CN111961011B - Preparation method of C2 substituted 2H-benzothiazole hydroxyalkylated derivative - Google Patents
Preparation method of C2 substituted 2H-benzothiazole hydroxyalkylated derivative Download PDFInfo
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- CN111961011B CN111961011B CN202010855532.9A CN202010855532A CN111961011B CN 111961011 B CN111961011 B CN 111961011B CN 202010855532 A CN202010855532 A CN 202010855532A CN 111961011 B CN111961011 B CN 111961011B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- WOHLSTOWRAOMSG-UHFFFAOYSA-N 2,3-dihydro-1,3-benzothiazole Chemical class C1=CC=C2SCNC2=C1 WOHLSTOWRAOMSG-UHFFFAOYSA-N 0.000 title description 9
- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 claims abstract description 88
- 238000006243 chemical reaction Methods 0.000 claims abstract description 79
- 238000000034 method Methods 0.000 claims abstract description 32
- 239000002904 solvent Substances 0.000 claims abstract description 21
- 238000012544 monitoring process Methods 0.000 claims abstract description 15
- 238000004809 thin layer chromatography Methods 0.000 claims abstract description 15
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 150000002191 fatty alcohols Chemical class 0.000 claims abstract description 7
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000002156 mixing Methods 0.000 claims abstract description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- 238000006467 substitution reaction Methods 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 23
- 238000004440 column chromatography Methods 0.000 claims description 17
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 239000012046 mixed solvent Substances 0.000 claims description 14
- 239000003208 petroleum Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- ZBQZBWKNGDEDOA-UHFFFAOYSA-N eosin B Chemical group O1C(=O)C2=CC=CC=C2C21C1=CC([N+]([O-])=O)=C(O)C(Br)=C1OC1=C2C=C([N+]([O-])=O)C(O)=C1Br ZBQZBWKNGDEDOA-UHFFFAOYSA-N 0.000 claims description 11
- 239000012295 chemical reaction liquid Substances 0.000 claims description 10
- 238000000926 separation method Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- -1 Hydrogen Chemical class 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 102100037487 Histone H1.0 Human genes 0.000 claims description 2
- 101001026554 Homo sapiens Histone H1.0 Proteins 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 1
- 230000003197 catalytic effect Effects 0.000 abstract description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 34
- 238000005160 1H NMR spectroscopy Methods 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 238000003786 synthesis reaction Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 238000005303 weighing Methods 0.000 description 12
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 8
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- 229940079593 drug Drugs 0.000 description 3
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- 239000007800 oxidant agent Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 230000029936 alkylation Effects 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012363 selectfluor Substances 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 150000003624 transition metals Chemical class 0.000 description 2
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 229910002567 K2S2O8 Inorganic materials 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000003281 allosteric effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- YQGOJNYOYNNSMM-UHFFFAOYSA-N eosin Chemical compound [Na+].OC(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C(O)=C(Br)C=C21 YQGOJNYOYNNSMM-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 150000002503 iridium Chemical class 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000006263 metalation reaction Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 150000001451 organic peroxides Chemical class 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
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)
Abstract
The invention discloses a C2 substituted 2H-a process for the preparation of a benzothiazole hydroxyalkylated derivative, said process comprising: will substitute 2HMixing benzothiazole with fatty alcohol, using organic dye photosensitizer as catalyst, under the protection of nitrogen gasStirring and reacting in a solvent at normal temperature under the irradiation of an LED white light lamp, monitoring by TLC (thin layer chromatography) until the reaction is finished, and separating and purifying the reaction solution to obtain C2 substituted 2H-benzothiazolyloxyalkylated derivatives. The invention adopts the technology, takes cheap and easily obtained organic dye as a catalyst, and synthesizes 2 through visible light inductionHThe method for preparing the (E) -benzothiazole C2 hydroxyalkylated derivative has the advantages of simple catalytic system, mild reaction condition, cheap and easily obtained catalyst and good yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to C2 substituted 2HA process for the preparation of (a) benzothiazole hydroxyalkylated derivatives.
