Hydrochloric Acid → 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-piperidinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

HRID 1910058Notes

Reaction equation

HRID 1910058 reaction equation
[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16]([C:20](=[O:30])[CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[CH2:15][CH2:14]4)=[CH:9][N:8]([CH2:31][CH2:32][CH:33]3[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]3)[C:4]=2[N:5]=[CH:6][N:7]=1.Cl>O1CCOCC1>[F:29][C:23]1[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=1[CH2:21][C:20]([N:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=4[N:8]([CH2:31][CH2:32][CH:33]4[CH2:34][CH2:35][NH:36][CH2:37][CH2:38]4)[CH:9]=3)=[CH:19][CH:18]=2)[CH2:14][CH2:15]1)=[O:30]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 668239521,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate

Product 1

HCID 668236715-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-piperidinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amineYield 87.3%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

To 1,1-dimethylethyl 4-[2-(4-amino-5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethyl]-1-piperidinecarboxylate (157 mg, 0.255 mmol) was added 4N HCl (5 mL, 20.00 mmol) in dioxane and the mixture was allowed to stir at room temperature overnight. The reaction was concentrated and the solid was isolated by filtration and washed with diethyl ether to isolated 115 mg of the desired product as an HCl salt, which was then dissolved in 2 ml of DMSO and purified on HPLC: (HPLC condition: Gilson using Trilution software with a Sunfire 5u C18(2) 100A. 50×30.00 mm 5 micron. 7.3-minute run (47 ml/min, 10% ACN/H2O, 0.1% TFA to 35% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the MeCN. The water left behind was added saturated NaHCO3 and then extracted with EtOAc (3×15 mL). The organic was combined wash with saturated NaCl solution, dried over MgSO4, filtered and concentrated. The material was then transferred into a 40 mL vial with MeCN. Water was added and then it was freeze-dried to give 5-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-7-[2-(4-piperidinyl)ethyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (116 mg, 88% yield) as a white solid. LC-MS (ES) m/z=517.6 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (br. s., 1H), 8.14 (s, 1H), 8.09 (d, J=8.08 Hz, 1H), 7.35 (d, J=4.04 Hz, 2H), 7.15-7.30 (m, 4H), 6.09 (br. s., 2H), 4.29 (t, J=8.34 Hz, 2H), 4.21 (t, J=6.95 Hz, 2H), 3.95 (s, 2H), 3.22-3.30 (m, 4H), 2.77-2.85 (m, 2H), 1.91 (d, J=12.13 Hz, 2H), 1.77 (q, J=6.65 Hz, 2H), 1.47 (br. s., 1H), 1.26-1.38 (m, 2H).

Workup

  1. concentrationThe reaction was concentrated
  2. customthe solid was isolated by filtration
  3. washwashed with diethyl ether

Sources & evidence

ORD record
ord-02931446e0fc47a4ba0aab769a7bc271
Source dataset
uspto-grants-2013_12
Patent number
US08598156B2

Reaction notes

Loading…