Methylamine → HCID 178485523, compound

HRID 1014518Notes

Reaction equation

HRID 1014518 reaction equation
Cl.Cl[C:3]1[N:16]2[C:7](=[N:8][C:9]3[C:14]([C:15]2=[O:17])=[C:13]([F:18])[CH:12]=[CH:11][CH:10]=3)[C:6]2[CH:19]=[CH:20][N:21](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]=2[N:4]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][C:43]=1[NH2:44])[N:40]([C:45](=[O:52])[C@@H:46]1[CH2:50][CH2:49][CH2:48][N:47]1[CH3:51])[CH2:39][CH2:38][CH2:37]2.[CH3:53][NH2:54].[OH-].[K+]>C1COCC1.C(OCC)(=O)C>[F:18][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:7]2[N:16]=[C:3]([NH:44][C:43]3[CH:42]=[C:41]4[C:36]([CH2:37][CH2:38][CH2:39][N:40]4[C:45](=[O:52])[C@@H:46]4[CH2:50][CH2:49][CH2:48][N:47]4[CH3:51])=[CH:35][C:34]=3[O:33][CH3:32])[NH:4][C:5]3=[N:21][CH:20]=[CH:19][C:6]=23)[C:14]=1[C:15]([NH:54][CH3:53])=[O:17]

Participants

7

Reactant 4

HCID 6329MethylamineHCID 14797Potassium HydroxideHCID 673162535-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2',3':4,5]pyrimido[6,1-b]quinazolin-7(3H)-one HCl saltHCID 67316534HCID 67316534, compound

Product 1

HCID 178485523HCID 178485523, compoundYield 28%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
65 °C

Procedure

A suspension of 5-chloro-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one hydrogen chloride (300 mg, 0.63 mmol) and 6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinamine 217 mg, 0.75 mmol) in THF (50 ml) was heated at 65° C. for 4 hrs. The reaction was diluted with ethyl acetate (200 ml) and washed with saturated NaHCO3 (300 ml). Organic layer was removed, concentrated by rotary evaporation, solids triturated from ethyl acetate/hexanes, and dried under house vacuum prior to next step. The solids were then added to THF (50 ml) followed by a solution of methylamine (2M in THF, 7.40 ml, 3.7 mmol) and the resulting mixture was stirred at rt overnight. Next, the crude reaction was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min). ESIMS (M+H)+=727. The isolated pure amide was redissolved in 1,4-dioxane (10 ml), potassium hydroxide (2.497 ml, 12.49 mmol) added and the reaction was heated in the microwave at 120° C. for 20 min. The resulting solution was adsorbed onto silica gel and purified by silica gel chromatography (DCM to 10% MeOH/DCM) to afford 2-fluoro-N-methyl-6-[(2-{[6-(methyloxy)-1-(1-methyl-L-prolyl)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (0.1 g, 28% over three steps). ESIMS (M+H)+=573; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.72-1.98 (m, 6 H) 2.06 (s, 3 H) 2.11-2.20 (m, 1 H) 2.58-2.73 (m, 2 H) 2.78 (d, J=4.41 Hz, 3 H) 2.85-2.97 (m, 1 H) 3.41-3.52 (m, 2 H) 3.88 (s, 3 H).

Workup

  1. washwashed with saturated NaHCO3 (300 ml)
  2. customOrganic layer was removed
  3. concentrationconcentrated by rotary evaporation, solids
  4. customtriturated from ethyl acetate/hexanes
  5. customdried under house vacuum
  6. additionThe solids were then added to THF (50 ml)
  7. customNext, the crude reaction
  8. custompurified by silica gel chromatography (DCM to 10% MeOH/DCM over 30 min)
  9. dissolutionThe isolated pure amide was redissolved in 1,4-dioxane (10 ml)
  10. temperaturethe reaction was heated in the microwave at 120° C. for 20 min
  11. custompurified by silica gel chromatography (DCM to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-d4c66bf8cf5f40209b60e82e71a23b29
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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