Background
C2 substituted 2HThe benzothiazole derivative is a nitrogen-containing heterocyclic compound widely existing in nature, has spectral biological activity and pharmacological activity, and has high selectivity, so that the benzothiazole derivative plays an important role in many fields such as medicines, pesticides and the like. For example, in the field of agricultural chemicals, biological activities such as weeding (bioorg. med. chem. lett., 2016, 26, 1854), killing insects (Pharmazie, 2003, 58, 527), killing bacteria (Molecules, 1997, 2, 36), and resisting viruses (chi. j. org. chem., 2007, 27, 279) are possessed; in the medical field, the compound has biological activities such as antibacterial (eur. j. med. chem., 2010, 45, 1323), antitumor (brit. j. Cancer, 88, 470), anticancer (eur. j. med. chem., 54, 447), and the like. And is in 2HThe structure of introducing hydroxyalkyl group at C2 of benzothiazole is also present in various drugs because of its various pharmacological activities, such as muscarinic antagonists (j. med. chem., 1995, 38, 473), antifungal drugs (chem. pharm. bull., 1997, 45, 1169) and CaS receptor allosteric modulators (brit. j. pharmacol., 2015, 172, 185).
2HThe alkylation of the-benzothiazole C2 hydroxy group is referred to at 2HReaction of introduction of an alkyl group bearing a hydroxyl group at position C2 of benzothiazole. According to the literature report, 2HThe processes for the C2 hydroxyalkylation of benzothiazole are numerous and the conventional processes consist essentially of the addition of aldehydes and ketones of benzothiazole C2. For example, first by additive base pair 2HDeprotonation of benzothiazole followed by functionalization to give C2 hydroxyalkylated 2HBenzothiazole (chem. Commun. 2012, 48, 9771-9773); another type of reaction is first through Li/Mg (eur. j. org. chem. 2009, 2009, 1781),n-BuLi（J. Heterocycl. Chem. 1971, 8, 257），t-BuLi (Heterocycles, 1985, 23, 295) ort-BuOLi (j. org. chem. 2009, 74, 8309) implements 2HMetallation of benzothiazole followed by hydrolysis to C2 Hydroxyalkylation 2H-benzothiazole. However, these methods have many disadvantages such as the necessity of pretreatment of reactants, severe reaction conditions and complicated reaction process. Thus, direct hydroxyalkylation of benzothiazole with alcohol has attracted considerable attention from scientists. In 2011, Wang project group reported alkylation of benzothiazole with alcohol using t-butyl hydroperoxide as an oxidant at 120 ℃ (org. lett. 2011, 13, 5016). However, this method has limitations such as relatively high reaction temperature, inflammable and explosive characteristics of the organic peroxide oxidizing agent, and the like. In 2019, the subject group is K2S2O8As the oxidizing agent, direct hydroxyalkylation of benzothiazole with alcohol was explored in water at 65 ℃ (ACS Omega 2019, 4, 11285). Although this process is milder than the above reaction, it is carried out under heating.
In recent years, visible light has received wide attention from chemists as a new energy source having advantages of being inexpensive and readily available, environmentally friendly, and simple to use (chi. j. org. chem. 2018, 38, 2807, chi. j. org. chem. 2019, 39, 3065). Generally, the visible light-promoted organic synthesis reaction has milder conditions and simpler reaction system compared with the reaction of thermochemical reaction. Thus, 2HThe reaction of-benzothiazole hydroxyalkylation has become the current direction of research. In 2016, the DiRocco topic group reported a benzothiazole hydroxyalkylation reaction with iridium complexes as catalysts (j. org. chem., 2016, 81, 6980). The method has simple reaction steps and is carried out at room temperature, but the method has the problems of high price, certain toxicity, difficult avoidance of metal residue and the like by using the transition metal iridium as a catalyst. In 2020, 2 was synthesized by the subject group with Selectfluor/TFA catalytic systemHBenzothiazolyl hydroxyalkylated derivatives (DOI: https:// doi.org/10.1016/j.cccet.2020.05.022). Although this method avoids contamination of the transition metal catalyst, Selectfluor is also relatively expensive. Accordingly, the development of inexpensive catalysts and mild reaction conditions are of positive significance.
