KR101345394B1 - Process for preparing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl)phenylthiol compounds - Google Patents

Abstract

The present invention relates to a method for preparing 5-(3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2h)-pyrimidinyl) phenylthiol compounds in a reactor. The method improves manufacturing yields and product purity of products by reducing simplifying processes, reaction time, and the generation of byproducts.

Description

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

The present invention provides a method for preparing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound represented by the following Chemical Formula 1 It is about.

[Formula 1]

In Formula 1, R ¹ and R ² are the same as or different from each other, and represent a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkyl group, and R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group.

5- (3,6-Dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compounds are sulfides in organic synthesis such as pharmaceuticals and pesticides. It is an important intermediate compound used to synthesize (-S-) group containing compounds.

Korean Patent Application Publication No. 2010-0038052 discloses 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) represented by Chemical Formula 1 above. A uracil compound having the following structure having herbicidal activity was synthesized using a phenylthiol compound as an intermediate.

Therefore, the 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound represented by Chemical Formula 1 may be used in food, medicine, Pesticides and the like can be used as an important intermediate in the field of organic synthesis.

Accordingly, the present inventors have completed the present invention by research to develop an improved manufacturing method that can more easily synthesize the compound represented by the general formula (1) for a variety of industrial uses.

It is an object of the present invention to provide a process for the preparation of 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound. .

Specifically, the present invention provides 5- (3,6-dihydro-2 represented by Chemical Formula 1, which is useful as an intermediate compound in the field of organic synthesis for synthesizing foods, drugs, and pesticides including sulfide (-S-) groups. To provide a method for directly preparing a 6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound by a one-pot reaction. do.

As shown in Scheme 1, the present invention provides 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl represented by Formula 2 below. Phenylsulfonyl chloride compound in the presence of a reducing agent, acetic acid and hydrochloric acid To prepare a 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound represented by the following formula (1) It features.

[Reaction Scheme 1]

In Scheme 1, R ¹ , R ² , and R ³ are each as defined in Chemical Formula 1.

In the preparation method of the present invention, by using a compound represented by Chemical Formula 2 including a sulfonyl chloride (-SO ₂ Cl) group as a starting material, a thiol (- Switch to the SH) group, which simplifies the process.

In addition, the production method of the present invention can shorten the reaction time, it can also reduce the production of by-products.

Since the production method of the present invention improves the production yield and purity of the target by reducing the process, shortening the reaction time and by-product generation, the compound represented by the formula (1) can be used directly in subsequent manufacturing process without a separate purification process It is possible.

The present invention relates to a process for converting sulfonylchloride (-SO ₂ Cl) groups to thiol (-SH) groups in one reactor.

Specifically, the present invention is a 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylsulfonyl chloride compound represented by the following Chemical Formula 2 In the presence of a reducing agent, acetic acid and / or hydrochloric acid Regarding a method for preparing 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound represented by the following Chemical Formula 1 will be.

(2)

[Formula 1]

In Formula 1 or 2, R ¹ and R ² are the same as or different from each other, and represent a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkyl group, and R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group. . In the compound represented by Chemical Formula 1, preferably, R ¹ and R ² are the same as or different from each other, such as pullouro (F), chloro (Cl), bromo (Br), or iodo (I), R <^3> is a compound which is a hydrogen atom, a methyl group, an ethyl group, or a propyl group. More preferably, in the compound represented by Chemical Formula 1, 2-chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl- 1 ( 2H ) -pyrimidinyl) phenylthiol.

The kind of reducing agent used to achieve the object of the present invention is not limited, but may be selected from lithium aluminum hydride (LiAlH ₄ ), Lewis acid, red phosphorus (Red P) and zinc metal (Zn). The reducing agent is preferably used in 1 to 10 mole ratio, preferably 3 to 6 mole ratio based on 1 mole of the compound represented by the formula (2). Lewis acid used as the reducing agent is a chloride of a metal selected from aluminum, tin, zinc, and specifically, AlCl ₃ , SnCl ₄ , SnCl ₂ , or ZnCl ₂ may be used. In addition, when red phosphorus (Red P) is used as a reducing agent, the reaction is preferably performed under conditions in which iodine (I ₂ ) is added in a catalytic amount. In this case, iodine (I ₂ ) may be used in the range of 0.001 to 0.1 molar ratio based on the amount of red phosphorus used. The reaction under the reducing agent described above may be carried out in the presence of an acid, preferably using acetic acid (AcOH) and / or hydrochloric acid (HCl).

