CN113861223B - A kind of synthetic method and application of thiazolo[3,2-a]benzimidazole compounds - Google Patents

Abstract

The invention provides a method for synthesizing thiazolo[3,2-a]benzimidazole compounds. The synthesizing method does not require pre-functionalization of alkynes, and the synthesis steps are simple; the reaction conditions are mild, and the reaction can be performed at room temperature. Reduce the energy consumption during the reaction process; at the same time, it also has the advantage of good functional group compatibility. The method can also provide a new route for synthesizing the drug molecule ticlomisole.

Description

A kind of synthetic method and application of thiazolo[3,2-a]benzimidazole compounds

technical field

The invention belongs to the technical field of chemical substances and their preparation. More specifically, it relates to a method for synthesizing a thiazolo[3,2-a]benzimidazole compound and its application.

Background technique

Thiazolo[3,2-a]benzimidazole is the core structural unit that constitutes many natural products and biologically active molecules, because it contains highly electronegative heteroatoms such as sulfur and nitrogen, which are closely related to many biological macromolecules. It has strong intermolecular force and is a kind of active compound with special structure, which has attracted wide attention in drug design (Chem. Rev. 2016, 116, 7818; Chem. Rev. 2014, 114, 10369). Thiazolo[3,2-a]benzimidazoles are the raw materials for the synthesis of various drug molecules, such as the drug molecule Tilomisole, which has a good inhibitory effect on colon cancer cells (J.Med.Chem.1976 , 19, 524); Compound B with high selectivity glutamate receptor antagonist (Neuroscience2009, 163, 933); Compound C with good antioxidant activity (J.Med.Chem.2011,54,949); Can be applied to Alzheimer’s disease Compound D (Bioorg.Med.Chem.2015, 23, 6317) for brain imaging of silent patients, its molecular structure is as follows:

Synthetic chemists have developed a variety of synthetic methods for thiazolo[3,2-a]benzimidazoles, such as Subhajit Mishra et al. Obtained by cyclization of olefins and carbonyl compounds (Org. Lett. 2014, 16, 6084; Green Chem. 2017, 19, 4294; Chem. Commun. 2019, 55, 1813; J. Org. Chem. 2014, 79, 10367; Adv. Synth. Catal. 2018, 360, 2402; Org. Lett. 2020, 22, 8261). However, the starting material of this reaction is limited to 2-mercaptobenzimidazole, which is not conducive to the modification of product diversity; the alkynes and alkenes used need to be functionalized in advance, and the synthesis steps are long; high temperature heating is required during the reaction process, the reaction conditions are harsh, and the functional groups Compatibility is limited.

SUMMARY OF THE INVENTION

The technical problem to be solved by the present invention is to overcome the defects and deficiencies of the existing synthesis methods of thiazolo[3,2-a]benzimidazole compounds, such as complex synthesis steps, harsh reaction conditions, and limited functional group compatibility, and provide a synthetic method of Synthesis of thiazolo[3,2-a]benzimidazoles with simple steps, mild reaction conditions and good functional group compatibility.

Another object of the present invention is to provide a method for synthesizing ticlomisole.

The above-mentioned purpose of the present invention is achieved through the following technical solutions:

A method for synthesizing thiazolo[3,2-a]benzimidazole compounds, comprising the following steps:

The o-iodophenyl isothiocyanate 1 and the propargylamine compound 2 are dissolved in an organic solvent, and then a copper catalyst, a base and a ligand are added to react completely under an inert gas atmosphere, and the separation is obtained. The synthetic step is as shown in the formula (I) shows:

Wherein R ¹ is a kind of hydrogen, methyl, tert-butyl, methoxy, fluorine, bromine, trifluoromethyl; R ² is a kind of methyl, ethyl, benzyl; R ³ is hydrogen , one of methyl and phenyl.

Preferably, the molar ratio of the o-iodophenyl isothiocyanate 1 to the propargylamine compound 2 is 1:1 to 1:3.

Preferably, the organic solvent is any one of DMF, DMSO, EtOH, MeOH, and MeCN.

More preferably, the organic solvent is DMSO.

