4-Methylmorpholine → 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide

HRID 1713215ノート

反応式

HRID 1713215 の反応式
[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12](O)=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.Cl.[NH2:45][CH2:46][C:47]([NH2:49])=[O:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:13])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]

参加物

7

反応物 4

HCID 79724-Methylmorpholine2 回HCID 62365Isobutyl chloroformateHCID 2723639Glycinamide hydrochlorideHCID 210893063-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid

生成物 1

HCID 210890083-[5-chloro-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-N-[1-(aminocarbonyl)methyl]-4-methylbenzamide収率 27.3%

試薬・触媒・溶媒 2

HCID 142844-(Dimethylamino)pyridine触媒HCID 31374Dimethylacetamide溶媒2 回

反応条件

温度
0 °C

実験手順

To a cooled (0° C.) solution of 3-[5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 3) (0.25 g, 0.61 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.96 mL stock solution prepared 0.1 mL in 0.9 mL DCM, 0.74 mmol) and 4-methylmorpholine (0.88 mL stock solution prepared 0.1 mL in 0.9 mL DMA, 0.80 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added NMM (0.1 mL, 0.92 mmol), glycineamide HCl (0.10 g, 0.92 mmol), and DMAP (0.01 g, 0.06 mmol) and stirred at ambient temperature for 1.5 h. Removed DMA under reduced pressure. Purified crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=463) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as an off-white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ8.32 (s, 1H), 7.96 (m, 1H), 7.80 (s, 1H), 7.61 (m, 1H), 7.54 (m, 1H), 7.01 (m, 2H), 5.60 (m, 2H), 4.01 (s, 2H), 2.20 (s, 3H). ESHRMS m/z 463.0990 (M+H calculated for C21H18ClF2N4O4 requires 463.0979).

後処理

  1. customPurified crude product by preparatory HPLC
  2. customa 10-90% CH3CN/H2O (30 min) gradient
  3. additioncontaining 0.5% TFA at a flow rate of 80 mL/min
  4. concentrationconcentrated to approximately 20 mL under reduced pressure
  5. additionAdded 5% NaHCO3 (20 mL)
  6. extractionextracted with DCM (3×15 mL)
  7. dry with materialThe organic extracts were dried over Na2SO4
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customdried in vacuo

出典と根拠

ORDレコード
ord-ed957f25bb2047e99c8a9c84db53c2cf
出典データセット
uspto-grants-2010_09
特許番号
US07795271B2

反応ノート

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