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WO2021212535A1 - 一种盐酸苯海索精制方法 - Google Patents

一种盐酸苯海索精制方法 Download PDF

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WO2021212535A1
WO2021212535A1 PCT/CN2020/087368 CN2020087368W WO2021212535A1 WO 2021212535 A1 WO2021212535 A1 WO 2021212535A1 CN 2020087368 W CN2020087368 W CN 2020087368W WO 2021212535 A1 WO2021212535 A1 WO 2021212535A1
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refining
solution
hydrochloride
purified water
trihexyphenid
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PCT/CN2020/087368
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English (en)
French (fr)
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梁志祥
朱占元
刘文杰
刘文丽
孔凯丽
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江苏天士力帝益药业有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/092—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings with aromatic radicals attached to the chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/84—Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/82—Purification; Separation; Stabilisation; Use of additives
    • C07C209/86—Separation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/94—Oxygen atom, e.g. piperidine N-oxide

Definitions

  • the invention belongs to the technical field of medicine synthesis, and relates to the purification of medicines, in particular to a method for refining trihexyphenid hydrochloride.
  • Trihexyphenidyl hydrochloride is a central anticholinergic and antiparkinsonian drug. Its mechanism of action is to selectively block the cholinergic nerve pathways in the striatum, thereby helping to restore the balance of dopamine and acetylcholine in the brain and improve the patient’s Parkinson’s. symptom.
  • the synthetic route of the company's trihexyphenid hydrochloride is roughly as follows: 3-(1-piperidinyl) phenylacetone hydrochloride reacts with Grignard reagent to add reaction, and hydrochloric acid is added to produce a hydrolysis reaction to produce crude trihexyphenid hydrochloride.
  • the specific route is as follows In the figure, after multiple batches of liquid phase testing, it is found that there is an unknown impurity at 1.6min with a content of about 1.0%. The impurity can not be removed well by recrystallization with conventional solvents or mixed solvents, although it can be Recrystallization was repeated many times, but the product yield dropped severely.
  • the purpose of the present invention is to provide a method for refining trihexyphenid hydrochloride.
  • the present invention adopts a method of alkaline washing and acid conditioning, which can obtain pure trihexyphenid hydrochloride with high yield and high purity, thereby
  • the method of recrystallizing and refining trihexyphenid hydrochloride with organic solvents is used. Not only does the product obtained have good appearance, high yield, no organic solvent residues, and the product meets the requirements of pharmaceutical standards, but also the process is simple and convenient to save costs, which is beneficial Industrial production of trihexyphenidyl hydrochloride.
  • a method for refining trihexyphenidyl hydrochloride includes the following steps:
  • Step 1 Add the crude trihexyphenid hydrochloride to purified water and stir evenly. After the alkaline solution adjusts the pH, it is heated and pulped, filtered and washed, and the filter cake is collected;
  • Step two add the filter cake obtained in step one to purified water and stir evenly, adjust the pH of the hydrochloric acid solution to 2 ⁇ 3, decolorize the activated carbon, filter, adjust the pH of the filtrate with hydrochloric acid solution to salt, then heat up and keep it warm, then cool down and crystallize. Filter, wash, and dry under reduced pressure to obtain pure trihexyphenidyl hydrochloride.
  • the improved scheme of the present invention is:
  • the weight of the purified water in step one is 5-20 times the weight of the crude trihexyphenidyl hydrochloride, preferably 8-12 times.
  • the alkaline solution in step one is sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, potassium carbonate solution, sodium bicarbonate solution.
  • the mass concentration of the alkaline solution in step one is 15% to 32%.
  • step 1 the alkaline solution is adjusted to pH 10-14, preferably 11-13.
  • the temperature of the heat preservation and beating in step one is 20 to 80°C, preferably 30 to 60°C, and the time is 1 to 3 hours.
  • the weight of the purified water in step 2 is 20-60 times the weight of the filter cake, preferably 30-50 times.
  • the pH of the hydrochloric acid solution is adjusted to 1-4, preferably 1-2.
  • the holding temperature is 50-100°C, preferably 60-80°C, and the holding time is 40min-80min; the temperature for cooling and crystallization is 0-20°C, preferably 5-10°C, The time is 1 ⁇ 3h.
  • the mass concentration of the hydrochloric acid solution in step 2 is 8%-25%.
  • the refined trihexyphenidyl hydrochloride obtained by the method of the invention has good appearance, high content and yield, and the product quality meets the requirements of the pharmacopoeia. It is particularly advantageous that the technical solution of the present invention can be refined at one time, and can effectively remove the unknown impurities of 1.6 min that are difficult to remove in the prior art, so that the content of trihexyphenidyl hydrochloride after refining can reach more than 99.5%, and the related substances can be detected by HPLC During the 1.6min, the impurities are basically controlled at about 0.05%, the remaining single impurities are less than 0.01%, and the molar yield range reaches more than 90%.
  • the method of the invention avoids organic solvents, has a large safety factor, is simple to operate, saves costs, and is easier to realize industrialized production.
  • Figure 1 is the HPLC spectrum of crude trihexyphenidyl hydrochloride with batch number 201909022;
  • Fig. 2 is an HPLC chart of the fine trihexyphenidyl hydrochloride prepared in Example 1.
  • Injection volume 20 ⁇ L
  • the content of fine trihexyphenid hydrochloride was determined to be 99.5%, and the unknown single impurities at about 1.6min were 0.05%.
  • the spectrum is shown in Figure 2.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

