Dimethylformamide → 1-benzyl 3-methyl (3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-1,3-dicarboxylate

HRID 535091Notes

Reaction equation

HRID 535091 reaction equation
[CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6]1)=[O:4].CN(C)C=O.Cl.Cl.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:35]#[N:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:45][CH2:44][N:43]([C:11]([C@H:10]3[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])[CH2:6][C@@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:42][CH2:41]2)=[C:32]([CH3:31])[CH:33]=1)#[N:36]

Participants

6

Reactant 5

HCID 6228DimethylformamideHCID 81531DiisopropylethylamineHCID 2724699PyBOPHCID 673040383-Methyl-4-piperazin-1-ylbenzonitrile dihydrochlorideHCID 67304370(3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester

Product 1

HCID 1317319311-benzyl 3-methyl (3R,4S)-4-[4-(4-cyano-2-methylphenyl)piperazin-1-yl]carbonylpiperidine-1,3-dicarboxylate

Procedure

To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) in N,N-dimethylformamide (8.500 mL, 0.1098 mol) was added 3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g, 0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.017 g, 0.001896 mol), and, N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixture was stirred overnight at room temp. Reaction quenched with KH2PO4(sat solution). Layers separated and aq layer extracted with ethyl acetate 3×. Organic layers were washed with brine and dried over magnesium sulfate. Filtered and concentrated. The residue was purified by Combiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS (ESI): (M+H)+=505.

Workup

  1. customReaction
  2. customquenched with KH2PO4(sat solution)
  3. customLayers separated
  4. extractionaq layer extracted with ethyl acetate 3×
  5. washOrganic layers were washed with brine
  6. dry with materialdried over magnesium sulfate
  7. filtrationFiltered
  8. concentrationconcentrated
  9. customThe residue was purified by Combiflash with 40-70% EtOAc/Hex
  10. customto give
  11. customthe product (75% in yield)

Sources & evidence

ORD record
ord-95944d243b7340ff8b0ce845d2e3c17b
Source dataset
uspto-grants-2014_10
Patent number
US08853243B2

Reaction notes

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