Potassium Carbonate → HCID 131733697, compound

HRID 706374Notes

Reaction equation

HRID 706374 reaction equation
[CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[CH:5]([NH:14]C(=O)OC(C)(C)C)[CH2:4][C@H:3]1[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[F:30].C1(C)C=CC(S(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[C:47]([NH:50][C@H:51]([C:59]([OH:61])=[O:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)(=[O:49])[CH3:48]>OC1C=CC([N+]([O-])=O)=CC=1C=O>[C:47]([NH:50][C@@H:51]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:59]([O-:61])=[O:60])(=[O:49])[CH3:48].[CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([F:10])([F:12])[F:11])[C:6](=[O:13])[C@@H:5]([NH3+:14])[CH2:4][C@H:3]1[C:22]1[C:27]([F:28])=[CH:26][CH:25]=[C:24]([F:29])[C:23]=1[F:30]

Participants

6

Reactant 4

HCID 11430Potassium CarbonateHCID 74839N-Acetyl-L-phenylalanineHCID 89821792tert-Butyl((5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl)carbamateHCID 178427284HCID 178427284, compound

Product 1

HCID 131733697HCID 131733697, compoundYield 89%

Reagents, catalysts & solvents 1

HCID 668085-NitrosalicylaldehydeCatalyst

Conditions

Temperature
55 °C

Procedure

iPAc solution of 22 (529 g assayed, 1.2 mol), obtained from previous step, was diluted to 6 L with iPAc, p-toluenesulfonic acid monohydride (343 g, 1.8 mol) was added and the solution was heated to 55° C. After 4 h, the reaction completed (>99% conversion). Aqueous K2CO3 (530 g in 3 L of water) was charged into the solution after cooled to 15-25° C. The aqueous layer was separated and was back-extracted with iPAc (2 L). The iPAc solutions were combined and the total volume was adjusted to 10 L by adding iPAc. The solution was heated to 50-60° C. About 20 g of N-acetyl L-phenylalanine was added and the solution was agitated for 15 min or until solids precipitated out. The remaining N-acetyl L-phenylalanine (total 250 g, 1.2 mol) was charged slowly and 2-hydroxy-5-nitrobenzaldehyde (2 g) was charged. The suspension was agitated for 12 h at 20° C. and then cooled to 0° C. for 3 h. The suspension was filtrated, washed with iPAc three times and dried to give 23 (583 g, 89% yield) as crystals. Mp 188-190° C.; 1H NMR (DMSO-d6, 400 MHz): δ 7.96 (d, J=8.0 Hz, 1H), 7.48 (m, 1H), 7.15-7.25 (m, 6H), 4.65 (ddd, J=19.4, 15.3, 9.6 Hz, 1H), 4.33 (ddd, J=8.7, 8.4, 4.9 Hz, 1H), 3.70-3.87 (m, 3H), 3.57 (dd, J=11.5, 6.6 Hz, 1H), 3.04 (dd, J=13.7, 4.9 Hz, 1H), 2.82 (dd, J=13.7, 8.9 Hz, 1H), 2.59 (m, 1H), 2.24 (m, 1H), 2.95 (s, 3H), 1.10 (d, J=6.4 Hz, 1H); 19F NMR (DMSO-d6, 376 MHz): δ −69 (s), −118 (d, J=15 Hz), −137 (d, J=21 Hz), −142 (dd, J=21, 15 Hz); 13C NMR (DMSO-d6, 100 MHz): δ 173.6, 171, 0.1, 168.7, 156.3 (ddd, J=243.5, 7.0, 3.1 Hz), 148.7 (ddd, J=249, 14.4, 9.1 Hz), 146.8 (ddd, J=245, 13.7, 3.1 Hz), 138.5, 129.2, 128.0, 126.1, 124.9 (q, J=280.9 Hz), 117.4.0 (dd, J=19.3, 13.8 Hz), 116.7 (dd, J=19.3, 10.6 Hz), 111.8 (ddd, J=26.0, 6.7, 3.6 Hz), 56.6, 54.3, 51.2, 44.3 (q, J=32.5 Hz), 37.2, 34.8, 26.9 (br t, J=4 Hz), 22.5, 14.1.

Workup

  1. additionwas added
  2. temperatureafter cooled to 15-25° C
  3. customThe aqueous layer was separated
  4. extractionwas back-extracted with iPAc (2 L)
  5. additionby adding iPAc
  6. temperatureThe solution was heated to 50-60° C
  7. additionAbout 20 g of N-acetyl L-phenylalanine was added
  8. customprecipitated out
  9. stirringThe suspension was agitated for 12 h at 20° C.
  10. temperaturecooled to 0° C. for 3 h
  11. filtrationThe suspension was filtrated
  12. washwashed with iPAc three times
  13. customdried

Sources & evidence

ORD record
ord-5ce46fe8863045cbadbd0c6220d18e27
Source dataset
uspto-grants-2015_11
Patent number
US09174989B2

Reaction notes

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