CN113861223A - Synthesis method and application of thiazolo [3,2-a ] benzimidazole compound - Google Patents
Synthesis method and application of thiazolo [3,2-a ] benzimidazole compound Download PDFInfo
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Abstract
The invention provides a synthesis method of thiazolo [3,2-a ] benzimidazole compounds, which has the advantages that alkyne does not need to be functionalized in advance, and the synthesis steps are simple; the reaction condition is mild, and the reaction can be carried out at room temperature, so that the energy consumption generated in the reaction process is greatly reduced; and simultaneously has the advantage of good functional group compatibility. The method can also provide a new path for synthesizing the drug molecule, namely the thiaclomidazole.
Description
Technical Field
The invention belongs to the technical field of chemical substances and preparation thereof. More particularly, relates to a synthesis method and application of a thiazolo [3,2-a ] benzimidazole compound.
Background
Thiazolo [3,2-a ] benzimidazole is a core structural unit which forms a plurality of natural products and has bioactive molecules, and is an active compound with a special structure because the thiazolo [3,2-a ] benzimidazole contains heteroatoms with stronger electronegativity of sulfur and nitrogen and has stronger intermolecular force with a plurality of biological macromolecules, and the thiazolo [3,2-a ] benzimidazole is widely concerned in drug design (chem.Rev.2016,116, 7818; chem.Rev.2014,114, 10369). Thiazolo [3,2-a ] benzimidazoles are synthetic raw materials for various drug molecules, such as the drug molecule, tichloromisole (Tilomisole), which has a good inhibitory effect on colon cancer cells (j.med.chem.1976,19,524); compound B (Neuroscience 2009,163,933) which is a highly selective glutamate receptor antagonist; compound C (j.med.chem.2011,54,949) having good antioxidant activity; compound D (bioorg.med.chem.2015,23,6317), applicable for brain imaging in alzheimer patients, has the following molecular structure:
synthetic chemists have developed a variety of synthetic methods for thiazolo [3,2-a ] benzimidazoles, such as Subhajit Mishra et al, by cyclization with alkynes, reactive alkenes and carbonyl compounds starting with 2-mercaptobenzimidazoles (org. Lett.2014,16,6084; Green chem.2017,19, 4294; chem. Commun.2019,55,1813; J. org. chem.2014,79,10367; adv. Synth. Cat.2018, 360, 2402; org. Lett.2020,22,8261). However, the starting material of the reaction is limited to 2-mercaptobenzimidazole, which is not beneficial to product diversity modification; the alkyne and the olefin used need to be functionalized in advance, and the synthesis step is longer; high-temperature heating is needed in the reaction process, the reaction conditions are harsh, and the compatibility of functional groups is limited.
Disclosure of Invention
The invention aims to solve the technical problems of complex synthesis steps, harsh reaction conditions and limited functional group compatibility of the existing synthesis method of the thiazolo [3,2-a ] benzimidazole compound and provides the synthesis method of the thiazolo [3,2-a ] benzimidazole compound, which has simple synthesis steps, mild reaction conditions and good functional group compatibility.
Another objective of the present invention is to provide a method for synthesizing tichloromiso.
The above purpose of the invention is realized by the following technical scheme:
a synthetic method of a thiazolo [3,2-a ] benzimidazole compound comprises the following steps:
dissolving o-iodophenyl isothiocyanate 1 and propargylamine compounds 2 in an organic solvent, adding a copper catalyst, alkali and a ligand, reacting completely in an inert gas atmosphere, and separating to obtain the compound, wherein the synthesis steps are shown as formula (I):
wherein R is1Is one of hydrogen, methyl, tert-butyl, methoxy, fluorine, bromine and trifluoromethyl; r2Is one of methyl, ethyl and benzyl; r3Is one of hydrogen, methyl and phenyl.
Preferably, the molar ratio of the o-iodophenyl isothiocyanate 1 to the propargylamine compounds 2 is 1: 1-1: 3.
Preferably, the organic solvent is any one of DMF, DMSO, EtOH, MeOH, MeCN.
More preferably, the organic solvent is DMSO.
Preferably, the catalyst is CuI, CuBr, CuCl, CuCN, CuOTf, CuSO4，CuCl2， Cu(OAc)2Any one of them.