Preferably, the catalyst is any one of CuI, CuBr, CuCl, CuCN, CuOTf, CuSO ₄ , CuCl ₂ , and Cu(OAc) ₂ .

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 any one of K ₂ CO ₃ , Cs ₂ CO ₃ , K ₃ PO ₄ , NaOH, KOH, CSOH, and CsF.

More preferably, the base is K ₃ PO ₄ .

Preferably, the molar amount of the base is 2-4 times that of 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 the o-iodophenyl isothiocyanate.

Preferably, the inert gas is nitrogen or argon.

Preferably, the temperature of the reaction is 25-100°C.

Preferably, the reaction time is 1-24 h.

More preferably, the temperature of the reaction is 25°C.

More preferably, the reaction time is 8h.

Preferably, the separation method is a column chromatography separation method.

The present invention also protects a kind of synthetic method of ticlomisole (Tilomisole), comprises the steps:

S1. Thiazolo[3,2-a]benzimidazole compound 3a undergoes bromination oxidation reaction to generate compound 4;

S2. compound 4 and 4-chlorophenylboronic acid generate Suzuki coupling reaction under the condition of palladium catalyst to obtain compound 5;

S3. Compound 5 is condensed with sodium trichloroacetate, and hydrolyzed to obtain the drug molecule Ticlomisole;

The synthetic steps are shown in 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, and then adding a copper catalyst, a base and a ligand. It can be obtained by separation after reaction under inert gas atmosphere,

Wherein R ¹ is hydrogen; R ² is methyl; R ³ is hydrogen.

Preferably, in step S1., the bromooxidation uses 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 one of Pd(PPh ₃ ) ₄ , Pd(OAc) ₂ or PdCl ₂ .

Compared with the prior art, the present invention has the following beneficial effects:

The invention provides a method for synthesizing thiazolo[3,2-a]benzimidazole compounds. The synthesizing method does not require pre-functionalization of alkynes, and the synthesis steps are simple; the reaction conditions are mild, and the reaction can be performed at room temperature. Reduce the energy consumption in the reaction process; at the same time, it also has the advantage of good functional group compatibility. The method can also provide a new route for synthesizing the drug molecule ticlomisole.

Detailed ways

The present invention is further described below in conjunction with specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

Example 1

To the reaction flasks containing 52.0 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1a and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3a as a white solid (29.4 mg, yield: 78%). ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.73 (d, J=8.0 Hz, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.39 (t, J=7.6 Hz, 1H), 7.29 ( t, J=8.0 Hz, 1H), 7.01 (s, 1H), 2.67 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 146.7, 133.3, 131.9, 130.6, 125.8, 124.3, 124.2, 124.1, 112.5, 11.14; HRMS calcd for C ₁₀ H ₉ N ₂ S ⁺ (M+H) ⁺ 189.0481, found 189.0481.

Example 2

To the reaction flask containing 56.0 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1b and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ba as a white solid (33.0 mg, yield: 80%). ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.63 (q, J=4.4 Hz, 1H), 7.37 (dd, J=8.0, 2.4 Hz, ¹ H), 7.09 (td, J=8.8, 2.8 Hz, 1H), 6.99 (s, 1H), 2.63 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 159.2 (d, J=243.0 Hz), 146.3, 132.0 (d, J=10.0 Hz) , 131.9, 129.8, 124.1, 113.3 (d, J = 23.0 Hz), 113.1 (d, J = 7.0 Hz), 111.2 (d, J = 27.0 Hz), 10.9; HRMS calcd for C ₁₀ H ₈ FN ₂ S ⁺ (M+H) ⁺ ,207.0387, found207.0382.

Example 3

To the reaction flask containing 59.0 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1c and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ca as a white solid (37.3 mg, yield: 84%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.58 (m, 2H), 7.31 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (s, 1H), 2.61 (s, 3H); ¹³ CNMR ( 100 MHz, CDCl ₃ ), δ146.3, 132.1, 132.0, 131.7, 129.6, 126.0, 124.2, 123.9, 113.0, 10.9; HRMS calcd for C ₁₀ H ₈ ClN ₂ S ⁺ (M+H) ⁺ 223.0091, found 223.0087.

