PROCESS FOR THE PREPARATION OF AMINO-PYRAZOLES

Abstract

The present invention discloses an efficient preparation of 3-amino-1-((2,6-di-substituted)phenyl)pyrazoles.

Claims

1. Process for preparation of a compound of formula (I) ##STR00021## wherein R.sup.1, R.sup.2 and R.sup.3 represent independently of one another halogen, cyano, nitro, (C.sub.1-C.sub.6)alkyl, (C.sub.2-C.sub.6)alkenyl, (C.sub.2-C.sub.6)alkynyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.2-C.sub.6)alkenoxy, (C.sub.2-C.sub.6)alkynoxy, (C.sub.3-C.sub.6)cycloalkoxy, phenyl(C.sub.1-C.sub.6)alkyl, aryl, cyano(C.sub.1-C.sub.6)alkyl, halogen(C.sub.1-C.sub.6)alkyl with 1-9 identical or different halogen atoms, halogen(C.sub.3-C.sub.6)cycloalkyl with 1-9 identical or different halogen atoms, halogen(C.sub.1-C.sub.6)alkoxy with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio, halogen(C.sub.1-C.sub.6)alkylthio with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfinyl, halogen(C.sub.1-C.sub.6)alkylsulfinyl with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfonyl, halogen(C.sub.1-C.sub.6)alkylsulfonyl with 1-9 identical or different halogen atoms, n represents a number from the group consisting of 0, 1 and 2, where for n>1 R.sup.3 may be identical or different and R.sup.4 and R.sup.5 represent independently of one another hydrogen, cyano, nitro, (C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.6)cycloalkyl, (C.sub.1-C.sub.6)alkoxy, (C.sub.3-C.sub.6)cycloalkoxy, phenyl(C.sub.1-C.sub.6)alkyl, aryl, heteroaryl, cyano(C.sub.1-C.sub.6)alkyl, halogen(C.sub.1-C.sub.6)alkyl with 1-9 identical or different halogen atoms, halogen(C.sub.1-C.sub.6)alkoxy with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkoxycarbonyl(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkylthio, halogen(C.sub.1-C.sub.6)alkylthio with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfinyl, halogen(C.sub.1-C.sub.6)alkylsulfinyl with 1-9 identical or different halogen atoms, (C.sub.1-C.sub.6)alkylsulfonyl, halogen(C.sub.1-C.sub.6)alkylsulfonyl with 1-9 identical or different halogen atoms comprising (i) reacting, a compound of formula (IV) or a salt thereof ##STR00022## in which R.sup.1, R.sup.2, R.sup.3 and n have the above mentioned meanings, with a compound of formula (V) as either E- or Z-isomer ##STR00023## in which-R.sup.4 and R.sup.5 have the above mentioned meanings, in the presence of a catalytic amount of base, to obtain a compound of formula (III) ##STR00024## in which-R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the above mentioned meanings, and (ii) said compound of formula (III) is, cyclized in the presence of an acid to provide a compound of formula (II) ##STR00025## in whichR.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and n have the above mentioned meanings, and (iii) said compound of formula (II) is, converted in the presence of an oxidant, a catalytic amount of an iodide source and an organic acid, to a compound of formula (I).

2. Process according to claim 1 wherein R.sup.1 represents fluoro R.sup.2 represents fluoro n represents 0, R.sup.4 represents hydrogen and R.sup.5 represents hydrogen.

3. Process according to claim 2 additionally comprising reacting the compound obtained by the process according to claim 2 with a compound of formula (VI) ##STR00026## wherein M represents halogen, hydroxy, alkoxy, alkylsulphanyl, acyloxy, N-heterocyclyl or represents hydroxyl, to obtain the compound of formula (VII) ##STR00027##

4. Process according to claim 1, comprising (ii) and (iii).

5. Process according to claim 4, comprising (iii).

6. The compound of formula ##STR00028## and/or a salt thereof.

7. Process for preparation of the compound according to claim 6 wherein the compound of formula ##STR00029## or a salt thereof is reacted with acrylonitrile of formula ##STR00030## as either E- or Z-isomer in the presence of a catalytic amount of base.

Description

EXAMPLES

Example 1: Synthesis of 3-(N-amino-2,6-difluoro-anilino)propanenitrile

[0069] ##STR00015##

[0070] A solution of (2,6-difluorophenyl)hydrazine (88.6 g, 0.62 mol) in 250 mL MeCN was treated with 2.6 mL (0.05 mol) NaOH (50%) and heated to 50 C. Subsequently, acrylonitrile (34.3 g, 0.65 mol) was added dropwise over a period of 20 min. The temperature was kept below 60 C. After stirring for 1 h at 50 C., most of the MeCN was distilled off. The reaction was diluted with 200 mL of water extracted three times with 150 mL EtOAc. The combined organic phases were washed once with brine, dried over Na.sub.2SO.sub.4 and the solvent was evaporated to give 3-(N-amino-2,6-difluoro-anilino)propanenitrile (110.0 g, 90% yield, 96.2% HPLC-purity) as white solid.

