Triethylamine → (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide

HRID 1482995ノート

反応式

HRID 1482995 の反応式
[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([C:28]([OH:30])=O)=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:17])[CH3:16])[C:9]3=[N:8][C:7]=2[CH:31]=1.C[N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CC[N:62](CC)CC.[NH4+].[Cl-]>CN(C=O)C.O>[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:37])=[O:30])=[CH:20][N:19]=4)[C@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1.[OH:1][CH2:2][C:3]1[C:4]([S:32]([CH3:35])(=[O:33])=[O:34])=[CH:5][C:6]2[N:10]3[CH2:11][CH2:12][N:13]([C:18]4[N:23]=[C:22]([C:24]([F:25])([F:27])[F:26])[C:21]([C:28]([NH2:62])=[O:30])=[CH:20][N:19]=4)[C@@H:14]([CH:15]([CH3:16])[CH3:17])[C:9]3=[N:8][C:7]=2[CH:31]=1

参加物

8

反応物 4

HCID 8471TriethylamineHCID 25517Ammonium ChlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 71736481(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid

生成物 2

HCID 71736631(R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide収率 56.7%HCID 71736632(S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide収率 10.8%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 6228Dimethylformamide溶媒

実験手順

To a solution of (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylic acid (100 mg, 0.19 mmol, partially racemized) in DMF (2 mL) was added HATU (97 mg, 0.25 mmol) and Et3N (52 mg, 0.51 mmol). The mixture was stirred at rt for 1 h. NH4Cl (19 mg, 0.34 mmol) was added in one portion. The mixture was stirred at rt for 16 h. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (4×10 mL). The combined organic layers were washed with water (3×10 mL) and brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative TLC and SFC separation to afford (R)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (55.2 mg, 56.7% yield, isomer 1) as a white solid and (S)-2-(8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxamide (10.5 mg, 10.8% yield, isomer 2) as white solid.

後処理

  1. stirringThe mixture was stirred at rt for 16 h
  2. extractionthe aqueous layer was extracted with EtOAc (4×10 mL)
  3. washThe combined organic layers were washed with water (3×10 mL) and brine
  4. dry with materialdried over anhydrous Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customThe residue was purified by preparative TLC and SFC separation

出典と根拠

ORDレコード
ord-c4576e83d9624c7994838cd7cab2781b
出典データセット
uspto-grants-2016_08
特許番号
US09416135B2

反応ノート

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