CN114605320B - 一种5-硝基-6-甲基烟酸乙酯的合成方法 - Google Patents
一种5-硝基-6-甲基烟酸乙酯的合成方法 Download PDFInfo
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- WQJCHEKAIFDWTN-UHFFFAOYSA-N ethyl 6-methyl-5-nitropyridine-3-carboxylate Chemical compound CCOC(=O)C1=CN=C(C)C([N+]([O-])=O)=C1 WQJCHEKAIFDWTN-UHFFFAOYSA-N 0.000 title abstract description 8
- 238000001308 synthesis method Methods 0.000 title abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 19
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 14
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- 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 abstract description 6
- 229910000365 copper sulfate Inorganic materials 0.000 claims abstract description 6
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 claims abstract description 6
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims abstract description 6
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910017604 nitric acid Inorganic materials 0.000 claims abstract description 5
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
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- 230000032050 esterification Effects 0.000 claims abstract description 3
- 238000005886 esterification reaction Methods 0.000 claims abstract description 3
- 238000006698 hydrazinolysis reaction Methods 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims abstract 7
- 238000006396 nitration reaction Methods 0.000 claims abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 45
- 230000002194 synthesizing effect Effects 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- -1 2-hydrazino-5-nitro-6-methylnicotinic acid ethyl ester Chemical compound 0.000 abstract description 10
- NUVZYXLETRLZFB-UHFFFAOYSA-N 6-methyl-5-nitro-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound CC1=NC(O)=C(C(O)=O)C=C1[N+]([O-])=O NUVZYXLETRLZFB-UHFFFAOYSA-N 0.000 abstract description 5
- SXXJYOHLMTWRAG-UHFFFAOYSA-N CCOC(=O)C1=CC(=C(C)N=C1Cl)[N+]([O-])=O Chemical compound CCOC(=O)C1=CC(=C(C)N=C1Cl)[N+]([O-])=O SXXJYOHLMTWRAG-UHFFFAOYSA-N 0.000 abstract description 5
- XRIHTJYXIHOBDQ-UHFFFAOYSA-N 6-methyl-2-oxo-1h-pyridine-3-carboxylic acid Chemical compound CC1=CC=C(C(O)=O)C(=O)N1 XRIHTJYXIHOBDQ-UHFFFAOYSA-N 0.000 abstract description 4
