CHEMICAL PROCESS

Abstract

The present invention provides, inter alia, a process for producing a compound of formula (I) wherein the substituents are as defined in claim 1. The present invention further provides intermediate compounds utilised in said process, and methods for producing said intermediate compounds.

##STR00001##

Claims

1. A process for the preparation of a compound of formula (I) or a salt thereof: ##STR00071## wherein R.sup.1 is C.sub.3-C.sub.7cycloalkyl; said process comprising: reacting a compound of formula (II) ##STR00072## with a compound of formula (III) ##STR00073## wherein R.sup.1 a is C.sub.3-C.sub.7cycloalkyl and X is halogen or hydroxy; or R.sup.1a is C.sub.3-C.sub.7cycloalkenyl and X is hydrogen; in the presence of an acid to give a compound of formula (I).

2. A process according to claim 1, wherein R.sup.1 is cyclopentyl or cyclohexyl.

3. A process according to claim 1, wherein a compound of formula (III) is selected from the group consisting of chlorocyclopentane, chlorocyclohexane, cyclopentanol, cyclohexanol, cyclopentene and cyclohexene.

4. A process according to claim 1, wherein R.sup.1 is cyclohexyl and the compound of formula (III) is chlorocyclohexane or cyclohexanol.

5. A process according to claim 1, wherein the acid is a lewis acid.

6. A process according to claim 5, wherein the lewis acid is selected from the group consisting of aluminium(III) chloride, iron(III) chloride, titanium(IV) chloride, zirconium(IV) chloride and zirconium(IV) oxide chloride.

7. A process according to claim 6, wherein the lewis acid is aluminium(III) chloride.

8. A process according to claim 1, wherein the compound of formula (II) is used in an amount of at least 2 molar equivalents per mole of a compound of formula (III).

9. A process according to claim 1, wherein the compound of formula (II) is used in an amount of from 3 to 5 molar equivalents per mole of a compound of formula (III).

10. A process according to claim 1, wherein the acid is used in an amount of at least 1.1 molar equivalents per mole of a compound of formula (II).

11. A process according to claim 1, wherein the compound of formula (I) is further reacted with a compound of formula (IV), ##STR00074## wherein Y is a suitable leaving group and R.sup.2 is hydrogen or C.sub.1-C.sub.6alkyl; to give a compound of formula (V), ##STR00075## wherein R.sup.1 is as defined in claim 1 and R.sup.2 is as defined above.

12. A process according to claim 11, wherein Y is chloro.

13. A process according to claim 1, wherein the compound of formula (I) is further converted to a compound of formula (VI) ##STR00076## wherein R.sup.1 is as defined in claim 1.

14. A process according to claim 11, wherein the compound of formula (V) is further converted to a compound of formula (VI) ##STR00077##

15. A compound selected from the group consisting of a compound of formula (V-I), (V-II), (V-III) and (V-IV) below, ##STR00078##

16. Use of a compound of formula (I), ##STR00079## wherein R.sup.1 is as defined in claim 1, for preparing a compound of formula (VI).

Description

EXAMPLES

[0099] The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

[0100] The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet; GC=gas chromatography, R.sub.t=retention time, MH.sup.+=molecular mass of the molecular cation, M=molar, RT=room temperature.

[0101] .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm. Samples are measured in CDCl3 as solvent unless indicated otherwise.

LCMS Methods

[0102] Throughout this description, temperatures are given in degrees Celsius and m.p. means melting point. LC/MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus and the methods is as follows:

Method G

[0103] Spectra were recorded on a Mass Spectrometer from Waters (SQD, SQDII Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 3.00 kV, Cone range: 30V, Extractor: 2.00 V, Source Temperature: 150? C., Desolvation Temperature: 350? C., Cone Gas Flow: 50 L/h, Desolvation Gas Flow: 650 L/h, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment, diode-array detector and ELSD detector. Column: Waters UPLC HSS T3, 1.8 ?m, 30?2.1 mm, Temp: 60? C., DAD Wavelength range (nm): 210 to 500, Solvent Gradient: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH, gradient: 10-100% B in 2.7 min; Flow (mL/min) 0.85