Example 4

To the reaction flask containing 67.6 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1d and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3da as a white solid (39.9 mg, yield: 75%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.75 (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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 146.3, 132.4, 132.2, 132.1, 128.8, 126.7, 124.2, 116.8, 113.4, 11.0; HRMS calcd for C ₁₀ H _{8BrN 2} S ⁺ (M+H) ⁺ 266.9586, found 266.9581.

Example 5

To the reaction flasks containing 65.6 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1e and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ea as a white solid (34.8 mg, yield: 68%). ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.94 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.05 (s, 1H), 2.68 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 147.0, 135.3, 132.7, 131.3, 126.6 (q, J=33.0 Hz), 124.4, 123.7 (q, J=270.0 Hz), 123.1 (q , J=4.0Hz), 121.6 (q, J=4.0Hz), 112.4, 11.1; HRMS calcd for C ₁₁ H ₈ F ₃ N ₂ S ⁺ (M+H) ⁺ 257.0355, found 257.0353.

Example 6

To the reaction flask containing 54.8 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1f and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3fa as a white solid (28.2 mg, yield: 70%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.54 (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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 146.4, 134.1, 131.5, 131.1, 130.5, 126.6, 124.2, 123.9, 112.0, 21.1, 11.0; HRMS calcd for C ₁₁ H ₁₁ N ₂ S+(M+H)+203.0637, found 203.0633.

Example 7

To the reaction flask containing 58.2 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1 g and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave white solid 3ga (29.2 mg, yield: 67%) ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.62 (d, J=8.8 Hz, 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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 156.60, 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 C ₁₁ H ₁₁ N ₂ OS ⁺ (M+H) ⁺ 219.0687, found 219.0587 .

Example 8

To the reaction flasks containing 55.8 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1h and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, were added 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dimethyl sulfoxide. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ha as a white solid (31.3 mg, yield: 76%). ¹ H NMR (400MHz, CDCl ₃ ), 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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 161.1 (d, J=243.0 Hz), 147.8, 133.6 (d, J= 11.0 Hz), 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 C ₁₀ H ₈ FN ₂ S ⁺ (M+H) ⁺ 207.0387, found 207.0384.

Example 9

To the reaction flask containing 58.9 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1i and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ia as a white solid (35.9 mg, yield: 81%). ¹ H NMR (400MHz, CDCl ₃ ), 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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 147.1, 133.7, 132.3, 131.7, 128.8, 124.9, 124.3, 124.1, 112.8, 11.0; HRMS calcd for C ₁₀ H ₈ ClN ₂ S ⁺ (M+H) ⁺ 223.0091, found223.0089.

Example 10

To the reaction flasks containing 67.6 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1j and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ja as a white solid (39.9 mg, yield: 75%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.79 (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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 146.8, 133.9, 132.3, 129.4, 127.1, 125.2, 124.1, 119.0, 115.6, 11.0; HRMS calcd for C ₁₀ H ₈ BrN ₂ S ⁺ (M+H) ⁺ 266.9586, found 266.9584.

Example 11

To the reaction flask containing 55.0 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1k and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ka as a white solid (28.6 mg, yield: 71%). ¹ H NMR (400MHz, CDCl ₃ ), 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 = 1.2 Hz, 3H), 2.47 (s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 147.1, 136.1, 133.4, 131.8, 127.2, 125.2, 124.0, 123.8, 113.0, 21.6, 11.2; HRMS calcd for C ₁₁ H ₁₁ N ₂ S ⁺ (M+H) ⁺ 203.0637, found 203.0638.

Example 12

Under a nitrogen atmosphere, 2 mL of dry dimethyl sulfoxide, 3.8 mg of dry dimethyl sulfoxide were added to the reaction flask containing 58 mg (0.2 mmol) of o-iodophenyl isothiocyanate 11 and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively. (0.02 mmol) cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C for 8 hours under nitrogen atmosphere, and then concentrated under reduced pressure to remove the solvent, The residue was separated by column chromatography to obtain 3la as a white solid (29.6 mg, yield: 68%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.51 (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); ¹³ C NMR (100MHz, CDCl ₃ ), δ 158.4, 147.9, 134.0, 131.9, 124.6, 123.9, 121.7, 110.4, 99.4 , 55.8, 11.1; HRMS calcd for C ₁₁ H ₁₁ N ₂ OS ⁺ (M+H) ⁺ 219.0587, found 219.0586.

