(2-Thienylmethyl)amine → methyl (3S*,5R*)-5-[({2-tert-butyl-4-[(thiophen-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylate

HRID 2192846Notes

Reaction equation

HRID 2192846 reaction equation
[C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[S:45]1[CH:49]=[CH:48][CH:47]=[C:46]1[CH2:50][NH2:51].C(=O)([O-])O.[Na+]>CN(C=O)C>[C:1]([C:5]1[N:10]=[C:9]([NH:51][CH2:50][C:46]2[S:45][CH:49]=[CH:48][CH:47]=2)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@H:15]2[CH2:20][NH:19][CH2:18][C@@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

6

Reactant 4

HCID 34005(2-Thienylmethyl)amineHCID 81531DiisopropylethylamineHCID 516892Sodium BicarbonateHCID 593565701-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate

Product 1

HCID 86649297methyl (3S*,5R*)-5-[({2-tert-butyl-4-[(thiophen-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]piperidine-3-carboxylateYield 6.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
80 °C

Procedure

To a solution of 1-tert-butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](isobutyl)amino}piperidine-1,3-dicarboxylate (51.1 mg) and diisopropylethylamine (38 mg) in DMF (0.5 ml) was added a solution of 1-thiophen-2-ylmethanamine (23 mg) in DMF (0.5 ml) and the mixture was stirred at 80° C. overnight. 2% Aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower. The residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated by a nitrogen gas blower. The residue was neutralized with triethylamine (1 ml), and saturated aqueous sodium hydrogen carbonate was added. The mixture was extracted with ethyl acetate, and the extract was concentrated by a nitrogen gas blower. The residue was purified by reversed-phase preparative HPLC, and the object fraction was concentrated by a nitrogen gas blower to give the object compound (3.1 mg).

Workup

  1. extractionthe mixture was extracted with ethyl acetate
  2. concentrationthe extract was concentrated by a nitrogen gas blower
  3. customThe residue was purified by reversed-phase preparative HPLC
  4. concentrationthe object fraction was concentrated by a nitrogen gas blower
  5. dissolutionThe residue was dissolved in trifluoroacetic acid/acetonitrile solution (20% (V/V), 1.0 ml)
  6. stirringthe mixture was stirred at room temperature for 6 hr
  7. concentrationThe reaction mixture was concentrated by a nitrogen gas blower
  8. additionwas added
  9. extractionThe mixture was extracted with ethyl acetate
  10. concentrationthe extract was concentrated by a nitrogen gas blower
  11. customThe residue was purified by reversed-phase preparative HPLC
  12. concentrationthe object fraction was concentrated by a nitrogen gas blower

Sources & evidence

ORD record
ord-dc2c9a5964074520ba357c920abe9a57
Source dataset
uspto-grants-2012_12
Patent number
US08329691B2

Reaction notes

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