CN114181145B - 一种依匹哌唑中间体的制备方法 - Google Patents
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- WHWZLSFABNNENI-UHFFFAOYSA-N epinastine Chemical compound C1C2=CC=CC=C2C2CN=C(N)N2C2=CC=CC=C21 WHWZLSFABNNENI-UHFFFAOYSA-N 0.000 title claims abstract description 7
- 229960003449 epinastine Drugs 0.000 title claims abstract description 7
- -1 1, 4-disubstituted butane Chemical class 0.000 claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 239000003513 alkali Substances 0.000 claims description 12
- 238000003786 synthesis reaction Methods 0.000 claims description 8
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- 229910052783 alkali metal Inorganic materials 0.000 claims description 5
- 150000001340 alkali metals Chemical class 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 5
- 229940125782 compound 2 Drugs 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
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- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 claims description 3
- 150000002496 iodine Chemical class 0.000 claims description 3
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 125000003158 alcohol group Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
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- 125000001424 substituent group Chemical group 0.000 abstract description 8
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical class 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
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- 239000003814 drug Substances 0.000 abstract description 2
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- 238000000034 method Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical group [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
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- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 2
- QPBSEYFVZDMBFW-UHFFFAOYSA-N 4-bromo-1-benzothiophene Chemical compound BrC1=CC=CC2=C1C=CS2 QPBSEYFVZDMBFW-UHFFFAOYSA-N 0.000 description 2
- DBSPUDKBNOZFMX-UHFFFAOYSA-N 7-hydroxyquinolin-2(1H)-one Chemical compound C1=CC(=O)NC2=CC(O)=CC=C21 DBSPUDKBNOZFMX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 229940125898 compound 5 Drugs 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
