CN117466808B - 一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 - Google Patents
一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 Download PDFInfo
- Publication number
- CN117466808B CN117466808B CN202311810665.4A CN202311810665A CN117466808B CN 117466808 B CN117466808 B CN 117466808B CN 202311810665 A CN202311810665 A CN 202311810665A CN 117466808 B CN117466808 B CN 117466808B
- Authority
- CN
- China
- Prior art keywords
- alkyl
- dihydroxypyridine
- reaction
- producing
- derivatives according
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 150000001733 carboxylic acid esters Chemical class 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 11
- 238000003379 elimination reaction Methods 0.000 claims abstract description 8
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 8
- WDJHALXBUFZDSR-UHFFFAOYSA-N Acetoacetic acid Natural products CC(=O)CC(O)=O WDJHALXBUFZDSR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 7
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims abstract description 3
- -1 acetoacetic acid ester Chemical class 0.000 claims description 35
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 2
- 125000005599 alkyl carboxylate group Chemical group 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 abstract description 2
- 125000003262 carboxylic acid ester group Chemical class [H]C([H])([*:2])OC(=O)C([H])([H])[*:1] 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- JCINCSYDDSRQQC-UHFFFAOYSA-N 4-hydroxy-6-nonyl-1H-pyridin-2-one Chemical compound C(CCCCCCCC)C1=CC(=CC(=N1)O)O JCINCSYDDSRQQC-UHFFFAOYSA-N 0.000 description 12
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- 238000001819 mass spectrum Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- YRHYCMZPEVDGFQ-UHFFFAOYSA-N methyl decanoate Chemical compound CCCCCCCCCC(=O)OC YRHYCMZPEVDGFQ-UHFFFAOYSA-N 0.000 description 6
- ZAZKJZBWRNNLDS-UHFFFAOYSA-N methyl tetradecanoate Chemical compound CCCCCCCCCCCCCC(=O)OC ZAZKJZBWRNNLDS-UHFFFAOYSA-N 0.000 description 6
- 239000002904 solvent Substances 0.000 description 5
- 102100033864 G-protein coupled receptor 84 Human genes 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 4
- 101001069589 Homo sapiens G-protein coupled receptor 84 Proteins 0.000 description 3
- 239000005640 Methyl decanoate Substances 0.000 description 3
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000556 agonist Substances 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 150000007942 carboxylates Chemical class 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001291 vacuum drying Methods 0.000 description 2
