1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Prepared from 1-(2-amino-5-chloro-phenyl)-2,2,2-trifluoro-ethanone by addition of methylmagnesium bromide followed by treatment of the resultant carbinol with 1,1′-carbonyldiimidazole according to the procedure of Example 2. White solid: mp 216-216° C.; 1H-NMR (DMSO-d6) δ10.91 (bs, 1H, D2O exchangeable), 7.64 (d, 1H, J=1.6 Hz), 7.49 (dd, 1H, J=8.6, 2.3 Hz), 6.95 (d, 1H, J=8.6 Hz), 1.91 (s, 3H); 19F-NMR (DMSO-d6) δ−82.0 (s, 1F); MS (EI) m/z 264 ([M−H]−, 100%), 266 ([M−H]31 , 33%). Anal. Calc. For C10H7ClF3NO2: C, 45.22, H, 2.66, N, 5.27. Found: C, 45.32, H, 2.77, N, 4.83.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of N-(4-chlorophenyl)-2,2-dimethylpropanamide (6.7 g, 30 mmol) in anhydrous THF (100 mL) under nitrogen at 0° C. was added a solution of n-BuLi (2.5M, 30 mL, 70 mmol) in hexane in a dropwise fashion. After addition, the solution was kept stirring at 0° C. for 40 minutes and treated with a solution of 1-(trifluoroacetyl)imidazole (9 mL, 78 mmol) in anhydrous THF (10 mL). The reaction mixture was warmed to ambient temperature and kept for 18 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution (50 mL) followed by addition of ethyl acetate (100 mL). The organic layer was separated and the solvent was removed in vacuo. The residue obtained was suspended in 3N aqueous hydrochloride solution (50 mL) and heated at reflux overnight. The reaction solution was cooled to room temperature and treated with a cold ammonium hydroxide solution to a pH above 8. The aqueous mixture was extracted with ethyl acetate (3×50 mL) and the organic layers were washed with brine and dried (MgSO4). After removal of solvent, the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1) to afford the title compound as a yellow solid (1 g, 15%): mp 93-94° C.; 1H-NMR (CDCl3) δ7.70 (m, 1H), 7.33 (dd, 1H, J=9.0, 2.3 Hz), 6.70 (d, 1H, J=9.1 Hz), 6.45 (bs, 2H); MS (ESI) m/z 222(M−H, 100%), 224(M−H, 33%). After addition The reaction mixture was warmed to ambient temperature kept for 18 hours The organic layer was separated the solvent was removed in vacuo The residue obtained heated at reflux overnight The reaction solution was cooled to room temperature The aqueous mixture was extracted with ethyl acetate (3×50 mL) the organic layers were washed with brine dried (MgSO4) After removal of solvent the residue was purified by a flash chromatography (silica gel, hexane:ethylacetate/4:1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0 g, 22.4 mmol) was dissolved in dichloromethane (50 mL) and (R)-2-chloro-2-oxo-1-phenylethyl pivalate (8.54 g, 33.5 mmol) was added. To this mixture N,N-dimethylaniline (2.8 mL, 22.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (50 mL), treated with 1N HCl, washed with brine and the organic layer was separated and evaporated to give (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethyl pivalate (12) as an brown oil. washed with brine the organic layer was separated evaporated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone hydrochloride hydrate (48.5 g, 174.4 mmol), 300 mL toluene, and 150 mL water was stirred at room temperature for 30 minutes. The pH of the solution was adjusted to 7-8 via the addition of saturated aqueous NaHCO3 solution. The resulting mixture was then separated, and the toluene layer was collected and evaporated to dryness to give 38.2 g 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2) as a yellow solid. The resulting mixture was then separated the toluene layer was collected evaporated to dryness

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Chloro-2-trifluoroacetylaniline, hydrochloride hydrate (17.1 g, 62 mmol) was stirred in a mixture of toluene (100 mL) and water (50 mL). The mixture was neutralized to pH 7 with saturated NaHCO3. The organic phase was concentrated in vacuo and the residue recrystallized from heptane to give 12.5 g (91%) of the title compound as yellow needles: mp 98-99° C.; 1H NMR (300 MHz, CDCl3) δ7.70 (t, J=2 Hz, 1H), 7.32 (dd, J=2, 9 Hz, 1H), 6.7 (d, J=9 Hz, 1H), 6.44 (brs, 2H); 13C NMR (75 MHz CDCl3) δ 180.0, 151.6, 136.9, 130.1 , 120.9, 119.0, 116.8, 111.4; 19F NMR (282 MHz, CDCl3) δ-70.3. The organic phase was concentrated in vacuo the residue recrystallized from heptane

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (1S,2R)—PNE (18.7%-w/w, 19.7 g, 18.0 mmol) in THF/toluene (9:1-w/w) was charged to a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature for 30 min, 1-hexyne (97%-w/w, 6.10 g, 72.0 mmol) was added at 18° C. and the resulting solution was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.8 g, 55.0 mmol) and a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (CN23315) in toluene/THF (1:1 w/w) (39.6%-w/w, 33.8 g, 60.0 mmol) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN23315 addition. After completed addition of CN23315 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 89.6% conversion. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid solution (1 M, 44.1 g). After stirring for 15 min the phases were separated and the organic phase successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g) and water (12.0 g). The organic phase was partially concentrated (51 g residual solution), diluted with toluene (30 g), and partially concentrated again (58 g residue). The residue was diluted with toluene (59 g) and isopropyl alcohol (1.50 g). Methanesulfonic acid (10.48 g, 114 mmol) was added at 30° C. over a period of 30 min and the mixture was stirred for 30 min. A second portion methanesulfonic acid (2.89 g, 30 mmol) was added at 30° C. over a period of 30 min. The mixture was stirred at 30° C. for 30 min, cooled to 5° C. over a period of 60 min, and aged at 5° C. for 30 min. The crystals were filtered, washed with cold toluene (10 g) and dried under vacuum at 40° C. The crude product (19.3 g) was obtained as yellowish solid with a purity of 93.3% and 99.6% ep according to method B. The product was further purified by slurring it in a mixture of toluene (100 mL) and isopropyl alcohol (2 mL) at room temperature for 3 h. The product (MSA salt of (R)—CN47583, compound of formula II, wherein R1 is trifluoromethyl, R2 is hex-1-ynyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) was filtered, washed with toluene (10 mL) and dried at 40° C. under vacuum. The product was obtained as white solid (17.1 g, 35.3 mmol, 59% yield) with a purity of 93.3% and 99.9% ep according to method B, and an assay of 92.8%w-/w according to 1H-NMR. for 30 min was started 10 min in advance of the CN23315 addition addition of CN23315 the reaction mixture heated to 30° C. over a period of 60 min aged for 6 h at 30° C The reaction mixture was stirred at 0° C. overnight quenched by addition of aqueous citric acid solution (1 M, 44.1 g) After stirring for 15 min the phases were separated the organic phase successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g) and water (12.0 g) The organic phase was partially concentrated (51 g residual solution) diluted with toluene (30 g) partially concentrated again (58 g residue) The residue was diluted with toluene (59 g) and isopropyl alcohol (1.50 g) the mixture was stirred for 30 min The mixture was stirred at 30° C. for 30 min cooled to 5° C. over a period of 60 min aged at 5° C. for 30 min The crystals were filtered washed with cold toluene (10 g) dried under vacuum at 40° C The crude product (19.3 g) was obtained as yellowish solid with a purity of 93.3% and 99.6% ep The product was further purified in a mixture of toluene (100 mL) and isopropyl alcohol (2 mL) at room temperature for 3 h R10 is hydrogen) was filtered washed with toluene (10 mL) dried at 40° C. under vacuum

Conditions: temp:20.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (1S,2R)—PNE (18.7%-w/w, 19.7 g, 18.0 mmol) in THF/toluene (9:1-w/w) was charged to a vessel at room temperature. A solution of diethylzinc in toluene (29.9%-w/w, 6.10 g, 14.8 mmol) was added at 17 to 25° C. and the mixture was aged at said temperature for 30 min, 1-hexyne (97%-w/w, 6.10 g, 72.0 mmol) was added at 18° C. and the resulting solution was aged at 20° C. for 60 min. A solution of BuLi in toluene (3.09 mol/kg, 17.8 g, 55.0 mmol) and a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (CN23315) in toluene/THF (1:1 w/w) (39.6%-w/w, 33.8 g, 60.0 mmol) were added in parallel to the reaction mixture at 20° C. within 3 h. The addition of BuLi was started 10 min in advance of the CN23315 addition. After completed addition of CN23315 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight. HPLC (Method B) indicated 89.6% conversion. The reaction mixture was diluted with toluene (25.8 g) and quenched by addition of aqueous citric acid solution (1 M, 44.1 g). After stirring for 15 min the phases were separated and the organic phase successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g) and water (12.0 g). The organic phase was partially concentrated (51 g residual solution), diluted with toluene (30 g), and partially concentrated again (58 g residue). The residue was diluted with toluene (59 g) and isopropyl alcohol (1.50 g). Methanesulfonic acid (10.48 g, 114 mmol) was added at 30° C. over a period of 30 min and the mixture was stirred for 30 min. A second portion methanesulfonic acid (2.89 g, 30 mmol) was added at 30° C. over a period of 30 min. The mixture was stirred at 