Diisopropylamine → HCID 76121399, compound

HRID 1873190Notes

Reaction equation

C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:29]=[C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)[CH:27]=[C:26]([Br:48])[C:15]=1[O:16][C@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].BrC[C:51]1[C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=[CH:53][CH:52]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[C:21]([O:20][C:18](=[O:19])[CH:17]([O:16][C:15]1[C:26]([Br:48])=[CH:27][C:28]([C:30]2[C:39]3[C:40]4[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=4[S:42][C:38]=3[C:37]([Br:47])=[C:36]3[C:31]=2[CH:32]=[CH:33][CH:34]=[CH:35]3)=[CH:29][C:14]=1[Br:13])[CH2:25][C:53]1[CH:52]=[CH:51][C:60]2[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:54]=1)([CH3:24])([CH3:23])[CH3:22]

Participants

Conditions

Temperature: -74 °C

Procedure

Diisopropylamine (distilled over CaH2, 0.233 mL, 1.78 mmol) was added to anhydrous tetrahydrofuran (0.91 mL) and cooled to -74° C. under a dry argon atmosphere. n-Butyllithium (2.5 M in hexane, 0.71 mL, 1.78 mmole) was added dropwise and the mixture was warmed to 0° C. for ca. 20 minutes then recooled to -75° C. Hexamethylphosphoramide (2 mL) was added followed 10 minutes later by the slow (0.5 hour) dropwise addition of a solution of (R)-2-[2,6-dibromo-4-(6-bromo-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-propionic acid, tert-butyl ester (1.004 g, 1.48 mmole) in anhydrous tetrahydrofuran (3 mL). After stirring one hour at -75° C., 2 bromomethylnaphthalene (0.393 g, 1.78 mmol) was added dropwise. After stirring 0.5 hour at -80° C. the reaction mixture was allowed warm to room temperature overnight. The reaction mixture was quenched with dilute aqueous ammonium chloride and was partritioned between water (100 mL) and a 1:1 methylene chloride: ether solution (200 mL). After one more extraction with methylene chloride the organic layers were combined, washed with water (100 mL) and purification by flash chromatographed (eluent 7:3 pet ether:ethyl acetate) and HPLC (2 times) (First column:Waters Silica Prep Pak; isocratic, 98:2 hexane:ethyl acetate; Flow rate =225 mL/min; Second column: Waters Silica Prep Pak; gradient, 75:25 to 60:40 petroleum ether:methylene chloride) to provide the title compound as a white solid (0.280 g, 23%); NMR (CDCl3); δ8.35 (d, J=8 Hz, 1 H), 7.88-7.80 (m, 5 H), 7.66 (ddd, J=6, 5, 1 Hz, 1 H), 7.61 (d, J=2 Hz, 1 H), 7.60 (d, J=2 Hz 1 H) 7.58-7.56 (m, 2 H), 7.51-7.41 (m, 4 H), 7.18 (ddd, J=7, 1, 1 Hz, 1 H), 6.83 (dd, J=7, 1 Hz, 1 H) 5.44 (t, J =8 Hz, 1 H), 1.34 (s, 9 H); MS (FAB+): [M+], 3 bromine pattern, 814 (30%) 816 (95%) 818 (100%) 820 (42%); Anal. Calc. for C39H29Br3O3S: C, 57.30; H, 3.58, N, 0.00. Found: C, 57.55; H, 3.75, N, 0.02.

Workup

temperaturethe mixture was warmed to 0° C. for ca. 20 minutes
customthen recooled to -75° C
stirringAfter stirring 0.5 hour at -80° C. the reaction mixture
temperaturewas allowed warm to room temperature overnight
customThe reaction mixture was quenched with dilute aqueous ammonium chloride
extractionAfter one more extraction with methylene chloride the organic layers
washwashed with water (100 mL) and purification by flash
customchromatographed (eluent 7:3 pet ether:ethyl acetate) and HPLC (2 times) (First column:Waters Silica Prep Pak; isocratic, 98:2 hexane:ethyl acetate; Flow rate =225 mL/min; Second column: Waters Silica Prep Pak; gradient, 75:25 to 60:40 petroleum ether:methylene chloride)

Sources & evidence

ORD record: ord-ff8cc290f4304effbd39a9f01c942c2b
Source dataset: uspto-grants-2000_08
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US06110962

Reaction notes

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