EA003609B1

EA003609B1 - Method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids

Info

Publication number: EA003609B1
Application number: EA200000406A
Authority: EA
Inventors: Кевин Вебб; Вилфорд Мендельсон; Дзианхао Чен
Original assignee: Смитклайн Бичам Корпорейшн
Priority date: 1997-10-10
Filing date: 1998-10-07
Publication date: 2003-06-26
Also published as: AU9687498A; PL339759A1; WO1999018793A1; BG104302A; TW440557B; KR20010015709A; ZA989228B; ID25536A; IL135434A0; HUP0003905A2; TR200000945T2; AP2000001782A0; UA67753C2; KR100560038B1; SK4902000A3; CN1192025C; CN1275052A; HUP0003905A3; AR015952A1; NO20001777D0

Abstract

1. A method for preparing substituted 4-phenyl-4-cyanocyclohexanoic acids of formula I in which R1 is (CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a C1-2alkyl; R6 is a C3-6cycloalkyl or C4-6cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; X is YR2, halogen, nitro, NH2, or formylamine; X2 is O or NR8; Y is O or S (O) m'; m' is 0, 1, or 2; R2 is independently selected from-CH3 or-CH2CH3 optionally substituted by 1 or more halogens; R3 is hydrogen, halogen, C1-4alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4alkyl, -CH=CR8'R8',cyclopropyl optionally substituted by R8',CN2OR8, NR8R10, CH2NR8R10, C(Z')H, C(O)OR8, C(O) NR8R10, or C [triple bond] CR8'; R8 is hydrogen or C1-4alkyl optionally substituted by one to three fluorines; R8'is R8 or fluorine; R10 is OR8 or R11; R11 is hydrogen, or C1-4alkyl optionally substituted by one to 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 where X is hydrogen or Li; which method comprises: a) combining a Group I(a) or Group II(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula II(a) or II(b), where R1, R3, X2 and X are the same as for formula (I); b) heating the combination to a temperature of at least about 60 degree for several hours, optionally under an inert atmosphere; wherein further carrying out: c) precipitating out a compound of formula (I) by adding a sufficient LiOH amount to said combination to form a compound of formula (I), in which X is Li in a -C(O)OX group; d) removing the amide-based solvent and water from said precipitate, and optionally i) purifying further the precipitate, or ii) acidifying the precipitate to obtain the free acid. 2. The process of claim 1 wherein the product is a compound wherein R1 is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN. 3. The process of claim 1 or 2 wherein the Group I(a) or II(a) metal halide is lithium or magnesium halide. 4. The process of any one of claims 1-3 wherein the Group I(a) or II(a) metal halide is lithium bromide or magnesium bromide. 5. The process of any one of claims 1-4 in which the aprotic dipolar amidebased solvent is dimethylformamide, dimethylacetamide, or N-methyl pyrrolidinone. 6. The process of any one of claims 1-5 wherein the Group I(a) or II(a) metal halide is lithium bromide and the amide-based solvent is dimethylformamide. 7. The process of any one of claim 1-6 wherein water is present in an amount greater than 0.1 % by weight/weight of the contents of the reaction vessel. 8. The process of any one of claim 1-7 wherein the compound of formula II(a) or II(b) is cis-6-[3-(cyclopentyloxy)-4-methoxyphenyl)]-1-oxaspiro [2.5] octane-2,6-dicarbonitrile. 9. A product of the process of any one of claims 1-8 which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate. 10. A compound which is cis-lithium-4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate. 11. A composition of matter comprising essentially pure cis-lithium-4-cyano4-(3-cyclopentyloxy-4-methoxyphenyl)-r-1-cyclohexanecarboxylate.

Description

This invention encompasses intermediates and synthetic pathways for the preparation of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) cyclohexanoic acid and its analogues. This acid and its analogues selectively inhibit the catalytic site (site) of the phosphodiesterase IV isoenzyme (hereafter, PDE IV) and, being such, these acids are useful in the treatment of many diseases that can be mitigated by affecting the PDE IV enzyme and its subtypes.

Scope of invention

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

The identification of new therapeutic agents for asthma is hampered by the fact that many mediators are responsible for the development of the disease. Therefore, it is unlikely that the exclusion of the influence of a single mediator will lead to a significant impact on all the main components of chronic asthma. An alternative to the “mediator approach” is the regulation of the activity of cells responsible for the pathophysiology of this disease.

One of these ways is to increase the level of cAMP (cyclic adenosine 3 ', 5'monophosphate). Cyclic DMF has been shown to be a secondary mediator that mediates biological responses to a wide range of hormones, neurotransmitters and drugs; those. which is an intermediate link between the first and the second [КгЬз Еббосппододу Ргосеебтдд о £ 4 ¹ ' ^{1 1} Т1гпайопа1 Sopdgezz Esegr1a MeFs, 17-29, 1973]. When a suitable agonist binds to specific cell surface receptors, adenylate cyclase is activated, which transforms Md ^{+ 2} -ATP into cAMP at an elevated rate.

