Diisopropylethylamine → ZD6021

HRID 840408Notes

Reaction equation

HRID 840408 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.CN(C)C(F)=[N+](C)C.[Cl:40][C:41]1[CH:42]=[C:43]([C@H:48]([CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][CH:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[S@:66]([CH3:68])=[O:67])[CH2:56][CH2:55]2)[CH2:49][NH:50][CH3:51])[CH:44]=[CH:45][C:46]=1[Cl:47]>C(Cl)Cl.C(O)(=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([C@H:48]([CH2:52][CH2:53][N:54]2[CH2:55][CH2:56][CH:57]([C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=3[S@:66]([CH3:68])=[O:67])[CH2:58][CH2:59]2)[CH2:49][N:50]([CH3:51])[C:13]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:15])[CH:44]=[CH:45][C:46]=1[Cl:47]

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 2774761Tetramethylfluoroformamidinium hexafluorophosphateHCID 111715903-cyanonaphthalene-1-carboxylic AcidHCID 57302211N-[(S)-2-(3,4-dichlorophenyl)4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine

Product 1

HCID 9852253ZD6021Yield 79%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 6344DichloromethaneSolvent4×

Procedure

A stirred solution containing 3-cyano-1-naphthoic acid (0.1 g, 0.5 mmol), N,N-diisopropylethylamine (0.16 g, 1.26 mmol), and dry DCM (2.5 mL) was treated with a solution of tetramethylfluoroformamidinium hexafluorophosphate (TFFH) (0.16 g, 0.60 mmol) in dry DCM (1.0 mL). After 10 min, a solution containing N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methylamine (0.22 g, 0.5 mmol) and dry DCM (0.6 mL) was added, and the solution stirred for 60 h, then diluted with DCM and 1M aqueous acetic acid. After mixing, the layers were allowed to separate, the organic layer was removed, and the aqueous layer was extracted with additional DCM (2×). The organic extracts were combined, washed (saturated NaHCO3), dried (Na2SO4), filtered, and the DCM evaporated in vacuo. The residue was purified by chromatography (0-10% CH3OH in DCM) to give the title compound (0.25 g) as a white, foamy residue. MS: m/z 632 (M+H). The product was converted to the citrate salt and isolated by filtration from Et2O to afford the N-[(S)-2-(3,4-dichlorophenyl)-4-[4-[(S)-2-methylsulfinylphenyl]-1-piperidinyl]butyl]-N-methyl-3-cyano-1-naphthamide citrate hydrate (1:1:0.75) (290 mg) as a white solid. MS: m/z 632 (M+H). Analysis for C35H35Cl2N3O2S C6H8O7.0.75 H2O: calculated: C, 58.74; H, 5.35; N, 5.01. found: C, 58.74; H, 5.24; N, 5.02. The title compound could also be converted, in similar maimer, to the citrate hydrate (1.0:1.0:1.0).

Workup

  1. additionwas added
  2. additionAfter mixing
  3. customto separate
  4. customthe organic layer was removed
  5. extractionthe aqueous layer was extracted with additional DCM (2×)
  6. washwashed (saturated NaHCO3)
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customthe DCM evaporated in vacuo
  10. customThe residue was purified by chromatography (0-10% CH3OH in DCM)

Sources & evidence

ORD record
ord-44d2b1d2d829482e89fad29ad7d0539d
Source dataset
uspto-grants-2002_04
Patent number
US06365602B1

Reaction notes

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