Disclosure of Invention
In view of the above problems in the prior art, the present invention aims to provide a method for preparing a C2 substituted 2 under the induction of visible light by using an inexpensive organic dye as a catalystHA process for the preparation of (a) benzothiazole hydroxyalkylated derivatives.
One C2 substitution 2HA preparation method of (E) -benzothiazole hydroxyl alkylated derivative, which is characterized in that the substituted 2 shown in the formula (II)HMixing benzothiazole and fatty alcohol shown as a formula (III), stirring and reacting at normal temperature in a solvent under the protection of nitrogen and the irradiation of an LED white light lamp under the action of an organic dye photosensitizer, monitoring by TLC (thin layer chromatography) until the reaction is finished, and separating and purifying reaction liquid to obtain C2 substituted 2 shown as a formula (I)H-a benzothiazole hydroxyalkylated derivative;
in the formulae (I) and (III), the substituent R1Selected from hydrogen or C1-C2 alkyl; substituent R2Selected from C1-C4 alkyl or C1-C2 hydroxyalkyl.
In the formulae (I) and (II), 2H-H on the benzothiazole ring is mono-, poly-or unsubstituted with a substituent R, and 2H-the C2 position of the benzothiazole ring is not substituted by a substituent R; n is an integer of 0 to 4, and n represents 2H-the number of substituents R on the benzothiazole ring; when n =0, represents 2H-H on the benzothiazole ring is unsubstituted; when n =1, represents 2H-H on the benzothiazole ring is monosubstituted with a substituent R; when n =2~4, represents 2H-H on the benzothiazole ring is polysubstituted with a substituent R, the substituents R in different substitution positions being identical or different; the substituent R is hydrogen, C1-C4 alkyl, C1-C2 alkoxy, cyano, halogen or nitro.
One C2 substitution 2HA process for the preparation of a benzothiazolyl hydroxyalkylated derivative, characterized in that in formula (I) and formula (II), n = an integer of 0 to 1.
One C2 substitution 2HA process for the preparation of (a) a benzothiazole hydroxyalkylated derivative, characterized in that in formula (I) and formula (III) the substituent R1Is hydrogen or methyl; substituent R2Is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or hydroxymethyl.
One C2 substitution 2H-a process for the preparation of a benzothiazolyloxyalkylated derivative, characterized in that in formula (I) and formula (II), (R) n is hydrogen, 6-methoxy, 6-cyano, 5-chloro or 6-nitro; in the formulae (I) and (III), R1Is hydrogen or methyl, R2Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or hydroxymethyl.
One C2 substitution 2HA process for the preparation of (a) -benzothiazole hydroxyalkylated derivatives, characterized by the substitution 2 as shown in formula (II)HThe amount ratio of the benzothiazole to the fatty alcohol represented by the formula (III) is 1: 5.0-50.0, preferably 1: 10.0-30.0.
One C2 substitution 2HThe preparation method of the (E) -benzothiazole hydroxyl alkylated derivative is characterized in that the organic dye photosensitizer is Eosin B, Eosin Y-2Na, Rhodamine B and Rose Bengal, preferably Eosin B and Rose Bengal, and the dosage of the organic dye is substituted 2 shown in formula (II)H1.0 to 10.0 mol%, preferably 1.5 to 5.0 mol%, of benzothiazole.
One C2 substitution 2H-a process for the preparation of a hydroxy alkylated derivative of benzothiazole characterised in that the solvent is acetonitrile, tetrahydrofuran; acetonitrile is preferred.
One C2 substitution 2HThe preparation method of the benzothiazole hydroxyl alkylated derivative is characterized in that the power of an LED white light lamp is 10-50W, preferably 20-40W; the stirring reaction time is 8-38 hours, preferably 16-30 hours.
