2-fluoroethyl carbonochloridate

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: The title compound (0.105 g, 90%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.12 g, 0.27 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.2 mL) and 2-fluoroethyl chloroformate (42 μL, 0.32 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.13 (d, 2H, J=8.3 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H, 4.70-4.55 (m, 2H), 4.40-4.15 (m, 4H), 3.91 (d, 2H, J=6.4 Hz), 3.06 (s, 3H), 2.84 (bs, 2H), 2.10-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 437 (M+H). The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2

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: was also prepared by an alternative route: 36 mg 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1,4-dioxaspiro[4.5]decan-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline was dissolved in dichloromethane (0.5 mL) containing triethylamine (100 uL). 93 uL 2-fluoroethyl chloroformate was added and the mixture was stirred for 30 minutes. The mixture was concentrated and the title compound was obtained after HPLC purification. MS: 553.2 [M+H], RT 2.42. was also prepared by an alternative route The mixture was concentrated

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

Procedure: The title compound (0.105 g, 90%) was prepared as a white solid from 1,1-dimethylethyl 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarboxylate (0.12 g, 0.27 mmol) and TFA (0.20 mL) in CH2Cl2 (6 mL) then diisopropylethylamine (1.2 mL) and 2-fluoroethyl chloroformate (42 μL, 0.32 mmol) in a manner similar to Example 74. The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2 to give the title compound as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=2.7 Hz), 8.13 (d, 2H, J=8.3 Hz), 8.00 (d, 2H, J=8.5 Hz), 7.73 (d, 1H, J=8.8 Hz), 7.35-7.25 (m, 1H, 4.70-4.55 (m, 2H), 4.40-4.15 (m, 4H), 3.91 (d, 2H, J=6.4 Hz), 3.06 (s, 3H), 2.84 (bs, 2H), 2.10-1.95 (m, 1H), 1.95-1.80 (m, 2H), 1.40-1.25 (m, 2H); LRMS (ESI), m/z 437 (M+H). The crude material was purified by chromatography on a silica gel column eluted with 1:7 acetone/CH2Cl2

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

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

Procedure: Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 2-fluoroethyl chloroformate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34–7.26, 5.21, 4.70–4.58, 4.56, 4.42, 4.34, 4.10, 3.99, 3.75–3.30, 2.71, 2.47, 1.32–1.26, 1.15; IR (liq.) 2973 (s), 2347 (b), 2181 (w), 1709 (s), 1567 (s), 1553 (s), 1500 (s), 1470 (s), 1445 (s), 1426 (s), 1396 (s), 1347 (s), 1140 (s), 1103 (s), 1060 (s), cm−1 HRMS (FAB) calcd for C23H29Cl2FN4O3+H 499.1679, found 499.1673. Anal. Calcd for C23H29Cl2FN4O3: C, 55.32; H, 5.85; N, 11.22. Found: C, 55.20; H, 5.91; N, 10.95.

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

Procedure: A solution of (3aS,7aS)-1-[1-(3-methylpyrrolidin-3-yl)-4-piperidyl]-3a,4,5,6,7,7a-hexahydro-3H-benzoimidazol-2-one (1 mmol) in water (10 mL) was added with potassium carbonate (4.0 equiv.) followed by 2-fluoroethyl chloroformate (1.2 equiv.) at room temperature and stirred at rt for 30 minutes. Extracted in ethyl acetate (2×10 mL), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography by eluting with methanol in ethyl acetate (0 to 5%) to afford the title compound (93 mg). 1H NMR (CD3OD, 400 MHz): δ 4.65 (t, 2H), 4.53 (t, 1H), 4.34 (m, 1H), 4.27 (m, 1H), 3.62 (m, 3H), 3.48-3.37 (m, 2H), 3.25 (t, 1H), 3.03-2.90 (m, 3H), 2.77 (br t, 1H), 2.47 (m, 3H), 1.98-1.60 (br m, 9H), 1.43 (m, 3H), 1.11 (s, 3H); MS (M+1): 397.30. Extracted in ethyl acetate (2×10 mL) the combined organic layers were washed with brine dried over anhydrous sodium sulfate concentrated in vacuo The crude product was purified by flash chromatography by eluting with methanol in ethyl acetate (0 to 5%)

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

Procedure: To a solution of 1-[1-methyl-6-(pyridin-2-ylmethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl]piperazin-2-one, hydrochloride (0.15 g, 0.40 mmol) and triethylamine (0.121 g, 1.20 mmol) in DCM (15 mL) is added dropwise 2-fluoroethyl carbonochloridate (0.076 g, 0.602 mmol) at room temperature, and the reaction mixture is stirred for 3 h. The reaction is quenched with a saturated solution of sodium bicarbonate (20 mL) at 0° C. and extracted with DCM (3×50 mL). The combined organic layers are dried over sodium sulphate, filtered and concentrated in vacuo. The residue is purified on neutral alumina, eluting with 1% MeOH in DCM to give a product, which on triturating in Et2O, affords the title compound (0.07 g, 0.164 mmol) as an off-white solid. MS (m/z): 428 (M+1). 1H-NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 3.77 (m, 4H), 4.17 (bs, 2H), 4.28 (t, 1H), 4.35 (t, 1H), 4.58 (t, 1H), 4.71 (t, 1H), 5.49 (s, 2H), 6.66 (d, 1H), 7.30-7.34 (m, 2H), 7.50 (d, 1H), 7.77-7.83 (m, 2H), 8.56 (d, 1H). The reaction is quenched with a saturated solution of sodium bicarbonate (20 mL) at 0° C. extracted with DCM (3×50 mL) The combined organic layers are dried over sodium sulphate filtered concentrated in vacuo The residue is purified on neutral alumina eluting with 1% MeOH in DCM to give a product, which on triturating in Et2O

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

Procedure: Following the procedure for the preparation of N-[(cis)-1-acetyl-4-ethoxypyrrolidin-3-yl]-5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-amine but substituting 2-fluoroethyl chloroformate and making non-critical variations provided the title compound as an oil: 1H NMR (400 MHz, CDCl3) δ) 7.49, 7.34-7.26, 5.21, 4.70-4.58, 4.56, 4.42, 4.34, 4.10, 3.99, 3.75-3.30, 2.71, 2.47, 1.32-1.26, 1.15; IR (liq.) 2973 (s), 2347 (b), 2181 (w), 1709 (s), 1567 (s), 1553 (s), 1500 (s), 1470 (s), 1445 (s), 1426 (s), 1396 (s), 1347 (s), 1140 (s), 1103 (s), 1060 (s), cm−1HRMS (FAB) calcd for C23H29Cl2FN4O3+H 499.1679, found 499.1673. Anal. Calcd for C23H29Cl2FN4O3: C, 55.32; H, 5.85; N, 11.22. Found: C, 55.20; H, 5.91; N, 10.95.