Method H

[0104] Spectra were recorded on a Mass Spectrometer from Waters Corporation (SQD, SQDII or QDA Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive and negative ions), Capillary: 0.8-3.00 kV, Cone: 5-30 V, Source Temperature: 120-150? C., Desolvation Temperature: 350-600? C., Cone Gas Flow: 50-150 l/h, Desolvation Gas Flow: 650-1000 l/h, Mass range: 110 to 950 Da and an Acquity UPLC from Waters Corporation: Binary pump, heated column compartment, diode-array detector and ELSD. Column: Waters UPLC HSS T3, 1.8 ?m, 30?2.1 mm, Temp: 60? C., DAD Wavelength range (nm): 210 to 400, Runtime: 1.5 min; Solvents: A=water+5% MeOH+0.05% HCOOH, B=Acetonitrile+0.05% HCOOH; Flow (ml/min) 0.85, Gradient: 10% B isocratic for 0.2 min, then 10-100% B in 1.0 min, 100% B isocratic for 0.2min, 100-10% B in 0.05min, 10% B isocratic for 0.05 min.

GCMS Method

[0105] GCMS was conducted on a Thermo, MS: ISQ and GC: Trace GC 1310 with a column from Zebron phenomenex: Phase ZB-5ms 15 m, diam: 0.25 mm, 0.25 ?m, He flow 1.2 ml/min, temp injector: 250? C., temp detector: 220? C., method: hold 2 min at 40? C., 40? C./min until 320? C., hold 2 min at 320? C., total time 11min.

[0106] Cl reagent gas: Methane, flow 1 ml/min.

Example 1: Preparation of methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate

[0107] ##STR00056##

Step 1: 5-cyclohexyl-2-methyl-phenol

[0108] ##STR00057##

[0109] Procedure A: from O-cresol and Chlorocyclohexane:

##STR00058##

[0110] To a solution of o-cresol (27.4 g, 250 mmol, 3.00 equiv.) in dichloromethane (33.4 mL) cooled to 0? C., was added aluminum chloride (36.9 g, 271.3 mmol, 3.25 equiv.) the reaction mixture was stirred at 0? C. for 15 min. then chlorocyclohexane (10.0 mL, 83.5 mmol, 1.00 equiv.) was added dropwise, and after the reaction mixture was stirred at rt for 2h. The resultant reaction mixture was carefully poured into ice-water and extracted with dichloromethane. The total combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in tert-butyl methylether and washed three times with 2.0 M aqueous sodium hydroxide solution (70 mL per wash). The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by distillation under reduced pressure to give (12.03 g, 58.2 mmol, 70% isolated yield, purity by Q1H NMR: 92%) of 5-cyclohexyl-2-methyl-phenol as a pale-yellow oil.

[0111] LC-MS (Method G), Rt=1.13 min, MS: (M+H)=191; 1H NMR (400 MHz, CDCl3) ? ppm: 7.07 (d, 1H), 6.74 (m, 1H), 6.67 (d, 1H), 4.87 (br s, 1H), 2.38-2.50 (m, 1H), 2.25 (s, 3H), 1.83-1.93 (m, 4H), 1.73-1.83 (m, 1 H), 1.33-1.50 (m, 4H), 1.25-1.33 (m, 1H).

[0112] Procedure B: from O-cresol and Cyclohexanol:

##STR00059##

[0113] To a solution of o-cresol (0.998 g, 9.13 mmol, 1.05 equiv.) in dichloromethane (8.7 mL) cooled to 0? C., was added aluminum chloride (2.37 g, 17.4 mmol, 2.00 equiv.) the reaction mixture was stirred at 0? C. for 15 min. then cyclohexanol (0.889 g, 8.7 mmol, 1.00 equiv.) was added dropwise, and after the reaction mixture was stirred at rt for 5 h 30 min. The resultant reaction mixture was carefully poured into ice-water and extracted with dichloromethane. The total combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give (1.13 g, 4.76 mmol, 55% isolated yield, purity by Q1H NMR: 80%) of 5-cyclohexyl-2-methyl-phenol as a pale-yellow oil.