One C2 substitution 2HA method for preparing benzothiazole hydroxyalkylated derivatives, which is characterized in that the method for separating and purifying reaction liquid comprises the following steps: after the reaction is finished, concentrating the reaction solution to remove the solvent, and carrying out column chromatography separation on the concentrated solution to obtain C2 substituted 2 shown in the formula (I)H-benzothiazolyl hydroxylAnd (3) carrying out column chromatography on the alkylated derivative by using a mixed solvent of petroleum ether and ethyl acetate, wherein the volume ratio of the eluent used for column chromatography is 1-10: 1.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a synthesis method 2 by using cheap and easily available organic dye as a catalyst and inducing the organic dye by visible lightHThe invention relates to a novel method for preparing a C2 hydroxyalkylated derivative of benzothiazole by using an excess of fatty alcohol, using the cheap raw material and controlling the raw material ratio and simultaneously making the substitution 2HThe benzothiazole can be fully reacted to obtain the optimal yield, and the method has the advantages of simple catalytic system, mild reaction conditions, cheap and easily-obtained catalyst, good yield, good reaction repeatability, wide substrate range and suitability for popularization and application.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
In the following examples, the structural formula of the derivatives Ia to Il is shown as the formula (I), and substituent groups R are respectively disclosed in the corresponding examples1、R2And (R) n.
Example 1 derivative Ia ((R) n = H, R1= H, R2Synthesis of = methyl)
Weighing 2HBenzothiazole (0.3 mmol, 40.6 mg), ethanol (6.0 mmol, 276.4 mg) and 1.5 mol% Eosin B are put into a 25 mL reaction tube, 2 mL acetonitrile is added, the reaction is carried out under the irradiation of an LED white light lamp with 20W power, the reaction is stirred at room temperature, the TLC monitoring is carried out, the reaction is finished after about 16 h, the reaction solution is concentrated to remove the solvent, and the concentrated solution is separated by column chromatography (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 1: 1) to obtain yellow solid, namely the derivative Ia. The yield thereof was found to be 78%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 7.96 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.45 (dd, J = 8.0, 7.0 Hz, 1H), 7.36 (t, J = 8.0 Hz, 1H), 5.25 (q, J= 6.5 Hz, 1H), 3.81 (br, 1H), 1.70 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, DMSO) δ 179.55, 153.17, 134.40, 125.91, 124.67, 122.29, 67.09, 23.85.
example 2 derivative Ib ((R) n = H, R)1= H, R2Synthesis of = ethyl)
Weighing 2HAnd (3) adding benzothiazole (0.3 mmol, 40.6 mg), n-propanol (6.0 mmol, 360.6 mg) and 3.0 mol% of Eosin B into a 25 mL reaction tube, adding 2 mL of acetonitrile, placing the tube under the irradiation of an LED white light lamp with 20W power for reaction, stirring the tube at room temperature for reaction, monitoring by TLC, finishing the reaction after about 18 h, concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the concentrated liquid (eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 1: 1) to obtain a white solid, namely a derivative Ib. The yield thereof was found to be 70%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.41 – 7.35 (m, 1H), 5.05 (dd, J = 7.5, 5.0 Hz, 1H), 3.70 (br, 1H), 2.09 (m, 1H), 2.01 – 1.93 (m, 1H), 1.07 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 176.19, 152.75, 134.81, 126.07, 125.00, 122.83, 121.83, 73.39, 31.13, 9.40.
example 3 derivative Ic ((R) n = H, R)1= methyl, R2Synthesis of = methyl)
Weighing 2HPlacing benzothiazole (0.3 mmol, 40.6 mg), isopropanol (3.0 mmol, 180.3 mg) and 1.5 mol% Eosin B in a 25 mL reaction tube, adding 2 mL acetonitrile, placing under a 20W LED white light lamp for reaction, stirring at room temperature for reaction, monitoring by TLC, after about 16 h, the reaction is finished, concentrating the reaction solution to remove the solvent, and separating the concentrated solution by column chromatography (elution)The solvent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 1: 1) to obtain a white solid, namely the derivative Ic. The yield thereof was found to be 85%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.38 (t, J = 7.0 Hz, 1H), 3.35 (br, 1H), 1.77 (s, 6H). 13C NMR (125 MHz, CDCl3) δ 180.10, 153.05, 135.30, 126.02, 124.90, 122.84, 121.77, 73.59, 30.80.
