Citric Acid → 2,4-Dichloro-5-methoxy-6-vinylpyrimidine

2,6-Dichloro-5-methoxy-6-vinyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (10 g, 56 mmol) was dissolved in THF (15 mL). The solution was added dropwise to vinyl magnesium bromide (60 mL of 1 M, 60 mmol) over approximately 15 minutes while keeping the temperature of the mixture below 30° C. by external cooling. Rapid, clean formation of a dihydro-vinyl pyrimidine intermediate (having a molar weight of 206 g/mol) was observed using GC-MS and HPLC. The mixture was stirred for approximately 3 h at room temperature. Conversion of greater than 95% was observed by GC/FID. The mixture was cooled to below 10° C. and treated in portions with citric acid (150 mL of 10% citric acid). It was then diluted with ethyl acetate (75 mL). The phases were separate and the organic phase extracted using ethyl acetate (1×50 mL). The organic phases were then combined and washed with saturated sodium chloride (1×50 mL), then dried, and evaporated to provide a crude dihydro intermediate. This material was dissolved in DCM (200 mL) and treated with manganese dioxide (10.4 g, 120 mmol) while stirred at room temperature. The rapid formation of 2,6-dichloro-5-methoy-4-vinyl pyrimidine (having a molar weight of 204 g/mol) was observed. After about 1 h, an additional amount of manganese dioxide (15 g) was added and the mixture stirred overnight. The manganese dioxide was removed by filtration through celite. The filtrate was washed with DCM and acetone. The filtrate was then concentrated by allowing the solvents to evaporate and purified by column chromatography using silica with a ramp of 0-10% ethyl acetate/hexane. This provided the title compound (approximately 500 mg, approximately 4% yield): mp 59-60° C.

1. customthe temperature of the mixture below 30° C.
2. temperatureThe mixture was cooled to below 10° C.
3. customThe phases were separate
4. extractionthe organic phase extracted
5. washwashed with saturated sodium chloride (1×50 mL)
6. customdried
7. customevaporated
8. customto provide a crude dihydro intermediate
9. stirringwhile stirred at room temperature
10. waitAfter about 1 h
11. stirringthe mixture stirred overnight
12. customThe manganese dioxide was removed by filtration through celite
13. washThe filtrate was washed with DCM and acetone
14. concentrationThe filtrate was then concentrated
15. customto evaporate
16. custompurified by column chromatography

ORD 기록

ord-64356456b87d4a8e8463d341f88459da

출처 데이터셋

uspto-grants-2015_12

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09216958B2