Hydrochloric Acid → HCID 10876117, compound

HRID 47870Notes

Reaction equation

HRID 47870 reaction equation
[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[N:7]([CH2:19][C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:28][N:29]([C:33]1[CH:45]=[CH:44][C:36]([C:37]([O:39]C(C)(C)C)=O)=[CH:35][CH:34]=1)[CH2:30][C:31]#[CH:32].[NH2:46][CH2:47][C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[OH-].[Na+]>ClCCl.FC(F)(F)C(O)=O.CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[N:7]([CH2:19][C:20](=[O:26])[N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])[C:8]([CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:9]2)=[CH:4][C:3]=1[CH2:28][N:29]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([NH:46][CH2:47][C:48]2[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=2)=[O:39])=[CH:44][CH:45]=1)[CH2:30][C:31]#[CH:32]

Participants

10

Reactant 5

HCID 313Hydrochloric AcidHCID 14798Sodium HydroxideHCID 310183-PyridinemethanamineHCID 2724699PyBOPHCID 11082746HCID 11082746, compound

Product 1

HCID 10876117HCID 10876117, compound

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 6422Trifluoroacetic acidSolvent

Procedure

A solution of tert-butyl 4-[N-[7-chloro-3-diethylcarbamoylmethyl-4-oxo-2-(piperidin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.065 g, 0.10 mmol) (Preparation Example 29) in dichloromethane (1 ml) and trifluoroacetic acid (1.3 ml) was stirred at room temperature for 1 hour with protection from the light. The solvent was then removed in vacuo and the remainder was treated with toluene/dichloromethane, concentrated in vacuo and the residue was dried in vacuo over P2O5. This material was dissolved in anhydrous DMF (1.3 ml) under argon and the solution was placed in.an ice-bath. A solution of 3-(aminomethyl)pyridine (0.016 g, 0.15 mmol) in DMF (0.3 ml) was then added followed by PyBOP® (0.055 g, 0.10 mmol) and diusopropylethylamine (0.077 g, 0.60 mmol). Stirring was continued at 0° C. for 3 min; then the ice-bath was removed and the reaction mixture was stirred for an additional 3 hours before being partitioned between ethyl acetate (100 ml) and saturated aqueous bicarbonate (80 ml). The aqueous layer was extracted with more ethyl acetate (2×50 ml). The combined organic extracts were washed With brine (80 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography using a gradient of methanol in dichloromethane (2 to 5%). The product was reprecipitated from dichloromethane/hexanes to give a white solid. This was suspended in water (5 ml) and the pH was first adjusted to ˜1 with 1N HCl, then to ˜11 with 1N NaOH; a white precipitate was obtained. This was collected by filtration , washed with water and dried in vacuo over P2O5 (0.040 g, 60%), mp>105° C.; 1H-NMR (DMSO-d6), 1.00, 1.18 (2×t, 6H, 2×CH2CH3), 1.40 (br s, 6H, piperidine CH2CH2CH2), 2.32 (br s, 4H, piperidine CH2NCH2), 3.24, 3.40 (2×q obscured by water peak, 4H, 2×CH2CH3), 4.37 (s, 2H, CH2C≡C), 4.43 (d, J=5.6 Hz, 2H, CONHCH2), 4.77 (s, 2H, 6-CH2), 5.10 (s, 2H, N3—CH2), 6.77 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.31 (dd, J=4.8, 7.8 Hz, 1H, pyr 5-H), 7.67 (d, J=7.8 Hz, 1H, pyr 4-H), 7.73 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.83, 7.86 (2×s, 2H, 5-H, 8-H), 8.42 (d, J=3.2 Hz, 1H pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.73 (t, J=5.6 Hz, 1H, CONH).; MS (ESI, m/z) 668, 670 [(M+H)+, 100%, 37% respectively; Cl isotopic pattern].

Workup

  1. customThe solvent was then removed in vacuo
  2. additionthe remainder was treated with toluene/dichloromethane
  3. concentrationconcentrated in vacuo
  4. dry with materialthe residue was dried in vacuo over P2O5
  5. dissolutionThis material was dissolved in anhydrous DMF (1.3 ml) under argon
  6. customthen the ice-bath was removed
  7. stirringthe reaction mixture was stirred for an additional 3 hours
  8. custombefore being partitioned between ethyl acetate (100 ml) and saturated aqueous bicarbonate (80 ml)
  9. extractionThe aqueous layer was extracted with more ethyl acetate (2×50 ml)
  10. washThe combined organic extracts were washed With brine (80 ml)
  11. dry with materialdried (Na2SO4)
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by column chromatography
  14. customThe product was reprecipitated from dichloromethane/hexanes
  15. customto give a white solid
  16. customa white precipitate was obtained
  17. filtrationThis was collected by filtration
  18. washwashed with water
  19. dry with materialdried in vacuo over P2O5 (0.040 g, 60%), mp>105° C.

Sources & evidence

ORD record
ord-d19547ab55834b9889a7685dcaa34184
Source dataset
uspto-grants-2004_03
Patent number
US06699861B1

Reaction notes

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