Piperidine → {(3R*,5S*)-5-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-Piperidin-3-yl}-carbamic acid tert-butyl ester

HRID 1698334Notes

Reaction equation

HRID 1698334 reaction equation
C1C2C(COC([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]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.C(N(C(C)C)C(C)C)C.CN1CCCC1=O.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:76]1([NH:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([Cl:87])[C:82]=2[Cl:88])[CH2:78][CH2:77]1.N1CCCCC1>C(Cl)Cl.CC#N>[C:28]([O:27][C:25](=[O:26])[NH:24][C@@H:22]1[CH2:21][C@H:20]([C:32](=[O:34])[N:79]([CH:76]2[CH2:77][CH2:78]2)[CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[C:83]([Cl:87])[C:82]=2[Cl:88])[CH2:19][NH:18][CH2:23]1)([CH3:29])([CH3:30])[CH3:31]

Participants

9

Reactant 6

HCID 8082PiperidineHCID 13387N-methyl-2-pyrrolidoneHCID 81531DiisopropylethylamineHCID 834599Cyclopropyl-(2,3-dichloro-benzyl)-amineHCID 42624899O-(6-Chlorobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphateHCID 57870323HCID 57870323, compound

Product 1

HCID 57870361{(3R*,5S*)-5-[Cyclopropyl-(2,3-dichloro-benzyl)-carbamoyl]-Piperidin-3-yl}-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

To a stirred, ice-cooled mixture of (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester (300 mg, 0.643 mmol) in CH2Cl2 (7 mL) a 2M solution of N-ethyldiisopropylamine in 1-methyl-2-pyrrolidone (161 μl, 0.322 mmol) is added, followed by a solution of O-(1H-6-chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU) (292 mg, 0.707 mmol) in CH3CN (7 mL). After 15 min cyclopropyl-(2,3-dichloro-benzyl)-amine (139 mg, 0.643 mmol) is added. The mixture is stirred for 15 min at 0° C. and for 14 h at RT. After evaporation of the solvents in vacuo, the residue is diluted with CH2Cl2 and washed with a 10% aqueous K2CO3 solution, 2M HCl solution and brine. The organic layer is dried over Na2SO4, evaporated in vacuo and the residue purified by flash chromatography (SiO2, CH2Cl2/acetone 96:4). Part of the crude product (50 mg, 0.075 mmol) is dissolved in CH2Cl2 (1 mL), treated with piperidine (0.222 mL, 2.25 mmol) and stirred for 1 h at RT. After evaporation in vacuo, the residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min). The combined pure fractions are treated with solid K2CO3, CH3CN is removed in vacuo, and the residual aqueous phase is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated to afford the title compound as a colourless foam. MS: 442.2/444.2 [M+H]+; tR (HPLC, Lichrospher RP8; 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min, then 100% CH3CN+0.1% TFA for 2.5 min, flow 1.5 ml/min): 5.08 min.

Workup

  1. temperatureTo a stirred, ice-cooled
  2. additionis added
  3. customAfter evaporation of the solvents in vacuo
  4. additionthe residue is diluted with CH2Cl2
  5. washwashed with a 10% aqueous K2CO3 solution, 2M HCl solution and brine
  6. dry with materialThe organic layer is dried over Na2SO4
  7. customevaporated in vacuo
  8. customthe residue purified by flash chromatography (SiO2, CH2Cl2/acetone 96:4)
  9. stirringstirred for 1 h at RT
  10. customAfter evaporation in vacuo
  11. customthe residue is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 mL/min)
  12. additionThe combined pure fractions are treated with solid K2CO3, CH3CN
  13. customis removed in vacuo
  14. extractionthe residual aqueous phase is extracted twice with CH2Cl2
  15. dry with materialThe combined organic layers are dried (Na2SO4)
  16. customevaporated

Sources & evidence

ORD record
ord-35a2b8331b6b4958a61257cacd189dda
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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