Hydrochloric Acid → (3S*,5R*)-5-(3,3-Dimethyl-butyrylamino)-piperidine-3-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

HRID 1698325Notes

Reaction equation

HRID 1698325 reaction equation
C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24]C(OC(C)(C)C)=O)[CH2:21][C@H:20]([C:32](O)=[O:33])[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH:35]1([NH:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[CH2:37][CH2:36]1.C(N([CH:54]([CH3:56])[CH3:55])C(C)C)C.[CH3:57]CCP(=O)=O.Cl.C[CH:65]([OH:67])[CH3:66]>CC(N(C)C)=O>[CH:35]1([N:38]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([Cl:46])[C:41]=2[Cl:47])[C:32]([C@H:20]2[CH2:21][C@@H:22]([NH:24][C:65](=[O:67])[CH2:66][C:54]([CH3:56])([CH3:57])[CH3:55])[CH2:23][NH:18][CH2:19]2)=[O:33])[CH2:36][CH2:37]1

Participants

8

Reactant 6

HCID 313Hydrochloric AcidHCID 3776IsopropanolHCID 81531DiisopropylethylamineHCID 834599Cyclopropyl-(2,3-dichloro-benzyl)-amineHCID 16167369Propylphosphoric anhydrideHCID 57870323HCID 57870323, compound

Product 1

HCID 15984734(3S*,5R*)-5-(3,3-Dimethyl-butyrylamino)-piperidine-3-carboxylic acid cyclopropyl-(2,3-dichloro-benzyl)-amide

Reagents, catalysts & solvents 1

HCID 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 (2.33 g, 5 mmol), cyclopropyl-(2,3-dichloro-benzyl)-amine (see WO 03/093267) (1.12 g, 5.2 mmol) and N-ethyldiisopropylamine (6.85 ml, 40 mmol) in dimethylacetamide (30 ml), propylphosphonic anhydride solution (˜50% in DMF, 4.8 ml, ˜7.5 mmol) is added. After stirring for 14 h at RT, DMA is evaporated and the residue is distributed between ethyl acetate and 10% aqueous K2CO3 solution. The organic layer is dried (Na2SO4), evaporated in vacuo and the residue 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 layer is extracted twice with CH2Cl2. The combined organic layers are dried (Na2SO4) and evaporated. The residue is stirred with HCl in 2-propanol (5 N, 10 ml, 50 mmol) and evaporated to afford the title compound as a white amorphous solid. tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 6.22 min.

Workup

  1. temperatureTo a stirred, ice-cooled
  2. additionis added
  3. customDMA is evaporated
  4. dry with materialThe organic layer is dried (Na2SO4)
  5. customevaporated in vacuo
  6. customthe residue purified by preparative HPLC (YMC-Pack, Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 ml/min)
  7. additionThe combined pure fractions are treated with solid K2CO3, CH3CN
  8. customis removed in vacuo
  9. extractionthe residual aqueous layer is extracted twice with CH2Cl2
  10. dry with materialThe combined organic layers are dried (Na2SO4)
  11. customevaporated
  12. customevaporated

Sources & evidence

ORD record
ord-b7a57d6b944b4038a13ef83bc2662b21
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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