Lithium Chloride → 5-(3-fluoro-4-(2-(4-(morpholine-4-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

HRID 1676339Notes

Reaction equation

HRID 1676339 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16](I)[S:17][C:10]=12.[N:34]1([C:40]([C:42]2[CH:47]=[CH:46][C:45](B(O)O)=[CH:44][CH:43]=2)=[O:41])[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].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>[F:1][C:2]1[CH:3]=[C:4]([C:19]2[C:20](=[O:33])[N:21]([CH3:32])[C:22]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][CH:24]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:45]3[CH:44]=[CH:43][C:42]([C:40]([N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[O:41])=[CH:47][CH:46]=3)[S:17][C:10]=12

Participants

7

Reactant 3

HCID 433294Lithium ChlorideHCID 2773546[4-(Morpholine-4-carbonyl)phenyl]boronic acidHCID 673484955-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

Product 1

HCID 589494655-(3-fluoro-4-(2-(4-(morpholine-4-carbonyl)phenyl)thieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one

Reagents, catalysts & solvents 3

HCID 178418397HCID 178418397, compoundCatalystHCID 10340Sodium CarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

A suspension of 5-(3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (Example 143, Step F, 0.018 g, 0.0316 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.009 g, 0.038 mmol), Pd(PPh3)4 (0.002 g, 0.002 mmol) and lithium chloride (0.005 g, 0.126 mmol) in dioxane (1 mL) and 2 M aqueous Na2CO3 (1 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 10:1 CH2Cl2/MeOH. The product was obtained (12.9 mg; 65%) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.04 (br s, 1H), 8.55 (d, 1H), 8.17 (s, 1H), 8.12 (s, 1H), 7.99 (m, 2H), 7.89 (dd, 1H), 7.69 (m, 1H), 7.58-7.49 (m, 5H), 7.38 (m, 2H), 7.17 (m, 1H), 6.70 (dd, 1H), 3.63 (m, 8H), 3.59 (s, 3H). LRMS (APCI pos) m/e 634 (M+1).

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. custompartitioned between EtOAc and H2O
  3. customThe layers were separated
  4. extractionthe aqueous layer was re-extracted with EtOAc (1×)
  5. dry with materialThe combined organic layers were dried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by flash column chromatography
  9. washeluting with 10:1 CH2Cl2/MeOH
  10. customThe product was obtained (12.9 mg; 65%) as a pale yellow solid

Sources & evidence

ORD record
ord-12aa2289803648cc99833d80aa723c0b
Source dataset
uspto-grants-2011_08
Patent number
US08003662B2

Reaction notes

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