Process for the preparation of a spiroheterocyclic pyrrolidine dione

Abstract

A process for making certain spiroheterocyclic pyrrolidine dione derivatives.

Claims

1. A process for the preparation of a spiroheterocyclic pyrrolidine dione compound of formula (II) ##STR00059## wherein X, Y and Z independently of each other are hydrogen, C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, halogen, cyano, C.sub.2-6alkenyl, C.sub.2-6alkynyl, phenyl, or phenyl substituted by C.sub.1-4alkyl, C.sub.1-4haloalkyl, halogen or cyano; m and n, independently of each other, are 0, 1, 2 or 3 and m+n is 0, 1, 2 or 3; A is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.3-6cycloalkyl, C.sub.3-6cycloalkyl(C.sub.1-4)alkyl, C.sub.2-6alkenyl, C.sub.2-6haloalkenyl, C.sub.3-6alkynyl, C.sub.1-4alkoxy(C.sub.1-4)alkyl, benzyl, phenyl or phenyl substituted by C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, C.sub.1-4haloalkoxy, halogen or cyano; and W is a group selected from W.sup.1 to W.sup.15: ##STR00060## wherein R is hydrogen, C.sub.1-6alkyl, C.sub.1-6haloalkyl, C.sub.1-6cyanoalkyl, C.sub.2-6alkenyl, C.sub.2-6haloalkenyl, C.sub.3-6alkynyl, benzyl, C.sub.1-4alkoxy(C.sub.1-4)alkyl or C.sub.1-4alkoxy(C.sub.1-4)alkoxy(C.sub.1-4)alkyl; R.sup.q is R or Q.sup.2; p is 0, 1 or 2; and Q.sup.2 is hydrogen, formyl, C.sub.1-6alkylcarbonyl or C.sub.1-6alkoxycarbonyl; which process comprises (a) treating a compound of the formula I or a salt thereof with a suitable base in an appropriate solvent (or diluent) ##STR00061## wherein X, Y, Z, m, n, A, and W have the meanings given in the formula (II) above and Q.sup.1 is C.sub.3-6cycloalkyl, C.sub.1-6alkoxycarbonyl (C.sub.1-6)alkyl, p-tolylsulfonylmethyl, phenyl or phenyl substituted by one or more substituent selected from the group consisting of C.sub.1-4alkyl, C.sub.1-4haloalkyl, C.sub.1-4alkoxy, halogen, and nitro; and Q.sup.2 is hydrogen, formyl, C.sub.1-6alkylcarbonyl or C.sub.1-6alkoxycarbonyl; (b) optionally a compound of formula (III) is included in step (a), ##STR00062## wherein Q.sup.3 is hydrogen, halogen, C.sub.1-6alkyl or C.sub.1-6alkoxy, L is O or N(C.sub.1-6alkyl) and Q.sup.4 is C.sub.1-6alkyl, provided the solvent (or diluent), and if necessary the compound of formula (III), is selected to activate the NQ.sup.1Q.sup.2 group to become a leaving group.

2. The process according to claim 1, wherein at least one of the solvent (or diluent), or if present, the compound of formula (III), is a dipolar aprotic solvent.

3. The process according to claim 1, wherein the base is selected from alkali metal or alkaline earth metal hydroxides, alkali metal or alkaline earth metal hydrides, alkali metal or alkaline earth metal amides, alkali metal or alkaline earth metal alkoxides, alkali metal or alkaline earth metal acetates, alkali metal or alkaline earth metal carbonates, alkali metal or alkaline earth metal dialkylamides or alkali metal or alkaline earth metal alkylsilylamides, alkylamines, alkylenediamines, free or N-alkylated saturated or unsaturated cycloalkylamines, basic heterocycles, ammonium hydroxides and carbocyclic amines.

4. The process according to claim 1, wherein Q.sup.2 is hydrogen.

5. The process according to claim 1, wherein Q.sup.1 is phenyl or phenyl substituted by one or more substituent selected from methyl, ethyl, iso-propyl, trifluoromethyl, methoxy, ethoxy, fluoro, chloro and nitro.

6. The process according to claim 1, wherein A is methyl.

7. The process according to claim 1, wherein X, Y and Z independently of one another are selected from methyl, ethyl, iso-propyl, n-propyl, methoxy, fluoro, bromo or chloro, and wherein m+n is 1 or 2.

