Citric Acid → HCID 89415622, compound

HRID 591089Notes

Reaction equation

HRID 591089 reaction equation
Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C[CH2:22][N:21]2C(=NCCC2)CC1.C(O)(=O)C[C:26]([CH2:31][C:32]([OH:34])=O)([C:28]([OH:30])=[O:29])O.[CH3:37][S:38]([OH:41])(=[O:40])=[O:39].C[C:43](N(C)C)=[O:44]>CC(OC)(C)C.C(OCC)(=O)C>[CH3:37][S:38]([O-:41])(=[O:40])=[O:39].[Cl:12][C:11]1[C:2]([O:34][C@H:32]2[CH2:22][NH2+:21][C@H:26]([C:28]([O:30][CH3:37])=[O:29])[CH2:31]2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:44][CH3:43])[CH:5]=2

Participants

8

Reactant 5

HCID 311Citric AcidHCID 6395Methanesulfonic AcidHCID 166592,3-DichloroquinoxalineHCID 31374DimethylacetamideHCID 811841,8-Diazabicyclo(5.4.0)undec-7-ene

Product 1

HCID 89415622HCID 89415622, compound

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 15413tert-Butyl methyl etherSolvent

Conditions

Temperature
42.5 °C

Procedure

To a slurry of 2,3-dichloroquinoxaline 11 (100 g, 0.437 mol) and N-Boc-4-trans-hydroxy-L-proline methyl ester (12, 118 g, 0.48 mol) in DMAc (500 ml, KF <150) at ambient temperature was added DBU (86 g, 0.568 mol). The slurry was agitated at 40-45° C. for ˜35 hours. The batch was then cooled to 15° C. Ethyl acetate (1.2 L) followed by citric acid (10%, 504 mL, 162 mmol) was added while the internal temperature was maintained <25° C. The organic phase was washed with a solution of 10% citric acid (200 mL) and water (200 mL) followed by water (400 mL×2). The organic phase was azeotropically dried and solvent switched to MeCN at a final volume of ˜880 mL. MeSO3H (36 mL, 0.555 mol) was added and the reaction mixture was aged at 40° C. for ˜16 hours. To the reaction slurry was added MTBE (1.05 L) dropwise over 2 hours at 35° C. Then, the batch was further cooled to 0-5° C. and aged for 2-3 hours before filtration. The wet cake was displacement washed with 30% MeCN in MTBE (600 mL×2), and vacuum oven dried at 40° C. to give the product 14.

Workup

  1. temperatureThe batch was then cooled to 15° C
  2. additionwas added while the internal temperature
  3. temperaturewas maintained <25° C
  4. washThe organic phase was washed with a solution of 10% citric acid (200 mL) and water (200 mL)
  5. customThe organic phase was azeotropically dried
  6. waitthe reaction mixture was aged at 40° C. for ˜16 hours
  7. temperatureThen, the batch was further cooled to 0-5° C. and aged for 2-3 hours before filtration
  8. washwashed with 30% MeCN in MTBE (600 mL×2), and vacuum oven
  9. customdried at 40° C.

Sources & evidence

ORD record
ord-44dee0d064ba423d9d5550c725a6ed09
Source dataset
uspto-grants-2016_01
Patent number
US09238604B2

Reaction notes

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