WO2012113325A1 - 一种制备氨氯地平的方法 - Google Patents

一种制备氨氯地平的方法 Download PDF

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WO2012113325A1
WO2012113325A1 PCT/CN2012/071413 CN2012071413W WO2012113325A1 WO 2012113325 A1 WO2012113325 A1 WO 2012113325A1 CN 2012071413 W CN2012071413 W CN 2012071413W WO 2012113325 A1 WO2012113325 A1 WO 2012113325A1
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sodium
amlodipine
equivalents
potassium
combination
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PCT/CN2012/071413
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English (en)
French (fr)
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高曼⋅西格弗里德
郭兴州
周东生
官京鹏
吴加梁
江丽娇
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广东东阳光药业有限公司
宜昌长江药业有限公司
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Priority to CN201280003318.4A priority Critical patent/CN103168030B/zh
Publication of WO2012113325A1 publication Critical patent/WO2012113325A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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
    • C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of medicinal chemistry, and in particular to a method for preparing amlodipine.
  • Calcium Channel Blockers are also known as calcium antagonists ( Calcium Antagonists). In order to treat diseases such as angina pectoris, by blocking calcium channels on the membrane of myocardial and vascular smooth muscle cells, inhibiting extracellular calcium influx, and lowering intracellular calcium levels to cause changes in cardiovascular and other tissues and organs. Hypertension has a good effect.
  • Amlodipine is a long-acting calcium channel blocker with the structural formula shown in formula I:
  • Amlodipine shows good bioavailability and long half-life in the body, and the rate of binding and dissociation with the receptor is slow. Therefore, the drug acts late and lasts for a long time, and has a selective effect on vascular smooth muscle. Heart disease shows a good pharmacological response.
  • Amlodipine is currently the drug of choice for the treatment of hypertension, and its sales rank first in the world in cardiovascular medicine. Therefore, a process route with high development yield, low production cost and suitable for industrial production will be in an extremely advantageous competitive advantage in the fierce market competition.
  • the impurities present in the drug have no therapeutic effect or affect the stability and efficacy of the drug, and even harmful to human health. Therefore, in order to ensure the effectiveness and safety of drugs, strict control of impurities introduced in the production process is a major task of synthetic drugs. European drug standards clearly stipulate that the total impurity content should not be higher than 0.3%.
  • the method for producing amlodipine needs to remove the amino protecting group to form amlodipine free base after forming the dihydropyridine ring, and removing the amino protecting group often uses hydrazine or hydroxylamine or methylamine to form impurities A and impurities during the reaction.
  • B its structural formula is as follows:
  • Impurity A and impurity B in amlodipine prepared by the above method It is difficult to remove and reduces the stability and quality of the drug, so it is necessary to develop a method for preparing a higher purity amlodipine.
  • the present invention provides a method for preparing amlodipine, which is obtained by a one-step reaction from a known raw material to obtain amlodipine, and the intermediate is eliminated.
  • the steps of amino protection and deamination protection control the drug impurities brought in the production process, and the prepared amlodipine has high purity.
  • Amlodipine is obtained by nucleophilic substitution reaction of a compound represented by formula (II) with aminoethanol in the presence of a base,
  • X is a leaving group, preferably -OSO 2 CH 3 , -OSO 2 Ph, -OSO 2 Ph-Me or Br or Cl or I.
  • X is a leaving group, and the leaving group may be any pharmaceutically acceptable leaving group such as -OSO 2 CH 3 , -OSO 2 Ph, -OSO 2 Ph-Me or Halogen (such as Cl, Br or I), in some embodiments X is Br, and in other embodiments, X is Cl; in certain embodiments, X is I.
  • the leaving group may be any pharmaceutically acceptable leaving group such as -OSO 2 CH 3 , -OSO 2 Ph, -OSO 2 Ph-Me or Halogen (such as Cl, Br or I), in some embodiments X is Br, and in other embodiments, X is Cl; in certain embodiments, X is I.
  • the reaction can be carried out at different temperatures in different inert solvents.
  • the base is a strong base, a weak base, or a combination thereof.
