4-Methylmorpholine → benzhydryl (6R,7R)-3-(chloromethyl)-7-[[(2Z)-2-[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]oxyimino-2-[2-[(2-methylpropan-2-yl)oxycarbonylamino]-1,3-thiazol-4-yl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate

HRID 525865Notes

Reaction equation

[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13](O)=[O:14])([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].P(Cl)(Cl)(=O)OC1C=CC=CC=1.CN1CCOCC1>ClCCl>[C:1]([O:5][C:6](=[O:29])[C:7]([O:10]/[N:11]=[C:12](/[C:16]1[N:17]=[C:18]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[S:19][CH:20]=1)\[C:13]([NH:31][C@@H:32]1[C:39](=[O:40])[N:38]2[C@@H:33]1[S:34][CH2:35][C:36]([CH2:57][Cl:58])=[C:37]2[C:41]([O:43][CH:44]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:42])=[O:14])([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]

Participants

Conditions

Temperature: -40 °C

Procedure

To a solution of (Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (30.5 g, 71.0 mmol) and (6R,7R)-benzhydryl 7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, hydrochloride (32.1 g, 71.0 mmol) in dichloromethane (500 mL), stirred under nitrogen at −30° C., was added neat phenyl phosphorodichloridate (12.93 mL, 85 mmol). The reaction mixture was cooled to −40° C. and N-methylmorpholine (23.42 mL, 213 mmol) was added dropwise over 30 min, and stirred for an additional 2 hours at −40° C. The reaction was then quenched by addition of 150 mL of a 10% aq. solution of citric acid, and the phases were separated. The organic phase was concentrated and the residue was then dissolved in 500 mL of ethyl acetate. The organic solution was washed with 100 mL of a 5% aq. sodium bicarbonate, 100 mL of brine, dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified on a 330 g silica gel column eluting with 0-80% ethyl acetate in hexanes to afford (6R,7R)-benzhydryl 7-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate (42 g, 50.8 mmol, 71.6% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (s, 9 H) 1.55 (s, 9 H) 1.63 (s, 3 H) 1.66 (s, 3 H) 3.52 (d, J=18.19 Hz, 1 H) 3.66 (d, J=18.19 Hz, 1 H) 4.43 (d, J=4.29 Hz, 2 H) 5.12 (d, J=5.05 Hz, 1 H) 6.08 (dd. J=8.84, 5.05 Hz, 1 H) 6.99 (s, 1 H) 7.30-7.49 (m, 12 H) 8.25 (d, J=8.84 Hz, 1 H). LCMS: (M+H)+: 826.5.

Workup

customThe reaction was then quenched by addition of 150 mL of a 10% aq. solution of citric acid
customthe phases were separated
concentrationThe organic phase was concentrated
dissolutionthe residue was then dissolved in 500 mL of ethyl acetate
washThe organic solution was washed with 100 mL of a 5% aq. sodium bicarbonate, 100 mL of brine
dry with materialdried over sodium sulfate
concentrationconcentrated under reduced pressure
customthe residue was purified on a 330 g silica gel column
washeluting with 0-80% ethyl acetate in hexanes

Sources & evidence

ORD record: ord-1ec21961345e4a7da4ea7be9357413da
Source dataset: uspto-grants-2016_05
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09340556B2

Reaction notes

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