Dimethyl Sulfoxide → {(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic acid tert-butyl ester

HRID 729416

Reaction equation

HRID 729416 reaction equation
[NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[C:6]([O:15][CH3:16])[C:7](F)=[C:8]([F:13])[CH:9]=2)[N:4]([CH:17]2[CH2:19][CH2:18]2)[C:3]1=[O:20].[C:21]([O:25][C:26](=[O:35])[NH:27][C@H:28]([C@@H:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)[CH3:29])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C.CS(C)=O>O>[C:21]([O:25][C:26](=[O:35])[NH:27][C@@H:28]([C@H:30]1[CH2:34][CH2:33][N:32]([C:7]2[C:6]([O:15][CH3:16])=[C:5]3[C:10]([C:11](=[O:12])[N:2]([NH2:1])[C:3](=[O:20])[N:4]3[CH:17]3[CH2:19][CH2:18]3)=[CH:9][C:8]=2[F:13])[CH2:31]1)[CH3:29])([CH3:22])([CH3:23])[CH3:24]

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 8471TriethylamineHCID 10242357(3R,1S)-3-(1-(t-butoxycarbonylamino)ethyl)pyrrolidineHCID 111968242,4(1H,3H)-Quinazolinedione, 3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-

Product 1

HCID 58681877{(R)-1-[(S)-1-(3-Amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}-carbamic acid tert-butyl esterYield 96.3%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

A solution of 0.57 g (2.0 mmol) of 3-amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione (Example 24d), 0.64 g (3.0 mmol) of ((S)-(R)-1-pyrrolidin-3-ylethyl)carbamic acid tert-butyl ester (J. Het. Chem., 1992; 29:1481), 0.81 g (8.0 mmol) of triethylamine and 10 mL of dimethyl sulfoxide is heated at 110° C. for 4 hours. The reaction mixture is cooled to room temperature, poured into 150 mL of ice and water, and extracted with ethyl acetate (2×125 mL). The combined organic layers are washed with water, dried (MgSO4), filtered and evaporated in vacuo to give 1.1 g of crude product. Chromatography on flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (9:1) provided 0.92 g of the title compound, mp 96-98° C.

Workup

  1. extractionextracted with ethyl acetate (2×125 mL)
  2. washThe combined organic layers are washed with water
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customto give 1.1 g of crude product
  7. washChromatography on flash grade silica gel (230-400 mesh) eluting with dichloromethane/ethanol (9:1)

Sources & evidence

ORD record
ord-cb5a24778b804aeeafc4e4cb45eb5e40
Source dataset
uspto-grants-2009_09
Patent number
US07582627B2

Linked notes

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