Acetic Anhydride → Acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl ester

HRID 2089692Notes

Reaction equation

HRID 2089692 reaction equation
Cl.[F:2][C:3]1[C:8]([O:9][CH2:10][CH2:11][OH:12])=[CH:7][C:6]([O:13][CH3:14])=[CH:5][C:4]=1[C@@H:15]([NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[NH:34])=[CH:31][CH:30]=1)[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].[C:44](=[O:57])(OC1C=CC=CC=1)[O:45][CH2:46][C:47]([CH3:49])=[CH2:48].[C:58](OC(=O)C)(=[O:60])[CH3:59].C(=O)([O-])O.[Na+]>CS(C)=O.CN(C)C1C=CN=CC=1.COC(C)(C)C.C(OCC)(=O)C.O1CCCC1>[NH2:34][C:33](=[N:35][C:44]([O:45][CH2:46][C:47]([CH3:49])=[CH2:48])=[O:57])[C:32]1[CH:31]=[CH:30][C:29]([NH:28][C@@H:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[N:23]=[CH:24][CH:25]=[CH:26][N:27]=3)[N:17]=2)[C:4]2[C:3]([F:2])=[C:8]([CH:7]=[C:6]([O:13][CH3:14])[CH:5]=2)[O:9][CH2:10][CH2:11][O:12][C:58](=[O:60])[CH3:59])=[CH:37][CH:36]=1

Participants

11

Reactant 5

HCID 7918Acetic Anhydride2×HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 151790822-Methyl-allyl phenyl carbonateHCID 1363340354-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzamidine hydrochloride

Product 1

HCID 136334037Acetic acid 2-{3-[(R)-{4-[amino(2-methylallyloxycarbonylimino)methyl]phenylamino}-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]-2-fluoro-5-methoxyphenoxy}ethyl esterYield 62.6%

Reagents, catalysts & solvents 5

HCID 142844-(Dimethylamino)pyridineCatalystHCID 679Dimethyl SulfoxideSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolventHCID 15413tert-Butyl methyl etherSolvent

Procedure

At room temperature, 4-{[(R)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl](5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]-triazol-3-yl)methyl]amino}benzamidine hydrochloride (5.058 g, 9.42 mmol) was dissolved in dimethyl sulfoxide (15 mL), and potassium carbonate (3.91 g, 28.3 mmol) was added thereto. To the resulting mixture, 2-methyl-allyl phenyl carbonate (1.81 g, 9.42 mmol) was added under stirring at room temperature, and the resulting mixture was stirred for 18 hours. Thereafter, 4-dimethylaminopyridine (57.5 mg, 0.471 mmol) and acetic anhydride (2.23 mL, 23.6 mmol) were added to the reaction solution, and the resulting mixture was stirred for 1.5 hours. Further, acetic anhydride (0.223 mL, 2.36 mmol) was added to the mixture, and the resulting mixture was stirred for 2 hours. To the reaction solution, tetrahydrofuran (20 mL) and ethyl acetate (40 mL) were added, and 5% aqueous sodium hydrogen carbonate solution (50 g) was added to quench the reaction, after which the layers were separated at 50° C. Furthermore, the aqueous layer was extracted twice with a mixture of tetrahydrofuran (20 mL) and ethyl acetate (40 mL). The organic layer was combined, washed twice with 5% aqueous sodium hydrogen carbonate solution (25 g) and once with 5% saline, and then concentrated under reduced pressure. Acetone (30 mL) was added to the residue obtained, and the resulting mixture was stirred at room temperature for 3 hours, after which tert-butyl methyl ether (25 mL) was added to the mixture, and the resulting mixture was stirred at 4° C. for 16 hours. The precipitate was filtered and dried to obtain the captioned compound (3.74 g) as a pale yellow solid.

Workup

  1. stirringthe resulting mixture was stirred for 18 hours
  2. stirringthe resulting mixture was stirred for 1.5 hours
  3. stirringthe resulting mixture was stirred for 2 hours
  4. customto quench
  5. customthe reaction
  6. customafter which the layers were separated at 50° C
  7. extractionFurthermore, the aqueous layer was extracted twice with a mixture of tetrahydrofuran (20 mL) and ethyl acetate (40 mL)
  8. washwashed twice with 5% aqueous sodium hydrogen carbonate solution (25 g) and once with 5% saline
  9. concentrationconcentrated under reduced pressure
  10. additionAcetone (30 mL) was added to the residue
  11. customobtained
  12. stirringthe resulting mixture was stirred at room temperature for 3 hours
  13. stirringthe resulting mixture was stirred at 4° C. for 16 hours
  14. filtrationThe precipitate was filtered
  15. customdried

Sources & evidence

ORD record
ord-67013ed13f5043f5a2152e656fa4cf3b
Source dataset
uspto-grants-2013_05
Patent number
US08436009B2

Reaction notes

Loading…