Reaktion #11272

Reaktionsgleichung

KOH

hydrochloride

(2S)-4,4-Difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide

K2CO3

Pyridine

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

SOCl2

→

(2S)-4,4-difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide

Ausbeute 96.9%

Lösungsmittel

methanol

acetonitrile

acetonitrile

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturcooling
2. 2
   TemperaturThe mixture was warmed to ambient temperature for 1 h
3. 3
   Temperaturwas then cooled to 10° C
4. 4
   TemperaturThe mixture was warmed to ambient temperature for 1 h
5. 5
   Einengenwas then concentrated to a weight of 1.5 kg
6. 6
   Sonstigea rotary evaporator
7. 7
   SonstigeThe resulting mixture was partitioned between 0.5 N HCl (1.6 L) and ethyl acetate (1.4 L)
8. 8
   Sonstigethe layers were separated
9. 9
   WaschenThe organic fraction was sequentially washed with saturated aqueous NaHCO3 (1.4 L), 0.5 N HCl (1.6 L)
10. 10
    EinengenThe organic fraction was concentrated to a wet solid
11. 11
    Sonstigea rotary evaporator
12. 12
    Sonstigewas then further dried in a vacuum oven at 50° C. for 24 h
13. 13
    workup.DISSOLUTIONThe resulting solid was dissolved in absolute ethanol (800 mL)
14. 14
    Einengenwas then concentrated on a rotary evaporator
15. 15
    workup.DISSOLUTIONThe resulting solid was once again dissolved in ethanol (600 mL)
16. 16
    Einengenconcentrated on a rotary evaporator
17. 17
    Sonstigedried in a vacuum oven at 50° C. for 24 h
18. 18
    workup.DISSOLUTIONThe solid was dissolved in ethanol
19. 19
    workup.ADDITION0.11 N HCl (620 mL) was then slowly added
20. 20
    workup.ADDITIONH2O (950 mL) was slowly added
21. 21
    workup.ADDITIONthe resulting suspension of crystals
22. 22
    workup.STIRRINGwas stirred overnight
23. 23
    FiltrationThe solid was filtered
24. 24
    Waschenwashed with ethanol/H2O (1:3, 200 mL)
25. 25
    Sonstigedried in a vacuum oven at 55° C.

Vorschrift

Pyridine (149 g, 1.89 mol) was added to a solution of (2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyric acid (193 g, 468 mmol) and acetonitrile (1.6 L) at ambient temperature, and the mixture was then cooled to 10° C. A solution of SOCl2 (62.3 g, 523 mmol) and acetonitrile (50 mL) was added over 15 min., and cooling was then discontinued. 15 minutes later, additional SOCl2 (0.80 g, 6.7 mmol) was added. After stirring at ambient temperature for 25 min., the mixture was cooled to 10° C. (2S)-4,4-Difluoro-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide; hydrochloride (139 g, 468 mmol) was added in portions over 15 min. The mixture was warmed to ambient temperature for 1 h, and was then cooled to 10° C. A 5° C. solution of KOH (85% assay; 186 g, 2.82 mol) and methanol (1.1 L) was then added over 10 min, followed by addition of K2CO3 (51.8 g, 375 mmol). The mixture was warmed to ambient temperature for 1 h, and was then concentrated to a weight of 1.5 kg using a rotary evaporator. The resulting mixture was partitioned between 0.5 N HCl (1.6 L) and ethyl acetate (1.4 L), and the layers were separated. The organic fraction was sequentially washed with saturated aqueous NaHCO3 (1.4 L), 0.5 N HCl (1.6 L), and then H2O (1.4 L). The organic fraction was concentrated to a wet solid using a rotary evaporator, and was then further dried in a vacuum oven at 50° C. for 24 h. The resulting solid was dissolved in absolute ethanol (800 mL), and was then concentrated on a rotary evaporator. The resulting solid was once again dissolved in ethanol (600 mL), then concentrated on a rotary evaporator, and then dried in a vacuum oven at 50° C. for 24 h. The solid was dissolved in ethanol and 0.11 N HCl (620 mL) was then slowly added. H2O (950 mL) was slowly added and the resulting suspension of crystals was stirred overnight. The solid was filtered, washed with ethanol/H2O (1:3, 200 mL), and dried in a vacuum oven at 55° C. to provide 259 g (96.9%) of (2S)-4,4-difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-3,3-dimethyl-pyrrolidine-2-carboxylic acid (2,2,2-trifluoro-ethyl)-amide as a white crystalline solid: 1H NMR (300 MHz, DMSO-d6) displayed a ˜20:1 mixture of rotamers. Major rotamer resonances δ 9.34 (s, 1H), 8.66 (app t, J=6.3 Hz, 1H), 8.13 (d, J=8.3 Hz, 1H), 7.15–7.35 (m, 5H), 6.96 (app t, J=7.7 Hz, 1H), 6.79 (d, J=7.3 Hz, 1H), 6.55 (d, J=6.7 Hz, 1H), 5.56 (d, J=6.4 Hz, 1H), 4.26–4.54 (m, 5H), 3.81–4.07 (m, 2H), 2.86–2.90 (m, 1H), 2.71 (app dd, J=10.5, 13.6 Hz, 1H), 1.82 (s, 3H), 1.22 (s, 3H), 1.04 (s, 3H) [characteristic minor rotamer resonances δ 8.62 (5, J=6.5 Hz), 5.35 (d, J=7.6 Hz), 1.86 (s)]; 13C NMR (75 MHz, DMSO-d6) displayed a ˜20:1 mixture of rotamers. Major rotamer resonances δ 171.5, 169.6, 168.6, 155.7, 139.6, 139.4, 129.8, 128.2, 127.9 (dd, JCF=251.7, 253.5 Hz), 126.2, 126.0, 125.0 (q, JCF=279.2 Hz), 121.8, 117.9, 115.6, 73.2, 68.3, 53.0, 51.4 (t, JCF=32.6 Hz), 43.8 (t, JCF=20.8 Hz), 34.5, 22.4 (d, JCF=4.1 Hz), 16.9 (d, JCF=7.3 Hz), 12.5 [characteristic minor rotamer resonances δ 171.7, 139.1, 129.5, 68.7, 47.0 (t), 16.5 (d)]; MS (CI) m/z 572.2189 (527.2184 calcd for C27H31N3O5F5, M+H+).

Quelle