Process for the preparation of amides from hindered anilines containing a perhaloalkyl group

Abstract

The present invention provides a novel and improved process for the production of the production of hindered anilines containing perfluoroalky groups in good yield any by using close to stoichiometric amounts of acylating agent.

Claims

1. A method for the preparation of ##STR00049## comprising reacting a compound of formula (I) with a compound of formula (II) in the presence of acid to obtain a compound of formula (III): ##STR00050## then Step b) reacting the compound of formula (III) with a compound of formula (IV) to obtain a compound of formula (V): ##STR00051## then Step c) reacting the compound of formula (V) with aqueous base to obtain a compound of formula (VI): ##STR00052## wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 alkoxymethyl, C.sub.1-C.sub.4-alkylsulphonyl, C.sub.1-C.sub.4-haloalkylsulphonyl, C.sub.1-C.sub.4-alkylsulphinyl, C.sub.1-C.sub.4-haloalkylsulphinyl, C.sub.1-C.sub.4-alkylthio, C.sub.1-C.sub.4-haloalkylthio, X.sub.3 is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O, phenyl-C(O)O, C.sub.1-C.sub.6-alkoxy-C(O)O, phenoxy-C(O)O, benzyloxy-C(O)O and imidazol-1-yl; R.sub.1 is H, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, R.sub.2 is C.sub.1-C.sub.4-alkyl R.sub.3 is H, fluorine, methoxy; R.sub.3a is H or CN, Q.sub.1 is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl.

2. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 alkoxymethyl, X.sub.3 is heptafluoroprop-2-yl, 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl or nonafluorobut-2-yl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O, phenyl-C(O)O, C.sub.1-C.sub.6-alkoxy-C(O)O; R.sub.1 is H, C.sub.1-C.sub.4 alkyl, R.sub.2 is methyl or ethyl Q.sub.1 is 4-cyano-phenyl, 3-pyridyl or 4-pyridyl.

3. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.4 alkoxymethyl, X.sub.3 is 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl, 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O, phenyl-C(O)O, C.sub.1-C.sub.6-alkoxy-C(O)O; R.sub.1 is H, C.sub.1-C.sub.4 alkyl, R.sub.2 is methyl or ethyl Q.sub.1 is 3-pyridyl or 4-pyridyl.

4. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, X.sub.3 is heptafluoroprop-2-yl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O; R.sub.1 is H, methyl, R.sub.2 is ethyl Q.sub.1 is 4-pyridyl.

5. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, X.sub.3 is heptafluoroprop-2-yl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O; R.sub.1 is H, methyl, R.sub.2 is ethyl Q.sub.1 is 4-pyridyl.

6. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, X.sub.3 is 1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O; R.sub.1 is H, methyl, R.sub.2 is ethyl Q.sub.1 is 4-pyridyl.

7. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, X.sub.3 is 1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O; R.sub.1 is H, methyl, R.sub.2 is ethyl Q.sub.1 is 4-pyridyl.

8. A method according to claim 1 wherein X.sub.1 and X.sub.2 each independently are halogen, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.4 haloalkoxy, X.sub.3 is nonafluorobut-2-yl; X.sub.4 is a leaving group selected from halogen, C.sub.1-C.sub.6-alkyl-C(O)O; R.sub.1 is H, methyl, R.sub.2 is ethyl Q.sub.1 is 4-pyridyl.

9. A method according to claim 1 wherein R.sub.3 is methoxy and R.sub.3a is H.

10. A method according to claim 1 wherein R.sub.3 is fluorine and R.sub.3a is H.

11. A method according to claim 1 wherein R.sub.3 is H and R.sub.3a is CN.

12. A method according to claim 1 wherein R.sub.3 is H and R.sub.3a is H.

Description

PREPARATION EXAMPLES

Examples

(1) The following abbreviations were used throughout this section: s=singlet; bs=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, sept=septet; m=multiplet; Me=methyl; Et=ethyl; Pr=propyl; Bu=butyl; M.p.=melting point.