Description

PREPARATORY EXAMPLES

Example 1: Preparation of 4-(N-[2-(2,4-dichlorophenyl)acetyl]anilino)-1-methoxy-N-phenyl-piperidine-4-carboxamide (Compound P1.1)

(1) ##STR00018##

(2) A round bottom flask, equipped with a magnetic stirrer bar, was charged with 1-methoxypiperidin-4-one (250.5 mg, 1.9 mmol), aniline (180.6 mg, 1.9 mmol) and methanol (0.5 mL). This was stirred at room temperature for 10 min, then 2-(2,4-dichlorophenyl)acetic acid (397.7 mg, 1.9 mmol) was added. This was stirred an additional 5 min, and isocyanobenzene (200.0 L, 1.9 mmol) was added dropwise. An additional 0.5 mL of methanol was added to ensure stirring. The mixture was stirred for 2 days at room temperature. A precipitate had formed which was dissolved in dichloromethane. The mixture was evaporated under vacuum and the crude residue was taken up in dichloromethane and purified by flash column chromatography (DCM/EtOAc) to afford 4-(N-[2-(2,4-dichlorophenyl)acetyl]anilino)-1-methoxy-N-phenyl-piperidine-4-carboxamide (900.0 mg) as a light brown oil. .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.27 (br. s, 1H), 7.54 (app. d, J=7.7 Hz, 2H), 7.43 (br. s, 3H), 7.30-7.37 (m, 3H), 7.22-7.28 (m, 2H), 7.10-7.18 (m, 2H), 7.02-7.08 (m, 1H), 3.49 (s, 3H), 3.33 (br. s, 2H), 3.27 (br. s, 2H), 2.93-3.13 (br. m, 2H), 2.50-2.70 (br. m, 3H), 1.75-1.91 (br. m, 1H). .sup.13C NMR (100 MHz, CHLOROFORM-d) 172.0, 169.3, 139.4, 138.0, 135.0, 133.6, 132.3, 130.2, 129.6 (2C), 129.2 (2C), 129.0 (3C), 127.1 (2C), 124.4, 120.5 (2C), 65.2, 59.1, 54.1, 52.5, 41.6, 38.0, 33.6. LCMS, R.sub.t 1.20 min, (MH)=510/512 and (M+H)=512/514.

Example 2: Preparation of 2-(2,4-dichlorophenyl)-1-hydroxy-8-methoxy-4-phenyl-4,8-diazaspiro[4.5]dec-1-en-3-one (Compound P2.1)

(3) ##STR00019##

(4) A microwave vial, equipped with a magnetic stirrer bar, was charged with 4-(N-[2-(2,4-dichlorophenyl)acetyl]anilino)-1-methoxy-N-phenyl-piperidine-4-carboxamide (200.0 mg, 0.39 mmol), potassium tert-butoxide (88.5 mg, 0.78 mmol) and DMF (2 mL). The vial was sealed and the mixture was heated to 130 C. for 45 min in the microwave. The reaction mixture was diluted with EtOAc (5 mL), and quenched with 1M HCl. The layers were separated and the organic layer was washed once more with 1M HCl. Combined aqueous layers were extracted twice with EtOAc. The solvents was removed under vacuum and the crude material was purified reversed phase HPLC to afford 2-(2,4-dichlorophenyl)-1-hydroxy-8-methoxy-4-phenyl-4,8-diazaspiro[4.5]dec-1-en-3-one (50 mg) as a white fluffy solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 8.96 (s, 1H), 7.42-7.56 (m, 3H), 7.38-7.42 (m, 1H), 7.13-7.28 (m, 3H), 6.95-7.05 (m, 1H), 3.16-3.35 (m, 5H), 3.01 (br. s, 2H), 2.60 (br. s, 1H), 2.40 (br. s, 1H), 2.00 (br. s, 1H), 1.48 (br. s, 1H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) 169.5, 138.8, 134.5, 133.3, 132.0, 130.6, 129.4, 128.2 (2C), 126.9, 123.5, 121.3 (2C), 58.4, 51.4 (2C), 40.0, 31.6 (2C) (C-3 and C-4 not observed). LCMS, R.sub.t 0.95-1.00 min, (MH)=417/419, (M+H)=419/421.

Example 3: Preparation of 1-[benzyl-[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]amino]-N-phenyl-cyclohexanecarboxamide (Compound P1.2)

(5) ##STR00020##

(6) A round bottom flask, equipped with a magnetic stirrer bar, was charged with cyclohexanone (190.3 mg, 1.9 mmol), benzylamine (212.0 L, 1.9 mmol) and methanol (0.5 mL). This was stirred at room temperature for 10 min, then 2-(4-choro-2,6-dimethylphenyl)acetic acid (385.3 mg, 1.9 mmol) was added. This was stirred an additional 5 min, and isocyanobenzene (200.0 L, 1.9 mmol) was added dropwise. An additional 0.5 mL of methanol was added to ensure stirring. The mixture was stirred for 2 days at room temperature. A precipitate had formed which was dissolved in dichloromethane. The mixture was evaporated under vacuum and the crude residue was taken up in dichloromethane and purified by flash column chromatography (DCM/EtOAc) to afford 1-[benzyl-[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]amino]-N-phenyl-cyclohexanecarboxamide (200.0 mg) as a yellow solid. .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.14 (s, 1H), 7.46 (d, J=7.7 Hz, 2H), 7.36-7.39 (m, 4H), 7.30 (t, J=7.9 Hz, 3H), 7.09 (t, J=7.3 Hz, 1H), 7.01 (s, 2H), 4.88 (s, 2H), 3.67 (s, 2H), 2.64-2.73 (m, 2H), 2.12 (s, 6H), 1.93-2.04 (m, 2H), 1.59-1.71 (m, 5H), 1.30-1.42 (m, 1H). .sup.13C NMR (100 MHz, CHLOROFORM-d) 173.8, 170.8, 138.8 (2C), 138.3, 138.2, 132.2, 131.3, 129.1 (2C), 128.9 (2C), 127.8 (2C), 127.5, 125.9 (2C), 123.9, 120.1 (2C), 67.9, 48.8, 36.7, 33.2 (2C), 25.3, 23.2 (2C), 20.2 (2C). LCMS, R.sub.t 1.28 min, (MH)=487/489.

