Potassium Carbonate → 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester

HRID 2406998ノート

反応式

HRID 2406998 の反応式
Cl.[CH3:2][CH:3]([CH3:23])[CH2:4][C@H:5]([NH2:22])[C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:10][CH:11]=1.[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](F)=[N:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>N#N>[CH3:24][O:25][C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([NH:22][C@H:5]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:10][CH:11]=2)[CH2:4][CH:3]([CH3:23])[CH3:2])=[N:29][CH:28]=1

参加物

5

反応物 3

HCID 11430Potassium CarbonateHCID 13758765Methyl 6-fluoropyridine-3-carboxylateHCID 67980895(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride

生成物 1

HCID 679808636-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester収率 94.5%

試薬・触媒・溶媒 1

HCID 947Nitrogen溶媒

反応条件

温度
100 °C

実験手順

(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamine hydrochloride (31.33 g, 90.60 mmol) was combined with 6-fluoro-nicotinic acid methyl ester (16.9 g, 109 mmol) and K2CO3 (37.6 g, 272 mmol, 325 mesh) in a 500 mL N2-purged round bottom. Anhydrous dimethylformamide (115 mL) was added. The reaction was heated to 100° C. as a suspension. At 35 min another 3.00 g of 6-fluoro-nicotinic acid methyl ester was added. At 20 h, the reaction was placed in an ice bath and when the internal temperature was below room temperature sat. NH4Cl (500 mL) was added. This was stirred for a couple minutes in the bath and then the bath was removed and stirred at room temperature. Ethyl acetate (600 mL) and a small amount of water were added and the layers separated. The aqueous was extracted with ethyl acetate (150 mL) and the combined organics were washed with additional sat. NH4Cl (125 mL). The aqueous was back extracted with ethyl acetate (50 mL). The combined organics were dried over MgSO4. Purification was done by silica gel flash chromatography (ethyl acetate/heptane) to give impure 6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]butylamino}-nicotinic acid methyl ester (38.07 g) as a pale yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.85 (s, 2 H) 8.69 (d, J=1.6 Hz, 1 H) 8.55 (d, J=8.2 Hz, 2 H) 8.01 (dd, J=8.8, 2.1 Hz, 1 H) 7.74 (d, J=8.4 Hz, 2 H) 6.39 (d, J=8.8 Hz, 1 H) 5.01 (q, J=6.9 Hz, 1 H) 3.86 (s, 3 H) 1.85-1.98 (m, 1 H) 1.70-1.82 (m, 2 H) 1.05 (d, J=6.2 Hz, 3 H) 1.01 (d, J=6.0 Hz, 3 H); MS (M+1): 445.3.

後処理

  1. custompurged round bottom
  2. additionAnhydrous dimethylformamide (115 mL) was added
  3. additionAt 35 min another 3.00 g of 6-fluoro-nicotinic acid methyl ester was added
  4. customthe reaction was placed in an ice bath
  5. customwas below room temperature
  6. additionwas added
  7. customthe bath was removed
  8. stirringstirred at room temperature
  9. additionEthyl acetate (600 mL) and a small amount of water were added
  10. customthe layers separated
  11. extractionThe aqueous was extracted with ethyl acetate (150 mL)
  12. washthe combined organics were washed with additional sat. NH4Cl (125 mL)
  13. extractionThe aqueous was back extracted with ethyl acetate (50 mL)
  14. dry with materialThe combined organics were dried over MgSO4
  15. customPurification

出典と根拠

ORDレコード
ord-61d7a90457c64df6b9407bcf2b6df222
出典データセット
uspto-grants-2014_08
特許番号
US08809342B2

反応ノート

読み込み中…