Trifluoroacetic acid → 6-(4-Chlorophenyl)-3-[4-[(2R)-2-cyclopropyl-2-(phosphonooxy)ethoxy]-3-methoxyphenyl]thieno[3,2-d]pyrimidin-4(3H)-one

Temperature

20 °C

A mixture of (R)-2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenoxy)-1-cyclopropyl-ethyl bis(2-(trimethylsilyl)ethyl) phosphate (35.27 g, 47.06 mmoles), prepared in Part B, and anhydrous CH2Cl2 (315 mL) in a 500 mL CHEMGLASS® jacketed reactor (glycol) equipped with mechanical stirrer, temperature inlet, nitrogen/vacuum switch inlet, addition funnel and reflux condenser was stirred at 20° C. until dissolution was complete; whereupon, the internal temperature was reduced to −2° C. Once the temperature had stabilized, TFA (30.2 mL; 399.40 mmoles) was added dropwise to the stirred solution resulting in a 1.6° C. temperature rise. The reaction temperature was maintained between −0.5° C. and 1° C. (internal) as aliquots were periodically withdrawn to monitor the reaction progress by HPLC analysis. Immediately following completion of the TFA addition, HPLC analysis revealed the composition to be 9.29% starting bis ester, 44.78% monodeprotection, 42.2% desired product, 1.21% (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)-thieno[3,2-d]pyrimidin-4(3H)-one and 1.25% of the main side-product. After 64 min, the composition was 0.0% starting ester, 0.62% monodeprotection, 94.36% desired product, 1.52% (R)-6-(4-chlorophenyl)-3-(4-(2-cyclopropyl-2-hydroxyethoxy)-3-methoxyphenyl)-thieno[3,2-d]pyrimidin-4(3H)-one and 2.69% of main side-product. After 95 minutes, the reaction was cooled to ˜3° C. prior to the addition of MeOH (28.5 mL) over 5 min. After stirring for 30 min, the reaction was concentrated at 50 mm Hg and 15° C. to a residual volume of ˜134 mL. The solution temperature was increased to 19° C. prior to slow addition of 120 mL of MTBE (ca 12 min). Although seeding was begun after addition of ˜30 mL, about 42-45 mL of MTBE was added before a white precipitate started to form. After stirring for 2 hours at 19-20° C., the solid was collected by filtration. Both the reactor and the filter cake were washed twice with 120 mL of MTBE/CH2Cl2 2.5:1 v/v. The very sandy white/off-white material was air-dried for 15 min with vacuum suction before drying overnight in a vacuum oven at 45° C. to obtain 25.58 g of crude product. This material, which contained some TFA by F NMR, was recrystallized by heating 24.3 g of the crude product in 200 mL of THF and 16 mL of water in a CHEMGLASS® jacketed reactor with stirring to 55-57° C. to achieve complete dissolution. The solution was heated at 60° C. for an additional 15 min, cooled to 45° C. over 10 min; whereupon 50 mL of acetone was added over Ca 5 min while maintaining the temperature above 44° C. throughout the addition. Upon completion of addition the faintly cloudy solution was seeded with previously crystallized product. Once rapid crystallization began, an additional 245 mL of acetone over 30 minutes was added maintaining the temperature above 42.5° C. throughout the addition, The resultant thick slurry was cooled to 22° C. (jacket) over ca 60 minutes and stirred for 90 min at 20-21° C. before collecting the solid by filtration. Both the reactor and the filter cake were washed first with 120 mL of acetone/THF 3:1 v/v and then with acetone (110 mL). After air drying for 40 min with vacuum suction, the solid was dried in a vacuum oven at 50° C. for 18 hr to yield 18.96 g of (R)-2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenyloxy)-1-cyclopropylethyl dihydrogen phosphate (99.2% ee, 99.4% purity in 73% yield). M.P. 166° C. 1H NMR (500 MHz, DMSO-d6) δ ppm 0.41 (m, 2H), 0.52 (m, 2H)3, 1.26 (m, 1H), 3.82 (m, 1H), 4.20 (d, 2H, J=4.29 Hz), 3.80 (s, 3H), 7.06 (dd, 1H, J=8.57, J=2.34 Hz), 7.15 (d, 1H, J=8.57 Hz), 7.22 (d, 1H, J=2.34 Hz), 7.58 (d, 2H, J=8.57 Hz), 7.93 (2H, J=8.57 Hz), 7.98 (s, 1H), 8.40 (s, 1H). 1H NMR (126 MHz, DMSO-d) δ ppm 2.4, 3.1, 13.1, 56.0, 71.0, 77.9, 112.2, 113.1, 119.8, 121.9, 122.1, 128.0, 129.4, 130.1, 131.3, 134.4, 148.4, 149.1, 149.6, 149.9, 156.2, 157.5. 31P NMR δ (162 MHz, DMSO-d6): −0.75. HPLC: 95.4% API; 0.69%. LC/MS: m/e 549.1 (M+H); 4 min gradient. High Res. Mass: C24H23O7N2CIPS calc. 549.06522; exp. 549.06531.