More preferably, the catalyst is CuI.
Preferably, the molar amount of the catalyst is 5-20% of the molar amount of o-iodophenyl isothiocyanate.
Preferably, the base is K2CO3、Cs2CO3、K3PO4NaOH, KOH, CSOH, CsF.
More preferably, the base is K3PO4。
Preferably, the molar amount of the base is 2-4 times of that of the o-iodophenyl isothiocyanate.
Preferably, the ligand is 2, 2' -bipyridine or 1, 10-phenanthroline.
More preferably, the ligand is 1, 10-phenanthroline.
Preferably, the molar amount of the ligand is 5-20% of that of the o-iodophenyl isothiocyanate.
Preferably, the inert gas is nitrogen or argon.
Preferably, the reaction temperature is 25-100 ℃.
Preferably, the reaction time is 1-24 h.
More preferably, the temperature of the reaction is 25 ℃.
More preferably, the reaction time is 8 h.
Preferably, the method of separation is column chromatography.
The invention also provides a method for synthesizing the tichloraz (Tilomiosole), which comprises the following steps:
s1, carrying out bromination oxidation reaction on a thiazolo [3,2-a ] benzimidazole compound 3a to generate a compound 4;
s2, carrying out Suzuki coupling reaction on the compound 4 and 4-chlorobenzene boric acid under the condition of a palladium catalyst to obtain a compound 5;
s3, carrying out condensation reaction on the compound 5 and sodium trichloroacetate, and hydrolyzing to obtain a drug molecule, namely the thiaclomidazole;
the synthesis steps are shown as a formula (II):
the thiazolo [3,2-a ] benzimidazole compound 3a is obtained by dissolving o-iodophenyl isothiocyanate 1 and propargylamine compound 2 in an organic solvent, adding a copper catalyst, alkali and a ligand, reacting in an inert gas atmosphere, and separating,
wherein R is1Is hydrogen; r2Is methyl; r3Is hydrogen.
Preferably, in step s1. the bromooxidation employs N-bromosuccinimide as a reagent.
Preferably, in step s2. the palladium catalyst is a zero-valent palladium catalyst or a divalent palladium catalyst. As an example, the palladium catalyst may be Pd (PPh)3)4，Pd(OAc)2Or PdCl2One kind of (1).
Compared with the prior art, the invention has the following beneficial effects:
the invention provides a synthesis method of thiazolo [3,2-a ] benzimidazole compounds, which has the advantages that alkyne does not need to be functionalized in advance, and the synthesis steps are simple; the reaction condition is mild, and the reaction can be carried out at room temperature, so that the energy consumption generated in the reaction process is greatly reduced; and simultaneously has the advantage of good functional group compatibility. The method can also provide a new path for synthesizing the drug molecule, namely the thiaclomidazole.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way. The reagents, methods and apparatus employed in the present invention are conventional in the art, unless otherwise specified.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1
To a reaction flask containing 52.0mg (0.2mmol) of o-iodophenyl isothiocyanate 1a and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen atmosphere for 8 hours, and then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3a (29.4mg, yield: 78%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.73 (d,J＝8.0Hz,1H),7.66(d,J＝8.0Hz,1H),7.39(t,J＝7.6Hz,1H),7.29(t,J＝8.0 Hz,1H),7.01(s,1H),2.67(s,3H)；13C NMR(100MHz,CDCl3)，δ146.7,133.3, 131.9,130.6,125.8,124.3,124.2,124.1,112.5,11.14；HRMS calcd for C10H9N2S+ (M+H)+189.0481,found 189.0481.
Example 2
To a reaction flask containing 56.0mg (0.2mmol) of o-iodophenyl isothiocyanate 1b and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethylsulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen for 8 hours, and then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3ba (33.0mg, yield: 80%) as a white solid.1H NMR(400MHz,CDCl3),δ7.63 (q,J＝4.4Hz,1H),7.37(dd,J＝8.0,2.4Hz,1H),7.09(td,J＝8.8,2.8Hz,1H),6.99 (s,1H),2.63(s,3H)；13C NMR(100MHz,CDCl3),δ159.2(d,J＝243.0Hz),146.3, 132.0(d,J＝10.0Hz),131.9,129.8,124.1,113.3(d,J＝23.0Hz),113.1(d,J＝7.0 Hz),111.2(d,J＝27.0Hz),10.9；HRMS calcd for C10H8FN2S+(M+H)+,207.0387, found 207.0382.
