반응 #511383

반응 방정식

1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid

(1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester

Triethylamine

N-Methylmorpholine

→

N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide

수율 78.0%

용매

acetonitrile

반응 조건

후처리

1. 1
   온도The suspension was cooled to 0° C.
2. 2
   workup.STIRRINGThe mixture was stirred at 0° C. for 3 h
3. 3
   온도to warm to 23° C.
4. 4
   workup.STIRRINGstirred overnight
5. 5
   온도the mixture was then heated at 50° C. for 3 h
6. 6
   농축The mixture was partially concentrated in vacuo at 45° C.
7. 7
   workup.ADDITIONwas then diluted with ethyl acetate (22.5 L)
8. 8
   세척washed with 2.0 M aqueous hydrochloric acid solution (22.6 L)
9. 9
   추출The resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L)
10. 10
    세척The combined organic extracts were washed with 1.0 M aqueous hydrochloric acid solution (10.4 L)
11. 11
    여과The resulting organic fraction was filtered through Celite (600 g)
12. 12
    농축the filtrate was then partially concentrated in vacuo at 45° C
13. 13
    workup.ADDITIONAbsolute ethanol (5.6 L) was added to the residue
14. 14
    온도the mixture was then heated at 50° C.
15. 15
    workup.STIRRINGwith stirring
16. 16
    workup.ADDITIONDichloromethane (400 mL) was added in portions until crystallization
17. 17
    workup.ADDITIONAbsolute ethanol (20.7 L) was added in portions over 1 h
18. 18
    workup.STIRRINGthe resulting mixture was stirred at 23° C. overnight
19. 19
    여과The mixture was filtered
20. 20
    세척the solid was then washed with absolute ethanol (1.9 L)
21. 21
    기타The solid was further dried in vacuo at 45° C.

실험 절차

(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 1.88 kg, 5.63 mol) and (1S,2R,3S,4R)-3-(4-fluoro-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 61, 1.72 kg, 5.91 mol) were dissolved in acetonitrile (18.8 L) at 23° C. N-Methylmorpholine (1.25 kg, 12.4 mol) was added and the resulting suspension was stirred at 23° C. for 1 h. The suspension was cooled to 0° C. and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.19 kg, 6.20 mol) was added in one portion. The mixture was stirred at 0° C. for 3 h, and was then allowed to warm to 23° C. and stirred overnight. Triethylamine (1.88 kg, 18.6 mol) was added and the mixture was then heated at 50° C. for 3 h. The mixture was partially concentrated in vacuo at 45° C., and was then diluted with ethyl acetate (22.5 L) and washed with 2.0 M aqueous hydrochloric acid solution (22.6 L). The resulting aqueous fraction was extracted with ethyl acetate (2×9.4 L). The combined organic extracts were washed with 1.0 M aqueous hydrochloric acid solution (10.4 L) and then with water (18.8 L). The resulting organic fraction was filtered through Celite (600 g), and the filtrate was then partially concentrated in vacuo at 45° C. Absolute ethanol (5.6 L) was added to the residue, and the mixture was then heated at 50° C. with stirring. Dichloromethane (400 mL) was added in portions until crystallization initiated. Absolute ethanol (20.7 L) was added in portions over 1 h, and the resulting mixture was stirred at 23° C. overnight. The mixture was filtered and the solid was then washed with absolute ethanol (1.9 L). The solid was further dried in vacuo at 45° C. to afford the desired product, N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (2.46 kg, 4.39 mol, 78%), as an off-white crystalline solid.

출처