WO2007086559A1 - Method for producing tetrahydropyran compound - Google Patents

Method for producing tetrahydropyran compound Download PDF

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Publication number
WO2007086559A1
WO2007086559A1 PCT/JP2007/051387 JP2007051387W WO2007086559A1 WO 2007086559 A1 WO2007086559 A1 WO 2007086559A1 JP 2007051387 W JP2007051387 W JP 2007051387W WO 2007086559 A1 WO2007086559 A1 WO 2007086559A1
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formula
carboxylic acid
represented
alkali metal
general formula
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PCT/JP2007/051387
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French (fr)
Japanese (ja)
Inventor
Shigeyoshi Nishino
Kenji Hirotsu
Hidetaka Shima
Shoji Shikita
Keiji Iwamoto
Takashi Harada
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Ube Industries, Ltd.
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Priority to JP2007556037A priority Critical patent/JP5205971B2/en
Publication of WO2007086559A1 publication Critical patent/WO2007086559A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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

Definitions

  • the present invention relates to a process for producing 4-cyananotetrahydropyran-4-carboxylic acid ester from bis (2-halogenoethyl) ether and cyanoacetic acid ester, 4-cyananotetrahydropyran-4-carboxylic acid ester Furthermore, the present invention relates to a method for producing 4-cianotetrahydropyran and 4-cyanotetrahydropyranca also relates to a method for producing tetrahydropyran-4-carboxylic acid amide.
  • 4-cianotetrahydropyran-4-carboxylic acid ester, 4-cianotetrahydropyran and tetrahydropyran-4-carboxylic acid amide are useful compounds as raw materials and synthetic intermediates for pharmaceuticals and agricultural chemicals, for example (for example, see Patent Documents 1 and 2.)
  • 4-cianotetrahydropyran from 4-cianotetrahydropyran-4-carboxylic acid ester
  • 4-cianotetrahydropyran-4-carboxylic acid ester is hydrolyzed.
  • 4-cianotetrahydropyran-4-carboxylic acid obtained by heating to 180-200 ° C. is known to obtain 4-cianotetrahydropyran in an isolated yield of 66%.
  • this method requires a high reaction temperature, which is not satisfactory as an industrial production method of 4-cianotetrahydropyran.
  • tetrahydropyran-4-carboxylic acid amide for example, tetrahydropyran-4-carboxylic acid methyl is reacted in a mixed solution of ammonia water Z methanol to give tetrahydropyran-4.
  • a method for producing a carboxylic acid amide is known (for example, see Patent Document 2).
  • this method has a problem in that it is necessary to use a strong ammonia water.
  • Patent Document 1 Pamphlet of International Publication No. 2005/514389
  • Patent Document 2 International Publication No. 2005/032848 Pamphlet
  • Patent Document 3 International Publication No. 2005/028410 Pamphlet
  • Non-patent document 1 J. Chem. Soc, 1930, 2525
  • the first problem of the present invention is to solve the above-mentioned problems and from 4-bisnotetrahydropyran from bis (2-halogenoethyl) ether and cyanate ester by a simple method under mild conditions. -To provide an industrially suitable method for producing 4-cyanotetrahydropyran-4-carboxylic acid ester capable of producing 4-carboxylic acid ester in high yield.
  • the second problem of the present invention is to solve the above-mentioned problems, and to increase 4-cyantetrahydropyran 4-carboxylic acid ester strength by a simple method under mild conditions. An industrially suitable process for producing 4-cianotetrahydropyran, which can be produced in a yield, is provided.
  • the third object of the present invention is to solve the above-mentioned problems and to give high yields of 4-cyantetrahydropyranca and tetrahydropyran-4-carboxylic acid amide by a simple method under mild conditions.
  • the first subject of the present invention is the general formula (1):
  • X represents a halogen atom
  • R 1 represents an alkyl group having 2 to 6 carbon atoms
  • R 2 is the same as or different from R 1 to display the alkyl group having 1 to 6 carbon atoms also, M represents an alkali metal atom,
  • R 1 and R 2 are as defined above.
  • At least one 4-cianotetrahydropyran-4-carboxylic acid ester selected from the group consisting of It is solved by the manufacturing method of Tell.
  • the second problem of the present invention is that at least one of the 4-cyantetrahydropyran-4-carboxylic acid esters represented by the general formulas (4a) and (4b), an alkali metal alkoxide, and a carboxylic acid. It is characterized by reacting an alkali metal salt or a mixture thereof in at least one solvent selected from the group consisting of carbonates, amides, amines, ureas, sulfoxides and sulfones.