一种盐酸苯海索精制方法，包括如下步骤：步骤一，将盐酸苯海索粗品加入纯化水中搅拌均匀，碱性溶液调节pH后，保温，过滤、洗涤，滤饼收集；步骤二，将步骤一所得滤饼再加到纯化水中搅拌均匀，盐酸溶液调节pH至2～3，活性炭脱色，过滤，盐酸溶液调节pH成盐，再升温并保温，再降温析晶，过滤、洗涤、减压干燥即得盐酸苯海索纯品。通过采用碱洗酸调的方法，能高收率、高纯度的得到盐酸苯海索纯品，从而替代现有技术采用含有机溶剂重结晶精制盐酸苯海索的方法，不仅所得精品外观好，收率高，无有机溶剂残留，产品符合药用标准要求，而且工艺操作简便，节约成本，利于工业化生产。

Description

一种盐酸苯海索精制方法 技术领域
本发明属于药物合成技术领域，涉及药物的纯化，特别涉及一种盐酸苯海索的精制方法。
背景技术
1949年盐酸苯海索已经出现在治疗帕金森临床研究中，2003年正式获得美国FDA批准，其化学名1-环己基-1-苯基-3-(1-哌啶基)-丙醇盐酸盐，结构式如下：
Figure PCTCN2020087368-appb-000001
盐酸苯海索是一种中枢抗胆碱抗帕金森病药，作用机制为选择性阻断纹状体胆碱能神经通路，从而有利于恢复脑内多巴胺和乙酰胆碱的平衡，改善患者的帕金森症状。
本公司盐酸苯海索合成路线大致为：3-(1-哌啶基)苯丙酮盐酸盐与格式试剂反应加成反应，再加盐酸发生水解反应，生成盐酸苯海索粗品，具体路线如下图，经过多批次液相检测均发现，在1.6min处有一个未知杂质，含量在1.0％左右，该杂质用常规溶剂或混合溶剂重结晶均达不到很好的清除效果，虽然可经过多次重结晶去除，但产品收率严重下降。
Figure PCTCN2020087368-appb-000002
发明内容
针对现有技术的不足，本发明的目的在于提供一种盐酸苯海索的精制方法，本发明采用碱洗酸调的方法，能高收率、高纯度的得到盐酸苯海索纯品，从而替代现有技术采用含有机溶剂重结晶精制盐酸苯海索的方法，不仅所得精品外观好，收率高，无有机溶剂残留，产品符合药用标准要求，而且工艺操作简便，节约成本，有利于盐酸苯海索工业化生产。
本发明是通过以下技术方案实现的：
一种盐酸苯海索的精制方法，包括如下步骤：
步骤一，将盐酸苯海索粗品加入纯化水中搅拌均匀，碱性溶液调节pH后，保温打浆，过滤、洗涤，滤饼收集；
步骤二，将步骤一所得滤饼再加到纯化水中搅拌均匀，盐酸溶液调节pH至2～3，活性炭脱色，过滤，滤液用盐酸溶液调节pH成盐，再升温并保温，再降温析晶，过滤、洗涤、减压干燥即得盐酸苯海索纯品。
本发明的改进方案为：
步骤一中所述纯化水的重量为所述盐酸苯海索粗品重量的5～20倍，优选为8～12倍。
进一步的，步骤一中所述碱性溶液为氢氧化钠溶液、氢氧化钾溶液、碳酸钠溶液，碳酸钾溶液、碳酸氢钠溶液。
进一步的，步骤一中所述碱性溶液的质量浓度为15％～32％.
进一步的，步骤一中所述碱性溶液调节pH至10～14，优选为11～13。
进一步的，步骤一中所述保温打浆温度为20～80℃，优选为30～60℃，时间为1～3h。
进一步的，步骤二中所述纯化水的重量为所述滤饼重量的20～60倍，优选为30～50倍。
进一步的，步骤二中活性炭脱色后，盐酸溶液调节pH至1～4，优选为1～2。
进一步的，步骤二中所述保温温度为50～100℃，优选为60～80℃，保温时间为40min～80min；所述降温析晶的温度为0～20℃，优选为5～10℃，时间为1～3h。
进一步的，步骤二中所述盐酸溶液的质量浓度为8％～25％。
本发明的有益效果为：
用本发明方法精制所得到盐酸苯海索精品外观良好，含量和收率高，产品质量符合药典要求。尤其有利的是，本发明技术方案能一次精制，即可有效去除现有技术中难以一次去除的1.6min的未知杂质，使得精制后的盐酸苯海索含量可达99.5％以上，有关物质HPLC检测过程中1.6min杂质基本控制0.05％左右，其余单杂均小于0.01％，摩尔收率范围达到90％以上。
