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Diisopropylethylamine → (3R)-N-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-3-[(2-chloro-benzoyl)amino]-N-methyl-2,3-dihydro-1H-indene-5-carboxylic acid amide

HRID 1193426
Notes
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Reaction equation

HRID 1193426 reaction equation
[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C@H:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([N:18]([CH3:25])[CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:17])[CH:14]=2)[CH2:9][CH2:8]1)=[O:5].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH2:37])[N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[NH2:37][C:33]1[N:34]=[C:35]([N:22]2[CH2:21][CH2:20][CH:19]([N:18]([CH3:25])[C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[CH2:9][CH2:8][C@H:7]4[NH:6][C:4](=[O:5])[C:3]3[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=3[Cl:1])=[O:17])[CH2:24][CH2:23]2)[CH:36]=[CH:31][N:32]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 2233322-Amino-4-chloropyrimidineHCID 66798745(R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide

Product 1

HCID 66798873(3R)-N-[1-(2-Amino-pyrimidin-4-yl)-piperidin-4-yl]-3-[(2-chloro-benzoyl)amino]-N-methyl-2,3-dihydro-1H-indene-5-carboxylic acid amideYield 45%

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

A mixture of (R)-3-(2-chlorobenzamido)-N-methyl-N-(piperidin-4-yl)-2,3-dihydro-1H-indene-5-carboxamide (stage 2H-214) (200 mg, 0.486 mmol, 1.0 eq), 4-chloro-pyrimidin-2-ylamine (94 mg, 0.728 mmol, 1.5 eq) and DIPEA (0.125 ml, 0.728 mmol, 1.5 eq) in dioxane (10 ml) was refluxed for 16 h. When the reaction was complete according to TLC monitoring, concentration under reduced pressure was carried out, and the reside was taken up in dichloromethane (50 ml) and washed with water (30 ml) and saturated sodium chloride solution (30 ml). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane). Yield: 45% (110 mg, 0.267 mmol) Analytical Data—Single Substances Method 1: Equipment and methods for HPLC-MS analysis: HPLC: Waters Alliance 2795 with PDA Waters 2998; MS: Micromass Quattro Micro™ API; column: Waters Atlantis® T3, 3 μm, 100 Å, 2.1×30 mm; column temperature: 40° C., eluent A: purified water+0.1% formic acid; eluent B: acetonitrile (gradient grade)+0.1% formic acid; gradient: 0% B to 100% B in 8.8 min, 100% B for 0.4 min, 100% B to 0% B in 0.01 min, 0% B for 0.8 min; flow: 1.0 ml/min; ionization: ES+, 25 V; batch: 100 μl/min 70% methanol+0.2% formic acid; UV: 200-400 nm.

Workup

  1. temperaturewas refluxed for 16 h
  2. concentrationWhen the reaction was complete according to TLC monitoring, concentration under reduced pressure
  3. washwashed with water (30 ml) and saturated sodium chloride solution (30 ml)
  4. dry with materialThe organic phase was dried over sodium sulfate
  5. concentrationconcentrated under reduced pressure
  6. customThe crude product was purified by column chromatography (silica gel, 6% methanol in dichloromethane)
  7. customcolumn temperature: 40° C., eluent A: purified water+0.1% formic acid
  8. wait100% B for 0.4 min
  9. wait100% B to 0% B in 0.01 min
  10. wait0% B for 0.8 min

Sources & evidence

ORD record
ord-f59ae764db5145eabc4608e55837563c
Source dataset
uspto-grants-2014_03
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08680159B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes