New tetrahydropyrimidodiazepin and tetrahydropyridodiazepin compounds for treating pain and pain related conditions
A technology of compound and hydrogen atom, which is applied in the field of preparing the compound and can solve problems such as drug resistance
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[0329] In the following examples, the preparation of two intermediate compounds as well as compounds according to the invention is disclosed.
[0330] Use the following abbreviations:
[0331] ACN: Acetonitrile
[0332] Aq: water-based
[0333] CH: Cyclohexane
[0334] DCM: dichloromethane
[0335] DIAD: Diisopropyl azodicarboxylate
[0336] DIBAL: diisobutylaluminum hydride
[0337] DIPEA: N,N-Diisopropylethylamine
[0338] DMA: N,N-Dimethylacetamide
[0339] EtOAc: ethyl acetate
[0340] EtOH: ethanol
[0341] Ex: example
[0342] h: hour / s
[0343] HPLC: High Performance Liquid Chromatography
[0344] MeOH: Methanol
[0345] MS: mass spectrometry
[0346] Min: minutes
[0347] PPh 3 :Triphenylphosphine
[0348] Ret: retention time
[0349] rt: room temperature
[0350] Sat: saturated
[0351] TBAF: Tetrabutylammonium fluoride
[0352] TBAI: Tetrabutylammonium iodide
[0353] TFA: Trifluoroacetic acid
[0354] THF: Tetrahydrofuran
[0355] The followin...
example 1
[0358] Example 1: (S)-1-methyl-4-(2-methyl-4-(3-(methylamino)-1-phenylpropoxy)benzyl)-1,2,3,4- Tetrahydro-5H-pyrido[4,3-e][1,4]diazepine-5-one.
[0359]
[0360] a) Methyl (S)-4-(3-((tert-butoxycarbonyl)(methyl)amino)-1-phenylpropoxy)-2-methylbenzoate. To tert-butyl(S)-(3-hydroxy-3-phenylpropyl)(methyl)carbamate (1.8g, 6.78mmol) and methyl 4-fluoro-2-methylbenzoate (2.28 g, 13.57 mmol) in DMA (36 mL) was added NaH (60% suspension in mineral oil, 407 mg, 10.18 mmol) and the mixture was stirred at rt for 2.5 h. Water was added, extracted with EtOAc, with Na 2 SO 4 Dry, filter and concentrate under vacuum. Purification by flash silica gel chromatography (Gradient: CH to 100% EtOAc) gave the title product (1.8 g, 65% yield).
[0361] HPLC (Method B): Ret, 7.0 min; ESI + - MS m / z, 436.2 (M+Na).
[0362] b) tert-butyl (S)-(3-(4-(hydroxymethyl)-3-methylphenoxy)-3-phenylpropyl)(methyl)carbamate. To a solution of the compound obtained in step a (2.7 g, 6.53 mmol) in toluene ...
example 8
[0371] Example 8: (S)-4-(2-fluoro-4-(3-(methylamino)-1-phenylpropoxy)benzyl)-1-methyl-1,2,3,4-tetra Hydrogen-5H-pyrido[4,3-e][1,4]diazepine-5-one.
[0372]
[0373] a) (S)-tert-butyl((4-(3-chloro-1-phenylpropoxy)-2-fluorobenzyl)oxy)dimethyl-silane. To a solution of (R)-3-chloro-1-phenylpropan-1-ol (850 mg, 4.98 mmol) in THF (25 mL) was added 4-(((tert-butyldimethylsilyl)oxy base) methyl)-3-fluorophenol (1.34g, 5.23mmol) in THF (12mL) and PPh 3 (1.57 g, 5.98 mmol). The reaction mixture was cooled at 0 °C, DIAD (1.25 mL, 5.98 mmol) was added dropwise, and the mixture was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum. Purification by flash silica gel chromatography (Gradient: CH to 100% EtOAc) gave the title product (1.30 g, 64% yield).
[0374] HPLC (Method B): Ret, 8.8 min; ESI + - MS m / z, 409.1 (M+H).
[0375] b) (S)-3-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluorophenoxy)-N-methyl-3-phenylpropan- 1-amine. To a solution of the compo...
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