the solution. In this way, the preferred practice is to use two or more equivalents of the base. A strong base for purposes of the invention is any base that will form a salt with the cyanide ion. It is possible to use any base strong enough to form these salts; The formation of the cyanide salt is the most critical of the two criteria to determine if a particular base is useful in 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 hydroxides or NH 4 OH. Lithium hydroxide is preferred because the lithium cyanide salt is highly soluble in the solvent based on aqueous dipolar aprotic amide, and therefore effects more efficient and more complete removal of the cyanide ion from the salt of acid when the amide-based solvent is removed. Lithium cyanide is more soluble in DMF than sodium cyanide or potassium cyanide. Therefore, it is more advantageous to produce the lithium cation in the strong base in the process salt step. A preferred practice of the invention is one in which the solvent (s) are charged to the reaction vessel, lithium bromide and then epoxide are added. Once the reaction has been completed, two or more equivalents of an aqueous solution of lithium hydroxide are added, the cyclohexanoic acid salt is precipitated out of the solution and filtered, and the solvent is discarded. The lithium salt of the cyclohexane acid can be further purified if it is necessary to remove the residual contaminants such as cyanide salts, or convert to the acid by dissolving or suspending the salt in a solvent and acidifying said material to obtain the free acid. A representative scheme of the procedure is established in schemes I and II. These graphic representations use specific examples to illustrate the general methodology used in the invention.

Scheme I Isovanillin H "2) Crystallize from Methyl Clclohexane xylenos (optional) Step 9 1) LIBr / H20 DMF / CH 3 CN 2) LiOH aq. 3) Wash crystals with EtOAc Scheme II illustrates a second set of very similar conditions that can be used in the invention. This scheme follows the same route as that shown in scheme I; some of the conditions are changed in certain steps.

Scheme II Isovanillin Step 7 1) NaOMe, Na HC03 Dioxane 2) HCl Conc. 3) Cyclohexapo / toluene 4) Recrystallize from xylene (optional) e no The chemicals illustrated in Scheme I are set forth in a co-pending application by E.U.A. which has been assigned USSN 60/061613 (filed February 12, 1997) and also filed as PCT application serial number PCT / US98 / 02749 designated among others to E.U.A.; it has been published as WO98 / 34584. Said application is incorporated herein by reference, particularly as regards the chemical substances mentioned in steps 1-7. The chemical substances in Scheme II are set forth in the PCT application number PCT / EP98 / 05504 filed on August 26, 1998, which, among others, designates E.U.A. as a selected state. The full description of said application is incorporated herein by reference. In addition the details of the second set of chemical substances are given below. A general description of the chemical substances in Schemes I and II is as follows: A mixture of cyclopentyl chloride, sovaylin and potassium carbonate in dimethylformamide is stirred at about 125 ° C until the formation of the product of Cyclopentyloxy is complete (approximately 2 hours). The mixture is cooled to 20-25 ° C, the solid (potassium chloride and potassium bicarbonate) is removed by centrifugation and washed with methanol before discarding. The solution of dimethylformamide and methanol wash solution are combined for use in the next step. The 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. After the mixture is stirred at 0 to 10 ° C for 30 minutes and at 25-30 ° C until it is considered that the reduction reaction has been completed (approximately one hour). 50% acetic acid is added to destroy the excess borohydride and the dimethylformamide and methanol are removed by vacuum distillation. After cooling to 20-25 ° C the mixture is divided between water and toluene. The toluene phase, which contains the alcohol, is washed with demineralized water, which passes through a filter for use in the next stage. The alcohol solution in toluene is treated with concentrated hydrochloric acid (min 36%) at 15 to 25 ° C. The organic phase, which contains the chlorine compound, is separated and treated with sodium bicarbonate to neutralize the HCl residues. The solid (sodium chloride, sodium bicarbonate) is removed by filtration. The solution of the chloro compound is concentrated by distillation in vacuo. After cooling to about 20 ° C, demineralized water, tetrabutylammonium bromide and sodium cyanide are added. After this the mixture is heated to 80 ° C and stirred at this temperature until it is considered that the cyanidation reaction has been completed (approximately 2 hours). After cooling to < 60 ° C the mixture is divided between water and toluene. The toluene phase, which contains the cyano compound, is washed at 30 to 25 ° C with demineralized water, distilled in vacuo to a minimum volume and to this is added acetonitrile. The product solution in acetonitrile is used directly in the next step.

