Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/24—Preparation of carboxylic acid nitriles by ammoxidation of hydrocarbons or substituted hydrocarbons
  • C07C253/28—Preparation of carboxylic acid nitriles by ammoxidation of hydrocarbons or substituted hydrocarbons containing six-membered aromatic rings, e.g. styrene
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C253/00—Preparation of carboxylic acid nitriles
  • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
• • 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 relates to a method and intermediates for preparing certain nitriles which are useful for making cyclohexanoic acids.
• the latter are pharmaceutically active agents.
• the process and intermediates of this invention provide a means for making certain 4-substituted-4-(3,4-disubstituted phenyl)cyclohexanoic acids which are useful for treating asthma and other diseases which can be moderated by affecting the PDE 4 enzyme.
• the final products of particular interest are fully described in U.S. patent 5,552,438 issued 03 September 1996.
• the information and representations disclosed therein, in so far as that information and those representations are necessary to the understanding of this invention and its practice, are incorporated herein by reference, in total.
• This invention discloses a method for preparing a cyclohexanoic acid by cyanohydrin homologation of a cyclohexanone precursor. Summary of the Invention
• this invention relates to a process for preparing an ⁇ , ⁇ - unsaturated cyclohexene carboxylic acid of formula (A)
• this invention relates to a process for preparing a compound of formula (I) by the cyanohydrin homologation of cyclohexanone (X) as described herein
• This invention can be used to homologate any cyclohexanone.
• the cyclohexanone has a 4-position nitrile group with or without another group at that 4 position. Since the homologation is believed to be independent of the 4-position substitutent(s), the scope of the compounds which are homologated herein are simply examples of the chemistries being done on the 1 -position carbon.
• the invention is exemplified by compounds which have an aromatic group at the 4 position in addition to the nitrile group.
• a preferred group of compounds which can be prepared by this homologation route are those of formula (la)
• R j is -(CR4R5) r R6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
• R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens
• R3 is -CN; r is 0 to 6;
• R4 and R5 are independently selected from hydrogen or a Cj-2 alkyl
• R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCj-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C ⁇ . ⁇ ⁇ 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;
• R7 is hydrogen or C ] _6 alkyl
• X is YR2; X2 is O or NR 7 ;
• Y is O or S(0) m where m is 0, 1 or 2; and one of R' or R" is hydrogen and the other is COOH or a salt thereof.
• Preferred X groups for formula (la) are those wherein Y is oxygen.
• the preferred X2 group for formula (la) is that wherein X2 is oxygen.
• Preferred R2 groups are a Ci-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 C]_2 alkyl, such as a - CF3, -CHF2, or -CH2CHF2 moiety. Most preferred are the -CHF2 and -CH3 moieties.
• R] is -CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H;
• X is YR2;
• Y is oxygen;
• X2 is oxygen; and
• R2 is CF2H or methyl.
• the most preferred compounds are cis and trans 4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid, in particular the cis iso er, which is the equitorial form the acid.
• R] is -(CR4R5) r R6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
• R2 is -CH3 or -CH2CH3 optionally substituted by 1 or more halogens
• R3 is -CN; r is 0 to 6; R4 and R5 are independently selected from hydrogen or a Ci-2 alkyl; R is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyCi-3 alkyl, halo substituted aryloxyCi-3 alkyl, indanyl, indenyl, C7-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;
• R7 is hydrogen or C ⁇ _ alkyl
• X is YR2;
• X2 is O or NR 7 ; Y is O or S(0) m where is 0, 1 or 2.
• Preferred X groups for formula (A) are those wherein Y is oxygen.
• X2 group for formula (A) is that wherein X2 is oxygen.
• Preferred R2 groups are a Cj-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 C]_2 alkyl, such as a -
• CF3, -CHF2, or -CH2CHF2 moiety are preferred. Most preferred are the -CHF2 and -CH3 moieties.
• This invention can be applied generally to the preparation and reduction of an oc, ⁇ - unsaturated cyclohexene carboxylate as illustrated in Scheme 2.
• Compound 4 is prepared by the hydrolysis of the ⁇ , ⁇ unsaturated nitrile 3 with base (for example 2 equivalents of Ba(OH) 2 ). This produces the unsaturated carboxylic acids which are stable and can be characterized. Although the catalytic hydrogenation of 3 is difficult to achieve, hydrogenation of 4 occurs readily and produces the saturated carboxylate as a mixture of cis and trans acid. This mixture can be converted to the cis isomer by equilibration of the methyl esters.
• base for example 2 equivalents of Ba(OH) 2
• Reaction Scheme 3 illustrates how a by-product of the base hydrolysis of compound 7 in Scheme 1 can be converted to the 4-cyanocyclohexanoic acid.
• Trimethylsilyl Cyanide Method To a 100 ml round bottom flask equipped with magnetic stirrer and a nitrogen inlet was charged 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (prepared as illustrated in, for example, U.S. patent 5,552,438) (12.50 g, 40 mmol), zinc iodide (0.35 g, 1.1 mmol) and methylene chloride (50 mL). Stirring produced a clear solution. This solution was charged with trimethylsilyl cyanide (TMSCN).(8 mL, 5.952 g, 59.9 mmol). After stirring for 1 hour under nitrogen 5 drops of the solution was quenched into dilute acid and examined by reverse phase HPLC.
• TMSCN trimethylsilyl cyanide
• the reaction was cooled to 15 °C and treated with a stream of HC1 (gas) for 15 min.
• the reaction was evaporated on the rotovap and the resulting thick oil was suspended in ethyl acetate (150 mL) and washed with 2 x 50 mL 3N HC1, brine (25 mL) and finally evaporated to a residue.
• the residue was treated with ethanol (95%) (15 mL) and the solution cooled to 0 °C overnight. No crystallization had occurred.
• the solution was refluxed and treated sequentially with acetone (5 mL) and water (deionized, 15 mL).
• the solution was cooled to room temperature and treated with 5 mg and seeds of authentic cyanohydrin.
• the reaction was cooled to 0 °C and stirred for 1.5 hours.
• the resultant solids were filtered and washed with cold H 2 0-EtOH ( 1 : 1 ) ( 10 mL) .
• Example 2 Alternative Preparation of 4-[3-(Cyclopentyloxy)-4-methoxyphenyll-l ,4-dicarbonitrile cyclohexan- l-ol: Sodium Cyanide Method To a 20 mL round bottom flask equipped with magnetic stirrer and internal thermometer was added 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-l-one (1.00 g, 3.19 mmol) and sodium cyanide (0.325 g, 6.6 mmol) in water (5 mL).
• Example 4 Alternative Method for Dehydrating 4-r3-(Cvclopentyloxy)-4-methoxyphenyll-l ,4- dicarbonitrile cyclohexan- l-ol
• a pressure equalizing dropping funnel and a nitrogen inlet was charged crude 4- [3- (cyclopentyloxy)-4-methoxyphenyl]-l,4-dicarbonitrile cyclohexan- l-ol (2) along with toluene (140 mL) and pyridine (40 mL).
• a clear solution was produce with stirring.
• the reaction was cooled to 10 °C and thionyl chloride (about 20 mL) was added at a rate to keep the reaction ⁇ 15° C.
• the reaction was refluxed and monitored by HPLC (4.6 x 250 mm Beckman Ultrasphere; wavelength at 230 nm, flow rate 1.0 mL/min) until essentially all of the starting material had disappeared, approximately 2.5 hours.
• the reaction was cooled to 40 °C in an ice bath and quenched with 6N HCl ( 100 mL) followed by addition of ethyl acetate (400 mL). The organic layer was separated and washed with two 100 mL portions of 3N HCl, 10% aqueous sodium bicarbonate (100 mL), and finally brine (100 mL). The organic layer was evaporated to constant weight and dissolved in warm isopropanol (50 mL). The solution was cooled to 0 °C and the solid was stirred at that temperature for 2 hours, and filtered and washed with cold isopropanol (10 mL).
• the reaction mixture was cooled to ⁇ 30 °C and treated with 6N HCl.
• the reaction solvent was evaporated on the rotovap (40 °C) to constant weight and the residue treated with ethyl acetate (200 mL).
• the isolated organic layer after filtration was washed with water (2 x 50 mL) and brine (2 15 mL).
• the organic layer was concentrated on a rotovap to an oil, i.e. 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-l-cyclohexane- 1,4- dicarbonitrile, compound 7 in Scheme 1.
• the product was diluted with absolute ethanol and used directly in the hydrolysis of the nitrile with potassium hydroxide.
• reaction mixture was reduced to one- half volume on the rotovap and partitioned between ethyl acetate (50 mL) and 6 N HCl (12 mL). The organic layer was separated and washed with deionized water (2 x 15 mL), brine (1 x 15 mL), and evaporated to give a mixture of cis and trans isomers of 4-cyano-4-[3- (cyclopentyloxy)-4-methoxyphenyl]-l -cyclohexane- 1 -carboxylic acid as an oil.
• Example 8 Hydrolysis of 4-r3-(Cvclopentyloxy)-4-methoxyphenyll- 1 -cyclohexane- 1 ,4-dicarbonitrile
• a 50 mL 3-necked round bottom flask equipped with magnetic stirrer, an internal thermometer, and a reflux condenser was charged equal amounts of cis saturated nitrile (compound 7 in Scheme 1 , 4-[3-(cyclopentyloxy)-4-methoxyphenyl]-l -cyclohexane- 1 ,4- dicarbonitrile) (0.5016 g, 1.54 mmol) and the corresponding trans dicarbonitrile (0.5016 g, 1.54 mmol) (total 3.08 mmol) and absolute ethanol ( 10 mL).
• the reaction was heated to reflux for 5 min, to obtain a solution.
• the reaction was treated slowly with a solution of NaOH ( 1.16 g, 29 mmol, 9.4 eq) in deionized water ( 10 mL).
• the rate of addition was adjusted to avoid precipitation of the starting nitriles.
• the solution was stirred and refluxed for 4-5 h.
• the HPLC showed (80% PAR) of the desired product a cis/trans mixture of acids and a side product identified as an acid-amide, that is, the 4-position nitrile had converted to -CONH2.
• the solvent was evaporated to give an oil which was treated with 6 N HCl (10 mL) and ethyl acetate (35 mL).
• Toluene (9.0 mL) was added and then thionyl chloride (1.0 mL, 1.6 g) and the reaction heated at 70-75 °C. The reaction was judged to be complete after 3 h.
• the reaction was evaporated on the rotovap to 4 mL, and transferred to a separatory funned with ethyl acetate (30 mL). The top layer was washed with water (2 x 5.5 mL), 3 N HCl (1 x 5 mL), water (1 5 mL) and brine (1 x 5 mL) before drying with magnesium sulfate.
• the resulting organic layer was evaporated to constant weight (1.15 g) and dissolved in boiling ethyl acetate and treated with hexane.
• the product was further treated by using a base-acid treatment of the combined aqueous layers, followed by extraction into ethyl acetate. Evaporating the ethyl acetate gave a residue which was dissolved then re-dissolved in ethyl acetate (5 mL) and hexane (4 mL).
• Example 9 Alternative Process for Hydrolyzing 4- 3-(Cvclopentyloxy)-4-methoxyphenyn-l- cyclohexene- 1 ,4-dicarbonitrile
• a 100 mL 3-necked round bottom flask equipped with magnetic stirrer, an internal thermometer, and a reflux condenser was charged the cisltrans saturated nitriles (compound 7, 4-[3-(cyclopentyloxy)-4-methoxyphenyl]- 1 -cyclohexene- 1 ,4-dicarbonitrile) (2.12 g, 6.54 mmol) and absolute ethanol (10 mL). The reaction was heated to reflux; a solution was obtained.
• the reaction was treated slowly with a solution of KOH (3.4 g, 60.6 mmol, 9.3 eq) in deionized water (10 mL). The addition was done dropwise over 10 min.. The solution was stirred and refluxed for 4-5 h. At that time the HPLC showed the absence of starting material and the presence of 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]- 1 -cyclohexane- 1 -carboxylic acid and the side product, the 4-carboxamide 8 (15 % PAR). The reaction was evaporated to 1/2 volume and treated with 6 N HCl (12 mL) and ethyl acetate (50 mL).
• Example B Transfer hydrogenation of 4-Cyano-4-[3-(cvclo ⁇ entyloxy)-4-methoxyphenyll-l- cyclohexene-1 -carboxylic acid (4) to c-4-Cvano-4-(3-cyclopentyloxy-4-methoxyphenyl)-r- cvclohexanecarboxylic acid (5)
• 4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]-l- cyclohexene- 1 -carboxylic acid (4 in Scheme 1) ( 0.021 g, 0.06 mmol) and dimethyl formamide (DMF) (0.5 L).

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• 2001
  • 2001-01-10 AR ARP010100094A patent/AR029788A1/es not_active Application Discontinuation
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  • 2001-01-12 EP EP01942356A patent/EP1246794A4/en not_active Withdrawn
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