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3-Azabicyclo[3.1.0]hexane hydrochloride → 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide

HRID 2200865
Notes
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Reaction equation

HRID 2200865 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.Cl.[CH:32]12[CH2:37][CH:36]1[CH2:35][NH:34][CH2:33]2>C1COCC1.C(N(CC)CC)C>[CH:32]12[CH2:37][CH:36]1[CH2:35][N:34]([C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:13]([NH:15][CH2:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:11][N:10]=1)[CH2:33]2
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 2

HCID 223352893-Azabicyclo[3.1.0]hexane hydrochlorideHCID 86342163Avanafil Impurity K

Product 1

HCID 732144712-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamideYield 39%

Reagents, catalysts & solvents 2

HCID 8471TriethylamineCatalystHCID 8028
Tetrahydrofuran
Solvent

Procedure

In absolute anhydrous THF (10 mL) was dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methylsulphinyl)-N-(pyrimidin-2-ylmethyl) pyrimidine-5-formamide (100 mg, 0.22 mmol). Several drops of triethylamine were added, then 3-azabicyclo[3.1.0]hexan hydrochloride salt (42 mg, 0.35 mmol) was added. The reaction mixture was heated to reflux overnight. The solvent was removed by rotary evaporation, and water was added, followed by extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1 to 10/1). 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid was obtained (40 mg, 39% yield).

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureto reflux overnight
  3. customThe solvent was removed by rotary evaporation, and water
  4. additionwas added
  5. extractionfollowed by extraction with DCM
  6. dry with materialThe organic phase was dried over sodium sulfate
  7. custompurified by silica gel column chromatography (DCM/methanol=20/1 to 10/1)

Sources & evidence

ORD record
ord-1131e03a8a7a4daa893f65f732202ed1
Source dataset
uspto-grants-2016_06
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09359371B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes