JPWO2007010744A1 - Method for producing thiocarbamate derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing a thiocarbamate derivative useful as a medicine, agricultural chemical or the like safely, with few steps, simply and inexpensively. SOLUTION: 6-Alkoxy-2-alkylaminopyridine is reacted with thiocarbonyldiazaaryl to form an intermediate 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine. Then, a method of producing O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate by reacting the intermediate with an aryl alcohol in the presence of a base or an arylalkoxide. [Selection figure] None

Description

priority

  This application claims the priority of Article 4 of the Paris Convention based on Japanese Patent Application No. 2005-212653 filed on July 22, 2005, the entire disclosure of the above-mentioned patent application is incorporated herein by reference. It shall be.

（式中、Ｒ_１及びＲ_２はアルキル基、Ａｒ_１はアリール基を表す。）The present invention relates to a novel process for producing a thiocarbamate derivative represented by the following general formula (I), and more particularly an O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate.

(In the formula, R ₁ and R ₂ represent an alkyl group, and Ar ₁ represents an aryl group.)

background

  O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate is a useful compound as a pharmaceutical agent such as an athlete's foot therapeutic agent, an agrochemical such as a herbicide, or an intermediate material thereof. In particular, O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate is known to be a useful compound as a therapeutic agent for athlete's foot. Yes.

Traditionally, O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamates have generally been prepared by a process using thiophosgene. For example, Patent Document 1 discloses O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N represented by the following reaction formula i) or ii): A process for the production of -methylthiocarbamate (4) is disclosed.

  In these production methods, it was produced by reacting either 5,6,7,8-tetrahydro-2-naphthol (1) or 6-methoxy-2-methylaminopyridine (3) as a raw material with thiophosgene. 5,6,7,8-tetrahydro-2-naphthylchlorothioformate (2) in the intermediate raw material (reaction formula i), N- (6-methoxy-2-pyridyl) -N- in reaction formula ii) Methylthiocarbamoyl chloride (5) is reacted with the other raw material to produce target compound (4). That is, in these conventional methods, it is essential to use highly toxic thiophosgene. The production and use of thiophosgene must be carried out in a facility that is strictly controlled in terms of occupational safety and health, and its movement is limited. Therefore, the conventional method using thiophosgene is very troublesome and must be said to be unsuitable for industrial production.

Therefore, several production methods that do not use thiophosgene have been proposed so far. Among them, the methods described in Patent Documents 2 and 3 are methods for obtaining a target compound from the same raw material as in the conventional method using carbon disulfide instead of thiophosgene, and are useful as a safe and inexpensive method. . These methods described in Patent Documents 2 and 3 can be summarized in the following reaction formula iii).

That is, after one raw material 6-methoxy-2-methylaminopyridine (3) is reacted with carbon disulfide to obtain an intermediate raw material sodium dithiocarbamate (6), the other raw material 5,6 , 7,8-tetrahydro-2-naphthol (1) to obtain the target compound (4).
Japanese Examined Patent Publication No. 61-30671 Japanese Patent Publication No. 6-35442 Japanese Examined Patent Publication No. 6-74250

However, in the methods of Patent Documents 2 and 3, the first intermediate raw material sodium dithiocarbamate (6) is reacted with the other raw material 5,6,7,8-tetrahydro-2-naphthol (1). Either one is reacted with 1-chloro-2,4-dinitrobenzene (8), and 5,6,7, which is a second intermediate raw material having a 2,4-dinitrophenyl group as a protecting group. The step of producing 8-tetrahydro-2-naphthyl-2,4-dinitrophenyl ether (7) or dithiocarbamic acid active ester (9) is essential. Further, when the methods disclosed in these documents were further tested, it was found that there was a problem in yield and reproducibility. In addition, the removal of 2,4-dinitrothiophenol produced after the reaction of the second intermediate raw material has a problem that it can be an obstacle in the final purification step of the target product.
As a result of intensive investigations on a new, industrially safe method that overcomes the drawbacks of the above-described prior art, with a small number of steps, in a simple and inexpensive manner, the present inventors have achieved the present invention. It was.

