CN106632139A - 苯并噻唑‑2‑甲醛及其衍生物合成的新方法 - Google Patents
苯并噻唑‑2‑甲醛及其衍生物合成的新方法 Download PDFInfo
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- RHKPJTFLRQNNGJ-UHFFFAOYSA-N 1,3-benzothiazole-2-carbaldehyde Chemical compound C1=CC=C2SC(C=O)=NC2=C1 RHKPJTFLRQNNGJ-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000000034 method Methods 0.000 title claims abstract description 21
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- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 239000002904 solvent Substances 0.000 claims abstract description 14
- 238000001953 recrystallisation Methods 0.000 claims abstract description 9
- 238000000967 suction filtration Methods 0.000 claims abstract description 9
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- -1 Hydrogen Chemical class 0.000 claims description 23
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims description 13
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- 125000005997 bromomethyl group Chemical group 0.000 claims description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
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- 241000790917 Dioxys <bee> Species 0.000 claims description 2
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- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims 1
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- DXYYSGDWQCSKKO-UHFFFAOYSA-N 2-methylbenzothiazole Chemical class C1=CC=C2SC(C)=NC2=C1 DXYYSGDWQCSKKO-UHFFFAOYSA-N 0.000 description 4
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- OIPIPWSTKLCZOS-UHFFFAOYSA-N 5-fluoro-1,3-benzothiazole-2-carbaldehyde Chemical compound FC1=CC=C2SC(C=O)=NC2=C1 OIPIPWSTKLCZOS-UHFFFAOYSA-N 0.000 description 1
- GJIVKSSGLJFDDL-UHFFFAOYSA-N 5-methoxy-1,3-benzothiazole-2-carbaldehyde Chemical compound COC1=CC=C2SC(C=O)=NC2=C1 GJIVKSSGLJFDDL-UHFFFAOYSA-N 0.000 description 1
- UFTPERVCLGXNNM-UHFFFAOYSA-N 5-methyl-1,3-benzothiazole-2-carbaldehyde Chemical compound CC1=CC=C2SC(C=O)=NC2=C1 UFTPERVCLGXNNM-UHFFFAOYSA-N 0.000 description 1
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- 239000002246 antineoplastic agent Substances 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000010504 bond cleavage reaction Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- ORTQZVOHEJQUHG-UHFFFAOYSA-L copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
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- 125000000623 heterocyclic group Chemical group 0.000 description 1