本发明方法避免有机溶剂，安全系数大，操作简便，节约成本，更加易于实现工业化生产。
附图说明
图1为批号201909022的盐酸苯海索粗品的HPLC图谱；
图2为实施例1制得的盐酸苯海索精品的HPLC图谱。
具体实施方式
实施例1
将批号为201909022的盐酸苯海索粗品20g用200g纯化水搅拌均匀，15wt％氢氧化钠溶液调节pH至12，50℃下打浆2小时，过滤，纯化水洗涤滤饼至中性，再用800g纯化水搅拌均匀，8wt％盐酸溶液调节pH至2.5左右，待固体全溶后，加入适量活性炭脱色30分钟，过 滤，滤液用15wt％盐酸溶液调节pH至2，升温至70℃保温1小时，再降温至5℃析晶2小时，抽滤，纯化水洗涤，75℃减压干燥至恒重即得白色固体粉末盐酸苯海索精品18.4g，收率92.2％，取样盐酸苯海索精品，采用中国药典的HPLC方法测定，测定方法如下：
色谱仪：Shimadzu；
检测器：Shimadzu PDA；
色谱柱：十八烷基硅烷键合硅胶柱
测定波长：210nm
流动相：0.1％三乙胺溶液(用磷酸调节pH值至4.0)-乙腈(70：30)
流速：1.0ml/min；
进样量：20μL；
按照上述方法，测得盐酸苯海索精品含量为99.5％，1.6min左右的未知单杂0.05％，图谱见附图2。
实施例2
将批号为201909022的盐酸苯海索粗品20g用240g纯化水搅拌均匀，氢氧化钾溶液调节pH至13，40℃下打浆2小时，过滤，纯化水洗涤滤饼至中性，再用1000g纯化水搅拌均匀，盐酸溶液调节pH至2.5左右，待固体全溶后，加入适量活性炭脱色30分钟，过滤，滤液用盐酸溶液调节pH至1，升温至80℃保温1小时，再降温至10℃析晶2小时，抽滤，纯化水洗涤，75℃减压干燥至恒重即得白色固体粉末盐酸苯海索精品，收率93.4％，按照实施例1的检测方法检测含量，含量为99.6％，1.6min左右的单杂由0.07％。
实施例3
将批号为201909022的盐酸苯海索粗品50g用450g纯化水搅拌均匀，氢氧化钠溶液调节pH至11，30℃下打浆2小时，过滤，纯化水洗涤滤饼至中性，再用2000g纯化水搅拌均匀，盐酸溶液调节pH至2.5左右，待固体全溶后，加入适量活性炭脱色30分钟，过滤，滤液用盐酸溶液调节pH至2，升温至65℃保温1小时，再降温至8℃析晶2小时，抽滤，纯化水洗涤，75℃减压干燥至恒重即得白色固体粉末盐酸苯海索精品，收率90.3％，按照实施例1的检测方法检测含量，含量为99.7％，1.6min左右的单杂由0.06％。
实施例4
将批号为201909022的盐酸苯海索粗品30g用330g纯化水搅拌均匀，氢氧化钾溶液调节pH至11，60℃下打浆2小时，过滤，纯化水洗涤滤饼至中性，再用900g纯化水搅拌均匀，盐酸溶液调节pH至2.5左右，待固体全溶后，加入适量活性炭脱色30分钟，过滤，滤液用盐酸溶液调节pH至2，升温至60℃保温1小时，再降温至7℃析晶2小时，抽滤，纯化水洗 涤，75℃减压干燥至恒重即得白色固体粉末盐酸苯海索精品，收率94.3％，按照实施例1的检测方法检测含量，含量为99.7％，1.6min左右的单杂由0.04％。
实施例5
将盐酸苯海索粗品100g用1200g纯化水搅拌均匀，氢氧化钾溶液调节pH至12，45℃下打浆2小时，过滤，纯化水洗涤滤饼至中性，再用4000g纯化水搅拌均匀，盐酸溶液调节pH至2.5左右，待固体全溶后，加入适量活性炭脱色30分钟，过滤，滤液用盐酸溶液调节pH至1，升温至75℃保温1小时，再降温至6℃析晶2小时，抽滤，纯化水洗涤，75℃减压干燥至恒重即得白色固体粉末盐酸苯海索精品，收率93.5％，按照实施例1的检测方法检测含量，含量为99.8％，1.6min左右的单杂由0.03％。

