反应 #1755487

反应方程式

TFA

(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

TFA

→

(R)-2-(4-(6-(4-chlorophenyl)-4-oxothieno[3,2-d]pyrimidin-3(4H)-yl)-2-methoxyphenyloxy)-1-cyclopropylethyl dihydrogen phosphate

收率 73.4%

溶剂

CH2Cl2

反应条件

后处理

1. 1
   其他equipped with mechanical stirrer, temperature inlet
2. 2
   workup.ADDITIONnitrogen/vacuum switch inlet, addition funnel
3. 3
   温度reflux condenser
4. 4
   其他was reduced to −2° C
5. 5
   其他resulting in a 1.6° C. temperature rise
6. 6
   温度The reaction temperature was maintained between −0.5° C. and 1° C. (internal) as aliquots
7. 7
   其他were periodically withdrawn
8. 8
   workup.ADDITIONcompletion of the TFA addition, HPLC analysis
9. 9
   workup.WAITAfter 95 minutes
10. 10
    温度the reaction was cooled to ˜3° C.
11. 11
    workup.ADDITIONto the addition of MeOH (28.5 mL) over 5 min
12. 12
    workup.STIRRINGAfter stirring for 30 min
13. 13
    浓缩the reaction was concentrated at 50 mm Hg and 15° C. to a residual volume of ˜134 mL
14. 14
    温度The solution temperature was increased to 19° C.
15. 15
    workup.ADDITIONaddition of 120 mL of MTBE (ca 12 min)
16. 16
    workup.ADDITIONafter addition of ˜30 mL, about 42-45 mL of MTBE
17. 17
    workup.ADDITIONwas added before a white precipitate
18. 18
    其他to form
19. 19
    workup.STIRRINGAfter stirring for 2 hours at 19-20° C.
20. 20
    过滤the solid was collected by filtration
21. 21
    洗涤Both the reactor and the filter cake were washed twice with 120 mL of MTBE/CH2Cl2 2.5:1 v/v
22. 22
    其他The very sandy white/off-white material was air-dried for 15 min with vacuum suction
23. 23
    其他before drying overnight in a vacuum oven at 45° C.
24. 24
    其他to obtain 25.58 g of crude product
25. 25
    其他was recrystallized
26. 26
    温度by heating 24.3 g of the crude product in 200 mL of THF and 16 mL of water in a CHEMGLASS®
27. 27
    workup.STIRRINGwith stirring to 55-57° C.
28. 28
    workup.DISSOLUTIONdissolution
29. 29
    温度The solution was heated at 60° C. for an additional 15 min
30. 30
    温度cooled to 45° C. over 10 min
31. 31
    workup.ADDITIONwhereupon 50 mL of acetone was added over Ca 5 min
32. 32
    温度while maintaining the temperature above 44° C.
33. 33
    workup.ADDITIONthroughout the addition
34. 34
    workup.ADDITIONUpon completion of addition the faintly cloudy solution
35. 35
    其他Once rapid crystallization
36. 36
    workup.ADDITIONan additional 245 mL of acetone over 30 minutes was added
37. 37
    温度maintaining the temperature above 42.5° C.
38. 38
    workup.ADDITIONthroughout the addition
39. 39
    温度The resultant thick slurry was cooled to 22° C. (jacket) over ca 60 minutes
40. 40
    workup.STIRRINGstirred for 90 min at 20-21° C.
41. 41
    其他before collecting the solid
42. 42
    过滤by filtration
43. 43
    洗涤Both the reactor and the filter cake were washed first with 120 mL of acetone/THF 3:1 v/v
44. 44
    其他After air drying for 40 min with vacuum suction
45. 45
    其他the solid was dried in a vacuum oven at 50° C. for 18 hr

实验过程

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.

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