KR20200143796A - Method for synthesizing thioaurones - Google Patents

Abstract

In an embodiment of the present invention, provided is a method for manufacturing a thioauron-based compound comprising the following steps: manufacturing a 2-(benzylthio)benzoic acid compound by conducting a reaction of thiosalicylic acid with a strong basic substance and benzyl halide; manufacturing N-methoxy-N-methyl-2-(benzylthio)benzamide by conducting a reaction of the 2-(benzylthio)benzoic acid compound with N-methoxy-N-methylcarbamoyl chloride; treating the N-methoxy-N-methyl-2-(benzylthio)benzamide with an aryl ethynyl salt to obtain 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one; and treating the 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one with an acid material. According to an embodiment of the present invention, a thioauron derivative having various structures can be manufactured at a high yield.

Description

Manufacturing method of thioauron compound {METHOD FOR SYNTHESIZING THIOAURONES}

The present invention relates to a method for synthesizing a thiaurones compound, and more specifically, to a method for efficiently preparing a thiauron-based compound from thiosalicylic acid in a simple process and mild conditions will be.

A thio-auron-based compound is a ring in which an oxygen (O) atom forming a ring in an aurones compound is substituted with a sulfur (S) atom, and has a photoswitch property, cytotoxicity to cancer cells, and fat affinity. It is also used in dyes and is an important compound with a wide range of applications.

In general, as a conventional manufacturing method for a thioauron-based compound, one by condensation reaction of benzothiophen-3-one and arylaldehyde, α-(arylthio )Cinnamic acid (α-(Arylthio) cinnamic acid) by the Friedel-Craft acylation reaction and the intramolecular cyclization of 2'-methylthiochalcone, etc. are known. have.

Recently, arylaldehyde and N, N-diethyl-2-(methylsulfanyl)arylamide (N, N-diethyl-2-(methylsulfanyl)arylamide) were synthesized in the presence of LDA (Lithium diisopropylamide). And the intramolecular cyclization reaction of 2'-(4-methoxybenzylthio)-2-methylsulfurylchalcone) to obtain a thioauron compound. The method of synthesis was studied.

However, the previously known method for preparing thioauron does not have regioselectivity during cyclization, has low yield, requires harsh conditions for the reaction, and reduces efficiency due to complicated steps to obtain the final product. It has the same problem as

Accordingly, it is an object of the present invention to provide a method for efficiently synthesizing a thioauron-based compound under mild conditions.

In addition, another object of the present invention is excellent in regioselectivity and the sulfur (S) atom is protected 1-phenyl-3-phenylalkyn-1-one (1-Phenyl-3-phenylalkyn-1-one) It is to improve the yield of the target compound by providing a cyclization production method.

In addition, by reducing the reaction step and reaction time, it is to improve economic efficiency.

In order to solve such a problem, an embodiment of the present invention includes the steps of attaching a sulfur (S) protecting group to prepare a 2-(benzylthio)benzoic acid compound by reacting thiosalicylic acid with a strong basic substance and benzyl halide; The 2-(benzylthio)benzoic acid compound is reacted with N-methoxy-N-methylcarbamoyl chloride to produce benzamide to produce N-methoxy-N-methyl-2-(benzylthio)benzamide step; Treating the N-methoxy-N-methyl-2-(benzylthio)benzamide with an arylethynyl salt to give 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one Nucleophilic acyl substitution step to prepare; It provides a method for producing a thioauron-based compound comprising a cyclization step of treating the 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one with an acid material.

The thioauron-based compound is represented by the following formula (1),

[Formula 1]

Here, R1 to R5 are each independently any one of hydrogen, an alkyl group, an alkoxy group, and a halide.

The arylethynyl salt is represented by the following formula (2),

[Formula 2]

Here, R1 to R5 are each independently any one of hydrogen, an alkyl group, an alkoxy group, and a halide.

The method for preparing the thioauron-based compound is represented by Scheme 1 below.

[Scheme 1]

The step of attaching the sulfur (S) protecting group is represented by Scheme 2 below.

[Scheme 2]

The step of generating benzamide is represented by Scheme 3 below.

[Scheme 3]

The nucleophilic acyl substitution step is represented by Scheme 4 below.

[Scheme 4]

The cyclization step is represented by Scheme 5 below.

[Scheme 5]

The strongly basic substance includes a substance having a pKa of 16 or higher.

In addition, the strongly basic material is any one of lithium diisopropylamide, sodium amide, and organic base.

In addition, the strongly basic substance contains 2 equivalents or more.

The acid substance is assumed to have a pKa 4 or less.

Here, the acid material is any one of formic acid, acetic acid, phosphoric acid and trifluoroacetic acid.

The thioauron-based compound is a method of preparing a thioauron-based compound represented by any one of the following Chemical Formulas 7 to 15.

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]

According to an embodiment of the present invention, a target compound can be efficiently synthesized by providing a method for preparing a thioauron-based compound under a mild reaction condition and excellent regioselectivity. In addition, according to an embodiment of the present invention, it is possible to reduce the reaction steps until synthesis of the final product. In addition, according to an embodiment of the present invention, it is possible to improve the yield of the thioauron-based compound. In particular, according to an embodiment of the present invention, a necessary substituent may be attached to the B-benzene ring (shown in Chemical Formula 1).

According to an embodiment of the present invention, thio-auron derivatives having various structures can be prepared in high yield.

Advantages and features of the present invention, and a method of achieving them will become apparent with reference to embodiments described below. However, the present invention is not limited to the embodiments disclosed below, but will be implemented in various forms different from each other, and the embodiments merely make the disclosure of the present invention complete, and those skilled in the art to which the present invention pertains. It is provided to fully inform the person of the scope of the invention. The scope of the invention is only defined by the scope of the claims.

In the description of the temporal relationship, for example, when the temporal predecessor relationship is described as'after','following','after after','before', etc.,'right' or'direct' It may also include cases that are not continuous unless this is used.

Hereinafter, the present invention will be described in detail with reference to Examples.

According to an embodiment of the present invention, the following thioauron-based compound may be prepared from thiosalicylic acid by a four-step reaction.

[Formula 1]

Specifically, in the method for preparing a thioauron-based compound according to an embodiment of the present invention, a thiosalicylic acid is reacted with a strong base and a benzyl halide to react 2-(benzyl halide). The 2-(benzylthio)benzoic acid compound prepared in the step of attaching a sulfur (S) protecting group and attaching a sulfur protecting group to prepare a thio) benzoic acid (2-(benzylthio) benzoic acid) compound is N-methoxy-N-methyl N-methoxy-N-methyl-2-(benzylthio)benzamide by reacting with N-methoxy-N-methylcarbamoylchloride (N-Methoxy-N-methyl-2-(benzylthio)benzamide) Benzamide production step to prepare, N-methoxy-N-methyl-2-(benzylthio)benzamide prepared in the previous step was treated with an arylethynyl salt to treat 1-(2-benzylthio) ) Phenyl-3-phenyl-2-propyn-1-one (1- (2-benzylthio) phenyl-3-phenyl-2-propyn-1-one) to prepare a nucleophilic acyl substitution step, prepared in the previous step And a cyclization step of treating the resulting 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one with an acid material.

All steps of the above-described method for preparing a thioauron-based compound can be schematically expressed as in Scheme 1 below.

[Scheme 1]

First, the step of attaching a sulfur (S) protecting group may be briefly represented by Scheme 2 below, and may be represented by Scheme 2-1 below as one of several predictable mechanisms.

[Scheme 2]

[Scheme 2-1]

Before entering, the step of attaching the sulfur protector is referred to as step A for convenience. Specifically, step A is further subdivided and reacted with thiosalicylic acid (Chemical Formula 3) with 2 equivalents of strong base to form an intermediate in the form of dianion (Chemical Formula 3-1) and benzyl halide thereto. It is divided into A-2 step of preparing 2-(benzylthio)benzoic acid (Chemical Formula 4) by adding (benzyl halide).

The benzyl group added in step A serves as a protecting group to prevent other reactions from occurring until the sulfur atom undergoes a cyclization reaction in the subsequent cyclization step by bonding with the sulfur (S) atom as shown in Formula 4 above.

According to an embodiment of the present invention, any strong base used in step A-1 is a strong base capable of removing the hydrogen cation (H ⁺ ) of the carboxyl group and the thiol group (conjugate base of a compound having a pKa of 16 or more). It is possible. Typically, the usable base is any one of organic basic substances such as lithium diisopropylamide (LDA) and sodium amide (NaNH ₂ ).

The benzyl halide of step A-2 may also be any substituent (X) as long as it is not only a halide-based, but is generally considered a good leaving group. Good leaving groups include chlorine (Cl), bromine (Br), iodine (I), tosyl groups (TsO-, p-toluenesulfonate), mesyl groups (MsO-, methanesulfonate), carboxyl groups (R-COO-). Some form stable ions or compounds.

The step of generating benzamide can be briefly represented by Scheme 3 below.

[Scheme 3]

The benzamide production step is referred to as B step for convenience. Specifically, in step B, N-methoxy-N-methylcarbamoyl chloride and triethylamine were reacted with 2-(benzylthio)benzoic acid (Chemical Formula 4) prepared in step A to react N-methylamine. Toxic-N-methyl-2-(benzylthio)benzamide (Chemical Formula 5) was prepared.

The nucleophilic acyl substitution step may be briefly represented by Scheme 4 below, and may be represented by Scheme 4-1 below as one of several predictable mechanisms.

[Scheme 4]

[Reaction Scheme 4-1]

The nucleophilic acyl substitution step is referred to as step C for convenience. Specifically, in step C, when an arylethynyl salt is added to N-methoxy-N-methyl-2-(benzylthio)benzamide (formula 5) prepared in step B, nucleophilic acyl substitution The reaction (nucleophilic acyl substitution) proceeds. In this reaction, an arylethynyl salt having a large nucleophilicity is added to an acyl group having a large electrophilic carbon to form an intermediate (Chemical Formula 5-1), and an amine group (-N(OMe)(Me)) is released. -(2-Benzylthio)phenyl-3-phenyl-2-propyn-1-one (Formula 6) is produced. Since there is no hydrogen (H) having strong acidity, arylethynyl salt, which is a nucleophile and a strong base, proceeds as a nucleophilic acyl substitution reaction rather than an acid-base reaction. At this time, the reaction at other positions is prevented by the sulfur protecting group added in step A.

According to an exemplary embodiment of the present invention, arylethynyl lithium may be used as the arylethynyl salt, and any arylethynyl salt having high nucleophilicity may be used. The arylethynyl salt is represented by the following formula (2).

[Formula 2]

At this time, the substituents (R1 to R5) of the arylethynyl salt are each independently hydrogen (H), an alkyl group (Alkyl group), an alkoxy group (Alkoxyl group), a halide (halide) is any one of the group consisting of. Although there are slight differences depending on the number, type and position of the substituents of the arylethynyl salt, smooth progress is possible in step C and subsequent steps regardless of electron-withdrawing group or electron-donating group. Do. Substituents R1 to R5 of the arylethynyl salt are the same as the substituents R1 to R5 of Formula 1, respectively.

The cyclization step can be briefly represented by Scheme 5 below.

[Scheme 5]

The cyclization step is referred to as D step for convenience. Specifically, in step D, 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one prepared in step C/THF (1/1, v When /v) is added, debenzylation and intramolecular cyclization proceed, thereby preparing a thioauron-based compound (Chemical Formula 1).

The benzyl group, which is a protecting group of sulfur, is debenzylated by the addition of an acid, and sulfur is cyclized with a C≡C triple bond to form a ring. During ring formation, 5-exo cyclization occurs regioselectively rather than 6-endo cyclization.

In addition, since the steric repulsion of the B-benzene ring and the carbonyl group is strong, the exo-cyclic C=C double bond is a (Z)-structure ((Z )-form) is more preferred over the (E)-structure ((E)-form).

In Scheme 5, R1, R2, R3, R4, and R5 are the same as described in step C, and R1 to R5 are each independently hydrogen (H), an alkyl group, an alkoxy group (Alkoxyl group), a halide ( halide).

In one embodiment of the present invention, the acid material is generally any acid having pKa 4 or less. Typically, formic acid (Formic acid), acetic acid (acetic acid), phosphoric acid (H ₃ PO ₄ ), trifluoroacetic acid (trifluoroacetic acid) can be used.

The thioauron-based compound prepared by the manufacturing method according to an embodiment of the present invention may be represented by any one of the following Chemical Formulas 7 to 15. However, the presented compounds are only examples according to the present invention, and the present invention is not limited to the presented compounds.

[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]

Hereinafter, the present invention will be described in more detail with reference to specific preparation examples.

