1,2-Dichloroethane → HCID 69002685, compound

HRID 1821396Notes

Reaction equation

HRID 1821396 reaction equation
C(OC([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=O)(C)(C)C.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)=[O:34])=[CH:29][C:28]=2[NH:41][C:42]([C:44]2[S:45][CH:46]=[CH:47][C:48]=2[CH3:49])=[O:43])=[N:17]1.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl>C1COCC1.C(OCC)(=O)C>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](/[CH:25]=[CH:26]/[C:27]2[CH:32]=[CH:31][C:30]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([C:10]([C@@H:9]4[CH2:13][CH2:14][CH2:15][NH:8]4)=[O:12])[CH2:39][CH2:40]3)=[O:34])=[CH:29][C:28]=2[NH:41][C:42]([C:44]2[S:45][CH:46]=[CH:47][C:48]=2[CH3:49])=[O:43])=[N:17]1

Participants

7

Reactant 4

HCID 111,2-DichloroethaneHCID 850831,2-Pyrrolidinedicarboxylic acid, 1-(1,1-dimethylethyl) ester, (2S)-HCID 27960291-Hydroxybenzotriazole hydrateHCID 56847651HCID 56847651, compound

Product 1

HCID 69002685HCID 69002685, compoundYield 58.6%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

N-(tert-butoxycarbonyl)-L-proline (0.20 g, 0.42 mmol) was dissolved in THF (10 mL) and the solution was added with Compound 99 (0.14 g, 0.42 mmol), 1-hydroxybenzotriazole monohydrate (75 mg, 0.54 mmol) and EDC (0.11 g, 0.59 mmol), followed by stirring at 60° C. for 2 hours. After the reaction, the reaction mixture was added with ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate solution and the organic layer was concentrated under reduced pressure. The obtained (S)-(E)-N-2-(4-{4-[2-(1H-indazol-3-yl)vinyl]-3-[(3-methylthiophene-2-carbonyl)amino]benzoyl}piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in methanol (5.0 mL) and 4 mol/L hydrogen chloride-methanol solution (1.0 mL) was added thereto, followed by heating under reflux at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate and then extracted. The obtained crude product was crystallized from ethanol to obtain Compound 231 (0.14 g, 56%).

Workup

  1. customAfter the reaction
  2. washwashed with saturated aqueous sodium hydrogencarbonate solution
  3. concentrationthe organic layer was concentrated under reduced pressure
  4. dissolutionThe obtained (S)-(E)-N-2-(4-{4-[2-(1H-indazol-3-yl)vinyl]-3-[(3-methylthiophene-2-carbonyl)amino]benzoyl}piperazine-1-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in methanol (5.0 mL)
  5. addition4 mol/L hydrogen chloride-methanol solution (1.0 mL) was added
  6. temperatureby heating
  7. temperatureunder reflux at 60° C. for 2 hours
  8. concentrationThe reaction mixture was concentrated under reduced pressure
  9. additionthe residue was added with saturated aqueous sodium hydrogencarbonate solution and ethyl acetate
  10. extractionextracted
  11. customThe obtained crude product
  12. customwas crystallized from ethanol

Sources & evidence

ORD record
ord-259e10aebd174bfea8c81997907d85c8
Source dataset
uspto-grants-2009_10
Patent number
US07605272B2

Reaction notes

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