- FUKUFMFMCZIRNT-UHFFFAOYSA-N hydron;methanol;chloride Chemical compound Cl.OC FUKUFMFMCZIRNT-UHFFFAOYSA-N 0.000 description 2
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- FYRHIOVKTDQVFC-UHFFFAOYSA-M potassium phthalimide Chemical compound [K+].C1=CC=C2C(=O)[N-]C(=O)C2=C1 FYRHIOVKTDQVFC-UHFFFAOYSA-M 0.000 description 2
- 230000008569 process Effects 0.000 description 2
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- DQHKCMPDSGCTHI-UHFFFAOYSA-N 1-bromo-1-chlorobutane Chemical compound CCCC(Cl)Br DQHKCMPDSGCTHI-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 1
- 102100022738 5-hydroxytryptamine receptor 1A Human genes 0.000 description 1
- 101710138638 5-hydroxytryptamine receptor 1A Proteins 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010001540 Akathisia Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 208000001431 Psychomotor Agitation Diseases 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- 241000204066 Tsukamurella Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 1
- 150000008041 alkali metal carbonates Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
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- 125000005843 halogen group Chemical group 0.000 description 1
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- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- MSQACBWWAIBWIC-UHFFFAOYSA-N hydron;piperazine;chloride Chemical compound Cl.C1CNCCN1 MSQACBWWAIBWIC-UHFFFAOYSA-N 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
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- 208000024714 major depressive disease Diseases 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明属于医药生产技术领域，具体是涉及一种依匹哌唑中间体的制备方法，合成路线如下：
Description
技术领域
本发明属于医药生产技术领域，具体是涉及一种依匹哌唑中间体的制备方法。
背景技术
依匹哌唑由日本大冢制药和丹麦灵北制药共同研发，美国FDA于2015年7月10日批准上市。北京康立生医药技术开发有限公司于2016年11月获得依匹哌唑片批件(受理号：JXHL1000032)。其中文化学名称：7-[4-(4-(苯并[b]噻吩-4-基)-哌嗪-1-基)丁氧基]-1H喹啉-2-酮，英文名称：7-[4-(4-(Benzo[b]thien-4-yl)-piperazin-1-yl)butoxy]-1H-quin-olin-2-one。属于5-HT/DA受体调节剂，用于治疗成人精神分裂症，也可与抗抑郁药联合用于治疗成人重度抑郁。依匹哌唑是首个多巴胺、部分5-HT1A受体激动剂以及5-HT2A受体拮抗剂类化合物，具有良好的疗效及耐受性，可降低患者静坐不能、不安和失眠等不良反应的发生率。
目前关于依匹哌唑的合成方法较多，有关文献报道的方法总结如下：
WO2018172463关于依匹哌唑的制备方法如下：
