تفاعل #331245

معادلة التفاعل

TBTU

HCl

3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid

DIEA

TBTU

1-aminocyclohexanecarboxylic acid

3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid

→

1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride

المردود 100.4%

المذيبات

NMP

acetonitrile

water

DCM MeOH

ظروف التفاعل

المعالجة

1. 1
   أخرىis brought to 90° C.
2. 2
   workup.DISSOLUTIONthe medium dissolves completely
3. 3
   workup.STIRRINGAfter stirring for 2 hours at room temperature
4. 4
   workup.STIRRINGstirring
5. 5
   workup.WAITis continued for 18 hours
6. 6
   استخلاصAfter extraction
7. 7
   استخلاصthe aqueous phase is again extracted with 10 mL of a 9/1 DCM/MeOH mixture
8. 8
   تجفيفdried over Na2SO4
9. 9
   تركيزconcentrated under reduced pressure
10. 10
    أخرىThe residue is then purified by reverse-phase HPLC (RP18)
11. 11
    تركيزAfter concentrating under reduced pressure
12. 12
    أخرىfreeze-drying

الإجراء التجريبي

To a solution of 1.49 g (3.1 mmol) of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid in 15 mL of anhydrous NMP are added under argon 1.62 mL (9.3 mmol) of DIEA and 2.83 g (8.82 mmol) of TBTU. In parallel, a mixture of 421 mg (2.94 mmol) of 1-aminocyclohexanecarboxylic acid and 1.51 mL (6.19 mmol) of BSA in 15 mL of anhydrous acetonitrile is brought to 90° C. with stirring and under argon. After 2 hours, the medium dissolves completely and the solution is cooled to room temperature and then added to the solution of 3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridine-6′-carboxylic acid activated with TBTU. After stirring for 2 hours at room temperature, 10 mL of aqueous 0.5N HCl solution are added and stirring is continued for 18 hours. The reaction medium is then poured into a mixture of 100 mL of 9/1 DCM/MeOH and 10 mL of water. After extraction, the aqueous phase is again extracted with 10 mL of a 9/1 DCM/MeOH mixture. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The residue is then purified by reverse-phase HPLC (RP18) using an aqueous 10−2N HCl/acetonitrile gradient of from 5% to 100% acetonitrile. After concentrating under reduced pressure and freeze-drying, 1 g of 1-{[(3,5-dichloro-2′-{4-chloro-3-[3-(dimethylamino)propoxy]phenyl}-2,3′-bipyridin-6′-yl)carbonyl]amino}cyclohexanecarboxylic acid hydrochloride is obtained in the form of a white powder.

المصدر