  • the base is sodium, potassium, potassium hydride, sodium hydride, lithium hydride, calcium hydride or a similarly active base or a combination thereof.
  • the base is potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium isopropoxide or a similar active base or a combination thereof.
  • the base is lithium hydroxide, sodium hydroxide, potassium hydroxide, or a combination thereof.
  • the base is potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate or a similarly active base or a combination thereof.
  • the base is sodium, potassium, potassium hydride, sodium hydride, lithium hydride, calcium hydride, potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium isopropoxide, lithium hydroxide, hydrogen Sodium oxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, or potassium hydrogencarbonate or a combination thereof.
  • the inert solvent is an aprotic solvent, a weakly nucleophilic alcohol solvent, or a combination thereof.
  • the inert solvent is an aprotic solvent such as tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether or combination.
  • the inert solvent is a weakly nucleophilic alcohol such as methanol, ethanol, isopropanol, t-butanol or a combination thereof.
  • the weakly nucleophilic alcohol is isopropanol.
  • the weakly nucleophilic alcohol described in other embodiments is tert-butanol.
  • the weakly nucleophilic alcohol is methanol.
  • the inert solvent is an aprotic solvent DMF, DMSO, tetramethyl sulfone, dimethyl sulfone, or a combination thereof.
  • the inert solvent is an aprotic solvent such as benzene, toluene, xylene or a combination thereof.
  • the reaction can be carried out at a temperature of from -30 ° C to the reflux temperature of the inert solvent. In some embodiments the reaction temperature is -10 °C to inert solvent reflux temperature. In some embodiments the reaction temperature is room temperature.
  • the amount of aminoethanol used in the process may be an equivalent or excess relative to the compound of formula (II), in some embodiments from 1 to 7 Equivalent. In some embodiments, it is from 1 to 5 equivalents. In other embodiments, it is 2 to 5 equivalents. In other embodiments, it is 3 to 5 equivalents.
  • the amount of base used in the process may be equivalent to (molar) or excess (mole) relative to the compound of formula (II), in certain embodiments 1 to 7 equivalents. In some embodiments, it is from 1 to 5 equivalents. In other embodiments, it is 2 to 5 equivalents. In other embodiments, it is 3 to 5 equivalents.
  • the starting materials and reagents used in the present invention can be prepared according to known methods, and are also commercially available; for example, the compound of the formula (II) can be used according to the literature Synthetic Commun. 16(5), The preparation method reported in 529-534 (1986) or European Patent EP212340 or WO 2000047560 is prepared.
  • the methods described herein may additionally include the use of suitable reaction conditions, some non-limiting examples including the use of other inert solvents, reagents such as bases, catalysts, or salt forms for the production of amlodipine.
  • suitable reaction conditions such as crystallization, chromatography (liquid phase and gas phase, etc.), extraction, distillation, trituration, and reversed phase HPLC.
  • the reaction conditions such as temperature, reaction time, pressure, and gas (e.g., inert gas, air) can be appropriately adjusted depending on the reaction.
  • amlodipine prepared by the present invention may be purified or may be directly subjected to various pharmaceutically acceptable salts for the preparation of amlodipine.
  • amlodipine prepared according to the present invention may form amlodipine salt with any acid capable of reacting with an amine, or may be obtained by other methods such as ion exchange methods described in the literature.
  • examples of some non-limiting salts include hydrochlorides, besylates, hydrobromides, phosphates, sulfates, perchlorates, and organic acid salts such as acetates, oxalates, maleates. , tartrate, citrate, succinate, malonate.
  • Examples of other pharmaceutically acceptable salts include adipate salts, Alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate, camphole, camphor sulfonate, cyclopentyl propionate , digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconate, hemisulfate, heptanoate , hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, malonate, methanesulfonate, 2- Naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, 3- Phenylprop
  • the method for preparing amlodipine described herein has the advantage that the amino group does not need to be protected, and amlodipine is obtained by a one-step reaction from a known raw material, thereby eliminating the step of amino-protecting and deamination protection of the intermediate, and the yield is high.
  • the production cost is greatly saved.