Example 13

To the reaction flasks containing 55.0 mg (0.2 mmol) of o-iodophenyl isothiocyanate 11 and 13.2 mg (0.24 mmol) of propargylamine 2a, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of dry dimethyl sulfoxide were added. Cuprous iodide, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was passed through a column Chromatography gave 3ma as a white solid (25.8 mg, yield: 64%). ¹ H NMR (400 MHz, CDCl ₃ ), δ 7.54 (d, J=8.4 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.09 (d, J=7.6 Hz, 1H), 7.00 ( s, 1H), 2.64(s, 3H), 2.44(s, 3H); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 146.7, 133.8, 133.0, 131.7, 130.4, 125.7, 124.7, 124.1, 109.9, 19.9, 11.0 ;HRMS calcd for C ₁₁ H ₁₁ N ₂ S ⁺ (M+H) ⁺ 203.0637, found 203.0635.

Example 14

To the reaction flask containing 54 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1a and 16.8 mg (0.24 mmol) of propargylamine 2b, respectively, 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of iodine were added. Cuprous compound, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography 3ab was isolated as a white solid (29.4 mg, yield: 73%). ¹ H NMR (400MHz, CDCl ₃ ), δ 7.71 (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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 144.9, 139.6, 133.5, 130.2, 125.7, 124.2, 123.8, 119.3, 112.1, 13.0, 10.3; HRMS calcd for C ₁₁ H ₁₁ N ₂ S ⁺ (M+H) ⁺ 203.0637, found 203.0638.

Example 15

To the reaction flask containing 54 mg (0.2 mmol) of o-iodophenyl isothiocyanate 1a and 31.4 mg (0.24 mmol) of propargylamine 2c, respectively, were added 2 mL of dry dimethyl sulfoxide, 3.8 mg (0.02 mmol) of iodine Cuprous compound, 127.2 mg (0.6 mmol) potassium phosphate and 7.2 mg (0.04 mmol) 1,10-phenanthroline ligand were stirred at 25°C under nitrogen atmosphere for 8 hours, then concentrated under reduced pressure to remove the solvent, and the residue was subjected to column chromatography 3ac was isolated as a white solid (32.2 mg, yield: 61%). ¹ H NMR (400MHz, CDCl ₃ ), 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 _HRMS ^_ calcd for C ₁₆ H ₁₃ N ₂ S ⁺ (MH) ⁺ 265.0794, found 265.0795.

Example 16

Synthesis of compound 4: Under an oxygen atmosphere, 38 mg (0.2 mmol) of compound 3a, 107 mg (0.6 mmol) of N-bromosuccinimide (NBS) and 3.2 mg (0.02 mmol) of azodiiso 2 mL of carbon tetrachloride was added to the reaction flask of nitrile (AIBN) and reacted at 80° C. for 12 hours, then concentrated under reduced pressure to remove the solvent, and the residue was separated by column chromatography to obtain white solid 4 (18 mg, yield: 32%). ¹ H NMR (400MHz, CDCl ₃ ), δ 9.84 (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); ¹³ C NMR (100MHz, CDCl ₃ ), 176.6, 153.9, 135.5, 133.4, 129.0, 127.1, 126.7, 126.3, 123.5, 118.6; HRMScalcd for C ₁₀ H ₆ BrN ₂ OS ⁺ (M+H) ⁺ 280.9379, found 280.9382.

Synthesis of compound 5: under an argon atmosphere, sequentially add 56 mg (0.2 mmol) of compound 4, 31 mg (0.2 mmol) of p-chlorophenylboronic acid and 23 mg (0.02 mmol) of tetrakistriphenylphosphine palladium to the reaction flask. 2 mL of methanol and 39 mg (0.3 mmol) of potassium carbonate were 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 obtain white solid 5 (52 mg, yield: 83%). ¹ H NMR (400MHz, CDCl ₃ ), δ 9.65(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); ¹³ C NMR (100 MHz, CDCl ₃ ), δ 182.5, 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 C ₁₆ H ₁₀ ClN ₂ OS ⁺ (M+H) ⁺ 313.0197, found313.0195.