Cyclic AMP affects the activity of most, if not all, cells that contribute to the pathophysiology of external (allergic) asthma. As such, an increase in cAMP has a beneficial effect, including: 1) relaxation of airway smooth muscle, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of activation of monocytes and macrophages. Consequently, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing undesirable activation of the airway smooth muscle and a wide range of inflammatory cells. The main cellular mechanism of inactivation of cAMP is the hydrolysis of the 3'-phosphodiester bond with one or more families of isoenzymes attributed to cyclic nucleotide phosphodiesterase (PDE).

Currently, it has been shown that a certain cyclic nucleotide phosphodiesterase enzyme PDE IV is responsible for the destruction of cAMP in the smooth muscles of the respiratory tract and inflammatory cells [Togré, Pérébroticus Egase Po / ushez: RokepPa1 Taggézér ogérnuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuetu vasi № \ ν Egidz £ og Azkša, Vagpez, eb. GC Tesbshsa1 8guansez Ib., 1989]. Studies show that inhibition of this enzyme not only leads to relaxation of smooth muscles of the respiratory tract, but also suppresses the degranulation of mast cells, basophils and neutrophils, along with inhibition of the activation of monocytes and neutrophils. Moreover, the beneficial effect of PDE IV inhibitors is clearly enhanced with an increase in the adenylate cyclase activity of target cells under the action of the corresponding hormones or autocoids, as is the case. Thus, PDE IV inhibitors are effective in asthmatic lungs, where levels of prostaglandin E ₂ and prostacyclin (acenilate cyclase activators) increase. Such compounds offer a unique approach to the pharmacotherapy of bronchial asthma and have important therapeutic advantages over agents currently available on the market.

The method and intermediates of this invention provide the means to obtain certain 4-substituted-4- (3,4-substituted phenyl) cyclohexanoic acids, which are useful in the treatment of asthma and other diseases that can be mitigated by the action of PDE IV enzyme and its subtypes. The final products of particular interest are fully described in US Pat. No. 5,52483 issued September 3, 1996. The information and illustrations presented here are because this information and illustrations are necessary to understand the present invention and put it into practice are included here for information.

Summary of the Invention

This invention relates to a method for obtaining compounds of formula I

group in

(CK ₄ K ₅ ) PS (O) O (CK ₄ K ₅ ) shK ₆ , in which the alkyl moieties may optionally be substituted with one or more halogens;

g = 0-6;

P. ₄ and K _{5 are} independently selected from hydrogen or C1-2 alkyl;

C ₆ is C _3-6 cycloalkyl or C _4-6 cycloalkyl containing one or two unsaturated bonds in which cycloalkyl and heterocyclic fragments can be optionally substituted with 1–3 methyl groups or one ethyl group;

X is ΥΚ ₂ , halogen, nitro, ΝΗ _2, or formylamine;

X ₂ is O or ΝΚ ₈ ;

Υ represents O or 8 (O) t ';

t 'is 0, 1 or 2;

K _{2 is} independently selected from —CH ₃ or —CH ₂ CH ₃ , optionally substituted with 1 or more halogens;

K ₃ is hydrogen, halogen, C _1-4 alkyl, No. _2, nos. (Ο) ^ Ο) ΝΗ ₂ , halogen-substituted C _1-4 alkyl, —CH = CK ₈ 'K ₈ ', cyclopropyl, optionally substituted with K ₈ group ', SC OK ₈ , СН2ОК ₈ , ΝΒ.8Κ10, СН2К ^ 8Кю, С (Г) Н, С (О) ОКв, С (О) КК ₈ К ₁₀ , or С = СК ₈ ';

K ₈ is hydrogen or C _1-4 alkyl, optionally substituted with one to three fluoro;

K ₈ 'represents K ₈ or fluorine;

K ₁₀ is OK ₈ or K ₁₁ ;

K ₁₁ is hydrogen or C _1-4 alkyl, optionally substituted with one to three fluorine;

Ζ 'represents O, ΝΚ ₉ , MF ₈ , ^ Ν, CC-С ^, СК ₈ СК С ^ О2, СК8С (О) ОК8, С [КС (О) \ 1К.Ш С (-С ^^ 2, C (-C ^ C (O) OK9 or C (-C ^ C (O) G8K8;

K 'and K independently represent hydrogen or -C (O) OT, in which T represents hydrogen or L;

The method includes:

a) the combination of a metal halide of group 1 (a) or group 11 (a) with an aprotic bipolar solvent based on amide and water and

by the formula A or B n cm x MG M / g BUT AT where k] , K3, X2 and X have those same values as

for formula (I);

b) heating said combination to a temperature of at least about 60 ° C for several hours, optionally in an inert atmosphere;

characterized in that exercise

c) precipitating a compound of formula (I) by adding a sufficient amount of BUN to the above combination to form a compound of formula (I) in which T in the C (O) OT group is L;

g) removing the solvent based on amide and water from the specified sediment and optional

1) further purification or B1 salt to obtain the free acid; or

2) acidification of the B1 salt to obtain the free acid.

