Reaktion #7301

Reaktionsgleichung

ammonia

N-ethyldiisopropylamine

(S)-2-benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid

isobutyl chloroformate

→

Benzyl (S)-[1-carbamoyl-2-(pyridin-3-yl)-ethyl]carbamate

Lösungsmittel

tetrahydrofuran

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturthe internal temperature in the end increasing to −6° C
2. 2
   Sonstigein the course of 3 h
3. 3
   Temperaturthe reaction mixture was warmed to 16° C.
4. 4
   Sonstigewhich gave a thick but still stirrable crystal slurry
5. 5
   SonstigeAt a jacket temperature of 30° C., the solvent was removed under reduced pressure
6. 6
   workup.ADDITIONA solution of sodium hydrogen carbonate (3.0 kg) in water (50 l) was added
7. 7
   workup.DISSOLUTIONafter which all of the solid had dissolved
8. 8
   SonstigeThe organic phase was separated off
9. 9
   Trocknendried over sodium sulfate (1.0 kg)
10. 10
    Filtrationthe drying agent was filtered off
11. 11
    Einengenthe filtrate was concentrated under reduced pressure at a bath temperature of 30° C. to a volume of about 6 l
12. 12
    FiltrationThe resulting precipitate was filtered off with suction
13. 13
    Waschenwashed with ethyl acetate (1.5 l)
14. 14
    Sonstigedried at 30° C. under reduced pressure
15. 15
    SonstigeThe chemical purity was 99.9% (HPLC: 125×4.0 mm RP18 Purospher, 40° C., detection 210 nm)
16. 16
    Sonstigethe enantiomeric purity was 100% ee (HPLC: 250×4.6 mm CSP Chiralpak AD Daicel, 40° C.; detection 248 nm; mobile phase: n-hexane/isopropanol/ethanol 84/12/4+0.1% diethylamine; tret [(S)-isomer] 14.93 min)

Vorschrift

A suspension of (S)-2-benzyloxycarbonylamino-3-(pyridin-3-yl)propionic acid (2.60 kg, 8.65 mol) in tetrahydrofuran (60 l) was cooled to −9° C. At this temperature, N-ethyldiisopropylamine (1.33 kg, 10.29 mol) was added over a period of 5 min. At −9° C., isobutyl chloroformate (1.36 kg, 9.96 mol) was then added within 20 min, the internal temperature in the end increasing to −6° C. After 10 min of vigorous stirring, ammonia gas (2.1 kg, about 123 mol) was introduced at a constant temperature of (−5)–(−6)° C. into the resulting thin suspension in the course of 3 h. The reaction was initially strongly exothermic (requires initially slow introduction), later on less exothermic. Over a period of 30 min, the reaction mixture was warmed to 16° C., which gave a thick but still stirrable crystal slurry. At a jacket temperature of 30° C., the solvent was removed under reduced pressure. The white, greasy residue was suspended in ethyl acetate (125 l). A solution of sodium hydrogen carbonate (3.0 kg) in water (50 l) was added and the mixture was stirred vigorously for 30 min, after which all of the solid had dissolved. The organic phase was separated off and dried over sodium sulfate (1.0 kg), the drying agent was filtered off and the filtrate was concentrated under reduced pressure at a bath temperature of 30° C. to a volume of about 6 l. The resulting precipitate was filtered off with suction, washed with ethyl acetate (1.5 l) and dried at 30° C. under reduced pressure. Yield: 2.26 kg (7.55 mol, 87.3% of theory). The chemical purity was 99.9% (HPLC: 125×4.0 mm RP18 Purospher, 40° C., detection 210 nm); the enantiomeric purity was 100% ee (HPLC: 250×4.6 mm CSP Chiralpak AD Daicel, 40° C.; detection 248 nm; mobile phase: n-hexane/isopropanol/ethanol 84/12/4+0.1% diethylamine; tret [(S)-isomer] 14.93 min). M.p.: 152.8° C. (by DSC); MS (ESI+): m/z (%): 300 ([M+H+], 100); 1H-NMR (200 MHz, DMSO-d6): δ=2.77 (dd, J=9.5 and 7.0 Hz, 1H), 3.02 (dd, J=9.5 and 3.5 Hz, 1H), 4.19 (m, 1H), 4.96 (s, 3H), 7.00–7.40 (m, 7H), 7.40–7.60 (m, 2H), 7.60–7.76 (m, 1H), 8.36–8.53 (m, 2H); IR (KBr): ν=3306.8, 1674.9, 1537.7, 1424.0, 1271.6, 1251.3 cm−1.

Quelle