The solutions of methyl acrylate in acetonitrile and Triton B and acetonitrile are prepared. About 16.6% of the methyl acrylate solution is added to the solution of cyano compound at < 25 ° C. About 12.5% of the Triton B solution is added, the mixture is stirred for a few minutes and then cooled back to < 25 ° C. This addition sequence is repeated three times, then the final 33% of the methyl acrylate solution and the final 50% of the Triton B solution are added in two portions. The reaction mixture is stirred at 20 to 25 ° C until the reaction is considered complete (approximately 2-3 hours). The acetonitrile is removed by vacuum distillation at minimum volume. The mixture is divided between cyclohexane / toluene and water at 50 ° C. The cyclohexane / toluene phases, which contain the pimelate, are aged for about 1 hour at about 0 ° C. The product is isolated by centrifugation and washed with cold cyclohexane / toluene (<0 ° C). The wet cake is dried under vacuum at a maximum of 50 ° C to give the pimelate as a white to beige powder. A 29% methanolic solution of sodium methoxide is added in a batch to a solution of the pimelate in dioxane. The mixture is heated to about 75 ° C (reflux) and maintained until temperature until the formation of 2-carbomethoxy-hexoan-1-one is concluded (about 1 hour). Most of the methanol is distilled and replaced with dioxane. Sodium bicarbonate and demineralized water are added to the mixture and heated to reflux (approximately 85 to 88 ° C) and maintained at this temperature until the formation of cyclohexan-1-one is considered complete (approximately 10 hours) ). Then, the mixture is cooled to < 60 ° C and concentrated hydrochloric acid solution is added to reduce the pH from > 10 to 7.5. Most of the dioxane and methanol is removed by distillation in vacuo. After this the mixture is divided between cyclohexane / toluene and water at about 70 ° C. The organic phase, which contains the ketone, is washed twice with demineralized water at about 70 ° C. The product solution is cooled to 10 ° C and aged for about 1 hour at 9 to 11 ° C. The product is isolated by filtration and washed with cold cyclohexane / toluene (10 ° C). The wet cake is dried under vacuum at a maximum of 50 ° C to give the ketone as a white powder. The 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 charged to a mixture of strong base (aqueous potassium hydroxide) and BTEAC and a water-soluble solvent such as tetrahydrofuran at reduced temperature, at about 0 ° C. The reaction is maintained at about said temperature for the duration of the reaction, usually 1 hour. The product can be isolated or used as a crude oil. The dicarbonitrile is converted to the cyclohexanecarboxylic acid using a metal halogenide of group l (a) or ll (a). This reaction is carried out by charging a container with solvents; in this regard exemplified by DMF, acetonitrile and water, and the metal halide of group l (a) or ll (a) (preferably about 1.5 equivalents), LiBr is illustrated; purify the vessel with an inert gas; add dicarbonitrile A or B, or a mixture of A and B; and heating the container and its contents to around 100 ° C for a number of hours, for example 8 hours. The reaction is diluted with DMF and optionally water. LiOH dissolved in water is added (about 50% molar excess is preferred). A suspension is formed. This is stirred at a slightly elevated temperature (40 to 80 ° C) for one hour or more. The lithium salt is recovered by conventional means. The acid is prepared, for example, by suspending the lithium salt in an organic solvent of ethyl acetate type, and the suspension is treated with aqueous mineral acid. The organic solvent is recovered, washed and concentrated. The product is isolated by conventional means. The following examples are provided to illustrate specific embodiments of the invention, not to limit them. What is reserved for the inventors is set forth in the claims appended hereto.

SPECIFIC EXAMPLES EXAMPLE 1 Preparation of 3-cyclopentyloxy-4-methoxybenzaldehyde A mixture of cyclopentyl chloride (8.48 g, 0.08 mol), isovainillin (6.12 g, 0.04 mol) and potassium carbonate (1.1 g, 0.08 mol) in dimethylformamide (4.04 g) was stirred in the reactor (100 mL) of 120 at 125 ° C for 1.5 hours. A sample was taken to verify the container conversion. Result (GC): area of 0.5% isovainillin (objective: <1.0 area%). 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 solution of dimethylformamide and methanol wash solution of Example 1 were combined and transferred back to the clean reactor. An additional amount of methanol (8.52 g) was added and the vessel was cooled to 0 ° C. Sodium borohydride (0.49 g, 0.0129 mol) was added in small portions for 1 hour and 10 minutes maintaining the temperature between 4 and 9 ° C. The vessel was stirred at 7.2 to 10 ° C for 30 minutes and then heated to 25 ° C. A sample was taken and analyzed (GC) after 110 minutes with stirring at 25 to 31 ° C until the reaction is considered complete. 50% acetic acid (1.80 g) was charged to the reactor to mitigate any remaining sodium borohydride. The container temperature of 24 to 25 ° C was maintained during this charge. 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 captured compound) was washed with demineralized water (2.65 g).