Claims (10)

  1. 一种盐酸苯海索精制方法，其特征在于，包括如下步骤：
    步骤一，将盐酸苯海索粗品加入纯化水中搅拌均匀，碱性溶液调节pH后，保温打浆，过滤、洗涤，滤饼收集；
    步骤二，将步骤一所得滤饼再加到纯化水中搅拌均匀，盐酸溶液调节pH至2～3，活性炭脱色，过滤，滤液用盐酸溶液调节pH成盐，再升温并保温，再降温析晶，过滤、洗涤、减压干燥即得盐酸苯海索纯品。
  2. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤一中所述纯化水的重量为所述盐酸苯海索粗品重量的5～20倍。
  3. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤一中所述碱性溶液为氢氧化钠溶液、氢氧化钾溶液、碳酸钠溶液，碳酸钾溶液、碳酸氢钠溶液。
  4. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤一中所述碱性溶液调节pH至10～14。
  5. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤一中所述保温打浆温度为20～80℃，时间为1～3h。
  6. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤二中所述纯化水的重量为所述滤饼重量的20～60倍。
  7. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤二中活性炭脱色后，盐酸溶液调节pH至1～4。
  8. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤二中所述保温温度为50～100℃，保温时间为40min～80min；所述降温析晶的温度为0～20℃，时间为1～3h。
  9. 根据权利要求1所述的一种盐酸苯海索精制方法，其特征在于：步骤二中所述盐酸溶液的质量浓度为8％～25％。
  10. 根据权利要求1或3任意一项所述的一种盐酸苯海索精制方法，其特征在于：步骤一中所述碱性溶液的质量浓度为15％～32％。
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