Sodium Carbonate → tert-butyl[1-(4-{2-[4-(morpholin-4-ylmethyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamate

HRID 1047003Notes

Reaction equation

HRID 1047003 reaction equation
Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CC1(C)C(C)(C)OB([C:46]2[CH:58]=[CH:57][C:49]([CH2:50][N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[CH:48][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:46]3[CH:47]=[CH:48][C:49]([CH2:50][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[CH:57][CH:58]=3)=[CH:21][CH:22]=2)[CH2:29][CH2:28][CH2:27]1)([CH3:35])([CH3:34])[CH3:36]

Participants

7

Reactant 3

HCID 10340Sodium CarbonateHCID 27955024-((Morpholino)methyl)phenylboronic acid pinacol esterHCID 136331866tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate

Product 1

HCID 69087640tert-butyl[1-(4-{2-[4-(morpholin-4-ylmethyl)phenyl]-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl}phenyl)cyclobutyl]carbamateYield 44.1%

Reagents, catalysts & solvents 3

HCID 11714597Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)CatalystHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.097 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (59 mg, 0.20 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (7 mg, 0.1 mmol), and 2M Na2CO3 aq. (0.097 mL, 0.20 mmol) in DMF (1.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water (×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified twice by preparative thin-layer chromatography (CH2Cl2/MeOH=10:1×2) and (AcOEt/MeOH=10:1) to afford the desired product (28 mg, 44%) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.17 (dd, J=8.0 Hz and 1.7 Hz, 1H), 8.00 (d, J=4.6 Hz, 1H), 7.54 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.30 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.17-7.13 (m, 3H), 6.94 (d, J=8.0 Hz, 1H), 6.80 (d, J=6.9 Hz, 1H), 6.59 (dd, J=8.0 Hz and 5.2 Hz, 1H), 6.24 (s, 1H), 5.10 (br s, 1H), 3.70 (t, J=4.6 Hz, 4H), 3.47 (s, 2H), 2.57-2.50 (m, 2H), 2.45-2.42 (m, 4H), 2.19-2.10 (m, 2H), 1.93-1.85 (m, 2H), 1.39 (br s, 9H). LCMS: 655 [M+H].

Workup

  1. additionwas treated with microwave (160° C. for 1 hour)
  2. washwashed with water (×3), brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltrated through Celite pad
  5. concentrationThe filtrate was concentrated
  6. customthe residue was purified twice by preparative thin-layer chromatography (CH2Cl2/MeOH=10:1×2) and (AcOEt/MeOH=10:1)

Sources & evidence

ORD record
ord-6c4ec33fa8ce4c05a3fc12207d33d31e
Source dataset
uspto-grants-2013_10
Patent number
US08569331B2

Reaction notes

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