|
Stage #1: (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid With triethylamine; chlorophosphoric acid diphenyl ester In ethyl acetate at 0 - 2℃; for 0.116667h;
Stage #2: 1-amino-2-propene In ethyl acetate at 0 - 20℃; for 0.5h; |
1 Preparation of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic Acid Tert-Butyl Ester
(4R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester (which can be prepared according to the methods of Ikunaka, M. et al., Tetrahedron Asymm. 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem. 1999, 42, 1789; and Mimoto, T. et al., European Patent Application 0574135A1 (1993), 250 g; 0.957 mol) was added to an argon-purged 5-L flask and was dissolved in EtOAc (1.25 L). The solution was cooled to 2° C. and (PhO)2POCl (208 mL; 1.00 mol) was then added in one portion. NEt3 (280 mL; 2.01 mol) was added dropwise via addition funnel and the resulting suspension was then stirred at 0° C. Seven minutes later, allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath was removed and the suspension was allowed to warm to room temperature. One-half hour later, 1 N HCl (750 mL; 0.750 mol) was added. The mixture was transferred to a 4-L separatory funnel using EtOAc (50 mL) for rinsing. The layers were separated. The organic fraction was washed with 7.2% aqueous Na2CO3 (2×1.25 L), and was then transferred to a 3-L distillation flask and was diluted with EtOAc (400 mL). The solution was dried azeotropically and concentrated to a volume of 800 mL by distillation of EtOAc at one atmosphere. After cooling to 25° C., the resulting clear yellowish EtOAc solution of (4R)-4-allylcarbamoyl-5,5dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester was carried on directly into the next step. An aliquot was removed and concentrated to give (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester as a white crystalline solid: mp=94-98° C., 1H NMR (300 MHz, CDCl3) δ 6.12 (br s, 1H), 5.88 (app ddt, J=10.2, 17.1, 5.6 Hz, 1H), 5.28 (app dq, J=17.1, 1.5 Hz, 1H), 5.18 (app dd, J=1.2, 10.2 Hz, 1H), 4.68 (s, 2H), 4.14 (br s, 1H), 3.95 (br t, J=5.4 Hz, 2H), 1.62 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 170.0, 154.0, 134.4, 116.9, 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6; MS (Cl) m/z 301.1599 (301.1586 calcd for C14H25N2O3S, M+H+); elemental analysis calcd for C14H24N2O3S: C, 55.97; H, 8.05; N, 9.32; found: C, 56.11; H, 8.01; N, 9.11. |
|
Stage #1: (R)-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid With chlorophosphoric acid diphenyl ester In ethyl acetate at 2℃;
Stage #2: With triethylamine In ethyl acetate at 0 - 5℃; for 0.116667 - 2h;
Stage #3: 1-amino-2-propene In ethyl acetate at 0 - 20℃; for 0.5h; |
38; 44
Example 38: Preparation of (4R)-4-allylcarbamoyl-5, 5-dimethyl-thiazolidine-3-carboxylic acid tert- butyl ester; (4R) -5, 5-Dimethyl-thiazolidine-3, 4-dicarboxylic acid 3-tert-butyl ester (which can be prepared according to the methods of Ikunaka, M. et al., Tetrahedron Asymm. 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem. 1999,42, 1789; and Mimoto, T. et al., European Patent Application 0574135A1 (1993), 250 g ; 0.957 mol) was added to an argon-purged 5-L flask and was dissolved in EtOAc (1.25 L). The solution was cooled to 2 °C and (PhO) 2POCI (208 mL; 1.00 mol) was then added in one portion. NEt3 (280 mL; 2.01 mol) was added dropwise via addition funnel and the resulting suspension was then stirred at 0 °C. Seven minutes later, allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath was removed and the suspension was allowed to warm to room temperature. One-half hour later, 1 N HCI (750 mL; 0.750 mol) was added. The mixture was