tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]heptane-2-carboxylate synthesis

Yield:1239320-10-5 11 g

Reaction Conditions:

with Zn-Cu in 1,2-dimethoxyethane;diethyl ether at 10 - 20;Inert atmosphere;

Steps:

1-(propylsulfonyl)dispiro[azetidine-3,1'-cyclobutane-3',1''-[1,2]oxaborolo[4,3- d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol

The title compound was prepared by the scheme and procedures shown below: To a solution of PPh3CH3Br (41.8 g, 117 mmol) in Et2O (200 mL) was added t-BuOK (13.1 g, 117 mmol) and the mixture was stirred at rt for 1 h before being treated with a solution of tert-butyl 3-oxoazetidine-1-carboxylate ( 20.0 g, 117 mmol) in Et2O (100 mL). The resulting mixture was stirred at rt overnight, poured into water and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1) to give tert-butyl 3-methyleneazetidine-1-carboxylate (12.0 g, yield 60%) as a light oil. ¹H NMR (300 MHz, CDCl₃): δ 5.08-4.88 (m, 2H), 4.49 (t, J = 2.3 Hz, 4H), 1.46 (s, 9H) ppm. To a solution of tert-butyl 3-methyleneazetidine-1-carboxylate (12.0 g, 71.0 mmol) in Et₂O (100 ml) was added Zn-Cu (36.6 g, 284.0 mmol) at 10^oC under N2 atmosphere. And then CCl3CCOCl (25.8 g, 0.142 mol) in DME (100 mL) was added. The mixture was stirred at room temperature overnight, quenched with aq. NaHCO₃ and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica-gel chromatography to give tert-butyl 5,5-dichloro-6-oxo-2-azaspiro[3.3]- heptane-2-carboxylate (11.0 g) as a yellow oil. To a solution of tert-butyl 5,5-dichloro-6-oxo-2- azaspiro[3.3]-heptane-2-carboxylate (11 g) in MeOH (100 mL) were added Zn (25.4 g, 0.39 mol) and sat. NH₄Cl (40 mL). The reaction was stirred at room temperature for 3 h, filtered and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromate- graphy to give tert-butyl 6-oxo-2-azaspiro[3.3]-heptane-2-carboxylate (6.1 g, yield 41%) as a white solid.¹H NMR (400 MHz, CDCl₃): δ 4.14 (s, 4H), 3.30 (s, 4H), 1.46 (s, 9H) ppm. To a solution of 5-bromo-4-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (12.0 g, 25.1 mmol) in THF (100 mL) was added i-PrMgCl-LiCl (25.0 mL, 32.5 mmol) at -20 ^oC under N2. The reaction was stirred at -20^oC for 1 h, and then tert-butyl 6-oxo-2-azaspiro[3.3]-heptane-2-carboxylate (5.3 g, 25.1 mmol) in THF (50 mL) was added slowly. The reaction was stirred at room temperature for 3 h, quenched with H2O and extracted with EtOAc. The organic was concentrated, and the residue was purified by column chromatography (PE/EtOAc = 100/1 to 10/1) to give tert-butyl 6- (5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (9.0 g, yield 64%) as a light-yellow solid.¹H NMR (300 MHz, CDCl₃): δ 8.28 (s, 1H), 7.32-7.30 (m, 1H), 6.59 (d, J = 2.9 Hz, 1H), 4.24 (s, 2H), 3.87 (s, 2H), 3.08-2.85 (m, 4H), 1.89- 1.73 (m, 3H), 1.45 (s, 9H), 1.09 (d, J = 7.4 Hz, 18H) ppm. To a solution of tert-butyl 6-(5-bromo- 1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-hydroxy-2-azaspiro[3.3]heptane-2- carboxylate (2.8 g, 5.0 mmol) in THF (50 mL) were added (PinB)₂ (2.5 g, 10.0 mmol), KOAc (1.5 g, 15.0 mmol) and Pd(dppf)Cl₂ (1.6 g, 2.0 mmol) under N₂ atmosphere. The reaction was stirred at 75^oC overnight, filtered and concentrated. The residue was dissolved in THF (40 mL) and 6N HCl (5 mL) was added. The reaction was stirred for 30 min and extracted with EtOAc. The organic was concentrated to give a residue (3.4 g) as a black solid, which was dissolved in DCM (30 mL) and then TFA (10 mL) was added. The reaction was stirred for 1h, poured into water and extracted with DCM. The aqueous solution was concentrated to give dispiro[azetidine-3,1'- cyclobutane-3',1''-[1,2]oxaborolo[4,3-d]pyrrolo[2,3-b]pyridin]-3''(6''H)-ol TFA salt (2.0 g, crude) as a yellow solid. MS (ESI⁺): m/z =256.2 (M+1)⁺. To a solution of this amine TFA salt (500 mg, crude) in THF (10 mL) were added Et₃N (0.4 mL) and propane-1-sulfonyl chloride (142 mg, 1.0 mmol) at 0^oC. The reaction was stirred at room temperature for 30 min and concentrated. The residue was purified by pre-HPLC (TFA in ACN and H2O) to give the product (28.3 mg, yield 8%) as a white solid.¹H NMR (400 MHz, DMSO-d₆): δ 12.12 (s, 1H), 9.32 (br s, 1H), 8.50 (s, 1H), 7.63 (t, J = 2.8 Hz, 1H), 6.65 (t, J = 1.7 Hz, 1H), 4.14 (d, J = 14.4 Hz, 4H), 3.13 (t, J = 7.6 Hz, 2H), 3.03 (d, J = 14.3 Hz, 2H), 2.60 (d, J = 14.3 Hz, 2H), 1.81-1.63 (m, 2H), 1.01 (t, J = 7.4 Hz, 3H) ppm. HPLC purity: 99.27 % at 210 nm. MS (ESI+): m/z = 362.1 (M+1)⁺.

References:

WO2021/61823,2021,A1 Location in patent:Paragraph 0191-0193