Synthesis of Tilomisole: To the reaction flask containing 62.4 mg (0.2 mmol) of compound 5 and 56.1 mg (0.3 mmol) of sodium trichloroacetate, 2 mL of tert-butanol was added and stirred at 35°C for 8 hours, then Aqueous sodium hydroxide solution was added dropwise until the pH was 8 to 9, then 19 mg (0.5 mmol) of sodium borohydride was added and stirred for half an hour. After the reaction was completed, the reaction solution was adjusted to weak acidity with acetic acid solution, extracted with ethyl acetate, and concentrated. , the organic phase was dried, and finally column chromatography gave yellow solid 6 (Ticlomisole) (27.4 mg, yield: 40%). ¹ H 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=8.0 Hz, 1H), 3.70 (s, 2H); ¹³ C NMR (100 MHz, DMSO), δ 170.7, 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 C ₁₇ H ₁₂ ClN ₂ O ₂ S ⁺ (M+H) ⁺ 343.0303, found 343.0301.

The above-mentioned embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited by the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, The simplification should be equivalent replacement manners, which are all included in the protection scope of the present invention.

Claims (6)

1. a synthetic method of thiazolo[3,2-a] benzimidazole compound, is characterized in that, comprises the steps: Dissolve the o-iodophenyl isothiocyanate 1 and the propargylamine compound 2 in an organic solvent, then add a copper catalyst, a base and a ligand to react under an inert atmosphere and separate and obtain, and the synthetic step is such as formula (I ) as shown:

Formula (I); wherein R ¹ is one of hydrogen, methyl, tert-butyl, methoxy, fluorine, bromine, and trifluoromethyl; in compound 2, described R ² is one of hydrogen, methyl, and phenyl ; In compound 3, R ² is a kind of in methyl, ethyl, benzyl; R ³ is a kind of in hydrogen, methyl and phenyl; The copper catalyst is at least one of CuI, CuBr, CuCl, CuCN, and CuOTf; The ligand is 2,2'-bipyridine or 1,10-phenanthroline; Described organic solvent is at least one in DMF, DMSO, EtOH, MeOH, MeCN; The base is at least one of K ₂ CO ₃ , Cs ₂ CO ₃ and K ₃ PO ₄ . 2. The synthetic method according to claim 1, wherein the inert atmosphere is nitrogen or argon. 3. a synthetic method of Ticlomisole, is characterized in that, comprises the steps: S1. Thiazolo[3,2-a]benzimidazole compound 3a undergoes bromination oxidation reaction to generate compound 4; S2. Compound 4 generates Suzuki coupling reaction with 4-chlorophenylboronic acid under the condition of palladium catalyst to obtain compound 5; S3. Compound 5 is condensed with sodium trichloroacetate, and hydrolyzed to obtain the drug molecule Ticlomisole; The synthetic steps are shown in formula (II):

Formula (II). 4. The synthetic method according to claim 3, wherein the thiazolo[3,2-a]benzimidazole compound 3a is a combination of o-iodophenyl isothiocyanate 1 and propargylamine compound 2 Dissolve in organic solvent, then add copper catalyst, alkali and ligand to react under inert gas atmosphere and then separate.

Formula (I); wherein R ¹ is hydrogen; in compound 2, said R ² is hydrogen; in compound 3a, R ² is methyl; R ³ is hydrogen; The copper catalyst is at least one of CuI, CuBr, CuCl, CuCN, and CuOTf; The ligand is 2,2'-bipyridine or 1,10-phenanthroline; Described organic solvent is at least one in DMF, DMSO, EtOH, MeOH, MeCN; The base is at least one of K ₂ CO ₃ , Cs ₂ CO ₃ and K ₃ PO ₄ . 5. synthetic method according to claim 3 is characterized in that, in step S1., described bromooxidation adopts N-bromosuccinimide as reagent. 6. The synthetic method according to claim 3, characterized in that, in step S2., the palladium catalyst is a zero-valent palladium catalyst or a divalent palladium catalyst.