The butyl-ester 17 (130 g, 0.25 mol) was mixed in 2-propanol (1040 mL) at 25 °C. KOH (4 M, 95 mL, 0.37 mol) was charged, and the reaction mixture was heated at 55 °C for 6 h. HCl (2 M, 189 mL, 0.38 mol) diluted with water (780 mL) was charged to the reaction solution over 45 min, while 55 °C was maintained. The slurry was cooled to 15 °C over 2 h and left for 1 h. The solids were collected, washed with water (380 mL), and dried at 55 °C with vacuum to give the butyl acid (122.8 g, 98% yield, corrected for 98.5 wt % 1H NMR assay) as a yellow solid. MS (ESI) m/z452 [M + H]+; 1H NMR (DMSO-d6) δ 1.88–1.94 (m, 2H), 2.10–2.18 (m, 2H), 3.23 (t, 2H, J = 11.4 Hz), 3.81 (dd, 2H, J = 11.6 and 4.0 Hz), 4.77–4.84 (m, 1H), 7.57 (d, 1H, J = 2.0 Hz), 7.78 (d, 2H, J = 8.8 Hz), 7.88 (d, 2H, J = 8.8 Hz), 8.83 (d, 1H, J = 1.6 Hz), 10.22 (s, 1H), 12.61 (br s, 1H); 13C NMR (DMSO-d6) δ 32.02, 55.96, 66.43, 118.08, 118.89 (CF3, JC,F = 267.9 Hz), 123.66, 127.43, 130.24, 132.45 (C–H, JC,F = 5.4 Hz), 136.48 (C–CF3, JC,F = 38.2 Hz), 144.08, 144.21 (C–C, JC,F = 12.6 Hz), 147.94 (C–H, JC,F = 24.4 Hz), 150.22 (C–F, JC,F = 251.9 Hz), 155.76 (C–N, JC,F = 3.1 Hz), 167.01; 99.8% HPLC purity. Reaction monitoring (acid, tR 7.25 min) was conducted by HPLC analysis with UV detection at 292 nm. HRMS m/z found 452.1345 [M + H]+, C20H18N5O3F4 requires 452.1346.

The butyl acid (112.6 g, 0.24 mol) was mixed in THF (675 mL) at 25 °C. N-Methyl-piperazine (29.3 mL, 0.26 mol), NMM (41 mL, 0.37 mol), and HOBt as a water solution (17 mL, 24.4 mmol, 19.4%) were added to the reaction solution. EDCI (72.7 g, 0.34 mol) dissolved in water (220 mL) was added over 10 min. The reaction mixture was heated at 45 °C for 1 h. EtOAc (675 mL) was added, and the reaction solution was heated at 55 °C. The lower water phase was separated off, and the organic phase was washed with 5% NaCl in water (225 mL), and then the organic solution was left stirring at 55 °C. Heptane (675 mL) was added over 1.5 h to initiate crystallization. The slurry was cooled to 5 °C over 8 h and left for at least 2 h. The solids were collected, washed with a cooled mixture of EtOAc and heptane (1:1, 600 mL), and dried at 60 °C with vacuum to give compound 9 (120.8 g, 89% yield, corrected for 96.1 wt % 1H NMR assay) as a light-yellow solid.

MS (ESI) m/z 534 [M + H]+;

1H NMR (DMSO-d6) δ 1.86–1.93 (m, 2H), 2.08–2.18 (m, 2H), 2.19 (s, 3H), 2.23–2.38 (m, 4H), 3.22 (t, 2H, J = 11.4 Hz), 3.34–3.68 (m, 4H), 3.80 (dd, 2H,J = 11.4 and 3.8 Hz), 4.77–4.88 (m, 1H), 7.35 (d, 2H, J = 8.8 Hz), 7.57 (d, 1H, J = 2.4 Hz), 7.70 (d, 2H, J = 8.8 Hz), 8.05 (d, 1H, J = 1.6 Hz), 10.04 (s, 1H);

13C NMR (DMSO-d6) δ 32.01, 45.57, 54.49 (piperazine), 55.96, 66.44, 118.65, 118.90 (CF3, JC,F = 267.8 Hz), 127.53, 127.89, 129.08, 132.39 (C–H, JC,F = 5.6 Hz), 136.42 (C–CF3, JC,F = 38.3 Hz), 141.07, 144.06 (C–C, JC,F = 12.5 Hz), 147.96 (C–H, JC,F = 24.7 Hz), 150.02 (C–F, JC,F = 251.2 Hz), 156.04 (C–N, JC,F = 2.9 Hz), 168.89; 99.6% HPLC purity.

