Reaktion #2257260

Reaktionsgleichung

EDCI.HCl

3-(2-dipropylcarbamoylmethoxycarbonyl-ethylsulfamoyl)-benzoic acid

N-methylmorpholine

HOBt hydrate

3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride

3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride

2-MeTHF

Na2CO3

→

3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid dipropylcarbamoylmethyl ester

Lösungsmittel

THF

water

Reaktionsbedingungen

Aufarbeitung

1. 1
   TemperaturThe internal temperature was maintained at ≦20° C
2. 2
   Sonstigehad formed
3. 3
   workup.STIRRINGthe reaction was stirred at RT for 24 h
4. 4
   SonstigeThe layers were separated
5. 5
   Waschenthe aqueous phase washed with additional 2-MeTHF (100 ml)
6. 6
   WaschenThe combined organic layers were washed with 2% aq. Na2CO3 (200 ml) and water (2×200 ml)
7. 7
   workup.ADDITIONAcetonitrile (100 ml) was added
8. 8
   Einengenthe solution concentrated at 30° C. to a volume of 70 ml
9. 9
   workup.ADDITIONAcetonitrile (300 ml) was added
10. 10
    Einengenthe solution concentrated again at 30° C. to a volume of 150 ml
11. 11
    workup.ADDITIONmaleic acid (1.62 g) was added to the resulting solution
12. 12
    SonstigeAn off-white precipitate formed immediately
13. 13
    Temperaturto cool to RT over 1 h
14. 14
    FiltrationThe solid was collected by filtration

Vorschrift

To a stirred solution of 3-(2-dipropylcarbamoylmethoxycarbonyl-ethylsulfamoyl)-benzoic acid (Int. AA) (6.1 g, 12.60 mmol) in THF (50 ml) was added sequentially water (25 ml), N-methylmorpholine (7 ml, 63 mmol) and HOBt hydrate (2.9 g, 18.9 mmol). The internal temperature was maintained at ≦20° C. 3,5-Diamino-6-chloro-pyrazine-2-carboxylic acid [1,3,8-triaza-spiro[4.5]dec-(2E)-ylidene]-amide hydrochloride (WO09074575, Ex. 38, page 123) (65% purity, 6.3 g, 12.6 mmol) was added and stirred until a clear solution had formed. EDCI.HCl (3.6 g, 18.9 mmol) was added, and the reaction was stirred at RT for 24 h. 2-MeTHF (200 ml) and 2% aq. Na2CO3 (150 ml) were added to the reaction mixture. The layers were separated, and the aqueous phase washed with additional 2-MeTHF (100 ml). The combined organic layers were washed with 2% aq. Na2CO3 (200 ml) and water (2×200 ml). Acetonitrile (100 ml) was added, and the solution concentrated at 30° C. to a volume of 70 ml. Acetonitrile (300 ml) was added, and the solution concentrated again at 30° C. to a volume of 150 ml. The solution was heated to 50° C. and maleic acid (1.62 g) was added to the resulting solution. An off-white precipitate formed immediately, the temperature was allowed to cool to RT over 1 h. The solid was collected by filtration to afford 3-(3-{2-[(E)-3,5-Diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonylamino)-propionic acid dipropylcarbamoylmethyl ester as a maleate salt; DCM (200 ml) and 2% aq. Na2CO3 (200 ml) were added and stirred until the solid had fully dissolved. The organic layer was separated, washed with water (2×100 ml) and concentrated in vacuo to afford the title compound. LC-MS 722.1 [M+H]+, Method (i); 1H NMR (400 MHz, DMSO-d6) δ 9.12-7.57 (4H, br), 7.88 (1H, m), 7.77 (1H, m), 7.70 (1H, m), 7.68 (1H, m), 7.05-6.50 (2H, br s), 6.95-6.20 (1H, br s), 4.73 (2H, s), 3.81-3.39 (2H, m), 3.61-3.31 (2H, m), 3.43 (2H, br s), 3.15-3.11 (4H, m), 3.04 (2H, t), 2.51 (2H, t), 1.79-1.69 (m, 4H), 1.51-1.43 (4H, m), 0.84 (3H, t), 0.78 (3H, t)

Quelle