EXAMPLE 3 Preparation of 4-chloromethyl-2-cyclopentyl! Oxy-1-methoxybenzene The toluene solution of Example 2 was cooled to 20 ° C and concentrated, hydrochloric acid (37.5%, 9.80 g) was added maintaining the temperature between 20 and 22.7 ° C. a sample was taken 40 minutes after the addition was completed and analyzed (GC) until the reaction is considered complete. The phases were allowed to separate and the minor aqueous phase was discarded. Sodium bicarbonate (1.20 g) was charged 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 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 < 25 ° C was added tetra-butylammonium bromide (0.205 g, 0.63 mmol), demineralized water (2.775 g) and sodium cyanide (1.976 g, 0.039 mol), the mixture was heated to 80 ° C and then stirred from 78.1 a 80.4 ° C for 1 hour and 50 minutes. A sample was taken to verify the container conversion. Toluene (5.841 g) and demineralized water (8.76 g) were added, the phases were allowed to separate (at about 54 ° C) and the minor aqueous phase was discarded. The toluene phase (containing the product) was washed with demineralized water (13.32 g). The 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-phen-p-pimelate) The cyanomethyl compound prepared in Example 4 (9.05 g to 85.4%, 7.73 g to 100%, 0.0334 mol) was charged to the reactor (0.5 L) at room temperature. Acetonitrile (28.56 g) and demineralised water (0.07 g) were charged to the reactor. The methyl acrylate solutions (6.88 g, 0.029 mole) in acetonitrile (4.02 g) and methanolic Triton B (40.2% 0.94 g, 2,269 mM Triton B) in acetonitrile (4.06 g) were prepared. A first portion, about 16.6% of the methyl acrylate solution (1.81 g) was added at 20 ° C. Then a first portion was added, about 12.5% of the Triton B solution (0.63 kg). The temperature of the vessel after the addition was 31 ° C. A second portion was added, about 16.6% of the methyl acrylate solution (1.82 g) at 28 ° C. Then a second portion was added about 12.5% of the Triton B solution (0.63 g). The temperature of the vessel after the addition was 36 ° C. A third portion, about 16.6% of the methyl acrylate solution (1.81 g) was added at 35 ° C. Then a third portion was added, about 12.5% of the Triton B solution (0.62 g). The temperature of the vessel after the addition was 32 ° C. A fourth portion, about 16.6% of the methyl acrylate solution (1.81 g) was added at 32 ° C. Then a fourth portion was added, about 12.5% of the Triton B solution (0.63 g). The temperature of the vessel after the addition was 36 ° C. A fifth portion, about 33.2% of the methyl acrylate solution (3.64 g) was added at 34 ° C. Then a fifth portion was added, about 25% of the Triton B solution (1.25 g). The temperature of the container after the addition was 38 ° C. Finally the last portion was added, around 25 ° C of the solution of Triton B (1.25 g). The temperature of the vessel after the addition was 36 ° C. The reaction mixture was stirred for 1.5 hours at 20-25 ° C. The acetonitrile was removed by vacuum distillation (end of distillation: 59 ° C, 20 mbar). The mixture was divided at about 50 ° C between cyclohexane / toluene (1 145.9 / 254.6 g) and water (559.8 g). The cyclohexane / toluene phase (containing the product) was washed with demineralized water (559.8 g) from 50 to 52 ° C. To crystallize the captured product, the vessel was cooled for 50 minutes at 0 ° C. The vessel was then seeded with pimelate 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 recovered by conventional means.

EXAMPLE 6 Preparation of 4-cyano-4- (3-cyclopentyloxy-4-methoxifemT) cyclohexane-1 -one The pimelate prepared in Example 5 (76.52 g, 1.8112 mol) was charged to the reactor (100 mL). Dioxane (2214 g) and a methanolic to 29.1% sodium methoxide (0.44 g, 24 mmol) were added. The mixture was heated to reflux (77 ° C) and stirred at this temperature for 1 hour. A sample was taken to verify the container conversion. The methanol was removed by distillation (distillation 16.82 g) at a background temperature of 97 ° C. The loss of dioxane during this distillation was compensated by adding fresh dioxane (121.6 g). Sodium bicarbonate (22.2 g, 26. mmoles) and demineralized water were added. The mixture was heated to reflux (2.47 g) and stirred at about 87 ° C for 10 hours. A sample was taken to verify the conversion of the container. The content of the reactor was cooled to 78 ° C. Dioxane (0.13 g) and demineralized water (0.12 g) were added to simulate a jet wash. After cooling to < 60 ° C concentrated hydrochloric acid (37%, 0.265 g) was added to adjust the pH to 7.5. The dioxane, methanol and one part of water (distilled 27.73 g) were removed by vacuum distillation (end of distillation: 66 ° C, 305 mbar). Under 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 were separated at 70 ° C and the minor aqueous phase was discarded. The organic phase containing the captured ketone was washed in two portions with demineralized water (169.4 g total) at about 70 ° C. Cyclohexane (165.0 g) was added to the reactor to simulate a jet. To crystallize the product, the vessel was cooled to 10 ° C for 1 hour. It was then aged for 6 hours at 9 to 11 ° C to complete the crystallization. The product vessel was filtered and washed with cyclohexane / toluene (81.5 g / 27.2 g).

EXAMPLE 7 Preparation of c / s-6-r3- (cyclopentyloxy) -4-methoxyphenyl-1-l-oxaspyrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr A 500 mL round bottom flask equipped with a stir bar, an internal thermometer and a nitrogen inlet was flushed with nitrogen. The flask was charged with 50% potassium hydroxide in water (22.0 g) and tetrahydrofuran (55.0 mL). While stirring at room temperature, benzyltriethylammonium chloride (0.81 g, 35 mmol, 0.05 equivalent) was added. The solution was cooled to 0 ° C. A solution containing tetrahydrofuran (55.0 mL), 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-one (23.0 g, 73 mmol, 1.0 equivalent) was charged to a pressure equalization addition funnel. ), and chloroacetonitrile (5.9 g, 78 mmol, 1.07 equivalent) at room temperature. At the same time that the contents of the flasks were stirred at 0 ° C, the solution in the pressure addition funnel was added for 15 minutes. The temperature was maintained between 0 and 5 ° C, and it was stirred for one hour. The reaction was warmed to 25 ° C, diluted with water (90.0 mL) and ethyl acetate (90.0 mL). The solution was stirred and allowed to stand for 30 minutes. The layers were separated, the organic layer was isolated, and concentrated by vacuum distillation to a residue. Methylcyclohexane / THF (5: 1) (54.0 mL) was added and the solution was heated to 60 ° C and then cooled to 20 ° C for 90 minutes; the product began to crystallize around 40 ° C. The suspension was then cooled to 0 ° C and maintained at -0 to 5 ° C for 2 hours. The product was filtered and washed with a mixture of methanol (46.0 mL) at 0 ° C. The product was dried to obtain the product taken up as a white crystalline solid.

EXAMPLE 8 Preparation of 4-cyano-4- (3-cyclopentyloxy-4-nr? Ethoxypheni0-r-1-cyclohexanecarboxylate of c / s-tithium, 2.

A dimethylformamide (200 mL), acetonitrile (200 mL), lithium bromide (32.4 g) was charged to a 1.0 L three neck round bottom flask with a stir bar, an internal thermometer and a reflux condenser connected to a caustic scavenger. 0.37 moles) and water (5.6 g, 0.31 moles). The suspension was stirred until a solution was evident, followed by the addition of c / s-6- [3- (cyclopentyloxy) -4-methoxy-phenyl)] - 1-oxaspiro [2.5] octane-2,6-dicarbonitrile, 1_, (90.0 g, 0.25 mol). The contents of the flask were heated between 90 and 95 ° C for 8 to 12 hours. The reaction was cooled to 60 ° C and diluted with dimethylformamide (270 mL). To the solution (60 ° C) an aqueous solution of lithium hydroxide (21.65 g, 0.51 mol) of lithium hydroxide monohydrate dissolved in 112.5 mL of water was quickly added). 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 dried with air to provide 2 in a yield of 79.5%.

EXAMPLE 9 Preparation of c / s-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate, 3.

To a 1.0 L 3-necked round bottom flask equipped with a stir bar and an internal thermometer was added cis-lithium 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate. (58.5 g, 0.167 mol) and ethyl acetate (500 mL). The light suspension was stirred at room temperature followed by the addition of 3N aqueous HCl (70 mL, 0.21 mol). The reaction 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 isolated and filtered into a clean 1.0 L three necked round bottom flask with a distillation head and a stir bar. The reaction was concentrated by distillation of 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, kept at 5 ° C for 2 hours, filtered, and washed with cold heptane (5 ° C) (50 mL). The product was dried in a vacuum oven at a constant weight to obtain 50.0 g (85%) of 3.

Claims (12)

NOVELTY OF THE INVENTION CLAIMS

1. - A method for making a compound of formula

Ri is - (CR4R5) nC (O) O (CR4R5) mR6, - (CR4R5) nC (O) NR4 (CR4R5) mR6, - (CR4R5) nO (CR4R5) mR6, or - (CR4Rs) rR6 wherein the portions alkyl may be optionally substituted with one or more halogens; m is 0 to 2; n is 1 to 4; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C? -2 alkyl; Re is hydrogen, methyl, hydroxyl, aryl, substituted halogen aryl, aryloxyC de -3alkyl, substituted aryloxyC de -3 halogen alkyl, indanyl, indenyl, C7-n polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C 3-6 cycloalkyl, or a C 4-6 cycloalkyl containing one or more unsaturated bonds, wherein the cycloalkyl and heterocyclic portions may be optionally substituted by 1 to 3 methyl groups or a group ethyl; with the proviso that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when Re is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or d) when R6 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 R6 is different from H in - (CR4R5) nO (CR4R5) mR6; X is YR2, halogen, nitro, NH2) or formylamine; X2 is O or NR8; And it is O or S (O) m; m 'is 0, 1 or 2; R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC (O) C (O) NH2, C2 alkyl, substituted halogen, -CH = CR8'Rs', cyclopropyl optionally substituted by R8-, CN, OR8, CH2OR8 , NR8R? O, CH2NR8R? O, C (Z ') H, C (O) OR8, C (O) NR8R? O, or C = CR8-; R8 is hydrogen or C? -4 alquiloalkyl optionally substituted by one to three fluorines; R8- is R8 or fluorine; R10 is OR8 or R11;

Rn is hydrogen, or C ?4 alkyl optionally substituted by one or three fluorines; Z is O, NR9, NOR8, NCN, C (-CN) 2, CR8CN, CR8NO2, CR8C (O) OR8, CR8C (O) NR8R8) C (-CN) NO2, C (-CN) C (O) OR9 , or C (-CN) C (O) NR8R8; R 'and R "are independently hydrogen or -C (O) OX wherein X is hydrogen or metal or ammonium cation, which method comprises: a) combining a metal halogenide of group l (a) or group ll (a) , with a solvent based on dipolar aprotic amide and water and a compound of formula ll (a) or ll (b), (llb) (lia) wherein Ri, R3, X2 and X are the same as for formula (I); b) heating the combination to a temperature of at least about 60 ° for several hours, optionally under an inert atmosphere; c) precipitating a compound of formula (I) by adding a strong base to said combination; d) removing the amide-based solvent and water from said precipitate, and optionally 1) further purifying the precipitate, or 2) acidifying the precipitate to obtain the free acid. 2. The process according to claim 1, further characterized in that the product is a compound wherein Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; And it's oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN. 3. The process according to claim 1 or 2, further characterized in that the metal halogenide of group l (a) or ll (a) is lithium or magnesium halide.

4. The process according to any of claims 1-3, further characterized in that the metal halogenide of group l (a) or II (a) is lithium bromide or magnesium bromide.

5. The process according to any of claims 1-4, further characterized in that the solvent based on dipolar aprotic amide is dimethylformamide, dimethylacetamide, or N-methylpyrrolidinone.

6. The process according to any of claims 1-5, further characterized in that the metal halogenide of group l (a) or ll (a) is lithium bromide and the solvent based on amide is dimethylformamide.

7. The process according to any of claims 1-6, further characterized in that water is present in an amount greater than 0.1% weight / weight of the content of the reaction vessel.

8. - The method according to any of claims 1-7, further characterized in that the strong base is lithium hydroxide.

9. The process according to any of claims 1-8, further characterized in that the compound of formula ll (a) or ll (b) is c / s-6- [3- (cyclopentyloxy) -4-methoxyphenyl) ] -1-oxaspiro [2.5] octane-2,6-dicarbonitrile.

10. A product of the process according to any of claims 1-9, which is c / s-lithium 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate.

11. A compound that is 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate of c / s-lithium.

12. A composition in question comprising essentially 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -r-1-cyclohexanecarboxylate of pure c / s-lithium.