example 4 derivative Id ((R) n = H, R1= H, R2Synthesis of = n-propyl)
Weighing 2HBenzothiazole (0.3 mmol, 40.6 mg), n-butanol (6.0 mmol, 444.7 mg) and 3.0 mol% Eosin B are put into a 25 mL reaction tube, 2 mL acetonitrile is added, the reaction is carried out under the irradiation of an LED white light lamp with 20W power, the reaction is stirred at room temperature, the TLC monitoring is carried out, the reaction is finished after about 24 h, the reaction solution is concentrated to remove the solvent, and the concentrated solution is separated by column chromatography (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain yellow solid, namely the derivative Id. The yield thereof was found to be 77%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.50 – 7.44 (m, 1H), 7.40 – 7.35 (m, 1H), 5.12 (dd, J = 8.0, 4.6 Hz, 1H), 3.41 (br, 1H), 2.04 – 1.88 (m, 2H), 1.63 – 1.47 (m, 2H), 0.98 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ176.80, 152.64, 134.69, 126.08, 125.00, 122.75, 121.82, 72.03, 40.16, 18.47, 13.80.
example 5 derivative Ie ((R) n = H, R)1= H, R2Synthesis of = isopropyl) or a salt thereof
Weighing 2HBenzothiazole (0.3 mmol, 40.6 mg), isobutanol (6.0 mmol, 444.7 mg) and 1.5 mAdding 2 mL of acetonitrile into an ol% Eosin B in a 25 mL reaction tube, placing the mixture under the irradiation of an LED white light lamp with power of 20W for reaction, stirring the mixture at room temperature for reaction, monitoring by TLC, finishing the reaction after about 16 h, concentrating the reaction solution to remove the solvent, and performing column chromatography separation on the concentrated solution (eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a yellow oily substance, namely a derivative Ie. The yield thereof was found to be 71%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 8.01 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.53 – 7.47 (m, 1H), 7.43 – 7.38 (m, 1H), 4.94 (d, J = 4.7 Hz, 1H), 3.06 (br, 1H), 2.35 – 2.25 (m, 1H), 1.10 (d, J = 7.0 Hz, 3H), 0.99 (d, J = 7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 175.45, 152.32, 134.79, 126.14, 125.09, 122.81, 121.82, 35.25, 19.05, 16.30.
example 6 derivative If ((R) n = H, R1= methyl, R2Synthesis of = ethyl)
Weighing 2HAnd (3) adding benzothiazole (0.3 mmol, 40.6 mg), 2-butanol (9.0 mmol, 667.1 mg) and 5 mol% of Eosin B into a 25 mL reaction tube, adding 2 mL acetonitrile, placing the tube under the irradiation of an LED white light lamp with power of 20W for reaction, stirring the tube at room temperature for reaction, monitoring by TLC, finishing the reaction after about 30 h, concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the concentrated liquid (eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a yellow oily substance, namely the derivative If. The yield thereof was found to be 79%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.51 – 7.44 (m, 1H), 7.38 (t, J = 7.5 Hz, 1H), 3.30 (br, 1H), 2.09 – 1.98 (m, 2H), 1.72 (s, 3H), 0.94 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 179.36, 152.97, 135.46, 125.98, 124.85, 122.87, 121.76, 76.07, 36.29, 29.14, 8.00.
