Reaktion #11268

Reaktionsgleichung

(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester

1H-Indole-4-carboxylic acid {(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

HCl

1,4-dioxane

DCC

4

4,4-Difluoro-1-[2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylic acid isobutyl-amide

HOBt

oxalyl chloride

oil 26

amino ketone

3-butenylmagnesium bromide

→

title compound

N-[(1S,2S)-1-Benzyl-3-((R)-5,5-dimethyl-4-pent-4-enoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-3-hydroxy-2-methyl-benzamide

Lösungsmittel

benzene

EtOAc

MeOH

EtOAc

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe title compound was prepared
2. 2
   Einengenthe solution was concentrated to a yellow/red residue
3. 3
   workup.DISSOLUTIONThe material was dissolved in dry THF (10 mL)
4. 4
   Temperaturcooled to −78° C. with magnetic stirring
5. 5
   workup.WAITat −55° C. for 30 min
6. 6
   SonstigeThe reaction was quenched at −55° C.
7. 7
   workup.ADDITION(3 mL) and then poured into H2O (50 mL)
8. 8
   ExtraktionThe mixture was extracted with EtOAc (2×50 mL)
9. 9
   WaschenThe combined organics were washed with brine (1×100 mL)
10. 10
    Trocknendried over Na2SO4
11. 11
    Filtrationfiltered
12. 12
    Einengenconcentrated
13. 13
    workup.STIRRINGThe mixture was stirred at room temperature 1 h
14. 14
    Temperaturcooled to 0° C
15. 15
    TemperaturThe mixture was warmed to room temperature
16. 16
    workup.STIRRINGstirred overnight
17. 17
    FiltrationThe mixture was filtered
18. 18
    Waschenthe filtrate was washed with 1N HCl (10 mL), saturated NaHCO3 (10 mL), brine (10 mL)
19. 19
    Trocknendried over Na2SO4
20. 20
    Einengenconcentrated
21. 21
    Sonstigeto give a crude white solid (contaminated with DCU)
22. 22
    SonstigeThe DCU was removed by flash chromatography (30% to 50% EtOAc in hexanes)
23. 23
    Sonstigeto provide a white solid, which
24. 24
    workup.STIRRINGThe reaction was stirred at room temperature overnight
25. 25
    Sonstigethen partitioned between 1N HCl (10 mL) and EtOAc (10 mL)
26. 26
    WaschenThe organic layer was washed with saturated sat. NaHCO3 (1×25 mL)
27. 27
    Trocknendried over Na2SO4
28. 28
    Filtrationfiltered
29. 29
    Einengenconcentrated to a residue which
30. 30
    Sonstigewas purified by flash chromatography (60% EtOAc in hexanes)

Vorschrift

The title compound was prepared as follows. (R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1 (1.0 g, 3.80 mmol) was dissolved in benzene (10 mL) and cooled to 0° C. with magnetic stirring. Two drops of DMF were added followed by a drop wise addition of oxalyl chloride (0.33 mL, 3.80 mmol). When gas evolution ceased, the solution was concentrated to a yellow/red residue. The material was dissolved in dry THF (10 mL) and cooled to −78° C. with magnetic stirring. The grignard reagent, 3-butenylmagnesium bromide (7.7 mL, 3.80 mmol) was added dropwise over 10 min. The result was stirred at −78° C. for 1 h then at −55° C. for 30 min. The reaction was quenched at −55° C. with sat NH4Cl soln. (3 mL) and then poured into H2O (50 mL). The mixture was extracted with EtOAc (2×50 mL). The combined organics were washed with brine (1×100 mL), dried over Na2SO4, filtered, and concentrated. The result was the amino ketone 26 that was sufficiently pure to use in the subsequent step. The clear oil 26 (0.24 g, 1.15 mmol) was dissolved in EtOAc (10 mL). AMB-AHPBA 4 (0.40 g, 1.09 mmol) was added followed by HOBt (0.15 g, 1.09 mmol). The mixture was stirred at room temperature 1 h, then cooled to 0° C. DCC (0.24 g, 1.15 mmol) was slowly added as solution in EtOAc (6 mL). The mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the filtrate was washed with 1N HCl (10 mL), saturated NaHCO3 (10 mL), brine (10 mL), dried over Na2SO4 and concentrated to give a crude white solid (contaminated with DCU). The DCU was removed by flash chromatography (30% to 50% EtOAc in hexanes) to provide a white solid, which was dissolved in MeOH (2 mL) and treated with 4N HCl in 1,4-dioxane (0.26 mL, 1.1 mmol). The reaction was stirred at room temperature overnight then partitioned between 1N HCl (10 mL) and EtOAc (10 mL). The organic layer was washed with saturated sat. NaHCO3 (1×25 mL) dried over Na2SO4, filtered, and concentrated to a residue which was purified by flash chromatography (60% EtOAc in hexanes) to provide the title compound as a white amorphous solid: 1H NMR (DMSO-d6) □ 9.36 (s, 1H), 8.23 (d, J=8.1, 1H), 7.35–7.14 (m, 5H), 6.96 (t, J=7.5, 1H), 6.78 (d, J=8.2, 1H), 6.52 (d, J=7.5, 1H), 5.81–5.69 (m. 2H), 5.32 (d, J=9.7, 1H), 5.11–5.91 (m, 3H), 4.40 (m, 3H), 2.89–2.61 (m, 4H), 2.37–2.14 (m, 2H), 1.81 (s, 3H), 1.55 (s, 3H), 1.30 (s, 3H); Anal. Calcd for C28H34N2O5S: C, 65.86; H, 6.71; N, 5.49. Found: C, 65.52; H, 6.55; N, 5.81. The following examples were synthesized using the specific method outlined above using the appropriate grignard reagent for the desired compound.

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