- 229940064982 ethylnicotinate Drugs 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- XBLVHTDFJBKJLG-UHFFFAOYSA-N nicotinic acid ethyl ester Natural products CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 229940079593 drug Drugs 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 4
- 238000010907 mechanical stirring Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical class O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 3
- 150000007660 quinolones Chemical class 0.000 description 3
- 102000015087 Poly (ADP-Ribose) Polymerase-1 Human genes 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- HETSDWRDICBRSQ-UHFFFAOYSA-N 3h-quinolin-4-one Chemical class C1=CC=C2C(=O)CC=NC2=C1 HETSDWRDICBRSQ-UHFFFAOYSA-N 0.000 description 1
- SQBMDSYKQUZMRS-UHFFFAOYSA-N 4-fluoro-1h-quinolin-2-one Chemical class C1=CC=C2C(F)=CC(=O)NC2=C1 SQBMDSYKQUZMRS-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108010054814 DNA Gyrase Proteins 0.000 description 1
- 102000003844 DNA helicases Human genes 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000001546 nitrifying effect Effects 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明提供了一种5‑硝基‑6‑甲基烟酸乙酯的合成方法，属于有机合成技术领域，包括以下步骤：(1)以2‑羟基‑6‑甲基烟酸（I）为原料，经浓硫酸和浓硝酸组成的混酸硝化得到2‑羟基‑5‑硝基‑6‑甲基烟酸（II）(2)2‑羟基‑5‑硝基‑6‑甲基烟酸经三氯氧磷氯代、乙醇酯化得到2‑氯‑5‑硝基‑6‑甲基烟酸乙酯（III）；(3)2‑氯‑5‑硝基‑6‑甲基烟酸乙酯经水合肼肼解得到2‑肼基‑5‑硝基‑6‑甲基烟酸乙酯（IV）；(4)2‑肼基‑5‑硝基‑6‑甲基烟酸乙酯经硫酸铜水溶液得目标产物5‑硝基‑6‑甲基烟酸乙酯（V）。本发明提供的方法原料易得，成本低、收率高、操作简单，适合工业大生产的要求。
Description
技术领域：
本发明属药物化学合成领域，具体涉及一种喹诺酮类药物中间体5-硝基-6-甲基烟酸乙酯的合成方法。
背景技术：
喹诺酮类（quinolones）是人工合成的含4-喹诺酮基本结构，对细菌DNA螺旋酶（DNA gyrase）具有选择性抑制作用的抗菌药物。目前发展迅速，临床广为使用。80年代合成的4-氟喹诺酮类如环丙沙星、氧氟沙星等由于具有广谱、口服有效、副作用较少、耐药性强等优点。喹诺酮类药物目前已发展到***药物，发展迅速，临床广为使用，代表了特别重要的治疗进展。
关于目前该喹诺酮类药物中间体5-硝基-6-甲基烟酸乙酯（V），主要用于PARP1抑制剂药物领域。是合成PARP1抑制剂药物所需的重要中间体。目前还没有公开报道的合成方法。
发明内容：
本发明设计了一条新的路线，即以2-羟基-6-甲基烟酸（I）为起始原料，通过合成化合物（II）、（III）、（IV），最终得到化合物5-硝基-6-甲基烟酸乙酯（V）。
本发明提供了式V化合物的合成方法，其由以下路线制得：
其中，（1）以式1化合物为原料，经浓硫酸和浓硝酸组成的混酸硝化得到式II化合物；(2) 式II化合物经三氯氧磷氯代、乙醇酯化得到式III化合物；(3) 式III化合物经水合肼肼解得到式IV化合物；(4)IV化合物经硫酸铜水溶液处理得到式V化合物。
优选地，式1化合物合成式II化合物步骤中，混酸与式1化合物的质量比为2.0~3.0:1.0，浓硝酸与浓硫酸质量比1:2.-2.5，进一步优选地，式1化合物合成式II化合物步骤中，混酸的滴加温度为-5~5oC，反应温度为85~90oC。