将Boc保护发哌嗪与1,4-二取代丁烷反应，取代1,4-二取代丁烷中的一个取代基，得到含有Boc保护哌嗪的丁烷衍生物，将所得的衍生物再和7-羟基喹啉酮反应，得到Boc保护的7-(4-(哌嗪-1-基)丁氧)喹啉-2-(1H)酮，经脱保护后得到7-(4-(哌嗪-1-基)丁氧)喹啉-2-(1H)酮，再与4-溴苯并噻吩反应得到依匹哌唑。该法第一步反应收率不高，1,4-二取代丁烷两端有同时被哌嗪取代的可能。
WO2017/025987对上述合成路线进行了改进：
该方法存在原料价格昂贵、生成工序繁琐、生产周期长及所用试剂毒性大等问题，特别是甲磺酰氯对设备腐蚀大，环境不友好，不太适合于工业化生产。
WO2018/087775，CN105440026，CN106496206采取类似的方法经7-(4-(哌嗪-1-基)丁氧)喹啉-2-(1H)酮合成依匹哌唑。以7-羟基喹啉酮为起始原料，先和溴氯丁烷反应得到4-氯丁氧喹啉酮，再和哌嗪盐酸盐或Boc保护哌嗪反应，得到7-(4-(哌嗪-1-基)丁氧)喹啉-2-(1H)酮后再与4-溴苯并噻吩反应得到依匹哌唑。该法的缺点是接哌嗪一步后处理不便于工业化。
发明内容
本发明要解决的技术问题是提供一种依匹哌唑中间体的制备方法，该制备方法原料易得，易于操作，绿色环保，易于工业化，产物收率和纯度较高。
本发明的内容包括一种依匹哌唑中间体的制备方法，合成路线如下：
1,4-二取代丁烷的1位和4位取代基X独立或分别为相同或不同的卤元素、羟基，比如1位取代基X为溴，同时4位取代基X为氯或者羟基；所述R为碱金属离子。
优选的，1,4-二取代丁烷的1位和4位取代基X为溴，即优选为1.4-二溴丁烷。
优选的，R为钾，即优选为邻苯二甲酰亚胺钾。
优选的，化合物1的合成反应中，加入有碱，碱为碱金属的碳酸盐、碱金属氢氧化物、吡咯、哌啶、吡啶、吗啉、三乙胺或N,N-二异丙基乙胺，优选碳酸钾，溶剂为丙酮、乙腈或DMF，优选丙酮。
优选的，化合物2的合成反应中，加入有碱，碱为碱金属的碳酸盐、碱金属氢氧化物、吡咯、哌啶、吡啶、吗啉、三乙胺或N,N-二异丙基乙胺，温度为60-100℃，溶剂为二甲基亚砜、丙酮、乙腈、N,N-二甲基甲酰胺或N-甲基吡咯烷酮。
优选的，化合物2和水合肼反应，水合肼的重量浓度优选为80％，溶剂为醇溶液，所述醇溶液为甲醇、乙醇或正丙醇，得到化合物3。
优选的，化合物4的合成反应中，加入有碱和碘盐，碱为碱金属的碳酸盐、碱金属酸式碳酸盐、三乙胺或N,N-二异丙基乙胺，溶剂为二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、乙二醇单甲醚或正丁醇，碘盐优选为碘化钾，起催化作用，实际上是进行卤素交换，使原料中的其他卤原子置换成碘原子，反应活性更大，反应完后又重新释放碘离子，再循环使用。
优选的，还包括如下步骤，化合物4脱保护后得到化合物5，反应中加入有酸，所述酸为盐酸(HCl)，溶剂为甲醇、乙醇或丙酮，即形成浓盐酸醇溶液、浓盐酸丙酮溶液或氯化氢的甲醇溶液等，化合物5的结构式如下：
本发明的有益效果是，本发明所采用的原料都是普通原料，未涉及到特殊试剂；整个工艺路线中没有涉及到高温、高压、低温等特殊反应，操作方面，便于实现工业化；未涉及到有毒试剂，所用溶剂可以回收套用，避免对环境污染。
本发明得到的产物的纯度和收率较高，有利于降低企业成本，提高产品质量。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并非局限于此。
实施例1化合物1的合成
将0.011mol(2.375克)1.4-二溴丁烷加入到50mL反应瓶中，分别加入0.005mol(0.926克)邻苯二甲酰亚胺钾、0.006mol(0.829克)无水碳酸钾和20mL丙酮，搅拌升温至回流，保温反应，TLC跟踪反应(展开剂：PF/EA＝4/1)，反应完毕，冷至室温，抽滤，滤饼每次用10mL丙酮洗，洗两次，合并滤液，减压蒸除溶剂，剩余物加入10mL石油醚，充分搅拌，置于冰箱过夜，抽滤，滤饼分别用5mL石油醚洗两次，干燥后得到0.956克白色固体化合物1，收率67.77％，纯度为98.75％。1H NMRδ:7.82(d,J＝7.8Hz,2H,Ph-H),7.71(d,J＝7.7Hz,2H,Ph-H),3.72(t,J＝3.7Hz,2H,-CH2),3.44(t,J＝3.4Hz,2H,-CH2),1.88-1.82(m,4H,2-CH2)；MS(ESI):m/z(100％)283(M+H)。
实施例2化合物2的合成
将0.956克(3.39mmol)化合物1加入到50mL单口反应瓶中，分别加入0.5463克(3.39mmol)7-羟基喹啉-(1H)-2-酮、0.937克(6.78mmol)无水碳酸钾和30mL N,N-二甲基甲酰胺，搅拌升温至70℃，保温反应，TLC跟踪反应(展开剂：PE/EA＝1/1)，反应完成后，冷至室温，过滤，滤液于搅拌下缓慢倒入50mL冰水中，产生白色固体，抽滤，滤饼分别以20mL水洗两次，干燥后得0.934克产品，收率75.79％，纯度为98.16％。δ:11.32(s,1H,-NH),7.83-7.81(m,2H,Ph-H),7.70-7.68(m,3H,Ph-H),7.40(d,J＝7.4Hz,1H,Ph-H),6.80(s,1H,Ph-H),6.77(d,J＝6.8Hz,1H,Ph-H),6.53(d,J＝6.5Hz,1H,Ph-H),4.08(t,J＝4.1Hz,2H,-CH2),3.78(t,J＝3.8Hz,2H,-CH2),1.90-1.85(m,4H,2-CH2)；MS(ESI):m/z(100％)363(M+H)。
实施例3化合物3的合成
将0.931克(2.57mmol)化合物2加入到50mL单口反应瓶中，分别加入1.286克(25.7mmol)水合肼(80％)、无水乙醇30mL，搅拌升温回流，保温反应，TLC跟踪反应(展开剂：甲醇/二氯甲烷＝1/5)，反应完成后，冷至室温，抽滤，滤饼分别以10mL乙醇洗两次，合并滤液，减压蒸除溶剂得黄色固体0.441克，收率73.94％，纯度为95.83％。δ:11.82(s,1H,-NH),7.76(d,J＝7.7Hz,1H,Ph-H),7.50(d,J＝7.5Hz,1H,Ph-H),6.75-6.71(m,2H,Ph-H),6.26(d,J＝6.2Hz,1H,Ph-H),4.51(s,1H,-NH2),3.95(t,J＝4.0Hz,2H,-CH2),2.58-2.54(m,2H,-CH2),1.71-1.69(m,2H,-CH2),1.49-1.46(m,2H,-CH2)；13C NMRδ:162.9,161.3,141.3,140.7,130.2,119.0,114.1,111.4,99.4,68.0,41.2,29.1,26.5；MS(ESI):m/z(100％)233(M+H)。
实施例4化合物4的合成
将0.232克(1mmol)化合物3加入到反应瓶中，分别加入0.266克(1mmol)Boc-双-2-氯乙基胺和N,N-二甲基甲酰胺5mL，搅拌下加入0.332克(2mmol)碘化钾和0.415克(3mmol)无水碳酸钾。氮气保护下升温至70℃，保温反应，TLC跟踪反应进程(展开剂：氨水/二氯甲烷/甲醇＝1/6/18)。反应完成后，冷至室温，搅拌下倒入15mL冰水中，抽滤，滤饼水洗，干燥得类白色固体，收率80.9％，纯度为98.27％。1H NMRδ:12.51(s,1H,-NH),7.75(d,J＝7.8Hz,1H,Ph-H),7.45(d,J＝7.6Hz,1H,Ph-H),6.83-6.79(m,2H,Ph-H),6.56(d,J＝6.6Hz,1H,Ph-H),4.10(t,J＝4.1Hz,2H,-CH2),3.45-3.43(m,2H,-CH2),2.44-2.41(m,2H,-CH2),1.72-1.69(m,2H,-CH2),1.48(s,9H,3-CH3)；MS(ESI):m/z(100％)402(M+H)。
实施例5化合物5的合成
将0.402克(1mmol)化合物4加入到反应瓶中，加入饱和HCl甲醇10mL，于室温搅拌2小时，置于冰箱冷冻，抽滤，滤饼甲醇洗，干燥得白色固体，收率73.1％，纯度为99.05％。1HNMRδ:11.59(s,1H,-NH),7.76(d,J＝7.8Hz,1H,Ph-H),7.49(d,J＝7.5Hz,1H,Ph-H),6.75-6.72(m,2H,Ph-H),6.26(d,J＝6.2Hz,1H,Ph-H),4.20(t,J＝4.2Hz,2H,-CH2),3.98(t,J＝4.0Hz,2H,-CH2),3.53(t,J＝3.5Hz,2H,-CH2),3.19(t,J＝3.2Hz,2H,-CH2),2.68(t,J＝2.7Hz,2H,-CH2),2.55(t,J＝2.6Hz,2H,-CH2),1.84(s,1H,-NH),1.72-1.69(m,2H,-CH2),1.56-1.51(m,2H,-CH2)；MS(ESI):m/z(100％)302(M+H)。
所属领域的普通技术人员应当理解：以上任何实施例的讨论仅为示例性的，并非旨在暗示本公开的范围(包括权利要求)被限于这些例子；在本公开的思路下，以上实施例或者不同实施例中的技术特征之间也可以进行组合，步骤可以以任意顺序实现，并存在如上所述的本申请中一个或多个实施例的不同方面的许多其它变化，为了简明它们没有在细节中提供。
本申请中一个或多个实施例旨在涵盖落入所附权利要求的宽泛范围之内的所有这样的替换、修改和变型。因此，凡在本申请中一个或多个实施例的精神和原则之内，所做的任何省略、修改、等同替换、改进等，均应包含在本公开的保护范围之内。
Claims (2)
1.一种依匹哌唑中间体的制备方法，其特征是，合成路线如下：
1,4-二取代丁烷的1位和4位取代基X为溴，R为钾；
化合物1的合成反应中，加入有碱，碱为碱金属的碳酸盐或碱金属氢氧化物；
化合物2的合成反应中，加入有碱，碱为碱金属的碳酸盐或碱金属氢氧化物，温度为60-100℃，溶剂为二甲基亚砜、丙酮、乙腈、N,N-二甲基甲酰胺或N-甲基吡咯烷酮；
化合物2和水合肼反应，溶剂为醇溶液，得到化合物3；
化合物4的合成反应中，加入有碱和碘盐，碱为碱金属的碳酸盐，溶剂为二甲基亚砜、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮或乙二醇单甲醚。
2.如权利要求1所述的依匹哌唑中间体的制备方法，其特征是，所述醇溶液为甲醇、乙醇或正丙醇。
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