Maleic Acid → (1R,3R)-1-{4-[(E)-2-carboxyethenyl]-2,6-difluorophenyl}-2-(2-fluoro-2-methylpropyl)-3-methy-2,3,4,9-tetrahydro-1H-beta-carbolin-2-ium maleate

HRID 1749040Notes

Reaction equation

HRID 1749040 reaction equation
[C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5].[F:9][C:10]1[CH:11]=[C:12](/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39])[CH:13]=[C:14]([F:35])[C:15]=1[C@@H:16]1[C:21]2[NH:22][C:23]3[C:28]([C:20]=2[CH2:19][C@@H:18]([CH3:29])[N:17]1[CH2:30][C:31]([F:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=[CH:25][CH:24]=3>CC(C)=O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[C:38](/[CH:37]=[CH:36]/[C:12]1[CH:13]=[C:14]([F:35])[C:15]([C@@H:16]2[C:21]3[NH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH2:19][C@@H:18]([CH3:29])[NH+:17]2[CH2:30][C:31]([F:34])([CH3:32])[CH3:33])=[C:10]([F:9])[CH:11]=1)([OH:40])=[O:39].[C:1](/[CH:2]=[CH:3]/[C:4]1[CH:11]=[C:10]([F:9])[C:15]([C@@H:16]2[C:21]3[NH:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH2:19][C@@H:18]([CH3:29])[NH+:17]2[CH2:30][C:31]([CH3:33])([F:34])[CH3:32])=[C:14]([F:35])[CH:13]=1)([OH:8])=[O:7]

Participants

4

Reactant 2

HCID 444266Maleic Acid2×HCID 86287635Azd-9496

Product 1

HCID 117719350(1R,3R)-1-{4-[(E)-2-carboxyethenyl]-2,6-difluorophenyl}-2-(2-fluoro-2-methylpropyl)-3-methy-2,3,4,9-tetrahydro-1H-beta-carbolin-2-ium maleateYield 110.3%

Reagents, catalysts & solvents 1

HCID 180AcetoneSolvent2×

Procedure

A solution of maleic acid (1.31 g, 11.29 mmol) in acetone (15 ml) was stirred under nitrogen. A solution of (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (Example 1) (5.00 g, 11.3 mmol) in acetone (25 ml) was added to the maleic acid solution to give a yellow solution. The reaction vessel was covered in foil to protect from light and purged with a stream of nitrogen gas overnight until the solvent evaporated. A solid was obtained which was dried in vacuo for 2 hours to give the title compound as a cream solid (6.23 g, 98%). 1H NMR (500 MHz, DMSO, 27° C.) 0.95-1.34 (9H, m), 2.24-2.45 (1H, m), 2.54-2.66 (1H, m), 2.8-2.99 (2H, m), 3.52 (1H, s), 5.22 (1H, s), 6.26 (2H, s), 6.67 (1H, d), 6.89-7.07 (2H, m), 7.19 (1H, d), 7.39-7.51 (3H, n), 7.55 (1H, d), 10.59 (1H, s). An XRPD trace of this maleate salt is shown in FIG. 8 and a DSC trace shown in FIG. 9.

Workup

  1. customto give a yellow solution
  2. custompurged with a stream of nitrogen gas overnight until the solvent
  3. customevaporated
  4. customA solid was obtained which
  5. customwas dried in vacuo for 2 hours

Sources & evidence

ORD record
ord-da1188deae2d4e30af502ca410238238
Source dataset
uspto-grants-2015_10
Patent number
US09155727B2

Reaction notes

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