Bromotrimethylsilane → [2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid

HRID 272107

Reaction equation

HRID 272107 reaction equation
C([O:3][P:4]([CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24](=[O:46])[NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][C:34]4[N:39]=[C:38]([C:40]5[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=5)[CH:37]=[CH:36][N:35]=4)[CH:27]=3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>CN(C=O)C>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][N:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][P:4](=[O:3])([OH:5])[OH:8])[CH2:16][CH2:15]3)=[CH:23][CH:22]=2)=[O:46])=[CH:27][C:28]=1[NH:33][C:34]1[N:39]=[C:38]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH:37]=[CH:36][N:35]=1

Participants

4

Reactant 2

HCID 76113Bromotrimethylsilane2×HCID 59772964[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid diethyl ester

Product 1

HCID 9873184[2-(4-{4-[4-Methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acidYield 59.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of [2-(4-{4-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenylcarbamoyl]-benzyl}-piperazin-1-yl)-ethyl]-phosphonic acid diethyl ester (8 mg, 0.012 mmol) in DMF (1 mL) was added TMSBr (15 μL, 0.12 mmol) at room temperature. The reaction was allowed to proceed at room temperature for 14 hours. Another portion of TMSBr (20 μL) was added and heated at 110° C. for 12 hours when completion of the reaction was detected by LCMS. The reaction was cooled down to room temperature and quenched with addition of MeOH. The reaction mixture was dried under reduced pressure and the residue was purified by RP HPLC using a C18 column with a gradient of H2O— Acetonitrile (5-100%) over 20 minutes to provide 4.2 mg (50%) of the product as mono-TFA salt. 1H NMR (300 MHz, CD3OD) δ 1.80-1.84 (m, 2H), 2.08-2.02 (m, 2H), 2.23 (s, 3H), 3.07 (bs, 4H), 3.30-3.32 (2H, possible overlap with solvent), 3.89 (m, 2H), 4.01 (s, 2H), 6.87 (s, 1H), 7.23-7.3 (m, 3H), 7.52-7.60 (m, 3H), 8.01 (d, 2H, J=8 Hz), 8.08 (dd, 1H, J=2, 5 Hz), 8.30 (s, 1H), 8.58 (d, 1H, J=5 Hz), 8.89 (d, 1H, J=2 Hz), 9.22 (dd, 1H, J=2, 5 Hz), 9.63 (s, 1H); 31P (121.4 MHz, CD3OD) δ 21.9; MS (m/z) 588 [M+H]+.

Workup

  1. temperatureThe reaction was cooled down to room temperature
  2. customquenched with addition of MeOH
  3. customThe reaction mixture was dried under reduced pressure
  4. customthe residue was purified by RP HPLC
  5. customover 20 minutes

Sources & evidence

ORD record
ord-ac52a00359b74f4d8ab38ae25cc8d444
Source dataset
uspto-grants-2008_11
Patent number
US07452901B2

Linked notes

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