Hydrochloric Acid → (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

HRID 1515067Notes

Reaction equation

HRID 1515067 reaction equation
[NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][C@@H:13]([OH:17])[C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[Cl:18].N1([C:24]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:38][CH2:37][C:36]4[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=4[NH:34][C:33]3=[O:43])[CH2:28][CH2:27]2)=[O:25])C=CN=C1.CC(C)([O-])C.[K+].Cl>C(O)(CC)(C)C.C1COCC1.CC(C)=O.O>[O:43]=[C:33]1[N:32]([CH:29]2[CH2:28][CH2:27][N:26]([C:24]([O:17][C@@H:13]([C:14]([OH:16])=[O:15])[CH2:12][C:5]3[CH:6]=[C:7]([C:8]([F:9])([F:10])[F:11])[C:2]([NH2:1])=[C:3]([Cl:18])[CH:4]=3)=[O:25])[CH2:31][CH2:30]2)[CH2:38][CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=2[NH:34]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 23665647Potassium tert-butoxideHCID 24815279HCID 24815279, compoundHCID 66941893(R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-2-hydroxy-propionic acid

Product 1

HCID 58202073(R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 180AcetoneSolventHCID 962WaterSolventHCID 64052-Methyl-2-butanolSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
25 °C

Procedure

5.00 kg (17.63 mol) (R)-3-(4-amino-3-chloro-5-trifluoromethyl-phenyl]-2-hydroxy-propionic acid (G) and 6.28 kg (19.39 mol) 1-(1H-imidazol-1-yl-carbonyl)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-piperidine (F) were suspended in 40.0 L tert.-amylalcohol, before 20 L solvent were distilled off under normal pressure. Then the reaction mixture was cooled to 25° C., 21.76 kg (38.78 mol) potassium tert.butoxide solution in THF was added, before the mixture was heated to 35° C. for 1.5 hours. After the reaction was complete the mixture was cooled to 25° C. cooled and 9.64 kg (79.33 mol) hydrochloric acid (30%), 25.0 L water and 25.0 L acetone were added successively, before the mixture was inoculated with 5 g ethyl (1R)-4-(1,2,4,5-tetrahydro-2-oxo-3H-1,3-benzodiazepin-3-yl)-1-carboxy-2-[4-amino-3-chloro-5-trifluoromethyl-phenyl]-1-piperidinecarboxylate. After stirring overnight the suspension was cooled to 0° C. and stirred for a further hour. The product was separated off, washed twice with 15.0 L water and 15.0 L acetone and dried.

Workup

  1. distillationwere distilled off under normal pressure
  2. temperaturewas heated to 35° C. for 1.5 hours
  3. temperaturewas cooled to 25° C.
  4. temperaturecooled
  5. temperaturewas cooled to 0° C.
  6. stirringstirred for a further hour
  7. customThe product was separated off
  8. washwashed twice with 15.0 L water and 15.0 L acetone
  9. customdried

Sources & evidence

ORD record
ord-e57fd32b007246938e5cc41e4848662e
Source dataset
uspto-grants-2012_07
Patent number
US08222402B2

Reaction notes

Loading…