Lithium hydroxide, monohydrate → (s)-9-((1h-Imidazol-2-yl)methyl)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4h)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3h)-one

HRID 132271Notes

Reaction equation

HRID 132271 reaction equation
[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:20](=[O:21])[C@H:19]([CH2:22][C:23](OC)=[O:24])[CH2:18][C:17]2[CH:16]=[C:15]([Cl:27])[C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH2:8]1.O.[OH-].[Li+].[B-](F)(F)(F)F.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.Cl.[O:54]=[C:55]1[N:64]([CH:65]2[CH2:70][CH2:69][NH:68][CH2:67][CH2:66]2)[CH2:63][C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[NH:56]1>O.O1CCCC1.CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:20](=[O:21])[C@H:19]([CH2:22][C:23](=[O:24])[N:68]2[CH2:67][CH2:66][CH:65]([N:64]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:54])[CH2:70][CH2:69]2)[CH2:18][C:17]2[CH:16]=[C:15]([Cl:27])[C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[CH2:8]1

Participants

8

Reactant 4

HCID 168937Lithium hydroxide, monohydrateHCID 2733207O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborateHCID 183213553-(Piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one hydrochlorideHCID 59731852(S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate

Product 1

HCID 11977526(s)-9-((1h-Imidazol-2-yl)methyl)-4-chloro-7-(2-oxo-2-(4-(2-oxo-1,2-dihydroquinazolin-3(4h)-yl)piperidin-1-yl)ethyl)-6,7,9,10-tetrahydroazepino[3,4-e]indazol-8(3h)-oneYield 28%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

(S)-Methyl 2-(9-((1H-imidazol-2-yl)methyl)-4-chloro-8-oxo-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (58 mg, 0.15 mmol) was dissolved in a mixture containing methanol (2 mL), tetrahydrofuran (2 mL), and water (2 mL). Lithium hydroxide monohydrate (20 mg, 0.48 mmol) was added to the mixture. Reaction stirred at room temperature for 15 hours. Reaction was quenched with 1N hydrochloric acid (0.5 mL). Mixture was concentrated in vacuo. Residue was dissolved in DMF (2 mL). N,N-Diisopropylethylamine was added to the mixture followed by o-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium Tetrafluoroborate (60 mg, 0.19 mmol). Mixture stirred at room temperature for 30 minutes. 4-(2-Oxo-1,4-dihydro-2H-quinazolin-3-yl) piperidine hydrochloride (50 mg, 0.19 mmol) was added to the mixture. Reaction stirred at room temperature for 3 hours. Reaction mixture was purified by preparatory HPLC. Desired fractions were identified. Acetonitrile was removed from the fractions in vacuo. Remaining aqueous was made basic with sodium bicarbonate. Mixture was extracted twice with ethyl acetate. Combined extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. Title compound was obtained as white solid in 28% yield. MS m/e (M+H)+=587.2. 1H NMR (500 MHz, DMSO-D6): δ=13.46 (s, 1H), 11.75 (s, 1H), 9.20 (s, 1H), 8.14 (s, 1H), 7.19 (s, 1H), 7.12 (m, 2H), 6.84 (m, 2H), 6.77 (d, J=7.93, 1H), 5.23 (d, J=15.16, 1H), 4.76 (m, 1H), 4.69 (dd, J1=15.26, J2=5.19, 1H), 4.53 (d, J=13.43, 1H), 4.47 (d, J=15.26, 1H), 4.40 (m, 1H), 4.29 (d, J=3.97, 2H), 4.08 (m, 1H), 3.89 (d, J=9.77, 1H), 3.15 (m, 2H), 3.00 (m, 1H), 2.91 (m, 3H), 2.60 (m, 1H) 2.44 (m, 2H), 1.80 (m, 1H), 1.60 (m, 3H).

Workup

  1. customReaction
  2. customReaction
  3. customwas quenched with 1N hydrochloric acid (0.5 mL)
  4. concentrationMixture was concentrated in vacuo
  5. dissolutionResidue was dissolved in DMF (2 mL)
  6. additionN,N-Diisopropylethylamine was added to the mixture
  7. stirringMixture stirred at room temperature for 30 minutes
  8. customReaction
  9. stirringstirred at room temperature for 3 hours
  10. customReaction mixture
  11. customwas purified by preparatory HPLC
  12. customAcetonitrile was removed from the fractions in vacuo
  13. extractionMixture was extracted twice with ethyl acetate
  14. dry with materialCombined extracts were dried (magnesium sulfate)
  15. filtrationfiltered
  16. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-63a8f6da24b1468c8967e09d393b6ec4
Source dataset
uspto-grants-2008_06
Patent number
US07384930B2

Reaction notes

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