Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
  • C07D303/02—Compounds containing oxirane rings
  • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C255/00—Carboxylic acid nitriles
  • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
  • C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
  • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
  • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
  • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
  • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
  • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C47/00—Compounds having —CHO groups
  • C07C47/52—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings
  • C07C47/575—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing ether groups, groups, groups, or groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
  • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

Definitions

• This invention covers intermediates and a synthetic route for making 4-cyano-4- (3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and its analogs.
• This acid and its named analogs are selective for inhibiting the catalytic site in the phosphodiesterase isoenzyme denominated IV (PDE IV hereafter) and as such the acids are useful in treating a number of diseases which can be moderated by affecting the PDE IV enzyme and its subtypes.
• PDE IV phosphodiesterase isoenzyme denominated IV
• Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyper-reactivity of the respiratory tract to external stimuli.
• cAMP adenosine cyclic 3 ',5 - monophosphate
• Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973].
• adenylate cyclase is activated, which converts Mg + 2-ATP to cAMP at an accelerated rate.
• Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation.
• compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells.
• the principal cellular mechanism for the inactivation of c AMP is hydrolysis of the 3 -phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
• PDE IV cyclic nucleotide phosphodiesterase
• PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo.
• PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated.
• Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
• This invention relates a method for making a compound of formula I
• Ri is -(CR4R5)nC(O)O(CR4R5)mR6.
• R4 and R5 are independently selected from hydrogen or a -2 alkyl
• R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-I I polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: a) when R6 is hydroxyl, then m is 2; or b) when R6 is hydroxyl, then r is 2 to 6; or c) when R ⁇
• X is YR2, halogen, nitro, NH 2 , or formyl amine
• X2 is O or NR8;
• Y is O or S(O) m ';
• m' is O, 1, or 2;
• R2 is independently selected from -CH3 or -CH2CH3 optionally substituted by 1 or more halogens;
• Rg is hydrogen or C .A alkyl optionally substituted by one to three fluorines;
• Rg' is R or fluorine
• RlO is OR ⁇ or Rn;
• R ⁇ 1 is hydrogen, or C ⁇ .A alkyl optionally substituted by one to three fluorines;
• Z' is O, NR9, NOR8, NCN, C(-CN)2, CRgCN, CRgNO2, CRgC(O)OR8, CR8C(O)NR8R8, C(-CN)NO2, C(-CN)C(O)OR9, or C(-CN)C(O)NRgR8;
• R' and R" are independently hydrogen or -C(O)OX where X is hydrogen or metal or ammonium cation; which method comprises: a) combining a Group 1(a) or Group 11(a) metal halide, with an aprotic dipolar amide-based solvent and water and a compound of formula A or B,
• This process involves the synthesis of certain 4-substituted-4-(3,4- disubstitutedphenyl)cyclohexanoic acids. It allows for converting a cyanoepoxide to its corresponding homologated acid via the use of a Group 1(a) or 11(b) salt intermediate.
• the compounds which are made by this process are PDE IV inhibitors. They are useful for treating a number of diseases as described in U.S. patent 5,552,438 issued
• Ri substitutents for the compounds of all named formulas are CH2- cyclopropyl, CH2-C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with
• OHC7-H polycycloalkyl (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C 1-2 alkyl unsubstituted or substituted by 1 or more fluorines, -(CH 2 )l-3C(O)O(CH2)0-2CH 3 , -(CH 2 )l-3 ⁇ (CH 2 )0-2CH3, and -(CH 2 )2-4OH.
• Preferred X groups for Formula (I) or (II) are those wherein X is YR2 and Y is oxygen.
• the preferred X2 group for Formula (I) is that wherein X2 is oxygen.
• Preferred R2 groups are a C 1-2 alkyl unsubstituted or substituted by 1 or more halogens.
• the halogen atoms are preferably fluorine and chlorine, more preferably fluorine.
• More preferred R2 groups are those wherein R2 is methyl, or the fluoro- substituted alkyls, specifically a Ci-2 alkyl, such as a -CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
• Ri is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H
• X is YR2
• Y is oxygen
• X2 is oxygen
• R2 is CF2H or methyl
• R3 is CN.
• the lithium salt of these compound represent a sub-set of preferred compounds.
• the lithium salt of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- 1 - cyclohexanecarboxylic acid i.e., lithium-4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)-r-l-cyclohexanecarboxylate represents a preferred embodiment.
• the compound cw-lithium-4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)-r-l-cyclohexanecarboxylate is most preferred.
• the carboxylate is made by opening the epoxide with a Group 1(a) or 11(a) metal halide to get the acyl nitrile which hydrolyzes to the acid in the presence of water.
• a problem in preparing the acid from the acyl nitrile is that when the carboxylate is formed from the acyl nitrile, hydrogen cyanide (HCN) is generated. The challenge is one of removing this HCN in a cost-effective way.
• a feature of this invention is a means for effecting a more efficient removal of HCN.
• the Group 1(a) or 11(a) metal halides used in this invention are any of the halides of the alkali metals and the alkali earth metals, i.e., lithium, sodium, potassium, rubidium, cesium or francium; and beryllium, magnesium, calcium, strontium, barium, or radium.
• the preferred metals are lithium and magnesium.
• the 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.
• amide-based solvents they are illustrated by the likes of dimethylformamide (DMF), dimethylacetamide, and N-methyl pyrrolidinone. DMF is most preferred.
• a second organic solvent can be used in addition to the amide-based solvent.
• acetonitrile has been used successfully in the reaction illustrated below. Normally water is added to the reaction pot as it hydrolyzes the acyl nitrile in situ to give the alkanoic acid.
• a further preferred embodiment of this invention is to use an aprotic dipolar solvent which is water miscible.
• DMF, dimethylacetamide, and N-methyl pyrrolidinone meet this standard. While it is essential to have water in the reaction medium, the amount of water can vary widely.
• the reaction goes even when a minor amount of water is present. It is preferred to have at least 0.1% by weight/weight (wt/wt) present in the reaction vessel, calculated on the basis of both the liquids and the solids, if any, present in the vessel. A more preferred amount of water is at least about 1% wt/wt, and most preferably about 1-5% water by wt/wt. While not all possible combinations of water and amide-based solvent systems have been tested, it is known that the reaction will proceed with 20% water (wt/wt). Hence it is believed that even higher percentages of water can be used. Optimization of the organic solvent-to-water ratios can be achieved by the skilled practioner. The use of any amount of water in combination with an amide-based solvent is considered to be within the scope of this invention.
• the reaction can be run at any temperature above about 60 °C. Since there are numerous combinations of amide-based solvent and water that can be used, it is not practical to set an exact upper limit to the temperature since that will vary based on solvent selection and the ratio of the selected solvents.
• the Group 1(a) or 11(a) metal halide opens the epoxide to give an acyl nitrile. It is hydrolyzed to the acid in the presence of water. But rather than isolate 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 cyclohexanoic acid and a salt of HCN which is released in the hydrolysis of the acyl nitrile group.
• the metal cyanide it turns out is soluble in the solvent and the salt of the alkanoic acid precipitates out of 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, but that would possibly result in loss of the alkanoic acid because it would not precipitate out of solution, undesirable from an economic standpoint. And unreacted HCN could contaminate the alkanoic acid that did precipitate out of solution. Hence the preferred practice is to use 2 or more equivalents of the base.
• a strong base for the purposes of this invention is any base that will form a salt with the cyanide ion.
• Inorganic hydroxides are preferred. For example one can use LiOH, NaOH, or KOH.
• Lithium hydroxide is preferred because the lithium cyanide salt is highly soluble in the aqueous aprotic dipolar amide-based solvent, and thus effects more efficient and more complete removal of the cyanide ion from the acid salt when the amide-based solvent is removed.
• Lithium cyanide is more soluble in DMF than is sodium cyanide or potassium cyanide. So it is more advantageous to make lithium the cation in the strong base in the salt-forming step of the process.
• a perferred practice of this invention is one in which the solvent(s) are charged to the reaction vessel, lithium bromide is added, and then the epoxide. Once the reaction has gone to completion essentially, two or more equivalents of an aqueous solution of lithium hydroxide are added, the cyclohexanoic acid salt is precipitated out of solution and filtered out, and the solvent discarded.
• the lithium salt of the cyclohexanoic acid can be further purified if needs be to remove residual contaminants such as cyanide salts, or converted to the acid by dissolving or suspending the salt in a solvent and acidifying that material to obtain the free acid.
• Scheme II illustrates a second very similar set of conditions that can be used in this invention. This scheme follows the same route as the one outlined in Scheme I; some of the conditions in certain steps are changed.
• the mixture is cooled to 20-25°C, the solid (potassium chloride and potassium bicarbonate) is removed by centrifugation and is washed with methanol before being discarded.
• the dimethylformamide liquors and methanol wash 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 (approximately 1.5 hours). The temperature is maintained below 5°C. After that the mixture is stirred at 0 to 10°C for 30 minutes and at 25-30°C until the reduction reaction is deemed to be complete (approximately 1 hour).
• Acetic acid 50% is added to destroy the excess borohydride and the 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 the alcohol is washed with demineralised water, passed through a filter for use in the next step.
• the solution of alcohol in toluene is treated with concentrated hydrochloric acid (min 36%) at 15 to 25°C.
• the organic phase, containing the chloro compound is separated and treated with sodium bicarbonate to neutralize the HCI traces.
• 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, demineralised 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 deemed to be complete (approximately 2 hours).
• the product is isolated by centrifugation and washed with cold ( ⁇ 0°C) cyclohexane/toluene.
• the wet cake vacuum dried at max 50°C to give the pimelate as an off white to beige powder.
• a 29% methanolic solution of sodium methoxide is added in one lot to a solution of the pimelate in dioxane.
• the mixture is heated to about 75°C (reflux) and maintained at this temperature until formation of the 2-carbomethoxycyclohexan-l-one is deemed complete (approximately 1 hour).
• Much of the methanol is distilled out and replaced with dioxane.
• Sodium bicarbonate and deminieralised water are added to the .