  • the preparation method described in this paper strictly controls the drug impurities brought in the production process, and the final salt product directly obtained from the crude product has a high purity. 99.9% does ensure the safety and effectiveness of the drug.
  • FIG 1 is the structural formula (II);
  • Figure 2 is a nuclear magnetic spectrum of amlodipine
  • Figure 3 is a nuclear magnetic spectrum of amlodipine besylate
  • Figure 4 shows the HPLC chromatogram of amlodipine besylate.
  • the invention discloses a method for preparing amlodipine, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method of the present invention has been described in terms of a preferred embodiment, and it is obvious that the method and application described herein may be modified or appropriately modified and combined to implement and apply the present invention without departing from the spirit, scope and scope of the invention. Invention technology.
  • X is -OSO 2 CH 3 , -OSO 2 Ph, -OSO 2 Ph-Me or Br or I and nucleophilic substitution reaction with aminoethanol in the presence of a base in an inert solvent, the base being selected from the group consisting of sodium, potassium, Potassium hydride, sodium hydride, lithium hydride, calcium hydride, potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium isopropoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrogencarbonate Sodium, potassium bicarbonate or a combination thereof.
  • a base being selected from the group consisting of sodium, potassium, Potassium hydride, sodium hydride, lithium hydride, calcium hydride, potassium t-butoxide, sodium t-butoxide, sodium methoxide, sodium isopropoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, hydrogencarbonate
  • the inert solvent is selected from the group consisting of tetrahydrofuran, dioxane, methyl tert-butyl ether, dimethoxyethane, diethylene glycol dimethyl ether, triglyme, methanol, ethanol, isopropanol, uncle Butanol, DMF, DMSO, tetramethylsulfone, dimethyl sulfone or a combination thereof was reacted at room temperature for 3 hours.
