Diethyl Ether → 3-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-methylphenyl]amino}-4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

HRID 419356Notes

Reaction equation

HRID 419356 reaction equation
Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([CH3:53])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOCC>CC(O)C.C(Cl)Cl>[N:34]1([CH:40]2[CH2:45][CH2:44][N:43]([C:46]3[CH:52]=[CH:51][C:49]([NH:50][C:2]4[N:7]=[C:6]([C:8]5[N:12]6[CH:13]=[CH:14][CH:15]=[CH:16][C:11]6=[N:10][C:9]=5[C:17]5[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=5)[C:20]([NH:22][C:23]5[C:24]([F:30])=[CH:25][CH:26]=[CH:27][C:28]=5[F:29])=[O:21])[CH:5]=[CH:4][N:3]=4)=[C:48]([CH3:53])[CH:47]=3)[CH2:42][CH2:41]2)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 521998p-Toluenesulfonic acid monohydrateHCID 594529664-(1,4'-Bipiperidin-1'-yl)-2-(methyl)anilineHCID 594529693-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide

Product 1

HCID 594526623-[3-(2-{[4-(1,4'-bipiperidin-1'-yl)-2-methylphenyl]amino}-4-pyrimidinyl)-imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
175 °C

Procedure

To 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (120 mg, 0.25 mmol) and 4-(1,4′-bipiperidin-1′-yl)-2-(methyl)aniline (68 mg, 0.25 mmol) in iPrOH (2 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (110 mg, 0.60 mmol). The reaction was heated in a microwave at 175° C. for 800 seconds. After cooling to rt, the solvent was removed on a rotovap and the residue taken up in DCM. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was dissolved in DCM, and ether was added until the solution just turned cloudy. After two days, the solids were collected by vacuum filtration and washed with diethyl ether. The yellow crystals were separated from the beige powder using tweezers. The desired product was obtained as yellow crystals (23 mg, 0.033 mmol, 13% yield). 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 9.35 (br s, 1H), 8.81 (s, 1H), 8.32 (s, 1H), 8.16 (d, J=5.4 Hz, 1H), 8.06 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.62 (dd, J=7.9, 7.7 Hz, 1H), 7.48-7.34 (m, 2H), 7.25-7.14 (m, 3H), 6.85 (br s, 1H), 6.85 (s, 1H), 6.79 (dd, J=8.6, 2.6 Hz, 1H), 6.43 (d, J=5.3 Hz, 1H), 3.72 (d, J=12.5 Hz, 2H), 2.62 (dd, J=12.1, 10.6 Hz, 2H), 2.52-2.27 (m, 5H), 2.17 (s, 3H), 1.78 (d, J=11.8 Hz, 2H), 1.60-1.34 (m, 8H). MS (ESI) m/z=699 [M+1].

Workup

  1. temperatureAfter cooling to rt
  2. customthe solvent was removed on a rotovap
  3. additionSilica gel was added
  4. customthe solvent removed on the rotovap
  5. customThe preabsorbed solids were purified by flash chromatography
  6. customthe solvent removed on the rotovap
  7. customto give product
  8. filtrationthe solids were collected by vacuum filtration
  9. washwashed with diethyl ether
  10. customThe yellow crystals were separated from the beige powder

Sources & evidence

ORD record
ord-f6aab5e76ad9441dbbd413fc6c443e54
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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