反应详情

To a chilled solution of t-butoxycarbonyl D-alanine (9.45 g, 0.05 mol) and 1-(2-methoxyphenyl)piperazine (9.6 g, 0.05 mol) in 125 mL of CH2Cl2 was added diethyl cyanophosphonate (8.34 mL, 0.055 mol) in 50 mL of CH2Cl2 over 30 minutes followed by triethylamine (7.37 mL, 0.055 mol) in 50 mL of CH2Cl2 over 15 minutes. After 21/2 hours, the solution was washed with water (2×100 mL) and K2CO3 (2×100 mL of 10% aqueous), dried over anhydrous K2CO3 and evaporated to an oil. The crude 1-(t-butoxycarbonyl-D-alanyl)-4-(2-methoxyphenyl)piperazine was stirred in 200 mL of 4.5N HCl in ethyl acetate for 1 hour at room temperature, diluted with 400 mL of anhydrous diethyl ether, filtered, washed and dried in vacuo. The 1-(D-alanyl)-4-(2-methoxyphenyl)piperazine dihydrochloride was stirred in 200 mL of anhydrous tetrahydrofuran, treated with 225 mL of 1M BH3 in tetrahydrofuran, and refluxed 31/2 hours. After cooling in ice, the reaction was quenched with 140 mL of 2N aqueous HCl and refluxed 18 hours The tetrahydrofuran was removed on a Rotovapor, the aqueous solution was made basic with 6N sodium hydroxide and the amine was extracted into diethyl ether. The diethyl ether solution was dried over anhydrous K2CO3, filtered and acidified with 4.5N HCl in ethyl acetate. The salt was filtered, washed with diethyl ether, converted to free base in 2N NaOH and extracted into diethyl ether. After drying as above and evaporation, (R)-1-methyl-2-[4-(2-methoxyphenyl)-piperazinyl]ethylamine was obtained as an oil (11.8 g, 94.7% based on BOC-D-alanine). A sample was converted to the trihydrochloride sesquihydrate, mp. 219°-221° C.; [α]D25 =-26.4 c=0.99 MeOH. 1H NMR (DMSO-d6) δ: 1.32 (d, 3H), 3.8 (s, 3H), 6.9-7.0 (m, 4H). The IR curve was devoid of carbonyl peaks.

1. washAfter 21/2 hours, the solution was washed with water (2×100 mL) and K2CO3 (2×100 mL of 10% aqueous)
2. dry with materialdried over anhydrous K2CO3
3. customevaporated to an oil
4. additiondiluted with 400 mL of anhydrous diethyl ether
5. filtrationfiltered
6. washwashed
7. customdried in vacuo
8. stirringThe 1-(D-alanyl)-4-(2-methoxyphenyl)piperazine dihydrochloride was stirred in 200 mL of anhydrous tetrahydrofuran
9. additiontreated with 225 mL of 1M
10. temperaturein tetrahydrofuran, and refluxed 31/2 hours
11. temperatureAfter cooling in ice
12. customthe reaction was quenched with 140 mL of 2N aqueous HCl
13. temperaturerefluxed 18 hours The tetrahydrofuran
14. customwas removed on a Rotovapor
15. extractionthe amine was extracted into diethyl ether
16. dry with materialThe diethyl ether solution was dried over anhydrous K2CO3
17. filtrationfiltered
18. filtrationThe salt was filtered
19. washwashed with diethyl ether
20. extractionextracted into diethyl ether
21. customAfter drying as above and
22. customevaporation