example 7 derivative Ig ((R) n = 6-methoxy, R)1=H, R2Synthesis of = methyl)
Weighing 6-methoxy-2HAnd (3) adding benzothiazole (0.3 mmol, 49.5 mg), ethanol (6.0 mmol, 276.4 mg) and 1.5 mol% Rose Bengal into a 25 mL reaction tube, adding 2 mL acetonitrile, placing the tube under the irradiation of an LED white light lamp with power of 30W for reaction, stirring the tube at room temperature for reaction, monitoring by TLC, finishing the reaction after about 24 hours, concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the concentrated liquid (eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a yellow solid, namely the derivative Ig. The yield thereof was found to be 82%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 9.0 Hz, 1H), 7.34 (d, J = 2.5 Hz, 1H), 7.08 (dd, J = 9.0, 2.5 Hz, 1H), 5.22 (q, J = 6.5 Hz, 1H), 3.88 (br, 3H), 3.34 (s, 1H), 1.70 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ173.88, 157.59, 147.32, 136.25, 123.35, 115.48, 104.34, 68.49, 55.82, 23.97.
example 8 derivative Ih ((R) n = 6-cyano, R)1=H, R2Synthesis of = methyl)
Weighing 6-cyano-2HAnd (3) adding benzothiazole (0.3 mmol, 48.0 mg), ethanol (6.0 mmol, 276.4 mg) and 3.0 mol% Rose Bengal into a 25 mL reaction tube, adding 2 mL tetrahydrofuran, placing the tube under the irradiation of an LED white light lamp with power of 30W for reaction, stirring the tube at room temperature for reaction, monitoring by TLC, finishing the reaction after about 17 hours, concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the concentrated liquid (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a yellow solid, namely the derivative Ih. The yield thereof was found to be 72%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, CDCl3) δ 8.25 (d, J = 1.0 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.74 (dd, J = 8.5, 2.0 Hz, 1H), 5.30 (q, J = 6.5 Hz, 1H), 3.04 (br, 1H), 1.75 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 181.74, 155.60, 135.54, 129.30, 126.75, 123.74, 118.66, 108.55, 68.82, 23.97.
example 9 derivative Ii ((R) n = 5-chloro, R)1=H, R2Synthesis of = methyl)
Weighing 5-chloro-2HAnd (3) -benzothiazole (0.3 mmol, 50.7 mg), ethanol (6.0 mmol, 276.4 mg) and 3.0 mol% Rose Bengal are put into a 25 mL reaction tube, 2 mL acetonitrile is added, the reaction is carried out under the irradiation of an LED white light lamp with power of 30W, the reaction is stirred at room temperature, the TLC monitoring is carried out, the reaction is finished after about 22 h, the reaction liquid is concentrated to remove the solvent, and the concentrated liquid is separated by column chromatography (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a white solid, namely the derivative Ii. The yield thereof was found to be 78%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (CDCl3, 500 MHz) δ 7.96 (d, J = 2.0 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 8.5, 2.0 Hz, 1H), 5.25 (q, J = 6.5 Hz, 1H), 2.81 (br, 1H), 1.72 (d, J = 6.5 Hz, 3H); 13C NMR (CDCl3，125 MHz) δ 178.9, 153.8, 133.2, 132.2, 125.6, 122.67, 68.6, 24.0。
example 10 derivative Ij ((R) n = 6-nitro, R)1=H, R2Synthesis of = methyl)
Weighing 6-nitro-2HAnd (3) adding benzothiazole (0.3 mmol, 54.0 mg), ethanol (6.0 mmol, 276.4 mg) and 5.0 mol% Rose Bengal into a 25 mL reaction tube, adding 2 mL tetrahydrofuran, placing the tube under the irradiation of an LED white light lamp with power of 30W for reaction, stirring the tube at room temperature for reaction, monitoring by TLC, finishing the reaction after about 24 hours, concentrating the reaction liquid to remove the solvent, and carrying out column chromatography separation on the concentrated liquid (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 3: 1) to obtain a yellow solid, namely the derivative Ij. The yield thereof was found to be 70%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, DMSO) δ 9.15 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 9.0, 2.5 Hz, 1H), 8.12 (d, J = 9.0 Hz, 1H), 6.56 (d, J = 4.5 Hz, 1H), 5.12 (dd, J= 6.5, 4.0 Hz, 1H), 1.56 (d, J = 6.5 Hz, 3H). 13C NMR (125 MHz, DMSO) δ187.11, 157.16, 144.04, 135.06, 122.80, 121.29, 119.42, 67.32, 23.60.