  • the post-treatment method was as in Example 1 to obtain a crude amlodipine.
  • amlodipine besylate After stirring for one hour, the temperature was lowered and crystallization was carried out 2 After a few hours, filter to give amlodipine besylate from 3-ethyl ester -5-methyl ester-2-chloromethyl-4-(2-chlorophenyl)-6-methyl-1,4 Dihydropyridine to the final product amlodipine besylate in a two-step yield of 60%.
  • amlodipine besylate prepared in any of the examples 8 and 9 was subjected to purity detection by HPLC, and the detection conditions were as follows:
  • PH8.90Buffer 0.025moL/L dipotassium hydrogen phosphate trihydrate, adjusted to pH 8.90 with dilute phosphoric acid
  • Detection wavelength 240 nm, 215 nm.

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  • Organic Chemistry (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

一种制备氨氯地平的方法 技术领域
本发明涉及药物化学领域，具体涉及一种氨氯地平的制备方法 。
背景技术
钙通道阻滞剂（ Calcium Channel Blockers ）也称为钙拮抗剂（ Calcium Antagonists ），主要通过阻断心肌和血管平滑肌细胞膜上的钙离子通道，抑制细胞外钙离子内流，使细胞内钙离子水平降低而引起心血管等组织器官功能改变的药物，在治疗疾病如心绞痛、高血压有很好的疗效。
氨氯地平是一种长效钙通道阻滞剂，其结构式如式 Ⅰ 所示：
　
Figure PCTCN2012071413-appb-C000001
氨氯地平在体内显示良好的生物利用度和较长的半衰期，与受体结合和解离速度较慢，因此药物作用出现迟而维持时间长，对血管平滑肌的选择性作用大，对高血压等心脏疾病表现出很好的药理反应。氨氯地平是目前用于治疗高血压的首选药物，其销售额居世界心血管类药物的首位。因此，开发产率高、生产成本低并且适用于工业化生产的工艺路线将在激烈的市场竞争中处于极其有利的竞争优势。
目前氨氯地平的合成方法，如专利申请 CN200610116589.7 ，美国专利申请 US4,572,909, US6,492,523, 和 US6,046,337 等报道的方法，产率非常不理想，且都采用氨基被保护的中间体，由氨基保护基引入的杂质经常残留在最终产品中难以彻底除去。
药物中存在的杂质多无治疗作用或影响药物的稳定性和疗效，甚至对人健康有害。因此，为了保证药物的有效和安全，严格控制生产工艺中带入的杂质是合成药物的一重大任务，欧洲药品标准明确规定杂质总含量不可以高于 0.3% 。目前生产氨氯地平的方法在形成二氢吡啶环之后需要除去氨基保护基得到氨氯地平自由碱，除去氨基保护基常使用肼或羟胺或甲胺在反应过程形成杂质 A 和杂质 B ，其结构式如下：
Figure PCTCN2012071413-appb-C000002
上述方法制备的氨氯地平中杂质 A 和杂质 B 很难除去，降低了药物的稳定性和质量，因此需要开发纯度更高的氨氯地平的制备方法。
发明内容
针对现有技术中合成氨氯地平的方法中引入不易除去的杂质的问题，本发明提供一种制备氨氯地平的方法，由已知的原料经一步反应得到氨氯地平，免去了对中间体进行氨基保护及去氨基保护的步骤，控制了生产工艺中带入的药物杂质，制备的氨氯地平纯度高。
为了达到上述发明目的，本发明采用如下技术方案：
由式（ Ⅱ ）所示化合物与氨基乙醇在碱存在条件下发生亲核取代反应得到氨氯地平，
Figure PCTCN2012071413-appb-C000003
其中 ， X 为离去集团，优选为 -OSO2CH3, -OSO2Ph, -OSO2Ph-Me 或 Br 或 Cl 或 I 。
其反应式如下：
Figure PCTCN2012071413-appb-C000004
采用如结构式（ Ⅱ ）所示的化合物作为原料，与式 (Ⅲ) 所示氨基乙醇反应得到几乎与原料（ Ⅱ ）等当量的氨氯地平。