Example 4: Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-4-methyl-8-oxa-4-azaspiro[4.5]dec-1-en-3-one (Compound P2.3)

(7) ##STR00021##

(8) A microwave vial, equipped with a magnetic stirrer bar, was charged with 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-N-phenyl-tetrahydropyran-4-carboxamide (50.0 mg, 0.12 mmol), potassium tert-butoxide (27.3 mg, 0.24 mmol) and DMF (2 mL). The vial was sealed and the mixture was heated to 120 C. for 20 min in the microwave. The reaction mixture was diluted with EtOAc (5 mL), and quenched with 1M HCl. The layers were separated and the organic layer was washed once more with 1M HCl. Combined aqueous layers were extracted twice with EtOAc. The solvents was removed under vacuum and the crude material taken up in DCM then purified by FCC (DCM/EtOAc) to afford 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-4-methyl-8-oxa-4-azaspiro[4.5]dec-1-en-3-one (22 mg) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.04 (s, 1H), 7.14 (s, 2H), 3.95-4.04 (m, 2H), 3.85-3.92 (m, 2H), 2.79 (s, 3H), 2.02-2.14 (m, 8H), 1.57 (br. d, J=13.9 Hz, 2H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) 173.8, 168.7, 140.6 (2C), 131.6, 129.0, 126.3 (2C), 101.8, 63.2 (2C), 58.8, 31.4 (2C), 23.4, 19.6 (2C). LCMS, R.sub.t 0.80 min, (MH)=320/322, (M+H)=322/324.

Example 5: Preparation of 1-[[2-(2,5-dimethylphenyl)acetyl]amino]-4-methoxy-N-phenyl-cyclohexanecarboxamide (Compound P1.6)

(9) ##STR00022##

(10) A round bottom flask, equipped with a magnetic stirrer bar, was charged with 4-methoxycyclohexanone (234.2 mg, 1.8 mmol), ammonium carbonate (140.4 mg, 1.4 mmol) and 2,2,2-trifluoroethanol (4.0 mL). This was stirred at room temperature for 10 min, then cooled to 0 C. before 2-(2,5-dimethylphenyl)acetic acid (200.0 mg, 1.2 mmol) was added. This was stirred an additional 5 min, and isocyanobenzene (188.4 L, 1.2 mmol) was added dropwise. The mixture was allowed to warm up to room temperature and stirred for 2 days. A precipitate had formed which was dissolved in dichloromethane. The mixture was evaporated under vacuum and the crude residue was taken up in dichloromethane and purified by flash column chromatography (DCM/EtOAc) to afford 1-[[2-(2,5-dimethylphenyl)acetyl]amino]-4-methoxy-N-phenyl-cyclohexanecarboxamide (384.2 mg) as a 1.5:1 mixture of diastereoisomers.

(11) Major diastereoisomer: .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.79 (br. s, 1H), 7.53-7.60 (m, 2H), 7.32 (t, J=7.5 Hz, 2H), 7.05-7.17 (m, 3H), 7.02 (s, 1H), 5.40 (s, 1H), 3.64 (s, 2H), 3.30-3.33 (m, 1H), 3.28 (s, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 2.08-2.15 (m, 2H), 1.89-2.02 (m, 2H), 1.73-1.81 (m, 2H), 1.26-1.39 (m, 2H). .sup.13C NMR (CHLOROFORM-d) : .sup.13C NMR (CHLOROFORM-d) : 173.1, 171.3, 138.5, 136.5, 133.7, 132.6, 131.0, 130.9, 129.0, 128.9 (2C), 123.9, 120.0 (2C), 73.8, 61.1, 55.6, 42.4, 30.1 (2C), 25.2 (2C), 20.8, 19.0. LCMS, R.sub.t 0.99 min, (MH)=393.

(12) Minor diastereoisomer: .sup.1H NMR (400 MHz, CHLOROFORM-d) 9.87 (br. s, 1H), 7.54 (dd, J=8.5 Hz, 1.0 Hz, 2H), 7.31-7.36 (m, 2H), 7.06-7.17 (m, 3H), 7.04 (s, 1H), 5.35 (s, 1H), 3.66 (s, 2H), 3.35 (s, 3H), 3.13-3.25 (m, 1H), 2.33 (s, 3H), 2.29 (s, 3H), 2.22-2.28 (m, 2H), 1.86-1.98 (m, 4H), 1.11-1.26 (m, 2H). .sup.13C NMR (CHLOROFORM-d) : .sup.13C NMR (CHLOROFORM-d) : 173.2, 171.4, 138.4, 136.6, 133.7, 132.3, 131.1, 130.9, 129.1, 128.9 (2C), 124.0, 120.0 (2C), 76.9, 60.9, 55.8, 42.4, 29.8 (2C), 26.6 (2C), 20.8, 19.1. LCMS, R.sub.t 0.97 min, (MH)=393.

