Citric Acid → N-methyl-2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamide

HRID 2043783Notes

Reaction equation

HRID 2043783 reaction equation
[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:59][NH:60][C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[CH3:59][N:60]([C@H:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH2:64][CH2:63][CH2:62]1)[C:21]([C:19]1[N:20]=[C:16]([N:13]2[CH2:12][CH2:11][N:10]([C:8](=[O:9])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:24]([F:27])([F:26])[F:25])=[N:5]3)[CH2:15][CH2:14]2)[S:17][CH:18]=1)=[O:22]

Participants

7

Reactant 5

HCID 311Citric AcidHCID 8471TriethylamineHCID 2733084Methanaminium, N-((1H-benzotriazol-1-yloxy)(dimethylamino)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 7128544(R)-N-Methyl-1,2,3,4-tetrahydronaphthalen-1-amine2×HCID 671510882-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazinyl]-4-thiazolecarboxylic acid2×

Product 1

HCID 66795917N-methyl-2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazinyl]-N-[(1R)-1,2,3,4-tetrahydro-1-naphthalenyl]-4-thiazolecarboxamideYield 81.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

2-[4-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-1-piperazin yl]-4-thiazolecarboxylic acid (200 mg, 0.5 mmol) (i.e. the product of Example 30, Step D) was suspended in 5 mL of dry dichloromethane and treated with triethylamine (150 μl, 1.08 mmol) to give a homogeneous solution. To this reaction mixture was added O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 210 mg, 0.55 mmol) followed by (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine (106 mg, 0.60 mmol) (i.e. the product of Example 6, Step A). The reaction mixture was stirred at ambient temperature for 3 h, passed through a Varian Chem Elut™ CE1010 column pretreated with 5 mL of 20% aqueous citric acid solution. The column was flushed with three column volumes of dichloromethane, concentrated and purified by silica gel chromatography eluting with ethyl acetate to give 223 mg of the title product, the compound of present invention as white foam.

Workup

  1. customto give a homogeneous solution
  2. customThe column was flushed with three column volumes of dichloromethane
  3. concentrationconcentrated
  4. custompurified by silica gel chromatography
  5. washeluting with ethyl acetate

Sources & evidence

ORD record
ord-50c29d874f9e42e89324210b04f4e125
Source dataset
uspto-grants-2013_11
Patent number
US08586611B2

Reaction notes

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