其中结构式（ Ⅱ ）中 X 为离去基团，所述离去基团可以是任何药学上可接受的离去基团如 -OSO2CH3, -OSO2Ph, -OSO2Ph-Me 或卤素 ( 如 Cl, Br 或 I) ，在一些实施例中 X 为 Br, 在另一些实施例中， X 为 Cl ；在某些实施例中， X 为 I 。
在某些实施例中，该反应可以在不同惰性溶剂中在不同温度下进行。
在一些实施例中，所述的碱是强碱、弱碱或其组合。在另一些实施例中，所述的碱是钠、钾、氢化钾、氢化钠、氢化锂、氢化钙或相似活性的碱或其组合。在某些实施例中，所述的碱是叔丁醇钾、叔丁醇钠、甲醇钠、异丙醇钠或相似活性碱或其组合。在一些实施例中，所述的碱是氢氧化锂、氢氧化钠、氢氧化钾或其组合。在某些实施例中，所述的碱是碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾或相似活性的碱或其组合。在一些实施例中，所述的碱是钠、钾、氢化钾、氢化钠、氢化锂、氢化钙、叔丁醇钾、叔丁醇钠、甲醇钠、异丙醇钠、氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、或碳酸氢钾或其组合。
在某些实施例中，所述的惰性溶剂是非质子溶剂、弱亲核性的醇溶剂或其组合。
在一些实施例中，所述惰性溶剂为非质子溶剂四氢呋喃、二氧六环、甲基叔丁基醚、二甲氧乙烷、二乙二醇二甲醚、三甘醇二甲醚或其组合。
在某些实施例中，所述惰性溶剂为弱亲核性的醇，如甲醇、乙醇、异丙醇、叔丁醇或其组合。在一些实施例中 , 所述的弱亲核性的醇为异丙醇。在另一些实施例中所述的弱亲核性的醇为叔丁醇。 在另一些实施例中 , 所述的弱亲核性的醇为甲醇。
在一些实施例中，所述惰性溶剂为非质子溶剂 DMF 、 DMSO 、四甲基砜、二甲基砜或其组合。
在另一些实施例中，所述的惰性溶剂为非质子溶剂苯、甲苯、二甲苯或其组合。
在一些实施例中，该反应可以在为 -30 ℃ 至惰性溶剂回流温度进行。在某些实施例中反应温度为 -10 ℃ 至惰性溶剂回流温度。在一些实施例中反应温度为室温。
该方法所用氨基乙醇的量相对于式（ Ⅱ ）所示化合物可以为等当量或过量，在某些实施例中为 1 到 7 个当量。在一些实施例中为 1 到 5 个当量。在另一些实施例中为 2 到 5 个当量。在另一些实施例中为 3 到 5 个当量。
该方法所用碱的量相对于式（ Ⅱ ）所示化合物可以为等当量（摩尔）或过量（摩尔），在某些实施例中为 1 到 7 个当量。在一些实施例中为 1 到 5 个当量。在另一些实施例中为 2 到 5 个当量。在另一些实施例中为 3 到 5 个当量。
本发明所用原料及反应试剂可以按照已知的方法制备，也可以从市场上买到；如结构式（Ⅱ）所述化合物可以按照文献 Synthetic Commun. 16(5), 529-534(1986) 或 欧洲专利 EP212340 或 WO 2000047560 报道的制备方法制得。
本文描述的方法可以另外包括使用适宜的反应条件，一些非限制性的例子包括使用其他惰性溶剂、试剂例如碱、催化剂或生产氨氯地平的盐形式。本文描述的方法亦可包括已知的纯化方法如结晶、色谱法 ( 液相和气相等 ) 、萃取、蒸馏、研制、和反相 HPLC 等。反应条件例如温度、反应时间、压力和气体 ( 如惰性气体、空气 ) 可以根据反应进行适当调整。
本发明制备的氨氯地平可以经过纯化或可以直接进行用于制备氨氯地平的各种药学上可接受的盐。在一些实施例中，本发明制备的氨氯地平可以和任何一种能与胺反应的酸生成氨氯地平盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。一些非限制性的盐例子包括盐酸盐，苯磺酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐。其他药学上可接受的盐例子包括己二酸盐， 藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐， 2- 羟基 - 乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐， 2- 萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐， 3- 苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐等等 。
本文描述的制备氨氯地平的方法，其优点是氨基不需要保护，从已知原料出发经一步反应得到氨氯地平，免去了对中间体进行氨基保护及去氨基保护的步骤，收率高，大大地节省了生产成本，同时，本文描述的制备方法严格控制了生产工艺中带入的药物杂质，由粗品直接制得的最终盐产品纯度高达 99.9% ，确实保证了药物的安全与有效。
附图说明
图 1 为 结构式（Ⅱ）；
图 2 为氨氯地平的核磁谱图；
图 3 为氨氯地平苯磺酸盐的核磁谱图；
图 4 为氨氯地平苯磺酸盐 HPLC 图谱。
实施该发明的最佳实施例 具体实施方式