In general, chemical reactions can vary significantly depending on the physical and chemical properties, three-dimensional structure, etc. depending on the parent nucleus and substituents, reaction efficiency, type and amount of by-products, etc. It cannot be adopted as a manufacturing and / or production process for obtaining the desired material. In addition, the empirical rules of chemistry suggest that chemical reactions that are likely to be derived from chemical theory and common sense may actually proceed as unexpected reactions, so that the desired reaction proceeds substantially and the desired amount of the target is obtained. In order to confirm the results by substantially reacting each target compound. The reaction of converting the sulfonylchloride (-SO ₂ Cl) group of the substituted aromatic organic compound of the present invention into a thiol (-SH) group also depends on the structure of the parent nucleus and the reaction additives, the success of the reaction, the reaction rate, and the product. The amount, yield, etc. may vary. In addition, among a plurality of substances produced by a chemical reaction, in order to obtain a desired substance, only a substance which needs to participate in the final reaction in the middle stage of the multi-step reaction is extracted or separated, and undergoes a cumbersome step of participating in the reaction again. The production method of the present invention overcomes the difficulties and characteristics of the art and is a method that can achieve a high yield despite the reaction in a daily container without undergoing separate separation and identification. The present invention converts the sulfonylchloride (-SO ₂ Cl) group directly to a thiol (-SH) group in a single container, which is a very economical method suitable for industrial use.

The present invention will be described in more detail as follows.

In one embodiment, the one-group reaction according to the present invention is 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) represented by Chemical Formula 2 in one reactor. When pyrimidinyl) phenylsulfonyl chloride compound, a reducing agent, acetic acid and hydrochloric acid are added to react, 5- (3,6-dihydro-2,6-dioxo-4-trifluoro represented by Chemical Formula 1 above Methyl-1 ( 2H ) -pyrimidinyl) phenylthiol compounds can be prepared directly.

In another embodiment, the one-group reaction according to the present invention may be carried out in 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 (2) represented by Chemical Formula 2 in one reactor. H ) -pyrimidinyl) phenylsulfonyl chloride compound, a reducing agent, and acetic acid are added to the mixture, and then reacted by further adding hydrochloric acid to the reactor, where 5- (3,6-di represented by Chemical Formula 1 Hydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compounds can be prepared directly.

As a preferred embodiment for carrying out the preparation method of the present invention, (a) adding red phosphorus (Red P), iodine (I ₂ ), and acetic acid to the compound represented by Formula 2 in the reactor; (b) cooling the reaction solution after heating to reflux; (c) adding hydrochloric acid to the cooled reaction solution; And (d) heating and stirring the reaction solution to which the hydrochloric acid is added to obtain a compound represented by Chemical Formula 1. By carrying out, the compound represented by Chemical Formula 1 may be prepared.

In the production method of the present invention, as a reaction solvent, conventional organic solvents such as ethanol, methanol, tetrahydrofuran, 4-dioxane, N , N -dimethylformamide, dimethyl sulfoxide, acetone, dichloromethane, chloroform and the like Although may be used in addition, in the embodiment of the present invention, the reaction was carried out using an excess of acetic acid without additional organic solvent.

The reaction temperature maintains a reflux temperature range of 0 ° C. to the solvent, specifically 0 ° C. to 200 ° C., and preferably a heating temperature of 100 ° C. to 200 ° C.

In a preferred embodiment of carrying out the preparation method of the present invention, the compound represented by Chemical Formula 2, red phosphorus (Red P), iodine (I ₂ ), acetic acid and hydrochloric acid are added to one reactor at a temperature of 100 ° C. to 200 ° C. By refluxing, the compound represented by Chemical Formula 1 is prepared directly.

In addition, a preferred embodiment for carrying out the preparation method of the present invention is 120 ℃ to 200 ℃ by adding a compound represented by the formula (2), red phosphorus (Red P), iodine (I ₂ ), and acetic acid in one reactor After refluxing to temperature, the reactor internal temperature was cooled to 80 ° C to 110 ° C, hydrochloric acid was added, and the mixture was heated and stirred at 80 ° C to 110 ° C to directly prepare the compound represented by Chemical Formula 1.

The compound represented by Chemical Formula 1 obtained by performing the preparation method may be subjected to a simple vacuum distillation process to obtain a target product. In addition, when the desired product is to be obtained as a high-purity product, a conventional separation and purification process, for example, washing with an organic solvent, fractional distillation, and column chromatography may be performed.

The present invention as described above will be described in more detail based on the following examples, but the present invention is not limited thereto.

[Example]

Reference Example 1. 2-Chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl Synthesis of Phenylthiol (Lewis Acid Reaction)

2-Chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylsulfonyl Chloride (3.00 g, 7.12 mmol), acetic acid (22.5 mL), and concentrated hydrochloric acid (10.5 mL) were mixed, and then SnCl ₂ · 2H ₂ O (8.04 g, 35.6 mmol) was added thereto, and the mixture was heated to 80 ° C. and stirred for 2 hours. It was. After cooling to room temperature, the reaction solution was added to ice water (190 mL) and extracted with methyl tert -butyl ether (50 mL × 2). The combined organic layers were washed with water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Recrystallized with toluene and dried to obtain the title compound (1.53 g, 60.6%) as a white solid.

TLC R _f 0.25 (ethyl acetate: hexane, 1: 3 volume ratio); ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (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).

Reference Example 2. 2-Chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl Synthesis of Phenylthiol (Zinc Metal Reaction)

2-Chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyridine in acetic acid (50 mL) Midinyl) phenylsulfonyl chloride (5.00 g, 11.9 mmol) was added and stirred, followed by zinc metal (15.5 g, 237 mmol). The reaction mixture was heated to reflux overnight. The reaction solution was cooled to room temperature and filtered through celite to remove zinc metal. Water (100 mL) was added to the filtrate and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL × 2) and saturated aqueous sodium hydrogen carbonate solution (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was recrystallized with isopropanol and dried to obtain the target compound (2.00 g, 47.5%) as a white solid.

Example 1. 2-Chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl Synthesis of Phenylthiol (Red Phosphorus Reaction)

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 2-chloro-4-fluoro-5- (3,6 -Dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylsulfonyl chloride (15.0 g, 35.6 mmol) was added and heated to reflux for 2 hours. It was.

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

After cooling the reactor to room temperature, the reaction solution was filtered through a celite pad, and then the reaction solution was added to water (150 mL) and extracted with ethylene chloride (120 mL × 3). The combined organic layers were washed with water (180 mL) and brine (180 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The concentrated compound was solidified with ethylene chloride / hexane (1/5, 300 mL) and dried to obtain the target compound (12.6 g, 95%) as a white solid.

As described above, the present invention can be obtained in high purity and high yield of the compound represented by the formula (1) directly in one container. Therefore, the preparation method of the present invention is useful for mass production of intermediate compounds for synthesizing medicines and pesticides including sulfide (-S-) groups.

Claims (6)

To a red phosphorus (Red) 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylsulfonyl chloride compound represented by the following formula (2) P), iodine (I ₂ ), 5- (3,6-dihydro-2,6-dioxo-4-tri represented by the following formula 1, characterized in that the reaction is prepared in the presence of acetic acid and hydrochloric acid. Process for the preparation of fluoromethyl-1 ( 2H ) -pyrimidinyl) phenylthiol compound:
(2)

[Chemical Formula 1]

In the above formula (1) or (2)
R ¹ and R ² , which are the same as or different from each other, represent a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkyl group, and R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group.
The method according to claim 1,
R ¹ and R ² are the same as or different from each other and represent fluoro, chloro, bromo, or iodo, and R ³ represents a hydrogen atom, a methyl group, an ethyl group, or a propyl group.
The method according to claim 1,
The compound represented by Chemical Formula 1 is 2-chloro-4-fluoro-5- (3,6-dihydro-3-methyl-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -Pyrimidinyl) phenylthiol.
The method according to claim 1,
The reaction is characterized in that carried out at 100 ℃ to 200 ℃ temperature conditions.
5. The method according to any one of claims 1 to 4,
The reaction is a production method, characterized in that carried out by a one-pot reaction.
(a) 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H ) -pyrimidinyl) phenylsulfonyl chloride compound represented by the following general formula (2) in the reactor: Adding red phosphorus (Red P), iodine (I ₂ ), and acetic acid to;
(b) cooling the reactor after heating to reflux;
(c) adding hydrochloric acid to the cooled reaction solution; And
(d) 5- (3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1 ( 2H )-represented by the following Chemical Formula 1 by heating and stirring the reaction solution to which hydrochloric acid is added: Obtaining a pyrimidinyl) phenylthiol compound;
Method for preparing a compound represented by the following formula (1) comprising:
(2)

[Chemical Formula 1]

In the above formula (1) or (2)
R ¹ and R ² , which are the same as or different from each other, represent a hydrogen atom, a halogen atom, or a C ₁ -C ₆ alkyl group, and R ³ represents a hydrogen atom or a C ₁ -C ₆ alkyl group.