式II化合物合成式III化合物步骤中，溶剂选用甲苯、二甲苯、二氯甲烷、氯仿或氯苯；式II化合物与氯氧磷摩尔比为1.0：2.0~4.0，进一步优选1.0:3.0；氯代催化剂为N,N-二甲基甲酰胺、N,N-二异丙基乙胺或三乙胺，进一步优选为N,N-二甲基甲酰胺。
优选地，式III化合物合成式IV化合物步骤中，反应溶剂为乙醇或二氧六环；式III化合物与水合肼的反应摩尔比为1.0:2.0~4.0，进一步优选为1.0:2.0 ；反应温度为40~60oC，进一步优选反应温度50oC。
优选地，式IV化合物合成式V化合物的步骤中，式IV化合物与硫酸铜的摩尔比为1.0:1.0~5.0；进一步优选为1.0:3.0；反应温度为80~100oC，进一步优选反应温度95oC。
有益效果：本发明设计了一条新的路线，即以2-羟基-6-甲基烟酸（I）为起始原料，通过合成化合物（II）、（III）、（IV），最终得到化合物5-硝基-6-甲基烟酸乙酯（V）。该条路线，原料易得，制备方法简便，收率高、便于工业化生产。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合本发明具体实施例对本发明技术方案进行清楚、完整地描述。显然，所描述的实施例仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
1、2-羟基-5-硝基-6-甲基烟酸（II）的合成
在装有温度计、机械搅拌、恒压滴液漏斗装置的1L四口瓶中，加入浓硫酸150ml，2-羟基-6-甲基烟酸（15.3g ，100mmol），冰盐浴冷却至-5~0oC，控制温度在0oC左右滴加混酸溶液（18.8g ，200mmol 68%浓硝酸+15ml 98%浓硫酸）。滴加完毕，自然升温至室温搅拌1h，升温至90oC，继续搅拌1h。冷却至室温，将反应液缓慢加入到300ml冰水中，继续搅拌1h。过滤、水洗、干燥，得到黄色固体17.5g（88%）纯度98%。
Mp.270-272 oC m/z（ES+）199.3（M+1）+
2、2-氯-5-硝基-6-甲基烟酸乙酯（III）的合成
在装有温度计、机械搅拌装置的500ml四口瓶中，加入氯苯170ml，2-羟基-5-硝基-6-甲基烟酸（17.0g，85mmol），三氯氧磷（39.0g，255mmol），N,N-二甲基甲酰胺（2ml）；体系加热至130 oC，此温度下保温3h；降温至40 ~45oC，减压浓缩除去氯苯及过量的三氯氧磷；浓缩完后，剩余物加入30ml DCM，在25oC下滴加无水乙醇25ml，滴加完后此温度下继续搅拌5h；反应液浓缩至干，加入100ml水，150ml乙酸乙酯，搅拌分液，有机层用饱和碳酸氢钠水溶液洗涤至弱碱性；100ml饱和盐水洗涤一次。有机层浓缩，得到黄色粘稠状物，加入100ml石油醚打浆，过滤，得到黄色固体15.2克，收率73%，纯度98%。
3、2-肼基-5-硝基-6-甲基烟酸乙酯（IV）的合成
在装有温度计、机械搅拌装置的500ml四口瓶中，加入乙醇150ml，2-氯-5-硝基-6-甲基烟酸乙酯（15.0g，61.3mmol），80%水合肼（4.0g，122.6mmol）；体系加热至50℃，此温度下搅拌3h，冷却至20℃，继续搅拌1h，得到淡黄色固体。过滤，冷乙醇洗涤，干燥得到淡黄色固体7.3g，纯度98%，收率50%。
m/z（ES+）241.1（M+1）+
4、5-硝基-6-甲基烟酸乙酯（V）的合成
在装有温度计、机械搅拌装置的500ml四口瓶中，加入2-肼基-5-硝基-6-甲基烟酸乙酯（7.0g，29.1mmol），水（150ml），硫酸铜（21.8g，87.3mmol）。体系加热至95℃，此温度下反应8h，趁热过滤，滤液用乙酸乙酯（50mlx3）萃取，无水硫酸钠干燥，浓缩，得到粗品5.6g。粗品用石油醚/乙酸乙酯重结晶，得到淡黄色固体3.6g，GC纯度99%，收率59%。
1HNMR(400MHz，CDCl3)δ(ppm):9.31(s，1H)，8.85(s，1H)，4.47-4.52(m，2H)，2.96(s，3H)，1.45-1.72(m，3H)。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (5)
1.式V化合物的合成方法，其特征在于，其由以下路线制得：
,
式V化合物合成包括如下步骤：（1）以式1化合物为原料，经浓硫酸和浓硝酸组成的混酸硝化得到式II化合物；(2) 式II化合物经三氯氧磷氯代、乙醇酯化得到式III化合物；(3)式III化合物经水合肼肼解得到式IV化合物；(4)式IV化合物经硫酸铜水溶液处理得到式V化合物；
式1化合物合成式II化合物步骤中，混酸的滴加温度为-5 ~ 5 ℃，反应温度为85 ~ 90℃，式II化合物合成式III化合物步骤中，氯代催化剂为N,N-二甲基甲酰胺、N,N-二异丙基乙胺或三乙胺，式III化合物合成式IV化合物步骤中，反应温度为40 ~ 60 ℃， 式IV化合物合成式V化合物的步骤中，反应温度为80 ~ 100 ℃。
2.根据权利要求1所述的合成方法，其特征在于，式II化合物合成式III化合物步骤中，溶剂选用甲苯、二甲苯、二氯甲烷、氯仿或氯苯；式II化合物与三氯氧磷摩尔比为1.0：2.0 ~4.0。