example 11 derivative Ik ((R) n = H, R1=H, R2Synthesis of = hydroxymethyl)
Weighing 2HBenzothiazole (0.3 mmol, 40.6 mg), ethylene glycol (9.0 mmol, 558.6 mg) and 3.0 mol% Eosin B are put into a 25 mL reaction tube, 2 mL acetonitrile is added, the reaction is carried out under the irradiation of an LED white light lamp with the power of 30W, the reaction is stirred at room temperature, the TLC monitoring is carried out, the reaction is finished after about 18 h, the reaction solution is concentrated to remove the solvent, and the concentrated solution is separated by column chromatography (the eluent is a mixed solvent of petroleum ether and ethyl acetate with the volume ratio of 10: 1) to obtain a yellow oily substance, namely the derivative Ix. The yield thereof was found to be 75%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, DMSO) δ 8.08 (dd, J = 8.0, 0.5 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.53 – 7.46 (m, 1H), 7.44 – 7.38 (m, 1H), 6.41 (d, J = 5.0 Hz, 1H), 5.01 (t, J = 6.0 Hz, 1H), 4.92 (ddd, J = 6.5, 5.0, 4.0 Hz, 1H), 3.84 (ddd, J = 10.0, 5.5, 4.0 Hz, 1H), 3.67 (dt, J = 11.5, 6.5 Hz, 1H). 13C NMR (125 MHz, DMSO) δ176.26, 153.10, 134.42, 125.87, 124.66, 122.38, 122.16, 72.60, 65.87.
example 12 derivative Il ((R) n = H, R)1= methyl, R2Synthesis of = hydroxymethyl)
Weighing 2HBenzothiazole (0.3 mmol, 40.6 mg), 1, 2-propanediol (9.0 mmol, 684.8 mg) and 3.0 mol% Eosin B in a 25 mL reaction tubeAnd then adding 2 mL of acetonitrile, placing the mixture under the irradiation of an LED white light lamp with power of 30W for reaction, stirring the mixture at room temperature for reaction, monitoring by TLC, finishing the reaction after about 20 hours, concentrating the reaction solution to remove the solvent, and carrying out column chromatography separation on the concentrated solution (the eluent is a petroleum ether-ethyl acetate mixed solvent with the volume ratio of 10: 1) to obtain a yellow oily substance, namely the derivative Il. The yield thereof was found to be 79%.
Of the compound1H NMR and13the C NMR analytical data are as follows,
1H NMR (500 MHz, DMSO) δ 8.08 – 8.05 (m, 1H), 7.96 – 7.93 (m, 1H), 7.49 – 7.46 (m, 1H), 7.41 – 7.38 (m, 1H), 6.06 (s, 1H), 4.96 (t, J = 5.0 Hz, 1H), 3.64 (tt, J = 10.0, 5.0 Hz, 2H), 1.53 (s, 3H). 13C NMR (125 MHz, CDCl3) δ177.89, 152.88, 135.20, 126.17, 125.18, 122.94, 121.86, 75.74, 69.96, 25.54.
the statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (13)
1. C2 substituted 2HA preparation method of (E) -benzothiazole hydroxyl alkylated derivative, which is characterized in that the substituted 2 shown in the formula (II)HMixing benzothiazole and fatty alcohol shown as a formula (III), taking an organic dye photosensitizer as a catalyst, carrying out normal-temperature stirring reaction in a solvent under the protection of nitrogen and the irradiation of an LED white light lamp, and after TLC (thin layer chromatography) monitoring is carried out until the reaction is finished, separating and purifying reaction liquid to obtain C2 substituted 2 shown as a formula (I)H-a benzothiazole hydroxyalkylated derivative;
in the formulae (I) and (III), the substituent R1Selected from hydrogen or C1-C2 alkyl; substituent R2Selected from hydrogen, C1-C4 alkyl or C1-C2 hydroxyalkyl;
in the formulae (I) and (II), 2H-benzothiaH on the azole ring is mono-, poly-or unsubstituted with a substituent R, and 2H-the C2 position of the benzothiazole ring is not substituted by a substituent R; n is an integer of 0 to 4, and n represents 2H-the number of substituents R on the benzothiazole ring; when n =0, represents 2H-H on the benzothiazole ring is unsubstituted; when n =1, represents 2H-H on the benzothiazole ring is monosubstituted with a substituent R; when n =2~4, represents 2H-H on the benzothiazole ring is polysubstituted with a substituent R, the substituents R in different substitution positions being identical or different; the substituent R is hydrogen, C1-C4 alkyl, C1-C2 alkoxy, cyano, halogen or nitro; the organic dye photosensitizer is Eosin B or Rose Bengal.
