Phosphorus pentachloride → (6R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-ethoxyiminoacetyl]amino]-3-[[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

HRID 36015Notes

Reaction equation

HRID 36015 reaction equation
[NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]3[S:15][C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=4)=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH2:41]([O:43]/[N:44]=[C:45](/[C:49]1[N:50]=[C:51]([NH:54]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:52][CH:53]=1)\[C:46](Cl)=[O:47])[CH3:42].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:45](=[N:44]/[O:43][CH2:41][CH3:42])/[C:46]([NH:1][CH:2]2[C:27](=[O:28])[N:4]3[C:5]([C:24]([OH:26])=[O:25])=[C:6]([CH2:9][S:10][C:11]4[S:15][C:14]([C:16]5[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:23])[CH:17]=5)=[N:13][N:12]=4)[CH2:7][S:8][C@H:3]23)=[O:47])[N:50]=1

Participants

6

Reactant 4

HCID 24819Phosphorus pentachlorideHCID 11708267BistrimethylsilylacetamidHCID 88440379(2Z)-2-ethoxyimino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetyl chlorideHCID 1364355677-Amino-3-[2-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-5-ylthiomethyl]ceph-3-em-4-carboxylic acid

Product 1

HCID 136435570(6R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-ethoxyiminoacetyl]amino]-3-[[5-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-2-yl]sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acidYield 7%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

1 equivalent of 7-amino-3-[2-(3,4-dihydroxyphenyl)-1,3,4-thiadiazol-5-ylthiomethyl]ceph-3-em-4-carboxylic acid was silylated with 4 equivalents of bistrimethylsilylacetamide in anhydrous dichloromethane at room temperature for three hours. To this solution, cooled to 0° C. under argon, was added 1 equivalent of 2-[(Z)-ethoxyimino-2-(tritylaminothiazol-4-yl) acetic acid chloride (prepared from the corresponding acid (1 equivalent), 1 equivalent PCl5 and 1 equivalent TEA in dichloromethane at 0° C. for 2 hours followed by evaporation of the solvent and all POCl3, and redissolution in dichloromethane). After a few minutes at 0° C., the solvent was evaporated, and all the protecting groups removed by treating the crude reaction mixture with TFA/water for 1 hour at room temperature. The solvents were evaporated and the crude product dissolved in MeOH and precipitated in ether. Further purification was achieved by MPLC, to yield the title compound (7%), NMR (DMSOd6, AcOD, TFA), 1.25 (t,3H); 3.7 (m,2H); 4.2 and 4.25 (2d,2H); 4.4 (q,2H); 5.15 (d,1H); 5.75 (d,1H); 6.85 (d,1H); 7 (s,1H); 7.15 (d,1H); 7.3 (s,1H).

Workup

  1. customfollowed by evaporation of the solvent
  2. waitAfter a few minutes at 0° C.
  3. customthe solvent was evaporated
  4. customall the protecting groups removed
  5. additionby treating the crude
  6. customreaction mixture with TFA/water for 1 hour at room temperature
  7. customThe solvents were evaporated
  8. dissolutionthe crude product dissolved in MeOH
  9. customprecipitated in ether
  10. customFurther purification

Sources & evidence

ORD record
ord-55b34c143a0e4a11a9b1a408b5d9a37c
Source dataset
uspto-grants-1995_05
Patent number
US05412093

Reaction notes

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