Example 6: Preparation of 2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (Compound P2.4)

(13) ##STR00023##

(14) A microwave vial, equipped with a magnetic stirrer bar, was charged with 1-[[2-(2,5-dimethylphenyl)acetyl]amino]-4-methoxy-N-phenyl-cyclohexanecarboxamide (1.5:1 mixture of diastereoisomers, 100.0 mg, 0.25 mmol), potassium tert-butoxide (57.0 mg, 0.50 mmol) and DMF (2 mL). The vial was sealed and the mixture was heated to 210 C. for 30 min in the microwave. The reaction mixture was diluted with EtOAc (5 mL), and quenched with 1M HCl. The layers were separated and the organic layer was washed once more with 1M HCl. Combined aqueous layers were extracted twice with EtOAc. The solvents was removed under vacuum and the crude material was purified by flash column chromatography (DCM/EtOAc) to afford 2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (40 mg) as a 1.5:1 mixture of trans/cis diastereoisomer. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.66 (s., 2H), 8.16 (s, 2H), 7.11 (d, J=8.0 Hz, 2H), 7.04 (dd, J=8.0, 1.5 Hz, 2H), 6.94 (d, J=1.5 Hz, 2H), 3.47-3.51 (m, 1H), 3.31 (s, 3H), 3.29 (s, 3H), 3.12-3.23 (m, 1H), 2.30 (s, 6H), 2.14 (s, 6H), 1.98-2.07 (m, 2H), 1.89-1.98 (m, 5H), 1.74-1.86 (m, 3H), 1.52-1.65 (m, 2H), 1.43-1.50 (m, 2H), 1.15-1.22 (m, 2H). LCMS, R.sub.t 0.77 min, (MH)=300, (M+H)=302.

Example 7: Preparation of 4-allyl-2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (Compound P2.5)

(15) ##STR00024##

(16) A microwave vial, equipped with a magnetic stirrer bar, was charged with 1-[allyl-[2-(2,5-dimethylphenyl)acetyl]amino]-4-methoxy-N-phenyl-cyclohexanecarboxamide (100.0 mg, 0.26 mmol), potassium tert-butoxide (52.0 mg, 0.52 mmol) and DMF (2 mL). The vial was sealed and the mixture was heated to 120 C. for 30 min in the microwave. The reaction mixture was diluted with EtOAc (5 mL), and quenched with 1M HCl. The layers were separated and the organic layer was washed once more with 1M HCl. Combined aqueous layers were extracted twice with EtOAc. The solvents was removed under vacuum and the crude material was purified by reversed phase HPLC to afford 4-allyl-2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (65 mg) as a 1:1 mixture of diastereoisomer as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.71 (br. s, 1H), 7.03 (d, J=8.0 Hz, 1H), 6.94 (dd, J=8.0, 1.5 Hz, 1H), 6.83 (br. s, 1H), 5.65-5.82 (m, 1H), 5.06 (dd, J=17.0, 1.5 Hz, 1H), 4.97 (dd, J=10.5, 1.5 Hz, 1H), 3.80 (d, J=5.0 Hz, 2H), 3.18 (s, 4H), 2.19 (s, 3H), 2.02 (s, 3H), 1.78-1.92 (m, 6H), 1.55 (app. d, J=6.5 Hz, 2H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) : 174.1, 169.2, 136.1, 134.5, 133.8, 131.8, 130.3, 129.4, 127.8, 115.2, 103.7, 77.1, 61.5, 55.1, 40.1, 30.7, 27.0 (3C), 20.5, 19.0. LCMS, R.sub.t 0.95-1.09 min, (MH)=340, (M+H)=342.

(17) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.65 (br. s., 1H), 7.02 (d, J=8.0 Hz, 1H), 6.93 (dd, J=8.0, 1.5 Hz, 1H), 6.83 (br. s, 1H), 5.67-5.81 (m, 1H), 5.02 (dd, J=17.0, 1.5 Hz, 1H), 4.98 (dd, J=10.5, 1.5 Hz, 1H), 3.80 (d, J=5.0 Hz, 2H), 3.35 (br. s, 1H), 3.18 (s, 3H), 2.19 (s, 3H), 1.91-2.06 (m, 7H), 1.73-1.84 (m, 2H), 1.28-1.45 (m, 2H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) : 174.1, 169.2, 136.0, 134.5, 133.8, 131.7, 130.3, 129.4, 127.8, 115.0, 103.7, 73.0, 61.4, 55.0, 40.5, 27.5, 25.5 (3C), 20.4, 19.0. LCMS, R.sub.t 0.95-1.09 min, (MH)=340, (M+H)=342.