Specific Embodiments of the Invention

This method involves the synthesis of some 4-substituted-4 (3,4-disubstituted phenyl) cyclohexanoic acids. It allows cyanoepoxide to be converted to its corresponding homologized acid by using an intermediate salt of a metal of group 1 (a) or P (B).

Compounds that are obtained in this method are PDE IV inhibitors. They are useful for treating a number of diseases described in US Pat. No. 5,552,438, issued September 3, 1996. Preferred compounds that can be prepared by this method are as follows.

Preferred K ₁ substituents for the compounds of all the formulas indicated are CH2-cyclopropyl, CH2-C5-6 cycloalkyl, (3- or 4-cyclopentenyl), benzyl, or C _1-2 alkyl, unsubstituted or substituted by one or more fluorine.

Preferred X groups for formula (I) or (II) are those in which X is ΥΚ ₂ and Υ is oxygen. A preferred X ₂ group for formula (I) is a group in which X 2 is oxygen.

The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred K ₂ groups are those in which K ₂ is methyl or fluoro-substituted alkyls, in particular C _1-2 alkyl, such as —CB ₃ , —CHB ₂ or —CH ₂ SNB ₂ moiety. The most preferred are —SNB ₂ and —CH ₃ moieties.

The most preferred compounds are those in which K ₁ is —CH ₂ -cyclopropyl, cyclopentyl, methyl or SB ₂ H; X is ΥΚ ₂ ; Υ represents oxygen; X ₂ is oxygen; and K ₂ is SB ₂ N or methyl; and K8 is SC

The lithium salts of these compounds represent a subgroup of preferred compounds. In particular, the lithium salt of 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -g-1-cyclohexanecarboxylic acid is preferred, i.e. lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) -g-1-cyclohexanecarboxylate. More specifically, the most preferred compound is cis-lithium-4-cyano-4- (3-cyclopentyloxy-4 methoxyphenyl) -g-1-cyclohexanecarboxylate.

Carboxylates are prepared by opening the epoxide with a metal halide of Yes) or P (a) of a group to produce acyl nitrile, which hydrolyzes to acid in the presence of water. The problem with obtaining acid from acylnitrile is that when carboxylate is formed from acylnitrile, hydrogen cyanide is generated (NSC. The latter’s problem is to remove this Ηί, Ν in the most cost-effective way. of removing Ηί, Ν Было. It was found that if the reaction proceeds in an aprotic bipolar solvent based on an amide containing water, then adding a strong base produces a cyanide salt and remains in p At the same time, the carboxylate salt, which is formed at the same time, precipitates from the solution, this allows the precipitate to be collected and the solvent removed and, with this, to remove most or essentially all cyanide salt from the alkanoic acid precipitate additional purification steps, such as oxidation Ηί, 'Ν.

The halides of the metal of group 1 (a) or 11 (a) used in this invention are any alkali metal and alkaline earth metal halides, i.e. lithium, sodium, potassium, rubidium, cesium or France and beryllium, magnesium, calcium, strontium, barium or radium. Preferred metals are lithium and magnesium. Halides include fluoride, chloride, bromide, and iodide. The preferred halide is bromide. Lithium and magnesium halides are preferred. Lithium bromide and magnesium bromide are most preferred. Lithium bromide is particularly preferred.

As for amide-based solvents, dimethylformamide (DMF), dimethylacetamide and Ν-methylpyrrolidone, and similar DMF is most preferred, as illustrative examples. Another organic solvent may 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 tank because it hydrolyzes acyl nitrile ίη kyi to give alkanoic acid. Therefore, a more preferred embodiment of this invention is the use of an aprotic bipolar solvent that is miscible with water. DMF, dimethylacetamide and Ν methyl pyrrolidone satisfy this requirement. Although it is necessary to have water in the reaction medium, the amount of water can vary over a wide range. The reaction proceeds even when there is a small amount of water. It is preferable to have in the reaction vessel at least 1% w / w calculated on the basis of both liquids and solids, if any are present in the vessel. A more preferred amount of water is at least about 1% w / w. and most preferably about 1-5% water by weight. / weight. Although all possible combinations of water systems with an amide-based solvent were tested, it is known that the reaction will proceed with 20% water (w / w). On this basis, it is believed that an even higher percentage of water can be used. Optimization of the ratio of organic solvent and water can be achieved by experts in the field. It is believed that the scope of the present invention covers the use of any amount of water in combination with an amide-based solvent.

The reaction can proceed at any temperature above about 60 ° C. Since multiple combinations of amide-based solvent and water can be used, it is not advisable to set an exact upper temperature limit, since it will vary depending on the choice of solvent and the ratio of the selected solvents.

