CN100351240C - 瑞舒伐他汀钙的合成方法 - Google Patents
瑞舒伐他汀钙的合成方法 Download PDFInfo
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- 229960004796 rosuvastatin calcium Drugs 0.000 title abstract description 4
- 238000001308 synthesis method Methods 0.000 title abstract 2
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- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyridine Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种他汀类降血脂药瑞舒伐他汀钙的合成方法，以4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-甲醛为起始原料，首先将其甲醛基腈基化、再醛基化后扩侧链，将侧链上酮基还原后得到中间体Ⅳ取代嘧啶-5-二羟基庚烯酸乙酯，最后将乙酯基转化为钙盐即瑞舒伐他汀钙。本方法合成路线短，各步反应不需用毒性大的原料，也不需要复杂的分离设备，而且各步中间体大都为固体，易纯化，产品纯度好，光学纯度ee＞99%，收率高，五步收率达56.8%。
Description
一、技术领域
本发明涉及一种已知药物化合物的制备方法，特别涉及一种他汀类药物化合物的制备方法，确切地说是降血脂药瑞舒伐他汀钙的合成方法。
二、背景技术
瑞舒伐他汀钙(rosuvastatin calcium)是临床应用的降血脂药物，化学名称为(+)-(3R，5S)-7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰基氨基)嘧啶-5-基]-3，5-二羟基-6(E)-庚烯酸钙(2∶1)，
化学结构式如下：
文献报导的制备方法有以下三种
1、CN1340052A公开的
P1、P2是羟基保护基，P3是叔丁基
在强碱存在下，氧化二苯基[4-(4-氟苯基)-6-异丙基-2-[甲基(甲磺酰胺基)氨基]嘧啶-5-基甲基]膦与2-[(4R，6S)-6-甲酰基-2，2-二甲基-1，3-二氧杂-4-基]乙酸叔丁酯反应。接着断开产物中的二羟基保护基，碱性水解叔丁酯基团，再成为钙盐获得瑞舒伐他汀钙。
方法1中，合成膦化物(A)时反应周期长，收率低，同时要用毒性大，污染严重的PBr3。其侧链(B)的合成方法有多种(US5278313，EP0319847，US5399722，US5481009，US5998633，US6140527，EP0104750，WO0307733)，但大都存在合成路线长(7-9步)，中间体多为粘稠状物，需多步高真空(0.1mmHg左右)蒸馏和硅胶柱纯化，需用剧毒物氰化钾或氰化钠，产品纯度差，不稳定，难以工业化生产等问题。
2、US5260440所公开的
TBDMS是叔丁基二甲基硅保护基
方法2中，侧链(D)的合成困难(JP5-32680和J.Org.Chem.，1994，59(25).7849-7854)，路线长，各步中间体大都为粘稠状液体，分离纯化困难(需经多步硅胶柱纯化)，产品纯度差，不稳定。侧链(D)和主环(C)对接时收率低，产品纯度差。
(接下页)
3、WO2004/052867所公开的
方法3中，侧链(E)无合成方法，侧链与主环(C)对接时总收率低，需经过多步硅胶柱纯化。各中间体无任何物理常数，产品纯度及反应进程无检测方法，且仅为小量试验结果，无放大数据。
三、发明内容
药物化合物的制备方法，一方面随着起始原料的不同而不同，另一方面，就同一种起始原料，也可以使用不同的工艺路线而得到相同的目标产物，即所谓的殊途同归。本发明正是根据这一思路而研制的。
本发明也是以4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-甲醛(下简称取代嘧啶-5-甲醛)为起始原料(该起始原料与背景技术中第2、第3种方法的起始原料C相同)，但使用以下工艺路线合成瑞舒伐他汀钙(下简称目标产物)。该工艺路线包括腈基化、醛基化、扩侧链、酮基还原、乙酯基水解和中和反应或复分解反应各单元过程，具体方法如下：