Example 3
To a reaction flask containing 59.0mg (0.2mmol) of o-iodophenyl isothiocyanate 1c and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, followed by stirring at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was isolated by column chromatography to give 3ca (37.3mg, yield: 84%) as a white solid.1H NMR(400MHz,CDCl3),δ7.58 (m,2H),7.31(dd,J＝8.4,2.4Hz,1H),6.98(s,1H),2.61(s,3H)；13C NMR(100 MHz,CDCl3),δ146.3,132.1,132.0,131.7,129.6,126.0,124.2,123.9,113.0,10.9； HRMS calcd for C10H8ClN2S+(M+H)+223.0091,found 223.0087.
Example 4
To a reaction flask containing 67.6mg (0.2mmol) of o-iodophenyl isothiocyanate 1d and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen atmosphere for 8 hours, then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3da (39.9mg, yield: 75%) as a white solid.1H NMR(400MHz,CDCl3),δ7.75 (d,J＝1.6Hz,1H),7.54(d,J＝8.4Hz,1H),7.46(dd,J＝8.8,2.0Hz,1H),7.00(s, 1H),2.69(s,3H)；13C NMR(100MHz,CDCl3),δ146.3,132.4,132.2,132.1,128.8, 126.7,124.2,116.8,113.4,11.0；HRMS calcd for C10H8BrN2S+(M+H)+266.9586, found 266.9581.
Example 5
To a reaction flask containing 65.6mg (0.2mmol) of o-iodophenyl isothiocyanate 1e and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethylsulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen atmosphere for 8 hours, and then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3ea (34.8mg, yield: 68%) as a white solid.1H NMR(400MHz,CDCl3),δ7.94 (s,1H),7.80(d,J＝8.4Hz,1H),7.65(d,J＝8.4Hz,1H),7.05(s,1H),2.68(s, 3H)；13C NMR(100MHz,CDCl3),δ147.0,135.3,132.7,131.3,126.6(q,J＝33.0 Hz),124.4,123.7(q,J＝270.0Hz),123.1(q,J＝4.0Hz),121.6(q,J＝4.0Hz),112.4, 11.1；HRMS calcd for C11H8F3N2S+(M+H)+257.0355,found 257.0353.
Example 6
To a reaction flask containing 54.8mg (0.2mmol) of o-iodophenyl isothiocyanate 1f and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, and the mixture was stirred at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by removal of the solvent by concentration under reduced pressure, and the residue was separated by column chromatography to give 3fa (28.2mg, yield: 70%) as a white solid.1H NMR(400MHz,CDCl3), δ7.54(d,J＝8.4Hz,1H),7.41(s,1H),7.13(dd,J＝8.4,0.8Hz,1H),6.96(s,1H), 2.61(s,3H),2.40(s,3H)；13C NMR(100 MHz,CDCl3),δ146.4,134.1,131.5,131.1, 130.5,126.6,124.2,123.9,112.0,21.1,11.0；HRMS calcd for C11H11N2S+(M+H)+ 203.0637,found 203.0633.
Example 7
To a reaction flask containing 58.2mg (0.2mmol) of o-iodophenyl isothiocyanate 1g and 13.2mg (0.24mmol) of propargylamine 2a were added, respectively, in order, 2mL of dried dimethylsulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand, followed by stirring at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was isolated by column chromatography to give 3ga (29.2mg, yield: 67%)1H NMR(400MHz,CDCl3), δ7.62(d,J＝8.8Hz,1H),7.18(d,J＝2.4z,1H),6.97(s,1H),6.95(dd,J＝8.8,2.4 Hz),3.86(s,3H),2.64(s,3H)；13C NMR(100MHz,CDCl3),δ156.60,146.09, 131.97,131.42,127.54,123.89,113.00(d,J＝16.7Hz),108.71,77.32,77.00,76.68, 55.84,11.00；HRMS calcd for C11H11N2OS+(M+H)+219.0687,found 219.0587.