The halides of the 1 (a) or 11 (a) group of metals open epoxides, giving acyl nitrile. It hydrolyzes to acid in the presence of water. But instead of releasing the free acid, form the insoluble carboxylate salt by adding about 2 or more equivalents of a strong base to the reaction vessel. This base forms two salts, a salt of cyclohexanoic acid and a salt, which is released during the hydrolysis of the acylnitrile group. The cyanide metal is soluble in the solvent, and the alkanoic acid salt precipitates from the solution. This allows the alkanoic acid salt to be separated from the cyanide salt by simply removing the solvent. The invention may be practiced using less than 2 eq. base, but it can lead to undesirable from the economic point of view, the loss of alkanoic acid, because it does not precipitate from solution. And unreacted NSI can contaminate alkanoic acid, which precipitated out of solution. Therefore, it is preferable to use 2 or more equivalents of the base. A strong base for the purposes of this invention is lithium hydroxide, since lithium cyanide salt is highly soluble in an amide-based aqueous aprotic bipolar solvent, and thus acts more effectively and more completely removes the cyanide ion from the acid salt 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 form a lithium cation in a strong base at the salt formation stage of this method. The preferred implementation of this invention in practice is that in which the solvent (s) is loaded into a reaction vessel, lithium bromide is added, and then epoxide is added. When the reaction is substantially complete, two or more equivalents of an aqueous solution are added, lithium hydroxide, a cyclohexanoic acid salt is precipitated from the solution and filtered, and the solvent is discarded. The lithium salt of cyclohexanoic acid can optionally be purified to remove residual: impurities, such as cyanide salts, or turn into acid by dissolving or suspending the salt in a solvent and acidifying this material to obtain the free acid.

A schematic representation of this method is presented in schemes I and II. Specific examples are used in these graphic images to illustrate the general methodology used in this invention.

Scheme I

Stage 3

Stage 2

Izovanilin

Stage 4

2) Activated carbon

1) №ВН ₄ DMF ./MeON

2) SPLA / H ₂ O

1) Conc. Toluene

2) _a YaNSO

1) No. SI DMF.

2) Toluene / H ₂ O. CO ₂ CH ₃

Stage 7

СН ₃ СЦ, ВПМе ₃ Ы * ОН * Н ₂ О / СНЗОН

2) Crystallization from methylcyclohexane

Stage 6

MeO

Stage Θ e

IVG / N ₂ o

Stage 10

1) Manso _e , Naome, H ₂ 0, Dioxane

2) Conc. NA!

3) Crystallization from methylcyclohexane / ethyl acetate

4) Recrystallization from xylenes (if desired)

1) Naom Diox n / MeON

1) C1CH2CM |

THF / aq. KOH

C _in H ₅ CH2M (C ₂ H5) zC1

2) Crystallization from THF /

1) Ethylacetate aq. HC1

2) Crystallization from ethyl acetate / hexanes

Scheme II illustrates another very similar list of conditions that can be used in this invention. This scheme follows the same path as in scheme I; but some conditions are changed at some stages.

Scheme II

Stage 1

Stage 3

2) Hanso

Stage 5

Stage 7

Stage 8

MeO

Stage 10

K ₂ SOZMF: chlorocyclopentane

DMF / Meon

2) SPLA / H _g O

1) Konts.NS1 Toluene ⁾ - ^ ^h from _{2 to} ₃

ΟΗ ₃ ΟΝ, ΒηΜβ ₃ Ν * ΟΗ * H ₂ O / CH ₃ OH

2) Cyclohexane / Goluol

Stage 6

Naome Dioxa n / Meon

1) IaOMe ^ ANSOe, Dioxan

2) Conc. NA!

3) cyclohexane / goluol

4) Recrystallization from xylenes (if desired)

1) С1СН ₂ СЫ

THF / aq. KOH Sv ^ SNGG ^ CrHvbs!

2) Crystallization of methylcyclohexane from THGHG

3) Washing MeOH crystals

Stage 9 pivg / n ₂ about DMF / CH ₃ CN

Chemical

1) Ethylacetate aq. HC1

2) aq. and he

3) The crystallization from ethyl acetate / hexanes of the reaction shown in Scheme I is described in the US application that is simultaneously pending, No. 60/061613 (filed February 12, 1997), as well as in PCT / 98δ 98/02749, indicating along with other US countries, published as \ νϋ 98/34584. This application is included for information, especially with regard to chemical reactions in stages 1-7.

The chemical reactions in Scheme II are presented in the PCT application under PCT / EP 98/05504, filed on August 26, 1998, also indicating the United States as the selected state. Full disclosure of this application is included for information. Further details of this second set of chemical reactions are presented below.

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

A mixture of cyclopentyl chloride, isovaniline and potassium carbonate in dimethylformamide is stirred at about 125 ° C until the formation of the cyclopentyloxy product is considered complete (approximately 2

h) 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. Dimethylformamide liquids and washing methanol are combined for use in the next step.