1. customequipped with mechanical stirrer, temperature inlet
2. additionnitrogen/vacuum switch inlet, addition funnel
3. temperaturereflux condenser
4. customwas reduced to −2° C
5. customresulting in a 1.6° C. temperature rise
6. temperatureThe reaction temperature was maintained between −0.5° C. and 1° C. (internal) as aliquots
7. customwere periodically withdrawn
8. additioncompletion of the TFA addition, HPLC analysis
9. waitAfter 95 minutes
10. temperaturethe reaction was cooled to ˜3° C.
11. additionto the addition of MeOH (28.5 mL) over 5 min
12. stirringAfter stirring for 30 min
13. concentrationthe reaction was concentrated at 50 mm Hg and 15° C. to a residual volume of ˜134 mL
14. temperatureThe solution temperature was increased to 19° C.
15. additionaddition of 120 mL of MTBE (ca 12 min)
16. additionafter addition of ˜30 mL, about 42-45 mL of MTBE
17. additionwas added before a white precipitate
18. customto form
19. stirringAfter stirring for 2 hours at 19-20° C.
20. filtrationthe solid was collected by filtration
21. washBoth the reactor and the filter cake were washed twice with 120 mL of MTBE/CH2Cl2 2.5:1 v/v
22. customThe very sandy white/off-white material was air-dried for 15 min with vacuum suction
23. custombefore drying overnight in a vacuum oven at 45° C.
24. customto obtain 25.58 g of crude product
25. customwas recrystallized
26. temperatureby heating 24.3 g of the crude product in 200 mL of THF and 16 mL of water in a CHEMGLASS®
27. stirringwith stirring to 55-57° C.
28. dissolutiondissolution
29. temperatureThe solution was heated at 60° C. for an additional 15 min
30. temperaturecooled to 45° C. over 10 min
31. additionwhereupon 50 mL of acetone was added over Ca 5 min
32. temperaturewhile maintaining the temperature above 44° C.
33. additionthroughout the addition
34. additionUpon completion of addition the faintly cloudy solution
35. customOnce rapid crystallization
36. additionan additional 245 mL of acetone over 30 minutes was added
37. temperaturemaintaining the temperature above 42.5° C.
38. additionthroughout the addition
39. temperatureThe resultant thick slurry was cooled to 22° C. (jacket) over ca 60 minutes
40. stirringstirred for 90 min at 20-21° C.
41. custombefore collecting the solid
42. filtrationby filtration
43. washBoth the reactor and the filter cake were washed first with 120 mL of acetone/THF 3:1 v/v
44. customAfter air drying for 40 min with vacuum suction
45. customthe solid was dried in a vacuum oven at 50° C. for 18 hr

ORD record

ord-216e63940e064c39bb96862b834d158c

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07989433B2