Toluene → Benzyl 4-(4-((S)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)phenyl)piperazine-1-carboxylate

HRID 1051838Notes

Reaction equation

HRID 1051838 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][C@@H:11]3[N:17]([CH:18]=2)[C:16](=[O:19])[C:15]2[CH:20]=[C:21]([O:62][CH3:63])[C:22]([O:24][CH2:25][CH2:26][CH2:27][O:28][C:29]4[C:59]([O:60][CH3:61])=[CH:58][C:32]5[C:33](=[O:57])[N:34]6[CH:49]=[C:48](S(C(F)(F)F)(=O)=O)[CH2:47][C@H:35]6[C:36](=[O:46])[N:37]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[C:31]=5[CH:30]=4)=[CH:23][C:14]=2[N:13]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:12]3=[O:72])=[CH:5][CH:4]=1.CC1(C)C(C)(C)OB([C:81]2[CH:86]=[CH:85][C:84]([N:87]3[CH2:92][CH2:91][N:90]([C:93]([O:95][CH2:96][C:97]4[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=4)=[O:94])[CH2:89][CH2:88]3)=[CH:83][CH:82]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.O>[CH3:61][O:60][C:59]1[C:29]([O:28][CH2:27][CH2:26][CH2:25][O:24][C:22]2[C:21]([O:62][CH3:63])=[CH:20][C:15]3[C:16](=[O:19])[N:17]4[CH:18]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=5)[CH2:10][C@H:11]4[C:12](=[O:72])[N:13]([CH2:64][O:65][CH2:66][CH2:67][Si:68]([CH3:71])([CH3:70])[CH3:69])[C:14]=3[CH:23]=2)=[CH:30][C:31]2[N:37]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:44])[CH3:45])[C:36](=[O:46])[C@@H:35]3[CH2:47][C:48]([C:81]4[CH:82]=[CH:83][C:84]([N:87]5[CH2:88][CH2:89][N:90]([C:93]([O:95][CH2:96][C:97]6[CH:102]=[CH:101][CH:100]=[CH:99][CH:98]=6)=[O:94])[CH2:91][CH2:92]5)=[CH:85][CH:86]=4)=[CH:49][N:34]3[C:33](=[O:57])[C:32]=2[CH:58]=1

Participants

9

Reactant 4

HCID 1140TolueneHCID 10340Sodium CarbonateHCID 46739507Benzyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylateHCID 86676188HCID 86676188, compound

Product 1

HCID 71554199Benzyl 4-(4-((S)-7-methoxy-8-(3-(((S)-7-methoxy-2-(4-methoxyphenyl)-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)propoxy)-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-2-yl)phenyl)piperazine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 178418397HCID 178418397, compoundCatalystHCID 702EthanolSolventHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

(S)-2-(4-methoxyphenyl)-7-methoxy-8-(3-((S)-7-methoxy-2-(trifluoromethylsulphonyl)-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-pyrrolo[2,1-c][1,4]benzodiazepin-8-yloxy)propyloxy)-10-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H,11aH)-dione (1-Compound 17 in WO 2010/043880)(0.093 g, 0.086 mmol), benzyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate (2)(0.047 g, 0.110 mmol, 1.3 eq) and sodium carbonate (0.009 g, 0.140 mmol, 1.5 eq) were suspended in ethanol (1.5 mL), toluene (3 mL) and water (1.5 mL) under an argon atmosphere. Pd(PPh3)4 (0.002 g, 0.002 mmol, 0.02 eq) was added to the mixture, and the reaction was stirred overnight at room temperature. EtOAc (10 mL) was added to the mixture and the organic phase was washed with brine (15 mL) and dried over MgSO4, and the solvent was removed by rotary evaporation under reduced pressure. The crude was purified by flash column chromatography (silica gel, gradient 20% EtOAc/80% hexane-100% EtOAc). Compound 3 was obtained as a yellow solid (0.0549 g, 52%); Rf 0.21 [50% EtOAc-50% hexane]; LC-MS (5 min) 3.92 min, ES+ 1221.39.

Workup

  1. washthe organic phase was washed with brine (15 mL)
  2. dry with materialdried over MgSO4
  3. customthe solvent was removed by rotary evaporation under reduced pressure
  4. customThe crude was purified by flash column chromatography (silica gel, gradient 20% EtOAc/80% hexane-100% EtOAc)

Sources & evidence

ORD record
ord-bb814574cd754716b4e54e04aadd7363
Source dataset
uspto-grants-2016_07
Patent number
US09388187B2

Reaction notes

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