Pivaloyl chloride → HCID 57870340, compound

HRID 1698371Notes

Reaction equation

HRID 1698371 reaction equation
C1C2C(COC([N:18]3[CH2:23][C@H:22]([C:24](=[O:44])[N:25]([CH:41]4[CH2:43][CH2:42]4)[CH2:26][C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=4)[CH2:21][C@H:20]([NH:45][CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.[C:62](Cl)(=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64]>C(Cl)Cl>[CH:41]1([N:25]([CH2:26][C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:28]=2)[C:24]([C@@H:22]2[CH2:21][C@H:20]([N:45]([CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:62](=[O:67])[C:63]([CH3:66])([CH3:65])[CH3:64])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:42][CH2:43]1

Participants

5

Reactant 3

HCID 62493Pivaloyl chloride2×HCID 81531Diisopropylethylamine2×HCID 67273412(3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Product 1

HCID 57870340HCID 57870340, compound

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A solution of (3S,5R)-3-Benzylamino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (68.5 mg, 0.098 mmol) in CH2Cl2 is treated with i-Pr2NEt (40.2 μL, 0.235 mmol) and pivaloylchloride (23.9 μL, 0.196 mmol). The solution is stirred at room temperature for 18 h. Additional i-Pr2NEt (20 μL, 0.12 mmol) and pivaloylchloride (12 μL, 0.095 mmol) are added and stirring is continued for 9 h. The reaction mixture is partitioned between EtOAc and 1 M NaHCO3, the organic layer is washed with 1 M NaHCO3 and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is dissolved in THF/piperidine (5:1) (6 mL), the solution is stirred at room temperature for 2.5 h and then concentrated in vacuo. The crude product is purified by RP-HPLC to afford the title compound. MS: 559 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 3.40 min.

Workup

  1. stirringstirring
  2. waitis continued for 9 h
  3. customThe reaction mixture is partitioned between EtOAc and 1 M NaHCO3
  4. washthe organic layer is washed with 1 M NaHCO3 and brine
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. dissolutionThe residue is dissolved in THF/piperidine (5:1) (6 mL)
  9. stirringthe solution is stirred at room temperature for 2.5 h
  10. concentrationconcentrated in vacuo
  11. customThe crude product is purified by RP-HPLC

Sources & evidence

ORD record
ord-7113ee4d38a944dba5d1278e524c8e37
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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