WO2018128390A1 - Method for producing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compound - Google Patents

Abstract

The present invention relates to a method for producing a 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl)phenylthiol compound. The production method according to the present invention enables provision of stable yield and safety of production process by suppressing the runaway reaction by controlling the reaction rate when synthesizing a 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)pyrimidinyl)phenylthiol compound.

Description

Process for preparing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound

This application claims the benefit of priority based on Korean Patent Application No. 10-2017-0002309 dated January 06, 2017, and all the contents disclosed in the literature of that Korean patent application are incorporated as part of this specification.

The present invention relates to a method for producing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound represented by the following general formula (IV). It is about.

[Formula IV]

(In Formula IV, R ¹ , R ² and R ³ are as described in the specification.)

5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound represented by Formula IV and salts thereof are used in medicines and pesticides It is an important intermediate compound used to synthesize a sulfide (-S-) group-containing compound in the field of organic synthesis such as product.

For example, Korean Patent No. 1103840 (2012.01.02) has used the compound represented by Formula IV as an intermediate to synthesize a uracil compound having the following structure having herbicidal activity.

In addition, Korean Patent No. 1345394 (2013.12.18) discloses a method of synthesizing the compound represented by Chemical Formula IV by a one-pot reaction.

However, when the raw materials required for the reaction, such as reducing agents, catalysts, precursors, etc. are substantially added at a time, the daily container reaction proceeds with the reaction, which may cause serious safety problems due to the explosive reaction. Yield degradation may occur.

Accordingly, the present inventors have developed an improved manufacturing method capable of synthesizing the compound represented by Chemical Formula IV, which has various industrial uses, in a stable yield without safety problems, thereby completing the present invention.

In the present invention, the 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound can be safely produced in a stable yield. A method is provided.

According to the invention

Preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent;

A reduction reaction step of confirming the production and disappearance of a solution containing a compound represented by the following formula (I) by dropwise addition to the catalyst mixture to the production of the compound represented by the following formula (III) as a reaction product and to the generation and disappearance of the compound represented by the following formula (II) ; And

5- (3,6-dihydro-2,6-dioxo-, comprising a hydrolysis reaction step of adding hydrochloric acid to a solution containing the compound represented by Formula III to form a compound represented by the following Formula IV Methods of preparing 4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compounds are provided:

[Formula I]

[Formula II]

[Formula III]

[Formula IV]

In Chemical Formulas I to IV,

R ¹ and R ² are each independently hydrogen, halogen or alkyl of 1 to 4 carbon atoms; R ³ is hydrogen or alkyl having 1 to 4 carbon atoms.

The preparation process according to the invention is carried out by the reaction rate in the synthesis of 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound. By controlling the runaway reaction through the control it is possible to ensure the safety and stable yield of the manufacturing process.

Hereinafter, a method for preparing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound according to an embodiment of the present invention It will be described in detail.

Prior to this, the terminology is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention unless expressly stated otherwise.

As used herein, the singular forms “a”, “an” and “the” include plural forms as well, unless the phrases clearly indicate the opposite.

As used herein, the meaning of "includes" specifies a particular property, region, integer, step, operation, element, and / or component, and other specific properties, region, integer, step, operation, element, component, and / or group. It does not exclude the presence or addition of.

On the other hand, as a result of the continuous study of the present inventors, when changing the order of addition of the reactants in a series of reactions for synthesizing the compound represented by Formula (IV), it is possible to suppress the runaway reaction that proceeds explosive immediately after the start of the reaction Through this, it was confirmed that the safety and stable yield of the manufacturing process can be secured.

According to one embodiment of the invention, preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent;

A reduction reaction step of confirming the production and disappearance of a solution containing a compound represented by the following formula (I) by dropwise addition to the catalyst mixture to the production of the compound represented by the following formula (III) as a reaction product and to the generation and disappearance of the compound represented by the following formula ; And

5- (3,6-dihydro-2,6-dioxo-, comprising a hydrolysis reaction step of adding hydrochloric acid to a solution containing the compound represented by Formula III to form a compound represented by the following Formula IV Methods of preparing 4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compounds are provided:

[Formula I]

[Formula II]

[Formula III]

[Formula IV]

In Chemical Formulas I to IV,

R ¹ and R ² are each independently hydrogen, halogen or alkyl having 1 to 4 carbon atoms, preferably fluoro, chloro, bromo, or iodoyl, more preferably fluoro or chloro; R ³ is hydrogen or alkyl having 1 to 4 carbon atoms, preferably hydrogen, methyl, ethyl, or propyl, more preferably methyl or ethyl.

5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound and salts thereof represented by Chemical Formula IV are pharmaceuticals, pesticides It can be used as an important intermediate in the field of manufacturing the product and the like by the organic synthesis method.

In particular, the compound of formula IV has herbicidal activity and can be suitably used as an active substance of the weed removal composition or as an intermediate thereof.

