1,2-Dimethoxyethane → 4-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(pyrimidin-5-yl)benzamide

HRID 924121Notes

Reaction equation

HRID 924121 reaction equation
[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2Br)[CH2:3]1.[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].COCCOC>C(Cl)Cl.CCCCCC>[NH2:1][C@@H:2]1[C@@H:6]([OH:7])[CH2:5][N:4]([C:8]2[CH:27]=[CH:26][C:11]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([Cl:25])([F:24])[F:23])=[CH:17][CH:16]=3)=[O:13])=[CH:10][C:9]=2[C:33]2[CH:34]=[N:29][CH:30]=[N:31][CH:32]=2)[CH2:3]1

Participants

6

Reactant 4

HCID 80711,2-DimethoxyethaneHCID 10340Sodium CarbonateHCID 2795193(Pyrimidin-5-yl)boronic acidHCID 899064294-((3 S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide

Product 1

HCID 1181952014-((3S,4S)-3-Amino-4-hydroxypyrrolidin-1-yl)-N-(4-(chlorodifluoromethoxy)phenyl)-3-(pyrimidin-5-yl)benzamide

Reagents, catalysts & solvents 1

HCID 21226440Methylenechloride HexaneSolvent

Conditions

Temperature
80 °C

Procedure

4-((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)-3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)benzamide (Stage 245.1, 60 mg, 0.121 mmol), 5-pyrimidineboronic acid (22.46 mg, 0.181 mmol) and Na2CO3 aq. (0.181 mL, 0.362 mmol) were added to a vial containing DME (1.5 mL) under argon atmosphere. PdCl2(dppf)-(CH2Cl2) (5.92 mg, 7.25 μmol) was added. The RM was stirred at 80° C. for 2 h, then filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by preparative HPLC (Condition 14). Fractions containing the product were combined, treated with sat. aq. Na2CO3 and the MeCN was removed. The aq. residue was extracted with DCM and the combined extracts were dried over Na2SO4, filtered and the filtrate was evaporated off under reduced pressure to give a residue that was suspended in DCM/n-hexane. The obtained solid was filtered off and washed with n-hexane then purified by SFC. The residue diluted with sat. aq. Na2CO3 (20 mL) and DCM (20 mL). Aq. phase was extracted with DCM (2×10 mL) and with EtOAc (3×10 mL). The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to afford the title product as a beige solid. HPLC (Condition 10) tR=5.77 min, UPLC-MS (Condition 3) tR=0.79 min, m/z=476.1/478.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.65-2.73 (m, 2H) 3.09-3.15 (m, 1H) 3.21-3.30 (m, 2H) 3.71-3.79 (m, 1H) 5.00 (d, J=3.50 Hz, 1H) 6.95 (d, J=8.99 Hz, 1H) 7.34 (d, J=8.20 Hz, 2H) 7.83-7.90 (m, 3H) 7.94 (dd, J=8.60, 2.30 Hz, 1H) 8.86 (d, J=0.78 Hz, 2H) 9.17 (d, J=1.17 Hz, 1H) 10.10 (s, 1H).

Workup

  1. filtrationfiltered through Hyflo®
  2. customthe solvent was evaporated off under reduced pressure
  3. customto give the crude product which
  4. customwas purified by preparative HPLC (Condition 14)
  5. additionFractions containing the product
  6. additiontreated with sat. aq. Na2CO3
  7. customthe MeCN was removed
  8. extractionThe aq. residue was extracted with DCM
  9. dry with materialthe combined extracts were dried over Na2SO4
  10. filtrationfiltered
  11. customthe filtrate was evaporated off under reduced pressure
  12. customto give a residue that
  13. filtrationThe obtained solid was filtered off
  14. washwashed with n-hexane
  15. customthen purified by SFC
  16. additionThe residue diluted with sat. aq. Na2CO3 (20 mL) and DCM (20 mL)
  17. extractionAq. phase was extracted with DCM (2×10 mL) and with EtOAc (3×10 mL)
  18. dry with materialThe combined extracts were dried over Na2SO4
  19. customthe solvent was evaporated off under reduced pressure

Sources & evidence

ORD record
ord-1beb10ff468b42f79714080738280c53
Source dataset
uspto-grants-2016_03
Patent number
US09278981B2

Reaction notes

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