Reaktion #1463474

Reaktionsgleichung

HCl

SOCl2

(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid chloride

(R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide

KOH methanol

(2S,3 S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid

pyridine

(R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride

pyridine

acetic acid 3-{(1S,2S)-2-acetoxy-3-[(R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester

KOH methanol

KOH

→

(4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide

Ausbeute 59.6%

Lösungsmittel

ethyl acetate

H2O

CH3CN

CH3CN

methanol

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturwas then cooled to 15° C
2. 2
   Temperaturwhile maintaining the temperature at 15° C
3. 3
   workup.WAITThe mixture was held at 15° C. for 6 h
4. 4
   Sonstigeusing a 0° C.
5. 5
   Temperaturcooling jacket
6. 6
   Temperaturwhile maintaining the temperature at 10° C
7. 7
   workup.ADDITIONAfter addition
8. 8
   workup.WAITthe mixture was held at 25° C. for 3 h
9. 9
   Temperaturwhile maintaining the temperature at 20° C
10. 10
    SonstigeThe resulting layers were separated
11. 11
    WaschenThe organic fraction was sequentially washed with 6.8 wt. % aqueous NaHCO3 (770 L)
12. 12
    EinengenThe resulting organic fraction was partially concentrated by distillation at one atmosphere
13. 13
    workup.DISTILLATIONdistillation
14. 14
    Temperaturmaintaining the pot temperature at ≧70° C
15. 15
    workup.ADDITIONEthyl acetate was added such that the pot volume
16. 16
    TemperaturThe solution was then cooled to 20° C.
17. 17
    Sonstigeheld at this temperature until crystallization
18. 18
    workup.ADDITIONn-Heptane (280 L) was added
19. 19
    Waschenfor rinsing
20. 20
    SonstigeThe wet cake was dried under vacuum at 45° C.
21. 21
    Sonstigeto provide crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide
22. 22
    SonstigeDecolorization and recrystallization
23. 23
    workup.ADDITIONA mixture of crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide, ADP carbon (21 kg), Supercel (3 kg), and ethyl acetate (780 L)
24. 24
    Temperaturwas heated to 70° C
25. 25
    workup.ADDITIONCH3OH (40 L) was added to the mixture
26. 26
    FiltrationThe mixture was filtered
27. 27
    Temperaturthe resulting clear filtrate was heated
28. 28
    Temperaturto reflux at one atmosphere
29. 29
    workup.DISTILLATIONdistillation
30. 30
    workup.ADDITIONethyl acetate (388 L) was charged
31. 31
    Temperaturwhile maintaining the pot volume at approximately 840 L
32. 32
    Sonstigeat 70° C
33. 33
    workup.ADDITIONThe solution was slowly charged with n-heptane (316 L)
34. 34
    Temperaturwhile maintaining a temperature of 70° C
35. 35
    TemperaturThe mixture was then cooled to 20° C.
36. 36
    workup.WAITwas held at this temperature for 4 h
37. 37
    FiltrationThe crystals were filtered
38. 38
    Waschenfor rinsing
39. 39
    SonstigeThe wet cake was dried under vacuum at 45° C.