In general, the compound of formula (IV) comprises the steps of forming a compound represented by formula (III) by a reduction reaction of the compound represented by formula (I) in a reaction solvent in the presence of a reducing agent and a catalyst (reduction reaction step); And forming a compound represented by Chemical Formula IV by the hydrolysis reaction of the compound represented by Chemical Formula III (hydrolysis reaction step).

However, when the reaction proceeds by substantially adding all the raw materials necessary for the reaction such as a reducing agent, a catalyst, and a precursor (the compound of Formula I) in the reduction reaction step, the yield of the target product is not only lowered due to the runaway reaction, but also serious. Safety issues may arise.

In the manufacturing method according to the embodiment of the present invention, the above-described problem may be solved by changing the order of adding reactants in the reduction reaction step.

Specifically, according to an embodiment of the invention, the compound of formula (IV) comprises the steps of (i) preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent; (ii) separately from the catalyst mixture, preparing a solution comprising the compound of formula (I), and dropwise adding it to the catalyst mixture to reduce the reaction; And (iii) hydrolysis reaction by adding hydrochloric acid to the reaction solution of the reduction reaction.

In the case of the runaway reaction described above, the reduction reaction proceeds explosively, making it difficult to control the production rate of the desired product and by-products.

On the other hand, in the preparation method according to the embodiment of the present invention, as the steps (i) and (ii) are performed separately, the production of the compound of formula III, which is the reaction product of step (ii), and the intermediate thereof The production and disappearance of the compounds of II can be confirmed.

That is, while confirming the concentration change of the compound of Formula II, which is an intermediate in the reduction reaction, by controlling the rate of dropping the solution containing the compound of Formula I to the catalyst mixture, it is possible to suppress the runaway reaction, thereby It is possible to secure the process safety and stable yield.

According to an embodiment of the invention, the type of reducing agent included in the catalyst mixture is not particularly limited. However, preferably, as the reducing agent, lithium aluminum hydride (LiAlH ₄ ), red phosphorus (Red P), aluminum chloride (AlCl ₃ ), tin (IV) chloride (SnCl ₄ ), tin (II) chloride (SnCl ₂ ) One or more compounds selected from the group consisting of zinc chloride (ZnCl ₂ ), and zinc metal (Zn) can be used.

The reducing agent may be included in the catalyst mixture in a ratio of 1 to 10 mol, or 1 to 6 mol, or 1 to 4 mol based on 1 mol of the compound of Formula (I).

In addition, the catalyst included in the catalyst mixture may be iodine (I ₂ ).

The catalyst may be included in the catalyst mixture in an amount of 0.001 to 1 mol, or 0.005 to 1 mol, or 0.005 to 0.5 mol, or 0.005 to 0.1 mol based on 1 mol of the reducing agent.

In addition, the kind of reaction solvent contained in the catalyst mixture is not particularly limited. Preferably, the reaction solvent is selected from the group consisting of acetic acid, ethanol, methanol, tetrahydrofuran, 4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, acetone, dichloromethane, and chloroform One or more compounds may be used.

Meanwhile, apart from the catalyst mixture, a solution comprising the compound of formula I is prepared.

The solution containing the compound of formula (I) is a solution in which the compound of formula (I) is completely dissolved in the same type of organic solvent as the reaction solvent included in the catalyst mixture.

The reduction reaction is carried out by dropwise addition of a solution comprising the compound of formula I to the catalyst mixture. At this time, the dropping rate of the solution containing the compound of formula (I) can be adjusted in a range that can be suppressed runaway reaction according to the concentration change of the compound of formula (II) which is an intermediate of the reaction.

Specifically, the concentration change of the compounds of Formulas (II) and (III) in the reduction reaction step can be confirmed through conventional methods such as HPLC, and if the compound of Formula (II) is not detected, the reduction reaction step is terminated.

This reduction reaction step may be advantageous in terms of securing the reaction efficiency is carried out at a temperature of 80 ℃ or more, or 80 to 200 ℃, or 100 to 150 ℃.

For example, the reduction reaction step may be performed by dropwise adding a solution including the compound of formula I to the catalyst mixture heated to 100 to 150 ℃.

Subsequently, a hydrolysis reaction step is performed in which hydrochloric acid is added to a solution containing the compound represented by Formula III obtained through the reduction reaction step to form a compound represented by the following Formula IV.

The hydrolysis reaction step may be performed by adding hydrochloric acid and stirring the reaction system at 80 to 120 ℃.

The compound of Formula IV, which is produced through the hydrolysis reaction step, may be recovered through a crystallization process. And, if necessary, a high purity compound can be obtained through a conventional separation and purification process, for example, washing with an organic solvent, fractional distillation, column chromatography, and the like.

Hereinafter, preferred embodiments will be presented to aid in understanding the invention. However, the following examples are only to illustrate the invention, not limited to the invention only.

Example  One

Acetic acid (209.1 g), red phosphorus (30.8 g, 0.993 mol) and iodine (I ₂ , 2.5 g, 10 mmol) were mixed and heated to 80-90 ° C. and stirred for 0.5 h.

