4-Methylmorpholine → N-{[4-((2R,3R)-1-(4-Fluorophenyl)-3-{[2-hydroxy-2-(4-pentylphenyl)ethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-3-cyclohexyl-D-alanine

HRID 254055Notes

Reaction equation

[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15](=[O:27])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=3)[C@H:9]2[C:28]2[CH:38]=[CH:37][C:31]([O:32][CH2:33][C:34](O)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:68][CH2:69][C:70]([NH:72][C@@H:73]([C:81]([OH:83])=[O:82])[CH2:74][CH:75]1[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]1)=[O:71].[BH4-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([OH:27])[C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:18][CH:17]=3)[C@H:9]2[C:28]2[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH:68][CH2:69][C:70]([NH:72][C@@H:73]([C:81]([OH:83])=[O:82])[CH2:74][CH:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)=[O:71])=[O:35])=[CH:37][CH:38]=2)=[CH:4][CH:3]=1

Participants

Conditions

Temperature: 30 °C

Procedure

To a solution of [4-((2R,3R)-1-(4-fluorophenyl)-4-oxo-3-{[2-oxo-2-(4-pentylphenyl)ethyl]thio}azetidin-2-yl)phenoxy]acetic acid (0.020 g, 0.037 mmol) and NMM (0.012 ml, 0.109 mmol) in DMF (2 ml) at 30° C. was added TBTU (0.019 g, 0.059 mmol). After 15 min glycyl-3-cyclohexyl-D-alanine (0.009 g, 0.039 mmol) was added and the mixture was stirred at 30° C. for 22 h. The reaction was quenched by the addition of water (1 ml) before the mixture was diluted with MeOH (2 ml). To this solution was added NaBH4 (0.020 g, 0.529 mmol) and the mixture was stirred for 10 min. This reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) and most of the methanol was removed under reduced pressure. The remaining solution was purified by preparative HPLC using a gradient of 20-60% MeCN in a 0.1M ammonium acetate buffer as eluent. Freeze-drying of the pure fractions gave the desired product as a white solid (0.009 g, 32% yield).

Workup

customThe reaction was quenched by the addition of water (1 ml) before the mixture
additionwas diluted with MeOH (2 ml)
stirringthe mixture was stirred for 10 min
customThis reaction was quenched by the addition of a 0.1M ammonium acetate buffer (3 ml) and most of the methanol
customwas removed under reduced pressure
customThe remaining solution was purified by preparative HPLC
customFreeze-drying of the pure fractions

Sources & evidence

ORD record: ord-3efdf76d363d49538af4ca105e8c3590
Source dataset: uspto-grants-2011_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07871998B2

Reaction notes

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