Triphenylphosphine → (1S,2S)-2-[4-((R)-4-Bromo-7-fluoro-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester

HRID 625685Notes

Reaction equation

[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:5])[CH3:2].[Br:16][C:17]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]2[C:18]=1[CH2:19][CH2:20][C@@H:21]2O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:21]2[C:22]3[C:18](=[C:17]([Br:16])[CH:25]=[CH:24][C:23]=3[F:26])[CH2:19][CH2:20]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]

Participants

Conditions

Temperature: -20 °C

Procedure

(1S,2S)-2-(4-Hydroxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (Intermediate 1, 6.51 g, 31.6 mmol), (S)-4-bromo-7-fluoro-indan-1-ol (Intermediate 2, 7.29 g, 31.6 mmol) and triphenyl phosphine (9.11 g, 34.7 mmol) are dissolved in dry tetrahydrofuran (50 mL) and cooled to −20° C. under nitrogen atmosphere. Di-tert-butyl azodicarboxylate (8.00 g, 34.7 mmol) is added and the mixture stirred for 30 minutes at −20° C., then allowed to warm to room temperature and stirred overnight. The solvent is removed under vacuum and the residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane) to give the title compound (Yield 8.23 g). LC (METHOD 2): tR=8.72 min; Mass spectrum (ES+): m/z=460 [M+H+MeCN]+, e.e. 96% by chiral HPLC (Column: Daicel Chiralpak AS-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 80:20, 1 mL/min, 25° C.) tR=4.96 (4.63) min.

Workup

temperatureto warm to room temperature
stirringstirred overnight
customThe solvent is removed under vacuum
customthe residue purified by flash chromatography (0-10% ethyl acetate in cyclohexane)

Sources & evidence

ORD record: ord-7edcef59cedf4847af33bf053344aa3f
Source dataset: uspto-grants-2016_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09308194B2

Reaction notes

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