[0114] Procedure C: from O-cresol and Cyclohexene:

##STR00060##

[0115] To a solution of o-cresol (3.29 g, 30.1 mmol, 2.50 equiv.) in dichloromethane (6 mL) cooled to 0? C., was added trifluoromethanesulfonic acid (1.83 g, 12.05 mmol, 1.00 equiv.) the reaction mixture was stirred at 0? C. for 15 min. then cyclohexene (1 g, 12.05 mmol, 1.00 equiv.) was added dropwise over 10 min. at 0? C., and after the reaction mixture was stirred at rt for 16 h. The desired product (meta regioisomer) was obtained in the crude reaction mixture.

[0116] GC-MS: Rt=7.20 min, MS: (M+H)=191.

Step 2: methyl 2-(5-cyclohexyl-2-methyl-phenoxy)acetate

[0117] ##STR00061##

[0118] To a solution of 5-cyclohexyl-2-methyl-phenol (12.0 g, 58.0 mmol, 1 equiv.) in acetonitrile (116 mL) was added potassium carbonate (20.2 g, 145 mmol, 2.50 equiv.) the reaction mixture was heated at 70? C., then methyl chloroacetate (7.89 mL, 9.74 g, 87.0 mmol, 1.50 equiv.) was added dropwise, the reaction mixture was stirred for 4h at 70? C., an excess of methyl chloroacetate (2.63 mL, 3.25 g, 29.0 mmol, 0.5 equiv.) was added and the reaction mixture was stirred for 3h at 80? C. The reaction mixture was filtered, and the filter cake was washed with acetonitrile, the filtrate was concentrated under vacuum, to get a brown oil. This residue was dissolved in methanol and cooled down at 0? C. and the crystallized compound was filtered. The filter cake was washed with cold methanol and dried in vacuo to give 11.9 g, 44.83 mmol, 77.3% isolated yield, purity by Q1H NMR: 99%) of methyl 2-(5-cyclohexyl-2-methyl-phenoxy)acetate as a colorless solid.

[0119] LC-MS (Method G), Rt=1.23 min, MS: (M+H)=263; 1H NMR (400 MHz, CDCl3) ? ppm: 7.10 (d, 1H), 6.79 (m, 1H), 6.60 (d, 1H), 4.68 (s, 2H), 3.83 (s, 3H), 2.47 (m, 1H), 2.28 (s, 3H), 1.82-1.92 (m, 4H), 1.73-1.81 (m, 1H), 1.36-1.45 (m, 4H), 1.22-1.32 (m, 1H).

Step 3: methyl (E/Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate

[0120] ##STR00062##

[0121] To a solution of methyl 2-(5-cyclohexyl-2-methyl-phenoxy)acetate (1 g, 3.81 mmol, 1.00 equiv.) in tetrahydrofuran (3.8 mL) at rt, under argon atmosphere, were added methyl formate (0.584 g, 9.53 mmol, 2.50 equiv.) and sodium methanolate (0.325 g, 5.72 mmol, 1.50 equiv.). The reaction mixture was stirred at rt for 1 h. Ammonium chloride saturated solution in water was added to the reaction mixture which was extracted twice with ethyl acetate. The total combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to give methyl 2-(5-cyclohexyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate (1.165 g, 3.81 mmol, 100%) as gum which was used directly for the next step.

[0122] LC-MS (Method G), Rt=1.09 min, MS: (M+H)=291

Step 4: methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate

[0123] To a solution of methyl (E/Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate (1.05 g, 3.62 mmol, 1.00 equiv.) in acetonitrile (7.2 mL) were added potassium carbonate (1.01 g, 7.23 mmol, 2.00 equiv.) and dimethyl sulfate (0.691 g, 5.42 mmol, 1.50 equiv.). The reaction mixture was stirred at rt for 4 h. Ammonium hydroxide solution (25% in water) was added dropwise and the reaction mixture was further stirred at rt for 2 h. The reaction mixture was filtered and the solid was washed with ethyl acetate. The total combined organic layer was dried with Na2SO4, filtered, and concentrated in vacuo to give crude methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate (1.262 g, 3.48 mmol, 96% isolated yield, purity by Q1H NMR: 84%) as a yellow solid. The crude was recrystallized in cold methanol to give (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate (0.958 g, 3.17 mmol, 86% isolated yield, purity by Q1H NMR: 99%) as a colourless solid.