Separately, acetic acid (627.4 g) was added to a compound of formula (I ') (2-chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoro) Romethyl-1 (2H) -pyrimidinyl) phenylsulfonyl chloride; 209.1 g, 0.497 mol) was added to prepare a fully dissolved compound solution.

[Formula I ']

The compound solution was added dropwise to the catalyst mixture at a temperature of 105 to 115 ° C. for 4 hours. After completion of the dropwise addition, the mixture was stirred for 2 hours in the temperature range. In the course of the reduction reaction, the production of the compound of formula III ', which is a reaction product, and the generation and disappearance of the compound of formula II', which is an intermediate thereof, were confirmed. When the compound of formula II 'was not detected, the reduction reaction was terminated. It was. At this time, by checking the concentration change of the compound of Formula (II ′) was carried out a reduction reaction while controlling the rate of dropping.

[Formula II ']

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49-7.46 (m, 2H), 7.34-7.31 (m, 2H), 6.28 (s, 2H), 3.52 (s, 6H).

[Formula III ']

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 3.56 (s, 3H), 2.45 (s, 3 H).

The reaction solution of the reduction reaction was cooled to 80 ℃ and filtered through a celite pad (residue of red phosphorus). 10% HCl (72.4 g, 0.199 mol) was added dropwise at a temperature ranging from 100 to 110 ° C., followed by stirring at 105 to 110 ° C. for 2 hours, followed by hydrolysis. The reaction mixture was added dropwise to water, followed by stirring to precipitate the product as a solid. The precipitated solid was filtered and dried to obtain a compound of formula IV ′ as a white white solid (169.1 g, 96%).

[Formula IV ']

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36 (d, J = 9.1 Hz, 1H), 7.29 (d, J = 9.1 Hz, 1H), 6.38 (s, 1H), 3.88 (s, 1H), 3.58 (s, 3 H).

Comparative example  One

Acetic acid (30 mL), red phosphorus (2.21 g, 71.2 mmol), and iodine (I ₂ , 0.181 g, 0.712 mmol) were mixed and stirred, followed by addition of the compound of formula I '(15.0 g, 35.6 mmol) Heated to reflux for 2 hours while heating to 120 ° C.

As the reaction started, the reaction proceeded explosively and ended after the leakage of some reaction mixture and acetic acid vapor with rapid exotherm.

In this explosive reduction process, the production and disappearance of the intermediate compound of formula II 'could not be confirmed, and finally, the production of the compound of formula III' was confirmed.

After cooling the reaction solution to 100 ℃ slowly added 1N HCl (6 mL) and stirred at 110 ℃ for 3 hours.

After the reactor was cooled to room temperature, the reaction solution was filtered through a celite pad, and then the reaction solution was added to water and extracted with ethylene chloride.

The combined organic layers were washed with water and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was solidified with ethylene chloride / hexane and dried to give a white compound of formula IV ′ (10.5 g, 83%).

Claims (6)

Preparing a catalyst mixture comprising a reducing agent, a catalyst and a reaction solvent; A reduction reaction step of confirming the production and disappearance of a solution containing a compound represented by the following formula (I) by dropwise addition to the catalyst mixture to the production of the compound represented by the following formula (III) as a reaction product and to the generation and disappearance of the compound represented by the following formula ; And Hydrolysis reaction step of adding a hydrochloric acid to the solution containing the compound represented by Formula III to form a compound represented by the following formula (IV) Process for preparing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound comprising: [Formula I]

[Formula II]

[Formula III]

[Formula IV]

In Chemical Formulas I to IV, R ¹ and R ² are each independently hydrogen, halogen or alkyl of 1 to 4 carbon atoms, R ³ is hydrogen or alkyl having 1 to 4 carbon atoms. The method of claim 1, The reducing agent is lithium aluminum hydride (LiAlH ₄ ), red phosphorus (Red P), aluminum chloride (AlCl ₃ ), tin (IV) chloride (SnCl ₄ ), tin (II) chloride (SnCl ₂ ), zinc chloride (ZnCl ₂ ), and 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyri, which is at least one compound selected from the group consisting of zinc metal (Zn) Method for preparing midinyl) phenylthiol compound. The method of claim 1, Preparation of 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound wherein the catalyst is iodine (I ₂ ) Way. The method of claim 1, The reaction solvent is at least one compound selected from the group consisting of acetic acid, ethanol, methanol, tetrahydrofuran, 4-dioxane, N, N-dimethylformamide, dimethylsulfoxide, acetone, dichloromethane, and chloroform A process for producing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol compound. The method of claim 1, The reduction reaction step is carried out under a temperature of 80 to 200 ℃, 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenyl thi Process for the preparation of all compounds.  The method of claim 1, R ¹ and R ² are each independently fluoro, chloro, bromo, or iodo; R ³ is hydrogen, methyl, ethyl, or propyl, 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2H) -pyrimidinyl) phenylthiol Method of Preparation of the Compound.