Reaction monitoring (9, tR 2.90 min) was conducted by HPLC analysis with UV detection at 292 nm.

HRMS m/z found 534.2250 [M + H]+, C25H28N7O2F4 requires 534.2241.

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Scheme I:

Scheme 1

Anilines of formula (III) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Process b). Compounds of formula (IV) and amines of formula (V) may be reacted together under standard Buchwald conditions as described in Process a.

A synthesis of pyrimidines of formula (IV) is described in Scheme 2(R^X may be the same or different and is Q.βalkytyT should not be there

Scheme 2

Compounds of formula (V) are commercially available compounds, or they are known in the literature, or they are prepared by standard processes known in the art.

Compounds of formula (VI) in which R⁶ has the general structure R^a-CH-R^b (wherein R^a and R^b are as defined in formula I and R^x may be the same or different and is C_1-6alkyl) and R⁹ is F may be prepared according to Scheme 3

(VI) (VIf)

Scheme 3

Example 104

[4- [5-Fluoro-4- [3-tetr ahydropy r an-4-yl-2-(trifluor omethyl)imidazol-4-yl] -pyrimidin- 20 2-yl] aminophenyl]-(4-methylpiperazin-l-yl)-methanone hydrochloride

 

The title compound was prepared in accordance with the general method E and work-up procedure B. The product was purified by flash chromatography (CH₂Cl₂MeOH 30:1, 20:1 then 15:1). Using 5-fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- 25 imidazol-5-yl]pyrimidin-2-amme (obtained from Example 34(d)) (33 mg, 0.1 mmol), l-(4- bromobenzoyl)-4-methylpiperazine (0.027 g, 0.095 mmol), Cs₂CO₃ (65 mg, 0.2 mmol), Pd₂(dba)₃ (6.8 mg, 0.0075 mmol) and X-Phos (7 mg, 0.015 mmol), the base of the title compound (35 mg, 70%) was obtained as a solid. The hydrochloride was prepared in accordance with the method described in general method D. ¹H NMR (DMSO-<fc, 300 MHz) δ 10.60 (br s, 1 H), 10.11 (s, 1 H), 8.82 (s, 1 H), 7.74 (d, J = 8.4 Hz, 2 H), 7.56 (s, 1 H), 7.42 (d, J= 8.4 Hz, 2 H), 4.80 (t, 1 H), 3.80 (d, J= 8.4 Hz, 2 H), 3.22 (t, J= 11.5 Hz, 2 H), 3.2-3.0 (m, 2 H), 2.78 (s, 3 H), 2.2-2.1 (m, 2 H), 2.0-1.8 (m, 2 H); 6 Hydrogens were not assigned in the region 3.6 -2.2 ppm due to the presence of the water and DMSO peaks in this region; MS (ESI) m/z 534.5 (M+ 1); MS (ESI) m/z 532.5 (M-I).

 

 

Example 34 (d) 5-Fluoro-4-[l-(tetrahydro-2H-pyran-4-yl)-2-(trifluoromethyl)-lH- imidazol-5-yl]pyrimidin-2-amine

The title compound was prepared in accordance with the general method B with the exception that guanidine carbonate was used. Using (2Z)-3-dimethylamino-2-fluoro-l-[l- (tetrahydro-2H-pyran-4-yl)-2-trifluoromethyl- lH-imidazol-5 -y l]prop-2-en- 1 -one (0.330 g, 1.0 mmol, obtained from Example 34(c)) and guanidine carbonate (0.45 g, 2.50 mmol). After purification by flash chromatography (heptane/EtOAc 1 :2), the title compound was obtained (0.170 g, 51 %) as a white solid.

¹HNMR (CDCl₃₅ 300 MHz) δ 8.29 (s, 1 H)₅ 7.63 (d, J= 2.7 Hz, 1 H)₅ 5.10 (br.s., 2 H)₅ 4.88-4.76 (m, 1 H), 4.16-4.07 (m, 2 H)₅3.53-3.42 (m₅ 2 H)₅ 2.80-2.65 (m, 2 H), 1.89-1.81 (m, 2 H); MS (ES) m/z 332 (M+l).

REF………….