[0124] LC-MS (Method G), R.sub.t=1.21 min, MS: (M+H)=305; 1 H NMR (400 MHz, CDCl3) ? ppm ppm 7.35 (s, 1H), 7.10 (d, 1H), 6.79 (dd, 1H), 6.58 (d, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 2.38-2.47 (m, 1H), 2.34 (s, 3H), 1.80-1.89 (m, 4H), 1.75 (br, 1H), 1.33-1.42 (m, 4H), 1.22-1.32 (m, 1H).

Preparation of 2-(5-cyclohexyl-2-methyl-phenoxy)acetic acid

[0125] ##STR00063##

[0126] To a solution of methyl 2-(5-cyclohexyl-2-methyl-phenoxy)acetate (0.10 g, 0.36 mmol, 1 equiv.) in methanol (2 mL) was added lithium hydroxide (0.018 g, 0.72 mmol, 2. equiv.) and the reaction mixture was stirred overnight at RT. The contents were then concentrated in vacuo and the resultant crude residue was purified by column chromatography using a cyclohexane/ethyl acetate eluent gradient to afford 0.039 g of 2-(5-cyclohexyl-2-methyl-phenoxy)acetic acid as an off-white solid.

[0127] .sup.1H NMR (400 MHz, CDCl.sub.3) ? ppm: 7.09 (d, 1 H), 6.80 (d, 1 H), 6.61 (s, 1H), 4.68 (s, 2H), 2.50-2.40 (m, 1H), 2.26 (s, 3H), 1.89-1.75 (m, 4H), 1.41-1.36 (m, 4H), 1.32-1.22 (m, 2H).

Example 2: Preparation of methyl (Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate

[0128] ##STR00064##

Step 1: Preparation of 5-cyclopentyl-2-methyl-phenol

[0129] ##STR00065##

[0130] To a solution of o-cresol (3.10 g, 28.4 mmol, 3.00 equiv.) in dichloromethane (9.50 mL) cooled to 0? C., was added aluminum chloride (4.19 g, 30.8 mmol, 3.25 equiv.) and the reaction mixture was stirred at 0? C. for 15 min. Then cyclopentylchloride (1.00 g, 0.99 mL, 9.47 mmol, 1.00 equiv.) was added dropwise and the reaction mixture was stirred at RT for 4h. The reaction mixture was carefully poured into ice-water and extracted with dichloromethane. The residue was dissolved in tert-butyl methylether and washed three times with sodium hydroxide solution (2M) in water. The organic layer was dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography to give (1.17 g, 6.62 mmol, 70% isolated yield, purity by Q1H NMR: 98%) of 5-cyclopentyl-2-methyl-phenol as a pale-yellow oil.

[0131] LC-MS (Method G), Rt=1.07 min, MS: (M+H)=177; 1H NMR (400 MHz, CDCl3) ? ppm: 7.05 (d, 1H), 20 6.77 (m, 1H), 6.70 (d, 1H), 4.58 (s, 1H), 2.89-3.00 (m, 1H), 2.24 (s, 3H), 2.01-2.11 (m, 2H), 1.76-1.86 (m, 2H), 1.64-1.74 (m, 2H), 1.53-1.63 (m, 2H).

Step 2: Preparation of methyl 2-(5-cyclopentyl-2-methyl-phenoxy) acetate

[0132] ##STR00066##

[0133] At room temperature, to a solution of 5-cyclopentyl-2-methyl-phenol (300 mg, 1.70 mmol) in acetonitrile (3.40 mL) was added potassium carbonate (594 mg, 4.26 mmol). The resulting pale yellow suspension was heated at 70? C.; then, methyl chloroacetate (0.231 mL, 2.55 mmol) was added dropwise over 1 min. The reaction mixture was stirred at 70? C. for 16h; then, cooled down to room temperature and filtered off. The filter cake was washed with 10 mL of acetonitrile. The filtrate was concentrated to afford the crude title compound as a brown thick oil (chemical yield: 94.5%; purity: 89%). Purification by flash chromatography (Combiflash, silica gel, 0-50% ethyl acetate in cyclohexane) afforded methyl 2-(5-cyclopentyl-2-methyl-phenoxy) acetate as a colourless oil in 84% isolated yield (purity: 99.6%).

