CN117551027A - 一种吡啶地平的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 16
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 9
- 238000010992 reflux Methods 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 239000003960 organic solvent Substances 0.000 claims abstract description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
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- RWNNRGBCWXOVAC-UHFFFAOYSA-N 1,4-bis[bis(aziridin-1-yl)phosphoryl]piperazine Chemical compound C1CN1P(N1CCN(CC1)P(=O)(N1CC1)N1CC1)(=O)N1CC1 RWNNRGBCWXOVAC-UHFFFAOYSA-N 0.000 description 6
- 238000001819 mass spectrum Methods 0.000 description 6
- 229960004916 benidipine Drugs 0.000 description 5
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 description 5
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 5
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- WMFYOYKPJLRMJI-UHFFFAOYSA-N Lercanidipine hydrochloride Chemical compound Cl.COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 WMFYOYKPJLRMJI-UHFFFAOYSA-N 0.000 description 4
- 229960002162 lercanidipine hydrochloride Drugs 0.000 description 4
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- 150000001793 charged compounds Chemical class 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
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- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
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- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 2
- 229940127291 Calcium channel antagonist Drugs 0.000 description 2
- 239000002220 antihypertensive agent Substances 0.000 description 2
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- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 description 1
- KJEBULYHNRNJTE-DHZHZOJOSA-N Cinalong Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC\C=C\C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-DHZHZOJOSA-N 0.000 description 1
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229960000528 amlodipine Drugs 0.000 description 1
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 description 1
- 239000000400 angiotensin II type 1 receptor blocker Substances 0.000 description 1
- 229940127282 angiotensin receptor antagonist Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- OKLAEQBUDFSNDL-UHFFFAOYSA-N calcium;1,4-dihydropyridine Chemical compound [Ca].C1C=CNC=C1 OKLAEQBUDFSNDL-UHFFFAOYSA-N 0.000 description 1
- FAKRSMQSSFJEIM-RQJHMYQMSA-N captopril Chemical compound SC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O FAKRSMQSSFJEIM-RQJHMYQMSA-N 0.000 description 1
- 229960000830 captopril Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
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- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 229960002003 hydrochlorothiazide Drugs 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229960004294 lercanidipine Drugs 0.000 description 1
- ZDXUKAKRHYTAKV-UHFFFAOYSA-N lercanidipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)(C)CN(C)CCC(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZDXUKAKRHYTAKV-UHFFFAOYSA-N 0.000 description 1
