Triethylamine → benzhydryl (6R,7R)-3-(bromomethyl)-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-carboxylate

HRID 2164437Notes

Reaction equation

HRID 2164437 reaction equation
[C:1]([O:5][C:6]([CH2:8][O:9]/[N:10]=[C:11](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([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)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:12](O)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.Cl.[NH2:54][C@@H:55]1[C:80](=[O:81])[N:57]2[C:58]([C:64]([O:66][CH:67]([C:74]3[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=3)[C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])=[C:59]([CH2:62][Br:63])[CH2:60][S:61][C@H:56]12>ClCCl.O>[Br:63][CH2:62][C:59]1[CH2:60][S:61][C@@H:56]2[C@H:55]([NH:54][C:12](=[O:13])/[C:11](=[N:10]\[O:9][CH2:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])/[C:15]3[N:16]=[C:17]([NH:20][C:21]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[S:18][CH:19]=3)[C:80](=[O:81])[N:57]2[C:58]=1[C:64]([O:66][CH:67]([C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)[C:74]1[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=1)=[O:65]

Participants

7

Reactant 4

HCID 8471Triethylamine2×HCID 24819Phosphorus pentachloride2×HCID 13078701(2Z)-2-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethoxy]imino-2-[2-(tritylamino)-1,3-thiazol-4-yl]acetic acidHCID 131714150diphenylmethyl (6R,7R)-7-amino-3-bromomethyl-ceph-3-em-4-carboxylate hydrochloride

Product 1

HCID 172953016benzhydryl (6R,7R)-3-(bromomethyl)-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-carboxylateYield 85.6%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6344DichloromethaneSolvent3×

Procedure

(Z)-2-(t-Butoxycarbonylmethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid (1.1 g) (described in Example 3 of South African Specification No. 78/1630) was added to a stirred solution of phosphorus pentachloride (0.46 g) in dichloromethane (20 ml) at -20°. The solution was kept at -15°±5° for 40 35 minutes. More phosphorus pentachloride (0.05 g) was added after 30 minutes. The solution was cooled to -20° and triethylamine (0.6 ml) was added. The solution was stirred at -20° for 5 minutes and then added to a stirred solution of diphenylmethyl (6R,7R)-7-amino-3-bromomethylceph-3-em-4-carboxylate, hydrochloride salt (1 g) in dichloromethane (20 ml) containing triethylamine (0.3 ml) at -20°. The temperature did not exceed -20° during the addition. The mixture was stirred at -20° for 10 minutes and then warmed to 22° over 45 minutes. The mixture was diluted with water (25 ml) and dichloromethane (20 ml) and shaken. The organic phase was separated and the aqueous layer was backwashed once with dichloromethane. The organic phase was washed with dilute sodium bicarbonate solution and the aqueous phase was backwashed. The combined organic solutions were washed with dilute brine, dried over sodium sulphate, and evaporated to a foam. This was triturated with diisopropyl ether, filtered, and dried in vacuo at 60° for 2 hours followed by room temperature overnight to give the title compound, (1.7 g), [α]D21 -28° (c 1.0 CHCl3); λinf. (ethanol) 239 nm, E1 cm1% 252; 260 nm, E1 cm1% 196; 265.5 nm, E1cm1% 193; 273 nm, E1 cm1% 181.

Workup

  1. customwas kept at -15°±5° for 40 35 minutes
  2. temperatureThe solution was cooled to -20°
  3. additionThe temperature did not exceed -20° during the addition
  4. stirringThe mixture was stirred at -20° for 10 minutes
  5. temperaturewarmed to 22° over 45 minutes
  6. stirringshaken
  7. customThe organic phase was separated
  8. washThe organic phase was washed with dilute sodium bicarbonate solution
  9. washThe combined organic solutions were washed with dilute brine
  10. dry with materialdried over sodium sulphate
  11. customevaporated to a foam
  12. customThis was triturated with diisopropyl ether
  13. filtrationfiltered
  14. customdried in vacuo at 60° for 2 hours
  15. waitfollowed by room temperature overnight

Sources & evidence

ORD record
ord-c3d0195b0708452abf53825879b414dd
Source dataset
uspto-grants-1985_03
Patent number
US04504477

Reaction notes

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