tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.70 g (3.01 mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercial) and 1.11 g (3.31 mmol) of ethyl 5-(4-nitrophenoxycarbonyloxymethyl)isoxazole-3-carboxylate, obtained in step 14.1., 0.33 g of pure product is obtained in the form of an orange-coloured oil. obtained in step 14.1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.70 g (3.01 mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercial) and 1.11 g (3.31 mmol) of ethyl 5-(4-nitrophenoxycarbonyloxymethyl)isoxazole-3-carboxylate, obtained in step 14.1., 0.33 g of pure product is obtained in the form of an orange-coloured oil. obtained in step 14.1

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: After dissolving 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester (1071 mg, 4.61 mmol) in tetrahydrofuran (10 ml), FmocNCS (9-fluorenylmethoxycarbonyl isothiocyanate) (1425 mg, 5.07 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=10/1-5/1) to obtain 4-[({[(fluoren-9-ylmethoxy)carbonylamino] thioxomethyl}amino)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS. was added After completion of the reaction the mixture was concentrated purified by silica gel column chromatography (hexane/ethyl acetate=10/1-5/1)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and (E)-4-(dimethylamino)but-2-enoic acid hydrochloride with method S1, S2, S3, S4A. Yield 15.9%. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.93 (d, 1H), 6.74 (m, 1H), 4.47 (d, 1H), 3.98 (m, 3H), 3.75 (d, 2H), 3.41 (t, 1H), 3.03 (t, 1H), 2.97 (m, 6H), 1.81 (m, 2H), 1.62 (m, 2H). HPLC PURITY: 99%, MS: m/z=505[M+H]+

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and acrylic acid with method S1, S2, S3, S4A. Yield 16.1%. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 6.73 (m, 1H), 6.24 (d, 1H), 5.73 (d, 1H), 4.41 (d, 1H), 4.00 (d, 1H), 3.74 (d, 2H), 3.44 (m, 1H), 3.02 (t, 1H), 1.73 (m, 2H), 1.61 (m, 2H). HPLC PURITY: 94%, MS: m/z=448[M+H]+

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The 4-[(1,3-dioxoisoindolin-2-yl)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester was dissolved in ethanol (200 mL), and then hydrazine monohydrate (10.0 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was filtered out and the filtrate was concentrated under reduced pressure. The obtained crudely purified product was further purified by silica gel column chromatography (5% MeOH/CH2Cl2) to obtain 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by 1H-NMR. The yield was 3.23 g (76%). the precipitated solid was filtered out the filtrate was concentrated under reduced pressure The obtained crudely purified product was further purified by silica gel column chromatography (5% MeOH/CH2Cl2)

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: To a 0° C. solution of 4-3 (8.83 g, 38.7 mmol) in 75 mL dry THF was added a solution of 1 M borane in THF (155 mL, 155 mmol) over 30 min. After 30 min more, the cold reaction was slowly quenched with EtOH (200 mL) and all solvent was removed in vacuo. The residue was taken up in saturated aq. NH4Cl/EtOAc (150 mL) and extracted with EtOAc (3×150 mL). The organic layers were washed with 1 N aq. NaOH, brine, dried over MgSO4, filtered, and concentrated in vacuo, giving crude 4-4 as a pale yellow oil. The crude amine 4-4 was carried forward. 1H NMR (CDCl3, 300 MHz): 3.94 (br, 2H), 3.08 (m, 2H), 1.85 (m, 2H), 1.51 (m, 4H), 1.44 (s, 9H); MS (Electrospray): m/z 218.2 (M−Me+H), 177.2 (M−t−Bu+H). the cold reaction was slowly quenched with EtOH (200 mL) all solvent was removed in vacuo extracted with EtOAc (3×150 mL) The organic layers were washed with 1 N aq. NaOH, brine dried over MgSO4 filtered concentrated in vacuo

反応条件: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: A mixture of 3-3 (11.0 g) and 25 mL ethanolamine was stirred at 60° C. for 1 h. The reaction was then allowed to cool to room temperature, poured into ice-water (100 mL), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (150 mL), dried over MgSO4, filtered, and concentrated in vacuo, giving 5.82 g of crude 3-4 as a viscous amber oil. 1H NMR (CDCl3, 300 MHz): 3.94 (br, 2H), 3.08 (m, 2H), 1.85 (m, 2H), 1.51 (m, 4H), 1.44 (s, 9H); MS (Electrospray): m/z 218.2 (M−Me+H), 177.2 (M−t−Bu+H). to cool to room temperature extracted with CH2Cl2 (3×100 mL) The combined organic layers were washed with brine (150 mL) dried over MgSO4 filtered concentrated in vacuo

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1-yl)propan-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 4-(aminomethyl)-4-fluoropiperidine-1-carboxylate and 3-(piperidin-1-yl)propanoic acid with method S1, S2, S3, S4A. Yield 23.4%. 1H NMR (CD3OD) δ 8.26 (s, 1H), 7.14-7.40 (m, 9H), 4.29 (d, 1H), 3.80 (d, 1H), 3.62 (dd, 2H), 3.00 (m, 1H), 2.60-2.77 (m, 7H), 1.78 (m, 2H), 1.69 (m, 5H), 1.52 (m, 2H). HPLC PURITY: 99%, MS: m/z=533[M+H]+

反応条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

実験手順: The process is performed according to the procedure described in Example 1 (step 1.6.). Starting with 0.70 g (3.01 mmol) of tert-butyl 4-aminomethyl-4-fluoropiperidine-1-carboxylate (commercial) and 1.11 g (3.31 mmol) of ethyl 5-(4-nitrophenoxycarbonyloxymethyl)isoxazole-3-carboxylate, obtained in step 14.1., 0.33 g of pure product is obtained in the form of an orange-coloured oil. obtained in step 14.1