In the preparation example, 2-(benzylthio)benzoic acid can be synthesized by reacting thiosalicylic acid with 2 equivalents of LDA (Lithium diisopropylamide) in a THF solvent, and then adding benzyl chloride. N-methoxy-N-methyl-2-(benzylthio)benzamide can be synthesized by reacting the synthesized compound with N-methoxy-N-methylcarbamoyl chloride and triethylamine. Then, when THF is used as a solvent and arylethynyllithiums are added, nucleophilic acyl substitution occurs, 1-(2-benzylthio)phenyl-3-phenyl-2-propine. 1-one can be synthesized. When the obtained compound is reacted with formic acid/THF (1/1, v/v), a thioauron-based compound can be synthesized in a high yield under mild conditions.

Each step will be described in more detail as follows.

(1) Step of attaching sulfur protector (Step A)

According to a preparation example of the present invention, a dianion-type intermediate is formed by reacting thiosalicylic acid with 2 equivalents of LDA (Lithium diisopropylamide). And, when benzyl chloride is added, a benzyl group is added to the sulfur (S) atom. After all the reaction proceeds and equilibrium is reached, 2-(benzylthio)benzoic acid is prepared by finishing with 1N hydrochloric acid (HCl).

The strong base used in this step reaction can be used in addition to LDA, but sufficient basicity is required to remove the hydrogen of the thiol group and the carboxyl group. Therefore, the basicity of a strong base proceeds advantageously only when a conjugate base of a compound having a pKa of 16 or more is used.

Table 1 below shows the reaction time until the intermediate formation of this step is 0 ^o C, THF (tetrahydrofuran) was used as a solvent, 2 equivalents of LDA, and 152 ^o C, DMF was used as a solvent, potassium carbonate (K ₂ CO ₃ ). It was a comparison.

division Base/solvent Reaction temperature ( ^o C) Reaction time (h) Condition 1 LDA/THF 0 ^o C 0.5h Condition 2 K ₂ CO ₃ /DMF 152 ^o C 22h

Using potassium carbonate as a base takes a reaction time of 22 h, whereas LDA is only 0.5 h, so a fast reaction rate can be confirmed. In addition, the reaction temperature is also possible under mild conditions.

Again, the time taken to prepare 2-(benzylthio)benzoic acid by reacting benzyl chloride with the dianion intermediate at room temperature was 4h, and the final yield was 89%.

(2) Benzamide production step (B step)

N-methoxy-N-methylcarbamoyl chloride and triethylamine were reacted with 2-(benzylthio)benzoic acid prepared in step A to obtain N-methoxy-N-methyl-2-(benzylthio). O) Benzamide is manufactured. In this case, acetonitrile (CH ₃ CN) containing 0.05 equivalents of 4-(dimethylamino) pyridine (DMAP, 4-(dimethylamino) pyridine) is used as a solvent. According to step B, which was previously performed as a two-step reaction, N-methoxy-N-methyl-2-(benzylthio)benzamide can be prepared in one reaction. The reaction time takes about 1 h under room temperature conditions, and the final yield is an average of 81%.

(3) nucleophilic acyl substitution step (step C)

The substituent of the amide is acyl substituted by THF as a solvent and added arylethynyllithiums, and 1-(2-benzylthio)phenyl- 3-phenyl-2-propyn-1-one is made.

The reaction in this step proceeds at 0 ^o C to room temperature, and is completed within 1 h until separation by acid treatment (work-up) and silica gel column chromatography (silica gel column chromatography). At this time, the yield is 88-94%.

(4) Cyclization step (D step)

Formic acid/THF (1/1, v/v) was added to 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one prepared in step C. Oauron-based compounds are prepared. And formic acid and benzyl formate are evaporated by reducing the pressure.

As a result of comparing the yield using formic acid and other acids, 3h reaction was carried out at 65 ^o C using formic acid, yielding 91% of thioauron, trifluoroacetic acid, 85% phosphoric acid, and acetic acid, respectively, reaction time 1h, It took 8h and 12h, yielding 86,85,90%, respectively. All reaction temperatures are the same.

Reaction Schemes 6 and 7 below compare the reaction when there is a phenyl group (phenyl) and other substituents in step D.

