Methanol → Methyl(4S)-3-[({3-[4-(3-aminophenyl)-1-piperidinyl]propyl}amino)carbonyl]-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate

HRID 2087140Notes

Reaction equation

HRID 2087140 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[N:14]([C:15]([O:17]C3C=CC([N+]([O-])=O)=CC=3)=O)[C:13](=[O:27])[NH:12][C:11]([CH2:28][O:29][CH3:30])=[C:10]2[C:31]([O:33][CH3:34])=[O:32])[CH:5]=[CH:6][C:7]=1[F:8].[N+:35]([C:38]1[CH:39]=[C:40]([C:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH2:53])[CH2:48][CH:49]=2)[CH:41]=[CH:42][CH:43]=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].CO>ClCCl>[NH2:35][C:38]1[CH:39]=[C:40]([CH:44]2[CH2:45][CH2:46][N:47]([CH2:50][CH2:51][CH2:52][NH:53][C:15]([N:14]3[C@@H:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[C:10]([C:31]([O:33][CH3:34])=[O:32])=[C:11]([CH2:28][O:29][CH3:30])[NH:12][C:13]3=[O:27])=[O:17])[CH2:48][CH2:49]2)[CH:41]=[CH:42][CH:43]=1

Participants

6

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 155126495-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylateHCID 220487383-(4-(3-Nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine

Product 1

HCID 60078121Methyl(4S)-3-[({3-[4-(3-aminophenyl)-1-piperidinyl]propyl}amino)carbonyl]-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylateYield 52%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

A mixture of 3.02 g (6.33 mmol) 5-methyl 1-(4-nitrophenyl) (6S)-6-(3,4-difluorophenyl)-4-(methoxymethyl)-2-oxo-3,6-dihydro-1,5(2H)-pyrimidinedicarboxylate, 1.50 g (5.80 mmol) of 3-(4-(3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinyl)-1-propanamine, 7.94 g (75.5 mmol) of K2CO3 and 1.00 mL of methanol in 200 mL dichloromethane (under argon) was stirred at room temperature for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 100 mL of ethyl acetate and washed 3×50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgSO4) and concentrated in vacuo. The residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours. The reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine) to afford 1.65 g (52.0% yield) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.80 (s, 1H), 7.22-7.02 (m, 2H), 6.95 (t, J=8.70 Hz, 1H), 6.63-6.44 (m, 4H), 4.56 (Abq, 2H), 3.62 (s, 3H), 3.33 (s, 3H), 3.32-3.20 (m, 4H), 2.96 (br s, 2H), 2.33 (t, J=7.50 Hz, 2H), 2.11-1.94 (m, 3H), 1.81-1.64 (m, 4H); ESMS m/e: 572.3 (M+H)+;

Workup

  1. filtrationThe reaction mixture was filtered
  2. concentrationconcentrated in vacuo
  3. dissolutionThe residue was dissolved in 100 mL of ethyl acetate
  4. washwashed 3×50 mL of 5% aqueous NaOH solution
  5. dry with materialthe organic layer was dried (MgSO4)
  6. concentrationconcentrated in vacuo
  7. dissolutionThe residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C
  8. stirringthe reaction mixture was stirred under a hydrogen balloon for 24 hours
  9. washwashed with ethanol
  10. dry with materialthe filtrate was dried (MgSO4)
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by column chromatography (silica, 9.5:0.5, dichloromethane:methanol+1% isopropyl amine)

Sources & evidence

ORD record
ord-7173ffc739d64831aefeb67cd95ffff9
Source dataset
uspto-grants-2004_04
Patent number
US06727264B1

Reaction notes

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