Diisopropylcarbodiimide → (R)-(((5-(4-chlorophenyl)-1-ethyl-4-(3-(4-(4-(4-((4-(4-hydroxypiperidin-1-yl)-1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl) sulfonyl)phenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-2-methyl-1H-pyrrole-3-carbonyl)oxy)methyl)phosphonic acid
Reaction equation
[CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].CC(C)N=C=NC(C)C.O[CH2:83][P:84](=[O:89])([O:87]C)[O:85]C.C[Si](Br)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH2:83][P:84](=[O:85])([OH:89])[OH:87])=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1Participants
Reactant 4
HCID 12734Diisopropylcarbodiimide
HCID 76113Bromotrimethylsilane
HCID 11051732Dimethyl (hydroxymethyl)phosphonate
HCID 714569955-(4-chlorophenyl)-1-ethyl-4-[3-[4-[4-[[4-[[(2R)-4-(4-hydroxypiperidin-1-yl)-1-phenylsulfanylbutan-2-yl]amino]-3-(trifluoromethylsulfonyl)phenyl]sulfonylamino]phenyl]piperazin-1-yl]phenyl]-2-methylpyrrole-3-carboxylic acid2×Product 1
Reagents, catalysts & solvents 3
Procedure
To a solution of BM-957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added dimethyl (hydroxymethyl)phosphonate (40 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TMSBr (248 uL, 1.9 mmol). The solution was stirred at room temperature for 20 h until no starting material was observed by MS. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 8 (salt with TFA, 74 mg, yield 68% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. 1H NMR (300 M Hz, CD3OD): δ 7.92 (s, 1H), 7.73-7.70 (m, 2H), 7.34-6.82 (m, 17H), 4.28 (d, J=8.6 Hz, 2H), 4.06-3.35 (m, 14H), 3.20-2.92 (m, 5H), 2.65 (s, 3H), 2.24-1.67 (m, 6H), 1.10 (t, J=7.0 Hz, 3H). MS (ESI): m/z 1259.50 (M+H)+.
Workup
- washwashed with saturated NaHCO3 solution (50 mL), brine (50 mL)
- dry with materialdried over sodium sulfate
- customThe solvent was removed in vacuo
- customto give crude product which
- customwas used for next step without purification
- dissolutionThe resulting residue was dissolved in DCM (5 mL)
- concentrationThe reaction mixture was concentrated in vacuo
- customthe residue was purified by HPLC
Sources & evidence
- ORD record
- ord-c182d1245b0c43b0b0b7bf5d3784f9ca
- Source dataset
- uspto-grants-2015_08
- Patent number
- US09096625B2
Reaction notes
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