Triethylamine → (S)-{2-(4-Chlorobenzyl)-3-oxo-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propyl}-carbamic acid tert-butyl ester

HRID 1192348Notes

Reaction equation

HRID 1192348 reaction equation
CCN(CC)CC.Cl.Cl.[N:10]1([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:25]([O:29][C:30]([NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1)[C:35](O)=[O:36])=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[C:25]([O:29][C:30](=[O:31])[NH:32][CH2:33][C@H:34]([CH2:38][C:39]1[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=1)[C:35](=[O:36])[N:13]1[CH2:12][CH2:11][N:10]([C:16]2[C:17]3[CH:24]=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:15][CH2:14]1)([CH3:28])([CH3:26])[CH3:27]

Participants

8

Reactant 5

HCID 8471TriethylamineHCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 40153909(S)-3-((Tert-butoxycarbonyl)amino)-2-(4-chlorobenzyl)propanoic acidHCID 675378564-(Piperazin-1-yl)-1H-pyrrolo[2,3-d]pyrimidine dihydrochloride

Product 1

HCID 67540648(S)-{2-(4-Chlorobenzyl)-3-oxo-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propyl}-carbamic acid tert-butyl ester

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

NEt3 (150 μL, 1.1 mmol) was added to a stirred suspension of 4-Piperazin-1-yl-7H-pyrrolo[2,3-d]pyrimidine dihydrochloride (100 mg, 0.36 mmol), (S)-2-(tert-Butoxycarbonylamino-methyl)-3-(4-chlorophenyl)-propionic acid (130 mg, 0.40 mmol), EDCI (83 mg, 0.44 mmol) and HOBt (59 mg, 0.44 mmol) in DMF (15 mL) at RT. Stirred at RT overnight. Poured into EtOAc (100 mL), washed with water (100 mL), 1N NaOH (50 mL), dried over Na2SO4, concentrated in vacuo, purified by column chromatography on silica (100% EtOAc) to give (S)-{2-(4-Chlorobenzyl)-3-oxo-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propyl}-carbamic acid tert-butyl ester. LCMS (APCI+) m/z 499 [M+H]+; Rt: 2.70 minutes. This was taken up into DCM (50 mL) and stirred with TFA (5 mL) overnight. Poured into EtOAc (100 mL) and washed with 1N NaOH (2×100 mL), dried over Na2SO4 and concentrated in vacuo. Formed HCl salt (Et2O.HCl, 2M in diethyl ether) to give (S)-2-Aminomethyl-3-(4-chlorophenyl)-1-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperazin-1-yl]-propan-1-one dihydrochloride (100 mg, 59%.) LCMS (APCI+) m/z 399 [M+H]+; Rt: 1.82 min. [Free base: 1H NMR (CDCl3, 400 MHz) δ 9.97 (1H, br.s), 8.32 (1H, s), 7.24 (2H, d, J 7.4 Hz), 7.13 (2H, d, J 7.4 Hz), 7.09 (1H, d, J 2.4 Hz), 6.45 (1H, d, J 2.3 Hz), 4.00-3.68 (5H, m), 3.60-3.53 (1H, m), 3.46-3.40 (1H, m), 3.33-3.27 (1H, m), 3.16-3.05 (2H, m), 2.92-2.83 (2H, m), 2.77 (1H, dd, J 13.3 and 5.5 Hz.)]

Workup

  1. washwashed with water (100 mL), 1N NaOH (50 mL)
  2. dry with materialdried over Na2SO4
  3. concentrationconcentrated in vacuo
  4. custompurified by column chromatography on silica (100% EtOAc)

Sources & evidence

ORD record
ord-b6796e9513c04f3cbd38d3efdc0caf42
Source dataset
uspto-grants-2014_03
Patent number
US08680114B2

Reaction notes

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