5-aminoisoquinolin-1(2H)-one → (Rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2h)-one

HRID 420638Notes

Reaction equation

HRID 420638 reaction equation
ClC1C=CC(C(C)(C)CC(O)(C(F)(F)F)C=O)=C(OC)C=1F.C(O[C:26](=O)[C:27]([C:43]([F:46])([F:45])[F:44])([OH:42])[CH2:28][C:29]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([F:39])[C:33]=1[O:40][CH3:41])([CH3:31])[CH3:30])C.[NH2:48][C:49]1[CH:58]=[CH:57][CH:56]=[C:55]2[C:50]=1[CH:51]=[CH:52][NH:53][C:54]2=[O:59]>CC1C=CC=CC=1C.C(OCC)(=O)C.[Cl-].[Na+].O.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]([CH3:31])([CH3:30])[CH2:28][C:27]([OH:42])([C:43]([F:46])([F:44])[F:45])[CH:26]=[N:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][NH:53][C:54]3=[O:59])=[C:33]([O:40][CH3:41])[C:34]=1[F:39]

Participants

8

Reactant 3

HCID 20725-aminoisoquinolin-1(2H)-oneHCID 17989096(rac.) 4-(4-Chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl esterHCID 17989212(Rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal

Product 1

HCID 17989293(Rac.) 5-{[4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentylidene]amino}isoquinolin-1(2h)-oneYield 30.4%

Reagents, catalysts & solvents 4

HCID 11026Titanium isopropoxideCatalystHCID 7237O-XyleneSolventHCID 8857Ethyl AcetateSolventHCID 57417360Sodium chloride; waterSolvent

Procedure

560 mg of the mixture that consists of (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and (rac.) 4-(4-chloro-3-fluoro-2-methoxyphenyl)-4-methyl-2-(trifluoromethyl)-2-hydroxy-pentanoic acid ethyl ester (since the aldehyde constitutes two thirds in the mixture, the 560.2 mg mixture corresponds to 336.1 mg (0.981 mmol) of aldehyde) is heated for two hours to 120° C. with 157.1 mg (0.981 mmol) of 5-amino-isoquinolin-1(2H)-one and 0.557 mg (1.962 mmol) of titanium tetraisopropylate in 6 ml of o-xylene. After cooling, the batch is diluted with ethyl acetate and mixed with brine. The organic phase is separated and worked up as usual. After chromatography on a Flashmaster, 144.7 mg (30.4%) of the desired compound is obtained (relative to the aldehyde portion in the mixture).

Workup

  1. temperatureAfter cooling
  2. customThe organic phase is separated

Sources & evidence

ORD record
ord-5d9b6b1bbb614c8fb31a56d4b1fe109d
Source dataset
uspto-grants-2012_01
Patent number
US08097627B2

Reaction notes

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