で表される２-(Ｎ-アルキル-Ｎ'-アザアリールチオカルボニルアミノ)-６-アルコキシピリジン化合物、例えば２-[Ｎ-(１-イミダゾイルチオカルボニル)-Ｎ-メチル]アミノ-６-メトキシピリジン等を中間原料とする、Ｏ-アリール Ｎ-(６-アルコキシ-２-ピリジル)-Ｎ-アルキルチオカルバメートの新規な製造方法を提供する。That is, the present invention has the following formula:

2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine compounds represented by, for example, 2- [N- (1-imidazolylthiocarbonyl) -N-methyl] amino-6- Provided is a novel process for producing O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamates using methoxypyridine or the like as an intermediate raw material.

  According to the production method of the present invention, when producing O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate from a starting material similar to the conventional method, highly toxic thiophosgene is used as a sulfur source. Therefore, it is safer than the conventional method and has fewer steps, so it is suitable for industrial production.

BEST MODE FOR CARRYING OUT THE INVENTION

（式中、Ｒ_１、Ｒ_２は相互に依存せずＣ_１−Ｃ_４のアルキル基、Ａｒ_１はアリール基、Ａｒ_２はへテロアリール基を表す。）The production method of the present invention can be outlined by the following reaction formula.

(In the formula, R ₁ and R ₂ are not dependent on each other and represent a C ₁ -C ₄ alkyl group, Ar ₁ represents an aryl group, and Ar ₂ represents a heteroaryl group.)

  More specifically, in the production method of the present invention, 6-alkoxy-2-alkylaminopyridine (II) is reacted with thiocarbonyldiazaaryl (III) to give an intermediate 2- (N-alkyl- N′-azaarylthiocarbonylamino) -6-alkoxypyridine in the first step, and aryl alcohol (V) in the presence of a base or aryl alcohol (V) and a base in advance. And a second step of producing the target O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate by reacting the compound with the adjusted side.

The production method of the present invention is shown by the above reaction formula, and the meaning and examples of the words used in the definition of each symbol used in this formula and in the following explanation will be explained below.
“C ₁ -C ₄ ” means a group having 1 to 4 carbon atoms unless otherwise specified.
“C ₁ -C ₄ alkyl group” means an alkyl group having 1 to 4 carbon atoms, such as a straight chain such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, Examples thereof include a branched alkyl group, and methyl is particularly preferable.
Examples of the “alkali metal” include sodium and potassium.
“Halogen atom” includes fluorine, chlorine, bromine and iodine.
An “aryl group” is an optionally substituted or hydrogenated monocyclic or multicyclic aromatic group such as phenyl, tolyl, naphthyl, especially a C ₁ -C ₄ alkyl group. Good tetrahydronaphthyl group or phenyl group.
“Heteroaryl groups” include aryl groups containing at least one nitrogen atom in the ring, such as mono-, di-, or tri-azaaryl groups, especially substituted with C ₁ -C ₄ alkyl groups And an imidazole group or a 2 (1H) -pyridone group which may be used.
Examples of the “base” include sodium hydride, sodium amide, lithium aluminum hydride, sodium borohydride, lithium amide, lithium hydride, potassium hydride and the like.

According to the method of the present invention, there is an advantage that the target product can be synthesized in two steps starting from 6-alkoxy-2-alkylaminopyridine (II) as in the conventional method.
In the first step, the 6-alkoxy-2-alkylaminopyridine (II) and thiocarbonyldiazaaryl (III) are dissolved in a solvent and optionally heated to react. Examples of thiocarbonyldiazaaryl (III) include thiocarbonyldiimidazole, thiocarbonyldi-2 (1H) -pyridone and the like, and these are easily available as commercial products.

  The thiocarbonyldiazaaryls (III) are preferably used in an amount of about 1.0 to 1.1 times moles relative to 6-alkoxy-2-alkylaminopyridine (II). There is no great effect. As the reaction solvent, ethyl acetate, dichloromethane, chloroform, diethyl ether, tetrahydrofuran (THF), dioxane, benzene, toluene, xylene, N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and the like can be used.

  The reaction temperature is preferably maintained in the range of about 20 ° C to about 100 ° C, preferably about 50 to about 80 ° C. The 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine obtained by the above reaction may be isolated and purified using, for example, column chromatography, but is not isolated. It is also possible to continue using the reaction solution in the second step.

In the second step, 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine (IV) obtained in the first step is added to aryl alcohol (in the presence of a base). The target O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthiocarbamate is produced by reacting V).
As the aryl alcohol (IV), as shown in the definition of Ar ₁ above, tetrahydro-2-naphthol or phenol optionally substituted with a C ₁ -C ₄ alkyl group is preferably used.

Aryl alcohol is usually preferably used in an amount of at least 2 times the molar amount of 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine, and the yield is reduced at less than 2 times the molar amount. There is. The amount of the base used at that time is approximately the same molar amount as the aryl alcohol.
As the base to be used, sodium hydride, lithium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium amide and the like can be used. Is preferred.

  In another embodiment of the second step, an aryl alcohol is previously reacted with a base in a solvent to form an arylalkoxide, and 2- (N-alkyl-N′-azaarylthiocarbonylamino)-is added to the reaction solution. 6-alkoxypyridine is added and allowed to react.

As the reaction solvent used in the second step, good results can be obtained by using DMF, N, N-dimethylacetamide, DMSO, pyridine, quinoline, or a mixed system thereof, but DMF is particularly preferable.
The reaction temperature is preferably maintained in the range of about 10 to 70 ° C. Since this reaction is accelerated by heating, if the temperature is too low, the reaction rate is slow, and if it is too high, side reactions may occur and cause a decrease in yield. Most preferably, the reaction is carried out at about 60 ° C. for about 3 hours.

  In the second step of the method of the present invention, a metal salt such as zinc chloride can be added to the reaction solution, and this addition can reduce the amount of aryl alcohol (or aryl alkoxide) used in half. It becomes possible. That is, when no metal salt was added, it was necessary to use an aryl alcohol at least twice as much as 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine, but the metal salt was added. Thus, the target compound can be obtained in high yield only by using about an equimolar amount of aryl alcohol.

The metal salt _{used, ZnCl 2, ZnBr 2, ZnI} 2, Zn (OAc) 2, ZnSO 4, ZnCO 3, Zn (OH) 2, CuCl 2, PdCl 2, Pd (OAc) 2, NiCl 2, CoCl ₂ , Cu (OAc) ₂ , PdCl ₂ , Pd (PPh ₃ ) ₄ , MgCl ₂ , BiC ₆ H ₅ O ₇ , ZnO, Ni (acac) ₂ , SrCl ₂ 6H ₂ O, Yb (OTf) ₃ , NaH ₂ PO ₄ , CuI, KI, FeSO ₄ , Cu ₂ O, CuO, Fe and the like can be mentioned. In particular, Pd (OAc) ₂ , PdCl ₂ , NiCl ₂ , Cu (OAc) ₂ , MgCl ₂ , Ni (acac) ₂ , NaH ₂ PO ₄ , CuI, ZnCl ₂ , ZnBr ₂ , ZnI ₂ , Zn (OAc) ₂ When ZnSO ₄ , CoCl ₂ , CuCl ₂ is used, a yield of 70% or more is obtained. Among them, ZnCl ₂ , ZnBr ₂ , ZnI ₂ , Zn (OAc) ₂ , ZnSO ₄ , CoCl ₂ , When CuCl ₂ is used, a yield of 90% or more is obtained, and since it is inexpensive, it is particularly preferable from the viewpoint of economy. The amount of metal salt used can be about 0.1 to 2 equivalents, preferably 0.5 to 1 equivalents.

  Note that 6-alkoxy-2-alkylaminopyridine (II) which is a starting material for the method of the present invention is a compound known in the literature, for example, 2,6-dichloropyridine, an alkylamine, and then an alcohol in the presence of a base. Can be easily produced by the reaction, and commercially available products are also available.

メタノール (10ml)に、ナトリウムメトキサイド 0.54g(10.0mmol)を加え、室温で攪拌した。 そこに、５，６，７，８-テトラヒドロ-２-ナフトール 1.50g(10.0mmol)を加え、室温で１時間攪拌した。減圧下溶媒を留去し、白色粉末3.75g(quant.)を得た。デシケーター中で、一晩放置した。EXAMPLES Next, although an Example is shown and this invention is demonstrated in detail, this invention is not limited only to these Examples.
Example 1
1) Synthesis of sodium 5,6,7,8-tetrahydro-2-naphthoxide

To methanol (10 ml) was added sodium methoxide 0.54 g (10.0 mmol), and the mixture was stirred at room temperature. Thereto was added 1.50 g (10.0 mmol) of 5,6,7,8-tetrahydro-2-naphthol, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain 3.75 g (quant.) Of white powder. Left in a desiccator overnight.

酢酸エチル(30 ml)に、６-メトキシ-２-メチルアミノピリジン 2.07g(15.0mmol)と １，１’-チオカルボニルジイミダゾール 2.67g(15.0mmol)を加え、２時間加熱還流した。放冷後、減圧下溶媒を留去し、褐色オイル3.70gを得た。（収率99.3%）。必要に応じて、さらに、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製を行い、淡黄色結晶を得た。
融点：58.0〜60.0℃
NMR(CDCl₃)δppm:3.86(3H,s), 3.87(3H,s), 6.38 (1H,dd, J=7.5Hz, 0.7Hz), 6.61 (1H,dd, J=8.3Hz, 0.7Hz), 6.82 (1H,t, J=1.0Hz) , 7.03 (1H,t, J=1.0Hz) , 7.46 (1H,dd, J=8.3Hz, 7.5Hz), 7.72 (1H,t, J=1.0Hz)
IR(KBr)cm^-1: 1604, 1590, 1571, 1465, 1359, 1303, 1120, 1013, 986, 822, 798
MS m/z: 248(M⁺)2) Synthesis of 2- [N- (1-imidazolylthiocarbonyl) -N'-methyl] amino-6-methoxypyridine

To ethyl acetate (30 ml), 2.07 g (15.0 mmol) of 6-methoxy-2-methylaminopyridine and 2.67 g (15.0 mmol) of 1,1′-thiocarbonyldiimidazole were added and heated under reflux for 2 hours. After allowing to cool, the solvent was distilled off under reduced pressure to obtain 3.70 g of a brown oil. (Yield 99.3%). If necessary, the product was further purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain pale yellow crystals.
Melting point: 58.0-60.0 ° C
NMR (CDCl ₃ ) δppm: 3.86 (3H, s), 3.87 (3H, s), 6.38 (1H, dd, J = 7.5Hz, 0.7Hz), 6.61 (1H, dd, J = 8.3Hz, 0.7Hz) , 6.82 (1H, t, J = 1.0Hz), 7.03 (1H, t, J = 1.0Hz), 7.46 (1H, dd, J = 8.3Hz, 7.5Hz), 7.72 (1H, t, J = 1.0Hz) )
IR (KBr) cm ^-1 : 1604, 1590, 1571, 1465, 1359, 1303, 1120, 1013, 986, 822, 798
MS m / z: 248 (M ⁺ )

Ｎ，Ｎ-ジメチルホルムアミド（4ml）に２-[Ｎ-(１-イミダゾイルチオカルボニル)-Ｎ-メチル]アミノ-６-メトキシピリジン250mg（1.0mmol）を加えて溶解し、次いで室温で、ナトリウム ５，６，７，８-テトラヒドロ-２-ナフトキサイド360mg（2.0mmol）を加えた。一晩室温で攪拌した後、反応液を酢酸エチル（10mlｘ2）で抽出し、途中、不溶物を濾別した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、 硫酸マグネシウムを濾別し、減圧下、溶媒留去した。シリカゲルカラムクロマトグラフィー（ワコーゲルＣ−２００、ヘキサン：酢酸エチル＝１０：１）で精製し、表記化合物266.6mg（収率81.3%）を得た。
融点：99〜100℃
NMR(CDCl₃) δ ppm:1.77(4H,bs), 2.75(4H,bs), 3.75(3H,s), 3.93(3H,s), 6.65(1H,d, J=8.0Hz), 6.78-7.08(4H,m), 7.64(1H,t,J=8.0Hz)
IR(KBr)cm^-1: 1603, 1460, 1413, 1369, 1325, 1262, 1175, 1035, 808, 785
MS m/z: 328(M⁺)3) Synthesis of O- (5,6,7,8-tetrahydro-2-naphthyl) -N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate

N, N-dimethylformamide (4 ml) was dissolved by adding 250 mg (1.0 mmol) of 2- [N- (1-imidazolylthiocarbonyl) -N-methyl] amino-6-methoxypyridine, and then sodium chloride at room temperature. 5,6,7,8-Tetrahydro-2-naphthoxide 360 mg (2.0 mmol) was added. After stirring overnight at room temperature, the reaction mixture was extracted with ethyl acetate (10 ml × 2), and insoluble materials were filtered off along the way. The organic layer was washed with saturated brine, dried over magnesium sulfate, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (Wakogel C-200, hexane: ethyl acetate = 10: 1) gave 266.6 mg (yield 81.3%) of the title compound.
Melting point: 99-100 ° C
NMR (CDCl ₃ ) δ ppm: 1.77 (4H, bs), 2.75 (4H, bs), 3.75 (3H, s), 3.93 (3H, s), 6.65 (1H, d, J = 8.0Hz), 6.78- 7.08 (4H, m), 7.64 (1H, t, J = 8.0Hz)
IR (KBr) cm ^-1 : 1603, 1460, 1413, 1369, 1325, 1262, 1175, 1035, 808, 785
MS m / z: 328 (M ⁺ )

Ｎ，Ｎ-ジメチルホルムアミド（20ml）に60%水素化ナトリウム1.34g（33.6mmol）を加え、次いで、５，６，７，８-テトラヒドロ-２-ナフトール 4.65g（30.5mmol）を加えた。ガスの発生が終了した後、２-[Ｎ-(１-イミダゾイルチオカルボニル)-Ｎ-メチル]アミノ-６-メトキシピリジン 7.45g（30.0mmol）、塩化亜鉛2.05g（15.0mmol）を加えた。60℃で３時間加熱攪拌し、放冷後、反応液を酢酸エチル（150mlｘ2）で抽出し、途中、不溶物を濾別した。有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、硫酸マグネシウムを濾別し、減圧下、溶媒を留去した。得られた結晶を、次のいずれかの方法で精製した。(Example 2)
Synthesis of O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate

To N, N-dimethylformamide (20 ml) was added 1.34 g (33.6 mmol) of 60% sodium hydride, followed by 4.65 g (30.5 mmol) of 5,6,7,8-tetrahydro-2-naphthol. After completion of gas evolution, 7.45 g (30.0 mmol) of 2- [N- (1-imidazolylthiocarbonyl) -N-methyl] amino-6-methoxypyridine and 2.05 g (15.0 mmol) of zinc chloride were added. . The mixture was heated and stirred at 60 ° C. for 3 hours and allowed to cool, then the reaction mixture was extracted with ethyl acetate (150 ml × 2), and insolubles were filtered off. The organic layer was washed with saturated brine, dried over magnesium sulfate, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained crystal was purified by one of the following methods.

A) Purification by silica gel column chromatography (Wakogel C-200, hexane: ethyl acetate = 10: 1) gave 9.80 g (yield 99.5%) of the title compound.
B) Suspended in hexane (10 ml) and stirred for 30 minutes, and then the crystals were collected by filtration to obtain 9.65 g of crystals. The suspension was further suspended in methanol (10 ml) and stirred for 30 minutes. The crystals were collected by filtration to obtain 8.62 g (yield: 87.5%) of the title compound.
The physicochemical data of the obtained compound was in agreement with the compound obtained in the examples.

Table 1 below shows the yield of the final product obtained when no metal salt is added and when various metal salts are added under the above conditions.

酢酸エチル（15ml）に、６-メトキシ-２-メチルアミノピリジン 690mg（5.0mmol）と１，１’-チオカルボニル-ジ-２(１Ｈ)-ピリドン 1.16g（5.0mmol）を加え、１時間加熱還流した。放冷後、減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１０：１）で精製を行い、褐色オイル297.4mgを得た。（収率21.6%）。
NMR(CDCl₃) δ ppm:3.77(3H,s), 3.93(3H,s), 6.66 (1H,dd, J=8.0Hz, 0.7Hz), 7.07 (1H,d, J=8.0Hz), 7.14 (1H,d, J=7.5Hz) , 7.25 (1H,dd, J=8.0Hz, 4.0Hz) , 7.62 (1H,dd, J=8.0Hz, 7.5Hz), 7.78 (1H,dd, J=2.0Hz, 0.7Hz) , 8.43 (1H,dd, J=4.0Hz, 0.7Hz)
MS m/z: 275(M⁺)(Example 3)
1) Synthesis of 2- [N- [1-2 (1H) -pyridonylthiocarbonyl] -N-methyl] amino-6-methoxypyridine

To ethyl acetate (15 ml), add 690 mg (5.0 mmol) of 6-methoxy-2-methylaminopyridine and 1.16 g (5.0 mmol) of 1,1′-thiocarbonyl-di-2 (1H) -pyridone and heat for 1 hour. Refluxed. After allowing to cool, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 10: 1) to obtain 297.4 mg of a brown oil. (Yield 21.6%).
NMR (CDCl ₃ ) δ ppm: 3.77 (3H, s), 3.93 (3H, s), 6.66 (1H, dd, J = 8.0Hz, 0.7Hz), 7.07 (1H, d, J = 8.0Hz), 7.14 (1H, d, J = 7.5Hz), 7.25 (1H, dd, J = 8.0Hz, 4.0Hz), 7.62 (1H, dd, J = 8.0Hz, 7.5Hz), 7.78 (1H, dd, J = 2.0 Hz, 0.7Hz), 8.43 (1H, dd, J = 4.0Hz, 0.7Hz)
MS m / z: 275 (M ⁺ )

Ｎ，Ｎ-ジメチルホルムアミド（2ml）に、２-[Ｎ-[１-２(１Ｈ)-ピリドニルチオカルボニル]-Ｎ-メチル]アミノ-６-メトキシピリジン 297mg（1.08mmol）とナトリウム ５，６，７，８-テトラヒドロ-２-ナフトキサイド 390mg（2.16mmol）を加え、室温で終夜攪拌した。反応液を酢酸エチル（50mlｘ2）で抽出し、有機層を飽和食塩水で洗浄し、硫酸マグネシウムで乾燥し、硫酸マグネシウムを濾別し、減圧下、溶媒留去した。得られた結晶を、シリカゲルカラムクロマトグラフィー（ワコーゲルＣ−２００、ヘキサン：酢酸エチル＝１０：１）で精製し、表記化合物288.2mg（81.4%）を得た。
得られた化合物の物理化学的データは、実施例で得られた化合物と一致した。2) Synthesis of O- (5,6,7,8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthiocarbamate

To N, N-dimethylformamide (2 ml), 297 mg (1.08 mmol) of 2- [N- [1-2 (1H) -pyridonylthiocarbonyl] -N-methyl] amino-6-methoxypyridine and sodium 5,6 , 7,8-tetrahydro-2-naphthoxide 390 mg (2.16 mmol) was added and stirred at room temperature overnight. The reaction mixture was extracted with ethyl acetate (50 ml × 2), the organic layer was washed with saturated brine, dried over magnesium sulfate, the magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained crystals were purified by silica gel column chromatography (Wakogel C-200, hexane: ethyl acetate = 10: 1) to obtain 288.2 mg (81.4%) of the title compound.
The physicochemical data of the obtained compound was in agreement with the compound obtained in the examples.

The method of the present invention is a method for producing O-aryl N- (alkoxy-2-pyridyl) -N-alkylthiocarbamates useful as pharmaceuticals, agricultural chemicals or intermediates thereof, without using highly toxic thiophosgene. It is characterized by the fact that 1-thiocarbonylimidazole is used as a sulfur source and a metal salt is added as a reaction activator, so that it can be carried out safely and in high yield, and is suitable for industrial production.

Claims (9)

The following formula (I):

(Wherein R ₁ and R ₂ independently represent a C ₁ -C ₄ alkyl group, Ar ₁ represents an aryl group, and the same shall apply hereinafter).
Formula (II) below:

A 6-alkoxy-2-alkylaminopyridine represented by the following formula (III):

(Wherein Ar ₂ represents a heteroaryl group containing at least one nitrogen atom, and the same shall apply hereinafter)
Is reacted with thiocarbonyldiazaaryl represented by the following formula (VI):

A first step represented by 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine represented by:
Next, the intermediate (V)
Ar ₁ OH (V)
Is reacted in the presence of a base or with an aryl alkoxide prepared in advance from the aryl alcohol (V) and a base to produce the desired O-aryl N- (6-alkoxy). A process comprising a second step of obtaining (2-pyridyl) -N-alkylthiocarbamate. The aryl group is a 5,6,7,8-tetrahydro-2-naphthyl group or a phenyl group which may be substituted with a C ₁ -C ₄ alkyl group, and the heteroaryl group is a C ₁ -C ₄ The method according to claim 1, wherein the method is an imidazole group or a 2 (1H) -pyridone group which may be substituted with an alkyl group. In the first step, the thiocarbonyldiazaaryl is reacted at a temperature of 20 ° C. to 100 ° C. at a ratio of 1.0 to 1.1 times mol with respect to 6-alkoxy-2-alkylaminopyridine. The method according to claim 1 or 2, characterized in that In the second step, the aryl alcohol or aryl alkoxide is 10 to 10 moles of 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine at a ratio of 2 moles or more. The process according to claim 1, wherein the reaction is performed at a temperature of 70 ° C. The method according to claim 1, wherein the second step is performed in the presence of a metal salt. Metal salts are ZnCl ₂ , ZnBr ₂ , ZnI ₂ , Zn (OAc) ₂ , ZnSO ₄ , CoCl ₂ , CuCl ₂ , Pd (OAc) ₂ , PdCl ₂ , NiCl ₂ , Cu (OAc) ₂ , MgCl ₂ , Ni _{(acac) 2, NaH 2 PO} 4, characterized in that it is selected from CuI, the method of claim 5. Metal salts, characterized in _{ZnCl 2, ZnBr 2, ZnI 2} , Zn (OAc) 2, ZnSO 4, is selected from CoCl _2, CuCl _2, The method of claim 6. The method according to claim 5, wherein the amount of the metal salt is 0.1 to 2 equivalents. 9. The aryl alcohol or aryl alkoxide is reacted with 2- (N-alkyl-N′-azaarylthiocarbonylamino) -6-alkoxypyridine in an equimolar amount. The method according to any one of the above.