  • a third object of the present invention is to react the 4-cianotetrahydropyran represented by the general formula (5) with a base group in a solvent, the general formula (6):
  • the above three steps may be carried out continuously, or any two successive steps may be carried out continuously without isolating and purifying the target product.
  • 4-cianotetrahydropyran-4-carboxylic acid ester is increased from bis (2-halogenoethyl) ether and cyanoacetate by a simple method under mild conditions.
  • An industrially suitable method for producing 4-cyanotetrahydropyran-4-carboxylic acid ester that can be produced in a yield can be provided.
  • 4-cianotetrahydropyran-4-carboxylic acid ester 4-cianotetrahydropyran can be produced in a high yield by a simple method under mild conditions. It is possible to provide a method for producing 4-cianotetrahydropyran suitable for the above.
  • 4-cianotetrahydro Pilanka can also provide an industrially preferred method for producing tetrahydropyran-4-carboxylic acid amide, which can produce tetrahydropyran-4-carboxylic acid amide in high yield.
  • the bis (2-halogenoethyl) ether used in the first invention is represented by the general formula (1).
  • X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom or a bromine atom.
  • bis (2-halogenoethyl) ether examples include bis (2-chloroethyl) ether, bis (2-bromoethyl) ether, and bis (2-iodoethyl) ether.
  • bis (2-chloroethyl) ether or bis (2-bromoethyl) ether is used. Note that these bis (2-nitrogenoethyl) ethers may be used alone or in admixture of two or more.
  • R 1 is an alkyl group having 2 to 6 carbon atoms, and examples thereof include an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group.
  • the amount of the cyanoacetate used is preferably 0.8 to 20 mol, more preferably 1.0 to 4.0 mol, per 1 mol of bis (2-halogenoethyl) ether.
  • R 2 is a force indicating an alkyl group having 1 to 6 carbon atoms which may be the same as or different from R 1.
  • R 1 methyl group, ethyl group, propyl group, butyl group, pentyl group And hexyl group and the like, preferably a methyl group, an ethyl group, a butyl group and a pentyl group, more preferably a butyl group (note that these groups include various isomers).
  • Represents an alkali metal atom for example, a force including a lithium atom, a sodium atom and a potassium atom, preferably a sodium atom and a potassium atom, more preferably a sodium atom.
  • alkali metal alkoxide examples include, for example, sodium methoxide, strong methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium t- Butoxide, potassium t-butoxy Alkali metal alkoxides such as sodium and sodium t-pentoxide, preferably sodium methoxide, sodium ethoxide, sodium t-butoxide, sodium t-pentoxide and potassium t-butoxide are used. These bases may be used alone or in combination of two or more.
  • the amount of the base used is preferably 1.5-10.0 mol, more preferably 1.8-5.0 mol, per 1 mol of bis (2-halogenoethyl) ether.
  • the organic solvent used in the first invention is not particularly limited as long as it does not inhibit the reaction.
  • alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol
  • ⁇ , ⁇ -dimethyl Amides such as formamide, ⁇ , ⁇ -dimethylacetamide, and ⁇ ⁇ ⁇ -methylpyrrolidone
  • Ureas such as 1,3-dimethyl-2-imidazolidinone
  • Sulfoxides of dimethyl sulfoxide Sulfones such as sulfolane
  • Toluene And aromatic hydrocarbons such as xylene
  • -tolyls such as acetonitrile and propio-tolyl
  • ethers such as diethyl ether and tetrahydrofuran S, preferably amides and sulfoxides are used.
  • the amount of the organic solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 0.5 to 30 ml, more preferably 1 to 20 with respect to bis (2-halogenoethyl) ether lg. ml.
  • the first invention is carried out, for example, by a method of mixing bis (2-halogenoethyl) ether, cyanoacetic ester, a base group and an organic solvent and stirring them.
  • the reaction temperature at that time is preferably 10 to 150 ° C, more preferably 30 to 130 ° C, and the reaction pressure is not particularly limited.
  • a cyanoacetate and an alkali metal alkoxide are reacted in advance to form an alkali metal salt of cyanoacetate, and then mixed with bis (2-halogenoethyl) ether. And how to react.
  • the power to obtain at least one 4-cyanotetrahydropyran-4-carboxylic acid ester selected from the group consisting of the general formulas (4a) and (4b) may be obtained after completion of the reaction.
  • the reaction For example, filtration, concentration, extraction, distillation, recrystallization and column chromatography, etc. Isolated and purified by conventional methods. It is also possible to continuously carry out the following second invention without isolation and purification.