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 1
- ZPSJGADGUYYRKE-UHFFFAOYSA-N 2H-pyran-2-one Chemical group O=C1C=CC=CO1 ZPSJGADGUYYRKE-UHFFFAOYSA-N 0.000 description 1
- XLKOZYOVXNPWGT-UHFFFAOYSA-N 3-oxotetradecanoic acid Chemical compound CCCCCCCCCCCC(=O)CC(O)=O XLKOZYOVXNPWGT-UHFFFAOYSA-N 0.000 description 1
- 101710107771 G-protein coupled receptor 84 Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000003260 anti-sepsis Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- WQTNJLRLUQMQEL-UHFFFAOYSA-N ethyl 3-oxotetradecanoate Chemical compound CCCCCCCCCCCC(=O)CC(=O)OCC WQTNJLRLUQMQEL-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000006467 substitution reaction 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
- C07D213/60—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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/69—Two or more oxygen atoms
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明属于杂环化合物合成技术领域,涉及一种6‑烷基‑2,4‑二羟基吡啶类衍生物的制备方法,包括S1乙酰乙酸烷基酯(III)与羧酸酯(VIII)的亲核加成‑消除反应;S2吡啶环的合成。本发明从羧酸酯(VIII)出发,先与乙酰乙酸烷基酯经过亲核加成‑消除反应,得到3,5‑二氧代羧酸酯再与氨水环合,仅需两步反应即可快速高效合成6‑烷基‑2,4‑二羟基吡啶类衍生物,此方法反应路线极短、操作简便、成本低廉、绿色环保、生产效率高达38%,适合6‑烷基‑2,4‑二羟基吡啶类衍生物大规模制备。
Description
技术领域
本发明属于杂环化合物合成技术领域,尤其涉及一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法。
背景技术
6-烷基-2,4-二羟基吡啶类化合物或其骨架结构在药物化学领域广泛存在并具有重要用途,特别是G蛋白偶联受体84(GPR84)激动剂LY237,此化合物为上海药物所南发俊研究员团队和谢欣研究员团队合作发现的迄今为止最强的GPR84激动剂,其EC50值为0.189 nM(参见公开号为WO 2017076264 A1的PCT发明专利申请),相对于已报道的GPR84激动剂有了大幅度的提高,从而为GPR84的作用机制研究提供重要支持。LY237除了作为研究GPR84作用机制研究的工具小分子外,还为抗败血症药物的发现开辟新途径。
对于6-烷基-2,4-二羟基吡啶类衍生物的制备,目前已报道的合成路线如上所示,先通过1-溴癸烷与乙酰乙酸乙酯在强碱作用下亲核取代得到3-氧代十四烷酸乙酯,然后在氢氧化钠碱性条件下水解得到3-氧代十四烷酸,在羰基二咪唑作用下通过分子间环合得到吡喃酮骨架,再依次经过90%浓硫酸高温脱羧、氨水回流氮原子取代得到化合物I(即LY237)。此方法共需五步反应,且反应收率较低、纯化困难,第一步收率只有34%;第三步分子间的环合,只利用了一半原料,原子经济性较差,使得第三步收率只有16%;此外第四步使用了大量浓硫酸做溶剂,并于130℃下回流,导致反应危险性极高,且反应后产生大量废酸。经计算,上述路线综合收率只有2.2%。因此,有必要开发一条成本低、效率高、适合规模化制备的合成工艺为化合物LY237系列化合物的进一步开发提供保障。
发明内容
本发明针对上述现有技术存在的不足,提供一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法,具体的技术方案如下:
一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法,按照以下合成路线进行反应:
其中,R1,R2,R3均为烷基;
所述制备方法包括如下步骤:
S1、乙酰乙酸烷基酯(III)与羧酸酯(VIII)的亲核加成-消除反应:将乙酰乙酸烷基酯(III)溶解在有机溶剂中,在强碱的作用下生成碳负离子,与羧酸酯(VIII)进行亲核加成-消除反应,合成3, 5-二氧代羧酸酯(IX);
S2、吡啶环的合成:将S1合成的3, 5-二氧代羧酸酯(IX)与氨水在反应溶剂中反应获得目标产物6-烷基-2, 4-二羟基吡啶类衍生物(I)。
本发明提供的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,以乙酰乙酸烷基酯(III)为原料,先与羧酸酯(VIII)经亲核加成-消除反应得到3, 5-二氧代羧酸酯(IX)类化合物,然后与氨水环合得到化合物I,此方法仅需两步反应即可快速高效合成此类化合物,且原料成本低廉、反应路线极短,操作简便、绿色环保。
进一步地,所述S1中,所述羧酸酯(VIII)与乙酰乙酸酯(III)的摩尔比为1:(2.5-5);所述S2中,所述3, 5-二氧代羧酸酯与氨水的摩尔比为1:(10-15)。