[Scheme 6]

[Scheme 7]

1-(2-benzylthio)phenyl-3-(n-butyl)-2-propyn-1-one(1-(2-benzylthio)phenyl-3-(n-butyl)-2-propyn-1 As a result of adding formic acid/THF (1/1, v/v) to -one), unlike 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one, a pentagonal ring Hexagonal rings (65%) are the main products. Therefore, in the case of a phenyl substituent, it can be confirmed that it is advantageous to synthesize a thioauron-based compound due to regioselectivity. Therefore, in the intramolecular cyclization reaction, first, formic acid and 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one react, and 1-(2-mercaptophenyl)-3-phenyl -2-propyn-1-one (1-(2-mercaptophenyl)-3-phenyl-2-propyn-1-one) forms an intermediate, and a cyclization reaction occurs by successive α-carbon attack Can be seen.

In addition, because of the steric repulsion of the B-benzene ring and the carbonyl group, the thioauron-based compound according to the present preparation method is an exocyclic C=C double bond (Z) The -structure ((Z)-form) was preferred over the (E)-structure ((E)-form).

Hereinafter, the compounds represented by Chemical Formulas 7 to 15 are synthesized as follows.

<Synthesis Example 1>

Preparation of (Z)-thioaurone ((Z)-thioaurone)

(1) Step of attaching sulfur protector (Step A)

By reacting with thiosalicylic acid and 2 equivalents of LDA (Lithium diisopropylamide), a dianion-type intermediate is formed. And, when benzyl chloride is added, a benzyl group is added to the sulfur (S) atom. After all the reaction proceeds and equilibrium is reached, 2-(benzylthio)benzoic acid is prepared by finishing with 1N hydrochloric acid (HCl).

(2) Benzamide production step (B step)

N-methoxy-N-methyl-2-(benzyl) was reacted with 2-(benzylthio)benzoic acid prepared in the first step with N-methoxy-N-methylcarbamoyl chloride and triethylamine. Thio) benzamide is prepared. In this case, acetonitrile (CH ₃ CN) containing 0.05 equivalents of 4-(dimethylamino) pyridine (DMAP, 4-(dimethylamino) pyridine) is used as a solvent.

(3) nucleophilic acyl substitution step (step C)

1-(2-benzylthio)phenyl-3-phenyl-2-propine-1 by adding THF as a solvent, and adding arylethynyllithiums whose substituents are all hydrogen (H) at 0 ^o C to room temperature -On is made. The yield in step C is 90%.

(4) Cyclization step (D step)

Formic acid (5 mL) was added to 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one (657mg, 2.0 mmol) in THF solvent (5 mL), and then to 65 ^o C. Heat for 3 hours. By reducing the pressure using a vacuum pump, the solution and benzyl formate (bp 203 ^o C) are evaporated. The resulting residue was recrystallized by silica gel column chromatography using 25% EtOAc/n-hexane as an elution solvent to synthesize a thioauron compound represented by the following formula (7) as a yellow solid. The yield in step D is 91%, and the total yield by the total reaction is 59%. The measurement results for the compound are as follows. mp 129-130 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.71 (d, J = 7.5 Hz, 2H), 7.54-7.60 (m, 1H) , 7.40-7.51 (m, 4H), 7.24-7.32 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.6, 146.2, 135.3, 134.4, 133.5, 131.0, 130.5, 130.3, 130.1, 129.0, 127.1, 125.6, 123.9; FT-IR (KBr) 1675 (C=O) cm ^-1 ; MS m/z (%) 238 (M ⁺ , 59), 237 (100).

[Formula 7]

<Synthesis Examples 2 to 9>

Thioauron-based compounds of Synthesis Examples 2 to 9 were prepared in the same manner as in Synthesis Example 1 by differently only the valuation group of the arylethynyllithium used in step C.

<Synthesis Example 2>

Preparation of (Z)-2'-methylthioaurone ((Z)-2'-Methylthioaurone)

(Z)-2'-methylthioauron is (2-methylaryl)ethynyllithium added in step C, and a methyl group (Me-) is added to the second benzene ring (substituent R1 of Formula 2). have. The yield in step C is 92%, the yield in step D is 88%, and the total yield by the whole reaction is 58%. The structural formula of (Z)-2'-methylthioauron is represented by the following formula (8).

