Hydrochloric Acid → HCID 69370311, compound

HRID 969938Notes

Reaction equation

HRID 969938 reaction equation
[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]([O-:27])=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2].Cl>CC#N>[OH2:16].[OH2:16].[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][C:12]([CH2:14][CH2:15][O:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N+:20]([O-:27])=[CH:19][CH:18]=3)=[CH:13][C:8]=2[C:7](=[O:28])[N:6]([CH3:29])[C:5]2[CH:30]=[CH:31][CH:32]=[N:33][C:4]1=2)[CH3:2]

Participants

4

Reactant 2

HCID 313Hydrochloric AcidHCID 3010663BILR 355

Product 1

HCID 69370311HCID 69370311, compoundYield 137.7%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
70 °C

Procedure

29.1 Kg of crude 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one as a wet cake was charged to an inerted 400 L reactor. The reactor was again inerted, then 105 Kg MeCN and 8.3 Kg 0.002M HCl were charged, and the mixture heated to 70° C. in the dark and held there for 30 minutes. The solution was then cooled to 22° C. over 1 hour, held one hour, and the slurry thus obtained was centrifuged, washing the cake with 35 Kg of 8:1 MeCN:H2O. The recrystallized 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one wet cake (18.55 Kg) was then packed out and again returned to the reactor. The reactor was inerted, then 12.6 Kg H2O and 77.7 Kg EtOH (SDA-2B) were charged, and the mixture heated to 70° C. in the dark. Once in solution, the mixture was transferred hot into a second reactor through an in line polishing filter, using 22.1 Kg of 8:1 EtOH:H2O to aid the transfer and wash out the first reactor. About 22 L of solvent was then removed by atmospheric pressure distillation. To the resulting solution was then added 300 g of 6N HCl to protonate the impurity (˜2%) of ether 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one. The solution was then cooled to 50° C. over 1 hour and seeded with 100 g of 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one dihydrate. The mixture was then linearly cooled to 22° C. over 8 hours. The slurry thus obtained was then centrifuged, washing the cake with 15 Kg of 8:1 EtOH:H2O. The solid was dried in the centrifuge until KF water analysis reached 7.5% to give 14.45 Kg of 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(1-oxido-4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one dihydrate (67% overall yield from intermediate ether 5,11-dihydro-11-ethyl-5-methyl-8-{2-{(4-quinolinyl)oxy}ethyl}-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one C1) as a colorless solid with HPLC purity of 99.1%. M.p. 199° C.; 1H NMR (400 MHz, CDCl3)δ: 8.69 (d, J=7.0 Hz, 1H), 8.62 (d, J=8.7 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.21 (d, J=8.4 Hz, 1H), 8.18 (dd, J=4.7, 1.6 Hz, 1H), 7.8 (dd, J=5.4, 5.4 Hz, 1H), 7.70 (dd, J=7.2, 7.2 Hz, 1H), 7.47 (dd, J=8.0, 1.6 Hz, 1H), 7.07 (dd, J=7.9, 4.7 Hz, 1H), 6.78 (d, J=7.0 Hz, 1H), 4.42 (dd, J=6.2, 6.2 Hz, 2H), 4.18 (q, J=6.9 Hz, 2H), 3.50 (s, 3H), 3.22 (dd, J=6.2, 6.2 Hz, 2H), 1.24 (t, J=7.0 Hz, 3H). 13C NMR (125 MHz, d6-DMSO)δ: 166.25 (C6), 157.68 (C15), 153.95 (C12), 151.31 (C21), 151.13 (C9), 144.02 (C2), 141.21 (C7), 140.47 (C30), 135.36 (C23), 131.70 (C4), 131.11 (C13), 130.58 (C26), 128.86 (C8), 128.02 (C27), 122.28 (C28), 122.07 (C29), 120.24 (C3+C14), 119.24 (C25), 101.92 (C22), 68.87 (C20), 40.36 (C17), 36.71 (C16), 30.59 (C19), 13.40 (C18). Anal. Calcd for C25H27N5O5: C, 62.88; H, 5.70; N, 14.67. Found C, 62.86; H, 5.72; N, 14.54.

Workup

  1. temperatureThe solution was then cooled to 22° C. over 1 hour
  2. waitheld one hour
  3. customthe slurry thus obtained
  4. washwashing the cake with 35 Kg of 8:1 MeCN
  5. addition12.6 Kg H2O and 77.7 Kg EtOH (SDA-2B) were charged
  6. temperaturethe mixture heated to 70° C. in the dark
  7. customOnce in solution, the mixture was transferred hot into a second reactor
  8. filtrationthrough an in line polishing filter
  9. washwash out the first reactor
  10. customAbout 22 L of solvent was then removed by atmospheric pressure distillation
  11. additionTo the resulting solution was then added 300 g of 6N HCl
  12. temperatureThe solution was then cooled to 50° C. over 1 hour
  13. temperatureThe mixture was then linearly cooled to 22° C. over 8 hours
  14. customThe slurry thus obtained
  15. washwashing the cake with 15 Kg of 8:1 EtOH
  16. dry with materialThe solid was dried in the centrifuge until KF water analysis

Sources & evidence

ORD record
ord-4d62629fc705427e8dec345bd90796ac
Source dataset
uspto-grants-2007_12
Patent number
US07309700B2

Reaction notes

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