CN104803998B - 一种降低杂质含量的方法 - Google Patents
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- 238000000034 method Methods 0.000 title abstract description 9
- KGSXMPPBFPAXLY-UHFFFAOYSA-N azilsartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NOC(=O)N1 KGSXMPPBFPAXLY-UHFFFAOYSA-N 0.000 claims abstract description 61
- 239000005485 Azilsartan Substances 0.000 claims abstract description 52
- 229960002731 azilsartan Drugs 0.000 claims abstract description 51
- 239000003513 alkali Substances 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- 239000002585 base Substances 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 19
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
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- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 2
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- PCJFEVUKVKQSSL-UHFFFAOYSA-N 2h-1,2,4-oxadiazol-5-one Chemical compound O=C1N=CNO1 PCJFEVUKVKQSSL-UHFFFAOYSA-N 0.000 description 1
- HXXOPVULXOEHTK-UHFFFAOYSA-N 4-methyl-1,3-dioxol-2-one Chemical compound CC1=COC(=O)O1 HXXOPVULXOEHTK-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical class N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 102000008873 Angiotensin II receptor Human genes 0.000 description 1
- 108050000824 Angiotensin II receptor Proteins 0.000 description 1
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- PZZSUSOQPCMUND-UHFFFAOYSA-N CC(O1)=C(COC)OC1=O Chemical compound CC(O1)=C(COC)OC1=O PZZSUSOQPCMUND-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000005480 Olmesartan Substances 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004105 azilsartan derivatives Chemical class 0.000 description 1
- QJFSABGVXDWMIW-UHFFFAOYSA-N azilsartan medoxomil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C=3NC(=O)ON=3)C(OCC)=NC2=CC=CC=1C(=O)OCC=1OC(=O)OC=1C QJFSABGVXDWMIW-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 208000017574 dry cough Diseases 0.000 description 1
- 229940007183 edarbi Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
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- 239000000543 intermediate Substances 0.000 description 1
