HCID 11357453, compound → HCID 88924216, compound

HRID 877716Notes

Reaction equation

[CH3:1][Si](C[Li])(C)C.[CH2:7]([NH:14][C:15]([C:17]1([C:21]([O:23]CC)=O)[CH2:20][CH2:19][CH2:18]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[C:21]([C:17]1([C:15]([NH:14][CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[O:16])[CH2:18][CH2:19][CH2:20]1)(=[O:23])[CH3:1]

Participants

Conditions

Temperature: 0 °C

Procedure

((Trimethylsilyl)methyl)lithium (1.0 M in pentane) (908 mL, 908 mmol) was added dropwise over 1 hr 20 min to a 0° C. solution of ethyl 1-(benzylcarbamoyl)cyclobutanecarboxylate (52.7 g, 202 mmol) in THF (703 mL) under N2. Stirring @ 0° C. was continued for 2 hrs during which time the solution became red. LC/MS after 1 hr looked the same as after 30 minutes, a complete reaction (m/e 232.1, M+H for desired product). While still @ 0° C., the reaction was quenched by the addition of anhydrous methanol (246 mL, over 45 minutes). There was solid formation which after ca. 30 minutes cleared up to form a turbid yellow solution. Note: methanol addition was dropwise; when further addition no longer caused extensive precipitation, the addition was accelerated to a slow stream. After 5 minutes, the ice bath was removed and stirring was continued for 30 minutes. Brine was added (800 mL), the layers were separated, the brine layer was extracted twice with EtOAc (300 mL each), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to yield 50.19 g of a yellow solid. The crude product was stirred and sonicated for 30 minutes in 400 mL of hexane. The product was collected by filtration and rinsed with hexane to yield ca. 40 g of a yellow solid with some sticky lumps. The solid was sonicated again for several minutes in 400 mL of hexane, collected by filtration, rinsed with hexane, and dried under vacuum to yield 35.82 g of an off-white solid. The combined hexane filtrate was concentrated under vacuum to yield 8.67 g of a yellow oil, which by LC/MS contained desired product. Flash chromatography of the filtrate on silica gel (Teledyne-Isco RediSep Rf 80 g column), eluting with 250 mL of hexane, 400 mL of 80:20, and 400 mL of 40:60 hexane:EtOAc yielded 5.15 g of an off-white solid. The chromatographed solid was similar in purity to the triturated solid, and the two solids were combined to afford 40.97 g of the title compound as an off-white solid. LC/MS: m/e 232.1 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ 7.48-7.17 (m, 5H), 5.78 (br. s., 1H), 4.44 (d, J=5.9 Hz, 2H), 2.62-2.46 (m, 4H), 2.16 (s, 3H), 2.01-1.88 (m, 1H), 1.88-1.75 (m, 1H).

Workup

waitLC/MS after 1 hr looked
waitthe same as after 30 minutes

Sources & evidence

ORD record: ord-9726827c1aa64408b79a7b70cc55b9f9
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08987268B2

Reaction notes

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