1、首先所述的腈基化是起始原料与腈基化试剂制备新的中间体I
取代嘧啶-5-甲醛与腈基化试剂缩合得到4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯腈，即中间体I(下简称取代嘧啶-5-丙烯腈)。
所述的腈基化试剂可以是磷酸二乙酯乙腈，乙腈等。
若使用磷酸二乙酯乙腈，与起始原料一起在有机溶剂中于室温下滴加15～25％的NaOH溶液滴完后反应液呈粉红色清液，室温下继续反应2～4小时，产物析出，经分离、纯化后得到取代嘧啶-5-丙烯腈(中间体I)。
所述的有机溶剂可以是苯、甲苯、二甲苯等。
2、所述的醛基化是将丙烯腈基还原为丙烯醛基得到新的中间体II
取代嘧啶-5-丙烯腈(中间体I)与还原剂反应得到4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯醛，即中间体II(下简称取代嘧啶-5-丙烯醛)。
所述的还原剂可以是二异丁基氢化铝，红铝等。
若选用二异丁基氢化铝，则取代嘧啶-5-丙烯腈(中间体I)在有机溶剂中和氮气保护下于-15～-5℃时滴加10～55％二异丁基氢化铝甲苯溶液，滴完后继续反应1～2小时，反应结束后经分离和纯化得到取代嘧啶-5-丙烯醛。
所述的有机溶剂可以是苯、甲苯、二甲苯等。
3、所述的扩侧链是丙烯醛基通过缩合而扩链得到中间体III
将取代嘧啶-5-丙烯醛(中间体III)溶于四氢呋喃并用氮气保护，在联萘酚、钛酸异丙酯、氯化锂和四甲基乙二胺存在条件下搅拌均匀，加入1，3-二三甲基硅氧基-1-乙氧基-1，3-丁二烯于20～35℃条件下反应2～4小时，反应结束后经酸解脱保护基，并分离、纯化得到中间体III7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-3-氧代-(5R)-5-羟基-(E)-6-庚烯酸乙酯(下简称取代嘧啶-5-酮基、羟基庚烯酸乙酯)。
4、所述的酮基还原是将酮基、羟基庚烯酸乙酯基还原为二羟基庚烯酸乙酯基得到中间体IV
用还原剂将取代嘧啶-5-酮基、羟基庚烯酸乙酯(中间体III)中侧链上的酮基还原为羟基，得到中间体IV：7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸乙酯(下简称取代嘧啶-5-二羟基庚烯酸乙酯)。
所述的还原剂可以是NaBH4，KBH4等。
若使用NaBH4，反应如下：
将取代嘧啶-5-酮基、羟基庚烯酸乙酯(中间体III)溶于四氢呋喃和甲醇的混合溶剂中，在二乙基甲氧基硼烷存在条件于-80～-50℃时与NaBH4反应2～4小时，反应结束后经后处理并分离、纯化得到中间体IV：7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸乙酯(下简称取代嘧啶-5-二羟基庚烯酸乙酯)。
5、由中间体IV通过公知化学过程得到目标产物，这就是首先将乙酯基水解，若用酸，则得到相应的羧酸，若用碱，则得到相应的羧酸盐。前者可与Ca(OH)2通过中和反应生成目标产物，后者可与钙的可溶性无机盐通过复分解反应生成目标产物。
目标产物的物化数据：白色粉末或结晶性粉末；无嗅；味苦。在氯仿中易溶；在丙酮中溶解；在甲醇中微溶；在水中微溶。比旋度为+14°至+18°(C＝1，50％甲醇)。
本合成方法路线短，收率高，五步总收率达56.8％。各步中间体大都为固体，易纯化，因此产品纯度好。同时，不需用毒性大的原材料，也不需要高真空蒸馏或色层分离方法，因而易于工业化生产。使用本发明方法可以大大缩短生产周期，降低生产成本，减少“三废”。
四、具体实施方式
现以磷酸二乙酯乙腈为腈基化试剂、二异丁基氢化铝和NaBH4为还原剂为例，非限定实施例叙述如下：
(1)、4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯腈(中间体I)的合成
取4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-甲醛30g加入到500ml反应瓶中，加入甲苯130ml开始搅拌。再依次加入磷酸二乙酯乙腈20.5g和1.4g Aliquat336(三辛基甲基氯化铵)，25℃滴加20％的氢氧化钠溶液62.7g，反应液逐渐澄清，滴完呈粉红色清液。室温反应3小时，析出白色固体。抽滤，水洗，抽干，烘干，得白色固体30.5g，熔点136～140℃，收率95.4％。
(2)4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯醛(中间体II)的合成
取4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯腈30g加入到通有氮气保护的500ml四口反应瓶中，加入无水甲苯280ml，搅拌，冰盐浴降温-10℃以下滴加40％的二异丁基氢化铝甲苯溶液38ml，滴完，反应一小时后，先滴加无水乙醇16ml。加稀盐酸处理，分液，油层加200ml 1M盐酸洗一次，再用饱和NaHCO3洗到中性，无水Na2SO4干燥，旋转蒸去溶剂，残留物用已烷-石油醚结晶，得类白色固体26.3g，mp.92～94℃，收率87％。
(3)、7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-3-氧代-(5R)-5-羟基-(E)-6-庚烯酸乙酯(中间体III)的合成
取4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯醛25g加入到通有氮气保护的500ml四口反应瓶中，加入335g四氢呋喃溶解，加入S-联萘酚和钛酸异丙酸(摩尔比1∶1)共8.35g的甲苯溶液于上述溶液中。再加入1.5g氯化锂和8.14g四甲基乙二胺，搅拌均匀后，再加入1，3-二三甲基硅氧基-1-乙氧基-1，3-丁二烯31.34g。此混合物于20～30℃搅拌3小时，反应毕，于0℃加入50％H2SO421.9g，2小时后过滤，滤液加入乙酸乙酯，油层用水、饱和盐水洗涤，无水Na2SO4干燥；减压蒸除溶剂，残余物用已烷-石油醚结晶，得固体28.2g，收率83.9％。
(4)、7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸乙酯(中间体IV)的合成
取13g 7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-3-氧代-(5R)-5-羟基-(E)-6-庚烯酸乙酯溶解在350ml无水四氢呋喃和90ml甲醇中，于-78℃滴加1M的二乙基甲氧基硼烷四氢呋喃溶液31.7ml。混合物-78℃搅拌30分钟，加入1.3g NaBH4，于-78℃搅拌3小时。反应毕，加入16ml冰乙酸，用NaHCO3中和，用乙醚萃取，有机层水洗，干燥，减压脱溶，残余物用环已烷-正已烷结晶，得11.4g产品，mp.90～92℃，收率85％。
(5)、7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸钙(目标产物)的合成
取11.4g 7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸乙酯加入到500ml反应瓶中，搅拌冰水浴下滴加22.3ml 1N的氢氧化钠溶液，再于冰水浴下反应1小时，滴加1.3g CaCl2溶于180ml水的溶液于此反应液，反应液逐渐变浑浊，析出白色固体，滴完继续搅拌过夜，抽滤，水洗，干燥，得白色产物10.8g，收率96％，光学纯度ee＞99％。元素分析(％)(C22H27FN3O6S)2Ca：理论值C.52.78；H.5.43；N.8.39；F.3.79；S.6.39。实验值C.52.89；H.5.39；N.8.28；F.3.75；S.6.24。
Claims (4)
1、一种瑞舒伐他汀钙的合成方法，以4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-甲醛为原料，包括腈基化、醛基化、扩侧链、酮基还原、乙酯基水解和中和反应或复分解反应各单元过程，其特征在于：
(1)、所述的腈基化是原料与腈基化试剂反应生成中间体I：4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯腈；
(2)、所述的醛基化是中间体I与还原剂反应生成中间体II：4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-丙烯醛；
(3)、所述的扩侧链是中间体II与1，3-二三甲基硅氧基-1-乙氧基-1，3-丁二烯反应生成中间体III：7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-3-氧代-(5R)-羟基-(E)-6-庚烯酸乙酯，其工艺条件为：将中间体II溶于四氢呋喃中并用N2气保护，加入联萘酚、钛酸异丙酯、氯化锂和四甲基乙二胺，搅拌均匀后加入1，3-二三甲基硅氧基-1-乙氧基-1，3-丁二烯，于20～35℃条件下反应2～4小时；
(4)、所述的酮基还原是中间体III与还原剂反应生成中间体IV：7-[4-(4-氟苯基)-6-异丙基-2-(N-甲基-N-甲磺酰胺基)嘧啶-5-基]-(3R，5S)-二羟基-(E)-6-庚烯酸乙酯。
2、根据权利要求1所述的合成方法，其特征在于：腈基化所用的腈基化试剂为磷酸二乙酯乙腈，其工艺条件为：将反应物投入有机溶剂中，室温下滴加15～25％碱溶液，滴完后室温下反应2～4小时。
3、根据权利要求1或2所述的合成方法，其特征在于：醛基化所用的还原剂为二异丁基氢化铝，其工艺条件为：将中间体I投入有机溶剂中，在N2气保护下于-15～-5℃条件下滴加10～55％的二异丁基氢化铝甲苯溶液中，滴完后继续反应1～2小时。
4、根据权利要求3所述的合成方法，其特征在于：酮基还原所用的还原剂为NaBH4，其工艺条件为：将中间体III溶于四氢呋喃和甲醇的混合溶剂中，在二乙基甲氧基硼烷存在条件下于-80～-50℃时与NaBH4反应2～4小时。
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| US8212034B2 (en) * | 2006-12-13 | 2012-07-03 | Aurobindo Pharma Ltd. | Process for preparing rosuvastatin calcium |
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| CN102181493B (zh) * | 2011-01-12 | 2015-06-10 | 江苏阿尔法药业有限公司 | 一种瑞苏伐他汀钙侧链中间体的制备方法 |
| ITVI20130039A1 (it) * | 2013-02-20 | 2014-08-21 | F I S Fabbrica Italiana Sint I S P A | Processo per la preparazione di intermedi chiave per la sintesi di statine |
| CN104370827B (zh) * | 2013-08-13 | 2016-09-07 | 天津汉瑞药业有限公司 | 瑞舒伐他汀钙化合物 |
| US9850213B2 (en) * | 2013-11-25 | 2017-12-26 | Jiangxi Boya Seehot Pharmaceutical Co., Ltd. | Method for preparing rosuvastatin sodium |
| CN104744377B (zh) * | 2015-02-12 | 2017-04-26 | 上海弈柯莱生物医药科技有限公司 | 一种(e)‑3‑[4‑(4‑氟苯基)‑6‑异丙基‑2‑(n‑甲基‑n‑甲磺酰胺基)嘧啶‑5‑基]丙烯醛的制备方法 |
| CN104744378B (zh) * | 2015-02-12 | 2017-10-13 | 上海弈柯莱生物医药科技有限公司 | 一种(e)‑3‑[4‑(4‑氟苯基)‑6‑异丙基‑2‑(n‑甲基‑n‑甲磺酰胺基)嘧啶‑5‑基]丙烯醛的合成方法 |
| CN105566228B (zh) * | 2015-12-30 | 2019-01-04 | 安徽美诺华药物化学有限公司 | 一种瑞舒伐他汀的合成方法 |
| CN105461636A (zh) * | 2015-12-30 | 2016-04-06 | 安徽美诺华药物化学有限公司 | 一种瑞舒伐他汀甲酯的合成方法 |
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