[Formula 8]

<Synthesis Example 3>

Preparation of (Z)-2'-Methoxythioaurone ((Z)-2'-Methoxythioaurone)

(Z)-2'-methoxythioauron is obtained by adding (2-methoxyaryl)ethynyllithium in step C, and a methoxy group (MeO) at the second site of the benzene ring (substituent R1 of Formula 2) -). The yield in step C is 94%, the yield in step D is 86%, and the total yield by the whole reaction is 58%. The structural formula of (Z)-2'-methoxythioauron is represented by the following formula (9), and the measurement results for the compound are as follows. mp 152-153 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.43 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.46-7.58 (m, 2H) , 7.35-7.42 (m, 1H), 7.24-7.31 (m, 1H), 7.06 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 3.91 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.6, 159.2, 146.2, 135.1, 131.9, 130.8, 130.2, 129.9, 128.6, 127.0, 125.4, 123.9, 123.5, 120.7, 111.0, 55.6; FT-IR (KBr) 1677 (C=O) cm ^-1 ; MS m/z (%) 268 (M ⁺ , 25), 237 (100).

[Formula 9]

<Synthesis Example 4>

Preparation of (Z)-3'-chlorothioaurone ((Z)-3'-Chlorothioaurone)

(Z)-3'-chlorothioauron is (3-chloroaryl) ethynyllithium added in step C, and there is chlorine (Cl) at the 3rd position of the benzene ring (substituent R2 in Formula 2) . The yield in step C is 93%, the yield in step D is 90%, and the total yield by the whole reaction is 60%. The structural formula of (Z)-3'-chlorothioauron is represented by the following formula (10), and the measurement results for the compound are as follows. mp 161-162 ^o C; 1H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.6 Hz, 1H), 7.85 (s, 1H), 7.67 (s, 1H), 7.54-7.62 (m, 2H), 7.50 (d, J = 7.8 Hz, 1H), 7.34-7.44 (m, 2H), 7.25-7.34 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.5, 145.8, 136.1, 135.6, 135.1, 131.6, 130.5, 130.2 (overlapped), 130.0, 129.0, 127.2, 125.9, 124.0; FT-IR (KBr) 1684 (C=O) cm ^-1 ; MS m/z (%) 274 (M ⁺ +2, 27), 273 (46), 272 (M ⁺ , 74), 271 (100).

[Formula 10]

<Synthesis Example 5>

Preparation of (Z)-4'-Bromothioaurone ((Z)-4'-Bromothioaurone)

(Z)-4'-bromothioauron is obtained by adding (4-bromoaryl)ethynyllithium in step C, and bromine (Br) at position 4 of the benzene ring (substituent R3 in Formula 2) There is this. The yield in step C is 92%, the yield in step D is 92%, and the total yield by the whole reaction is 61%. The structural formula of (Z)-4'-bromothioauron is represented by the following formula (11), and the measurement results for the compound are as follows. mp 168-169 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.7 Hz, 1H), 7.85 (s, 1H), 7.54-7.62 (m, 5H), 7.47-7.54 (m, 1H), 7.26- 7.33 (m, 1H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.6, 145.8, 135.5, 133.2, 132.3, 132.2, 132.0, 130.9, 130.3, 127.2, 125.8, 124.6, 124.0; FT-IR (KBr) 1685 (C=O) cm ^-1 ; MS m/z (%) 318 (M ⁺ +2, 62), 316 (M ⁺ , 62), 237 (100).

[Formula 11]

<Synthesis Example 6>

Preparation of (Z)-4'-methylthioaurone ((Z)-4'-Methylthioaurone)

(Z)-4'-methylthioauron is (4-methylaryl)ethynyllithium added in step C, and a methyl group (Me-) is added to the benzene ring 4 position (substituent R3 in Formula 2). have. The yield in step C is 93%, the yield in step D is 83%, and the total yield by the whole reaction is 56%. The structural formula of (Z)-4'-methylthioauron is represented by the following formula (12), and the measurement results for the compound are as follows. mp 136-137 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (s, 1H), 7.93 (d, J = 7.4 Hz, 1H), 7.60 (d, J = 8.0 Hz, 2H), 7.46-7.57 (m, 2H) , 7.28 (d, J = 7.9 Hz, 2H), 7.27-7.31 (m, 1H), 2.40 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.7, 146.1, 140.9, 135.2, 133.8, 131.5, 131.1, 130.6, 129.9, 129.2, 127.0, 125.5, 123.9, 21.6; FT-IR (KBr) 1670 (C=O) cm ^-1 ; MS m/z (%) 252 (M ⁺ , 60), 237 (100).

