CN103739542B - 3-(2-腈乙基)-5-甲基-2,6-二甲基-4-(3-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸酯的制备方法 - Google Patents
3-(2-腈乙基)-5-甲基-2,6-二甲基-4-(3-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸酯的制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- MFYLRNKOXORIPK-UHFFFAOYSA-N (3-nitrophenyl)-phenylmethanone Chemical class [O-][N+](=O)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 MFYLRNKOXORIPK-UHFFFAOYSA-N 0.000 title claims description 16
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 claims abstract description 15
- 150000002148 esters Chemical class 0.000 claims abstract description 15
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 235000019257 ammonium acetate Nutrition 0.000 claims abstract description 10
- 239000000908 ammonium hydroxide Substances 0.000 claims abstract description 10
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000005695 Ammonium acetate Substances 0.000 claims abstract description 8
- 229940043376 ammonium acetate Drugs 0.000 claims abstract description 8
- 229960002992 barnidipine Drugs 0.000 claims abstract description 6
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 claims abstract description 6
- -1 (3 nitrobenzophenone) 1,4 dihydropyridines Chemical class 0.000 claims abstract description 4
- 238000004176 ammonification Methods 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims abstract 2
- 238000005809 transesterification reaction Methods 0.000 claims abstract 2
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 125000004494 ethyl ester group Chemical group 0.000 claims description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- UKVYVZLTGQVOPX-IHWYPQMZSA-N (z)-3-aminobut-2-enoic acid Chemical compound C\C(N)=C\C(O)=O UKVYVZLTGQVOPX-IHWYPQMZSA-N 0.000 claims description 16
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 claims description 13
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 7
- ZETIVVHRRQLWFW-UHFFFAOYSA-N 3-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=CC(C=O)=C1 ZETIVVHRRQLWFW-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000003054 catalyst Substances 0.000 claims description 4
- 235000019441 ethanol Nutrition 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical compound [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- 125000005909 ethyl alcohol group Chemical group 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 6
- 238000006555 catalytic reaction Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 150000007524 organic acids Chemical class 0.000 abstract description 2
- JNETYVLEGPSOFY-UHFFFAOYSA-N 3-bromopyrrolidine-2,5-dione Chemical class BrC1CC(=O)NC1=O JNETYVLEGPSOFY-UHFFFAOYSA-N 0.000 abstract 1