- KJJZZJSZUJXYEA-UHFFFAOYSA-N losartan Chemical compound CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C=2[N]N=NN=2)C=C1 KJJZZJSZUJXYEA-UHFFFAOYSA-N 0.000 description 1
- 229960004773 losartan Drugs 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 229960002237 metoprolol Drugs 0.000 description 1
- IUBSYMUCCVWXPE-UHFFFAOYSA-N metoprolol Chemical compound COCCC1=CC=C(OCC(O)CNC(C)C)C=C1 IUBSYMUCCVWXPE-UHFFFAOYSA-N 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229960001783 nicardipine Drugs 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
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- 229960000227 nisoldipine Drugs 0.000 description 1
- 229960005425 nitrendipine Drugs 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
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Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
将地平类药物加入到有机溶剂中，加入活性炭，通入氧气回流反应，以简易和低成本方式制备得到吡啶地平。
Description
技术领域
本发明涉及一种吡啶地平的制备方法，属于医药技术领域。
背景技术
目前国内降压药有数十种，指南推荐首选的降压药物主要包括5类：1.利尿剂，如氢氯噻嗪；2.钙离子拮抗剂（地平类），如氨氯地平；3.β-受体阻滞剂，如美托洛尔；4.血管紧张素转换酶抑制剂（普利类），如卡托普利；5.血管紧张素受体拮抗剂（沙坦类），如氯沙坦。
地平类的药物归属于钙通道阻滞剂，称为1,4-二氢吡啶类钙通道阻滞剂，在化学结构中含有共同的结构母核1,4-二氢吡啶，二氢吡啶环是这类药物必需的活性结构，如果脱氢芳构化成吡啶环，则药物的活性消失；
。
由于1,4-二氢吡啶的结构容易脱氢芳构化转变成吡啶结构，中国药典2020年版中对地平类药物中的吡啶地平杂质以特定杂质进行了控制，如盐酸尼卡地平（限度0.2%）、尼莫地平（限度0.1%）、尼索地平（限度0.2%）、尼群地平（限度0.1%）以及西尼地平（限度0.2%）等。
目前，已有多篇文献报道了各类可以使二氢吡啶脱氢芳构化的试剂与反应方法。但大多数二氢吡啶脱氢芳构化反应的实验条件苛刻，通常会使用大量的氧化剂，副产物多而复杂，后处理繁琐且环境污染严重。
其中，北京市药品检验所专利201810982144X中公开了一种相对较为优化的二氢吡啶类化合物脱氢芳构化方法：酸性水溶液中在含镍催化剂存在下进行氧化反应接着纯化。但该方法依旧存在使用价格较贵的镍催化剂、操作较为复杂，纯度不够高以及收率偏低等缺点。
杂质对照品常用于药品质量监控中，以简易和低成本方式制备这些杂质对照品仍然是本领域技术人员迫切期待的。
发明内容
本发明的目的在于提供一种简易的、低成本的方式制备吡啶地平，以用于此类药物的质量检测，本发明的另一目的在于为二氢吡啶类药物的合成工艺以及制剂生产工艺的设计提供参考。
发明人经对各个地平类药物工艺开发和优化过程中的试验条件和结果细心整理和研究，出人意料地发现，活性炭对吡啶地平的产生起着较强的促进作用，经进一步试验摸索和优化后开发出一条简易和低成本制备吡啶地平的合成路线：将地平类药物加入到适宜的有机溶剂中，加入地平1-50%重量比的活性炭，通入氧气回流1-4天，趁热过滤掉活性炭，滤液直接冷却析晶，或者将滤液减压蒸出有机溶剂再加入酯类，酮类、醇类溶剂析晶，即可高收率的获得对应的吡啶地平，纯度高于98.5%。
本发明不仅可以简便的制得吡啶地平杂质对照品，而且由吡啶地平杂质制备的反应条件可知，地平类药物在原料药合成工艺以及制剂生产工艺时不宜采用活性炭高温长时间脱色，以避免吡啶地平杂质的大量产生。同时还提示地平类药物在原料药以及制剂生产过程中应尽量避免与氧化剂接触。
附图说明
图1：吡啶盐酸尼卡地平HPLC图。
图2：吡啶盐酸尼卡地平高分辨质谱图。
图3：吡啶盐酸贝尼地平HPLC图。
图4：吡啶盐酸贝尼地平高分辨质谱图。
图5：吡啶盐酸乐卡地平HPLC图。
图6：吡啶盐酸乐卡地平高分辨质谱图。
具体实施方式
实施例1
向三口瓶中加入盐酸尼卡地平20g，甲醇120ml，活性炭1g，通入氧气，加热至回流反应36小时，趁热抽滤，滤液冷却至0-5℃析晶8小时，抽滤，滤饼50℃减压干燥，得吡啶盐酸尼卡地平18.4g，收率92.4%，纯度99.53%，高分辨质谱显示分子离子峰为478.1927（吡啶尼卡地平碱基+1）。
实施例2
向三口瓶中加入盐酸贝尼地平20g，氯仿80ml，活性炭2g，通入氧气，加热至回流反应42小时，趁热抽滤，滤液减压蒸干，加丙酮200ml，冷却至0-5℃析晶8小时，抽滤，滤饼50℃减压干燥，得吡啶盐酸贝尼地平17.7g，收率88.8%，纯度99.52%，高分辨质谱显示分子离子峰为504.2140（吡啶贝尼地平碱基+1）。
实施例3
向三口瓶中加入盐酸乐卡地平20g，乙酸乙酯80ml，活性炭4g，通入氧气，加热至回流反应40小时，趁热抽滤，滤液冷却至0-5℃析晶8小时，抽滤，滤饼50℃减压干燥，得吡啶盐酸乐卡地平17.2g，收率86.3%，纯度98.72%，高分辨质谱显示分子离子峰为610.2875（吡啶乐卡地平碱基+1）。
Claims (9)
1.一种制备吡啶地平的方法，该方法包括如下步骤：将地平类药物加入到有机溶剂中，加入活性炭，通入氧气回流反应，趁热过滤掉活性炭，滤液直接冷却析晶，或者将滤液减压蒸出有机溶剂再加入酯类，酮类、醇类溶剂析晶。
2.根据权利要求1的方法，所述有机溶剂选自：酯、醇以及卤代烃。
3.根据权利要求2中所述酯为甲酸乙酯、乙酸乙酯以及乙酸甲酯。
4.根据权利要求2中所述醇为甲醇、乙醇以及异丙醇。
5.根据权利要求2中所述卤代烃为二氯甲烷、三氯甲烷以及二氯乙烷。
6.根据权利要求1的方法，所述活性炭的用量为1-50%。
7.根据权利要求6所述活性炭的用量为5-20%。
8.根据权利要求1的方法，所述回流反应时间为1-4天。
9.根据权利要求8所述回流反应时间为1.5-2.5天。
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