Water → HCID 86703990, compound

HRID 1773911Notes

Reaction equation

HRID 1773911 reaction equation
I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[CH3:24].C([O-])([O-])=O.[K+].[K+].[OH:31][C@H:32]1[CH2:37][CH2:36][C@H:35]([NH:38][C:39]([C:41]2[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=2)=[O:40])[CH2:34][CH2:33]1.O>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[OH:31][CH:32]1[CH2:33][CH2:34][CH:35]([NH:38][C:39](=[O:40])[C:41]2[CH:46]=[CH:45][C:44]([C:2]3[N:11]=[C:10]4[N:4]([CH2:5][CH2:6][C:7]5[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=5[CH:9]4[O:12][CH:13]4[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]4)[C:3]=3[CH3:24])=[CH:43][CH:42]=2)[CH2:36][CH2:37]1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 86703973HCID 86703973, compoundHCID 178523805HCID 178523805, compound

Product 1

HCID 86703990HCID 86703990, compound

Reagents, catalysts & solvents 2

HCID 178418228Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
95 °C

Procedure

To a solution of 2-iodo-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 133) (50 mg, 0.114 mmoles) in THF (0.7 mL) in a screw-capped vial under argon are added a 1M aqueous solution of K2CO3 (0.5 mL, 0.5 mmole), PdCl2(dppf)2 (4.5 mg, 6 μmole) and 4-(trans-4-hydroxycyclohexylcarbamoyl)phenylboronic acid (45 mg, 0.150 mmole). The reaction mixture is heated at 95° C. overnight. Water is added to the reaction mixture and the aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is pre-purified by silica gel chromatography using (CH2Cl2:MeOH:NH4OH) with a gradient from (98:2:0.2) to (96.5:3.5:0.35). The residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1) to afford N-(4-hydroxycyclohexyl)-4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]benzamide.

Workup

  1. extractionthe aqueous phase is extracted three times with CH2Cl2
  2. dry with materialThe organic phase is dried over magnesium sulphate
  3. filtrationfiltered
  4. customthe solvent is removed under reduced pressure
  5. customThe residue is pre-purified by silica gel chromatography
  6. customThe residue is purified by preparative TLC over silica gel using (CH2Cl2:MeOH:NH4OH) with a gradient from (9:1:1)

Sources & evidence

ORD record
ord-850bf987aa6e4d31844cc2da1c5b9527
Source dataset
uspto-grants-2016_02
Patent number
US09255101B2

Reaction notes

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