(4-Methylpiperazin-2-yl)methanol → 5-(6-{[2-(hydroxymethyl)-4-methylpiperazin-1-yl]methyl}-1H-imidazo[4,5-c]pyridin-1-yl)-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

HRID 2391649Notes

Reaction equation

HRID 2391649 reaction equation
CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34](=[O:36])[NH2:35])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH:40]([CH2:44][OH:45])[CH2:39]1.C(OC(N1CCNCC1C(O)=O)=O)(C)(C)C.C(OC(N1CCNC[C@H]1C(O)=O)=O)(C)(C)C>ClCCl.O.C(N(CC)CC)C>[OH:45][CH2:44][CH:40]1[CH2:39][N:38]([CH3:37])[CH2:43][CH2:42][N:41]1[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:34]([NH2:35])=[O:36])=[C:19]([O:21][C@@H:22]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]([F:33])([F:32])[F:31])[CH3:23])[CH:20]=3)[C:9]=2[CH:8]=1

Participants

8

Reactant 4

HCID 12793177(4-Methylpiperazin-2-yl)methanolHCID 225075841-Boc-piperazine-2-carboxylic acidHCID 40419053(2S)-1-[(tert-butoxy)carbonyl]piperazine-2-carboxylic acidHCID 86647102[1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoro-methyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate

Product 1

HCID 687684275-(6-{[2-(hydroxymethyl)-4-methylpiperazin-1-yl]methyl}-1H-imidazo[4,5-c]pyridin-1-yl)-3-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 8471TriethylamineSolvent

Procedure

A mixture of 270 mg of [1-(5-carbamoyl-4-{(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate and 130 mg of (4-methylpiperazin-2-yl)methanol (synthesized starting from commercially available 1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid in one step in analogy to the synthesis of (2S)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid described in patent application WO2005/026152) in 10 ml dichloromethane is stirred at room temperature for 16 hours. 505 mg triethylamine is added and the reaction mixture is stirred additional 24 h at room temperature. Water (20 ml) is added to the mixture. After separation of the organic layer, the aqueous layer is extracted with dichloromethane (2×20 ml). The combined organic layers are dried over MgSO4. After filtration the solvent is removed under reduced pressure. The resulting residue is purified by flash chromatography [silica gel, eluent: ethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v)) to give the title product.

Workup

  1. customsynthesized
  2. stirringthe reaction mixture is stirred additional 24 h at room temperature
  3. customAfter separation of the organic layer
  4. extractionthe aqueous layer is extracted with dichloromethane (2×20 ml)
  5. dry with materialThe combined organic layers are dried over MgSO4
  6. filtrationAfter filtration the solvent
  7. customis removed under reduced pressure
  8. customThe resulting residue is purified by flash chromatography [silica gel, eluent
  9. washethyl acetate/methanol/aqueous solution of ammonia, 20/4/1 (v/v/v) and subsequently by preparative HPLC (ammonium formate buffer/acetonitrile, elution gradient 65/35 to 15/85 (v/v))

Sources & evidence

ORD record
ord-4118ae03b27140bbb123eecbfd9f99b6
Source dataset
uspto-grants-2012_09
Patent number
US08273890B2

Reaction notes

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