A solution of cyclopentyloxy compound in dimethylformamide and methanol is cooled to about 0 ° C and treated with sodium borohydride (approximately 1.5 hours). The temperature is maintained below 5 ° C. After that, the mixture is stirred at 0-10 ° C for 30 minutes and at 2530 ° C until the reduction reaction is considered complete (approximately 1 hour). 50% acetic acid is added to destroy the excess borohydride, dimethylformamide and methanol are removed by distillation 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, passed through a filter for use in the next stage.

The alcohol solution in toluene is treated with concentrated hydrochloric acid (min. 36%) at 15-25 ° C. The organic phase containing the chlorine compound is separated and treated with sodium bicarbonate to neutralize traces of HC1. The solid (sodium chloride, sodium bicarbonate) is removed by filtration.

The solution of the chlorine compound is concentrated by distillation in vacuo. After cooling to about 20 ° C, demineralized water, tetrabutylammonium bromide and sodium cyanide are added. After that, 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 <60 ° C, the mixture is partitioned between water and toluene. The toluene phase containing the cyano compound is washed with demineralized water at 30–25 ° C, distilled under vacuum to a minimum volume, and acetonitrile is added. A solution of the product in acetonitrile is directly used in the next step.

Prepare solutions of methyl acrylate in acetonitrile and Thyoy B and acetonitrile. About 16.6% of the methyl acrylate solution is added to the cyano compound solution at <25 ° C. Approximately 12.5% Thyoy B solution is added, the mixture is stirred for several minutes and then precipitated again to <25 ° C. The addition in this order is repeated three more times, then the final 33% solution of methyl acrylate and 50% solution of Tyoi B are added in two portions. The reaction mixture is stirred at 20-25 ° C until the reaction is complete (approximately 2-3 hours) . Acetonitrile is removed by distillation in vacuo to a minimum volume. The mixture is partitioned between cyclohexane / toluene and water at 50 ° C. The cyclohexane / toluene phases containing pimelate are incubated for about 1 hour at about 0 ° C.

The product is separated by centrifugation and washed with cold (<0 ° C) cyclohexane / toluene. The wet cake is dried in a vacuum at maximum 50 ° C to obtain pimelate as a beige powder.

A 29% solution of sodium methoxide in methanol is added in one portion to a solution of pimelate in dioxane. The mixture is heated to about 75 ° C (boiling under reflux) and maintained at this temperature until the formation of 2-carbomethoxycyclohexane 1-it is fully completed (approximately 1 hour). Most of the methanol is distilled off and replaced with dioxane. To the mixture heated to boiling under reflux (approximately 85-88 ° C), add sodium bicarbonate and demineralized water and maintain at this temperature until the formation of cyclohexan-1-it is fully completed (approximately 10 hours).

After that, the mixture is cooled to <60 ° C and a concentrated hydrochloric acid solution is added to lower the pH from> 10 to 7.5.

Most of the methanol and dioxane is removed by distillation in vacuo. After that, the mixture is distributed between a mixture of 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 maintained for 1 h at 9-11 ° C. The product is separated by filtration and washed with cold (10 ° C) cyclohexane / toluene. The wet cake is dried in a vacuum at maximum 50 ° C to obtain the ketone as an off-white powder.

Dicarbonitrile is obtained from ketone by treating the ketone with chloroacetonitrile in the presence of an inorganic base and catalytic amounts of benzyltriethylammonium chloride (BTEAH). Ketone and a slight excess of chloroacetonitrile in a suitable solvent, such as THF, are added to a mixture of a strong base (aqueous potassium hydroxide) and BTECA and a solvent that is miscible with water, such as tetrahydrofuran, at or below a reduced temperature of about 0 ° C. The reaction is maintained at about a given temperature during its course, usually about 1 hour. The product can be recovered or used as a crude oil.

Dicarbonitrile is converted to cyclohexanecarboxylic acid using a metal halide of Yes) or P (a) group. This reaction is carried out by loading into the vessel of solvents; in this case, as an example, of which is DMF, acetonitrile and water, and a metal halide Yes) or P (a) of the group (preferably about 1.5 eq.) represented by L1Br; filling the vessel with an inert gas; adding dicarbonitrile A or B or a mixture of A and B; and heating the vessel and its contents to about 100 ° C for several hours, for example, 8 hours. The reaction mixture is diluted with DMF and, optionally, with water. LUN dissolved in water (preferably about 50% molar excess) is added. Formed suspension. It is stirred at a slightly elevated temperature (40-80 ° C) for one hour or about an hour. The lithium salt is isolated using conventional methods.

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

The following examples are provided to illustrate specific embodiments of the present invention, but not to limit it. What remains for the inventors is presented in the claims appended to the description.

