CN105968054B - 匹莫苯丹关键中间体的制备 - Google Patents
匹莫苯丹关键中间体的制备 Download PDFInfo
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- GLBJJMFZWDBELO-UHFFFAOYSA-N pimobendane Chemical compound C1=CC(OC)=CC=C1C1=NC2=CC=C(C=3C(CC(=O)NN=3)C)C=C2N1 GLBJJMFZWDBELO-UHFFFAOYSA-N 0.000 title abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 11
- 229960002164 pimobendan Drugs 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 11
- 238000006243 chemical reaction Methods 0.000 claims description 24
- NGOOFAMQPUEDJM-UHFFFAOYSA-N (4-amino-3-nitrophenyl)-phenylmethanone Chemical class C1=C([N+]([O-])=O)C(N)=CC=C1C(=O)C1=CC=CC=C1 NGOOFAMQPUEDJM-UHFFFAOYSA-N 0.000 claims description 13
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- -1 4- acetylaminohydroxyphenylarsonic acid 3- nitrobenzophenones Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- 230000008569 process Effects 0.000 abstract description 2
- QABZKECKKQKKQZ-UHFFFAOYSA-N 3-(4-amino-3-nitrophenyl)-4-methyl-4,5-dihydro-1h-pyridazin-6-one Chemical compound CC1CC(=O)NN=C1C1=CC=C(N)C([N+]([O-])=O)=C1 QABZKECKKQKKQZ-UHFFFAOYSA-N 0.000 abstract 1
- 238000013341 scale-up Methods 0.000 abstract 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000005457 ice water Substances 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 4
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- 239000002585 base Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 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 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- UJVWPZIWWKDJNH-UHFFFAOYSA-N (4-acetamido-2-hydroxyphenyl)arsonic acid Chemical class CC(=O)NC1=CC=C([As](O)(O)=O)C(O)=C1 UJVWPZIWWKDJNH-UHFFFAOYSA-N 0.000 description 2
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- FZERHIULMFGESH-UHFFFAOYSA-N N-phenylacetamide Chemical compound CC(=O)NC1=CC=CC=C1 FZERHIULMFGESH-UHFFFAOYSA-N 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 150000003869 acetamides Chemical class 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 230000031709 bromination Effects 0.000 description 2
- 238000005893 bromination reaction Methods 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- 230000003177 cardiotonic effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 231100000004 severe toxicity Toxicity 0.000 description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical compound OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 description 1
- DPJCXCZTLWNFOH-UHFFFAOYSA-N 2-nitroaniline Chemical class NC1=CC=CC=C1[N+]([O-])=O DPJCXCZTLWNFOH-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 229940122434 Calcium sensitizer Drugs 0.000 description 1
