技术领域technical field
本发明属于医药合成技术领域，具体涉及一种依泽替米贝的制备方法。The invention belongs to the technical field of pharmaceutical synthesis, and in particular relates to a preparation method of ezetimibe.
背景技术Background technique
下述化合物结构式如下：The structural formula of the following compounds is as follows:
是制备依泽替米贝的中间体，其制备依泽替米贝的路线可参考专利WO2010113175（公开日2010-10-7，申请人：Matrix laboratories Ltd），具体如下：It is an intermediate for the preparation of ezetimibe, and the route for preparing ezetimibe can refer to the patent WO2010113175 (disclosure date 2010-10-7, applicant: Matrix laboratories Ltd), as follows:
。 .
上述WO2010113175同时提供了该中间体的制备路线，如下：The above-mentioned WO2010113175 also provides the preparation route of the intermediate, as follows:
， ,
其实施例9中制备得到了R为苯基的式6化合物，具体为以P1为苄基的式4化合物为起始原料，在特戊酰氯的作用下，与化合物5反应制备式6（R为苯基）化合物。In Example 9, a compound of formula 6 in which R is a phenyl group was prepared, specifically, a compound of formula4 in which P was benzyl was used as a starting material, and reacted with compound 5 under the action of pivaloyl chloride to prepare formula 6 ( R is phenyl) compound.
而WO2007017705（公开日2013-3-21，申请人：Astellas Pharma Inc., Japan）提供了一种上述WO2010113175依泽替米贝中间体化合物6的原料式4化合物的制备路线，如下：And WO2007017705 (publication date 2013-3-21, applicant: Astellas Pharma Inc., Japan) provides a preparation route of compound 4, the raw material compound 6 of ezetimibe intermediate compound 6 in WO2010113175, as follows:
。 .
从上可以看出，在制备上述结构的依泽替米贝中间体式6化合物时，可由WO2007017705中式Ⅲ化合物作为起始原料，先对羟基上保护基获得式Ⅳ化合物，将其水解得到式4化合物，再在特戊酰氯的作用下，与化合物5反应制备上述式6化合物。It can be seen from the above that when preparing the ezetimibe intermediate compound of formula 6 with the above structure, the compound of formula III in WO2007017705 can be used as the starting material, and the compound of formula IV can be obtained by first protecting the hydroxyl group, and then hydrolyzed to obtain the compound of formula 4 , and react with compound 5 under the action of pivaloyl chloride to prepare the compound of formula 6 above.
考虑到上述制备依泽替米贝中间体化合物的步骤甚多，而造成步骤多的原因在于反应位点中涉及羟基和羧基的反应，为避开参与反应时，二者的相互干扰，上述专利形成了一条复杂的工艺路线。因而有必要开发一条工艺简单，适合工业化生产的路线。Considering that there are many steps in the preparation of the ezetimibe intermediate compound, the reason for the many steps is that the reaction site involves the reaction of hydroxyl and carboxyl groups. In order to avoid the mutual interference between the two when participating in the reaction, the above patent Formed a complex process route. Thereby it is necessary to develop a process that is simple and suitable for industrialized production.
发明内容Contents of the invention
本发明提供了一种依泽替米贝的中间体化合物，与已公开路线相比，工艺简单，适合工业化生产。The invention provides an intermediate compound of ezetimibe. Compared with the disclosed route, the process is simple and suitable for industrial production.
本发明一方面提供了一种依泽替米贝的中间体式Ⅱ化合物，其结构式如下：One aspect of the present invention provides an intermediate compound of formula II of ezetimibe, the structural formula of which is as follows:
， ,
其中P1为C1-C8的烷氧羰基，C1-C8的烷羰基或苯甲酰基；优选地，P1为甲氧羰基（），乙氧羰基（）、叔丁氧羰基（）或三甲基乙酰基（）。Wherein P1 is C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl or benzoyl; preferably, P1 is methoxycarbonyl ( ), ethoxycarbonyl ( ), tert-butoxycarbonyl ( ) or trimethylacetyl ( ).