Specific examples

Example 1. Preparation of 3-cyclopentyloxy-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) stirred in a reactor (100 ml) at 120-125 ° C for 1.5 hours. A sample was taken to check the conversion of the charge. Result (GC (gas chromatography)): 0.5% of the isovanillin area (target: <1.0% of the area). The mixture was cooled to 20 ° C and filtered to remove solid (potassium bicarbonate, potassium chloride). The wet cake was washed with methanol.

Example 2. Preparation of 3-cyclopentyloxy-methoxybenzyl alcohol.

Dimethylformamide liquids and washing methanol from Example 1 were combined and transferred to a clean reactor. An additional amount of methanol (8.52 g) was added and the mixture was cooled to 0 ° C. Sodium borohydride (0.49 g, 0.0129 mol) was added in small portions over 1 hour and 10 minutes, maintaining the temperature between 4 and 9 ° C. The batch was stirred at 7.2-10 ° C for 30 minutes and then heated to 25 ° C. A sample was taken after 110 minutes of stirring at 25-31 ° C and analyzed (GC), and the reaction was considered complete. Acetic acid 50% (1.80 g) was loaded into the reactor to extinguish the remaining sodium borohydride. During this load, the mixture was maintained at a temperature of 24-25 ° C. Dimethylformamide and methanol were removed by distillation in vacuo (at the end of the distillation: 58 ° C, 6 mbar (600 Pa)). After cooling to 20-25 ° C, the mixture was distributed between water (3.13 g) and toluene (28.07 g). The toluene phase (containing the desired compound) was washed with demineralized water (2.65 g).

Example 3. Obtaining 4-chloromethyl-2cyclopentyloxy-1-methoxybenzene.

The toluene solution from Example 2 was cooled to 20 ° C and concentrated hydrochloric acid (37.5%; 9.80 g) was added, keeping the temperature between 20 and 22.7 ° C. A sample was taken 40 minutes after the addition was completed and analyzed (GC), and the reaction was considered complete. The phases were left to separate and the lower, aqueous phase was discarded. Sodium bicarbonate (1.20 g) was loaded into the reactor to neutralize the remaining hydrochloric acid. After stirring for 15 minutes, the mixture was cooled to 23 ° C and filtered to remove solid (sodium bicarbonate, sodium chloride). A portion of toluene (17.07 g) was removed by distillation in vacuo (at the end of the distillation: 28 ° C, 7 mbar (700 Pa)).

Example 4. Obtaining 4-cyanomethyl-2cyclopentyloxy-1-methoxybenzene.

After cooling the solution of example 3 to <25 ° C, tetrabutylammonium chloride (0.205 g, 0.63 mmol), demineralized water (2.775 g) and sodium cyanide (1.976 g, 0.039 mol) were added, the mixture was heated to 80 ° C and then stirred at 78.1-80.4 ° C for 1 h and 50 min. A sample was taken to check the conversion of the load.

Toluene (5.841 g) and demineralized water (8.76 g) were added, the phases were allowed to separate (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 distillation in vacuo (at the end of the distillation: 55 ° C, 1 mbar (100 Pa)).

Example 5. Obtaining dimethyl-4-cyano-4 (3-cyclopentyloxy-4-methoxyphenyl) pimelate.

The cyanomethyl compound obtained in Example 4 (9.05 g at 85.4%; 7.73 g at 100%; 0.0334 mol) was loaded into the reactor (0.5 l) at room temperature. Acetonitrile (2856 g) and demineralized water (0.07 g) were loaded into the reactor. Solutions of methyl acrylate (6.88 g, 0.029 mol) in acetonitrile (4.02 g) and methanolic Thyoi B (40.2% 0.94 g, 2.2269 Mmol Thyyo B) in acetonitrile (4.06 g) were prepared. The first portion, about 16.6% solution of methyl acrylate (1.81 g) was added at 20 ° C. Then the first portion was added, about 12.5% of Thyop B solution (0.63 kg). The loading temperature after the addition was 31 ° C. Then a second portion, about 16.6% of methyl acrylate solution (1.82 g) was added at 28 ° C. Then a second batch, about 12.5% of Tyop B solution (0.63 g) was added. The loading temperature after the addition was 36 ° C. At 35 ° C, a third portion was added, about 16.6% of the methyl acrylate solution (1.81 g). Then a third portion of approximately 12.5% Thyop B solution (0.62 g) was added. The loading temperature 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 of about 12.5% solution of Вηΐοπ В (0.63 g) was added. The loading temperature after the addition was 36 ° C. A fifth portion, about 33.2% solution of methyl acrylate (3.64 g) was added at 34 ° C. Then a fifth portion of about 25% solution of Вηΐοπ В (1.25 g) was added. The loading temperature after the addition was 38 ° C. Then add the last portion of approximately 25% solution of Ττίΐοπ В (1.25 g). The loading temperature after the addition was 36 ° C. The reaction mixture was stirred for 1.5 hours at 20-25 ° C. Acetonitrile was removed by distillation in vacuo (at the end of the distillation: 59 ° C, 20 mbar (2 kPa)). The mixture was distributed at about 50 ° C between a mixture of 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 desired product, the mixture was cooled for 50 minutes to 0 ° C. Then pimelate was added to the mixture as a seed and kept for 1 h at (-1) -1 ° С. 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- (3cyclopentyloxy-4-methoxyphenyl) cyclohexan1-one.

