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替卡格雷合成路线及中间体
Release Time：2020-07-18一、替卡格雷合成路线简介：
替卡格雷(ticagrelor,1),化学名为(1S,2S,3R,5S)-3-[7-[(1R,2S)-2-(3,4-二氟苯基)环丙胺基]-5-(丙硫基)-3H-[1,2,3]三唑[4,5-d]嘧啶-3-基]-5-(2-羟基乙氧基)环戊烷-1,2-二醇,是一种口服选择性小分子抗凝血药,能可逆性地作用于血小板上P2Y12受体,对腺苷二磷酸(ADP)引起的血小板聚集有较强抑制作用,且口服后迅速起效,因此可明显改善急性冠心病患者的症状。本品与氯吡格雷不同,不需要通过代谢激活,自身具有抗血小板活性，除结构中五元碳环的4个手性中心外,其侧链部分还有2个手性中心需在合成中构建。
二、替卡格雷合成路线步骤
一、经由2-丙硫基-4,6-二氯-5-硝基嘧啶合成替卡格雷
2-丙硫基-4,6-二氯-5-硝基嘧啶与(1S,2R,3S,4R)2,3-O-亚异丙基-4-氨基环戊烷-1,2,3-三醇在N,N-二异丙基乙胺作用下缩合,后经铁粉/乙酸还原、亚硝酸异戍酯(i-AmONO)环合、氨化得8-氮杂腺嘌呤类衍生物，然后在丁基锂作用下与2-三氟甲磺酰氧基乙酸甲酯反应后,再经溴代、与手性中间体缩合,最后经二异丁基氢化铝(DIBALH)还原酯基、酸解脱除亚异丙基保护得替卡格雷。
二、经由硫代巴比妥酸合成替卡格雷
硫代巴比妥酸经烷基化、与对甲苯胺重氮化缩合、三氯氧磷氯化及催化氢解反应制得2-丙硫基-4,6-二氯-5-氮基密啶，在三乙胺作用下与中间体(1S,2R,3S,4R)-1-羟乙基-2,3-O-亚异丙基-4-氨基环戊烷-1,2,3-醇缩合，后经亚硝酸钠/乙酸环合得8-氮杂嘌呤类衍生物，最后与(1R,2S)-2-(3,4-二氟苯基)环丙胺经缩合、酸解脱除亚异内基保护制得替卡格雷。
三、替卡格雷合成路线杂质：
| 序列 | 产品名 | 货号 | CAS | 备注 |
| 1 | Ticagrelor Impurity 103 | YPZZ60774 | 1487958-68-8 | |
| 2 | Ticagrelor Impurity A (Ticagrelor Enantiomer) | HCC348401 | 2096989-55-6 | |
| 3 | Ticagrelor Impurity C (Ticagrelor Isomer 3) | BSH75608 | 2096989-56-7 | |
| 4 | Ticagrelor Impurity D(UL127) | HCT005909 | 274693-26-4 | |
| 5 | Ticagrelor Impurity E (UL133) | BSH55723 | 1788033-05-5 | |
| 6 | Ticagrelor Impurity F(AZ13232789) | YPZZ60778 |
1616703-93-5 | |
| 7 | Ticagrelor Impurity G | LSH65260 | 220347-05-7 | |
| 8 | Ticagrelor Impurity H (UL134) | YPZZ60780 | 1251765-07-7 | |
| 9 | Ticagrelor Impurity I (UL136) | HCT006232 | 1445580-43-7 | |
| 10 | Ticagrelor Impurity 100 | YPZZ60783 | 1391594-37-8;1643378-57-7 | |
| 11 | Ticagrelor Impurity K | YPZZ60788 | 2248538-63-6 | |
| 12 | Ticagrelor Impurity 117 | 1549834-66-3 | ||
| 13 | Ticagrelor Impurity 118 | HCT005926 | 1345413-20-8 | |
| 14 | Ticagrelor Impurity 119 | HCT006233 | 1459719-81-3 | |
| 15 | Ticagrelor Impurity L (Mixture of Diastereomers) | HCC348409 | 1644461-85-7 | |
| 16 | Ticagrelor Impurity 129 | BSH64750 | 1207276-00-3 | |
| 17 | Ticagrelor Impurity M | HCC348408 | 274693-39-9 | |
| 18 | Ticagrelor Impurity 131 | YPZZ60808 | 1858267-99-8 | |
| 19 | Ticagrelor Impurity 132 | YPZZ60809 | 1456538-51-4 | |
| 20 | Ticagrelor Impurity N | HCR203040 | 1643378-47-5 | |
| 21 | Ticagrelor Impurity 142 | YPZZ60820 | 1378680-73-9 | |
| 22 | Ticagrelor Impurity 144 | YPZZ60822 | 274693-25-3 | |
| 23 | Ticagrelor Impurity 155 | 1482484-62-7 | ||
| 24 | Ticagrelor Impurity 159 | HCT016908 | 866551-95-3 | |
| 25 | Ticagrelor Impurity P | HCT005909 | 274693-26-4 | |
| 26 | Ticagrelor Impurity 160 | 1267560-63-3 | ||
| 27 | Ticagrelor Impurity 163 | 1431867-39-8 | ||
| 28 | Ticagrelor Impurity R | YPZZ60828 | 2205903-73-5 | |
| 29 | Ticagrelor Impurity T | HCT003946 | 1644461-81-3 | |
| 30 | Ticagrelor Impurity U | JT5933 | 145783-15-9 | |
| 31 | Ticagrelor Impurity Z | LSH67368 | 376608-75-2 | |
| 32 | Ticagrelor Impurity 1 | JM0151 | 376608-74-1 | |
| 33 | Ticagrelor Impurity 4 | HCY004579 | 274693-53-7 | |
| 34 | Ticagrelor Impurity 7 | 1823431-32-8 | ||
| 35 | Ticagrelor Impurity 8 | 1401318-10-2 | ||
| 36 | Ticagrelor Impurity 9 | 220241-60-1 | ||
| 37 | Ticagrelor Impurity 12 | YPZZ60846 | 1314324-00-9 | |
| 38 | Ticagrelor Impurity 13 | LSH32254 | 220353-83-3 | |
| 39 | Ticagrelor Impurity 14 | YPZZ60848 | 1427524-53-5 | |
| 40 | Ticagrelor Impurity 15 | YPZZ60850 | 1882095-51-3 | |
| 41 | Ticagrelor Impurity 19 | HCT006202 | 220352-36-3 | |
| 42 | Ticagrelor Impurity 22 | 145783-14-8 | ||
| 43 | Ticagrelor Related Compound I | 2165881-71-8 | ||
| 44 | Ticagrelor Related Compound II | HCR221939 | 274693-54-8 | |
| 45 | Ticagrelor Related Compound III | HCT005926 | 1345413-20-8 | |
| 46 | Ticagrelor Impurity Ⅶ | YPZZ60828 | 2205903-73-5 | |
| 47 | Ticagrelor Related Compound Ⅶ | 1402222-66-5 | ||
| 48 | Ticagrelor Related Compound VIII | HCT005926 | 1345413-20-8 | |
| 49 | Ticagrelor Impurity 63 | YPZZ60865 | 2227766-79-0 | |
| 50 | Ticagrelor Impurity 66 | YPZZ60868 | 1643378-48-6 | |
| 51 | Ticagrelor Impurity 74 | HCY004220 | 376608-65-0 | |
| 52 | Ticagrelor Impurity 80 | YPZZ60883 | 1006376-63-1 | |
| 53 | Ticagrelor Impurity 81 | YPZZ60884 | 1006376-60-8 | |
| 54 | Ticagrelor Impurity 82 | HCT018680 | 1006376-61-9 | |
| 55 | Ticagrelor Impurity 84 | YPZZ60887 | 2056269-94-2 | |
| 56 | Ticagrelor Impurity 88 | LSH71795 | 1414348-35-8 | |
| 57 | Ticagrelor Impurity 89 | 1265919-24-1 | ||
| 58 | Ticagrelor Impurity 90 | JT24089 | 367-11-3 | |
| 59 | Ticagrelor Impurity 91 | JM0179 | 51336-95-9 |
