Sodium Carbonate → (S)-tert-Butyl 2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylate

HRID 384720Notes

Reaction equation

HRID 384720 reaction equation
[H-].[Na+].ClC1C=C(N)C(I)=CN=1.S(OC[C@H]1OCCN(C(OC(C)(C)C)=O)C1)(C1C=CC(C)=CC=1)(=O)=O.[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41](I)=[CH:40][N:39]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:66][O:67][C:68]1[CH:73]=[CH:72][C:71](B(O)O)=[CH:70][CH:69]=1>CN(C=O)C.C(#N)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[Cl:37][C:38]1[CH:43]=[C:42]([NH:44][CH2:45][C@@H:46]2[O:51][CH2:50][CH2:49][N:48]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:47]2)[C:41]([C:71]2[CH:72]=[CH:73][C:68]([O:67][CH3:66])=[CH:69][CH:70]=2)=[CH:40][N:39]=1

Participants

11

Reactant 6

HCID 10340Sodium CarbonateHCID 24758Sodium hydride2×HCID 201262(4-Methoxyphenyl)boronic acidHCID 454803662-Chloro-5-iodopyridin-4-amineHCID 54043638(S)-tert-Butyl 2-((tosyloxy)methyl)morpholine-4-carboxylateHCID 86648391(R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate

Product 1

HCID 59613477(S)-tert-Butyl 2-((2-chloro-5-(4-methoxyphenyl)pyridin-4-ylamino)methyl)morpholine-4-carboxylateYield 94.3%

Reagents, catalysts & solvents 4

HCID 11979704Tetrakis(triphenylphosphine)palladiumCatalystHCID 962WaterSolventHCID 6228DimethylformamideSolvent2×HCID 6342AcetonitrileSolvent

Conditions

Temperature
80 °C

Procedure

NaH (0.024 g, 0.569 mmol) was added to a solution of 2-chloro-5-iodopyridin-4-amine (0.121 g, 0.474 mmol) in DMF (2.8 mL) at room temperature and stirred for 10 min. The temperature was raised to 80° C. and (S)-tert-butyl 2-(tosyloxymethyl)morpholine-4-carboxylate (0.264 g, 0.711 mmol) in DMF (0.6 mL) was added. The reaction mixture was stirred for 2 h, then further NaH (0.024 g, 0.569 mmol) was added at room temperature. The reaction mixture was further heated at 80° C. for 1 h then cooled. Water was added and the mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL). The organic phase was washed with brine, dried (MgSO4) and concentrated. The mixture was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (2/4), to give an inseparable mixture of starting material and product. LCMS (4) Rt=2.66 min; m/z (ESI+) 397 [MH+]. A solution of the crude (R)-tert-butyl 2-((2-chloro-5-iodopyridin-4-ylamino)methyl)morpholine-4-carboxylate (0.040 g, 0.088 mmol), sodium carbonate (0.5 M, 0.26 mL), 4-methoxyphenyl boronic acid (0.013 g, 0.088 mmol) and tetrakis(triphenylphosphine) palladium(0) (0.011 g, 0.01 mmol) in acetonitrile (2 mL) was heated under microwave irradiation at 100° C. for 20 min. The reaction mixture was concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with ethyl acetate/hexane (1/1), to give the title compound as a colorless oil (0.036 g, 94%).

Workup

  1. stirringThe reaction mixture was stirred for 2 h
  2. temperatureThe reaction mixture was further heated at 80° C. for 1 h
  3. temperaturethen cooled
  4. customthe mixture was partitioned between ethyl acetate (20 mL) and aq. NaHCO3 (20 mL)
  5. washThe organic phase was washed with brine
  6. dry with materialdried (MgSO4)
  7. concentrationconcentrated
  8. customThe mixture was purified by flash column chromatography on silica gel
  9. washeluting with ethyl acetate/hexane (2/4)
  10. customto give
  11. additionan inseparable mixture of starting material and product
  12. concentrationThe reaction mixture was concentrated
  13. customThe crude product was purified by flash column chromatography on silica gel
  14. washeluting with ethyl acetate/hexane (1/1)

Sources & evidence

ORD record
ord-2998c422ba974b37ba704f3c6e99b2af
Source dataset
uspto-grants-2013_02
Patent number
US08367658B2

Reaction notes

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