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- 238000012986 modification Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- VTRAEEWXHOVJFV-UHFFFAOYSA-N olmesartan Chemical compound CCCC1=NC(C(C)(C)O)=C(C(O)=O)N1CC1=CC=C(C=2C(=CC=CC=2)C=2NN=NN=2)C=C1 VTRAEEWXHOVJFV-UHFFFAOYSA-N 0.000 description 1
- 229960005117 olmesartan Drugs 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229940093956 potassium carbonate Drugs 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种降低杂质含量的方法，具体涉及一种阿齐沙坦四聚体杂质(4)的含量低的阿齐沙坦酯的制备方法，其包括：阿齐沙坦(2)与4‑羟甲基‑5‑甲基‑1,3‑二氧杂环戊烯‑2‑酮(3)
Description
技术领域
本发明涉及药物化学领域，具体涉及一种降低制备血管紧张素Ⅱ受体拮抗剂(ARBs)过程中产生的杂质的方法。
背景技术
阿齐沙坦酯，也称为(5-甲基-2-氧代-1,3-间二氧杂环戊烯-4-基)甲基2-乙氧基-1-{[2'-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)联苯-4-基]甲基}-1H-苯并咪唑-7-羧酸酯,由日本武田制药公司研发的血管紧张素Ⅱ受体拮抗剂(ARBs)，为阿齐沙坦(azilsartan)的前药，用于治疗高血压,结构如式(I)所示：
2011年2月25日，美国FDA批准阿齐沙坦酯的钾盐(商品名Edarbi)用于治疗成人高血压，临床研究证实其具有平稳持久的抗高血压作用。临床研究数据显示，与FDA已批准的其他两种选择性血管紧张素II受体抑制剂缬沙坦和奥美沙坦相比，该药在降低24小时血压方面效果更显著，还具有平稳降压，不会引起干咳的优点，同时还可能通过多种机制降低心血管疾病以及糖尿病的风险。
目前已报道的阿齐沙坦酯(1)的合成方法是通过阿齐沙坦(2)与侧链(3)缩合制得，如PCT申请WO2013156005实施例1的方法，对甲苯磺酰氯、DMAP、碳酸钾、阿齐沙坦(2)和侧链(3)加入二甲基乙酰胺中，在8-10摄氏度下反应3小时后，后处理得阿齐沙坦酯，产率80.1％，HPLC纯度97.6％，
采用该方法制备阿齐沙坦酯其HPLC纯度仅97.6％左右，其中有一种杂质的含量(HPLC峰面积)超过1.0％，一般为3.0％左右，中国专利申请公开CN 201410529424.7报道了这种杂质为四分子阿齐沙坦脱去四分子
水后形成的杂质(以下简称阿齐沙坦四聚体杂质)，其结构如式(4)所示：
这种阿齐沙坦四聚体杂质(4)含量较高，后续难以除去，使API难以满足ICH Q7规定的标准。在药物合成过程中，一般通过反复的重结晶来降低杂质，提高产品的纯度，但反复的重结晶容易导致产品损失，产量下降。
发明内容
本发明的一个目的是提供一种产率高且阿齐沙坦四聚体杂质，其结构如式(4)所示，含量低的阿齐沙坦酯的制备方法
为了达到本发明的目的，本发明提供以下技术方案：
一种阿齐沙坦四聚体杂质(4)的含量低的阿齐沙坦酯的制备方法，
其包括：阿齐沙坦(2)与4-羟甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(3)
在碱的存在下反应，其特征在于所述碱的用量相对于阿齐沙坦(2)为2.5当量以上。
作为优选，所述的碱的用量相对于阿齐沙坦(2)为约2.5当量至约4.0当量。
作为优选，所述的碱为无机碱如碳酸钾，碳酸钠等，或有机碱如三乙胺、乙二胺、N,N-二异丙基乙胺等，更优选的所述的碱为碳酸钾、碳酸钠、三乙胺、乙二胺或N,N-二异丙基乙胺。
作为优选，所述的反应在约-10摄氏度至约10摄氏度下进行，或在冰浴中进行。
作为优选，所述阿齐沙坦四聚体杂质(4)的含量低的阿齐沙坦酯的制备方法，其包括：向置于冰浴中的反应容器依次加入阿齐沙坦(8.59g，18.84mmol)、DMAc(80ml)、DMAP(0.5g)、TsCl(3.9g)、4-羟甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(2.4g)搅拌溶解后，加入碱(57.1mmol)，滴加完毕，混合物升温至10℃，保温搅拌3小时，反应完毕后向反应液中滴加0.3NHCl，调节pH至5，然后缓慢滴加60ml的水，析出固体，过滤，往所得的固体中加入滴加80ml丙酮/水(1：3)，在35℃下搅拌2小时后,再在冰浴中搅拌3小时、过滤,50℃真空干燥10h得阿齐沙坦酯。