transferred to a 4-L separatory funnel using EtOAc (50 mL) for rinsing. The layers were separated. The organic fraction was washed with 7.2% aqueous Na2CO3 (2 x 1.25 L), and was then transferred to a 3-L distillation flask and was diluted with EtOAc (400 mL). The solution was dried azeotropically and concentrated to a volume of 800 mL by distillation of EtOAc at one atmosphere. After cooling to 25 °C, the resulting clear yellowish EtOAc solution of (4R)-4-allylcarbamoyl-5, 5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester was carried on directly into the next step. An aliquot was removed and concentrated to give (4R)-4- allylcarbamoyl-5, 5-dimethyl-thiazolidine-3-carboxylic acid tert-butyl ester as a white crystalline solid : mp = 94-98 °C, 1H NMR (300 MHz, CDCb) õ 6. 12 (br s, 1H), 5.88 (app ddt, J = 10. 2, 17.1, 5.6 Hz, 1H), 5.28 (app dq, J = 17.1, 1.5 Hz, 1 H), 5.18 (app dd, J = 1.2, 10.2 Hz, 1H), 4.68 (s, 2H), 4.14 (br s, 1H), 3.95 (br t, J = 5.4 Hz, 2H), 1.62 (s, 3H), 1.49 (s, 9H), 1.46 (s, 3H) ;'3C NMR (75 MHz, CDCl3) No. 170.0, 154.0, 134.4, 116.9, 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6 ; MS (CI) m/z 301.1599 (301.1586 calcd for Ci4H25Ns03S, M + H+) ; elemental analysis calcd for C4H24N203S : C, 55.97 ; H, 8.05 ; N, 9.32 ; found: C, 56.11 ; H, 8.01 ; N, 9.11.; Example 44: Preparation of (R)-5, 5-dimethyl-thiazolidine-4-carboxylic acid allylamide ; hydrochloride; A solution of (R)-5, 5-Dimethyl-thiazolidine-3, 4-dicarboxylic acid 3-tert-butyl ester (105 kg, 402 mol) and ethyl acetate (690 L) was treated with diphenylchlorophosphate (113 kg, 422 mol) and was then cooled to 0 °C. NEt3 (85.5 kg, 844 mol) was added while maintaining the temperature at 5 °C, and the mixture was then held at this temperature for 2 h. The mixture was cooled to 0 °C, and allylamine (24.1 kg, 422 mol) was then added while maintaining the temperature at 5 °C. The mixture was warmed to 20 °C and was then quenched with 10 wt. % aqueous HCI (310 L). After separation of the layers, the organic fraction was washed with 8.6 wt. % aqueous Na2CO3 (710 L). After separation of the layers, the aqueous fraction was extracted with ethyl acetate (315 L). The combined ethyl acetate extracts containing AG-074278 were dried by azeotropic distillation at one atmosphere, while maintaining a minimum pot volume of approximately 315 L. The resulting suspension of (R)-4-Allylcarbamoyl-5, 5-dimethyl-thiazolidine- 3-carboxylic acid ter-butyl ester was cooled to 5 °C. A 13 wt. % solution of anhydrous HCI (36.8 kg, 1008 mol) in ethyl acetate (263 L) was cooled to 5 °C and was then added to the (R)-4- Allylcarbamoyl-5, 5-dimethyl-thiazolidine-3-carboxylic acid ter-butyl ester suspension while maintaining the temperature at 15 °C. The resulting suspension was held at 20 °C for 19 h, and was then cooled and held at 5 °C for 2 h. The suspension was then filtered, using cold ethyl acetate for rinsing. The wet cake was dried under vacuum at 45 °C to give 90.5 kg (95.2 %) of (R) -5, 5-Dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride as a white solid :'H NMR (300 MHz, DMSO-d6) 5 8.94 (app t, J = 5.5 Hz, 1 H), 5.82 (ddt, J = 10. 4, 17.2, 5.2 Hz, 1 H), 5.19- 5.25 (m, 1H), 5.10-5. 14 (m, 1 H), 4.38 (AB q, JAB= 9.8 Hz, Av = 14.5 Hz, 2H), 4.08 (s, 1H), 3.72- 3.91 (m, 2H), 1.58 (s, 3H), 1.32 (s, 3H) ; 13C NMR (75 MHz, DMSO-de) 6 161.7, 132.2, 114. 0, 67.9, 51.4, 43.5, 39.3, 25.3, 24.3 ; MS (Cl) m/z 201.1070 (201.1062 catcd for C9HX7N20S, M + H+) ; elemental analysis calcd for C9Hl7CIN20S : C, 45.65 ; H, 7.24 ; N, 11.83 ; CI, 14.97 ; found: C, 45.41 ; H, 7.33 ; N, 11.69 ; CI, 15.22. |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
