Phosphoric Acid → (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid

HRID 37985Notes

Reaction equation

HRID 37985 reaction equation
[C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([O:35]CC)=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].P(=O)(O)(O)O.C(Cl)Cl>C1COCC1.CCO.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH2:10][C:11]([C:33]([OH:35])=[O:34])=[CH:12][C:13]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[CH:22][C:23]([C:26]([N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)=[O:27])=[CH:24][CH:25]=3)=[CH:16][C:14]=2[N:15]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

7

Reactant 4

HCID 1004Phosphoric AcidHCID 3939Lithium Hydroxide2×HCID 6344DichloromethaneHCID 68026461HCID 68026461, compound

Product 1

HCID 66960164(1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acidYield 90.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 21873804Tetrahydrofuran ethanolSolvent

Procedure

To a solution of (1E,4E)-ethyl 2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylate (12.0 g, 23.8 mmol) in THF-EtOH (60 mL/60 mL) was added 4 N aq. LiOH (23.8 mL, 95.3 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 21 h. Additional 6 mL of 4 N aq LiOH was added twice after 21 h and 24 h. After stirring for additional 6 h, the resulting mixture was concentrated under reduced pressure to give the crude material that was diluted with water (50 mL) and acidified to a pH of ˜3.5 with 1 N aq phosphoric acid (˜450 mL). ˜250 mL of CH2Cl2 was added during acidification to extract the crude product out of the sticky suspension. The solids formed during acidification were filtered off using a glass filter packed with Celite. The aqueous layer was separated and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressures to give 10.2 g (90%) of the crude (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid that was used directly without further purification. MS APCI(+) m/z 476 (M+1) detected.

Workup

  1. stirringAfter stirring for additional 6 h
  2. concentrationthe resulting mixture was concentrated under reduced pressure
  3. customto give the crude material that
  4. extractionto extract the crude product out of the sticky suspension
  5. customThe solids formed during acidification
  6. filtrationwere filtered off
  7. filtrationfilter
  8. customThe aqueous layer was separated
  9. extractionextracted with CH2Cl2 (3×100 mL)
  10. dry with materialThe combined organic layers were dried over MgSO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressures

Sources & evidence

ORD record
ord-8ab732eb934048eda5128705219d5b1f
Source dataset
uspto-grants-2013_09
Patent number
US08524702B2

Reaction notes

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