[Formula 12]

<Synthesis Example 7>

Preparation of (Z)-4'-Methoxythioaurone ((Z)-4'-Methoxythioaurone)

(Z)-4'-methoxythioauron is obtained by adding (4-methoxyaryl)ethynyllithium in step C, and the methoxy group (MeO) at the fourth position of the benzene ring (substituent R3 in the formula 2) -). The yield in step C is 91%, the yield in step D is 85%, and the total yield by the entire reaction is 56%. The structural formula of (Z)-3'-chlorothioauron is represented by the following formula (13).

[Formula 13]

<Synthesis Example 8>

Preparation of (Z)-4'-methoxy-2'-methylthioaurone ((Z)-4'-Methoxy-2'-methylthioaurone)

(Z)-4'-methoxy-2'-methylthioauron is obtained by adding (4-methoxy-2-methylaryl)ethynyllithium in step C, and the benzene ring site 4 (Chemical Formula 2) There is a methoxy group (MeO-) in the substituent R3), and a methyl group (Me-) in the 2nd position (substituent R1 in the formula 2). The yield in step C is 94%, the yield in step D is 72%, and the total yield by the whole reaction is 49%. The structural formula of (Z)-4'-methoxy-2'-methylthioauron is represented by the following formula (14), and the measurement results for the compound are as follows. mp 137-138 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.18 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.46-7.59 (m, 2H) , 7.24-7.31 (m, 1H), 6.87 (dd, J = 8.6, 2.6 Hz, 1H), 6.81 (d, J = 2.2 Hz, 1H), 3.85 (s, 3H), 2.50 (s, 3H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.5, 161.0, 146.3, 142.3, 134.9, 131.1, 131.0, 130.8, 128.9, 127.0, 125.9, 125.4, 123.9, 116.6, 111.8, 55.4, 20.5; FT-IR (KBr) 1671 (C=O) cm ^-1 ; MS m/z (%) 282 (M ⁺ , 75), 267 (100).

[Formula 14]

<Synthesis Example 9>

Preparation of (Z)-3', 5'-dimethoxymethylthioaurone ((Z)-3', 5'-Dimethoxymethylthioaurone)

(Z)-3', 5'-dimethoxythioauron is (3, 5-dimethoxyaryl) ethynyllithium added in step C, and the benzene ring positions 3 and 5 (chemical formula 2 has a methoxy group (MeO-) in the substituents R2 and R4). The yield in step C is 88%, the yield in step D is 81%, and the total yield by the entire reaction is 51%. The structural formula of (Z)-3', 5'-dimethoxythioauron is represented by the following formula (15), and the measurement results for the compound are as follows. mp 167-168 ^o C; ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.93 (d, J = 7.7 Hz, 1H), 7.87 (s, 1H), 7.55-7.60 (m, 1H), 7.48 (d, J = 7.8 Hz, 1H) , 7.25-7.32 (m, 1H), 6.85 (d, J = 2.1 Hz, 2H), 6.53 (t, J = 2.2 Hz, 1H), 3.85 (s, 6H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 188.6, 161.0, 146.1, 136.0, 135.4, 133.7, 130.8, 130.4, 127.1, 125.7, 123.9, 108.7, 102.8, 55.5; FT-IR (KBr) 1675 (C=O) cm ^-1 ; MS m/z (%) 298 (M ⁺ , 57), 267 (100).

[Formula 15]

In Synthesis Examples 1 to 9, the arylethynyllithium used, the finally produced thioauron-based compound, each step and the total yield are shown in Table 2 below.