Example 8
To a reaction flask containing 55.8mg (0.2mmol) of o-iodophenyl isothiocyanate for 1 hour and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, and the mixture was stirred at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was isolated by column chromatography to give 3ha (31.3mg, yield: 76%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.59 (dd,J＝8.8,5.2Hz,1H),7.45(dd,J＝8.8,2.4Hz,1H),7.08～6.98(m,2H),2.65(s, 3H)；13C NMR(100MHz,CDCl3)，δ161.1(d,J＝243.0Hz),147.8,133.6(d,J＝ 11.0Hz),132.2,125.6,125.0(d,J＝9.0Hz),124.0,111.8(d,J＝34.0Hz),100.8(d,J ＝38.0Hz),10.9；HRMS calcd for C10H8FN2S+(M+H)+207.0387,found 207.0384.
Example 9
To a reaction flask containing 58.9mg (0.2mmol) of o-iodophenyl isothiocyanate 1i and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen atmosphere for 8 hours, and then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3ia (35.9mg, yield: 81%) as a white solid.1H NMR(400MHz, CDCl3)，δ7.66(d,J＝2.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.26～7.23(m,1H),7.00 (s,1H),2.63(s,3H)；13C NMR(100MHz,CDCl3)，δ147.1,133.7,132.3,131.7, 128.8,124.9,124.3,124.1,112.8,11.0；HRMS calcd for C10H8ClN2S+(M+H)+ 223.0091,found 223.0089.
Example 10
To a reaction flask containing 67.6mg (0.2mmol) of o-iodophenyl isothiocyanate 1j and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, and the mixture was stirred at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was isolated by column chromatography to give 3ja (39.9mg, yield: 75%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.79 (d,J＝1.6Hz,1H),7.48(d,J＝8.4Hz,1H),7.37(dd,J＝8.4,1.6Hz,1H),6.99(s, 1H),2.63(s,3H)；13C NMR(100MHz,CDCl3)，δ146.8,133.9,132.3,129.4,127.1, 125.2,124.1,119.0,115.6,11.0；HRMS calcd for C10H8BrN2S+(M+H)+266.9586, found 266.9584.
Example 11
To a reaction flask containing 55.0mg (0.2mmol) of o-iodophenyl isothiocyanate 1k and 13.2mg (0.24mmol) of propargylamine 2a were added 2mL of dried dimethylsulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, stirred at 25 ℃ under nitrogen for 8 hours, and then the solvent was removed by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3ka (28.6mg, yield: 71%) as a white solid.1H NMR(400MHz,CDCl3)，δ 7.54～7.48(m,2H),7.10(dd,J＝8.4,0.8Hz,1H),6.98(d,J＝1.2Hz,1H),2.66(d,J ＝1.2Hz,3H),2.47(s,3H)；13C NMR(100MHz,CDCl3)，δ147.1,136.1,133.4, 131.8,127.2,125.2,124.0,123.8,113.0,21.6,11.2；HRMS calcd for C11H11N2S+ (M+H)+203.0637,found 203.0638.
Example 12
To a reaction flask containing 58mg (0.2mmol) of o-iodophenyl isothiocyanate 1l and 13.2mg (0.24mmol) of propargylamine 2a were added, in this order, dried dimethylsulfoxide 2mL, cuprous iodide 3.8mg (0.02mmol), potassium phosphate 127.2mg (0.6mmol) and 1, 10-phenanthroline ligand 7.2mg (0.04mmol) under nitrogen at 25 ℃ for 8 hours, respectively, followed by concentration under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3la (29.6mg, yield: 68%) as a white solid.1H NMR(400MHz, CDCl3)，δ7.51(d,J＝8.8Hz,1H),7.27(d,J＝2.4Hz,1H),6.99(s,1H),6.87(dd,J ＝8.8,2.4Hz,1H),3.87(s,3H),2.65(s,3H)；13C NMR(100MHz,CDCl3)，δ158.4, 147.9,134.0,131.9,124.6,123.9,121.7,110.4,99.4,55.8,11.1；HRMS calcd for C11H11N2OS+(M+H)+219.0587,found 219.0586.