  • the 4-cyantetrahydropyran-4-carboxylic acid ester used in the reaction of the second invention is at least one of those represented by the general formulas (4a) and (4b). It is.
  • R 1 and R 2 are as defined above.
  • an alkali metal alkoxide or an alkali metal carboxylate is used.
  • the alkali metal alkoxide include the alkali metal alkoxides represented by the above formula (3).
  • sodium methoxide is used.
  • alkali metal carboxylate examples include alkali metal formate such as potassium formate and sodium formate; alkali metal acetate such as sodium acetate and potassium acetate; alkali metal propionate such as potassium propionate and sodium propionate
  • alkali metal benzoate such as potassium benzoate and sodium benzoate, and the like, preferably sodium acetate and potassium acetate are used.
  • the amount of the alkali metal alkoxide to be used is preferably 0.1 to 50 mol, more preferably 0.5 to 20 mol, particularly preferably 0.8 to 1 mol of 4-cyantetrahydropyran-4-carboxylic acid ester. ⁇ 5.0 monole.
  • the reaction of the second invention is carried out in at least one solvent selected from the group consisting of carbonates, amides, amines, ureas, sulfoxides and sulfones, and the solvent used is Carbonates such as dimethyl carbonate, jetyl carbonate and ethylene carbonate; amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide and ⁇ ⁇ ⁇ -methylpyrrolidone; 1,3-dimethyl- Ureas such as 2-imidazolidinone; amines such as tri- ⁇ -butylamine, tri- ⁇ -octylamine, pyridine, 2-picoline, 3-picoline, quinoline; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane Is mentioned.
  • the solvent used is Carbonates such as dimethyl carbonate, jetyl carbonate and ethylene carbonate; amides such as ⁇ , ⁇ -d
  • carbonates, amides, amines and ureas are used.
  • solvents may be used alone or in combination of two or more.
  • hydrocarbons for example, cycloheptane, toluene, xylene, etc.
  • hydrocarbons for example, cycloheptane, toluene, xylene, etc.
  • the amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.1 to 100 ml, more preferably 4-cyantetrahydropyran-4-carboxylic acid ester lg. Is 0.5 to 50 ml, particularly preferably 1.0 to 10 ml.
  • the reaction of the second invention is, for example, 4-cianotetrahydropyran-4-carboxylic acid ester, alkali metal alkoxide, carboxylic acid alkali metal salt, or a mixture thereof, as well as carbonates, amides, urea. And at least one solvent selected from the group that also has the ability to sulphate, amines, sulfoxides, and sulphones, and the like.
  • the reaction temperature at that time is preferably 20 to 170 ° C, more preferably 50 to 160 ° C, and the reaction pressure is not particularly limited! ,.
  • the final product 4-cianotetrahydropyran
  • the final product is isolated and purified by general methods such as filtration, extraction, concentration, distillation, recrystallization, and column chromatography after completion of the reaction.
  • the base used in the third invention is, for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as potassium carbonate and sodium carbonate; Salts; alkali metal alkoxides such as sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide
  • alkali metal hydroxides are used, more preferably sodium hydroxide and potassium hydroxide.
  • the amount of the base used is preferably 0.1 to 10 with respect to 1 mol of 4-cianotetrahydropyran.
  • the solvent used in the present invention is not particularly limited as long as it does not inhibit the reaction.
  • water methanol, ethanol, isopropyl alcohol, n-butyl alcohol And alcohols such as t-butyl alcohol; Amides such as ⁇ , ⁇ -dimethylformamide, ⁇ , ⁇ -dimethylacetamide and ⁇ -methylpyrrolidone; Ureas such as 1,3-dimethyl-2-imidazolidinone; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Ethers such as jetyl ether and tetrahydrofuran
  • alcohols such as methanol, ethanol, ⁇ -butyl alcohol and t-butyl alcohol are used. .
  • the amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.5 to 30 ml, more preferably 1 to 20 ml, relative to 4-cyantetrahydropyran lg.
  • the present invention is carried out by a method of, for example, mixing 4-cianotetrahydropyran, a base and a solvent and stirring them.
  • the reaction temperature at that time is preferably 20 to 150 ° C., more preferably 30 to 130 ° C., and the reaction pressure is not particularly limited. In the present invention, it is desirable that water be present during the reaction.
  • the amount of water used is preferably 0.01 to 50.0 mol, more preferably 0.1 to 10.0 mol, per 1 mol of 4-cyantetrahydropyran.
