Cesium carbonate → HCID 67279846, compound

HRID 1692880Notes

Reaction equation

HRID 1692880 reaction equation
Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:23][CH2:22][C:15]4([O:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16]4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:30]1([S:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41](B(O)O)=[CH:40]2)(=[O:38])=[O:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.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>[C:30]1([S:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:23][CH2:22][C:15]6([O:20][CH2:19][C:18](=[O:21])[NH:17][CH2:16]6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)=[CH:40]2)(=[O:38])=[O:37])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1

Participants

7

Reactant 3

HCID 10796Cesium carbonateHCID 27762171-(phenylsulfonyl)-1H-indol-3-ylboronic acidHCID 596035099-(2-Chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one

Product 1

HCID 67279846HCID 67279846, compound

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Procedure

A degassed solution of 9-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-3-one (150 mg, 0.34 mmol), 1-(phenylsulfonyl)-3-indoleboronic acid (155 mg, 0.51 mmol), Pd(PPh3)4 (40 mg, 0.035 mmol) and Cs2CO3 (225 mg, 0.69 mmol) in a mixture of 1,4-dioxane (6 mL) and water (3 mL) was subjected to microwave irradiation at 140° C. for 30 min. The reaction mixture was cooled to ambient temperature and loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to give 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one as a crude oil. Aqueous NaOH (12.5 M, 0.4 mL) was added to a solution of 9-[2-(1-benzenesulfonyl-1H-indol-3-yl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl]-1-oxa-4,9-diazaspiro[5.5]undecan-3-one in 1,4-dioxane (4 mL) and IMS (4 mL). The reaction mixture was stirred at ambient temperature for 90 min, and then concentrated in vacuo. The residue was dissolved in MeOH then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with MeOH and the desired product was subsequently eluted using 2 M NH3 in MeOH. The eluent was collected and concentrated to afford a sticky solid. The solid was purified by flash chromatography (Si-PPC, DCM: MeOH, 100:0 to 99:1 to 95:5) followed by reverse phase HPLC (Phenomenex Luna C-18, 20 mM Et3N in water on a gradient of 20 mM Et3N in acetonitrile 90:10 to 5:95) to afford 116 as a white solid (72 mg, 40%). LCMS: RT=5.05 min, [M+H]+=519.2. 1H NMR (CDCl3, 400 MHz): δ 8.69-8.64 (m, 1H); 8.45 (s, 1H); 8.15 (d, J=2.7 Hz, 1H); 7.44-7.40 (m, 1H); 7.30-7.22 (m, 3H); 5.91 (s, 1H); 4.17 (s, 2H); 4.08-4.03 (m, 4H); 3.94-3.89 (m, 4H); 3.85 (s, 2H); 3.26 (d, J=2.6 Hz, 2H); 2.78-2.69 (m, 2H); 2.47 (t, J=11.2 Hz, 2H); 1.96 (d, J=13.8 Hz, 2H); 1.77-1.67 (m, 2H)

Workup

  1. customirradiation at 140° C. for 30 min
  2. washThe cartridge was then washed with MeOH
  3. washthe desired product was subsequently eluted
  4. customThe eluent was collected
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-7a7a59234c764a1083f528699b4a8144
Source dataset
uspto-grants-2012_04
Patent number
US08158625B2

Reaction notes

Loading…