Hydrochloric Acid → HCID 66719153, compound

HRID 2390460Notes

Reaction equation

HRID 2390460 reaction equation
[N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[CH:22]=[CH:21][C:20]([Sn](C)(C)C)=[CH:19][C:18]4=[O:27])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35](SC)=[N:34][C:33]=2[CH:39]=1.[ClH:40]>C1COCC1.C(Cl)Cl.CCOCC.[Cu](Br)Br>[ClH:40].[CH3:28][C:29]1[CH:30]=[CH:31][C:32]2[O:36][C:35]([C:20]3[CH:21]=[CH:22][N:17]([C:13]4[CH:12]=[C:11]5[C:16](=[CH:15][CH:14]=4)[N:8]([CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[N:9]=[CH:10]5)[C:18](=[O:27])[CH:19]=3)=[N:34][C:33]=2[CH:39]=1

Participants

8

Reactant 3

HCID 313Hydrochloric AcidHCID 224958065-Methyl-2-(methylsulfanyl)-1,3-benzoxazoleHCID 57625542HCID 57625542, compound

Product 1

HCID 66719153HCID 66719153, compoundYield 24%

Reagents, catalysts & solvents 4

HCID 24611Copper bromide (CuBr2)CatalystHCID 3283Diethyl EtherSolventHCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
70 °C

Procedure

1-(1-(2-(Pyrrolidin-1-yl)ethyl)-1H-indazol-5-yl)-4-(trimethylstannyl)pyridin-2(1H)-one (prepared according to Example 30, step a) (250 mg, 0.530 mmol), 5-methyl-2-(methylthio)benzo[d]oxazole (198 mg, 1.11 mmol), copper(II) bromide (331 mg, 1.16 mmol) and palladium tetrakistriphenylphosphine (61 mg, 0.053 mmol) were stirred in dry THF (6 mL) under a nitrogen atmosphere. The mixture was heated to 70° C. for 20 h. Upon cooling, the mixture was diluted with THF, filtered through celite and rinsed with THF/methylene chloride. The organics were concentrated and purified by flash chromatography (40 g ISCO column eluting with methylene chloride and methanol/ammonia (10:1); 100% methylene chloride to 15% methanol/ammonia over 35 min at 40 mL/min) then further purified by Preparatory HPLC. The appropriate fractions were concentrated and partitioned between methylene chloride and Na2CO3. The organics were dried with Na2SO4, filtered, and concentrated to provide the free base. This was dissolved in methylene chloride (2 mL) and treated with 1 equivalent of 2 M HCl in Et2O, and the mixture was concentrated to provide the title compound (55.8 mg, 24%) as a yellow solid: mp 270-280° C.; 1H NMR (500 MHz, CD3OD) δ 8.27 (s, 1H), 7.94 (d, J=1.7 Hz, 1H), 7.88 (d, J=7.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.64-7.61 (m, 2H), 7.58-7.55 (dd, J=8.9, 1.9 Hz, 1H), 7.44 (d, J=1.7 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.24-7.22 (dd, J=7.1, 1.9 Hz, 1H), 4.89 (t, J=5.7, 2H), 3.88 (t, J=5.7, 2H), 3.74-3.70 (m, 2H), 3.21-3.16 (m, 2H), 2.51 (s, 3H), 2.20-2.16 (m, 2H) 2.04-2.01 (m, 2H); ESI MS m/z 440 [M+H]+; HPLC (Method C) 98.7% (AUC), tR=13.1 min.

Workup

  1. temperatureUpon cooling
  2. filtrationfiltered through celite
  3. washrinsed with THF/methylene chloride
  4. concentrationThe organics were concentrated
  5. custompurified by flash chromatography (40 g ISCO column eluting with methylene chloride and methanol/ammonia (10:1); 100% methylene chloride to 15% methanol/ammonia over 35 min at 40 mL/min)
  6. customthen further purified by Preparatory HPLC
  7. concentrationThe appropriate fractions were concentrated
  8. custompartitioned between methylene chloride and Na2CO3
  9. dry with materialThe organics were dried with Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customto provide the free base
  13. concentrationthe mixture was concentrated

Sources & evidence

ORD record
ord-18142b81c0324731a96608cdc27eeea9
Source dataset
uspto-grants-2012_09
Patent number
US08273770B2

Reaction notes

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