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- 229910052740 iodine Inorganic materials 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种苯并噻唑‑2‑甲醛及其衍生物的新合成方法,所述合成方法是将2‑羟甲基苯并噻唑或取代2‑羟甲基苯并噻唑溶于一定量的溶剂中,加入适量的二氧化锰,加热反应一段时间。抽滤,浓缩,重结晶,得到苯并噻唑‑2‑甲醛及其衍生物。本发明的反应式如下所示:
Description
技术领域
本发明涉及苯并噻唑-2-甲醛及其衍生物合成方法的改进。
背景技术
苯并噻唑类化合物是杂环化合物中重要的组成部分,其药物具有广泛的抗细菌、抗真菌、抗肿瘤、消炎、抗惊厥和镇痛等多种活性,因而在生物化工、医药、材料等诸多方面具有广泛的应用。对苯并噻唑类衍生物的修饰主要是在苯环上引入不同的取代基或在2位上引入不同的活性基团,其中2-位取代基对其活性影响最大,2-取代衍生物的合成是该类化合物合成研究中最受关注的部分。
苯并噻唑-2-甲醛具有反应活性很高的甲酰基,能进行多种化学变换反应,因而成为合成众多具有潜在生理或药理活性或具有多种材料功能属性的苯并噻唑类衍生物的重要中间体。虽然苯并噻唑-2-甲醛有着广泛的用途,但是迄今为止,其高效、节能的合成方法仍然有限。
文献(Zheng G,Liu H,Wang M.Copper-Catalyzed Aerobic Oxidation ofAzinylmethanes for Access to Trifluoromethylazinylols.Chinese Journal ofChemistry,2016,34(5):519-523.)报道了通过2-甲基苯并噻唑在以N,N-二甲基甲酰胺为溶剂,以氯化铜为催化剂且通入氧气的130℃高温密闭环境下反应36小时来制备苯并噻唑-2-甲醛。该方法需要高温高压的环境操作不便利,反应时间过长,产率较低。文献(NagasawaY,Tachikawa Y,Yamaguchi E,et al.Catalytic Aerobic Photo-oxidation of a MethylGroup on a Heterocycle to Produce an Aldehyde via,Homolytic C I Bond Cleavagecaused by Irradiation with Visible Light.Advanced Synthesis&Catalysis,2016,358(2):178-182.)报道了通过2-甲基苯并噻唑与碘和三氟乙酸在以乙酸乙酯为溶剂,70℃下搅拌8小时,再在荧光照射下通入氧气反应20小时来制备苯并噻唑-2甲醛。该方法反应时间长,反应条件较复杂,产率不高,不适合大规模生产。专利CN102977050A(公开日为2013年03月20日)公开了一种苯并噻唑-2-甲醛的合成方法,以苯并噻唑和甲醇为原料,在氧化剂的作用下反应制得2-苯并噻唑二甲缩醛,然后在酸催化剂的作用下反应制得苯并噻唑-2-甲醛。该方法第一步制得2-苯并噻唑二甲缩醛反应的收率为30-64%,收率偏低,进而制约了最终产物苯并噻唑-2-甲醛的总收率。文献(Wang R,Chen C,Zhang X,et al.Structure-Activity Relationship and Pharmacokinetic Studies of 1,5-Diheteroarylpenta-1,4-dien-3-ones:A Class of Promising Curcumin-Based Anticancer Agents.Journalof Medicinal Chemistry,2015,58(11):4713-4726.)报道了通过2-羟甲基苯并噻唑与邻苯二甲酸二甲酯先进行酯化反应,然后再用硫代硫酸钠溶液将其还原成苯并噻唑-2-甲醛。此方法合成出产物不纯,后处理较困难,产率不高。文献(Campaigne E,Thompson R L,Werth J E V.Some Heterocyclic Aldehyde Thiosemicarbazones Possing Anti-viralActivity.Journal of Medicinal&Pharmaceutical Chemistry,1959,1(6):577-599.)报道了通过以二氧化硒为氧化剂氧化2-羟甲基苯并噻唑来制备苯并噻唑-2-甲醛,这种方法需要使用有毒的氧化剂并且容易引起副反应,因此实际操作的产率很难提高,同样不适合大规模生产。
鉴于以上问题,本发明设计的苯并噻唑-2-甲醛及其衍生物的合成路线对于今后的工艺生产具有重要的突破和实际应用价值。
发明内容
本发明针对现有技术的不足之处,提供了一种方法简单,环境友好,原料廉价易得,产品品质提高明显,收率大幅度提升,反应副产物明显降低的新型苯并噻唑-2-甲醛及其衍生物的高效合成方法。
为解决上述技术问题,本发明通过以下技术方案实现:
将2-羟甲基苯并噻唑或取代2-羟甲基苯并噻唑溶于一定量的溶剂中,加入适量的二氧化锰,加热反应一段时间。抽滤,浓缩,重结晶,得到苯并噻唑-2-甲醛及其衍生物。
本发明的反应式如下所示:
其中,式中取代基R1、R2、R3、R4可以分别为氢,甲基,乙基,烯丙基,卤素,羧基,硝基,苄基,磺酰基,苯磺酰基,对甲苯磺酰基,一氟代甲基,二氟代甲基,三氟代甲基,一氯代甲基,二氯代甲基,三氯代甲基,一溴代甲基,二溴代甲基,三溴代甲基,氰基,甲氧基,甲酰氧基,乙氧基,乙酰氧基,乙酰基,乙酰氨基,甲氧羰基,乙氧羰基。
本发明使用的原料二氧化锰为商品化试剂,原料2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑可根据文献公开的方法制备,例如文献[Elshihawy,Hosam;Hammad,etal.Molecular modeling studies and synthesis of fused heterocyclic compoundswith potential inhibitory activities of menthionine synthase catalysedreaction.2013,9(2)41-57.或者Tao He,Lin Yu,Lei Zhang,Lei Wang,Min Wang.DirectC2-Alkylation of Azoles with Alcohols and Ethers through DehydrogenativeCross-Coupling under Metal-Free Conditions.Organic Letter,2011,13(19), 5016–5019.]