2. A C2 substitution 2 according to claim 1HA process for the preparation of a benzothiazolyl hydroxyalkylated derivative, characterized in that in formula (I) and formula (II), n = an integer of 0 to 1.
3. A C2 substitution 2 according to claim 1HA process for the preparation of (a) a benzothiazole hydroxyalkylated derivative, characterized in that in formula (I) and formula (III) the substituent R1Is hydrogen or methyl; substituent R2Is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl or hydroxymethyl.
4. A C2 substitution 2 according to claim 1H-a process for the preparation of a benzothiazolyloxyalkylated derivative, characterized in that in formula (I) and formula (II), (R) n is hydrogen, 6-methoxy, 6-cyano, 5-chloro or 6-nitro; in the formulae (I) and (III), R1Is hydrogen or methyl, R2Hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or hydroxymethyl.
5. A C2 substitution 2 according to claim 1HA process for the preparation of (a) -benzothiazole hydroxyalkylated derivatives, characterized by the substitution 2 as shown in formula (II)H-benzothiazole, the amount of the fatty alcohol represented by formula (III) is 1: 5.0-50.0.
6. A C2 substitution 2 according to claim 1HA preparation method of (E) -benzothiazole hydroxyl alkylated derivative, which is characterized in that the dosage of an organic dye photosensitizer is substituted 2 shown as a formula (II)H1.0 to 10.0 mol% of benzothiazole.
7. A C2 substitution 2 according to claim 1HA process for the preparation of a hydroxy alkylated derivative of benzothiazole characterised in that the solvent is acetonitrile, tetrahydrofuran.
8. A C2 substitution 2 according to claim 1HThe preparation method of the benzothiazole hydroxyl alkylated derivative is characterized in that the power of an LED white light lamp is 10-50W; the stirring reaction time is 8-38 hours.
9. A C2 substitution 2 according to claim 1HA process for the preparation of (a) -benzothiazole hydroxyalkylated derivatives, characterized by the substitution 2 as shown in formula (II)H-benzothiazole, the amount of the fatty alcohol represented by formula (III) is 1: 10.0-30.0.
10. A C2 substitution 2 according to claim 1HA preparation method of (E) -benzothiazole hydroxyl alkylated derivative, which is characterized in that the dosage of an organic dye photosensitizer is substituted 2 shown as a formula (II)H1.5 to 5.0 mol% of benzothiazole.
11. A C2 substitution 2 according to claim 1H-a process for the preparation of a hydroxy alkylated derivative of benzothiazole characterised in that the solvent is acetonitrile.
12. A C2 substitution 2 according to claim 1HThe preparation method of the benzothiazole hydroxyl alkylated derivative is characterized in that the power of an LED white light lamp is 20-40W; the stirring reaction time is 16-30 hours.
13. A C2 substitution 2 according to claim 1HA method for preparing benzothiazole hydroxyalkylated derivatives, which is characterized in that the method for separating and purifying reaction liquid comprises the following steps: after the reaction is finished, concentrating the reaction solution to remove the solvent, and carrying out column chromatography separation on the concentrated solution to obtain C2 substituted 2 shown in the formula (I)HAnd (3) a benzothiazole hydroxyalkylation derivative, wherein an eluant adopted by column chromatography is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 1-10: 1.
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