Dimethylformamide → HCID 73297109, compound

HRID 626322Notes

Reaction equation

HRID 626322 reaction equation
[NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[OH:22])[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.Cl[CH2:27][C:28]1[CH:40]=[CH:39][C:31]([CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[NH2:1][C:2](=[O:24])[C@@H:3]([N:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][C:19]=2[O:22][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:32][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:39][CH:40]=2)[C:14]1=[O:23])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:7]

Participants

7

Reactant 4

HCID 6228DimethylformamideHCID 11430Potassium CarbonateHCID 673677424-(4-(chloromethyl)benzyl)morpholine hydrochlorideHCID 89964450HCID 89964450, compound

Product 1

HCID 73297109HCID 73297109, compoundYield 86%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

(S)-tert-Butyl 5-amino-4-(4-hydroxy-1-oxoisoindolin-2-yl)-5-oxopentanoate (160 g), 4-(4-(chloromethyl)benzyl)morpholine hydrochloride (138 g, 0.87×) and potassium carbonate (165 g, 1.04×) were added to DMF (960 mL, 6×) in a 5 liter jacketed vessel. The mixture was heated to 40 to 50° C. and agitated for 12 to 24 hours. The mixture was cooled to 25 to 35° C., then ethyl acetate (1600 mL, 10×) and water (1600 mL, 10×) were added. The mixture was agitated at 25 to 35° C., settled, and split. Additional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added. The mixture was agitated at 25 to 35° C., settled, and split. The combined organic phase was washed four times with water (400 mL, 2.5×). The organic phase was distilled under vacuum below 50° C. to 6× volume. Additional ethyl acetate (2880 mL, 18×) was continuously added, and the distillation was continued to maintain about 6× volume. The temperature was adjusted to 40 to 45° C., then seeds (0.8 g, 0.005×) were added. The mixture was held for about 30 minutes to build seed bed, then heptane (960 mL, 6×) was added over about 1.5 hours. The mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours, agitated at 15 to 25° C. for at least one hour, and held for 16 hours. The solid was filtered, washed with heptane:ethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%, to give (S)-tert-butyl 5-amino-4-(4-((4-(morpholinomethyl)benzyl)oxy)-1-oxoisoindolin-2-yl)-5-oxopentanoate as a white solid (215.3 g, 86% yield); MS m/z: 524.3 (M+1); 1H NMR (DMSO-d6, 300 MHz) δ 7.57 (br s, 1H), 7.48-7.43 (m, 3H), 7.34 (d, J=8.1 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.19 (br s, 1H), 5.21 (s, 2H), 4.71 (dd, J=10.2, 4.2 Hz, 1H), 4.54 (d, J=17.4 Hz, 1H), 4.40 (d, J=17.7 Hz, 1H), 3.56 (dd, J=4.5, 4.5 Hz, 4H), 3.45 (s, 2H), 2.34 (dd, J=4.5, 4.5 Hz, 4H), 2.15-1.99 (m, 4H), 1.32 (s, 9H) ppm; 13C NMR (DMSO-d6, 75 MHz) δ 171.8, 171.3, 167.8, 153.4, 137.7, 135.3, 133.3, 130.2, 129.5, 129.0, 127.6, 115.1, 114.6, 79.7, 69.4, 66.2, 62.1, 53.5, 53.1, 44.8, 31.8, 27.6, 24.8 ppm.

Workup

  1. temperatureThe mixture was cooled to 25 to 35° C.
  2. stirringThe mixture was agitated at 25 to 35° C.
  3. customsplit
  4. additionAdditional ethyl acetate (800 mL, 5×) and water (800 mL, 5×) were added
  5. stirringThe mixture was agitated at 25 to 35° C.
  6. customsplit
  7. washThe combined organic phase was washed four times with water (400 mL, 2.5×)
  8. distillationThe organic phase was distilled under vacuum below 50° C. to 6× volume
  9. additionAdditional ethyl acetate (2880 mL, 18×) was continuously added
  10. distillationthe distillation
  11. temperatureto maintain about 6× volume
  12. customwas adjusted to 40 to 45° C.
  13. additionseeds (0.8 g, 0.005×) were added
  14. waitThe mixture was held for about 30 minutes
  15. additionheptane (960 mL, 6×) was added over about 1.5 hours
  16. temperatureThe mixture was cooled to 15 to 25° C. over about 1 to 1.5 hours
  17. stirringagitated at 15 to 25° C. for at least one hour
  18. waitheld for 16 hours
  19. filtrationThe solid was filtered
  20. washwashed with heptane
  21. dry with materialethyl acetate (5× total, 2.5× heptane, 2.5× ethyl acetate), and dried under reduced pressure with nitrogen sweep at 35 to 45° C. until LOD≦1%

Sources & evidence

ORD record
ord-31007e84d4cd4b92b59ee832a530a905
Source dataset
uspto-grants-2016_04
Patent number
US09309220B2

Reaction notes

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