Reaktion #473867

Reaktionsgleichung

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

succinic acid

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

→

title compound

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 succinate salt

Lösungsmittel

acetone

acetone

acetone

acetone

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturheating
2. 2
   workup.WAITcontinued at 45° C. for 1 h
3. 3
   TemperaturThe suspension was cooled to 25° C. over 1 h
4. 4
   workup.STIRRINGstirred for a further 1 h
5. 5
   FiltrationThe suspension was filtered over a glass frit
6. 6
   Waschenthe filter cake was washed with acetone (2×5 g)
7. 7
   SonstigeThe filter cake was dried at 50° C.

Vorschrift

The solution of succinic acid (0.50 g, 4.23 mmol) in acetone (20 ml) was heated at 45° C. for 1 h and treated with a portion of the solution of 3-(3-{2-[(E)-3,5-diamino-6-chloro-pyrazine-2-carbonylimino]-1,3,8-triaza-spiro[4.5]decane-8-carbonyl}-benzenesulfonyl amino)-propionic acid dipropylcarbamoylmethyl ester in acetone (1.62 g of solution) over 10 min. The resulting mixture was treated with a suspension of seed crystals of 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 prepared using method C, 20 mg) in acetone (300 mg) and stirred at 45° C. for 30 min. The remaining solution of 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 dipropylcarbamoyl methyl ester in acetone (31.38 g) was added to the mixture over 5 h and heating continued at 45° C. for 1 h. The suspension was cooled to 25° C. over 1 h and stirred for a further 1 h. The suspension was filtered over a glass frit and the filter cake was washed with acetone (2×5 g). The filter cake was dried at 50° C. to afford the title compound; HPLC Rt 4.02 min, method ii; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (1H, m), 7.78 (1H, m), 7.69 (1H, m), 7.68 (1H, m), 6.85 (2H, br s), 4.73 (2H, s), 3.84-3.20 (6H and water, br hump), 3.17-3.09 (4H, m), 3.04 (2H, t), 2.53 (2H, under DMSO), 2.39 (4H, s), 1.80 (2H, br s), 1.70 (2H, br s), 1.55-1.37 (4H, m), 0.85 (3H, t), 0.78 (3H, t) (Please note: The two exchangeable succinate protons and 3-4 acidic NH resonances were not observed directly due to the very broad nature of some of the exchangeable resonances; Melting Temperature Tm (DSC)=149° C.

Quelle