Example 8: Preparation of 4-benzyl-2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (Compound P2.6)

(18) ##STR00025##

(19) A microwave vial, equipped with a magnetic stirrer bar, was charged with 1-[benzyl-[2-(2,5-dimethylphenyl)acetyl]amino]-4-methoxy-N-phenyl-cyclohexanecarboxamide (200.0 mg, 0.41 mmol), potassium tert-butoxide (93.0 mg, 0.82 mmol) and DMF (4 mL). The vial was sealed and the mixture was heated to 130 C. for 45 min in the microwave. The reaction mixture was diluted with EtOAc (5 mL), and quenched with 1M HCl. The layers were separated and the organic layer was washed once more with 1M HCl. Combined aqueous layers were extracted twice with EtOAc. The solvents was removed under vacuum and the crude material was purified by reversed phase HPLC to afford 4-benzyl-2-(2,5-dimethylphenyl)-1-hydroxy-8-methoxy-4-azaspiro[4.5]dec-1-en-3-one (35 mg) as a 1:1 mixture of diastereoisomers as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.77 (br. s., 1H), 7.16-7.26 (m, 4H), 7.10-7.15 (m, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.93-6.99 (m, 1H), 6.89 (s, 1H), 4.44 (s, 2H), 3.10-3.18 (m, 4H), 2.21 (s, 3H), 2.07 (s, 3H), 1.79 (br. s, 6H), 1.46-1.52 (m, 2H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) : 174.8, 169.9, 140.2, 134.5, 133.9, 131.8, 129.4, 128.3, 128.1 (2C), 127.8, 126.7 (2C), 126.4, 103.7, 77.0, 61.8, 55.1, 40.8, 30.9, 27.0 (3C), 20.5, 19.1. LCMS, rt 1.0-1.5, (MH)=390, (M+H)=392. LCMS, R.sub.t 1.0-1.5 min, (MH)=390, (M+H)=392.

(20) .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.84 (br. s., 1H), 7.20-7.26 (m, 2H), 7.10-7.19 (m, 3H), 7.04 (d, J=7.5 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.89 (s, 1H), 4.43 (s, 2H), 3.29 (br. s, 1H), 3.12 (s, 3H), 2.20 (s, 3H), 2.07 (s, 3H), 1.80-2.02 (m, 4H), 1.60-1.72 (m, 2H), 1.34 (d, J=12.5 Hz, 2H). .sup.13C NMR (100 MHz, DMSO-d.sub.6) : 174.8, 169.9, 140.0, 134.5, 133.8, 131.8, 130.5, 129.4, 128.1 (2C), 127.8, 126.6 (2C), 126.4, 103.8, 73.0, 61.7, 55.0, 41.3, 27.7, 25.5 (3C), 20.5, 19.1. LCMS, R.sub.t 1.0-1.5 min, (MH)=390, (M+H)=392.

Example 9: Preparation of 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (Compound P1.9)

(21) ##STR00026##

(22) Solution A: A round bottom flask, equipped with a magnetic stirrer bar, was charged with 1-methoxypiperidin-4-one (5.7 g, 44 mmol) and methanamine (33% in ethanol, 4.2 g, 45 mmol). This was stirred at room temperature for 4 h, then methanamine (33% in ethanol, 0.8 g, 9 mmol) was added. This was stirred at room temperature for 1 h, then methanamine (33% in ethanol, 0.8 g, 9 mmol) was added.

(23) Another round bottom flask, equipped with a magnetic stirrer bar, was charged with 2-(4-choro-2,6-dimethylphenyl)acetic acid (4 g, 20 mmol) in methanol (48 mL). 5.8 g of the above prepared solution A was added to this in one portion. Then isocyanobenzene (2.3 g, 22 mmol) was added in one portion. The mixture was heated to 55 C. and stirred for 2 h at 55 C., then at room temperature overnight. The mixture was heated to 55 C. and stirred for 1.75 h, then 0.9 g of the above prepared solution A were added to this in one portion. The reaction mixture was stirred at 55 C. for 1.5 h, then heated under reflux for 4 h.

(24) The reaction mixture was diluted with dichloromethane (180 mL) and added to sat. aq. NaHCO3 at 0 C. The phases were separated and the organic phase washed with water (290 mL), dried over Na2SO4 and evaporated to dryness to afford crude 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (6.9 g) as an off-white solid.

(25) 1H NMR (400 MHz, DMSO-d6) ppm 2.08 (s, 6H), 2.20-2.40 (m, 2H), 2.82 (m, 2H), 3.16-3.27 (m, 4H) 3.32 (s, 3H), 3.42 (s, 3H), 3.70 (br. s., 2H), 6.97-7.00 (m, 3H), 7.24 (m, 2H), 7.48-7.50 (m, 2H), 9.20 (br. s., 1H). LCMS, Rt 0.99 min, (MH)=442, (M+H)=444.