Example 1

Methyl 3-(ethylamino)-2-methoxy-benzoate

(2) ##STR00017##

(3) A pressure vial was charged with Pd/C (10%, 0.021 g) and 2-propanol (3.4 ml). A solution of ammonium formiate (0.452 g, 7.10 mmol) in water (0.35 ml) was added and the resulting mixture was stirred for 5 min. Methyl 2-methoxy-3-nitro-benzoate (0.100 g, 0.473 mmol) was added and the reaction media was cooled to 0 C. Acetaldehyde (0.105 g, 2.37 mmol) was added and the reaction media was stirred for 16 h at ambient temperature. The reaction mixture was filtered through a short pad of celite and filtrate was evaporated under reduced pressure. The residue was dissolved in dichloromethane and washed with brine. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-30% EtOAc in cyclohexane) to give methyl 3-(ethylamino)-2-methoxy-benzoate (0.0839 g, 85%) as a beige oil. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.09 (dd, 1H), 7.01 (t, 1H), 6.77 (dd, 1H), 4.30 (bs, 1H), 3.90 (s, 3H), 3.82 (s, 3H), 3.16 (q, 2H), 1.27 (t, 3H) ppm.

Example 2

Methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate

(4) ##STR00018##

(5) To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (0.158 g, 0.754 mmol) in dichloromethane (2.6 ml) was added triethylamine (0.233 ml, 1.66 mmol) followed by 4-cyanobenzoyl chloride (0.140 g, 0.829 mmol). After stirring at ambient temperature for 16 h the reaction was quenched by addition of saturated aqueous NH.sub.4Cl. The mixture was extracted with dichloromethane (2) and organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was further purified by column chromatography on silica gel (eluent: 0-40% EtOAc in cyclohexane) to give methyl 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate (0.207 g, 81%) as a beige gum.

(6) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.77-7.58 (m, 1H), 7.55-7.35 (m, 4H), 7.32-7.20 (m, 1H), 7.12-6.99 (m, 1H), 4.20 (bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.73-3.61 (m, 1H), 1.33-1.21 (m, 3H) ppm

Example 3

3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid

(7) ##STR00019##

(8) To a solution of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoate (0.120 g, 0.354 mmol) in MeOH (1.2 ml) was added 5M NaOH (0.142 ml, 0.707 mmol). The reaction mixture was stirred for 1.5 h at ambient temperature before being quenched by addition of aqueous saturated NH.sub.4Cl. The mixture was extracted with dichloromethane (3), combined organic layers were washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid (0.0827 g, 72%) as a white solid sufficiently pure for further chemistry.

(9) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.98-7.78 (m, 1H), 7.68-7.29 (m, 5H), 7.25-7.10 (m, 1H), 4.30 (bs, 1H), 3.91 (s, 3H), 3.71-3.57 (m, 1H), 1.42-1.19 (m, 3H) ppm

Example 4

N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(10) ##STR00020##

(11) A solution of 2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (5.00 g, 12.0 mmol) in acetic anhydride (30 ml) was heated to 60 C and few drops of concentrated sulfuric acid was added. The heating was continued for further 90 min and then most of acetic anhydride was evaporated under reduced pressure. The residue was taken dissolved in THF (25 ml) and aqueous 2N NaOH (35 ml) was added. The reaction mixture was stirred at ambient temperature for 2 h before being extracted with dichloromethane (3). Combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-40% EtOAc in cyclohexane) to afford N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (5.00 g, 90%) as a beige solid.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.77 (s, 1H), 7.66 (s, 1H), 7.18 (brs, 1H), 2.24 (brs, 3H) ppm.

Example 5

N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide

(13) Step 1

(14) ##STR00021##

(15) Preparation of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoyl chloride. To a suspension of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoic acid (1.00 g, 3.08 mmol) in 1,2-dichloroethane was one drop of DMF followed by a slow addition of oxalyl chloride (0.284 ml, 3.24 mmol). The reaction mixture was stirred for further 30 min to afford a solution of 3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzoyl chloride which was used for the next step immediately.