进一步地,在所述S1中,所述反应的温度为-78~30℃,优选-50~30℃。反应时间4-6h。
进一步地,所述S1的方法:将碱悬浮于有机溶剂中,-5~10℃下滴加乙酰乙酸烷基酯(III),10~15min后滴加正丁基锂(n-BuLi)或二异丙基氨基锂(LDA)的THF溶液,-5~10℃下搅拌10~15min,将反应瓶置于-80~-60℃冷肼中,待内温低于-45~-70℃时滴加羧酸酯(VIII)及三氟化硼-***溶液,缓慢升至室温,搅拌1~2h后倒入1M稀盐酸中,乙酸乙酯萃取后的有机相洗涤、干燥,减压浓缩后硅胶柱层析,石油醚/乙酸乙酯洗脱,得到3, 5-二氧代羧酸酯(IX)。
其中,三氟化硼-***可以增强羧酸酯(VIII)的亲电能力,促进这一反应快速高效完成;三氟化硼-***用量一般大于或等于羧酸酯(VIII)的量。
进一步地,在所述S1中,所述强碱为氢化钠、氨基钠、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂中的一种或两种及以上的组合,优选氢化钠和正丁基锂。
进一步地,在所述S1中,所述有机溶剂为正己烷、***、四氢呋喃、甲基叔丁基醚中的一种或两种及以上的组合,优选四氢呋喃。
进一步地,在所述S1中,乙酰乙酸烷基酯(III)中R1可以为甲基、乙基、丙基、异丙基、正丁基、异丁基或戊基等的任意一种,优选甲基或乙基。
进一步地,在所述S1中,所述羧酸酯(VIII)中R2是碳数为1~18的烷基、环烷基、芳基等基团的任意一种;R3为甲基、乙基、丙基、异丙基、正丁基、异丁基或戊基等基团的任意一种,优选甲基、乙基。
进一步地,在所述S2中,所述反应溶剂为水、甲醇、乙醇、正丙醇、异丙醇中的一种或两种及以上的组合,优选甲醇。
进一步地,在所述S2中,所述反应的温度为0~50℃,优选15~30℃;反应时间为8~16小时。
本发明的有益效果为:
本发明提供的6-烷基-2,4二羟基吡啶类化合物的制备方法,从羧酸酯(VIII)出发,先与乙酰乙酸烷基酯经过亲核加成-消除反应,得到3, 5-二氧代羧酸酯再与氨水环合,仅需两步反应即可快速高效合成化合物I,此方法反应路线极短、操作简便、成本低廉、绿色环保、生产效率高达38%,适合式I化合物大规模制备。
附图说明
图1为本发明实施例1.1-1.3合成的3,5-二氧代十四烷酸甲酯核磁谱图;
图2为本发明实施例1.1-1.3合成的3,5-二氧代十四烷酸甲酯质谱图;
图3为本发明实施例2.1-2.3合成的6-壬基-2,4-二羟基吡啶核磁谱图;
图4为本发明实施例2.1-2.3合成的6-壬基-2,4-二羟基吡啶质谱图。
具体实施方式
以下结合实例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
1、3, 5-二氧代十四烷酸甲酯的制备(IX)
实施例1.1
称取氢化钠(4.4g,0.11mol)悬浮于100ml无水四氢呋喃(THF)中,冰浴下滴加乙酰乙酸甲酯 (11.6g,0.1mol),10min后滴加正丁基锂(n-BuLi)的THF溶液(40ml,0.1mol),30min后转移至-50℃冷肼中,滴加癸酸甲酯(5.6g,0.03mol)及三氟化硼***溶液(3.7ml,0.03mol),缓慢升至室温,搅拌1h后倒入100ml稀盐酸(1.0 mol/L)中,60mL乙酸乙酯萃取2次,合并有机相,有机相用150mL饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后硅胶柱层析,石油醚/乙酸乙酯(20:1)洗脱得到淡黄色油状物3,5-二氧代十四酸甲酯(IX)4.4g,收率:54.3%。
本实施例合成的3,5-二氧代十四烷酸甲酯(IX)的核磁谱图见图1,1H NMR(400MHz, CDCl3): 5.59 (s, 1H),3.75 (s, 3H),3.35 (s, 2H),2.31-2.27(m, 2H),1.64-1.56 (m, 1H),1.33-1.26 (m, 14H),0.88 (t, 3H)。质谱图见图2,ESI-MS (m/z):271.2 (M+H)+,293.1 (M+Na)+。
实施例1.2
称取氢化钠(4.4g,0.11mol)悬浮于100ml无水***中,冰浴下滴加乙酰乙酸甲酯(11.6g,0.1mol),10min后滴加n-BuLi的THF溶液(40ml,0.1mol),30min后转移至-78℃冷肼中,滴加癸酸甲酯(5.6g,0.03mol)及三氟化硼***溶液(3.7ml,0.03mol),缓慢升至室温,搅拌1h后倒入100ml稀盐酸(1mol/L)中,80mL***萃取2次,合并有机相,有机相用160mL饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后硅胶柱层析,石油醚/乙酸乙酯(20:1)洗脱得到淡黄色油状物3,5-二氧代十四酸甲酯(IX)4.1g,收率:50.1%。
本实施例合成的3,5-二氧代十四烷酸甲酯(IX)的核磁谱图同图1,质谱图同图2。
实施例1.3
称取氢化钠(4.4g,0.11mol)悬浮于100ml无水四氢呋喃中,冰浴下滴加乙酰乙酸甲酯 (11.6g,0.1mol),10min后滴加二异丙基氨基锂(LDA)的THF溶液(50ml,0.1mol),30min后转移至-78℃冷肼中,滴加癸酸甲酯(5.6g,0.03mol)及三氟化硼***溶液(3.7ml,0.03mol),缓慢升至室温,搅拌1h后倒入100ml稀盐酸(1mol/L)中,70mL乙酸乙酯萃取2次,合并有机相,有机相用150mL饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后硅胶柱层析,石油醚/乙酸乙酯(20:1)洗脱得到淡黄色油状物3,5-二氧代十四酸甲酯(IX)3.9g,收率:47.6%。
本实施例合成的3,5-二氧代十四烷酸甲酯(IX)的核磁谱图同图1,质谱图同图2。