3.根据权利要求1所述的合成方法，其特征在于，式III化合物合成式IV化合物步骤中，式III化合物与水合肼的反应摩尔比为1.0：2.0 ~ 4.0。
4.根据权利要求3所述的合成方法，其特征在于，式III化合物合成式IV化合物步骤中，反应溶剂为乙醇或二氧六环。
5.根据权利要求1所述的合成方法，其特征在于，式IV化合物合成式V化合物的步骤中，式IV化合物与硫酸铜的摩尔比为1.0:1.0 ~ 5.0。
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993002057A1 (en) * | 1991-07-17 | 1993-02-04 | Smithkline Beecham Corporation | Retroviral protease inhibitors |
| CN105061431A (zh) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-n-（2-（甲硫基）乙基）-2-（（3,3,3-三氟丙基）硫代）-9h-嘌呤及其制备方法和应用 |
| WO2016086674A1 (zh) * | 2014-12-04 | 2016-06-09 | 杭州杜易科技有限公司 | 一种卤代4-色满酮衍生物的制备方法 |
| CN110452180A (zh) * | 2019-06-25 | 2019-11-15 | 南京普锐达医药科技有限公司 | 一种合成2-氯-5-氨基-6-嘧啶甲酸乙酯的方法 |
| CN114230588A (zh) * | 2020-09-09 | 2022-03-25 | 北京卫蓝新能源科技有限公司 | 一种二元电解质及其制备和应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10266542B2 (en) * | 2017-03-15 | 2019-04-23 | Mirati Therapeutics, Inc. | EZH2 inhibitors |
| EP3738963A4 (en) * | 2018-01-09 | 2021-12-01 | Jiangsu Hengrui Medicine Co., Ltd. | PROCESS FOR PREPARING A PARP INHIBITOR AND INTERMEDIATE THEREOF |
-
2022
- 2022-04-06 CN CN202210355705.XA patent/CN114605320B/zh active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1993002057A1 (en) * | 1991-07-17 | 1993-02-04 | Smithkline Beecham Corporation | Retroviral protease inhibitors |
| WO2016086674A1 (zh) * | 2014-12-04 | 2016-06-09 | 杭州杜易科技有限公司 | 一种卤代4-色满酮衍生物的制备方法 |
| CN105061431A (zh) * | 2015-07-28 | 2015-11-18 | 济南百诺医药科技开发有限公司 | 6-n-（2-（甲硫基）乙基）-2-（（3,3,3-三氟丙基）硫代）-9h-嘌呤及其制备方法和应用 |
| CN110452180A (zh) * | 2019-06-25 | 2019-11-15 | 南京普锐达医药科技有限公司 | 一种合成2-氯-5-氨基-6-嘧啶甲酸乙酯的方法 |
| CN114230588A (zh) * | 2020-09-09 | 2022-03-25 | 北京卫蓝新能源科技有限公司 | 一种二元电解质及其制备和应用 |
Non-Patent Citations (5)
| Title |
|---|
| Kaviarasan L,et al.1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.Anticancer Agents Med Chem.2021,第21卷(第15期),第2050-2065页. * |
| 李小娜，等.2,6-二甲基-4-(间硝基苯基)-1,4-二氢吡啶-3,5-二羧酸甲酯氯乙酯的合成.华北煤炭医学院学报.2002,第12卷(第06期),第121-128页. * |
| 李昌新，等.4,6-二氯烟酸乙酯的合成新方法.浙江化工.2003,第15卷(第08期),第1552-1559页. * |
| 李昌新，等.4,6—二氯烟酸乙酯的合成新方法.浙江化工.2003,第34卷(第08期),第288-292页. * |
| 顺式那格列奈的合成;郭成，等;精细化工中间体;第34卷(第05期);第1009-1015页 * |
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