Vorschrift

A solution of (2S,3 S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid (140 kg, 339 mol), CH3CN (560 L), and pyridine (64.3 kg, 813 mol) was cooled to 15° C. SOCl2 (44.3 kg, 373 mol) was charged while maintaining the temperature at 15° C. The mixture was held at 15° C. for 1 h. A separate reactor was charged with (R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride (96.6 kg, 408 mol), CH3CN (254 L), and pyridine (29.5 kg, 373 mol), and was then cooled to 15° C. The (2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid chloride solution was added to the (R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide solution, while maintaining the temperature at 15° C. The mixture was held at 15° C. for 6 h. A separate reactor was charged with KOH (167 kg, 2709 mol) and methanol (280 L) using a 0° C. cooling jacket. The resulting KOH/methanol solution was cooled to 5° C. The crude acetic acid 3-{(1S,2S)-2-acetoxy-3-[(R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-3-oxo-propylcarbamoyl}-2-methyl-phenyl ester mixture was added to the KOH/methanol solution while maintaining the temperature at 10° C. After addition was complete, the mixture was held at 25° C. for 3 h. The mixture was charged with H2O (840 L) and ethyl acetate (840 L), and was then followed by acidification to pH 5–6.5 with concentrated HCl (85 kg) while maintaining the temperature at 20° C. The resulting layers were separated. The organic fraction was sequentially washed with 6.8 wt. % aqueous NaHCO3 (770 L), an aqueous HCl/NaCl solution (H2O: 875 L; conc. HCl: 207 kg; NaCl: 56 kg), 8.5 wt. % aqueous NaHCO3 (322 L), and then with 3.8 wt. % aqueous NaCl (728 L). The resulting organic fraction was partially concentrated by distillation at one atmosphere. The solvent was exchanged with ethyl acetate by continuing distillation and maintaining the pot temperature at ≧70° C. Ethyl acetate was added such that the pot volume remained at approximately 840 L. The solution was then cooled to 20° C. and held at this temperature until crystallization was observed. n-Heptane (280 L) was added and the suspension was agitated at 15° C. for 4 h. The crystals were, using cold 2.4:1 (v/v) ethyl acetate/n-heptane for rinsing. The wet cake was dried under vacuum at 45° C. to provide crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide. Decolorization and recrystallization was conducted as follows: A mixture of crude (R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide, ADP carbon (21 kg), Supercel (3 kg), and ethyl acetate (780 L) was heated to 70° C. CH3OH (40 L) was added to the mixture. The mixture was filtered, and the resulting clear filtrate was heated to reflux at one atmosphere to begin distillation. CH3OH was displaced as follows: ethyl acetate (388 L) was charged while maintaining the pot volume at approximately 840 L and at 70° C. The solution was slowly charged with n-heptane (316 L), while maintaining a temperature of 70° C. The mixture was then cooled to 20° C. and was held at this temperature for 4 h. The crystals were filtered, using cold 2.1:1 (v/v) ethyl acetate/n-heptane for rinsing. The wet cake was dried under vacuum at 45° C. to give 103 kg (59.6%) of (4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide as a white crystalline solid: mp=173–175° C., 1H NMR (300 MHz, DMSO-d6) displayed a ˜10:1 mixture of rotamers, major rotamer resonances δ 9.35 (s, 1H), 8.04–8.15 (m, 2H), 7.13–7.38 (m, 5H), 6.96 (t, J=7.7 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H), 5.71–5.87 (m, 1H), 5.45 (br d, J=6.2 Hz, 1H), 4.98–5.27 (m, 4H), 4.38–4.52 (m, 3H), 3.58–3.86 (m, 2H), 2.68–2.90 (m, 2H), 1.84 (s, 3H), 1.52 (s, 3H), 1.37 (s, 3H) [characteristic minor rotamer resonances δ 9.36 (s), 8.21 (d, J=10.5 Hz), 7.82 (5, J=5.8 Hz), 4.89 (s), 4.78 (AB q, JAB=9.8 Hz, Δν=27.1 Hz), 4.17–4.24 (m), 2.93–3.01 (m), 1.87 (s), 1.41 (s)]; 13C NMR (75 MHz, DMSO-d6) displayed a ˜10: 1 mixture of rotamers, major rotamer resonances δ 170.4, 169.5, 168.2, 155.7, 139.6, 139.4, 135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72.4, 72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristic minor rotamer resonances δ 171.4, 169.7, 168.6, 139.0, 129.5, 128.4, 70.6, 54.2, 49.1, 41.5, 31.4, 24.8]; MS (CI) m/z 512.2224 (512.2219 calcd for C27H34N3O5S, M+H+), elemental analysis calcd for C27H33N3O5S: C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.

Quelle