Hydrochloric Acid → 1-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)urea

HRID 868888

Reaction equation

HRID 868888 reaction equation
C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:3](=[O:4])C1.N1C=CC=CC=1.[NH2:25][C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH2:28][NH:29][C:30](=[O:37])[N:31]2[CH3:36].C(N(CC)C(C)C)(C)C.O[C@H](C1C=CC=CC=1)C([O-])=O.[CH3:58][C:59]1([CH3:70])[CH2:68][C@@H:67]([NH2:69])[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[O:60]1.Cl>CCOC(C)=O.C(#N)C>[CH3:58][C:59]1([CH3:70])[CH2:68][C@@H:67]([NH:69][C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:27]=2[CH2:28][NH:29][C:30](=[O:37])[N:31]3[CH3:36])=[O:4])[C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[O:60]1

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 1049PyridineHCID 81531DiisopropylethylamineHCID 676246Di(succinimido) carbonateHCID 5460269(R)-MandelateHCID 42157625(R)-2,2-dimethylchroman-4-amineHCID 574159275-amino-1-methyl-3,4-dihydroquinazolin-2(1H)-one

Product 1

HCID 716114831-[(4R)-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]-3-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinazolin-5-yl)ureaYield 88.2%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

A slurry of N,N-disuccinimidyl carbonate (434 mg, 1.69 mmol), acetonitrile (6 mL), pyridine (0.137 mL, 1.69 mmol), and 5-amino-1-methyl-3,4-dihydroquinazolin-2(1H)-one (A-1) (300 mg, 1.69 mmol) was stirred at room temperature. After 45 min, N,N-diisopropylethylamine (0.879 mL, 5.08 mmol) and (R)-2-hydroxy-2-phenylacetate salt of (R)-2,2-dimethylchroman-4-amine (B-2) (558 mg, 1.69 mmol) were added. After 30 minutes, EtOAc (50 mL) and 2N aqueous HCl (20 mL) were added and the layers separated. The organic extract was washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography (0-10% MeOH/EtOAc gradient) to afford the title compound (565 mg, 1.49 mmol, 88% yield). 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.42 (d, J=8.1 Hz, 1H), 7.25 (t, J=10.7 Hz, 1H), 7.16 (dd, J=16.6, 8.2 Hz, 3H), 6.89 (t, J=7.0 Hz, 1H), 6.73 (d, J=8.6 Hz, 2H), 6.63 (d, J=8.1 Hz, 1H), 4.94 (dd, J=15.2, 10.0 Hz, 1H), 4.18 (s, 2H), 3.14 (s, 3H), 2.13 (dd, J=13.2, 6.2 Hz, 1H), 1.69 (dd, J=30.9, 18.0 Hz, 1H), 1.39 (s, 3H), 1.27 (s, 3H). MS (ESI+) m/z 449 (M+H)+.

Workup

  1. waitAfter 30 minutes
  2. customthe layers separated
  3. extractionThe organic extract
  4. washwas washed with brine (10 mL)
  5. dry with materialdried (Na2SO4)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe residue was purified by silica gel chromatography (0-10% MeOH/EtOAc gradient)

Sources & evidence

ORD record
ord-c2f3ef860df64005a91eeb46460def2f
Source dataset
uspto-grants-2015_03
Patent number
US08969325B2

Linked notes

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