4-Methylmorpholine → (6R)-3-(azidomethyl)-7-[[(2Z)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

HRID 1722571Notes

Reaction equation

HRID 1722571 reaction equation
C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([CH2:14][O:15]/[N:16]=[C:17](/[C:21]1[N:22]=[C:23]([NH:26][C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:24][CH:25]=1)\[C:18]([OH:20])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].CN1CCOCC1.[NH2:53][CH:54]1[C:68](=[O:69])[N:56]2[C:57]([C:65]([OH:67])=[O:66])=[C:58]([CH2:61][N:62]=[N+:63]=[N-:64])[CH2:59][S:60][C@H:55]12.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C>ClCCl.O.CN(C=O)C>[N:62]([CH2:61][C:58]1[CH2:59][S:60][C@@H:55]2[CH:54]([NH:53][C:18](=[O:20])/[C:17](=[N:16]\[O:15][CH2:14][C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])/[C:21]3[N:22]=[C:23]([NH:26][C:27]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[S:24][CH:25]=3)[C:68](=[O:69])[N:56]2[C:57]=1[C:65]([OH:67])=[O:66])=[N+:63]=[N-:64]

Participants

9

Reactant 5

HCID 79724-MethylmorpholineHCID 65578Oxalyl chlorideHCID 6913588N,O-bis(trimethylsilyl)acetamideHCID 128022197-Amino-3-azidomethyl-3-cephem-4-carboxylic acidHCID 13078701(2Z)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acid

Product 1

HCID 145805289(6R)-3-(azidomethyl)-7-[[(2Z)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent2×

Procedure

The 3-aminomethylcephalosporin may be prepared as follows:-Oxalyl chloride (337 μl.) and DMF (330 μl.) were added to CH2Cl2 (20 ml.) at -10°, and stirred for 30 minutes. 2((Z)-t-Butoxycarbonylmethoxyimino)-2-(2 tritylaminothiazol-4-yl)acetic acid and N-methylmorpholine (510 μl.) were added and stirring continued for 30 minutes. Meanwhile in a separate flask, a suspension of 7-amino-3-azidomethylceph-3-em-4-carboxylic acid (987 mg.) in dichloromethane (8 ml.) was treated with N,O-bis(trimethylsilyl)acetamide (1.91 ml.), and stirred for 1 hour to give a clear solution, which was transferred by syringe to the acid chloride solution. After stirring the mixture for 1 hour at -10°, the temperature was allowed to rise to ambient. The mixture was poured into water (25 ml.) and organics extracted with EtOAc (3×25 ml.). The crude product was filtered through a short SiO2 column in EtOAc/HOAc 99:1 v/v, and evaporated to give 3-azidomethyl-7-[2-((Z)-t-butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetamido]ceph-3-em-4-carboxylic acid, having the following n.m.r. in solvent A:-1.4(s, 9H); 3.35(d, 1H); 3.63(d, 1H); 3.86(d, 1H); 4.38(d, 1H); 4.49(s, 2H); 5.09(d, 1H); 5.7(d, 1H); 6.73(s, 1H); 7.29(m, 15H).

Workup

  1. customThe 3-aminomethylcephalosporin may be prepared
  2. stirringstirring
  3. waitcontinued for 30 minutes
  4. stirringstirred for 1 hour
  5. customto give a clear solution, which
  6. stirringAfter stirring the mixture for 1 hour at -10°
  7. extractionorganics extracted with EtOAc (3×25 ml.)
  8. filtrationThe crude product was filtered through a short SiO2 column in EtOAc/HOAc 99:1 v/v
  9. customevaporated

Sources & evidence

ORD record
ord-af1f30bb3a934b128d839f93b6e47033
Source dataset
uspto-grants-1989_08
Patent number
US04855420

Reaction notes

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