Example 10: Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one (Compound P2.7)

(26) ##STR00027##

(27) In a microwave vial, equipped with a magnetic stirrer bar, was dissolved 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (50 mg, 0.11 mmol) in THF (1 mL). Ethylformate (82 mg, 0.22 mmol) and potassium tert-butoxide (1M in THF, 0.22 mL, 0.22 mmol) were then successively added. The vial was sealed and heated at 120 C. for 15 minutes. The reaction mixture was concentrated in vacuo to afford a white solid. .sup.1H NMR analysis of the crude mixture (against 1,3,5-trimethoxybenzene as internal standard) indicated 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one was formed in about 73% yield.

(28) .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.3-1.7 (br. m, 2H) 2.06 (s, 6H) 2.1-2.3 (br. m, 2H) 2.6-2.9 (br. m, 3H) 3.0-3.3 (br. m, 3H) 3.45 (s, 3H) 7.13 (s, 2H), 11.0 (br. s, 1H).

Example 11: Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one (Compound P2.7)

(29) ##STR00028##

(30) In a microwave vial, equipped with a magnetic stirrer bar, were dissolved 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (228 mg, 0.51 mmol) and triethylamine (0.22 mL, 1.6 mmol) in DMF (4.5 mL). At room temperature, methylchloroformate (0.060 mL, 0.77 mmol) was then added dropwise followed by potassium tert-butoxide (1M in THF, 1 mL, 1.02 mmol). The vial was sealed and heated at 120 C. for 30 min. The reaction mixture was cooled to room temperature and another portion of potassium tert-butoxide (1M in THF, 1 mL, 1.02 mmol) was added and the mixture was heated for another 15 minutes. LCMS analysis then indicated complete conversion and 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one was observed as indicated by LCMS analysis.

Example 12: Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one (Compound P2.7)

(31) ##STR00029##

(32) In a microwave vial, equipped with a magnetic stirrer bar, was dissolved 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (50 mg, 0.11 mmol) in DMF (1 mL). Butylformate (23 mg, 0.22 mmol) and potassium tert-butoxide (1M in THF, 0.22 mL, 0.22 mmol) were then successively added. The vial was sealed and heated at 120 C. for 6 h. The reaction mixture was concentrated in vacuo to afford a white solid. .sup.1H NMR analysis of the crude mixture (against 1,3,5-trimethoxybenzene as internal standard) indicated 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one was formed in about 84% yield.

Example 13: Preparation of 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one (Compound P2.7)

(33) ##STR00030##

(34) In a microwave vial, equipped with a magnetic stirrer bar, was suspended 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-phenyl-piperidine-4-carboxamide (0.45 g, 1.02 mmol) in dimethylcarbonate (3 mL). Triethylamine (0.43 mL, 3.0 mmol) and potassium tert-butoxide (1M in THF, 2.0 mL, 2.0 mmol) were then successively added. The vial was sealed and heated at 120 C. for 30 minutes. 2-(4-chloro-2,6-dimethyl-phenyl)-1-hydroxy-8-methoxy-4-methyl-4,8-diazaspiro[4.5]dec-1-en-3-one was observed as indicated by LCMS analysis, conversion of the starting material was about 50%.

Example 14: Preparation of 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-(p-tolyl)piperidine-4-carboxamide (Compound P1.10)

(35) ##STR00031##

(36) A round bottom flask, equipped with a magnetic stirrer bar, was charged with 2-(4-choro-2,6-dimethylphenyl)acetic acid (4.5 g, 23 mmol) and 1-isocyano-4-methyl-benzene (2.9 g, 25 mmol) in methanol (60 mL). The reaction mixture was heated to 55 C. In parallel, 1-methoxypiperidin-4-one (3.4 g, 26 mmol) and methanamine (33% in ethanol, 2.8 g, 30 mmol) were added dropwise to this over 30 min. The reaction mixture was stirred at 55 C. for 23 h, then cooled to room temperature. The reaction mixture was diluted with dichloromethane (360 mL) and added to saturated aqueous NaHCO.sub.3 (160 mL) at 0 C. The phases were separated and the organic phase washed with water (2100 mL), dried over Na.sub.2SO.sub.4 and evaporated to dryness to afford crude 4-[[2-(4-chloro-2,6-dimethyl-phenyl)acetyl]-methyl-amino]-1-methoxy-N-(p-toluyl)piperidine-4-carboxamide (8.8 g) as an off-white solid. LCMS, R.sub.t 1.88 min, (MH)=456, (M+H)=458.

(37) Compounds of the formula (I) from Table P1 and compounds of the formula (II) from Table P2 below can be prepared by analogous procedures. Either one of the following LC-MS methods was used to characterize the compounds:

(38) Method A

(39) Spectra were recorded on a ZQ Mass Spectrometer from Waters (Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 100 C., Desolvation Temperature: 250 C., Cone Gas Flow: 50 L/Hr, Desolvation Gas Flow: 400 L/Hr, Mass range: 100 to 900 Da) and an Agilent 1100 LC (Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Phenomenex Gemini C18, 3 m, 303 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: 0 min 0% B; 2-2.8 min 100% B; 2.9-3 min 0%. Flow (ml/min) 1.7

(40) Method B

(41) Spectra were recorded on a Mass Spectrometer from Waters (SQD or ZQ Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 350 C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Waters UPLC HSS T3, 1.8 m, 302.1 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: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85

(42) Method C

(43) MS Detector: LTQ Velos Orbitrap high resolution Mass Spectrometer from Thermo Scientific

(44) Ionisation: APCI positive/Vaporizer Temp. 350 C., Capillary Temp. 275 C.

