Diisopropylethylamine → (3R*,5S*)-3-tert-Butoxycarbonylamino-5-[(2-chloro-benzyl)-cyclopropylcarbamoyl]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

HRID 1698302Notes

Reaction equation

HRID 1698302 reaction equation
[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:35][C:36]1[CH:46]=[CH:45][CH:44]=[CH:43][C:37]=1[CH2:38][NH:39][CH:40]1[CH2:42][CH2:41]1.C(N(C(C)C)C(C)C)C.CCCP(=O)=O>CC(N(C)C)=O.C(OCC)(=O)C>[CH:10]1[C:11]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:19][C@@H:20]([C:32](=[O:33])[N:39]([CH2:38][C:37]4[CH:43]=[CH:44][CH:45]=[CH:46][C:36]=4[Cl:35])[CH:40]4[CH2:42][CH2:41]4)[CH2:21][C@@H:22]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:23]3)=[O:17])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 834606N-(2-chlorobenzyl)cyclopropanamineHCID 16167369Propylphosphoric anhydrideHCID 57870323HCID 57870323, compound

Product 1

HCID 69067630(3R*,5S*)-3-tert-Butoxycarbonylamino-5-[(2-chloro-benzyl)-cyclopropylcarbamoyl]-piperidine-1-carboxylic acid 9H-fluoren-9-ylmethyl ester

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent

Procedure

To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (233.3 mg, 0.5 mmol), (2-chlorobenzyl)-cyclopropylamine (99.9 mg, 0.55 mmol) and N-ethyldiisopropylamine (685 μL, 4 mmol) in dimethylacetamide (2.5 mL), propylphosphonic anhydride solution (˜50% in DMF, 480 μL, ˜0.75 mmol) is added. The reaction mixture is stirred for 14 h at RT, diluted with ethyl acetate and washed twice with an aqueous NaHCO3 solution. The combined organic layers are dried (Na2SO4) and evaporated in vacuo, and the residue is 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 Na2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted three times with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a white amorphous solid. MS: 630.7 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, then 100% CH3CN+0.1% TFA for 2 min, flow 1.5 ml/min): 8.24 min.

Workup

  1. temperatureTo a stirred, ice-cooled
  2. additionis added
  3. washwashed twice with an aqueous NaHCO3 solution
  4. dry with materialThe combined organic layers are dried (Na2SO4)
  5. customevaporated in vacuo
  6. customthe residue is 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 Na2CO3, CH3CN
  8. customis removed in vacuo
  9. extractionthe residual aqueous phase is extracted three times with CH2Cl2
  10. dry with materialThe combined organic layers are dried (Na2SO4)
  11. customevaporated

Sources & evidence

ORD record
ord-a01a058f9de744ffa0aa49a5fc115ccc
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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