作为优选，当所述的碱的用量相对于阿齐沙坦(2)为约2.5当量至约4.0当量，本发明制备得到的阿齐沙坦酯的阿齐沙坦四聚体杂质(4)的含量HPLC(峰面积)小于0.1％，优选小于0.05％。
本发明另一目的是提供一种“一锅法”制备阿齐沙坦(2)的方法，其包括：室温下(30℃)，向反应瓶中加入化合物01(180g,1eq)、甲苯(540mL)和三乙胺(47.6g,1.2eq)得到混合物，氯甲酸乙酯(51.1g,1.2eq)的甲苯(180mL)溶液滴加到上述反应液中，滴完后，继续搅拌2h，反应完后，将反应液冷却至室温，加入600mL水，分出甲苯层，往甲苯层中加入DMAP(57.5g,1.2eq)，升温至回流，搅拌3h，反应完后，将反应液冷却至室温，滴加2mol/L氢氧化钠水溶液1.2L搅拌反应3h,将反应液pH值调至3.0，保温搅拌1h，抽滤，固体用200mL水淋洗，固体在50℃真空干燥12h得到阿齐沙坦(2)
本发明上下文中，“约”或“大约”是指数值在+/-10％以内或+/-5％以内。
本发明上下文中，“室温”是指温度20摄氏度至35摄氏度之间。
本发明的有益效果如下：
1.在制备阿齐沙坦酯的过程中产生的阿齐沙坦四聚体杂质(4)含量高、难以除去，针对这个问题我们经过不断的探索，发现了当反应中碱的用量不足的情况下，会产生大量的阿齐沙坦四聚体杂质，但当碱的量相对于阿齐沙坦(2)为2.5当量以上，阿齐沙坦四聚体杂质含量即降低至0.1％以下。
2.本发明所提供的“一锅法”制备阿齐沙坦的方法，反应结束后，粗品高效液相色谱HPLC纯度在99.0％以上，总收率在80％以上，仅使用一种溶剂,利于回收,可工业化放大；且制备过程中无需分离中间体，无需后处理，操作简便。
具体实施方式
以下所述实施例详细的说明了本发明，并不是把本发明的保护范围限制在以下实施例。
本发明上下文中的简写表示如下：DMAc：N,N-二甲基乙酰胺，DMAP:4-二甲氨基吡啶，TsCl：对甲苯磺酰氯，HPLC高效液相色谱，h表示小时，eq表示当量。
实施例1阿齐沙坦的制备
室温下(30℃)，向反应瓶中加入化合物01(180g,1eq)、甲苯(540mL)和三乙胺(47.6g,1.2eq)得到混合物，氯甲酸乙酯(51.1g,1.2eq)的甲苯(180mL)溶液滴加到上述反应液中，滴完后，继续搅拌2h，反应完后，将反应液冷却至室温，加入600mL水，分出甲苯层，往甲苯层中加入DMAP(57.5g,1.2eq)，升温至回流，搅拌3h，反应完后，将反应液冷却至室温，滴加2mol/L氢氧化钠水溶液1.2L搅拌反应3h,将反应液pH值调至3.0，保温搅拌1h，抽滤，固体用200mL水淋洗，固体在50℃真空干燥12h得到阿齐沙坦(2)总收率约89％。
实施例2碱的用量对阿齐沙坦四聚体杂质含量的影响
向置于冰浴中的反应容器依次加入阿齐沙坦(8.59g，18.84mmol)、DMAc(80ml)、DMAP(0.5g)、TsCl(3.9g)、4-羟甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(2.4g)搅拌溶解后，加入表一中的碱，滴加完毕，混合物升温至10℃，保温搅拌3小时，反应完毕。向反应液中滴加0.3N HCl，调节pH至5，然后缓慢滴加60ml的水，析出固体，过滤，往所得的固体中加入滴加80ml丙酮/水(V/V为1：3)，在35℃下搅拌2小时后,再在冰浴中搅拌3小时、过滤,50℃真空干燥10h得阿齐沙坦酯7.8g，阿齐沙坦酯的HPLC纯度及阿齐沙坦四聚体杂质含量如表一所示：
表一、碱的用量对阿齐沙坦四聚体杂质含量的影响
实施例3实施例2的HPLC的检测条件
色谱柱：Agilent Eclipse XDB C18 4.6*250mm，5um
流动相：A相：10Mm醋酸铵缓冲盐(pH3.5)B相：乙腈
检测波长：254nm 流速：1.0ml/min 柱温：30℃
运行时间：60min 后运行时间：8min
洗脱梯度：
| Time(min) | A％ | B％ |
| 0 | 55 | 45 |
| 8 | 55 | 45 |
| 18 | 40 | 60 |
| 28 | 10 | 90 |
| 60 | 10 | 90 |
其中，阿齐沙坦四聚体杂质的保留时间：38.36min，相对保留时间2.24。
以上所述仅是本发明的较佳实施方式，故凡依本发明专利申请范围的条件、特征及原理所做的等效变化或修饰，均包括于本发明专利申请范围内。
Claims (2)
1.一种阿齐沙坦四聚体杂质(4)含量低的阿齐沙坦酯的制备方法，
其包括：阿齐沙坦(2)与4-羟甲基-5-甲基-1,3-二氧杂环戊烯-2-酮(3)
在碱的存在下反应，其特征在于所述的碱的用量相对于阿齐沙坦(2)为2.5当量至4.0当量,所述的碱为碳酸钾、碳酸钠、三乙胺、乙二胺或N,N-二异丙基乙胺,所述的反应在-10摄氏度至10摄氏度下进行。
2.根据权利要求1所述的制备方法，其特征在于：所述阿齐沙坦四聚体杂质(4)的含量HPLC(峰面积)小于0.1％。
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