(45) Detection: full scan 130-1500 Da/resolution 30000

(46) LC: HTS-xt PAL Autosampler, Thermo Accela Pump 1250, Thermo Accela PDA Detector

(47) Column: Macherey-Nagel Nucleodur 100 C18, 2504.6 mm, 3 m particle size UV Wavelength: 230 nm

(48) Gradient: (Solvent A=Acetonitrile/Solvent B=Trifluoroacetic acid 0.1% in Water)

(49) TABLE-US-00002 Time (min) A % B % Flow (ml/min) 00.00 30.0 70.0 0.8 25.00 100.0 00.0 0.8 30.00 100.0 00.0 0.8 31.00 30.0 70.0 0.8 40.00 30.0 70.0 0.8

(50) The characteristic values obtained for each compound were the retention time (R.sub.t, recorded in minutes) and the molecular ion as listed in Tables P1 and P2.

(51) Method D

(52) Spectra were recorded on a SQD Mass Spectrometer from Waters (Single quadrupole mass spectrometer) equipped with an electrospray source (Polarity: positive or negative ions, Capillary: 3.00 kV, Cone range: 30-60 V, Extractor: 2.00 V, Source Temperature: 150 C., Desolvation Temperature: 250 C., Cone Gas Flow: 0 L/Hr, Desolvation Gas Flow: 650 L/Hr, Mass range: 100 to 900 Da) and an Acquity UPLC from Waters: Binary pump, heated column compartment and diode-array detector. Solvent degasser, binary pump, heated column compartment and diode-array detector. Column: Phenomenex Gemini C18, 3 m, 302 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: gradient: 0 min 0% B, 100% A; 1.2-1.5 min 100% B; Flow (ml/min) 0.85.

(53) TABLE-US-00003 TABLE P1 Physical data of compounds of formula I: Comp. Melting No. Structure Point MS/NMR P1.1 gum LC/MS: 512/514 (M + H).sup.+ R.sub.t = 1.20 min (Method B) P1.2 solid LC/MS: 487/489 (M H).sup. R.sub.t = 1.28 min (Method B) P1.3 gum .sup.1H NMR (400 MHz, CDCl.sub.3) 9.27-9.97 (m, 1H), 7.48 (br. d, J = 7.7 Hz, 2H), 7.30 (br. t, J = 8.1 Hz, 2H), 7.04-7.12 (m, 1H), 6.91 (s, 2H), 3.73 (br. s., 2H), 3.54 (s, 3H), 3.28 (br. s, 3H), 3.14 (br. s, 3H), 2.58-2.96 (m, 3H), 2.29 (s, 3H), 2.23 (br. s, 6H), 1.97-2.18 (m, 2H). LC/MS: 422 (M H).sup. R.sub.t = 1.03 min (Method B) P1.4 solid .sup.1H NMR (400 MHz, CDCl.sub.3) 9.60 (br. s., 1H), 7.47-7.56 (m, 2H), 7.38-7.47 (m, 4H), 7.27-7.36 (m, 3H), 7.05-7.15 (m, 1H), 6.81 (s, 2H), 3.48 (s, 3H), 3.14-3.32 (m, 4H), 2.90-3.14 (m, 2H), 2.50- 2.85 (m, 3H), 2.22 (s, 3H), 2.09 (s,6H), 1.77-1.92 (m, 1H). LC/MS: 486 (M + H).sup.+ R.sub.t = 1.20 min (Method B) P1.5 solid .sup.1H NMR (400 MHz, CDCl.sub.3) 9.52 (br. s, 1H), 7.47-7.51 (m, 2H), 7.28-7.35 (m, 2H), 7.09-7.13 (m, 1H), 7.08 (s, 2H), 3.78-3.86 (m, 2H), 3.72-3.77 (m, 2H), 3.71 (s, 2H), 3.14 (s, 3H), 2.65-2.74 (m, 2H), 2.24 (s, 6H), 2.15-2.23 (m, 2H). LC/MS: 413/415 (M H).sup. R.sub.t = 1.01 min (Method B) P1.6 oil 1.5:1 mixture of diastereoisomers: Major: LC/MS: 393 (M H).sup. R.sub.t = 0.99 min Minor: LC/MS: 393 (M H).sup. R.sub.t = 0.97 min (Method B) P1.7 foam 1:1 mixture of diastereoisomers: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.15 (br. s, 1H), 9.12 (br. s, 1H), 7.45- 7.60 (m, 4H), 7.30 (t, J = 7.5 Hz, 4H), 7.04-7.11 (m,4H), 6.95- 7.00 (m, 2H), 6.87-6.92 (m, 2H), 5.80-6.03 (m, 2H), 5.20-5.40 (m, 4H), 4.03-4.10 (m, 4H), 3.69 (s, 2H), 3.72 (s, 2H), 3.35-3.39 (m, 1H), 3.35 (s, 3H), 3.33 (s, 3H), 3.23-3.32 (m, 1H), 2.80-2.90 (m, 2H), 2.36-2.47 (m, 2H), 2.25- 2.36 (m, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.18 (s,3H), 2.17 (s, 3H), 1.86-2.02 (m, 5H), 1.61-1.76 (m, 4H). LC/MS: 433 (M H).sup. R.sub.t = 1.10 and 1.13 min (Method B) P1.8 solid 1:1 mixture of diastereoisomers: .sup.1H NMR (400 MHz, CDCl.sub.3) 9.09 (s, 1H), 9.04 (s, 1H), 7.42-7.53 (m, 4H), 7.26-7.41 (m, 14H), 7.04-7.10 (m, 2H), 6.98-7.03 (m, 2H), 6.91-6.97 (m, 2H), 6.89 (br. s, 1H), 6.85 (br. s, 1H), 4.67 (s, 2H), 4.66 (s, 2H), 3.68 (s, 2H), 3.63 (s, 2H), 3.56-3.62 (m, 1H), 3.40 (s, 3H), 3.32-3.37 (m, 1H), 3.27 (s, 3H), 2.91-3.00 (m, 2H), 2.33-2.44 (m, 2H), 2.21-2.30 (m, 4H), 2.18 (s,3H), 2.14 (s, 3H), 2.05 (s, 3H), 2.04 (s, 3H), 1.87- 1.98 (m, 4H), 1.69-1.80 (m, 4H). LC/MS: 485 (M + H).sup.+ 483 (M H).sup. R.sub.t = 1.17 and 1.20 min (Method B) P1.9 0 solid LC/MS: 444 (M + H).sup.+ 442 (M H).sup. R.sub.t = 0.99 min (Method D) P1.10 solid LC/MS: 351, 458 (M + H).sup.+ 456 (M H).sup. R.sub.t = 1.88 min (Method A) P1.11 solid LC/MS: 351,462 (M + H).sup.+ 460 (M H).sup. R.sub.t = 1.82 min (Method A) P1.12 solid LC/MS: 472 (M H).sup. R.sub.t = 1.78 min (Method A) P1.13 solid LC/MS: 478 (M + H).sup.+, 476 (M H).sup. R.sub.t = 1.05 min (Method D) P1.14 solid LC/MS: 424/426 (M + H).sup.+ R.sub.t = 13.44 min (Method C) P1.15 solid LC/MS: 472/474 (M + H).sup.+ R.sub.t = 16.40 min (Method C) P1.16 solid LC/MS: 489/491 (M + H).sup.+ R.sub.t = 16.11 min (Method C) P1.17 solid LC/MS: 519/521 (M + H).sup.+ R.sub.t = 18.65 min (Method C) P1.18 solid LC/MS: 536/538 (M + H).sup.+ R.sub.t = 14.35 min (Method C)