[0134] .sup.1H NMR (400 MHz, CDCI3) 6 ppm 1.51-1.62 (m, 2 H) 1.65-1.75 (m, 2 H) 1.76-1.88 (m, 2 H) 1.98-2.14 (m, 2 H) 2.89-3.03 (m, 1 H) 3.81-3.87 (m, 3 H) 4.58-4.75 (m, 2 H) 6.06-6.18 (m, 3 H) 6.58-6.68 (m, 1 H) 6.79-6.88 (m, 1 H) 7.02-7.16 (m, 1 H)

[0135] LC-MS (Method H): retention time 1.21 min, m/z 249 [M+H.sup.+].

Step 3: Preparation of methyl (E/Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate

[0136] ##STR00067##

[0137] At room temperature, to a solution of methyl 2-(5-cyclopentyl-2-methyl-phenoxy) acetate (117 mg, 0.471 mmol) in tetrahydrofuran (0.471 mL) under argon was added methyl formate (0.178 mL, 2.83 mmol), followed by sodium methoxide (5.4 M in methanol, 0.170 mL, 0.942 mmol). The resulting pale yellow solution was stirred overnight at room temperature. Water and sat. aq. NH.sub.4Cl were added, and the reaction mixture was extracted twice with ethyl acetate. The organic layer was dried (Na2SO4), filtered and concentrated to afford methyl (E/Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate as a crude material, which was used in the next step without any purification.

[0138] LC-MS (Method H): retention time 1.11 min, m/z 277 [M+H.sup.+].

Step 4: Preparation of methyl (Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate

[0139] ##STR00068##

[0140] At room temperature, to a solution of methyl (E)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-hydroxy-prop-2-enoate (129 mg, 0.467 mmol) in acetonitrile (0.934 mL) was added potassium carbonate (130 mg, 0.934 mmol) under Argon. Then, dimethyl sulfate (0.0671 mL, 0.700 mmol) was added dropwise and the resulting yellow suspension was stirred at room temperature for 1.5 h. Ammonium hydroxide solution (25% in water, 0.120 mL, 0.934 mmol) was added and stirring continued at room temperature for additional 1.5 h before being filtered. The filter cake was washed with ethyl acetate and the filtrate was concentrated to afford the crude title compound as a yellow solid (chemical yield: 56%; purity: 55%). Purification by flash chromatography (Combiflash, silica gel, 0-60% ethyl acetate in cyclohexane) afforded methyl (Z)-2-(5-cyclopentyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate as a pale yellow solid in 52.5% isolated yield (purity: 90%).

[0141] .sup.1H NMR (400 MHz, CDCI3) 6 ppm 1.49-1.58 (m, 2 H) 1.63-1.72 (m, 2 H) 1.74-1.86 (m, 2 H) 1.96-2.10 (m, 2 H) 2.31-2.35 (m, 3 H) 2.86-2.99 (m, 1 H) 3.69-3.76 (m, 3 H) 3.85-3.92 (m, 3 H) 6.58-6.63 (m, 1 H) 6.78-6.84 (m, 1 H) 7.06-7.12 (m, 1 H) 7.30-7.36 (m, 1 H)

[0142] LC-MS (Method H): retention time 1.23 min, m/z 291 [M+H.sup.+].

Example 3: Preparation of (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoic acid

[0143] ##STR00069##

[0144] To a solution of methyl (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoate (1.2 g, 3.7 mmol) in tetrahydrofuran (11 mL) was added potassium trimethylsilanolate (0.58 g, 4.5 mmol, 1.2 equiv.) portionwise at RT. The reaction mixture was stirred for 14 hour, then diluted with water and acidified with 1N HCl to pH 5. The solution was extracted twice with ethyl acetate and the total combined organic layer was dried over sodium sulfate, filtrated and concentrated under reduced pressure to get a white wax. Purification by preparative reverse phase column chromatography afforded 550 mg (98% pure) of (Z)-2-(5-cyclohexyl-2-methyl-phenoxy)-3-methoxy-prop-2-enoic acid as an off white solid.

[0145] LC-MS (Method G), R.sub.t=1.07 min, MS: (M+H)=291.

[0146] During some reaction sequences to prepare Example 3, reverse phase column chromatography purification afforded a 2-(5-cyclohexyl-2-methyl-phenoxy)-3,3-dimethoxy-propanoic acid by-product which was isolated as a yellow gum:

##STR00070##