Hydrochloric Acid → HCID 46914737, compound

HRID 505747Notes

Reaction equation

HRID 505747 reaction equation
[CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[C@@H:30]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[C@@H:29]3[C:24]([C:25]4[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][C:26]=4[CH2:27][CH2:28]3)=[N:23]2)[CH:17]=[CH:18][C:19]=1[C:20]#[N:21].IC.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:13][C:14]1[CH:15]=[C:16]([N:22]2[C@@H:30]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C@:29]3([CH3:1])[C:24]([C:25]4[CH:39]=[CH:38][C:37]([C:40]([OH:42])=[O:41])=[CH:36][C:26]=4[CH2:27][CH2:28]3)=[N:23]2)[CH:17]=[CH:18][C:19]=1[C:20]#[N:21]

Participants

10

Reactant 7

HCID 313Hydrochloric AcidHCID 6328Methyl iodide3×HCID 7912DiisopropylamineHCID 14798Sodium HydroxideHCID 2733832Lithium HexamethyldisilazideHCID 46914736HCID 46914736, compoundHCID 178418339Butyllithium

Product 1

HCID 46914737HCID 46914737, compoundYield 30.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 8028TetrahydrofuranSolvent2×

Procedure

To a solution of diisopropylamine (0.0772 mL, 0.551 mmol) in tetrahydrofuran (1.5 mL) at −78° C. was added n-butyllithium (2.5 M in hexanes, 0.206 mL, 0.514 mmol). After 10 minutes, a solution of (3S,3aR)-methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylate, Example 93 (159 mg, 0.367 mmol) in tetrahydrofuran (3.0 mL) was added dropwise. After 1 hour at −78° C., iodomethane (0.0343 mL, 0.551 mmol) was added. The reaction was kept at −78° C. and monitored by LCMS. After 2 hours, another 0.015 mL of iodomethane was added. Lithium hexamethyldisilazide (1.0 M in tetrahydrofuran, 0.100 mL, 0.100 mmol) was added, followed by another 0.015 mL iodomethane. Allowed to slowly warm to room temperature overnight. The reaction was treated with 0.5 mL methanol and 0.5 mL 2.5 N NaOH. After 4 hours, the reaction mixture was neutralized with 0.5 mL of 3 N hydrogen chloride and concentrated under a stream of nitrogen. The residue was dissolved in dimethylformamide/methanol, filtered through a syringe filter and purified by reverse-phase HPLC (60 to 95% acetonitrile/water/0.05% trifluoroacetic acid) to give the title compound (yellow solid, 48.6 mg, 0.112 mmol, 30.5% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.06 (br. s., 1H), 8.10 (d, J=8.2 Hz, 1H), 7.87 (s, 1H), 7.81 (d, J=7.8 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 7.43 (s, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57 (d, J=5.9 Hz, 1H), 3.01-3.10 (m, 2H), 1.91-2.11 (m, 3H), 1.71-1.82 (m, 1H), 1.09-1.56 (m, 7H), 1.06 (s, 3H). ES-MS m/z 434 (M+H).

Workup

  1. waitAfter 1 hour at −78° C.
  2. customwas kept at −78° C.
  3. waitAfter 2 hours
  4. waitAfter 4 hours
  5. concentrationconcentrated under a stream of nitrogen
  6. dissolutionThe residue was dissolved in dimethylformamide/methanol
  7. filtrationfiltered through a syringe
  8. filtrationfilter
  9. custompurified by reverse-phase HPLC (60 to 95% acetonitrile/water/0.05% trifluoroacetic acid)

Sources & evidence

ORD record
ord-4498ef1fc86c4a9783f29ec8721e911d
Source dataset
uspto-grants-2010_08
Patent number
US07781428B2

Reaction notes

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