1,1-Dichloroethane → (3S*,5R*)-5-(3-Benzyl-ureido)-piperidine-3-carboxylic acid cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amide

HRID 1698309Notes

Reaction equation

HRID 1698309 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]([NH2:45])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.ClC(Cl)C.[CH2:50]([N:57]=[C:58]=[O:59])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>>[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]([NH:45][C:58]([NH:57][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:59])[CH2:19][NH:18][CH2:23]2)=[O:44])[CH2:43][CH2:42]1

Participants

4

Reactant 3

HCID 63651,1-DichloroethaneHCID 76639Benzyl isocyanate2×HCID 57870324(3R*,5S*)-3-Amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Product 1

HCID 15984530(3S*,5R*)-5-(3-Benzyl-ureido)-piperidine-3-carboxylic acid cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-amide

Conditions

Temperature
50 °C

Procedure

A mixture of (3R*,5S*)-3-amino-5-{cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester (91 mg, 0.15 mmol), dichloroethane (2 mL) and benzyl isocyanate (18.4 μL, 0.15 mmol) is shaken for 14 h at 50° C. A second portion of benzyl isocyanate (9.2 μL, 0.075 mmol) is added and shaking is continued for 5 h at 60° C. The mixture is evaporated in vacuo. The crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h, the mixture is evaporated and the residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with K2CO3, CH3CN is removed in vacuo and the residual aqueous phase extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a yellow resin. MS: 518.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.05 min.

Workup

  1. stirringshaking
  2. waitis continued for 5 h at 60° C
  3. customThe mixture is evaporated in vacuo
  4. stirringThe crude product is stirred with a solution of CH2Cl2/piperidine 4:1 (5 mL) for 2 h
  5. customthe mixture is evaporated
  6. customthe residue purified by preparative HPLC (C18 column, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min)
  7. additionThe combined pure fractions are treated with K2CO3, CH3CN
  8. customis removed in vacuo
  9. extractionthe residual aqueous phase extracted three times with CH2Cl2
  10. dry with materialThe combined organic layers are dried (Na2SO4)
  11. customevaporated

Sources & evidence

ORD record
ord-871d43f24dfc41959bc36400cea351c7
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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