Reaktion #426000

Reaktionsgleichung

NaHCO3

4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester

(S)-2-acetylsulfanyl-4-methylpentanoic acid

HCTU

→

title compound

4′-{5-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-2-ethoxy-4-ethylimidazol-1-ylmethyl}-3′-fluorobiphenyl-2-carboxylic Acid

Lösungsmittel

DCM

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.STIRRINGthe mixture was stirred for 15 minutes
2. 2
   SonstigeThe DCM layer was separated
3. 3
   workup.DISTILLATIONdistilled to ˜100 mL
4. 4
   workup.ADDITIONIPAc (150 mL) was added
5. 5
   workup.DISTILLATIONdistill to 150 mL
6. 6
   workup.ADDITIONAdditional IPAc (200 mL) was added
7. 7
   Waschenthe mixture was washed with 4% NaHCO3 (2×200 mL) and water (200 mL)
8. 8
   workup.STIRRINGThe solution was stirred with 15% NH4Cl (300 mL) for 15 minutes
9. 9
   workup.STIRRINGstirred for 1 hour
10. 10
    FiltrationThe solids were filtered off
11. 11
    WaschenThe filtrate was washed with IPAc (50 mL)
12. 12
    Sonstigethe IPAc layer separated
13. 13
    workup.STIRRINGThe IPAc layer was stirred with 15% NH4Cl (200 mL) for 3 hours
14. 14
    Filtrationany solids filtered off
15. 15
    WaschenThe filtrate was washed with saturated aqueous NaCl (150 mL)
16. 16
    workup.DISTILLATIONdistilled under vacuum to ˜60 mL
17. 17
    workup.ADDITIONDCM (50 mL) was added
18. 18
    workup.DISTILLATIONdistilled off
19. 19
    workup.ADDITIONDCM (200 mL) was added
20. 20
    Temperaturthe mixture was cooled 0-5° C
21. 21
    workup.ADDITIONTFA (70 mL) was added slowly (slightly exothermic) at below 15° C.
22. 22
    workup.STIRRINGthe mixture was stirred at 20° C. for 16 hours
23. 23
    EinengenThe mixture was concentrated to ˜150 ml, and IPAc (150 mL)
24. 24
    workup.ADDITIONwas added
25. 25
    workup.DISTILLATIONThe mixture was distilled to ˜150 mL
26. 26
    workup.ADDITIONAdditional IPAc (150 mL) was added
27. 27
    workup.DISTILLATIONagain distilled to ˜150 mL
28. 28
    workup.ADDITIONIPAc (200 mL) was added
29. 29
    workup.ADDITIONthe resulting solution was slowly added
30. 30
    Temperaturto pre-cooled K2CO3 (52 g) in water (250 mL) at below 10° C. (mildly exothermic, pH>7 must >6
31. 31
    Sonstigeduring quench) over 15 minutes
32. 32
    workup.ADDITIONwas added when the pH
33. 33
    workup.ADDITIONdropped below 6
34. 34
    SonstigeThe IPAc layer was separated
35. 35
    Waschenwashed with saturated aqueous NaCl (150 mL)
36. 36
    workup.DISTILLATIONThe IPAc solution was distilled to ˜50 mL
37. 37
    workup.ADDITIONMTBE (100 mL) was added
38. 38
    workup.DISTILLATIONthe mixture distilled to ˜50 mL
39. 39
    workup.ADDITIONAdditional MTBE (100 mL) was added
40. 40
    workup.STIRRINGthe mixture was stirred at room temperature for 3 hours
41. 41
    Sonstigeforming a slurry, which
42. 42
    workup.STIRRINGwas then stirred at 4° C. for 16 hours
43. 43
    FiltrationThe solids were filtered off
44. 44
    Waschenwashed with MTBE/diisopropyl ether (1:1; 100 mL)
45. 45
    SonstigeThe solids were then dried at room temperature for 60 hours under nitrogen

Vorschrift

Crystalline 4′-(5-aminomethyl-2-ethoxy-4-ethylimidazol-1-ylmethyl)-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester (dicyclohexylamine salt; 18 g, 40 mmol, 1 eq.), (S)-2-acetylsulfanyl-4-methylpentanoic acid (18 g, 48 mmol, 1.2 eq.), and HCTU (19 g, 48 mmol, 1.2 eq.) were combined in a pre-chilled vessel (0° C. for 10 minutes) and cold DCM (240 mL) was added. The mixture was stirred at 1±2° C. for 5-15 hours. 4% NaHCO3 (200 mL) was added and the mixture was stirred for 15 minutes. The DCM layer was separated and distilled to ˜100 mL. IPAc (150 mL) was added and distill to 150 mL. Additional IPAc (200 mL) was added and the mixture was washed with 4% NaHCO3 (2×200 mL) and water (200 mL). The solution was stirred with 15% NH4Cl (300 mL) for 15 minutes, the pH was adjusted to 5.5 with 1N HCl, and then stirred for 1 hour. The solids were filtered off. The filtrate was washed with IPAc (50 mL), and the IPAc layer separated. The IPAc layer was stirred with 15% NH4Cl (200 mL) for 3 hours and any solids filtered off. The filtrate was washed with saturated aqueous NaCl (150 mL) and distilled under vacuum to ˜60 mL. DCM (50 mL) was added and distilled off. DCM (200 mL) was added and the mixture was cooled 0-5° C. TFA (70 mL) was added slowly (slightly exothermic) at below 15° C., and the mixture was stirred at 20° C. for 16 hours. The mixture was concentrated to ˜150 ml, and IPAc (150 mL) was added. The mixture was distilled to ˜150 mL. Additional IPAc (150 mL) was added, and again distilled to ˜150 mL. IPAc (200 mL) was added and the resulting solution was slowly added to pre-cooled K2CO3 (52 g) in water (250 mL) at below 10° C. (mildly exothermic, pH>7 must >6 during quench) over 15 minutes. The pH was monitored during the transfer, and additional base (8 g) was added when the pH dropped below 6. The IPAc layer was separated and washed with saturated aqueous NaCl (150 mL). The IPAc solution was distilled to ˜50 mL. MTBE (100 mL) was added and the mixture distilled to ˜50 mL. Additional MTBE (100 mL) was added and the mixture was stirred at room temperature for 3 hours, forming a slurry, which was then stirred at 4° C. for 16 hours. The solids were filtered off and washed with MTBE/diisopropyl ether (1:1; 100 mL). The solids were then dried at room temperature for 60 hours under nitrogen to yield the title compound as a crystalline material (18.2 g).

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