本发明所述2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑与二氧化锰的摩尔比为3:1到1:20。
本发明所述的溶剂为下列一种或者任意两种一定比例的混合物:水,二氯甲烷,乙腈,乙醚,硝基甲烷,四氢呋喃,氯仿,甲醇,乙酸乙酯,乙醇,异丙醇,丙酮,甲苯,1,2-二氯乙烷,三氯甲烷,1,4-二氧六环,二甲基亚砜,N,N-二甲基甲酰胺,使用混合溶剂的体积比为1:1到1:50。
本发明所述的苯并噻唑-2-甲醛及其衍生物合成方法,反应时间为5~20小时。
本发明所述的2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑与溶剂的质量比为1:1到1:200。
本发明所述的重结晶溶剂为下列一种或者任意两种一定比例的混合物:水,二氯甲烷,乙醚,四氢呋喃,丙酮,氯仿,甲醇,乙酸乙酯,乙醇,异丙醇,1,2-二氯乙烷,使用混合溶剂的体积比为1:1到1:100。
与现有的技术相比较,本发明具有以下突破:本发明使用传统的氧化剂二氧化锰氧化2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑,来源廉价易得,操作步骤简单,环境友好,使得产物苯并噻唑-2-甲醛及其衍生物的收率达到90%以上,适用于工业上大规模的生产。
具体实施方式
下面结合具体实施例对本发明作进一步详细说明,但本发明的保护范围不限于此:
实施例1:
将2-羟甲基苯并噻唑(1.16g,7.0mmol)溶于40mL二氯甲烷中,加入二氧化锰(4.87g,56mmol),45℃回流反应12h,静置冷却,抽滤除去不溶性杂质,浓缩,乙醇重结晶,得到固体苯并噻唑-2-甲醛1.09g。
实施例2:
将2-羟甲基-5-硝基苯并噻唑(1.47g,7.0mmol)溶于35mL丙酮中,加入二氧化锰(4.26g,49mmol),60℃回流反应10h,静置冷却,抽滤除去不溶性杂质,浓缩,二氯甲烷重结晶,得到固体5-硝基苯并噻唑-2-甲醛1.40g。
实施例3:
将2-羟甲基-5-甲氧基苯并噻唑(1.37g,7.0mmol)溶于47mL四氢呋喃中,加入二氧化锰(3.65g,42mmol),70℃回流反应11h,静置冷却,抽滤除去不溶性杂质,浓缩,乙醚重结晶,得到固体5-甲氧基苯并噻唑-2-甲醛1.30g。
实施例4:
将2-羟甲基-5-氯苯并噻唑(1.39g,7.0mmol)溶于50mL乙醚中,加入二氧化锰(3.05g,35mmol),35℃回流反应13h,静置冷却,抽滤除去不溶性杂质,浓缩,乙酸乙酯重结晶,得到固体5-氯苯并噻唑-2-甲醛1.29g。
实施例5:
将2-羟甲基-5-甲基苯并噻唑(1.25g,7.0mmol)溶于38mL氯仿中,加入二氧化锰(2.44g,28mmol),65℃回流反应14h,静置冷却,抽滤除去不溶性杂质,浓缩,丙酮重结晶,得到固体5-甲基苯并噻唑-2-甲醛1.14g。
实施例6:
将5-氟-2-羟甲基苯并噻唑(1.28g,7.0mmol)溶于20mL二氯甲烷和20mL丙酮的混合溶液中,加入二氧化锰(1.83g,21mmol),60℃回流反应15h,静置冷却,抽滤除去不溶性杂质,浓缩,四氢呋喃重结晶,得到固体5-氟苯并噻唑-2-甲醛1.19g。
以上仅为本发明的具体实施例,但本发明的技术特征并不局限于此。任何以本发明为基础,为解决基本相同技术问题,实现基本相同的技术效果,所做出地简单变化、等同替换或者修饰等,皆涵盖于本发明的保护范围之中。
Claims (8)
1.苯并噻唑-2-甲醛及其衍生物合成的新方法,其特征在于:
将2-羟甲基苯并噻唑或取代2-羟甲基苯并噻唑溶于一定量的溶剂中,加入适量的二氧化锰,加热反应一段时间。抽滤,浓缩,重结晶,得到苯并噻唑-2-甲醛及其衍生物。
本发明的反应式如下所示:
其中,式中取代基R1、R2、R3、R4可以分别为氢,甲基,乙基,烯丙基,卤素,羧基,硝基,苄基,磺酰基,苯磺酰基,对甲苯磺酰基,一氟代甲基,二氟代甲基,三氟代甲基,一氯代甲基,二氯代甲基,三氯代甲基,一溴代甲基,二溴代甲基,三溴代甲基,氰基,甲氧基,甲酰氧基,乙氧基,乙酰氧基,乙酰基,乙酰氨基,甲氧羰基,乙氧羰基。
2.如权利要求1所述的苯并噻唑-2-甲醛及其衍生物合成方法,其特征在于,2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑与二氧化锰的摩尔比为3:1到1:20。
3.如权利要求1所述的苯并噻唑-2-甲醛及其衍生物合成方法,其特征在于,溶剂为下列一种或者任意两种一定比例的混合物:水,二氯甲烷,乙腈,乙醚,硝基甲烷,四氢呋喃,氯仿,甲醇,乙酸乙酯,乙醇,异丙醇,丙酮,甲苯,1,2-二氯乙烷,三氯甲烷,1,4-二氧六环,二甲基亚砜,N,N-二甲基甲酰胺。
4.如权利要求1所述的苯并噻唑-2-甲醛及其衍生物合成方法,其特征在于,反应时间为5~20小时。
5.如权利要求1所述的苯并噻唑-2-甲醛及其衍生物合成方法,其特征在于,2-羟甲基苯并噻唑或取代-2-羟甲基苯并噻唑与溶剂的质量比为1:1到1:200。
6.如权利要求1所述的苯并噻唑-2-甲醛及其衍生物合成方法,其特征在于,重结晶溶剂为下列一种或者任意两种一定比例的混合物:水,二氯甲烷,乙醚,四氢呋喃,丙酮,氯仿,甲醇,乙酸乙酯,乙醇,异丙醇,1,2-二氯乙烷。
7.如权利要求3所述的反应溶剂,如果使用混合溶剂,其特征在于,任意两种溶剂的体积比为1:1到1:50。
8.如权利要求6所述的重结晶溶剂,如果使用混合溶剂,其特征在于,任意两种溶剂的体积比为1:1到1:100。
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