division reagent product
(Thioaurones) Yield (%) Formula 6 Formula 1 Synthesis Example 1 Arylethynyllithium (Z)-Thioauron
((Z)-thioaurone) 90 91(59) Synthesis Example 2 Lithium (2-methylaryl)ethynyl (Z)-2'-methylthioauron
((Z)-2'-Methylthioaurone) 92 88(58) Synthesis Example 3 Lithium (2-methoxyaryl)ethynyl (Z)-2'-methoxythioauron
((Z)-2'-Methoxythioaurone) 94 86(58) Synthesis Example 4 Lithium (3-chloroaryl)ethynyl (Z)-3'-chlorothioauron
((Z)-3'-Chlorothioaurone) 93 90(60) Synthesis Example 5 Lithium (4-bromoaryl)ethynyl (Z)-4'-bromothioauron
((Z)-4'-Bromothioaurone) 92 92(61) Synthesis Example 6 Lithium (4-methylaryl)ethynyl (Z)-4'-methylthioauron
((Z)-4'-Methylthioaurone) 93 83(56) Synthesis Example 7 Lithium (4-methoxyaryl)ethynyl (Z)-4'-methoxythioauron
((Z)-4'-Methoxythioaurone) 91 85(56) Synthesis Example 8 Lithium (4-methoxy-2-methylaryl)ethynyl (Z)-4'-methoxy-2'-methylthioauron
((Z)-4'-Methoxy-2'-methylthioaurone) 94 72(49) Synthesis Example 9 Lithium (3,5-dimethoxyaryl)ethynyl (Z)-3', 5'-dimethoxythioauron
((Z)-3', 5'-Dimethoxymethylthioaurone) 88 81(51)

In Table 2, "arylethynyllithium" indicates the type of arylethynyllithium added in step C. "Thioaurones" refers to the final product depending on the arylethynyllithium added. Formula 6 and Formula 1 of "yield" refer to the yields in steps C and D, and the numbers in parentheses represent the total yield.

As disclosed in Table 2, the difference in yield in the third and fourth steps according to the substituents of the B-benzene ring is not significantly affected by the number, type and position of the substituents. In particular, in the case of compound e ((Z)-4'-bromothioauron), the highest value was shown with a total yield of 61%, and other compounds also showed an average yield of 56%, and the entire reaction was carried out without difficulty at room temperature. It goes on.

Claims (14)

Attaching a sulfur (S) protecting group to prepare a 2-(benzylthio)benzoic acid compound by reacting thiosalicylic acid with a strong basic substance and benzyl halide;
The 2-(benzylthio)benzoic acid compound is reacted with N-methoxy-N-methylcarbamoyl chloride to produce benzamide to produce N-methoxy-N-methyl-2-(benzylthio)benzamide step;
Treating the N-methoxy-N-methyl-2-(benzylthio)benzamide with an arylethynyl salt to give 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one Nucleophilic acyl substitution step to prepare;
A method for producing a thioauron-based compound comprising a cyclization step of treating the 1-(2-benzylthio)phenyl-3-phenyl-2-propyn-1-one with an acid material. The method of claim 1,
The thioauron-based compound is represented by the following formula (1),
[Formula 1]

Here, R1 to R5 are each independently hydrogen, an alkyl group, an alkoxy group, and any one of the group consisting of a halide. The method of claim 1,
The arylethynyl salt is represented by the following formula (2),
[Formula 2]

Here, R1 to R5 are each independently hydrogen, an alkyl group, an alkoxy group, and any one of the group consisting of a halide. The method of claim 1,
A method for preparing a thioauron-based compound represented by the following reaction formula 1.
[Scheme 1]

The method of claim 1,
The step of attaching the sulfur (S) atom protecting group is a method of preparing a thioauron-based compound represented by the following reaction formula 2.
[Scheme 2]

The method of claim 1,
The step of producing benzamide is a method of producing a thioauron-based compound represented by the following scheme 3.
[Scheme 3]

The method of claim 1,
The nucleophilic acyl substitution step is a method for producing a thioauron-based compound represented by the following Scheme 4.
[Scheme 4]

The method of claim 1,
The cyclization step is a method for producing a thio-auron-based compound represented by Reaction Scheme 5.
[Scheme 5]

The method of claim 1,
The method for producing a thioauron-based compound, wherein the strongly basic substance includes a substance having a pKa of 16 or more. The method of claim 1,
The method for producing a thioauron-based compound, wherein the strongly basic material is any one of lithium diisopropylamide, sodium amide, and an organic base. The method of claim 1,
The method for producing a thio-auron-based compound containing 2 equivalents or more of the strongly basic substance. The method of claim 1,
The method for producing a thio-auron-based compound, wherein the acid material is pKa 4 or less. The method of claim 1,
The acid material is any one of formic acid, acetic acid, phosphoric acid, and trifluoroacetic acid. The method of claim 1,
The thio-auron-based compound is a method for producing a thio-auron-based compound represented by any one of the following Chemical Formulas 7 to 15.
[Formula 7]

[Formula 8]

[Formula 9]

[Formula 10]

[Formula 11]

[Formula 12]

[Formula 13]

[Formula 14]

[Formula 15]