本发明公开了一种制备氨氯地平的方法，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
为了使本领域的技术人员更好地理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实施例 1 ： 本发明所述方法制备氨氯地平
氮气保护下，向圆底烧瓶中加入无水 THF ，加入叔丁醇钾（ 5.0eq ），搅拌至体系均匀， 在 25 ℃ 滴加乙醇胺（ 4.0eq ），滴加完毕后，继续搅拌 1 个小时，降温至 0 ℃ ，在此温度下滴加 3- 乙酯 -5- 甲酯 -2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶（ 1.0eq ）的四氢呋喃溶液，滴加完毕后缓慢升温到室温反应 3 个小时左右， 加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品。
实施例 2 ： 本发明所述方法制备氨氯地平
5 当量的氢化钠悬浮在干燥的四氢呋喃中，缓慢加入 5 当量的氨基乙醇。氢气释放完毕，回流 30min ，自然冷却至室温。室温下加入 1 当量 3- 乙酯 -5- 甲酯 2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶的四氢呋喃溶液，在室温下反应两小时。后处理方法如实施例 1 ，得到氨氯地平粗品。
实施例 3 ： 本发明所述方法制备氨氯地平
将 5 当量金属钠溶于 5 当量乙醇胺中，搅拌 0.5h ，冷却至 0 ℃ , 然后滴加 1 当量 3- 乙酯 -5- 甲酯 2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶的四氢呋喃溶液。室温下反应 4 小时。加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品。
实施例 4 ： 本发明所述方法制备氨氯地平
氮气保护下，向圆底烧瓶中加入无水甲苯，加入叔丁醇钾（ 5.0eq ），搅拌至体系均匀，在 25 ℃ 滴加乙醇胺（ 4.0eq ），滴加完毕后，继续搅拌 1 个小时，降温至 0 ℃ ，在此温度下滴加 3- 乙酯 -5- 甲酯 -2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶（ 1.0eq ）的四氢呋喃溶液，滴加完毕后缓慢升温到 25 ℃ 反应 3 个小时左右，加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品。
实施例 5 ： 本发明所述方法制备氨氯地平
1.1 当量的氢化锂悬浮在干燥的甲基叔丁基醚中，缓慢加入 1.2 当量的氨基乙醇。氢气释放完毕，回流 30min ，自然冷却至室温。室温下加入 1 当量 3- 乙酯 -5- 甲酯 2- 溴甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶的甲基叔丁基醚溶液，在室温下反应 3 小时。后处理方法如实施例 1 ，得到氨氯地平粗品。
实施例 6 ： 本发明所述方法制备氨氯地平
氮气保护下，向圆底烧瓶中加入无水 THF ，加入叔丁醇钾（ 3.0 eq ），搅拌至体系均匀，在 25 ℃ 滴加乙醇胺（ 3.0 eq ），滴加完毕后，继续搅拌 1 个小时，降温至 0 ℃ ，在此温度下滴加 3- 乙酯 -5- 甲酯 -2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶（ 1.0eq ）的四氢呋喃溶液，滴加完毕后缓慢升温到 25 ℃ 反应 3 个小时左右，加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品。
实施例 7 ： 本发明所述方法制备氨氯地平
按照实施例 1-6 所述方法，氮气保护下，使式（ Ⅱ ）所示化合物
Figure PCTCN2012071413-appb-C000005
其中， X 为 -OSO2CH3, -OSO2Ph, -OSO2Ph-Me 或 Br 或 I 与与氨基乙醇在碱存在条件、惰性溶剂中发生亲核取代反应，碱选自钠、钾、氢化钾、氢化钠、氢化锂、氢化钙、叔丁醇钾、叔丁醇钠、甲醇钠、异丙醇钠、氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾或其组合。所述惰性溶剂选自四氢呋喃、二氧六环、甲基叔丁基醚、二甲氧乙烷、二乙二醇二甲醚、三甘醇二甲醚、甲醇、乙醇、异丙醇、叔丁醇、 DMF 、 DMSO 、四甲撑砜、二甲基砜或其组合，在室温下反应 3 小时。后处理方法如实施例 1 ，得到氨氯地平粗品。
实施例 8 ： 氨氯地平苯磺酸盐的制备