(54) TABLE-US-00004 TABLE P2 Physical data of compounds of formula II: Compound Melting No. Structures Point MS/NMR P2.1 0 solid LC/MS: 419/421 (M + H).sup.+ R.sub.t = 0.95-1.00 min (method B) P2.2 solid .sup.1H NMR (400 MHz, DMSO-d.sub.6) 10.87 (s, 1H), 7.25-7.34 (m, 5H), 7.17 (S, 2H), 4.56 (s, 2H), 2.16 (s, 6H), 1.84-1.95 (m, 2H), 1.70-1.82 (m, 2H), 1.53-1.62 (m, 5H), 1.12-1.29 (m, 1H). LC/MS: 394/396 (M H).sup. R.sub.t = 1.15 min (method B) P2.3 solid LC/MS: 322/324 (M + H).sup.+ R.sub.t = 0.80 min (method B) P2.4 1.5:1 mixture of trans/cis diastereoisomers: LC/MS: 302 (M + H).sup.+, 300 (M H).sup. R.sub.t = 0.77 min (method B) P2.5 solid 1:1 mixture of diastereoisomers: LC/MS: 342 (M + H).sup.+ R.sub.t = 0.95-1.00 min (method B) P2.6 solid 1:1 mixture of diastereoisomers: LC/MS: 392 (M + H).sup.+ R.sub.t = 1.00-1.50 min (method B) P2.7 solid .sup.1H NMR (400 MHz, DMSO-d.sub.6) ppm 1.3-1.7 (br. m, 2H) 2.06 (s, 6H) 2.1-2.3 (br. m, 2H) 2.6-2.9 (br. m, 3H) 3.0-3.3 (br. m, 3H) 3.45 (s, 3H) 7.13 (s, 2H), 11.0 (br. s, 1H). LC/MS: 351 (M + H).sup.+, 349 (M H).sup. R.sub.t = 1.49 min (method A) P2.8 solid LC/MS: 329 (M H).sup. R.sub.t = 0.81 min (method B) P2.9 solid LC/MS: 391 (M H).sup., 393 (M + H).sup.+ R.sub.t = 0.95 min (method B)