Hydrochloric Acid → (S)-3-[(S)-Cyclopropyl(naphthalen-1-yloxy)methyl]pyrrolidine

HRID 1671390Notes

Reaction equation

C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:15]2[CH2:17][CH2:16]2)[OH:14])[CH2:9]1)=O)(C)(C)C.C1C=NC2C3N=CC=CC=3C=CC=2C=1.I[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.CCO>[Cu]I>[CH:15]1([C@H:13]([O:14][C:41]2[C:42]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:38]=[CH:39][CH:40]=2)[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH2:17]1

Participants

Conditions

Temperature: 105 °C

Procedure

(S)-3-((S)-Cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (35 mg, 140 μmmol), copper(I) iodide (8.3 mg, 43.5 μmmol), o-phenanthroline (15.7 mg, 87 μmmol), and 1-iodonaphthalene (73.7 mg, 290 μmmol) were combined. Toluene (463 μL, 4.4 mmol) was added, followed by the addition of cesium carbonate (94.5 mg, 290 μmmol). Air was bubbled through the mixture, the vessel was sealed, and the mixture was heated at 105° C. for 72 hours. The mixture was filtered, rinsed with DCM, and concentrated. The crude material was treated with 1.25M HCl in EtOH (1.2 mL, 1.5 mmol) and stirred overnight. The mixture was concentrated, redissolved in 1:1 AcOH:H2O and purified by preparative HPLC to yield the title compound as a mono-TFA salt (3.5 mg, 99% purity). MS m/z: [M+H]+ calcd for C18H21NO, 268.16; found 268.2.

Workup

customAir was bubbled through the mixture
customthe vessel was sealed
filtrationThe mixture was filtered
washrinsed with DCM
concentrationconcentrated
concentrationThe mixture was concentrated
dissolutionredissolved in 1:1 AcOH
customH2O and purified by preparative HPLC

Sources & evidence

ORD record: ord-84bfdd5631894dc78406bcc44af956a5
Source dataset: uspto-grants-2011_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07994209B2

Reaction notes

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