Methyl acetoacetate → 6-(2-[4-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam

HRID 1448382Notes

Reaction equation

HRID 1448382 reaction equation
[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O:19][CH3:20])(=[O:18])[CH2:14][C:15]([CH3:17])=O.ClC(OCC)=O.[NH2:27][CH:28]1[C:41](=[O:42])[N:30]2[CH:31]([C:36]3[NH:40][N:39]=[N:38][N:37]=3)[C:32]([CH3:35])([CH3:34])[S:33][C@H:29]12.[OH-].[Na+:44]>CN1CCOCC1.O.O1CCCC1>[CH3:20][O:19][C:13]([CH:14]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O-:12])=[O:11])=[CH:5][CH:4]=1)[CH:15]=[CH2:17])=[O:18].[Na+:44].[NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:27][CH:28]2[C:41](=[O:42])[N:30]3[CH:31]([C:36]4[NH:37][N:38]=[N:39][N:40]=4)[C:32]([CH3:34])([CH3:35])[S:33][C@H:29]23)=[O:12])=[CH:7][CH:8]=1

Participants

10

Reactant 5

HCID 7757Methyl acetoacetateHCID 10928Ethyl chloroformateHCID 14798Sodium HydroxideHCID 15141444-Aminomethylphenylacetic acidHCID 178431949HCID 178431949, compound

Product 2

HCID 23715223Sodium 4-[(1-methoxycarbonyl-2-propenyl)aminomethyl]phenylacetateHCID 1784319286-(2-[4-Aminomethylphenyl]acetamido)-2,2-dimethyl-3-(5-tetrazolyl)penamYield 11%

Reagents, catalysts & solvents 3

HCID 79724-MethylmorpholineCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

Sodium 4-[(1-methoxycarbonyl-2-propenyl)aminomethyl]phenylacetate is prepared from 4-aminomethylphenylacetic acid [Zaugg and Horrom, J. Am. Chem. Soc. 80, 4317 (1958)] and methyl acetoacetate by the method described by Dane and Dockner [Chem. Ber., 98, 789 (1965)]. A suspension of this salt (2.15 g, 7.5 mmole), 7 drops of N-methylmorpholine and 100 ml. of tetrahydrofuran is stirred at -20° C.; ethyl chloroformate (0.81 g. 7.5 mmole) is added and the mixture is stirred for 60 minutes. 6-Amino-2,2-dimethyl-3-(5-tetrazolyl)penam (1.80 g., 7.5 mmoles) is suspended in a 50:50 mixture of tetrahydrofuran and water (40 ml), and the pH is adjusted to 7.5 with 1 N sodium hydroxide solution whereby a homogeneous solution is obtained. This is added to the above suspension, in one portion, the new mixture is stirred at -20° C. for 1 hour and then it is allowed to warm to room temperature over 1 hour. Most of the tetrahydrofuran is removed in vacuo, the resultant aqueous solution is cooled in an ice bath, and the pH is adjusted to 1.5 with 3 N hydrochloric acid. After 30 minutes the pH is adjusted to 2.5, and the solution is extracted with ethyl acetate. The aqueous phase is adjusted to pH 6.0 and freeze-dried. The resultant lyophylate is combined with that from another preparation (5 mmoles) and chromatographed on Sephadex LH-20 (150 g) eluting with water. Like fractions (tlc analysis) are combined and freeze-dried, yielding the title compound as a colorless amorphous solid (570 mg., 11% yield), m.p. 190°-200° C. IR(KBr): 1770, 1650 and 1515 cm-1. NMR (DMSO-d6 -D2O): 7.4 ppm (s, 4H), 5.65 ppm (d, J=4 Hz, 1H), 5.45 ppm (d, J=4 Hz, 1H), 5.2 ppm (s, 1H), 4.1 ppm (s, 2H), 3.6 ppm (s, 2H), 1.6 ppm (s, 3H) and 1.0 ppm (s, 3H).

Workup

  1. customis obtained
  2. additionThis is added to the above suspension, in one portion
  3. stirringthe new mixture is stirred at -20° C. for 1 hour
  4. customMost of the tetrahydrofuran is removed in vacuo
  5. temperaturethe resultant aqueous solution is cooled in an ice bath
  6. waitAfter 30 minutes the pH is adjusted to 2.5
  7. extractionthe solution is extracted with ethyl acetate
  8. customfreeze-dried
  9. customfrom another preparation (5 mmoles)
  10. customchromatographed on Sephadex
  11. wash(150 g) eluting with water
  12. customfreeze-dried

Sources & evidence

ORD record
ord-26fbfbe3ffcc4cd8a7d3b7a805db5d78
Source dataset
uspto-grants-1979_12
Patent number
US04179511

Reaction notes

Loading…