[0071] .sup.1H NMR (CD.sub.3CN) (ppm)=7.1-7.2 (m, 1H), 6.9-7.0 (m, 2H), 4.1 (br s, 2H), 3.4 (t, 2H), 2.7 (t, 2H).

Example 2: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine

[0072] ##STR00016##

[0073] A solution of 3-(N-amino-2,6-difluoro-anilino)propanenitrile (110.0 g, 0.56 mol) in 200 mL MeCN was treated with 94 mL aq. HCl (32%) and heated to reflux for 5 h. The reaction mixture was cooled to 50 C. and 192 mL aq. NaOH (20%) were added. After stirring for 15 min at 50 C., the phases were separated and the organic phase was dried over Na.sub.2SO.sub.4. The solvent of the organic phase was removed under vacuum and the remaining solid was recrystallized from toluene to give 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (104.9 g, 95% yield, 96.8% HPLC-purity) as a light beige solid.

[0074] .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Example 3: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine via 3-(N-amino-2,6-difluoro-anilino)propanenitrile as One-Pot Procedure

[0075] ##STR00017##

[0076] A solution of (2,6-difluorophenyl)hydrazine (35.4 g, 0.25 mol) in 100 mL MeCN was treated with 1.0 mL (0.02 mol) NaOH (50%) and heated to 50 C. Subsequently, acrylonitrile (13.7 g, 0.26 mol) was added dropwise over a period of 20 min. The temperature was kept below 60 C. After stirring for 1 h at 50 C., 38 mL aq. HCl (32%) were added and the reaction was heated to reflux for 5 h. The reaction mixture was cooled to 50 C. and 77 mL aq. NaOH (20%) were added. After stirring for 15 min at 50 C., the phases were separated and the organic phase was dried over Na.sub.2SO.sub.4. The solvent of the organic phase was removed under vacuum and the remaining solid was recrystallized from toluene to give 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (41.9 g, 85% yield, 96.5% HPLC-purity) as a light beige solid.

[0077] .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Comparative Example 3: Synthesis of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine

[0078] ##STR00018##

[0079] A solution of acrylonitrile (345 mg, 6.4 mmol) in 5 mL EtOH was treated with NaOMe (1.94 g, 10.7 mmol) at room temperature and stirred for 30 min. Then, (2,6-difluorophenyl)hydrazine (1.0 g, 5.4 mmol) was added and the reaction mixture heated to reflux overnight. The reaction mixture was cooled to room temperature and 20 mL water were added. After extraction with DCM (320 mL) the combined organic phases were dried over Na.sub.2SO.sub.4 and evaporated. 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (770 mg, 32% yield, 44.3% HPLC-purity) was obtained as brown oil.

[0080] .sup.1H NMR (CD.sub.3CN) (ppm)=7.0-7.1 (m, 1H), 6.8-6.9 (m, 2H), 4.4 (br s, 2H), 3.6 (t, 2H), 2.8 (t, 2H).

Example 4: Synthesis of 1-(2,6-difluorophenyl)pyrazol-3-amine (Ia)

[0081] ##STR00019##

[0082] To a solution of 2-(2,6-difluorophenyl)-3,4-dihydropyrazol-5-amine (10.0 g, 50.7 mmol), KI (420 mg, 2.5 mmol) and AcOH (1.5 g, 25.0 mmol) in 50 mL MeCN was added H.sub.2O.sub.2 (3.5 g, 53.2 mmol, 50%) at 40 C. over a period of 1 h. The temperature was kept below 65 C. After stirring for 1 h at 50 C., the reaction was quenched with 9 mL aq. NaOH (20%) and 4 mL aq. NaHSO.sub.3 (40%). Then most of the MeCN was distilled off and a suspension was formed. Filtration and subsequent recrystallization of the solid gave 1-(2,6-difluorophenyl)pyrazol-3-amine (7.8 g, 80% yield, 96.7% HPLC-purity) as a beige solid.

[0083] .sup.1H NMR (CD.sub.3CN) (ppm)=7.5 (d, 1H), 7.4-7.5 (m, 1H), 7.1-7.2 (m, 2H), 5.8 (d, 1H), 4.1 (br s, 2H).

Example 5: Synthesis of N-[1-(2,6-difluorophenyl)pyrazol-3-yl]-2-(trifluoromethyl)benzamide (VII)

[0084] ##STR00020##

[0085] To a solution of 1-(2,6-difluorophenyl)pyrazol-3-amine (56.0 g, 0.29 mmol) in 425 mL toluene 2-(trifluoromethyl)benzoyl chloride (60.4 g, 0.29 mmol) was added at 50 C. over a period of 2 h and stirred for another 1 h at 50 C. After subsequent heating to reflux for 6 h the reaction mixture was cooled down, the precipitating solid was filtered and washed twice with 100 mL toluene. N-[1-(2,6-difluorophenyl)pyrazol-3-yl]-2-(trifluoromethyl)benzamide (96.8 g, 91% yield, 99.7% HPLC-purity) was obtained as brown solid.

[0086] NMR (CD.sub.3CN) (ppm)=9.2 (br. s, 1H), 7.8 (d, 1H), 7.6-7.7 (m, 4H), 7.4-7.5 (m, 1H), 7.2 (t, 2H), 7.0 (d, 1H).