6-羟基-2-氮杂螺[3.3]庚烷-2-甲酸叔丁酯

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The process is performed according to the procedure described in Example 6, step 6.1. Starting with 1.40 g (6.63 mmol) of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.2., dissolved in 17 mL of methanol and 0.376 g (9.94 mmol) of sodium borohydride. After evaporating off the solvent and crystallizing from a 70/30 mixture of petroleum ether and diisopropyl ether, 1.18 g of the expected product are obtained in the form of a white powder. obtained in step 11.2 After evaporating off the solvent crystallizing from a 70/30 mixture of petroleum ether and diisopropyl ether, 1.18 g of the expected product are obtained in the form of a white powder

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (330 μL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 μL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid. to warm to room temperature stirred at room temperature for 18 hrs stirred at room temperature for 10 min The layers were separated The aqueous phase was extracted with DCM (3×30 mL) The combined organic phase was dried over anhydrous Na2SO4 concentrated by evaporation in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: tert-Butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (505 mg, 2.37 mmol) was dissolved in DCM (6.0 mL). The solution was cooled to 0° C. with an external ice-bath. Et3N (330 μL, 2.37 mmol) and DMAP (3.0 mg, 0.0237 mmol) were added. Methanesulfonyl chloride (184 μL, 2.37 mmol) was then added dropwise by syringe. The solution was stirred at 0° C. for 2.0 hrs, was then allowed to warm to room temperature and stirred at room temperature for 18 hrs. A saturated solution of NH4Cl (20 mL) was added and stirred at room temperature for 10 min. The layers were separated. The aqueous phase was extracted with DCM (3×30 mL). The combined organic phase was dried over anhydrous Na2SO4, concentrated by evaporation in vacuo to afford tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (684 mg, 99%) as a white solid. to warm to room temperature stirred at room temperature for 18 hrs stirred at room temperature for 10 min The layers were separated The aqueous phase was extracted with DCM (3×30 mL) The combined organic phase was dried over anhydrous Na2SO4 concentrated by evaporation in vacuo

反应条件: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (507 mg, 2.4 mmol) in MeOH (5.0 mL) was added NaBH4 (182 mg, 4.8 mmol) at 0° C. under N2. It was stirred at 0° C. for 30 min. The solution was concentrated by evaporator in vacuo to give crude solid. A saturated solution of NaHCO3 (30 mL) was added. The aqueous mixture was extracted with DCM (4×30 mL). The combined organic solution was dried over anhydrous Na2SO4 and then concentrated by evaporation in vacuo to afford tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (511 mg, 100%) as a white solid. The solution was concentrated by evaporator in vacuo to give crude solid The aqueous mixture was extracted with DCM (4×30 mL) The combined organic solution was dried over anhydrous Na2SO4 concentrated by evaporation in vacuo

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: The process is performed according to the procedure described in Example 6, step 6.1. Starting with 1.40 g (6.63 mmol) of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate, obtained in step 11.2., dissolved in 17 mL of methanol and 0.376 g (9.94 mmol) of sodium borohydride. After evaporating off the solvent and crystallizing from a 70/30 mixture of petroleum ether and diisopropyl ether, 1.18 g of the expected product are obtained in the form of a white powder. obtained in step 11.2 After evaporating off the solvent crystallizing from a 70/30 mixture of petroleum ether and diisopropyl ether, 1.18 g of the expected product are obtained in the form of a white powder

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 0.494 g (13.06 mmoles) of sodium borohydride is added in portions at 0° C. to a solution of 2.30 g (10.89 mmoles) of tert-butyl 6-oxo-2-aza-spiro[3.3]-heptane-2-carboxylate, obtained in stage 10.2, in 55 ml of methanol. The reaction mixture is stirred for 1 hr at ambient temperature. After evaporation of the solvent, water is added to the reaction mixture, the aqueous phase is separated, it is extracted several times with dichloromethane, and the combined organic phases are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and the filtrate is concentrated under reduced pressure. After crystallisation of the residue in diisopropyl ether, filtration of the solid obtained and drying under vacuum at 60° C., 2.24 g of product are obtained in the form of a beige powder. After evaporation of the solvent, water is added to the reaction mixture the aqueous phase is separated it is extracted several times with dichloromethane the combined organic phases are washed with a saturated aqueous solution of sodium chloride dried over sodium sulphate the filtrate is concentrated under reduced pressure After crystallisation of the residue in diisopropyl ether filtration of the solid obtained drying under vacuum at 60° C.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and (E)-4-(3,3-difluoroazetidin-1-yl)but-2-enoic acid with method S1, S2, S3, S4A. Yield 2.7%. 1H NMR (CD3OD) δ 8.31 (s, 1H), 7.10-7.47 (m, 9H), 6.60 (m, 1H), 6.40 (t, 1H), 5.25 (m, 1H), 4.54 (qt, 4H), 4.27 (d, 2H), 4.08 (s, 1H), 4.00 (m, 3H), 2.74 (m, 2H), 2.27 (m, 2H). HPLC PURITY: 95%, MS: m/z=534[M+H]+

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en-1-one was prepared 5,6-dichloropyrimidin-4-amine, 4-phenoxyphenylboronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and (E)-4-(3-fluoroazetidin-1-yl)but-2-enoic acid with method S1, S2, S3, S4A. Yield 1.7%. 1H NMR (CD3OD) δ 8.28 (s, 1H), 7.10-7.47 (m, 9H), 6.62 (m, 1H), 6.40 (t, 1H), 5.41 (m, 1H), 5.25 (m, 1H), 4.27 (d, 2H), 4.04 (m, 4H), 2.74 (m, 2H), 2.27 (m, 2H). HPLC PURITY: 99%, MS: m/z=516[M+H]+

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was prepared 5,6-dichloropyrimidin-4-amine, (4-(pyridin-3-yloxy)phenyl)boronic acid, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate and acrylic acid with method S1, S2, S3, S4A. Yield 21.2%. 1H NMR (CD3OD) δ 8.31 (m, 2H), 8.13 (s, 1H), 7.52 (m, 1H), 6.97 (m, 1H), 7.41 (d, 2H), 7.19 (m, 2H), 6.25 (m, 2H), 5.75 (m, 1H), 5.24 (m, 1H), 4.21 (d, 2H), 4.03 (d, 2H), 2.72 (m, 2H), 2.25 (m, 2H). HPLC PURITY: 99%, MS: m/z=430[M+H]+

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate, 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)benzonitrile, and acryloyl chloride using methods A, C, D, and F. HPLC: 100%. MS: m/z=454 [M+H]+.

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, 6-hydroxyl-2-aza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester, (4-phenoxyphenyl)boronic acid and acryloyl chloride according to general scheme 3 using methods S1, S2, S3, and S4C. HPLC purity: 99%. MS: m/z=429 [M+H]+. 1H NMR (CD3OD) δ 8.36 (s, 1H), 7.09-7.45 (m, 9H), 6.25 (m, 2H), 5.74 (m, 1H), 5.28 (m, 1H), 4.33 (d, 2H), 4.09 (d, 2H), 2.74 (m, 2H), 2.32 (m, 2H).

反应条件: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one was prepared from 5,6-dichloropyrimidin-4-amine, tert-butyl 6-hydroxyl-2-azaspiro[3.3]heptane-2-carboxylate, (4-(pyridin-4-yloxy)phenyl)boronic acid and acrylic acid according to general scheme 3 using methods S1, S2, S3, and S4A. HPLC purity: 99%. MS: m/z=430 [M+H]+. 1H NMR (CD3OD) δ 8.75 (m, 2H), 8.31 (m, 1H), 7.56 (m, 4H), 7.44 (m, 2H), 6.27 (m, 1H), 5.73 (m, 1H), 5.24 (m, 1H), 4.26 (d, 2H), 4.01 (d, 2H), 2.73 (m, 2H), 2.25 (m, 2H).