- 238000007171 acid catalysis Methods 0.000 abstract 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000015572 biosynthetic process Effects 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 238000003786 synthesis reaction Methods 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 6
- 238000010792 warming Methods 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000005360 mashing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- XKORCTIIRYKLLG-ONEGZZNKSA-N methyl (e)-3-aminobut-2-enoate Chemical compound COC(=O)\C=C(/C)N XKORCTIIRYKLLG-ONEGZZNKSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- VBBRYJMZLIYUJQ-UHFFFAOYSA-N cyclopropanone Chemical compound O=C1CC1 VBBRYJMZLIYUJQ-UHFFFAOYSA-N 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- OENLEHTYJXMVBG-UHFFFAOYSA-N pyridine;hydrate Chemical compound [OH-].C1=CC=[NH+]C=C1 OENLEHTYJXMVBG-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/02—Preparation by ring-closure or hydrogenation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
本发明涉及一种巴尼地平中间体3‑(2‑腈乙基)‑5‑甲基‑2，6‑二甲基‑4‑(3‑硝基苯基)‑1，4‑二氢吡啶‑3，5‑二羧酸酯的制备方法，其特征在于，3‑羟基丙腈与乙酰乙酸甲酯在N‑溴代丁二酰亚胺(NBS)催化下进行酯交换，再与醋酸铵和氨水的混合物氨化，再经有机酸催化反应，得终产品。本发明解决了现有制备方法收率偏低等缺陷，提供了一种适合工业化生产的制备方法。
Description
技术领域：本发明涉及一种巴尼地平中间体3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3- 硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯的制备方法，属于制药技术领域。
背景技术
1，4-二氢吡啶类钙拮抗剂是目前临床上应用最广泛的，作用最强的一类钙拮抗剂。盐酸巴尼地平为日本山之内制药株式会社研发的产品。由于具有长效、显著的降压作用而受到患者的青睐。
3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯是盐酸巴尼地平的关键中间体。
CN101643469报道了一条该中间体的合成路线，该路线是以3-羟基丙腈，双乙烯酮，间硝基苯甲醛和3-氨基巴豆酸甲酯作为起始物料，以2-(3-硝基苯甲醛)乙酰乙酸腈基乙酯和 3-氨基巴豆酸甲酯进行Hantzsch环合。该方法虽然操作简单，关环收率高，但是其反应第一步的收率较低，只有54％，并且所采用的原料双乙烯酮具有强烈的刺激作用和催泪性，必须在0～5℃的条件下保存，加大了原料保存、运输以及工业生产的难度。
在中间体2的合成中，郑大硕士论文中采用低温通氨气的方法，反应后需要在冰箱冷冻才可以析出固体，这就限制了该方法的工业化应用；WO0024714A1和EP1 125924A1中采用醋酸铵作为氨化试剂，由于该方法反应温度较高，导致生成的氨化物颜色较深，基本为棕色固体，且难重复；天大论文中采用氨水作为氨化试剂，在室温下搅拌后放入冰箱冷冻结晶，不适合工业化生产。
欧洲专利EP0249245A和美国专利US4761420A采用3-羧基-5-甲氧羰基-2，6-二甲基 -4-(3-硝基苯基)-1，4-二氢吡啶和3-羟基丙腈进行酯化反应合成巴尼地平3-(2-腈乙基)-5- 甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯，精制过程采用柱层析纯化方法，柱层析方法的使用限制了该方法的工业化应用。
文献号为CN101643469A的中国专利申请和有机化学，2006，26(1)，93-98文献，采用3-氨基-2-丁烯酸2-氰基乙基酯与2-(取代亚苄基)乙酰乙酸酯进行Hantzsch环合反应，制备巴尼地平中间体3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5- 二羧酸酯。该2篇文献没有在环合反应中使用催化剂，特点是反应时间较长，产物纯度低、能耗高。
发明目的：解决现有技术-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯的制备方法复杂，收率偏低，且不宜工业化生产的缺陷，提供一种适合工业化生产、且收率高、质量好的制备方法。
发明内容：
本发明的技术方案是：一种巴尼地平关键中间体3-(2-腈乙基)-5-甲基-2，6-二甲基 -4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯的制备方法，其特征在于：
第一步将3-羟基丙腈与乙酰乙酸甲酯在N-溴代丁二酰亚胺(NBS)催化剂下进行酯交换，生成乙酰乙酸腈基乙酯(式1)。
第二步乙酰乙酸腈基乙酯经醋酸铵与氨水(摩尔比为1∶1.5～2∶2.5～3.5)的混合物氨化后生成3-氨基巴豆酸腈基乙酯(式2)。