2、6-壬基-2,4-二羟基吡啶(I)的制备
实施例2.1
称取3,5-二氧代十四烷酸甲酯(IX)5.4g(0.02mol)加入到盛有30mL甲醇的圆底烧瓶中,滴加28%氨水(15ml,0.22mol),加完后室温反应过夜,回收大部分溶剂,有固体析出,室温搅拌2h,抽滤、纯化水洗涤,40℃真空干燥,得到6-壬基吡啶-2,4二醇(I)粗品4.1g。然后将6-壬基吡啶-2,4二醇(I)粗品用41ml甲醇室温打浆过夜,抽滤、甲醇洗涤,40℃真空干燥,获得6-壬基-2,4二羟基吡啶(I)3.3g,收率:70%。
本实施例合成的6-壬基-2,4二羟基吡啶(I)的核磁谱图见图3,1H NMR (400MHz,DMSO-d6): 10.91(s, 1H), 10.33(s, 1H), 5.58 (d, 1H), 2.33 (t, 2H), 1.53-1.49(m, 2H), 1.29-1.24 (m, 12H), 0.85 (t, 3H)。质谱图见图4,ESI-MS (m/z): 238.2 (M+H)+,475.3(2M+H)+。
实施例2.2
称取3,5-二氧代十四烷酸甲酯(IX)5.4g(0.02mol)加入到盛有50mL乙醇的圆底烧瓶中,滴加28%氨水(17ml,0.25mol),加完后室温反应过夜,回收大部分溶剂,有固体析出,室温搅拌2h,抽滤、纯化水洗涤,40℃真空干燥,得到6-壬基吡啶-2,4二醇(I)粗品4.0g。然后将6-壬基吡啶-2,4二醇(I)粗品用40ml甲醇室温打浆过夜,抽滤、甲醇洗涤,40℃真空干燥,获得6-壬基-2,4二羟基吡啶(I)3.1g,收率:65.8%。
本实施例合成的6-壬基-2,4二羟基吡啶(I)的核磁谱图同图3,质谱图同图4。
实施例2.3
称取3,5-二氧代十四烷酸甲酯(IX)5.4g(0.02mol)加入到盛有60mL异丙醇的圆底烧瓶中,滴加28%氨水(17ml,0.25mol),加完后10℃反应过夜,回收大部分溶剂,有固体析出,室温搅拌2h,抽滤、纯化水洗涤,40℃真空干燥,得到6-壬基吡啶-2,4二醇(I)粗品3.8g。然后将6-壬基吡啶-2,4二醇(I)粗品用38ml甲醇室温打浆过夜,抽滤、甲醇洗涤,40℃真空干燥,获得6-壬基-2,4二羟基吡啶(I)2.8g,收率:59.4%。
本实施例合成的6-壬基-2,4二羟基吡啶(I)的核磁谱图同图3,质谱图同图4。
由此可见,本发明提供的6-烷基-2,4二羟基吡啶类化合物的制备方法,反应路线极短,仅需两步反应即可快速高效合成化合物I,且操作简便、成本低廉、绿色环保、生产效率高达38%,适合式I化合物大规模制备,具有显著的效果。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,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 (8)
1.一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,按照以下合成路线进行反应:
其中,R1,R2,R3均为烷基;
所述制备方法包括如下步骤:
S1、乙酰乙酸烷基酯III与羧酸酯VIII的亲核加成-消除反应:将乙酰乙酸烷基酯III溶解在有机溶剂中,在强碱的作用下生成碳负离子,碳负离子与羧酸酯VIII进行亲核加成-消除反应,合成3, 5-二氧代羧酸酯IX;
S2、吡啶环的合成:将S1合成的3, 5-二氧代羧酸酯IX与氨水在反应溶剂中反应获得目标产物6-烷基-2, 4-二羟基吡啶类衍生物I;所述3, 5-二氧代烷基羧酸酯与氨水的摩尔比为1:10-15;所述反应的温度为0~50℃,反应时间为8~16小时;所述反应溶剂为甲醇、乙醇、正丙醇、异丙醇中的一种或两种及以上的组合。
2.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,所述S1中,所述羧酸酯VIII与乙酰乙酸酯III的摩尔比为1:2.5-5。
3.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,在所述S1中,所述反应的温度为-78~30℃,反应时间为4-6h。
4.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,在所述S1中,所述强碱为氢化钠、氨基钠、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂中的一种或两种及以上的组合。
5.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,在所述S1中,所述有机溶剂为正己烷、***、四氢呋喃、甲基叔丁基醚中的一种或两种及以上的组合。
6.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,在所述S1中,所述R1为甲基、乙基、丙基、异丙基、正丁基、异丁基或戊基的任意一种。
7.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,所述R2是碳数为1~18的烷基。
8.根据权利要求1所述的6-烷基-2,4-二羟基吡啶类衍生物的制备方法,其特征在于,所述R3为甲基、乙基、丙基、异丙基、正丁基、异丁基或戊基的任意一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311810665.4A CN117466808B (zh) | 2023-12-27 | 2023-12-27 | 一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202311810665.4A CN117466808B (zh) | 2023-12-27 | 2023-12-27 | 一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN117466808A CN117466808A (zh) | 2024-01-30 |
