Water → HCID 86699661, compound

As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g, 1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mL water. The mixture was flushed with nitrogen gas for 30 minutes and Pd(PPh3)4 (22.05 g 19.08 mmol) was added. The resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes, heated to reflux, and a nitrogen-flushed solution of 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (140 g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. The resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours. After this time the mixture was cooled to RT and 300 mL of water was added. The mixture was then cooled to 5° C. and stirred for 40 minutes. The resulting precipitate (6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected by filtration, washed with 50 mL water, followed by washing with 150 mL EtOAc. The filtrate was separated into two layers and the aqueous layer extracted with EtOAc (2×1 L). The combined organics were dried over Na2SO4, concentrated under reduced pressure, diluted with 300 mL of DCM, and purified by medium pressure silica gel chromatography (0-100% EtOAc/DCM). Fractions containing pure product were concentrated under reduced pressure and the concentrate treated with 400 mL of hexanes to produce compound 2039 as a solid. This material was combined with the solid product previously collected and treated with 400 mL of 1:1 THF/DCM. The resulting suspension was heated and transferred to a filtration funnel containing a plug of Florisil®. The plug was washed with additional 1:1 THF/DCM to dissolve any remaining solid material and then washed with 4:1 EtOAc/DCM (2×1 L). The combined filtrates were concentrated under reduced pressure to produce a pink solid which was triturated with 500 mL hexanes, collected by filtration, and dried under reduced pressure to provide 6-chloro-2′-methyl-4,5′-bipyrimidine (compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 2.85 (s, 3H).

1. customThe mixture was flushed with nitrogen gas for 30 minutes
2. customThe resulting light yellow solution was flushed with nitrogen gas for an additional 40 minutes
3. temperatureheated
4. temperatureto reflux
5. additionwas added dropwise over 1.6 hours
6. temperatureThe resulting dark red solution was refluxed under an atmosphere of nitrogen for 16 hours
7. temperatureThe mixture was then cooled to 5° C.
8. filtrationThe resulting precipitate (6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected by filtration
9. washwashed with 50 mL water
10. washby washing with 150 mL EtOAc
11. customThe filtrate was separated into two layers
12. extractionthe aqueous layer extracted with EtOAc (2×1 L)
13. dry with materialThe combined organics were dried over Na2SO4
14. concentrationconcentrated under reduced pressure
15. additiondiluted with 300 mL of DCM
16. custompurified by medium pressure silica gel chromatography (0-100% EtOAc/DCM)
17. additionFractions containing pure product
18. concentrationwere concentrated under reduced pressure
19. additionthe concentrate treated with 400 mL of hexanes

ORD record

ord-df5c5fa641ea49c680a57ba32bb56233

Source dataset

uspto-grants-2016_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09296701B2