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Ammonia → 2-[1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinolin-4-ylamino]-thiazole-4-carboxylic acid

HRID 14694
Notes
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Reaction equation

HRID 14694 reaction equation
[C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[C:15]2[C:10](=[C:11]([O:18][CH3:19])[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9]([CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[N:8][CH:7]=1.C[CH2:33][N:34](C(C)C)C(C)C.N.BrC[C:44](=O)[C:45]([OH:47])=[O:46]>C1COCC1>[O:31]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[N:21]1[CH2:20][C:9]1[C:10]2[C:15](=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[C:6]([NH:5][C:33]2[S:2][CH:1]=[C:44]([C:45]([OH:47])=[O:46])[N:34]=2)=[CH:7][N:8]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 5

HCID 222AmmoniaHCID 10040ThiophosgeneHCID 70684Bromopyruvic AcidHCID 81531DiisopropylethylamineHCID 593410902-(4-Amino-6,8-dimethoxy-isoquinolin-1-ylmethyl)-isoindole-1,3-dione

Product 1

HCID 59341093
2-[1-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-6,8-dimethoxy-isoquinolin-4-ylamino]-thiazole-4-carboxylic acid
Yield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

Thiophosgene (146 μL, 1.92 mmol) was added to a solution of Example 45C (580 mg, 1.6 mmol) and DIEA (670 μL) in THF (10 mL). After stirring for 1 h, the reaction was poured over aqueous ammonia and extracted with EtOAc. Organics were dried (MgSO4) and concentrated. The resulting crude thiourea was dissolved in THF (5 mL). Bromopyruvic acid (320 mg, 1.92 mmol) was added, and the reaction stirred for 2 h. Purification by silica gel chromatography (10% MeOH/CHCl3) gave 590 mg (75%) of the title compound as a tan solid. H1-NMR (MeOD-d4): δ 9.95 (br s, 1H), 8.81 (br s, 1H), 7.87-7.96 (m, 4H), 7.60 (br s, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 5.41 (s, 2H), 4.09 (s, 3H), 3.94 (s, 3H). MS (ES) (M+H) calc'd for C24H18N4O6S, 491; found 491.

Workup

  1. extractionextracted with EtOAc
  2. dry with materialOrganics were dried (MgSO4)
  3. concentrationconcentrated
  4. dissolutionThe resulting crude thiourea was dissolved in THF (5 mL)
  5. stirringthe reaction stirred for 2 h
  6. customPurification by silica gel chromatography (10% MeOH/CHCl3)

Sources & evidence

ORD record
ord-aac9a72a39a84e959ebd805c61d91840
Source dataset
uspto-grants-2010_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US07732446B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes