4-{3-[2-Fluoro-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenylamino]-propyl}-tetrahydro-pyran-4-carboxylic acid methyl ester → 2-[2-Fluoro-4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-9-oxa-2-aza-spiro[5.5]undecan-1-one

HRID 391190Notes

Reaction equation

C[O:2][C:3]([C:5]1([CH2:11][CH2:12][CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][C@H:23]([N:26]4[CH2:30][CH2:29][CH2:28][C@@H:27]4[CH3:31])[CH2:22]3)=[CH:17][C:16]=2[F:32])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[Li]CCCC>C1COCC1>[F:32][C:16]1[CH:17]=[C:18]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])[CH2:22]2)[CH:19]=[CH:20][C:15]=1[N:14]1[CH2:13][CH2:12][CH2:11][C:5]2([CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)[C:3]1=[O:2]

Participants

Conditions

Temperature: 0 °C

Procedure

4-{3-[2-Fluoro-4-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamino]-propyl}-tetrahydro-pyran-4-carboxylic acid methyl ester (40 mg, 0.1 mmol, 1 eq) was dissolved in 2 mL of THF and cooled to 0° C., where a 2.5 M solution of n-BuLi in heptanes (0.11 mL, 0.17 mmol, 3 eq) was added drop-wise and the ice bath was removed. After 30 min the reaction mixture was quenched with water, transferred to a separatory funnel and extracted with diethyl ether (2×50 mL). The combined organics were dried over Na2SO4 and purified by column chromatography on silica gel (40 g column, 10% MeOH in CH2Cl2; 35 mL/min). This gave 38 mg (98%) of the title compound as an off-white gum.

Workup

customthe ice bath was removed
customAfter 30 min the reaction mixture was quenched with water
customtransferred to a separatory funnel
extractionextracted with diethyl ether (2×50 mL)
dry with materialThe combined organics were dried over Na2SO4
custompurified by column chromatography on silica gel (40 g column, 10% MeOH in CH2Cl2; 35 mL/min)

Sources & evidence

ORD record: ord-c982506dd75645f1b95169dd4f684d4e
Source dataset: uspto-grants-2013_02
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08383814B2

Reaction notes

Loading…