Pyridine → tert-butyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate

HRID 1444952

反応式

HRID 1444952 の反応式
Cl[Si](C)(C)C.Br[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C=C[C@@H]1[C@@H]2C[C@H]([C@@H](O)C3C4C(=CC=CC=4)N=CC=3)N(CC2)C1.N1C=CC=CC=1.[CH3:43][NH:44][C:45]([C:47]1[CH:56]=[CH:55][C:54]2[C:49](=[CH:50][CH:51]=[C:52]([C:57]([C:59]3[N:60]=[CH:61][N:62]([C:64]([C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)([C:71]4[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=4)[C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)[CH:63]=3)=[O:58])[CH:53]=2)[CH:48]=1)=[O:46]>C1COCC1.C(OCC)(=O)C.Cl.[Zn]>[OH:58][C@@:57]([C:52]1[CH:51]=[CH:50][C:49]2[C:54](=[CH:55][CH:56]=[C:47]([C:45]([NH:44][CH3:43])=[O:46])[CH:48]=2)[CH:53]=1)([C:59]1[N:60]=[CH:61][N:62]([C:64]([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)([C:77]2[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=2)[C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)[CH:63]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]

参加物

10

反応物 5

HCID 1049PyridineHCID 6397ChlorotrimethylsilaneHCID 79177tert-Butyl bromoacetateHCID 90454CinchonineHCID 18769037N-methyl-6-((trityl-1H-imidazol-4-yl)carbonyl)-2-naphthamide

生成物 1

HCID 57465810tert-butyl(3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate収率 108%

試薬・触媒・溶媒 4

HCID 23994Zinc触媒HCID 313Hydrochloric Acid溶媒2 回HCID 8028Tetrahydrofuran溶媒4 回HCID 8857Ethyl Acetate溶媒

反応条件

温度
25 °C

実験手順

8 mL of THF and 0.15 mL (1.18 mmol) of chlorotrimethylsilane were added to 1.04 g (16 mmol) of zinc powders, and the mixture was stirred at 35˜40° C. for 5 minutes. A solution of 2.36 mL (16 mmol) of tert-butyl bromoacetate in 20 mL of THF was added dropwise at 45˜52° C. over 10 minutes. The mixture was stirred at 65˜67° C. for 1 hour, and cooled to 25° C. 8.5 mL of THF was added to 1.32 g (4.5 mmol, 1.25 eq) of (+)-cinchonine. The above Reformatsky reagent was added dropwise at 4˜6° C. over 15 minutes. 1.16 mL (14.4 mmol, 4 eq) of pyridine was added dropwise at 5˜7° C. over 2 minutes. The mixture was stirred at 5˜6° C. for 30 minutes. A solution of 1.88 g (3.6 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide in 15 mL of THF was added dropwise at −44˜−39° C. over 7 minutes. The mixture was stirred at −44˜−35° C. for 5 hours and 20 minutes. 10 mL of 1N hydrochloric acid was added, and the mixture was warmed to 0° C. The mixture was diluted with 50 mL of ethyl acetate, 10 mL of 1N hydrochloric acid was added, and the layers were separated. The organic layer was washed successively with 20 mL of 1N hydrochloric acid 2 times, 20 mL of water, and 20 mL of an aqueous saturated sodium bicarbonate solution. To the organic layer were added 10 mL of 0.1N hydrochloric acid, 10 mL of water and 10 mL of ethyl acetate, and the layers were separated. The organic layer was washed with 20 mL of an aqueous saturated sodium chloride solution, and concentrated at 20° C. or lower under reduced pressure. 10 mL of n-hexane was added to the concentration residue, crystals were loosened, filtered, and washed with 10 mL of n-hexane. Air drying to a constant weight afforded 2.48 g of tert-butyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (enantiomer excess 95.0% ee).

後処理

  1. stirringThe mixture was stirred at 65˜67° C. for 1 hour
  2. additionThe above Reformatsky reagent was added dropwise at 4˜6° C. over 15 minutes
  3. stirringThe mixture was stirred at 5˜6° C. for 30 minutes
  4. stirringThe mixture was stirred at −44˜−35° C. for 5 hours and 20 minutes
  5. temperaturethe mixture was warmed to 0° C
  6. additionwas added
  7. customthe layers were separated
  8. washThe organic layer was washed successively with 20 mL of 1N hydrochloric acid 2 times, 20 mL of water, and 20 mL of an aqueous saturated sodium bicarbonate solution
  9. additionTo the organic layer were added 10 mL of 0.1N hydrochloric acid, 10 mL of water and 10 mL of ethyl acetate
  10. customthe layers were separated
  11. washThe organic layer was washed with 20 mL of an aqueous saturated sodium chloride solution
  12. concentrationconcentrated at 20° C. or lower under reduced pressure
  13. addition10 mL of n-hexane was added to the concentration residue, crystals
  14. filtrationfiltered
  15. washwashed with 10 mL of n-hexane
  16. customAir drying to a constant weight

出典と根拠

ORDレコード
ord-3d2649bd8b084a70bff7c0eb2fa3f8d3
出典データセット
uspto-grants-2010_02
特許番号
US07662974B2

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