5 当量的氢化钠悬浮在干燥的四氢呋喃中，缓慢加入 5 当量的氨基乙醇。氢气释放完毕，回流 30min ，自然冷却至室温。室温下加入 1 当量 3- 乙酯 -5- 甲酯 2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶的四氢呋喃溶液，在室温下反应两小时。加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品，对氨氯地平进行核磁共振检测，其核磁谱图如图2所示。
把异丙醇加入到氨氯地平粗品中，缓慢滴加苯磺酸的异丙醇溶液，同时加热到 55 ℃ ，滴加完毕继续搅拌一小时后开始降到室温，析晶 12 小时。过滤得到氨氯地平苯磺酸盐粗品 , 将粗品加入到异丙醇中加热到 55 ℃ 搅拌一小时之后降温，析晶 2 个小时，过滤，得到氨氯地平苯磺酸盐，从 3- 乙酯 -5- 甲酯 -2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶到最终产物氨氯地平苯磺酸盐两步产率 60% 。
实施例 9 ： 氨氯地平苯磺酸盐的制备
将 5 当量金属钠溶于 5 当量乙醇胺中，搅拌 0.5h ，冷却至 0 ℃ , 然后滴加 1 当量 3- 乙酯 -5- 甲酯 2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶的四氢呋喃溶液。室温下反应 4 小时。加入水淬灭反应，真空蒸出 THF ，二氯甲烷萃取，合并有机相，水洗，无水硫酸钠干燥，过滤，真空蒸出二氯甲烷，得氨氯地平粗品。
把异丙醇加入到氨氯地平粗品中，缓慢滴加苯磺酸的异丙醇溶液，同时加热到 55 ℃ ，滴加完毕继续搅拌一小时后开始降到 0 ℃ ，析晶 12 小时。过滤得到氨氯地平苯磺酸盐粗品 , 将粗品加入到异丙醇中加热到 55 ℃ 搅拌一小时之后降温，析晶 2 个小时，过滤，得到氨氯地平苯磺酸盐。对氨氯地平苯磺酸盐进行核磁共振检测，其核磁谱图如图 3 所示，从 3- 乙酯 -5- 甲酯 -2- 氯甲基 -4- （ 2- 氯苯基） -6- 甲基 -1,4 二氢吡啶到最终产物氨氯地平苯磺酸盐两步产率 58% 。
实施例10 ：氨氯地平苯磺酸盐纯度检测
对实施例 8 、 9 任一实施例制备的氨氯地平苯磺酸盐，用 HPLC 进行纯度检测，检测条件如下：
仪器： Agilent RRLC 1200 ； DAD 检测器
色谱柱： waters Xbridge C18 5um 4.6*250mm
流动相： PH8.90Buffe ：乙腈 =50 ： 50
PH8.90Buffer ： 0.025moL/L 三水合磷酸氢二钾，用稀磷酸调 PH 至 8.90
进样量： 1uL
流速： 1mL/min ，停止时间： 37min ，后运行时间： 6min ，柱温： 25 ℃
检测波长： 240nm 、 215nm 。
检测结果见图 4 ，显示本发明所述方法制备的氨氯地平苯磺酸盐纯度为 99.9146% 。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (11)

  1. 一种制备氨氯地平的方法，由式（Ⅱ）所示化合物与氨基乙醇在碱存在条件发生亲核取代反应得到氨氯地平，
    Figure PCTCN2012071413-appb-C000006
    其中 ， X 为离去基团。
  2. 如权利要求1所述的方法，所述X为-OSO2CH3, -OSO2Ph, -OSO2Ph-Me或Br或Cl或I。
  3. 如权利要求1所述的方法，所述亲核取代反应在惰性溶剂中进行。
  4. 如权利要求1-3任一项所述的方法，其特征在于，所述碱选自钠、钾、氢化钾、氢化钠、氢化锂、氢化钙、叔丁醇钾、叔丁醇钠、甲醇钠、异丙醇钠、氢氧化锂、氢氧化钠、氢氧化钾、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾或其组合。
  5. 如权利要求3所述的方法，所述惰性溶剂选自非质子溶剂或弱亲核性的醇溶剂或其组合。
  6. 如权利要求1-5任一项所述的方法，所述非质子溶剂选自DMF、DMSO、四甲基砜、二甲基砜、四氢呋喃、二氧六环、甲基叔丁基醚、二甲氧乙烷、二乙二醇二甲醚、三甘醇二甲醚、甲苯、二甲苯或其组合。
  7. 如权利要求1-6任一项所述的方法，所述非质子溶剂选自甲苯、二甲苯或其组合。
  8. 如权利要求5所述的方法，所述弱亲核性的醇溶剂为甲醇、乙醇、异丙醇、叔丁醇或其组合。
  9. 如权利要求3-8任一项所述的方法，所述亲核取代反应的反应温度为-30℃至所述惰性溶剂的回流温度
  10. 如权利要求1-9任一项所述的方法，所述氨基乙醇相对于式（Ⅱ）所示化合物为1-7个当量或1-5个当量或2-5个当量或3-5个当量。
  11. 如权利要求1-10任一项所述的方法，所述碱相对于式（Ⅱ）所示化合物为1-7个当量或1-5个当量或2-5个当量或3-5个当量。
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