Tetrahydrofuran → US10130617, Example 9

HRID 1749036Notes

Reaction equation

HRID 1749036 reaction equation
[OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([O:34]C)=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3.C1COCC1>CO>[F:3][C:4]1[CH:5]=[C:6](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])[CH:7]=[CH:8][C:9]=1[CH:10]1[C:15]2[NH:16][C:17]3[C:22]([C:14]=2[CH2:13][C:12]([CH3:24])([CH3:23])[N:11]1[CH2:25][C@H:26]([CH3:29])[CH2:27][F:28])=[CH:21][CH:20]=[CH:19][CH:18]=3

Participants

5

Reactant 3

HCID 8028TetrahydrofuranHCID 14798Sodium HydroxideHCID 117719328(E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate

Product 1

HCID 86342656US10130617, Example 9

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

2M Sodium hydroxide (3.31 ml, 6.63 mmol) was added to a solution of (E)-methyl 3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylate (600 mg, 1.33 mmol) (mixture of diastereoisomers) in methanol (5 ml), and THF (20 ml) and the mixture stirred at ambient temperature for 4 hours. The mixture was concentrated to a volume such that all of the organic solvent had been removed, diluted with water (50 ml), acidified with dilute HCl to pH 6 and extracted with ethyl acetate (2×50 ml). The extracts were combined and evaporated under reduced pressure. The residue was purified by preparative HPLC (Chiralpak IA column, 20 ml silica, 20 mm diameter, 250 mm length), Heptane:IPA 90:10, 0.2% acetic acid at 80 ml/min. Fractions containing the desired compounds were combined and analysed to yield (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 1, first eluted, 130 mg, 22.36%) and (E)-3-(3-fluoro-4-(2-((S)-3-fluoro-2-methylpropyl)-3,3-dimethyl-2,3,4,9-tetrahyrdo-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (isomer 2, second eluted, 30.0 mg, 5.16%). 1H NMR (500 MHz, DMSO, 30° C.) δ 0.49 (3H, d), 1.03 (3H, s), 1.14-1.21 (1H, m), 1.28 (3H, s), 2.17 (1H, dd), 2.59-2.71 (1H, m), 2.8-2.99 (2H, m), 4.09-4.34 (2H, m), 4.99 (1H, s), 6.59 (1H d), 6.86-7.07 (2H, m), 7.1-7.19 (1H, m), 7.18-7.29 (1H, m), 7.36-7.49 (2H, m), 7.49-7.66 (2H, n), 10.31 (1H, s), CO2H not observed. m/z: ES+ [M+H]+ 439. *Stereochemistry inferred to be (R) at the undefined centre by analogy with other examples.

Workup

  1. concentrationThe mixture was concentrated to a volume such that all of the organic solvent
  2. customhad been removed
  3. additiondiluted with water (50 ml)
  4. extractionextracted with ethyl acetate (2×50 ml)
  5. customevaporated under reduced pressure
  6. customThe residue was purified by preparative HPLC (Chiralpak IA column, 20 ml silica, 20 mm diameter, 250 mm length), Heptane:IPA 90:10, 0.2% acetic acid at 80 ml/min
  7. additionFractions containing the desired compounds

Sources & evidence

ORD record
ord-7c9a9a6b7c2a4f8cbcff13dd1ab92c9b
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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