The pimelate obtained in Example 5 (76.52 g, 1.8112 mol) was loaded into the reactor (100 ml). Dioxane (2214 g) and 29.1% methanol 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 check the charge conversion. Methanol was removed by distillation (16.82 g of distillate) at a bottom temperature of 97 ° C. The loss of dioxane during distillation was compensated by the addition of fresh 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. A sample was taken to check the feed conversion. The contents of the reactor were cooled to 78 ° C. To simulate a liquid jet, dioxane (0.13 g) and demineralized water (0.12 g) were added. After cooling to <60 ° C, concentrated hydrochloric acid (37%, 0.265 g) was added to adjust the pH to 7.5. Dioxane, methanol and part of water (27.73 g of distillate) were removed by distillation in vacuo (at the end of the distillation: 66 ° C, 305 mbar (30.5 kPa)).

With 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 left to separate at 70 ° C and the lower, aqueous phase was discarded. The organic phase containing the desired ketone was washed with two portions of demineralized water (169.4 g in total) at about 70 ° C. To simulate a jet of liquid, cyclohexane (165.0 g) was added to the reactor.

To crystallize the product, the batch was cooled for 1 h to 10 ° C. Then it was kept for 6 hours at 9-11 ° C to complete the crystallization. The product was filtered and washed for 1 h 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 air stirrer, internal thermometer and nitrogen inlet was filled with nitrogen. The flask was charged with 50% potassium hydroxide in water (22.0 g) and tetrahydrofuran (55.0 ml). Under stirring at room temperature, benzyltriethylammonium chloride (0.81 g, 35 mmol, 0.05 eq.) 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 eq.) Was charged through a pressure equilibration funnel. and chloroacetonitrile (5.9 g, 78 mmol, 1.07 eq.) at room temperature. While stirring the contents of the flask at 0 ° C, the solution in the funnel was added over 15 minutes. The temperature was maintained between 0 and 5 ° C and stirred for one hour. The reaction mixture was warmed to 25 ° C, diluted with water (90.0 ml) and ethyl acetate (90.0 ml). The solution was stirred and allowed to settle for 30 minutes. The layers were separated, the organic layer was separated and concentrated by distillation in vacuo to a residue. 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; the product began to crystallize at about 40 ° C. The suspension was then cooled to 0 ° C and kept 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, giving the desired product as a white crystalline solid.

Example 8. Preparation of cis-lithium-4-cyano4- (3-cyclopentyloxy-4-methoxyphenyl) -g-1 cyclohexanecarboxylate, 2.

A 1.0 liter 3-necked round-bottomed flask equipped with an air stirrer, an internal thermometer and a reflux condenser connected to a caustic scrubber was charged with dimethylformamide (200 ml), acetonitrile (200 ml), lithium bromide (32.4 g, 0.37 mol ) and water (5.6 g, 0.31 mol). The suspension was stirred until the solution became clear, with the following addition of cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl)] -1-oxaspiro [2.5] octane-2,6-dicarbonitrile, 1, ( 90.0 g, 0.25 mol). The contents of the flask were heated at a temperature between 90 and 95 ° C for 8-12 hours. The reaction mixture was cooled to 60 ° C and diluted with dimethylformamide (270 ml). An aqueous solution of lithium hydroxide (21.65 g, 0.51 mol lithium hydroxide monohydrate dissolved in 112.5 ml of water) was quickly added to the amber-colored solution (60 ° C). The suspension was stirred at 60 ° C for 1 h, cooled to 5 ° C and left at 5 ° C for 1 h. The suspension was filtered, washed with ethyl acetate (100 ml) and dried in air, yielding 2 with a corresponding yield of 79.5%.

Example 9. Preparation of cis-4-cyano-4- (3cyclopentyloxy-4-methoxyphenyl) -g-1-cyclohexanecarboxylate, 3.

h

In a 1.0 liter 3-necked round-bottomed flask equipped with an air stirrer and internal thermometer, cis-lithium-4-cyano-4 (3-cyclopentyloxy-4-methoxyphenyl) -g-1 cyclohexanecarboxylate, 2 (58.5 g, 0.167 mol) and ethyl acetate (500 ml). The bright suspension was stirred at room temperature followed by the addition of 3Ν aqueous HCl (70 ml, 0.21 mol). The reaction mixture was stirred for 10 minutes and transferred to a separatory funnel. The organic layer was isolated and washed once with water (1000 ml). The organic layer was separated and filtered into a clean 1.0 L 3-neck round bottom flask equipped with a distillation head and an air stirrer. The reaction mixture was concentrated by distilling off ethyl acetate (200 ml). The contents of the flask were cooled to 60 ° C, followed by the addition of heptane (275 ml). The suspension was cooled to 5 ° C, kept at 5 ° C for 2 h, filtered and washed with cold (5 ° C) heptane (50 ml). The product was dried in a vacuum oven to constant weight, yielding 50.0 g (85%) of compound 3.

Claims

1. A method of producing substituted 4-phenyl4-cyanocyclohexanoic acids of the formula I * O) in which K ₁ represents a group - (SK ₄ K ₅ ) _G K ₆ , in which the alkyl moieties may optionally be substituted with one or more halogens;

g = 0-6;

Cd and K _{5 are} independently selected from hydrogen or C _1-2 alkyl;

K6 represents C3-6 cycloalkyl or C4-6 cycloalkyl containing one or two unsaturated bonds, moreover, cycloalkyl moieties may optionally be substituted with 1-3 methyl groups or one ethyl group;

X represents ΥΚ ₂ , halogen, nitro, ΝΗ ₂ or formylamine;

X ₂ represents O or ΝΚ ₈ ;

Υ represents O or 8 (O) t ';

t 'represents 0, 1 or 2;

K _{2 is} independently selected from —CH ₃ or —CH ₂ CH ₃ optionally substituted with 1 or more halogens;

K3 represents hydrogen, halogen, C1-4 alkyl, CH ₂ CNS (O) C (O) KH ₂ , halogen-substituted C _1-4 alkyl, —CH — SK ₈ ′ K ₈ ′, cyclopropyl optionally substituted Κ ₈ ς SI OK ₈ , CH ₂ OK ₈ , ΝΚ8Κ10, SNAC ^ w, C (2 ') H, C (O) OK8, C (O) KK ₈ K ₁₀ , or C ^ SK ₈ <

K ₈ is hydrogen or C _1-4 alkyl optionally substituted with one to three fluoro;

K8 'represents K8 or fluorine;

K ₁₀ represents OK ₈ or K ₁₁ ;

K ₁₁ represents hydrogen or C _1-4 alkyl optionally substituted with one to three fluoro;

Ζ 'represents O, ΝΚ ₉ , NΟK ₈ , ^ Ν, C (-CH) 2, CK8SCh C1k \ O ·. SK8S (O) OK8, SK8S (О№К8, s (-Сн№О2, с (-снс (О) ok9, or С (-СН) С (ОЖ8К8;

K 'and K independently represent hydrogen or —C (O) OT, in which T represents hydrogen or L;

which includes

a) a combination of a metal halide of group 1 (a) or group 11 (a) with an aprotic bipolar solvent based on an amide and water and a compound of formula 11 (a) or 11 (b)

IN"

W ")

IN,

P (b) where K1, K3, X2 and X have the same meanings as for formula (I);

b) heating said combination to a temperature of at least about 60 ° for several hours, optionally in an inert atmosphere;

characterized in that exercise

c) precipitation of the compound of formula (I) by adding a sufficient amount of BJUN to said combination to form a compound of formula (I) in which T in the —C (O) OT group represents Y;

6) removal of the amide-based solvent and water from said precipitate, and optionally

ί) further purification of the b1 salt; or ίί) acidification of the b1 salt to give a free acid.

2. The method according to claim 1, wherein the product is a compound in which K ₁ is —CH ₂ -cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl, or CP ₂ H; X represents ΥΚ ₂ ; Υ represents oxygen; X ₂ represents oxygen; K ₂ represents CP ₂ H or methyl and K ₃ represents ΟΝ.

3. The method according to claim 1 or 2, in which the metal halide of group 1 (a) or 11 (a) is a lithium or magnesium halide.

4. The method according to any one of claims 1 to 3, in which the metal halide of group 1 (a) or 11 (a) of the group is lithium bromide or magnesium bromide.

5. The method according to any one of claims 1 to 4, wherein the amide-based aprotic bipolar solvent is dimethylformamide, dimethylacetamide or Ν-methylpyrrolidinone.

6. The method according to any one of claims 1 to 5, in which the metal halide of the group 1 (a) or 11 (a) is lithium bromide, and the amide-based solvent is dimethylformamide.

7. The method according to any one of claims 1 to 6, in which water is present in an amount exceeding 0.1% wt./weight. the contents of the reaction vessel.

8. The method according to any one of claims 1 to 7, in which the compound of formula 11 (a) or 11 (b) is cis-6- [3- (cyclopentyloxy) -4-methoxyphenyl] -1 oxaspiro [2.5] octan-2, 6-dicarbonitrile.

9. The product of the method according to any one of claims 1 to 8, which is cis-lithium-4-cyano-4- (3cyclopentyloxy-4-methoxyphenyl) g-1-cyclohexanecarboxylate.

10. A compound that is cislitium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) g-1-cyclohexanecarboxylate.

11. A composition comprising substantially pure cis-lithium-4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl) g-1-cyclohexanecarboxylate.