(16) Step 2

(17) ##STR00022##

(18) To a solution of N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (1.28 g, 3.08 mmol) in 1,2-dichlorethane (11 ml) was added triethylamine (1.08 ml, 7.70 mmol). The solution of acid chloride prepared in the step 1 was added dropwise at 0 C and the reaction mixture was stirred at room temperature for 4 h. The reaction was quenched by addition of aqueous saturated NaHCO3, the aqueous phase was extracted with DCM (3), the combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-30% EtOAc in cyclohexane) to afford N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (1.61 g, 71%) as a white solid.

(19) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (brs, 1H), 7.81-7.73 (m, 1H), 7.56-7.41 (m, 4H), 7.39-7.31 (m, 1H), 7.17-7.07 (m, 1H), 7.04-6.94 (m, 1H), 4.34-4.19 (m, 1H), 3.90 (s, 3H), 3.73-3.59 (m, 1H), 2.02-1.87 (m, 3H), 1.36-1.22 (m, 3H) ppm.

Example 6

N-[2-bromo-6-chloro-4-[1,1,1,2,3,3,3-heptafluoro-prop-2-yl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide

(20) ##STR00023##

(21) To a solution of N-acetyl-N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (0.0750 g, 0.0995 mmol) in THF (0.5 ml) was added 1N NaOH (0.40 ml, 0.40 mmol) and the resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (2). The combined organic layers were dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford pure N-[2-bromo-6-chloro-4-[1,1,1,2,3,3,3-heptafluoro-prop-2-yl]phenyl]-3-[(4-cyanobenzoyl)-ethyl-amino]-2-methoxy-benzamide (0.0706 g, 98%) as a beige solid.

(22) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.78 (bs, 1H), 8.04 (d, 1H), 7.81 (s, 1H), 7.70 (s, 1H), 7.55 (d, 1H), 7.40-7.55 (m, 4H), 7.43 (t, 1H), 4.34-4.48 (m, 1H), 3.96 (s, 3H), 3.67-3.80 (m, 1H), 1.48 (t, 3H) ppm.

Example 7

methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate

(23) ##STR00024##

(24) To a solution of methyl 3-(ethylamino)-2-methoxy-benzoate (1.168 g, 5.58 mmol) in DCM (20 ml) was added triethylamine (1.89 ml, 13.40 mmol) followed by isonicotinoyl chloride hydrochloride (1.217 g, 6.70 mmol) and the reaction mixture was stirred at 40 C for 1 h. The reaction mixture was cooled to room temperature and quenched by addition of aqueous saturated NaHCO.sub.3 and 1N NaOH was added until pH=8-9. The aqueous phase was extracted with DCM (3), combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (1.644 g, 94%) as a beige oil.

(25) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.44 (s, 2H), 7.65 (d, 1H), 7.30-7.11 (m, 3H), 7.09-6.98 (m, 1H), 4.31-4.17 (m, 1H), 3.88 (s, 3H), 3.84 (s, 3H), 3.71-3.59 (m, 1H), 1.33-1.23 (m, 3H) ppm.

Example 8

3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride

(26) ##STR00025##

(27) To a solution of methyl 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoate (0.108 g, 0.343 mmol) in a mixture of THF (0.82 ml) and water (0.28 ml) was added lithium hydroxide hydrate (0.0153 g, 0.36 mmol). The reaction mixture was stirred at 50 C for 1 h, cooled to room temperature and acidified with 1N HCl. The reaction mixture was extracted with DCM (3), the combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. Thus obtained crude 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride (0.060 g, 52%) was without further purification.

(28) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.48 (s, 2H), 7.89 (d, 1H), 7.43-7.32 (m, 1H), 7.27-7.09 (m, 3H), 4.38-4.24 (m, 1H), 3.92 (s, 3H), 3.70-3.58 (m, 1H), 1.40-1.27 (m, 3H) ppm.

