1,1,3,3-Tetramethylguanidine → (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester

HRID 1058453Notes

Reaction equation

HRID 1058453 reaction equation
CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:42])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:34].[N:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:46]=[C:45]([CH:53]=O)[CH:44]=1>ClCCl>[CH3:9][O:10][C:11](=[O:42])/[C:12](/[NH:13][C:14](=[O:35])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:33]=[C:32]3[C:28]([CH:29]=[CH:30][NH:31]3)=[CH:27][CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:34])=[CH:53]/[C:45]1[CH:44]=[N:43][C:52]2[C:47]([CH:46]=1)=[CH:48][CH:49]=[CH:50][CH:51]=2

Participants

5

Reactant 3

HCID 664601,1,3,3-TetramethylguanidineHCID 836413-QuinolinecarboxaldehydeHCID 23560740Rac.-n-[2-chloro-4-[[[(1h-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester

Product 1

HCID 70028702(Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl esterYield 71.1%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
5 °C

Procedure

1,1,3,3-Tetramethylguanidine (102 mg, 0.9 mmol) was added to a solution of rac.-N-[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 136; 300 mg, 0.6 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then quinoline-3-carboxaldehyde (186 mg, 1.2 mmol) was added. The solution was stirred overnight at room temperature, then it was washed with cold 1N hydrochloric acid solution and brine, dried, filtered and evaporated to give a mixture (230 mg) of (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid methyl ester and unreacted quinoline-3-carboxaldehyde. This mixture was dissolved in tetrahydrofuran/methanol (3:1; 4 mL) and the solution was added to a solution of lithium hydroxide monohydrate (28 mg, 0.7 mmol) in water (1 mL). The solution was allowed to stir at room temperature for 5 days and then concentrated to remove tetrahydrofuran and methanol. The remaining solution was diluted with water and acidified with 1N hydrochloric acid solution. The resulting mixture was extracted with ethyl acetate and the organic extracts were washed with brine, dried (MgSO4), filtered, concentrated and purified by reverse phase HPLC (5-95% acetonitrile/water with 0.1% trifluoroacetic acid). The appropriate fractions were combined and evaporated and the purified acid was lyophilized to give (Z)-2-[[2-chloro-4-[[[(1H-indol-6-yl)methyl]amino]carbonyl]benzoyl]amino]-3-(quinolin-3-yl)propenoic acid (37 mg, 12% yield).

Workup

  1. stirringThe solution was stirred overnight at room temperature
  2. washit was washed with cold 1N hydrochloric acid solution and brine
  3. customdried
  4. filtrationfiltered
  5. customevaporated

Sources & evidence

ORD record
ord-c838a697ac244668864f700d01d8f974
Source dataset
uspto-grants-2003_02
Patent number
US06515124B2

Reaction notes

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