Triethylamine → {8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester

HRID 10343

Reaction equation

HRID 10343 reaction equation
[C:1]([O:5][C:6](=[O:26])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:21])[C:13](F)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:22]2[CH2:24][CH2:23]2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[NH:27]1[CH2:31][CH2:30][CH:29](NC)[CH2:28]1.C([N:36]([CH2:39]C)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:26])[NH:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[C:12]([Cl:21])[C:13]([N:27]3[CH2:31][CH2:30][CH:29]([CH2:39][NH:36][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:28]3)=[C:14]([F:19])[CH:15]=2)[N:10]([CH:22]2[CH2:24][CH2:23]2)[C:9]1=[O:25])([CH3:3])([CH3:2])[CH3:4]

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 31297Methanesulfonyl chlorideHCID 11440606(8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acid tert-butyl esterHCID 117882683-(Methylamino)pyrrolidine

Product 1

HCID 21041214{8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl esterYield 8.4%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

A solution of (8-chloro-1-cyclopropyl-6,7-difluoro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)carbamic acid tert-butyl ester (Example 14, 0.37 g, 0.97 mmol) in acetonitrile (20 mL) is added pyrrolidin-3-yl-methylamine (0.115 g, 1.16 mmol) and triethylamine (2.7 mL, 19.3 mmol). After refluxing for 20 hours, the reaction mixture is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with saturated sodium bicarbonate, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated. The resulting residue is redissolved in methylene chloride (10 mL) at 0° C. and while stirring, triethylamine (0.33 mL, 2.34 mmol) and methanesulfonyl chloride (0.072 mL, 0.94 mmol) is added. After 2 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer is dried over MgSO4, filtered, and the filtrate concentrated and the product is purified via flash column chromatography (1:1 EtOAc/hexanes) to afford {8-chloro-1-cyclopropyl-6-fluoro-7-[3-(methanesulfonylaminomethyl)pyrrolidin-1-yl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}carbamic acid tert-butyl ester (0.043 g). MS CI: m/e 446 ((MH+)-Boc).

Workup

  1. temperatureAfter refluxing for 20 hours
  2. washThe organic layer is washed with saturated sodium bicarbonate, water, and brine
  3. dry with materialThe organic layer is dried over MgSO4
  4. filtrationfiltered
  5. concentrationthe filtrate concentrated
  6. dissolutionThe resulting residue is redissolved in methylene chloride (10 mL) at 0° C.
  7. washwashed with saturated sodium bicarbonate, water, and brine
  8. dry with materialThe organic layer is dried over MgSO4
  9. filtrationfiltered
  10. concentrationthe filtrate concentrated
  11. customthe product is purified via flash column chromatography (1:1 EtOAc/hexanes)

Sources & evidence

ORD record
ord-a33f3b286a854755b162b6197f8b9f3f
Source dataset
uspto-grants-2006_08
Patent number
US07094780B1

Linked notes

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