Dicyclohexylcarbodiimide → Ritonavir

HRID 52741

反応式

HRID 52741 の反応式
[NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1

参加物

6

反応物 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 9818282UreidovalineHCID 111019781,3-Thiazol-5-ylmethyl N-((1S,2S,4S)-4-amino-1-benzyl-2-hydroxy-5-phenylpentyl)carbamate

生成物 1

HCID 392622Ritonavir

試薬・触媒・溶媒 1

HCID 8028Tetrahydrofuran溶媒

実験手順

To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)-carbonyl)-L-valine (7.37 g, 23.5 mmol)in THF (170 mL) was added DCC (4.85 g, 23.5 mmol). The solution was stirred at ambient temperature for 16 hours (DCU precipitates). THF was removed under vacuum and the resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve the crude product. The DCU was removed by filtration and the filter cake was washed with 1N HCl (30 mL). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH). The aqueous layer was extrated with another 25 mL ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at ≤45° C. The residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. The solution was allowed to cool slowly and stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with 1:1 ethyl acetate/heptane (20 mL). The product was dried briefly at 55° C. in a vacuum oven to obtain an approximate weight prior to the second crystallization (12.85 g, 83%).

後処理

  1. custom(DCU precipitates)
  2. customTHF was removed under vacuum
  3. stirringthe resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours
  4. dissolutionto dissolve the crude product
  5. customThe DCU was removed by filtration
  6. washthe filter cake was washed with 1N HCl (30 mL)
  7. dissolutionKH2PO4 (3.2 g) was dissolved in the combined HCl filtrates
  8. additionThe solution was mixed with ethyl acetate (80 mL)
  9. washthe combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3)
  10. dry with materialThe organic layer was dried with Na2SO4 (13 g)
  11. filtrationfiltered
  12. concentrationconcentrated under vacuum at ≤45° C
  13. dissolutionThe residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C
  14. temperatureto cool slowly
  15. stirringstirred overnight at room temperature
  16. customto provide a thick slurry
  17. filtrationThe product was collected by filtration
  18. washwashed with 1:1 ethyl acetate/heptane (20 mL)
  19. customThe product was dried briefly at 55° C. in a vacuum oven
  20. customto obtain an approximate weight
  21. customto the second crystallization (12.85 g, 83%)

出典と根拠

ORDレコード
ord-494ac278722749a591726cbb5b8db62f
出典データセット
uspto-grants-1997_04
特許番号
US05616720

関連ノート

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