• the mixture is heated to reflux (about 85 to 88°C) and maintained at this temperature until formation of the cyclohexan-1-one is deemed to be complete (approximately 10 hours).
• 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).
• BTEAC benzyltriethylammonium chloride
• the ketone and a slight excess of chloroacetonitrile in a suitable solvent such as THF is charged into a mixture of strong base (aqueous potassium hydroxide) and BTEAC and a water miscible solvent such as tetrahydrofuran at reduced temperature, about 0° C or thereabouts.
• the reaction is maintained at about that temperature for the duration of the reaction, usually about 1 hour.
• the product can be isolated or used as a crude oil.
• the dicarbonitrile is converted to the cyclohexanecarboxylic acid using a Group 1(a) or 11(a) metal halide.
• This reaction is carried out by charging a vessel with solvents; in this instance exemplified by DMF, acetonitrile and water, and the Group 1(a) or 11(a) metal halide (preferably about 1.5 equivalents), LiBr is illustrated; sweeping the vessel with an inert gas; adding the dicarbonitrile A or B, or a mixture of A and B; and heating the vessel and its contents to about 100° C for a number of hours, 8 hours being an example.
• the reaction is diluted with DMF and optionally water. LiOH dissolved in water is added (about a 50% molar excess is preferred). A suspension is formed. This is stirred at a slightly elevated temperature(40 to 80 °C) for about an hour or so.
• the lithium salt is recovered by conventional means.
• the acid is prepared, for example, by suspending the lithium salt in an organic solvent of the likes of ethyl acetate, and treating the suspension with aqueous mineral acid. The organic solvent is then recovered, washed, and concentrated. The product is isolated by conventional means.
• the dimethylformamide liquors and methanol wash from Example 1 were combined and retransferred into the cleaned reactor.
• An additional amount of methanol (8.52 g) was added and the batch was cooled to 0°C.
• Sodium borohydride (0.49 g, 0.0129 moles) 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 to 10 °C for 30 minutes and then heated to 25 °C. A sample was taken after 110 minutes stirring at 25 to 31 °C and analysed (GC) and the reaction was deemed to be complete.
• Acetic acid 50% (1.80 g) was charged to the reactor to quench any remaining sodium borohydride.
• Example 3 Preparation of 4-Chloromethyl-2-cyclopentyloxy-l-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 complete and analysed (GC) and the reaction was deemed to be complete.
• the phases were allowed to separate and the lower, aqueous phase 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 part of the toluene (17.07 g) was removed by distillation in vacuo (end of distillation: 28 °C, 7 mbar).
• Example 4 Preparation of 4-Cvanomethyl-2-cyclopentyloxy-l-methoxybenzene After cooling the solution from Example 3 to ⁇ 25 °C tetra-butylammonium bromide (0.205 g, 0.63 mmoles), demineralised water (2.775 g) and sodium cyanide (1.976 g, 0.039 moles) were added, the mixture was heated to 80 °C and then stirred at 78.1 to 80.4 °C for 1 hour and 50 minutes. A sample was taken to verify the batch conversion. Toluene (5.841 g) and demineralised water (8.76 g) were added, the phases were allowed to separate (at about 54 °C) and the lower, aqueous phase discarded.
• Example 5 Preparation of Dimethyl-4-cvano-4-(3-cvclopentyloxy-4-methoxy-phenyl)pimelate The cyanomethyl compound prepared in Example 4 (9.05 g at 85.4%; 7.73 g at 100%; 0.0334 moles) was charged in the reactor (0.5 L) at room temperature.
• Acetonitrile (28.56 g) and demineralised water (0.07 g) was charged to the reactor.
• Solutions of methyl acrylate (6.88 g,0.029 moles) in acetonitrile (4.02 g) and methanolic Triton B (40.2% 0.94 g, 2.269 mmoles 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.
• a first portion, about 12.5% of the Triton B solution (0.63 kg) was then added.
• the batch temperature after the addition was 31 °C.
• the batch temperature after the addition was 36 °C.
• a fifth portion, about 25% of the Triton B solution (1.25 g) was then added.
• the batch temperature after the addition was 38 °C.
• the last portion, about 25% of the Triton B solution (1.25 g) was then added.
• the batch temperature after the addition was 36 °C.
• the reaction mixture was stirred for 1.5 hours at 20 - 25 °C.
• the acetonitrile was removed by distillation in vacuo (end of distillation: 59 °C, 20 mbar).
• Example 5 The pimelate made in Example 5 (76.52g, 1,8112 moles) was charged into the reactor (100 mL). Dioxane (2214g) and a 29.1% methanolic of sodium methoxide (0.44g, 24 mmoles) 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 batch conversion. The methanol was removed by distillation (16.82g distillate) to a bottom temperature of 97
• 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 distilling off ethyl acetate (200 mL).
• the contents of the flask were cooled to 60 °C followed by the addition of heptane (275 mL).
• the suspension was cooled to 5 °C, held at 5 °C for 2 hours, filtered, and washed with cold (5 °C) heptane (50 mL).
• the product was dried in a vacuum oven to constant weight to afford 50.0 g (85%) of 3.

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