Example 13
To a reaction flask containing 55.0mg (0.2mmol) of o-iodophenyl isothiocyanate 1l and 13.2mg (0.24mmol) of propargylamine 2a were added, respectively, in order, 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand, followed by stirring at 25 ℃ under a nitrogen atmosphere for 8 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 3ma (25.8mg, yield: 64%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.54 (d,J＝8.4Hz,1H),7.29(t,J＝8.0Hz,1H),7.09(d,J＝7.6Hz,1H),7.00(s,1H), 2.64(s,3H),2.44(s,3H)；13C NMR(100MHz,CDCl3)，δ146.7,133.8,133.0,131.7, 130.4,125.7,124.7,124.1,109.9,19.9,11.0；HRMS calcd for C11H11N2S+(M+H)+203.0637,found 203.0635.
Example 14
To a reaction flask containing 54mg (0.2mmol) of o-iodophenyl isothiocyanate 1a and 16.8mg (0.24mmol) of propargylamine 2b were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, and the mixture was stirred at 25 ℃ for 8 hours under a nitrogen atmosphere, followed by removal of the solvent by concentration under reduced pressure, and the residue was separated by column chromatography to give 3ab (29.4mg, yield: 73%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.71 (d,J＝8.4Hz,1H),7.64(d,J＝8.0Hz,1H),7.37(t,J＝8.0Hz,1H),7.26(t,J＝8.0 Hz,1H),2.60(s,3H),2.29(s,3H)；13C NMR(100MHz,CDCl3)，δ144.9,139.6, 133.5,130.2,125.7,124.2,123.8,119.3,112.1,13.0,10.3；HRMS calcd for C11H11N2S+(M+H)+203.0637,found 203.0638.
Example 15
To a reaction flask containing 54mg (0.2mmol) of o-iodophenyl isothiocyanate 1a and 31.4mg (0.24mmol) of propargylamine 2c were added 2mL of dried dimethyl sulfoxide, 3.8mg (0.02mmol) of cuprous iodide, 127.2mg (0.6mmol) of potassium phosphate and 7.2mg (0.04mmol) of 1, 10-phenanthroline ligand in this order, and the mixture was stirred at 25 ℃ for 8 hours under a nitrogen atmosphere, followed by removal of the solvent by concentration under reduced pressure, and the residue was isolated by column chromatography to give 3ac (32.2mg, yield: 61%) as a white solid.1H NMR(400MHz,CDCl3)，δ7.78 (d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),7.48～7.31(m,7H),7.28～7.23(m,1H), 4.12(s,2H)；13C NMR(100MHz,CDCl3)，δ156.4,147.4,137.3,129.4,128.9,128.6, 127.9,127.3,123.1,120.8,119.1,114.1,110.0,35.0；HRMS calcd for C16H13N2S+(M H)+265.0794,found 265.0795.
Example 16
Synthesis of Compound 4: to a reaction flask containing 38mg (0.2mmol) of compound 3a, 107mg (0.6mmol) of N-bromosuccinimide (NBS) and 3.2mg (0.02mmol) of Azobisisobutyronitrile (AIBN), respectively, 2mL of carbon tetrachloride was added in this order under an oxygen atmosphere to react at 80 ℃ for 12 hours, followed by concentration under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 4(18mg, yield: 32%) as a white solid.1H NMR(400MHz,CDCl3),δ9.84(s,1H),9.15(d,J＝8.4Hz,1H),7.75(dd,J＝8.0,0.8Hz,1H),7.59～7.52(m,1H),7.50～7.44(m,1H)；13C NMR(100MHz,CDCl3)， 176.6,153.9,135.5,133.4,129.0,127.1,126.7,126.3,123.5,118.6；HRMS calcd for C10H6BrN2OS+(M+H)+280.9379,found 280.9382.
Synthesis of Compound 5: to a reaction flask containing 56mg (0.2mmol) of compound 4, 31mg (0.2mmol) of p-chlorobenzeneboronic acid and 23mg (0.02mmol) of tetratriphenylphosphine palladium were added 2mL of methanol and 39mg (0.3mmol) of potassium carbonate, respectively, in this order under an argon atmosphere, reacted at room temperature for 6 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to give 5(52mg, yield: 83%) as a white solid.1H NMR(400MHz,CDCl3)，δ9.65(s,1H),7.78(d,J＝8.4Hz,1H),7.72～7.66(m, 4H),7.41～7.35(m,1H),7.14～7.08(m,1H),6.98(d,J＝8.2Hz,1H)；13C NMR(100 MHz,CDCl3)，δ182.5,155.6,149.3,142.1,138.5,131.3,129.9,129.7,126.4,125.2, 124.2,121.9,119.9,111.9；HRMS calcd for C16H10ClN2OS+(M+H)+313.0197,found 313.0195.
