CN114380737A - 一种4-吡啶甲醛的制备方法 - Google Patents
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- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims abstract description 20
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- 238000006243 chemical reaction Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- 238000001035 drying Methods 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 10
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 10
- QWXYZCJEXYQNEI-OSZHWHEXSA-N intermediate I Chemical compound COC(=O)[C@@]1(C=O)[C@H]2CC=[N+](C\C2=C\C)CCc2c1[nH]c1ccccc21 QWXYZCJEXYQNEI-OSZHWHEXSA-N 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 239000000126 substance Substances 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 208000006558 Dental Calculus Diseases 0.000 claims description 5
- -1 tetrafluoroborate Chemical compound 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 3
- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 claims description 3
- IYDGMDWEHDFVQI-UHFFFAOYSA-N phosphoric acid;trioxotungsten Chemical compound O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.O=[W](=O)=O.OP(O)(O)=O IYDGMDWEHDFVQI-UHFFFAOYSA-N 0.000 claims description 3
- XMVONEAAOPAGAO-UHFFFAOYSA-N sodium tungstate Chemical compound [Na+].[Na+].[O-][W]([O-])(=O)=O XMVONEAAOPAGAO-UHFFFAOYSA-N 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 4
- 238000007254 oxidation reaction Methods 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 230000008707 rearrangement Effects 0.000 abstract description 2
- 238000007039 two-step reaction Methods 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 4
- PTMBWNZJOQBTBK-UHFFFAOYSA-N pyridin-4-ylmethanol Chemical compound OCC1=CC=NC=C1 PTMBWNZJOQBTBK-UHFFFAOYSA-N 0.000 description 4
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 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 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229960003135 donepezil hydrochloride Drugs 0.000 description 1
