Triethylamine → (+/-)-3-[2-(4-Hydroxy-piperidin-1-yl)-thiazol-4-yl]-3-[4-(7-methoxy-quinolin-8-yl)-[1,4]diazepan-1-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-one

HRID 2063566Notes

Reaction equation

HRID 2063566 reaction equation
[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15](O)=[O:16])[N:12]=2)[CH2:4][CH2:3]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:16])[N:12]=2)[CH2:6][CH2:7]1

Participants

7

Reactant 4

HCID 8471TriethylamineHCID 531671-MethylpiperazineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59366189(+/-)-3-[2-(4-Hydroxy-piperidin-1-yl)-thiazol-4-yl]-3-[4-(7-methoxy-quinolin-8-yl)-[1,4]diazepan-1-yl]-propionic acid

Product 1

HCID 59366181(+/-)-3-[2-(4-Hydroxy-piperidin-1-yl)-thiazol-4-yl]-3-[4-(7-methoxy-quinolin-8-yl)-[1,4]diazepan-1-yl]-1-(4-methyl-piperazin-1-yl)-propan-1-oneYield 34.2%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Procedure

DMF (3.0 mL) was added to the product from step 2 (309 mg, 0.60 mmol), followed by N-methylpiperazine (0.08 mL, 0.72 mmol), and Et3N (0.17 mL, 1.20 mmol). HATU (274 mg, 0.72 mmol) was then added to the mixture, and the reaction was stirred for 2 h at room temperature. The solution was then diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was dried over MgSO4, filtered, and concentrated to give the crude. This was purified by silica gel chromatography (99:1 to 90:10 CH2Cl2:(9:1 MeOH:NH4OH)) and lyophilized from MeCN/H2O to give the product (122 mg, 34% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, 1H, J=1.4, 4.2 Hz), 8.02 (dd, 1H, J=2.0, 8.0 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.2, 8.2 Hz), 6.44 (s, 1H), 4.35 (bs, 1H), 3.95 (s, 3H), 3.95-3.76 (m, 2H), 3.67-3.45 (m, 7H), 3.24-2.78 (m, 8H), 2.42-2.33 (m, 2H), 2.28 (s, 3H), 2.32-2.10 (m, 5H), 2.02-1.92 (m, 4H), 1.68-1.58 (m, 2H). MS (ES) m/z 594.5 (M+H+).

Workup

  1. washwashed with H2O (4×50 mL)
  2. dry with materialThe organic was dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto give the crude
  6. customThis was purified by silica gel chromatography (99:1 to 90:10 CH2Cl2:(9:1 MeOH:NH4OH))

Sources & evidence

ORD record
ord-889582de825049f89292e465cd91100a
Source dataset
uspto-grants-2012_10
Patent number
US08288373B2

Reaction notes

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