Preparation of 2,4-dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester_Industrial additives

Preparation background and overview of 2,4-dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester

2,4-Dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester is a pharmaceutical intermediate that can be synthesized from 1-benzyl-4 -Oxopiperidine-3-carboxylic acid ethyl ester hydrochloride is used as the starting material and is prepared through a four-step reaction. 2,4-Dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester can be used to prepare inhibitors of P97 complexes with fused pyrimidine structures.

Preparation of 2,4-dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H)-carboxylic acid tert-butyl ester

To 1-benzyl-4-oxopiperidine-3-carboxylic acid ethyl ester hydrochloride 1 (6.0g, 20.2mmol), urea (2.54g, 42.42mmol) in MeOH (100ml) under nitrogen atmosphere Add NaOMe (6.14g, 113.7mmol) to the 0°C solution. The resulting mixture was stirred at 60°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to provide the desired compound 2 (2.2 g, 42%). LRMS(M+H+)m/z: calculated 258.29; actual 258.30.

A solution of intermediate 2 (2.2g, 8.56mmol) in POCl₃ (25ml) was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and slowly poured into ice water (50 mL), followed by extraction with DCM (3×50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, dichloromethylbenzene borate/methanol=10:1) to provide the desired compound 3 (830 mg, 33 %). LRMS(M+H+)m/z: calculated 295.18; actual 295.20.

To a solution of intermediate 3 (700 mg, 2.39 mmol) in 1,2-dichloroethane (15 mL) at 0°C, 1-chloroethyl chloroformate (1.02 g, 7.71 mmol) was added. The solution was stirred at 100°C for 6 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo, the residue was dissolved in MeOH (10 mL) and the resulting mixture was stirred at 70°C for 1 hour. It was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by flash chromatography using a mixture of hexane and ethyl acetate to provide the desired product 4 as a solid (270 mg, 55%). LRMS(M+H+)m/z: calculated value 205.06; actual value 205.14.

To a solution of intermediate 4 (270 mg, 1.33 mmol) in DCM (30 mL) at 0 °C was added (Boc)₂O (348 mg, 1.6 mmol) and TEA (200 mg, 2.0 mmol ). The resulting solution was stirred at room temperature for 16 hours. It was then diluted with water (30 mL) and DCM (30 mL), the layers were separated and the aqueous phase was extracted with DCM (30 mLx2). The combined organic p-pyridylthiourea layers were washed with brine and dried over sodium sulfate. Na2SO4 was removed by filtration and volatiles were removed under reduced pressure. The resulting residue was purified by flash chromatography using a mixture of hexane and ethyl acetate to provide product 5, 2,4-dichloro-5,6-dihydropyrido[3,4-D]pyrimidine-7(8H) – tert-butyl formate (300 mg, 74%). LRMS(M+H+)m/z: calculated value 305.17; actual value 305.24.

References

[1][Invented in China, authorized by China] CN201380048509.7 Fused pyrimidines as inhibitors of P97 complex