本发明另一方面提供了该依泽替米贝中间体式Ⅱ化合物的制备方法，其反应式如下：Another aspect of the present invention provides a method for preparing the ezetimibe intermediate compound of formula II, the reaction formula of which is as follows:
， ,
其中P1为C1-C8的烷氧羰基，C1-C8的烷羰基或苯甲酰基；优选地，P1为甲氧羰基（），乙氧羰基（）、叔丁氧羰基（）或三甲基乙酰基（）。Wherein P1 is C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl or benzoyl; preferably, P1 is methoxycarbonyl ( ), ethoxycarbonyl ( ), tert-butoxycarbonyl ( ) or trimethylacetyl ( ).
即在强碱的作用下，式Ⅰ化合物与P1-Cl和式Ⅲ化合物反应制备式Ⅱ化合物。That is, under the action of a strong base, the compound of formula I is reacted with P1 -Cl and the compound of formula III to prepare the compound of formula II.
具体为在强碱的作用下，式Ⅰ化合物中的羟基和羧基均与C1-C8的烷氧羰基氯，C1-C8的烷羰基氯或苯甲酰氯即P1-Cl反应分别生成含酯基和酸酐部分后，酸酐部分进一步与S-4-苯基-2-恶唑烷酮即式Ⅲ化合物Specifically, under the action of a strong base, the hydroxyl and carboxyl groups in the compound of formula I react with C1-C8 alkoxycarbonyl chloride, C1-C8 alkoxycarbonyl chloride or benzoyl chloride, namely P1 -Cl, to form ester-containing groups After the acid anhydride part, the acid anhydride part is further combined with S-4-phenyl-2-oxazolidinone, that is, the compound of formula III
反应制备式Ⅱ化合物。The reaction prepares the compound of formula II.
本发明优选的一种实施方式为在强碱的作用下，式Ⅰ化合物中的羟基和羧基均与特戊酰氯反应分别生成含酯基和酸酐部分后，酸酐部分进一步与式Ⅲ化合物A preferred embodiment of the present invention is that under the action of a strong base, the hydroxyl and carboxyl groups in the compound of formula I react with pivaloyl chloride to generate ester groups and acid anhydride moieties respectively, and the anhydride moiety is further combined with the compound of formula III
反应制备保护基为三甲基乙酰基的式Ⅱ化合物。The reaction prepares the compound of formula II whose protecting group is trimethylacetyl.
。 .
上述反应所述强碱可以为氢化碱金属，如钠氢、锂氢、钙氢等。The strong base described in the above reaction can be an alkali metal hydride, such as sodium hydrogen, lithium hydrogen, calcium hydrogen and the like.
上述反应温度可以为-20℃~40℃，具体地形成酸酐和酯的温度优选-10℃~5℃，后酸酐继续与S-4-苯基-2-恶唑烷酮反应的温度优选10℃~30℃。The above-mentioned reaction temperature can be -20°C~40°C, specifically the temperature for forming acid anhydride and ester is preferably -10°C~5°C, and the temperature for the subsequent reaction of acid anhydride with S-4-phenyl-2-oxazolidinone is preferably 10°C. ℃~30℃.
本发明的式Ⅱ化合物可进一步制备依泽替米贝的另一中间体式Ⅳ化合物，反应路线如下：The compound of formula II of the present invention can further prepare another intermediate compound of formula IV of ezetimibe, and the reaction scheme is as follows:
， ,
其中P1为C1-C8的烷氧羰基，C1-C8的烷羰基或苯甲酰基；优选地，P1为甲氧羰基（），乙氧羰基（）、叔丁氧羰基（）或三甲基乙酰基（）；更优选地，P1为三甲基乙酰基（），反应路线如下：Wherein P1 is C1-C8 alkoxycarbonyl, C1-C8 alkoxycarbonyl or benzoyl; preferably, P1 is methoxycarbonyl ( ), ethoxycarbonyl ( ), tert-butoxycarbonyl ( ) or trimethylacetyl ( ); More preferably, P1 is trimethylacetyl ( ), the reaction scheme is as follows:
。 .
本发明提供的依泽替米贝中间体式Ⅱ化合物的制备方法，反应工艺简单，制备得到的式Ⅱ化合物收率高、纯度高，该工艺适合工业化生产。The preparation method of the ezetimibe intermediate compound of formula II provided by the invention has a simple reaction process, and the prepared compound of formula II has high yield and high purity, and the process is suitable for industrial production.
具体实施方式Detailed ways
为了进一步理解本发明，下面结合实施例对本发明提供的一种依泽替米贝中间体及其制备方法进行详细说明。需要理解的是，这些实施例描述只是为进一步详细说明本发明的特征，而不是对本发明范围或本发明权利要求范围的限制。In order to further understand the present invention, an ezetimibe intermediate provided by the present invention and its preparation method will be described in detail below in conjunction with the examples. It should be understood that the descriptions of these embodiments are only for further detailing the characteristics of the present invention, rather than limiting the scope of the present invention or the scope of the claims of the present invention.
实施例1：Example 1:
取21.2g的式Ⅰ化合物用110ml的DMF溶解，并用氮气置换，氮气保护下降温至-10~0℃，控制温度，分批投入16g的钠氢，保温0.5h，缓慢滴加特戊酰氯30.2g，控制温度-10~0℃，滴加完毕后保温1h，升温至20~25℃，投入S-4-苯基-2-恶唑烷酮15.5g，投料结束，保温，反应完全，用水和甲基叔丁基醚萃取，静置分层，有机层用饱和食盐水洗涤，减压蒸馏，获得油状物。用乙酸乙酯和己烷的混合物搅拌结晶，抽滤用己烷洗涤，真空烘干得到白色固体38.9g，摩尔收率为93.1%，HPLC纯度95.8% 。不必精制，可直接用于下步。1H NMR(400 MHz,CDCl3) δ 7.393-7.313 (m，3H)，7.280-7.220 (m，2H )，6.990 (t, J= 8.6 , 2H)，5.632(dd, J= 6.0, 7.6, 1H)， 5.394 (dd, J= 3.6，8.4, 1H)， 4.679 (t,J =8.8,，1H),4.272 (dd, J= 3.6，9.2 , 1H)，3.016-2.886 (m，2H)，1.931-1.598 ( m, 4H)， 1.174(s,9H)Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of sodium hydrogen in batches, keep it warm for 0.5h, slowly add pivaloyl chloride 30.2 g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after the feeding is completed, keep warm, and the reaction is complete, then use water Extract with methyl tert-butyl ether, stand to separate the layers, wash the organic layer with saturated brine, and distill under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, wash with hexane by suction filtration, and dry in vacuo to obtain 38.9 g of a white solid with a molar yield of 93.1% and an HPLC purity of 95.8%. It does not need to be refined and can be directly used in the next step.1 H NMR (400 MHz, CDCl3 ) δ 7.393-7.313 (m, 3H), 7.280-7.220 (m, 2H), 6.990 (t, J= 8.6, 2H), 5.632 (dd, J= 6.0, 7.6, 1H), 5.394 (dd, J= 3.6, 8.4, 1H), 4.679 (t, J = 8.8, 1H), 4.272 (dd, J= 3.6, 9.2 , 1H), 3.016-2.886 (m, 2H), 1.931-1.598 (m, 4H), 1.174(s, 9H)
[α]D20 =+18.703°(C = 1mol/L,甲醇)。[α]D20 =+18.703° (C = 1 mol/L, methanol).
实施例2：Example 2:
取21.2g的式Ⅰ化合物用110ml的DMF溶解，并用氮气置换，氮气保护下降温至-10~0℃，控制温度，分批投入16g的氢化锂，保温0.5h，缓慢滴加氯甲酸甲酯30.2g，控制温度-10~0℃，滴加完毕后保温1h，升温至20~25℃，投入S-4-苯基-2-恶唑烷酮15.5g，投料结束，保温，反应完全，用水和甲基叔丁基醚萃取，静置分层，有机层用饱和食盐水洗涤，减压蒸馏，获得油状物。用乙酸乙酯和己烷的混合物搅拌结晶，抽滤用己烷洗涤，真空烘干得到白色固体38.8g产物，摩尔收率92.9%，HPLC纯度95%。不必精制，可直接用于下步。Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of lithium hydride in batches, keep it warm for 0.5h, slowly add methyl chloroformate dropwise 30.2g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after feeding, keep warm, the reaction is complete, Extract with water and methyl tert-butyl ether, stand to separate the layers, wash the organic layer with saturated brine, and distill under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, wash with hexane by suction filtration, and dry in vacuo to obtain 38.8 g of a white solid product with a molar yield of 92.9% and an HPLC purity of 95%. It does not need to be refined and can be directly used in the next step.