第三步3-氨基巴豆酸腈基乙酯与乙酰乙酸甲酯、间硝基苯甲醛在醇溶液中经有机酸催化反应，得终产品3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯(终产品)。
本步骤所用有机酸为乙酸。
本发明优选的技术方案是：第一步，3-羟基丙腈、乙酰乙酸甲酯与NBS的摩尔比为1∶1∶0.2～0.4，反应温度为90℃。
本发明优选的技术方案是：第二步，乙酰乙酸腈基乙酯、醋酸铵与氨水的摩尔比为1∶1.5～2∶2.5～3.5，反应温度为0℃。
本发明优选的技术方案是：第三步，3-氨基巴豆酸腈基乙酯、间硝基苯甲醛、乙酰乙酸甲酯与冰乙酸的摩尔比例为1∶1∶1∶0.1，反应温度为60～80℃，反应溶剂为甲醇或乙醇。
有益效果
1)采用无刺激性，室温下稳定的乙酰乙酸甲酯代替双乙烯酮参与反应，降低了保存、运输以及生产的难度要求，同时采用高效的N-溴代丁二酰亚胺做催化剂，提高了反应收率，简化了产品的纯化工艺。
2)采用醋酸铵+氨水的混合试剂制备3-氨基巴豆酸腈基乙酯，代替了文献中的单一氨化试剂，得到的产品外观好，纯度能达到99％以上。
3)去除了柱层析、冰箱冷冻结晶等不适合工业化生产的操作，降低了工业化难度。
4)最终产品采用一锅法，减少了反应步骤，降低了反应能耗，简化了操作过程、缩短了生产周期。
实施例：
实施例1、乙酰乙酸腈基乙酯的合成：
28.4g的3-羟基丙腈，46.4g的乙酰乙酸甲酯，14.2g的N-溴代丁二酰亚胺(NBS)加入至250ml的反应瓶内，加入150ml的甲苯，升温至90℃，反应3h后降至室温，过滤，滤液水洗三次后旋干得黄色液体59g，收率95.2％，HPLC纯度为92％。
实施例2、乙酰乙酸腈基乙酯的合成
28.4g的3-羟基丙腈，46.4g的乙酰乙酸甲酯，7.1g的N-溴代丁二酰亚胺(NBS)加入至250ml的反应瓶内，加入150ml的甲苯，升温至90℃，反应3h后降至室温，过滤，滤液水洗三次后旋干得黄色液体58.6g，收率94.6％，HPLC纯度为86％。
实施例3、乙酰乙酸腈基乙酯的合成
28.4g的3-羟基丙腈，46.4g的乙酰乙酸甲酯，10g的N-溴代丁二酰亚胺(NBS)加入至 250ml的反应瓶内，加入150ml的甲苯，升温至90℃，反应3h后降至室温，过滤，滤液水洗三次后旋干得黄色液体59.5g，收率95.9％，HPLC纯度为89％。
实施例4、3-氨基巴豆酸腈基乙酯的合成：
613g的乙酰乙酸腈基乙酯加入至2L的反应瓶内，降温至0℃，加入750g氨水，500g醋酸铵，在此温度下避光反应18h。抽滤得黄色固体，用水打浆洗涤至白色，抽干，70℃烘干得3-氨基巴豆酸腈基乙酯470g，收率77.2％，HPLC纯度为99.3％。
实施例5、3-氨基巴豆酸腈基乙酯的合成：
61.3g的乙酰乙酸腈基乙酯加入至500mL的反应瓶内，降温至0℃，加入75g氨水，35g 醋酸铵，在此温度下避光反应18h。抽滤得黄色固体，用水打浆洗涤至白色，抽干，70℃烘干得3-氨基巴豆酸腈基乙酯39g，收率63.9％，HPLC纯度为99.4％
实施例6、3-氨基巴豆酸腈基乙酯的合成：
61.3g的乙酰乙酸腈基乙酯加入至500mL的反应瓶内，降温至0℃，加入60g氨水，50g 醋酸铵，在此温度下避光反应18h。抽滤得黄色固体，用水打浆洗涤至白色，抽干，70℃烘干得3-氨基巴豆酸腈基乙酯45g，收率73.7％，HPLC纯度为99.3％
实施例7、3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯的合成：
139g的3-氨基巴豆酸腈基乙酯，104.7g的乙酰乙酸甲酯，136.3g的间硝基苯甲醛，5.4g 乙酸加入至2L的反应瓶内，2L的无水乙醇升温至回流反应8h，降温至室温析晶，抽滤，70℃烘干得323g3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯黄色固体，收率93.3％，HPLC纯度为98.5％。
实施例8、3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯的合成：
27.8g的3-氨基巴豆酸腈基乙酯(中间体2)，20.9g的乙酰乙酸甲酯，27.3g的间硝基苯甲醛，1.1g乙酸加加入至1L的反应瓶内，升温至回流反应8h，降温至室温析晶，抽滤，70℃烘干得49.7g 3-(2-腈乙基)-5-甲基-2，6-二甲基-4-(3-硝基苯基)-1，4-二氢吡啶-3，5-二羧酸酯黄色固体，收率71.5％，HPLC纯度为96.7％。
Claims (4)
1.一种巴尼地平中间体3-(2- 腈乙基)-5- 甲基-2，6- 二甲基-4-(3- 硝基苯基)-1，4- 二氢吡啶-3，5- 二羧酸酯的制备方法，其特征在于，
第一 步将3- 羟基丙腈与乙酰乙酸甲酯在N- 溴代丁二酰亚胺催化剂下进行酯交换，生成乙酰乙酸腈基乙酯；其中，3- 羟基丙腈、乙酰乙酸甲酯与N- 溴代丁二酰亚胺的摩尔比为1 ∶ 1 ∶ 0.2 ～ 0.4，反应温度为90℃；
第二步乙酰乙酸腈基乙酯经醋酸铵与氨水的混合物氨化后生成3- 氨基巴豆酸腈基乙酯；其中，乙酰乙酸腈基乙酯、醋酸铵与氨水的摩尔比为1 ∶ 1.5 ～ 2 ∶ 2.5 ～ 3.5，反应温度为0℃
第三步 3- 氨基巴豆酸腈基乙酯与乙酰乙酸甲酯、间硝基苯甲醛在醇溶液中经乙酸催化反应，得终产品3-(2- 腈乙基)-5- 甲基-2，6- 二甲基-4-(3- 硝基苯基)-1，4- 二氢吡啶-3，5- 二羧酸酯；
其反应方程式如下：
2.权利要求1 所述制备方法，其特征在于，第三步反应3- 氨基巴豆酸腈基乙酯、间硝基苯甲醛、乙酰乙酸甲酯与冰乙酸的摩尔比例为1 ∶ 1 ∶ 1 ∶ 0.1，反应温度为60 ～ 80℃，反应溶剂为甲醇或乙醇。
3.权利要求1 所述制备方法，其特征在于，第三步反应反应温度为70℃，反应溶剂为甲醇。
4.权利要求1所述制备方法，其特征在于，第三步反应3- 氨基巴豆酸腈基乙酯、间硝基苯甲醛、乙酰乙酸甲酯与冰乙酸的摩尔比例为1 ∶ 1 ∶ 1 ∶ 0.1，反应温度为80℃，反应溶剂为乙醇。
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