Example 9

N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide

(29) Step 1

(30) ##STR00026##

(31) Preparation of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoyl chloride hydrochloride. To a suspension of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoic acid hydrochloride (0.0985 g, 0.278 mmol) in 1,2-dichloroethane (0.83 ml) was added one drop of DMF followed by slow addition of oxalyl chloride (0.0256 ml, 0.292 mmol). The resulting reaction mixture was stirred at room temperature for 40 min to afford a solution of 3-[ethyl(pyridine-4-carbonyl)amino]-2-methoxy-benzoyl chloride hydrochloride which was immediately used for the next step.

(32) Step 2

(33) ##STR00027##

(34) To a solution of N-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide (0.116 g, 0.278 mmol) in 1,2-dichloroethane (0.83 ml) was added triethylamine (0.137 ml, 0.973 mmol) followed by a dropwise addition of the solution of acid chloride prepared in the step 1 at 0 C. The resulting reaction mixture was stirred at room temperature for 2 h and quenched by addition of aqueous saturated NaHCO.sub.3. The aqueous phase was extracted with DCM (3), combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude product was purified by silica gel chromatography (0-100% EtOAc in cyclohexane) to afford N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.116 g, 59%) as a white solid.

(35) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.56-8.41 (m, 2H), 7.87 (s, 1H), 7.75 (d, 1H), 7.44-7.32 (m, 1H), 7.26-7.08 (m, 3H), 7.05-6.93 (m, 1H), 4.34-4.20 (m, 1H), 3.91 (s, 3H), 3.71-3.58 (m, 1H), 2.67 (d, 3H), 1.35-1.21 (m, 3H) ppm.

Example 10

N-[3-[[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide

(36) ##STR00028##

(37) To a solution of N-[3-[acetyl-[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.106 g, 0.152 mmol) in THF (0.76 ml) was added 1M NaOH (0.61 ml, 0.61 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and ethyl acetate, phases were separated and the aqueous phase was extracted with ethyl acetate (3). Combined organic layers were dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford a pure N-[3-[[2-bromo-6-chloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-ethyl-pyridine-4-carboxamide (0.100 g, 96%) as a white solid.

(38) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.79 (s, 1H), 8.47 (s, 2H), 8.06 (d, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.53-7.47 (m, 1H), 7.35-7.27 (m, 1H), 7.23-7.13 (m, 2H), 4.46-4.33 (m, 1H), 3.96 (s, 3H), 3.76-3.64 (m, 1H), 1.48-1.38 (m, 3H) ppm.

Example 11

N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)phenyl]acetamide

(39) ##STR00029##

(40) From 200 mg 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)phenyl]acetamide was obtained (104 mg, 47%).

(41) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.77 (s, 1H), 7.48 (s, 1H), 6.93 (brs, 1H), 6.52 (t, 1H), 2.26 (s, 3H) ppm.

Example 12

2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline

(42) ##STR00030##

(43) 2.41 g N-bromosuccinimide was slowly added to a solution of 3.88 g 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline (Example 13) in 24 ml Dichloromethane at ambient temperature. A slightly exothermic reaction was observed. The mixture was stirred for 1 hour at ambient temperature. Then 100 ml of aqueous sodium hydroxide (1N) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (1N). The aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-(difluoromethoxy)aniline (4.58 g, 96%) was obtained as a dark brown oil.

(44) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.55 (s, 1H), 7.24 (s, 1H), 6.50 (t, 1H), 4.60 (brs, 2H) ppm.

Example 13

4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline

(45) ##STR00031##

(46) 6.8 g Sodium hydrosulphite, 2.8 g sodium bicarbonate, 0.69 g tetrabutylammonium hydrogensulphate and 10 g 1-chloro-1,1,2,3,3,3-hexafluoro-2-iodo-propane were added to a solution of 4.5 g 2-(difluoromethoxy)aniline in a mixture of 41 ml 2-methoxy-2-methyl-propane and 41 ml water. The reaction mixture was stirred for 3 days at ambient temperature. Then the layers were separated, the aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (1N), twice with 100 ml portions of water, once with 100 ml of brine, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-(difluoromethoxy)aniline (3.88 g, 41%) was obtained as an orange oil.

(47) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.28 (m, 2H), 6.82 (d, 1H), 6.49 (t, 1H), 4.12 (brs, 2H) ppm.

Example 14

N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide

(48) ##STR00032##

(49) From 200 mg 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (151 mg, 68%).

(50) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.51 (s, 1H), 7.74 (s, 1H), 6.91 (brs, 1H), 2.71 (q, 2H), 2.25 (s, 3H), 1.23 (t, 3H) ppm.

Example 15

2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline

(51) ##STR00033##

(52) 6.67 g N-bromosuccinimide was slowly added to a solution of 9.54 g 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline in 67 ml dichloromethane at ambient temperature. An exothermic reaction was observed. The mixture was stirred for 1.5 hours at ambient temperature. Then 100 ml of aqueous sodium hydroxide (1N) were added. The layers were separated and the organic layer was washed with 100 ml of aqueous sodium hydroxide (1N). The combined aqueous phases were washed twice with 100 ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to dryness. Thus, 2-bromo-4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline (12.0 g, 100%) was obtained as a dark brown oil.

(53) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.53 (s, 1H), 7.20 (s, 1H), 4.38 (brs, 2H), 2.56 (q, 2H), 1.27 (t, 3H) ppm.

Example 16

4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline

(54) ##STR00034##

(55) 9.66 Sodium hydrosulphite, 3.96 g sodium bicarbonate, 0.97 g tetrabutylammonium hydrogensulphate and 13.5 g 1-chloro-1,1,2,3,3,3-hexafluoro-2-iodo-propane were added to a solution of 4.86 g 2-ethylaniline in a mixture of 58 ml 2-methoxy-2-methyl-propane and 58 ml water. The reaction mixture was stirred 2 hours at ambient temperature. Then the layers were separated. The aqueous layer was washed twice with 2-methoxy-2-methyl-propane. The combined organic layers were washed twice with 100 ml portions of aqueous hyrochloric acid (1N), twice with 100 ml portions of water, once with 100 ml brine, dried over sodium sulfate, filtered and evaporated under vacuum. Thus, 4-[1-[chloro(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2-ethyl-aniline (9.54 g, 79%) was obtained as an orange oil.

(56) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.26 (m, 2H), 6.70 (d, 1H), 3.85 (brs, 2H), 2.53 (q, 2H), 1.27 (t, 3H) ppm.

Example 17

N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(57) ##STR00035##

(58) From 1.0 g 2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.98 g, 89%).

(59) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.82 (s, 2H), 7.00 (brs, 1H), 2.26 (brs, 3H) ppm.

Example 18

N-[2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(60) ##STR00036##

(61) From 1.0 g 2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-diethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.93 g, 82%).

(62) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.33 (s, 2H), 6.70 (brs, 1H), 2.63 (q, 4H), 2.24 (s, 3H), 1.20 (t, 6H) ppm.

Example 19

N-[2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(63) ##STR00037##

(64) From 323 mg 2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (232 mg, 64%).

(65) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.60 (s, 1H), 7.41 (s, 1H), 6.92 (brs, 1H), 6.53 (t, 1H), 2.24 (s, 3H) ppm.

Example 20

N-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(66) ##STR00038##

(67) From 1.0 g 2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (0.296 g, 26%).

(68) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.62 (s, 2H), 6.95 (brs, 1H), 2.25 (brs, 3H) ppm.

Example 21

N-[2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(69) ##STR00039##

(70) From 1.0 g 2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-methyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (1.038 g, 91%).

(71) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.52 (s, 1H), 7.39 (s, 1H), 6.96 ppm (brs, 1H), 2.37 (s, 3H), 2.26 (s, 3H) ppm.

Example 22

N-[2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(72) ##STR00040##

(73) From 1.0 g 2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (1.1 g, 97%).

(74) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.54 (s, 1H), 7.42 (s, 1H), 6.88 (brs, 1H), 2.70 (q, 2H), 2.27 (s, 3H), 1.23 (t, 3H) ppm.

Example 23

2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline

(75) ##STR00041##

(76) 27.9 g 1-chloropyrrolidine-2,5-dione was added in portions to a solution of 60.5 g 2-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline in 350 ml dichloromethane. The reaction mixture was stirred for 3 days at ambient temperature. Then, 150 ml of aqueous sodium hydroxide (1N) were slowly added, during addition an exothermic reaction was observed. The layers were separated and the organic layer was washed twice with 100 ml of aqueous sodium hydroxide (1N), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue, 64.2 g of a dark brown powder, was purified by flash chromatography using dichloromethane/cyclohexane as a solvent. Thus, 2-chloro-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (50.2 g, 74%) was obtained as a pale orange solid.

(77) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.88 (s, 1H), 7.17 (s, 1H), 4.33 brs, 2H), 2.56 (q, 2H), 1.28 (t, 3H) ppm.

Example 24

N-[2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(78) ##STR00042##

(79) From 1.0 g 2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-ethyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (098 g, 88%).

(80) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.70 (s, 1H), 7.45 (s, 1H), 6.87 (brs, 1H), 2.41 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm.

Example 25

N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide

(81) ##STR00043##

(82) From 1.0 g 2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline, following the same procedure as described in Example 4, N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide was obtained (954 mg, 86%).

(83) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.75 (s, 1H), 7.46 (s, 1H), 6.95 (brs, 1H), 6.52 (t, 1H), 2.24 (s, 3H) ppm.

Example 26

N-[2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide

(84) ##STR00044##

(85) From 500 mg 2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-aniline, following the same procedure as described in Example 4, N-[2-bromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-6-ethyl-phenyl]acetamide was obtained (520 mg, 95%).

(86) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.70 (s, 1H), 7.48 (s, 1H), 7.01 (brs, 1H), 2.70 (q, 2H), 2.25 (s, 3H), 1.22 (t, 3H) ppm.

Example 27

N-[2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]phenyl]acetamide

(87) ##STR00045##

(88) From 500 mg 2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]aniline, following the same procedure as described in Example 4, N-[2,6-dibromo-4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]phenyl]acetamide was obtained (340 mg, 71%).

(89) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.84 (s, 2H), 7.01 (brs, 1H), 2.28 (s, 3H) ppm.

Example 28

N-[4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-phenyl]acetamide

(90) ##STR00046##

(91) From 500 mg 4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-aniline, following the same procedure as described in Example 4, N-[4-[1-[bromo(difluoro)methyl]-1,2,2,2-tetrafluoro-ethyl]-2,6-dichloro-phenyl]acetamide was obtained (320 mg, 72%).

(92) .sup.1H NMR (400 MHz, CDCl.sub.3): 7.64 (s, 2H), 6.95 (brs, 1H), 2.27 (s, 3H) ppm.

Example 29

N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide

(93) ##STR00047##

(94) From 760 mg N-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]acetamide and 520 mg 2-methoxy-3-[methyl(pyridine-4-carbonyl)amino]benzoyl chloride, following the same procedure as described in Example 5, Step 2, N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide was obtained (446 mg, 37%).

(95) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.50 (brs, 2H), 7.77 (m, 1H), 7.43 (brs, 1H), 7.20-7.30 (m, broad, 4H), 7.05 (m, 1H), 6.45 (t, broad, 1H), 3.88 (s, 3H), 3.43 (brs, 3H), 1.96 (brs, 3H) ppm.

Example 30

N-[3-[[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide

(96) ##STR00048##

(97) From 278 g N-[3-[acetyl-[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide, following the same procedure as described in Example 6, N-[3-[[2-bromo-6-(difluoromethoxy)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide was obtained (259 mg, 99%).

(98) .sup.1H NMR (400 MHz, CDCl.sub.3): 8.73 (brs, 1H), 8.47 (brs, 2H), 8.03 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.45 (s, 1H), 7.35 (t, 1H), 7.17 (brs, 2H), 6.53 (t, 1H), 3.62 (brs, 3H), 3.58 (brs, 3H) ppm.