- XWAIAVWHZJNZQQ-UHFFFAOYSA-N donepezil hydrochloride Chemical compound [H+].[Cl-].O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 XWAIAVWHZJNZQQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- GPHQHTOMRSGBNZ-UHFFFAOYSA-N pyridine-4-carbonitrile Chemical compound N#CC1=CC=NC=C1 GPHQHTOMRSGBNZ-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000002910 solid waste Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- 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
- C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/48—Aldehydo radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明涉及一种4‑吡啶甲醛的制备方法,具体涉及以4‑甲基吡啶为原料,经氮氧化和重排两步反应,高效合成4‑吡啶甲醛,本发明提供的4‑吡啶甲醛的制备方法是一种高产率、低成本、简捷高效并适合工业化生产的制备方法。
Description
技术领域
本发明属于医药领域,具体涉及一种4-吡啶甲醛的制备方法。
背景技术
4-吡啶甲醛(4-Pyridinecarboxaldehyde)是盐酸多奈哌齐的重要中间体,在其它有机合成反应中也有重要应用,应用于染料和农药等生产中。其合成方法,主要有以下催化氧化为主,如下:
此方法以4-甲基吡啶为原料催化氧化,产物精馏分离后得到纯的产品。此方法适合工业化生产,成本较低,但需要大型专用设备,投资大。
JP2019/69908公开了以4-氰基吡啶为原料合成4-吡啶甲醛:
此方法需要用大量硫酸和氢氧化钠,需要氢气和加氢工艺,加氢设备需要耐强酸性,且产率较低。
CN107311918公开了以4-吡啶甲醇为原料合成4-吡啶甲醛:
此方法所用4-吡啶甲醇价格昂贵,所使用氧化剂PCC(氯铬酸吡啶盐)用量较大,极易吸附产品且产生大量固废。
CN109721528公开了以4-吡啶甲酸为原料合成4-吡啶甲醛:
此方法步骤较长,所用水合肼为为易爆物质,安全风险较大,反应时间长且产率较低。
发明内容
针对上述问题,本发明公开了一种4-吡啶甲醛的制备方法,具体涉及以4-甲基吡啶为原料,经氮氧化和重排两步反应,高效合成4-吡啶甲醛,本发明提供的4-吡啶甲醛的制备方法是一种高产率、低成本、简捷高效并适合工业化生产的制备方法。
反应方程式如下:
本发明解决以上技术问题的技术方案是:
(1)在反应瓶中加入质量浓度30%的双氧水和水,加入4-甲基吡啶1.0mol,加入催化剂Ⅰ,保持30℃~80℃条件下反应完全,过滤,淋洗,以溶剂Ⅰ溶解,过滤不溶物,分液后干燥,保持0℃~50℃条件下滴加三甲基钖四氟硼酸1.1-1.5mol,加毕反应至完全后以水洗涤,干燥并浓缩,用乙酸乙酯600ml重结晶,得中间体Ⅰ;
(2)将中间体Ⅰ0.84-0.94mol加入溶剂Ⅱ中,加入氟化铯1.9-2.8mol,保持10℃~60℃条件下反应完毕后,以水洗涤,干燥后减压浓缩,所得粘油状物精馏得4-吡啶甲醛。
步骤(1)中所述催化剂Ⅰ为磷钼酸、磷钨酸、钨酸钠中的一种。
步骤(1)中所述催化剂Ⅰ的质量为4-甲基吡啶质量的1%-5%。
步骤(1)中所述溶剂Ⅰ为二氯甲烷、二氯乙烷、氯苯中的一种。
步骤(2)中所述溶剂Ⅱ为乙酸乙酯、二氯甲烷、2-甲基四氢呋喃中的一种。
本发明一种4-吡啶甲醛的制备方法优点:
1)步骤短;
2)三废少;
3)成本低、收率高;
4)产品质量好。
具体实施方式
以下结合具体实施例对本发明作进一步说明。
实施例1
一种4-吡啶甲醛的制备方法,具体包括以下步骤:
(1)反应瓶中加质量浓度30%的双氧水800ml和水800ml,搅拌加入4-甲基吡啶93.1g,10分钟后加入磷钼酸4.7g,缓慢升温至70℃-80℃反应16小时。冷却至室温,过滤,用水200ml淋洗。将湿的滤饼加入二氯甲烷400ml中溶解,过滤不溶物,分去水相,二氯甲烷相以无水硫酸钠充分干燥并过滤后加入反应瓶中,控制温度0℃-10℃条件下滴加三甲基钖四氟硼酸221.8g,加毕搅拌反应4小时。用水400ml洗涤后以无水酸钠干燥,减压浓缩至干,用乙酸乙酯600ml重结晶后烘干,得中间体Ⅰ192.3g,类白色固体,产率91.1%。1 H NMR(400MHz, DMSO-d 6 , ppm):δ = 9.30 (s, 2H), 8.09 (s, 2H), 4.39 (s, 3H),2.63 (s,3H).
(2)反应瓶中加入乙酸乙酯2000ml和中间体Ⅰ192.3g,搅拌溶解,加氟化铯425.3g,在10℃-20℃条件下搅拌反应24小时。以水600ml洗涤,有机相以无水硫酸钠干燥,减压浓缩至干,得粘油状物,减压精馏,收集72℃-74℃(10mmHg)馏份,得4-吡啶甲醛77.2g,淡黄色液体,产率79.1%。1 H NMR(400 MHz, CDCl 3 , ppm): δ = 10.08 (s, 1H), 8.89(dd, J = 4.4 Hz, 1.6Hz, 2H), 7.70 (dd, J = 4.4 Hz, 1.6 Hz, 2H)
实施例2
一种4-吡啶甲醛的制备方法,具体包括以下步骤:
(1)反应瓶中加质量浓度30%的双氧水600ml和水600ml,搅拌加入4-甲基吡啶93.1g,10分钟后加入磷钨酸2.8g,升温40℃-50℃反应24小时。冷却至室温,过滤,用水200ml淋洗。将湿的滤饼加入二氯乙烷400ml中,分去水相,二氯乙烷相以无水硫酸钠充分干燥并过滤后加入反应瓶中,控制温度30℃-40℃条件下滴加三甲基钖四氟硼酸192.3g,加毕搅拌反应2小时。用水400ml洗涤后以无水酸钠干燥,减压浓缩至干,用乙酸乙酯600ml重结晶后烘干,得中间体Ⅰ197.5g,类白色固体,产率93.6%。
(2)反应瓶中加入二氯甲烷1500ml和中间体Ⅰ197.5g,搅拌溶解,加氟化铯350.1g,在30℃-40℃条件下搅拌反应24小时。以水600ml洗涤,有机相以无水硫酸钠干燥,减压浓缩至干,得粘油状物,减压精馏,收集72℃-74℃(10mmHg)馏份,得4-吡啶甲醛62.8g,淡黄色液体,产率63.7%。
(3)实施例3
一种4-吡啶甲醛的制备方法,具体包括以下步骤:
(1)反应瓶中加质量浓度30%的双氧水500ml和水500ml,搅拌加入4-甲基吡啶93.1g,10分钟后加入钨酸钠0.93g,升温30℃-40℃反应48小时。冷却至室温,过滤,用水200ml淋洗。将湿的滤饼加入氯苯400ml中溶解,过滤不溶物,分去水相,氯苯相以无水硫酸钠充分干燥并过滤后加入反应瓶中,控制温度50℃-60℃条件下滴加三甲基钖四氟硼酸162.7g,加毕搅拌反应2小时。用水400ml洗涤后以无水酸钠干燥,减压浓缩至干,用乙酸乙酯600ml重结晶后烘干,得中间体Ⅰ176.6g,类白色固体,产率83.7%。
(2)反应瓶中加入2-甲基四氢呋喃1300ml和中间体Ⅰ176.6g,搅拌溶解,加氟化铯287.3g,在50℃-60℃条件下搅拌反应12小时。以水600ml洗涤,有机相以无水硫酸钠干燥,减压浓缩至干,得粘油状物,减压精馏,收集72℃-74℃(10mmHg)馏份,得4-吡啶甲醛72.7g,淡黄色液体,产率81.1%。
Claims (5)
1.一种4-吡啶甲醛的制备方法,其特征在于:具体包括以下步骤:
在反应瓶中加入质量浓度30%的双氧水和水,加入4-甲基吡啶1.0mol,加入催化剂Ⅰ,保持30℃~80℃条件下反应完全,过滤,淋洗,以溶剂Ⅰ溶解,过滤不溶物,分液后干燥,保持0℃~50℃条件下滴加三甲基钖四氟硼酸1.1-1.5mol,加毕反应至完全后以水洗涤,干燥并浓缩,用乙酸乙酯600ml重结晶,得中间体Ⅰ;
将中间体Ⅰ0.84-0.94mol加入溶剂Ⅱ中,加入氟化铯1.9-2.8mol,保持10℃~60℃条件下反应完毕后,以水洗涤,干燥后减压浓缩,所得粘油状物精馏得4-吡啶甲醛。
2.根据权利要求1所述的4-吡啶甲醛的制备方法,其特征在于:步骤(1)中所述催化剂Ⅰ为磷钼酸、磷钨酸、钨酸钠中的一种。
3.根据权利要求1所述的4-吡啶甲醛的制备方法,其特征在于:步骤(1)中所述催化剂Ⅰ的质量为4-甲基吡啶质量的1%-5%。
4.根据权利要求1所述的4-吡啶甲醛的制备方法,其特征在于:步骤(1)中所述溶剂Ⅰ为二氯甲烷、二氯乙烷、氯苯中的一种。
5.根据权利要求1所述的4-吡啶甲醛的制备方法,其特征在于:步骤(2)中所述溶剂Ⅱ为乙酸乙酯、二氯甲烷、2-甲基四氢呋喃中的一种。
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Citations (5)
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