Hydrochloric Acid → methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid

HRID 1091557Notes

Reaction equation

HRID 1091557 reaction equation
C1([C:7]2[C:15]3[C:10](=[CH:11][C:12](C(NS(N(C)C)(=O)=O)=O)=[CH:13][CH:14]=3)[N:9]3[CH:25](O)[C:26]4[C:31]([C:8]=23)=[CH:30][CH:29]=[C:28](OC)[CH:27]=4)CCCCC1.COP([C:41](=[CH2:46])[C:42](OC)=O)(OC)=O.[C:47](=[O:50])([O-])[O-:48].[Cs+].[Cs+].Cl>CN(C=O)C.O>[CH3:42][C:41]1[C:46]2[C:8]3=[CH:7][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]3[CH2:25][C:26]([C:47]([OH:48])=[O:50])=[CH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 10796Cesium carbonate2×HCID 3016938Methyl 2-(dimethoxyphosphinyl)acrylate2×HCID 5968212111-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide

Product 1

HCID 66588728methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 11-cyclohexyl-N-[(dimethylamino)sulfonyl]-6-hydroxy-8-methoxy-6H-isoindolo[2,1-a]indole-3-carboxamide (cyclic hemiaminal) (63.0 g, 130 mmol), methyl 2-(dimethoxyphosphoryl)acrylate (60 g, 261 mmol), cesium carbonate (106 g, 326 mmol) in DMF (400 mL) was heated at 60° C. (bath temp) for 4.5 h. Additional methyl 2-(dimethoxyphosphoryl)acrylate (15 g, 65 mmol) and cesium carbonate (21.2 g, 65 mmol) were added and the reaction was heated at 60° C. overnight then and cooled to rt. The stirring reaction mixture was diluted with H2O (1 L), slowly neutralized with 1N aqueous HCl (800 mL), stirred 3 h, and then the precipitates were collected by filtration. The solids were triturated with Et2O (800 mL) and dried to yield methyl 7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid, 13-cyclohexyl-10-[[[(dimethylamino)sulfonyl]amino]carbonyl]-3-methoxy-, methyl ester (70.2 g, 127 mmol, 98%) as a yellow solid which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 8.67 (s, 1H), 8.09 (s, 1H), 7.86 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.8 Hz, 1H), 7.08 (dd, J=2.6, 8.8 Hz, 1H), 6.98 (d, J=2.6 Hz, 1H), 5.75-5.51 (m, 1H), 4.29-4.01 (m, 1H), 3.89 (s, 3H), 3.82 (s, 3H), 3.05 (s, 6H), 2.87-2.73 (m, 1H), 2.11-1.12 (m, 10H). LCMS: m/e 550 (M−H)−, ret time 3.21 min, column A, 4 minute gradient.

Workup

  1. temperaturecooled to rt
  2. customThe stirring reaction mixture
  3. filtrationthe precipitates were collected by filtration
  4. customThe solids were triturated with Et2O (800 mL)
  5. customdried

Sources & evidence

ORD record
ord-969d2f1ada894b90b77d8a19fa4d2b1c
Source dataset
uspto-grants-2012_03
Patent number
US08129367B2

Reaction notes

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