实施例3：Example 3:
取21.2g的式Ⅰ化合物用110ml的DMF溶解，并用氮气置换，氮气保护下降温至-10~0℃，控制温度，分批投入16g的氢化锂，保温0.5h，缓慢滴加氯甲酸苯酯30.2g，控制温度-10~0℃，滴加完毕后保温1h，升温至20~25℃，投入S-4-苯基-2-恶唑烷酮15.5g，投料结束，保温，反应完全，用水和甲基叔丁基醚萃取，静置分层，有机层用饱和食盐水洗涤，减压蒸馏，获得油状物。用乙酸乙酯和己烷的混合物搅拌结晶，抽滤用己烷洗涤，真空烘干得到白色固体38.8g产物，收率92.9%，HPLC纯度94%。不必精制，可直接用于下步。Take 21.2g of the compound of formula I dissolved in 110ml of DMF, and replace it with nitrogen, under the protection of nitrogen, lower the temperature to -10~0°C, control the temperature, add 16g of lithium hydride in batches, keep it warm for 0.5h, slowly add phenyl chloroformate dropwise 30.2g, control the temperature at -10~0°C, keep it warm for 1h after the dropwise addition, raise the temperature to 20~25°C, put in 15.5g of S-4-phenyl-2-oxazolidinone, after feeding, keep warm, the reaction is complete, It was extracted with water and methyl tert-butyl ether, and the layers were separated. The organic layer was washed with saturated brine and distilled under reduced pressure to obtain an oily substance. Stir and crystallize with a mixture of ethyl acetate and hexane, wash with hexane by suction filtration, and dry in vacuo to obtain 38.8 g of a white solid product with a yield of 92.9% and a purity of 94% by HPLC. It does not need to be refined and can be directly used in the next step.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410388343.XACN105461649B (en) | 2014-08-08 | 2014-08-08 | A kind of ezetimibe intermediate and preparation method thereof |
| Application Number | Priority Date | Filing Date | Title |
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| CN201410388343.XACN105461649B (en) | 2014-08-08 | 2014-08-08 | A kind of ezetimibe intermediate and preparation method thereof |
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| CN105461649A CN105461649A (en) | 2016-04-06 |
| CN105461649Btrue CN105461649B (en) | 2019-10-22 |
| Application Number | Title | Priority Date | Filing Date |
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| CN201410388343.XAActiveCN105461649B (en) | 2014-08-08 | 2014-08-08 | A kind of ezetimibe intermediate and preparation method thereof |
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|---|---|---|---|---|
| WO2010113175A2 (en)* | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN103102297A (en)* | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel atorvastatin |
| CN103450065A (en)* | 2013-07-15 | 2013-12-18 | 和鼎（南京）医药技术有限公司 | Preparation method of ezetimibe |
| CN103739537A (en)* | 2013-12-24 | 2014-04-23 | 连云港恒运医药科技有限公司 | New synthesis method of ezetimibe |
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010113175A2 (en)* | 2009-04-01 | 2010-10-07 | Matrix Laboratories Ltd | Enzymatic process for the preparation of (s)-5-(4-fluoro-phenyl)-5-hydroxy- 1morpholin-4-yl-pentan-1-one, an intermediate of ezetimibe and further conversion to ezetimibe |
| CN103102297A (en)* | 2012-09-28 | 2013-05-15 | 北京赛林泰医药技术有限公司 | Synthesis method of novel atorvastatin |
| CN103450065A (en)* | 2013-07-15 | 2013-12-18 | 和鼎（南京）医药技术有限公司 | Preparation method of ezetimibe |
| CN103739537A (en)* | 2013-12-24 | 2014-04-23 | 连云港恒运医药科技有限公司 | New synthesis method of ezetimibe |
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