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010054949 Metaplasia Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 1
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 description 1
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000015689 metaplastic ossification Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000001196 vasorelaxation Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/04—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having less than three double bonds between ring members or between ring members and non-ring members
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及匹莫苯丹关键中间体6‑(4‑氨基‑3‑硝基苯基)‑5‑甲基‑4,5‑二氢哒嗪‑3(2H)‑酮(式V)的制备工艺。该工艺合成路线短，操作简单，具有工业化放大生产前景。
Description
技术领域
本发明涉及匹莫苯丹关键中间体--6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮的制备。
背景技术
匹莫苯丹(Pimobendan,UD-CG115BS,Acardi，CAS:74150-27-9)是由德国Boehringer Ingelheim公司研制开发,于1994年首次在日本上市的一种具有血管扩张作用的强心药,属于磷酸二酯酶抑制剂,临床上主要用于心衰病的治疗。该药的作用机理区别于传统的强心药,其正性肌力效应主要归因于增强心肌收缩蛋白对Ca2+的敏感性和对磷酸二酯酶III(PDEIII)的抑制作用,系第一个上市的钙敏化剂类药物。本品的化学名为:4,5-二氢-6-[2-(4-甲氧基苯基)-1H-苯并咪唑-5-基]-5-甲基-3(2H)-哒嗪酮,具有如下化学结构式:
目前公开报道的制备匹莫苯丹的专利文献大多都涉及到关键中间体6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮，为此该关键中间体的制备方法以及产业化合成工艺成为了匹莫苯丹产业化生产的重要瓶颈。关键中间体6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)具有如下化学结构式:
王恩思等人(《中国药物化学杂志》，1997,7,185)报道了合成6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的方法。该方法从乙酰苯胺出发，首先通过付克酰基化反应制备得到N-(4-丙酰基苯基)乙酰胺,然后在HOAc/Br2作用下对N-(4-丙酰基苯基)乙酰胺进行溴代得到N-(4-(2-溴丙酰基)苯基)乙酰胺；使用NaH作碱，丙二酸二乙酯和N-(4-(2-溴丙酰基)苯基)乙酰胺进行亲核取代反应制备得到2-(1-(4-乙酰氨基苯基)-1-氧代丙-2-基)丙二酸二乙酯；随后对2-(1-(4-乙酰氨基苯基)-1-氧代丙-2-基)丙二酸二乙酯进行硝化得到2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸二乙酯；NaOH作碱条件下以及在HCl条件下2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸二乙酯发生水解反应和脱除乙酰基保护基，随后产物高温脱羧得到4-(4-氨基-3-硝基苯基)-3-甲基-4-氧代丁酸；最后4-(4-氨基-3-硝基苯基)-3-甲基-4-氧代丁酸和水合肼发生发应完成关健中间体6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的制备。该方法有三个不利因素导致不具有工业化生产前景：1)溴化一步，会产生溴直接接在苯环上的副产物；2)反应过程中涉及到NaH等危险试剂；3)硝化反应一步由于丙二酸二乙酯基团的影响而导致反应杂质较多、收率低。相关反应路线如下所示:
朴日阳等人(《中国药物化学杂志》，1994,4,41)报道了另外一条合成6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的方法。该方法同样通过付克反应制备N-(4-丙酰基苯基)乙酰胺；然后N-(4-丙酰基苯基)乙酰胺和甲醛/二甲胺盐酸盐以及碘甲烷反应制备得到碘代2-((4-乙酰胺基苯甲酰基)-丙基)-三甲铵；碘代2-((4-乙酰胺基苯甲酰基)-丙基)-三甲铵和KCN发生亲核取代反应制备得到3-(4′-乙酰胺基苯甲酰基)-丁腈，后者进一步发生硝化反应得到3-(4′-乙酰胺基-3′-硝基-苯甲酰基)-丁腈；浓盐酸条件下对腈基进行水解同时脱除乙酰基保护基得到3-(4′-氨基-3′-硝基-苯甲酰基)-丁酸；后者进一步和水合肼反应实现6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮的制备。该方法由于涉及到到使用剧毒的KCN不利于工业化生产。相关合成路线如下所示:
基于上述合成方法在工业化放大生产时遭遇的瓶颈和不利因素，新开发一条适合工业化放大生产的匹莫苯丹关键中间体6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮的合成路线显得尤为具有产业价值。
发明内容
本发明的关键在于新开发一条适合工业化生产的匹莫苯丹关键中间体6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的合成路线:
N-(2-硝基-4-丙酰基苯基)乙酰胺(式I)通过N-(4-丙酰基苯基)乙酰胺的硝化反应完成制备。硝化反应使用的试剂为发烟硝酸和浓硫酸，反应温度为-10至5℃，反应时间不超过10小时。
式I在HOAc/Br2条件下进行溴化，实现N-(4-(2-溴丙酰基)-2-硝基苯基)乙酰胺(式II)的制备。该反应反应温度为-5至50℃。
式II在碱作用下和丙二酸二乙酯发生亲核取代反应，实现2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸二乙酯(式III)的制备。该步反应使用的碱为叔丁醇钾、叔丁醇钠、钠氢或乙醇钠等；反应所使用的溶剂包括THF、DMF或DMSO。
式III在碱作用下发生水解反应脱除两个乙酯保护基完成2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸(式IV)的制备。该步反应所使用的碱包括氢氧化钾、氢氧化钠或氢氧化锂。
式IV在加热条件下和水合肼反应完成6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的制备。该步反应使用高温反应釜，所使用的溶剂包括DMF、二苯醚、均三甲苯等，反应温度为80-180℃。
本发明制备6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的工艺路线短，从N-(2-硝基-4-丙酰基苯基)乙酰胺(式I)出发，仅需5步反应即可完成，相比较朴日阳等人(《中国药物化学杂志》，1994，4，41)和王恩思等人(《中国药物化学杂志》，1997，7，185)的工艺路线均缩短1步，且反应过程中不涉及使用危险或剧毒的化学试剂，工业化生产具有明显的优势。
具体实施方式
通过下面的实施例可以更具体的理解本发明，但其是举例说明而不是限制本发明的范围。
实施例
1.制备N-(2-硝基-4-丙酰基苯基)乙酰胺(式I)
H2SO4(200mL)和硝酸(600mL)混合后降温至0℃以下，然后分批次加入N-(4-丙酰基苯基)乙酰胺(200g,1.05mol)，加入完毕后体系保持内温低于0℃反应5小时。将反应液缓慢倒入冰水(2000克)和二氯甲烷(2000mL)的混合物中，搅拌30min,待冰完全化为水后分出有机相。水相用二氯甲烷(800mL)进行萃取。合并有机相，饱和食盐水洗涤两次(2×2000mL)，减压脱除溶剂后，残余物庚烷/乙酸乙酯重结晶得到浅黄色固体(192g,77％)。
2.制备N-(4-(2-溴丙酰基)-2-硝基苯基)乙酰胺(式II)
将N-(2-硝基-4-丙酰基苯基)乙酰胺(150g,0.63mol)加入到2L冰醋酸中，然后升温至40℃，然后缓慢将33克溴的冰醋酸(400mL)溶液加入。加入完毕后体系保温搅拌1小时，TLC跟踪反应完毕，随后体系缓慢倒入15L冰水中搅拌，固体析出。过滤后，固体用水洗涤至产品无明显的醋酸残留。固体真空45℃干燥24小时后得浅黄色固体(168g,85％)。
3.制备2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸二乙酯(式III)
叔丁醇钾(60克,0.53mol)加入到反应瓶中，氮气保护下加入DMSO(300mL),搅拌30分钟，然后将丙二酸二乙酯(80克,0.5mol)少量多次加入，加入完毕后搅拌20分钟至无白色块状固体，整个反应体系呈半透明糊状。然后将N-(4-(2-溴丙酰基)-2-硝基苯基)乙酰胺(100g,0.32mol)分5次加入，加入完毕后室温搅拌反应至TLC跟踪原料消失。反应完毕后，体系缓慢倒入1L冰水中进行淬灭，然后用冰醋酸调节体系pH值为5左右。体系用二氯甲烷进行萃取(3×1L),合并后的有机相用饱和食盐水洗涤。减压脱除有机相后得到157克褐色粗品，该粗品用庚烷/乙酸乙酯重结晶得到黄色固体(102克，81％)。
4.制备2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸(式IV)
将2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸二乙酯(90克,0.23mol)加入120ml乙醇溶解，然后向反应溶液中加入42.6克氢氧化钠和600ml水配置的氢氧化钠水溶液。加入完毕后体系室温搅拌24小时。然后体系用盐酸调节PH值至1.0-1.5。反应液加入乙酸乙酯(3×600ml)萃取，合并有机相，饱和食盐水洗涤。减压脱除溶剂，得黄色泡沫状固体，然后用乙酸乙酯进行重结晶得浅黄色固体(65克,84％)。
5.制备6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)
2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸(35克,0.104mol)溶于DMF(40mL)中,然后加入水合肼(80mL),加入完毕后体系升温至125℃搅拌反应12小时。体系减压脱除溶剂后加入冰水(200mL)激烈搅拌3小时，过滤得到黄色固体(22.1克，85％)。
6.制备6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)
2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸(15克,0.044mol)溶于二苯醚(60mL)中,然后加入水合肼(100mL),加入完毕后体系升温至150℃搅拌反应12小时。体系减压脱除溶剂后加入冰水(100mL)激烈搅拌3小时，过滤得到黄色固体(8.6克，79％)。
Claims (3)
1.一种制备6-(4-氨基-3-硝基苯基)-5-甲基-4,5-二氢哒嗪-3(2H)-酮(式V)的方法，其特征在于：以2-(1-(4-乙酰氨基-3-硝基苯基)-1-氧代丙-2-基)丙二酸(式IV)为原料，在加热条件下和水合肼反应得到式V，反应式如下所示：
2.如权利要求1所述的方法，反应使用的溶剂为DMF、二苯醚或均三甲苯。
3.如权利要求1所述的方法，反应温度为80-180℃。
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