Hydrochloric Acid → HCID 178482338, compound

HRID 340843Notes

Reaction equation

HRID 340843 reaction equation
P(Cl)(Cl)(Cl)(Cl)[Cl:2].NC.[CH3:9][N:10]([CH2:15][C:16]1[O:17][C:18]2[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=2[C:20]=1[CH3:21])[C:11](=[O:14])[CH:12]=[CH2:13].CCN(C(C)C)C(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl.Br[C:59]1[CH:68]=[N:67][C:66]2[NH:65]/[C:64](=[N:69]/[CH3:70])/[C:63]([CH3:72])([CH3:71])[O:62][C:61]=2[CH:60]=1.ClC(Cl)C.BrC1C=NC2NC(=O)C(C)(C)OC=2C=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].CN(C=O)C>[ClH:2].[CH3:71][C:63]1([CH3:72])[O:62][C:61]2[CH:60]=[C:59](/[CH:13]=[CH:12]/[C:11]([N:10]([CH3:9])[CH2:15][C:16]3[O:17][C:18]4[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=4[C:20]=3[CH3:21])=[O:14])[CH:68]=[N:67][C:66]=2[NH:65]/[C:64]/1=[N:69]/[CH3:70]

Participants

13

Reactant 9

HCID 313Hydrochloric AcidHCID 6329Methylamine2×HCID 63651,1-DichloroethaneHCID 24819Phosphorus pentachloride2×HCID 80271Tri-o-tolylphosphineHCID 81531DiisopropylethylamineHCID 577420407-bromo-2,2-dimethyl-2H,3H,4H-pyrido(3,2-b)(1,4)oxazin-3-oneHCID 57742103N-methyl-N-(3-methylbenzofuran-2-ylmethyl)acrylamideHCID 178482337HCID 178482337, compound

Product 1

HCID 178482338HCID 178482338, compoundYield 89%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
-78 °C

Procedure

Reagents and conditions: a) PCl5, μwave then NH2Me, b) N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide, DIPEA, Pd(OAc)2, P(o-Tol)3, DMF, then HCl. a) (E)-N-(7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ylidene)methanamine: A dichloroethane (5 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (520 mg, 2 mmol) and phosphorus pentachloride (840 mg, 4 mmol) was irradiated in a microwave oven for 10 min at. 160° C. The solution was cooled to −78° C. and methylamine (2M in THF) was added it slowly until it became permanently basic. The mixture was diluted with CH2Cl2, washed with dilute solution of NaOH, dried, and evaporated. Crystallization from CH2Cl2/hexane afforded 480 mg (89%) of the title compound. 1H NMR (300 MHz, CDCl3, δ) 8.07 (d, J=2.1 Hz, 1H), 7.21 (d, J=2.1 Hz, 1H), 4.9 (s, br, 1H), 3.06 (d, J=4.5 Hz, 3H), 1.46 (s, 6H). MS (ESI) m/e 270 (M+H)+. b) (E)-3-((E)-2,2-dimethyl-3-(methylimino)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide: A DMF (3 mL) solution of (E)-N-(7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-ylidene)methanamine (271 mg, 1 mmol), N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide (345 mg, 1.5 mmol) and diisopropylethylamine (0.52 mL, 3 mmol) was purged with Argon for 10 min. Pd(OAc)2 (24 mg, 0.1 mmol) and P(o-tol)3 (61 mg, 0.2 mmol) was added and then the Argon purge was repeated. The mixture was irradiated in a microwave oven for 10 min at 160° C. under Argon. Upon cooling, the mixture was diluted with water and extracted with EtOAc. The crude product was purified by chromatography (silica, 0-4% MeOH in CH2Cl2). The free base was turned into the HCl salt by addition of HCl (1 ml, 1M m Et2O) to its CH2Cl2 solution and evaporation to afford 230 mg (55%) of the title compound, as a mixture of amide rotamers. 1H NMR (300 MHz, CDCl3, δ, free base) 8.20 (s, 1H), 7.69 and 7.85 (2s, 1H), 7.5-6.7 (m, 6H), 5.14 (s, br, 1H), 4.83 and 4.71 (2s, 2H), 3.21 and 3.10 (2s, 3H), 3.09 (d, J=4.8 Hz, 3H), 2.31 (s, 3H), 1.49 (s, 6H). MS (ESI) m/e 419 (M+H)+.

Workup

  1. custom160° C
  2. washwashed with dilute solution of NaOH
  3. customdried
  4. customevaporated
  5. customCrystallization from CH2Cl2/hexane

Sources & evidence

ORD record
ord-ff7943c480c14de9b3eb54c47dab7dc2
Source dataset
uspto-grants-2014_11
Patent number
US08895545B2

Reaction notes

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