CN117466808B true CN117466808B (zh) | 2024-03-12 |
Family
ID=89636500
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202311810665.4A Active CN117466808B (zh) | 2023-12-27 | 2023-12-27 | 一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN117466808B (zh) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101253173A (zh) * | 2005-09-02 | 2008-08-27 | 辉瑞有限公司 | 羟基取代的1h-咪唑并吡啶和方法 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120184562A1 (en) * | 2011-01-19 | 2012-07-19 | Kin-Chun Luk | 1,6- and 1,8-naphthyridines |
-
2023
- 2023-12-27 CN CN202311810665.4A patent/CN117466808B/zh active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101253173A (zh) * | 2005-09-02 | 2008-08-27 | 辉瑞有限公司 | 羟基取代的1h-咪唑并吡啶和方法 |
Non-Patent Citations (1)
Title |
---|
Yamaguchi, Masahiko.Synthesis of phenols by the intramolecular condensation of β, β', δ, δ'-tetraoxoalkanedioates. A novel BF3-promoted Claisen condensation of acetoacetate dianion with esters and amides.Tetrahedron.1988,第44卷(第15期),4767-75. * |
Also Published As
Publication number | Publication date |
---|---|
CN117466808A (zh) | 2024-01-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN109942593B (zh) | 一种消旋汉防己甲素的全合成方法 | |
CN117466808B (zh) | 一种6-烷基-2,4-二羟基吡啶类衍生物的制备方法 | |
CN109796351B (zh) | 一种盐酸屈他维林中间体的制备新方法 | |
CN113912562B (zh) | 一种氧氮杂卓衍生物的合成方法 | |
CN112209859B (zh) | 一种艾拉莫德中间体的制备方法 | |
CN112679363B (zh) | 一种制备喷他佐辛中间体的方法 | |
CN115010707A (zh) | 喹啉并吡咯衍生物的制备方法 | |
CN111662147B (zh) | 制备二炔及其类似物的方法 | |
CN111517975B (zh) | 一种2-氨基-5-氯-n,3-二甲基苯甲酰胺的制备方法 | |
CN111269128B (zh) | 1,1′-(六-2,4-二炔-1,6-二基)双(3-烷基脲)类化合物的合成方法 | |
CN114634515A (zh) | 一种(3aS,6aR)-内酯的立体选择性合成方法 | |
CN108440438B (zh) | 一种由苯乙酮类化合物与过硫酸铵及二甲基亚砜共同构建2,4二芳基噁唑的方法 | |
CN107721917B (zh) | 一种多取代烟酸酯类化合物的绿色合成方法 | |
CN107325049B (zh) | 一种来那替尼中间体的制备方法 | |
CN110563721A (zh) | 一种新的盐酸阿扎司琼的制备方法 | |
CN114057684B (zh) | 一种噻托溴铵中间体二(2-二噻吩基)羟乙酸甲酯的合成方法 | |
CN108358836B (zh) | 2-甲基-3-羟基吡啶-4,5-二甲酸酯还原制备维生素b6的方法 | |
CN112679383B (zh) | 一种多取代α-酮酯的制备方法 | |
CN111592451B (zh) | 一种4-(4-苯基丁氧基)苯甲酸的制备方法 | |
CN101033190B (zh) | 阿达帕林的一种新型制备方法 | |
CN111269097B (zh) | 一种多元环双取代的1,3-丙二酮类化合物的合成方法 | |
CN107151197B (zh) | 一种9-溴菲的制备方法 | |
CN116640085A (zh) | 一种合成咔唑衍生物的方法 | |
CN110092753B (zh) | 一种合成3-氮杂二环[4.1.0]庚烷-2-甲酸及其盐酸盐的制备方法 | |
Bez et al. | An efficient synthesis of open chain nitroalcohols by regioselective ring opening of cyclic tert-β-nitroalcohols by sodium borohydride: Short synthesis of (±)-tridecan-12-olide and (±)-9-tetradecanolide |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |