WO2007010744A1 - Procédé pour la production d'un dérivé de thiocarbamate - Google Patents

Procédé pour la production d'un dérivé de thiocarbamate Download PDF

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Publication number
WO2007010744A1
WO2007010744A1 PCT/JP2006/313330 JP2006313330W WO2007010744A1 WO 2007010744 A1 WO2007010744 A1 WO 2007010744A1 JP 2006313330 W JP2006313330 W JP 2006313330W WO 2007010744 A1 WO2007010744 A1 WO 2007010744A1
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WIPO (PCT)
Prior art keywords
group
alkyl
aryl
alkoxy
following formula
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PCT/JP2006/313330
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English (en)
Japanese (ja)
Inventor
Kenichi Saitoh
Tetsuo Watanabe
Sumio Terada
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Zenyaku Kogyo Kabushikikaisha
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Priority to JP2007525938A priority Critical patent/JPWO2007010744A1/ja
Publication of WO2007010744A1 publication Critical patent/WO2007010744A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the present invention relates to a novel process for producing a thiocarbamate derivative represented by the following general formula (I), more specifically 0-aryl ⁇ - (6-alkoxy-2-pyridyl) - ⁇ -alkylthio strength rubamate About.
  • R and R represent an alkyl group, and Ar represents an aryl group.
  • O-aryl N- (6-alkoxy-2-pyridyl) -N-alkylthio strength rubamate is a useful compound as a pharmaceutical agent such as a remedy for athlete's foot, an agrochemical such as a herbicide, or an intermediate material thereof.
  • 0- (5, 6, 7, 8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N-methylthio strength rubamate is known to be a useful compound as an athlete's foot treatment. ing.
  • Patent Document 1 discloses 0- (5, 6, 7, 8-tetrahydro-2-naphthyl) N- (6-methoxy-2-pyridyl) -N- represented by the following reaction formula 0 or ii): A process for producing methylthio strength rubamate (4) is disclosed.
  • 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, it can be said that the conventional method using thiophosgene is very troublesome and unsuitable for industrial production.
  • Patent Documents 2 and 3 are methods for obtaining a target compound from raw materials similar to the conventional method using disulfur carbon instead of thiophosgene, and are useful as a safe and inexpensive method. It is. These methods described in Patent Documents 2 and 3 can be summarized in the following reaction formula iii).
  • Patent Document 1 Japanese Patent Publication No. 61-30671
  • Patent Document 2 Japanese Patent Publication No. 6-35442
  • Patent Document 3 Japanese Patent Publication No. 6-74250
  • the present inventors have developed a new, industrially safe, and small amount that overcomes the drawbacks of the prior art. As a result of intensive studies on a method for producing the compound in a simple and inexpensive process, the present invention has been achieved.
  • 2- (N-alkyl- ⁇ '-azaarylthiocarbolamino) -6-alkoxypyridine compounds such as 2- [ ⁇ - (1-imidazolylthiocarbol) - ⁇ -methyl]
  • 2- [ ⁇ - (1-imidazolylthiocarbol) - ⁇ -methyl] Provided is a novel process for producing 0-aryl ⁇ - (6-alkoxy-2-pyridyl) - ⁇ -alkylthio rubbamate using amino-6-methoxypyridine as an intermediate raw material.
  • a starting material force similar to that in the conventional method is used as a thiol source in producing 0-aryl ⁇ - (6-alkyloxy-2-pyridyl) - ⁇ -alkylthiocarbamate.
  • This method is safer than conventional methods because it does not use highly toxic thiophosgene, and it has fewer steps, making it suitable for industrial production.
  • the production method of the present invention can be outlined by the following reaction formula.
  • R R is not dependent on C C alkyl group, Ar is aryl group, Ar is he
  • 6-alkoxy-2-alkylaminoviridine (II) is reacted with thiocarbodiazaryl (III) to give an intermediate 2_ (N-alkyl- ⁇ '-azaarylthiocarbo-lumino) -6-alkoxypyridine as the first step;
  • thiocarbodiazaryl (III) is reacted with thiocarbodiazaryl (III) to give an intermediate 2_ (N-alkyl- ⁇ '-azaarylthiocarbo-lumino) -6-alkoxypyridine as the first step;
  • allyl alcohol (V) in the presence of a base, or allylic alcohol (V) and a base and preparing a allylic alkoxide.
  • C C means a group having 1 to 4 carbon atoms unless otherwise specified.
  • C 1 -C alkyl group means an alkyl group having 1 to 4 carbon atoms, such as methyl
  • Examples include linear or branched alkyl groups such as til, n-propyl, iso-propyl, n-butyl, tert-butyl and the like, with methyl being particularly preferred.
  • alkali metal examples include sodium and potassium.
  • Halogen atom includes fluorine, chlorine, bromine and iodine.
  • aryl group is optionally substituted or hydrogenated, but may be substituted with a monocyclic or polycyclic aromatic group such as phenol, tolyl, naphthyl, in particular a C—C alkyl group.
  • a tetrahydronaphthyl group or a phenol group may be mentioned.
  • Heteroaryl group includes an aryl group containing at least one nitrogen atom in the ring, for example, a mono-, di-, or triazayl group, and in particular, a c-c alkyl group.
  • the imidazole group or the 2 (1H) -pyridone group may be mentioned.
  • base examples include sodium hydride, sodium amide, lithium aluminum hydride, sodium borohydride, lithium amide, lithium hydride, potassium hydride and the like.
  • the target product can be synthesized in two steps starting from 6-alkoxy-2-alkylaminoviridine (II) as in the conventional method.
  • the 6-alkoxy-2-alkylaminoviridine ( ⁇ ) and thiocarbodiazalyl (III) are dissolved in a solvent and optionally heated to react.
  • thiocarbodiazareal ( ⁇ ) include thiocarbodidiimidazole, thiocarbonyldi-2 (1H) -pyridone, etc., and these are readily available as commercial products.
  • Thiocarbodiazaryls ( ⁇ ) are 6-alkoxy-2-alkylaminopyridines. It is preferable to use about 1.0 to 1.1 moles of (II), and even if this amount is increased further, there is no effect.
  • As the reaction solvent ethyl acetate, dichloromethane, chloroform, jetyl 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- ⁇ '-azaarylthiocarbolamino) -6_alkoxypyridine obtained by the above reaction may be isolated and purified using, for example, column chromatography. It is also possible to use the reaction solution in the second step without isolation.
  • the 2- ( ⁇ -alkyl- ⁇ '-azaarylthiocarbo-lumino) -6-alkoxypyridine (IV) obtained in the first step is added to the allylic alcohol in the presence of a base.
  • the desired 0-aryl ⁇ - (6-alkoxy-2-pyridyl) - ⁇ -alkylthio strength rubamate is produced by reacting the alcohol (V).
  • the aryl alcohol (IV) is preferably tetrahydro-2-naphthol or phenol optionally substituted with a C 1 -C alkyl group as shown in the definition of Ar above.
  • Aryl alcohol is usually preferred to be used in an amount of at least 2 times the mole of 2- (N-alkyl- ⁇ '-azaarylthiocarbo-lumino) -6-alkoxypyridine. Then, the yield may decrease. In addition, the amount of base used at that time is approximately the same molar amount as that of aryl alcohol.
  • 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.
  • Sodium halide is preferred.
  • allyl alcohol is previously reacted with a base in a solvent to form allyl alkoxide, and 2- ( ⁇ -alkyl- ⁇ '-azaly is added to the reaction solution.
  • 2- ( ⁇ -alkyl- ⁇ '-azaly is added to the reaction solution.
  • (Luthiocarbo-lumino) -6-alkoxypyridine is added and reacted.
  • reaction solvent used in the second step good results can be obtained by using DMF, ⁇ , N-dimethylacetamide, DMSO, pyridine, quinoline, or a mixed system thereof. 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 too slow. If the temperature 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.
  • a metal salt such as zinc chloride can be added to the reaction solution, and by this additive, allylic alcohol (or allylic alkoxide) is added.
  • the amount used can be halved.
  • a force metal salt that required the use of 2- (N-alkyl-N′-azaarylthiocarbo-lumino) -6-alkoxypyridine at least twice the mole of alcohol was used.
  • the target compound can be obtained in high yield only by using about equimolar amount of aryl alcohol.
  • Metal salts used include ZnCl, ZnBr, Znl, Zn (OAc), ZnSO, ZnCO, Zn (OH)
  • the amount of metal salt used can be about 0.1 to 2 equivalents, preferably 0.5 to 1 equivalents.
  • 6-alkoxy-2-alkylaminoviridine (II) which is a starting material for the method of the present invention, is a known compound in the literature, such as 2,6-dichloropyridine, alkylamine, and then a base. It can be easily produced by reacting alcohol in the presence, and commercial products are also available.
  • N-dimethylformamide (20 ml) was added 1.34 g (33.6 mmol) of 60% sodium hydride, and then 4.65 g (30.5 mmol) of 5, 6, 7, 8-tetrahydro-2-naphthol was added. After gas evolution is complete, add 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. It was. The mixture was heated and stirred at 60 ° C. for 3 hours and allowed to cool, and then the reaction solution was extracted with ethyl acetate (150 ml ⁇ 2). The organic layer was washed with saturated brine, dried over magnesium sulfate, and magnesium sulfate was filtered off. Separately, the solvent was distilled off under reduced pressure. The obtained crystal was purified by one of the following methods.
  • the physicochemical data of the obtained compound was consistent with the compounds obtained in the examples.
  • Table 1 below shows the yield of the final product obtained when the metal salt was not added under the above conditions and when various metal salts were added.
  • N, N-dimethylformamide (2 ml) was mixed with 297 mg (1.08 mmol) of 2- [N- [1-2 (1H) -pyridonylthiocarbol] -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 solution was extracted with ethyl acetate (50 ml ⁇ 2), 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 physicochemical data of the obtained compound was consistent with the compounds obtained in the examples.
  • the method of the present invention uses highly toxic thiophosgene in producing 0-aryl N- (alkoxy-2-pyridyl) -N-alkylthio strength rubamates useful as pharmaceuticals, agricultural chemicals or intermediates thereof. It is characterized by the fact that it can be carried out safely and in high yield by using 1, 1-thiocarbonylimidazole as a io source and adding a metal salt as a reaction activator. Suitable for manufacturing.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

L'invention a pour objet un procédé servant à produire un dérivé de thiocarbamate, lequel est utile comme produit pharmaceutique, produit agrochimique ou similaire, sans danger, avec un plus petit nombre d'étapes, d'une manière simple et à faible coût. L'invention concerne un procédé servant à produire un O-aryl-N-(6-alcoxy-2-pyridyl)-N-alkylthiocarbamate comprenant la réaction d’une 6-alcoxy-2-alkylaminopyridine avec un thiocarbonyldiazaaryle pour produire une 2-(N-alkyl-N'-azaarylthiocarbonylamino)-6-alcoxypyridine en tant qu'intermédiaire et ensuite de faire réagir l'intermédiaire avec un alcool arylique en présence d'une base ou avec un arylalcoolate pour de cette manière produire le produit souhaité.
PCT/JP2006/313330 2005-07-22 2006-07-04 Procédé pour la production d'un dérivé de thiocarbamate WO2007010744A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2007525938A JPWO2007010744A1 (ja) 2005-07-22 2006-07-04 チオカルバメート誘導体の製造法

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JP2005212653 2005-07-22
JP2005-212653 2005-07-22

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WO2007010744A1 true WO2007010744A1 (fr) 2007-01-25

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5951265A (ja) * 1982-06-10 1984-03-24 Toyo Soda Mfg Co Ltd カ−バメ−ト誘導体
JPH04352782A (ja) * 1990-07-12 1992-12-07 Sankyo Co Ltd ピリジン誘導体及び選択性除草剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5951265A (ja) * 1982-06-10 1984-03-24 Toyo Soda Mfg Co Ltd カ−バメ−ト誘導体
JPH04352782A (ja) * 1990-07-12 1992-12-07 Sankyo Co Ltd ピリジン誘導体及び選択性除草剤

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JPWO2007010744A1 (ja) 2009-01-29
TW200734307A (en) 2007-09-16

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