30° C. for 30 min, cooled to 5° C. over a period of 60 min, and aged at 5° C. for 30 min. The crystals were filtered, washed with cold toluene (10 g) and dried under vacuum at 40° C. The crude product (19.3 g) was obtained as yellowish solid with a purity of 93.3% and 99.6% ep according to method B. The product was further purified by slurring it in a mixture of toluene (100 mL) and isopropyl alcohol (2 mL) at room temperature for 3 h. The product (MSA salt of (R)—CN47583, compound of formula II, wherein R1 is trifluoromethyl, R2 is hex-1-ynyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) was filtered, washed with toluene (10 mL) and dried at 40° C. under vacuum. The product was obtained as white solid (17.1 g, 35.3 mmol, 59% yield) with a purity of 93.3% and 99.9% ep according to method B, and an assay of 92.8%w-/w according to 1H-NMR. for 30 min was started 10 min in advance of the CN23315 addition addition of CN23315 the reaction mixture heated to 30° C. over a period of 60 min aged for 6 h at 30° C The reaction mixture was stirred at 0° C. overnight quenched by addition of aqueous citric acid solution (1 M, 44.1 g) After stirring for 15 min the phases were separated the organic phase successively washed with water (9.1 g), aqueous NaHCO3 solution (5%-w/w, 24.0 g) and water (12.0 g) The organic phase was partially concentrated (51 g residual solution) diluted with toluene (30 g) partially concentrated again (58 g residue) The residue was diluted with toluene (59 g) and isopropyl alcohol (1.50 g) the mixture was stirred for 30 min The mixture was stirred at 30° C. for 30 min cooled to 5° C. over a period of 60 min aged at 5° C. for 30 min The crystals were filtered washed with cold toluene (10 g) dried under vacuum at 40° C The crude product (19.3 g) was obtained as yellowish solid with a purity of 93.3% and 99.6% ep The product was further purified in a mixture of toluene (100 mL) and isopropyl alcohol (2 mL) at room temperature for 3 h R10 is hydrogen) was filtered washed with toluene (10 mL) dried at 40° C. under vacuum

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (1R,2S)—PNE (18.1%-w/w, 171.6 g, 151 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel and cooled to 17° C. A solution of diethylzinc in toluene (29%-w/w, 52.0 g, 122 mmol) was added at 15 to 20° C. and the mixture was aged at said temperature for 30 min. Ethane (approx. 1 equivalent in respect to diethylzinc) was formed during the diethylzinc addition and partially released from the reaction mixture. The ethane release is observed with a delay with respect to the diethylzinc addition, since ethane is first dissolved in the reaction solution and then released to the gas phase. According to 1H-NMR analysis some ethane remained dissolved in the reaction mixture. A solution of cyclopropylacetylene in toluene (70%-w/w, 57.0 g, 600 mmol) was added at 15 to 20° C. and the resulting mixture was aged at 20° C. for 1 h. During the addition of cyclopropylacetylene additional ethane (approx. 1 equivalent in respect to diethylzinc) was formed and released to the gas phase. A solution of butyllithium (BuLi) in toluene (157.6 g, 2.92 mol/kg, 460 mmol) and a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (SD570, 40.1%-w/w, 278.0 g, 500 mmol) in THF/toluene (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 180 min. The addition of BuLi was started 10 min in advance of the SD570 addition. Butane was formed during BuLi addition. However, most of the butane remained dissolved in the reaction mixture and only weak gas formation was observed. The course of reaction can be followed online, for example by calorimetric measurements or by “React IR” also called “in-situ FTIR”. After complete addition of SD570 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight, diluted with toluene (218 g) at 20° C. and quenched by addition of aqueous citric acid (1 M, 375 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (76 g), aqueous NaHCO3 solution (5%-w/w, 200 g), and again water (100 g). The organic phase was partially concentrated, then diluted with toluene (250 g), again partially concentrated and diluted with toluene (976 g residue). The enantiomeric purity (ep) of (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol (SD573) in the crude product was approx. 