Synthesis of tichloromiso (Tilomiosole): to a reaction vessel containing 62.4mg (0.2mmol) of Compound 5 and 56.1mg (0.3mmol) of trichloroethylene in this orderAdding 2mL of tert-butyl alcohol into a reaction bottle of sodium acid, stirring for 8 hours at 35 ℃, then dropwise adding an aqueous solution of sodium hydroxide until the pH value is 8-9, then adding 19mg (0.5mmol) of sodium borohydride, stirring for half an hour, after the reaction is finished, adjusting the reaction solution to be weakly acidic by using an acetic acid solution, extracting by using ethyl acetate, concentrating, drying an organic phase, and finally performing column chromatography to obtain yellow solid 6 (thiaclimax) (27.4mg, yield: 40%).1H NMR(400MHz,DMSO)，δ12.95(s,1H),7.75～7.65(m,5H),7.26 (t,J＝7.8Hz,1H),7.04(t,J＝7.8Hz,1H),6.79(d,J＝8.0Hz,1H),3.70(s,2H)；13C NMR(100MHz,DMSO)，δ170.7,154.6,147.5,135.3,131.9,129.5,129.4,128.8, 126.4,123.0,120.5,118.6,117.8,110.8,32.8；HRMS calcd for C17H12ClN2O2S+ (M+H)+343.0303,found 343.0301.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A synthetic method of a thiazolo [3,2-a ] benzimidazole compound is characterized by comprising the following steps:
dissolving o-iodophenyl isothiocyanate 1 and propargylamine compounds 2 in an organic solvent, adding a copper catalyst, alkali and a ligand, reacting in an inert gas atmosphere, and separating to obtain the compound, wherein the synthesis steps are shown as formula (I):
wherein R is1Is one of hydrogen, methyl, tert-butyl, methoxy, fluorine, bromine and trifluoromethyl; r2Is one of methyl, ethyl and benzyl; r3Is one of hydrogen, methyl and phenyl.
2. The method of claim 1, wherein the organic solvent is at least one of DMF, DMSO, EtOH, MeOH, and MeCN.
3. The method of claim 1, wherein the copper catalyst is CuI, CuBr, CuCl, CuCN, CuOTf, CuSO4，CuCl2，Cu(OAc)2At least one of (1).
4. The method of claim 1, wherein the base is K2CO3、Cs2CO3、K3PO4At least one of NaOH, KOH, CSOH and CsF.
5. The method of claim 1, wherein the ligand is 2, 2' -bipyridine or 1, 10-phenanthroline.
6. The method of claim 1, wherein the inert gas is nitrogen or argon.
7. A method for synthesizing tichloromiso is characterized by comprising the following steps:
s1, carrying out bromination oxidation reaction on a thiazolo [3,2-a ] benzimidazole compound 3a to generate a compound 4;
s2, carrying out Suzuki coupling reaction on the compound 4 and 4-chlorobenzene boric acid under the condition of a palladium catalyst to obtain a compound 5;
s3, carrying out condensation reaction on the compound 5 and sodium trichloroacetate, and hydrolyzing to obtain a drug molecule, namely the thiaclomidazole;
the synthesis steps are shown as a formula (II):
8. the synthesis method according to claim 7, wherein the thiazolo [3,2-a ] benzimidazole compound 3a is obtained by dissolving o-iodophenyl isothiocyanate 1 and propargylamine compound 2 in an organic solvent, adding a copper catalyst, an alkali and a ligand, reacting in an inert gas atmosphere, and separating,
wherein R is1Is hydrogen; r2Is methyl; r3Is hydrogen.
9. The synthesis method according to claim 7, wherein in step S1, N-bromosuccinimide is used as a reagent in the bromination oxidation.
10. The synthesis method according to claim 7, wherein in step S2, the palladium catalyst is a zero-valent palladium catalyst or a divalent palladium catalyst.
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