96 to 97% according to Method B. Although not belonging to the preparation process, described is also a process to transfer the product in a more stable form as a methanesulfonic acid salt. The residue was diluted with isopropyl alcohol (126.6 g). Then methanesulfonic acid (43.3 g) was added over a period of 30 min at 30° C. Seeding crystals (between 1 and 10 mg) were added and the mixture aged for 30 min at 30° C. A second portion of methanesulfonic acid (26.5 g) was added over a period of 60 min at 30° C. The resulting solution was aged for 30 min at 30° C. and later cooled to 5° C. over a period of 60 min. After further aging at 5° C. for 30 min, the product was filtered and washed with cold toluene/isopropyl alcohol (10:1-w/w, 262 g) at 5° C. The wet methanesulfonic acid salt of SD573 ((S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol mesylate (2:3 mol/mol, SD573-MSA, compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) was dried in vacuo at 40° C. to obtain 188.3 g (432 mmol, 86.5% yield). SD573-MSA was obtained with a purity of 99.9% and 99.7% ep, according to Method A. is first dissolved in the reaction solution remained dissolved in the reaction mixture was formed was started 10 min in advance of the SD570 addition

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of (1R,2S)—PNE (18.1%-w/w, 171.6 g, 151 mmol) in a THF/toluene mixture (9:1-w/w) was charged in a vessel and cooled to 17° C. A solution of diethylzinc in toluene (29%-w/w, 52.0 g, 122 mmol) was added at 15 to 20° C. and the mixture was aged at said temperature for 30 min. Ethane (approx. 1 equivalent in respect to diethylzinc) was formed during the diethylzinc addition and partially released from the reaction mixture. The ethane release is observed with a delay with respect to the diethylzinc addition, since ethane is first dissolved in the reaction solution and then released to the gas phase. According to 1H-NMR analysis some ethane remained dissolved in the reaction mixture. A solution of cyclopropylacetylene in toluene (70%-w/w, 57.0 g, 600 mmol) was added at 15 to 20° C. and the resulting mixture was aged at 20° C. for 1 h. During the addition of cyclopropylacetylene additional ethane (approx. 1 equivalent in respect to diethylzinc) was formed and released to the gas phase. A solution of butyllithium (BuLi) in toluene (157.6 g, 2.92 mol/kg, 460 mmol) and a solution of 1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (SD570, 40.1%-w/w, 278.0 g, 500 mmol) in THF/toluene (1:1-w/w) were added in parallel to the reaction mixture at 20° C. within 180 min. The addition of BuLi was started 10 min in advance of the SD570 addition. Butane was formed during BuLi addition. However, most of the butane remained dissolved in the reaction mixture and only weak gas formation was observed. The course of reaction can be followed online, for example by calorimetric measurements or by “React IR” also called “in-situ FTIR”. After complete addition of SD570 the reaction mixture was stirred for 30 min at 20° C., then heated to 30° C. over a period of 60 min and aged for 6 h at 30° C. The reaction mixture was stirred at 0° C. overnight, diluted with toluene (218 g) at 20° C. and quenched by addition of aqueous citric acid (1 M, 375 g). After stirring for 15 min the phases were separated and the aqueous phase was discarded. The organic phase was successively washed with water (76 g), aqueous NaHCO3 solution (5%-w/w, 200 g), and again water (100 g). The organic phase was partially concentrated, then diluted with toluene (250 g), again partially concentrated and diluted with toluene (976 g residue). The enantiomeric purity (ep) of (S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol (SD573) in the crude product was approx. 96 to 97% according to Method B. Although not belonging to the preparation process, described is also a process to transfer the product in a more stable form as a methanesulfonic acid salt. The residue was diluted with isopropyl alcohol (126.6 g). Then methanesulfonic acid (43.3 g) was added over a period of 30 min at 30° C. Seeding crystals (between 1 and 10 mg) were added and the mixture aged for 30 min at 30° C. A second portion of methanesulfonic acid (26.5 g) was added over a period of 60 min at 30° C. The resulting solution was aged for 30 min at 30° C. and later cooled to 5° C. over a period of 60 min. After further aging at 5° C. for 30 min, the product was filtered and washed with cold toluene/isopropyl alcohol (10:1-w/w, 262 g) at 5° C. The wet methanesulfonic acid salt of SD573 ((S)-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-ol mesylate (2:3 mol/mol, SD573-MSA, compound of formula II, wherein R1 is trifluoromethyl, R2 is 2-cyclopropyl-ethynyl, R8 is 5-chloro, R9 is hydrogen and R10 is hydrogen) was dried in vacuo at 40° C. to obtain 188.3 g (432 mmol, 86.5% yield). SD573-MSA was obtained with a purity of 99.9% and 99.7% ep, according to Method A. is first dissolved in the reaction solution remained dissolved in the reaction mixture was formed was started 10 min in advance of the SD570 addition