  • the ability to obtain tetrahydropyran-4-carboxylic acid amide according to the present invention is obtained after completion of the reaction, such as filtration, concentration, neutralization, extraction, distillation, recrystallization, column chromatography, etc. It is isolated and purified by a general method.
  • the reactivity is adjusted by the presence of a peroxide (for example, hydrogen peroxide, etc.) or a phase transfer catalyst (quaternary ammonium salt, quaternary phosphoric salt, etc.). You may do it.
  • a peroxide for example, hydrogen peroxide, etc.
  • a phase transfer catalyst quaternary ammonium salt, quaternary phosphoric salt, etc.
  • a glass flask with an internal volume of 200 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 60 ml of ⁇ , ⁇ -dimethylformamide and 18.9 g (346.4 mmol) of sodium methoxide with a purity of 99% in an argon atmosphere.
  • 39.6 g (343.1 mmol) of ethyl cyanoacetate having a purity of 98% was gently added dropwise.
  • the solution was stirred at 30 ° C. for 2 hours to prepare a solution containing sodium salt of cyanoacetate.
  • reaction solution was cooled to 0 ° C., and 23.2 g (174.7 mmol) of dimethyl sulfate having a purity of 95% was slowly added dropwise.
  • the mixture was reacted at room temperature for 1 hour to induce by-produced 4-cianotetrahydropyran-4-carboxylic acid to a methyl ester, and the abundance thereof was confirmed.
  • the amount of 4-cyantetrahydropyran-4-carboxylic acid produced was calculated to be 2.05 g. (It was 18.9% based on bis (2-chloroethyl) ether.)
  • a glass flask equipped with a stirrer, a dropping funnel and a thermometer with an internal volume of 500 ml was charged with 56.13 g (0.5 mol) of 4-cyantetrahydropyran with a purity of 99%, 281 ml of t-butyl alcohol and a hydroxide with 85% purity. Potassium 39.61 g (0.6 mol) was added, and the reaction was carried out at 100 ° C for 2 hours with stirring. After completion of the reaction, 112 ml of toluene and 112 ml of water were added, and 50 ml of 35% hydrochloric acid was added dropwise while maintaining the liquid temperature at 25 ° C. or lower to adjust the pH to 7.5.
  • the aqueous layer was separated at room temperature, and the aqueous layer was extracted with 281 ml of ethyl acetate. Combine the resulting organic layer and the extract, and reduce the pressure. The mixture was concentrated (60 ° C, 2.0 kPa) to obtain 43.47 g of tetrahydropyran-4-carboxylic acid amide having a purity of 92.5% by mass (internal standard method by gas chromatography) (isolated yield; 62.3%). Further, the aqueous layer was analyzed by gas chromatography (internal standard method) and found to contain 2.45 g of tetrahydropyran-4-carboxylic acid amide carbonate (19.3%). The physical properties of tetrahydropyran-4-carboxylic acid amide were as follows.
  • a glass flask with an internal volume of 500 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 289 ml of ⁇ , ⁇ -dimethylformamide and 68.2 g (1.25 mol) of sodium methoxide with a purity of 99% under an argon atmosphere.
  • 144.3 g (1.25 mmol) of 98% pure ethyl cyanoacetate was gently added dropwise. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 1 hour to prepare a solution containing sodium salt of cyanoacetate.
  • a glass flask with an internal volume of 1000 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 72.2 g (0.50 mol) of 99% pure bis (2-chloroethyl) ether, and the liquid temperature was adjusted. After the temperature was raised to 80 ° C., the solution containing the sodium salt of cyanoacetate was slowly added dropwise.
  • reaction solution was cooled to 10 ° C, and with stirring, 18.2 g (0.30 mol) of acetic acid was slowly added dropwise, followed by addition of 361 ml of water.
  • the aqueous layer and the organic layer (toluene layer) are separated, and the aqueous layer is extracted once with 144 ml of toluene, and then the organic layer and the toluene extract are combined and washed three times with 217 ml of 20 wt% brine.
  • reddish purple liquid was analyzed by gas chromatography (internal standard method), and methyl 4-cyantetrahydride pyran-4-carboxylate 43.lg (bis Yield based on (2-chloroethyl) ether: 51.0 %), And 25.9 g of 4-cianotetrahydropyran-4-carboxylate (yield based on bis (2-chloroethyl) ether: 28.3%).
  • This reddish purple liquid was distilled under reduced pressure (92 to 101 ° C, 0.71 to 1.08 kPa) to obtain 57.4 g of a colorless transparent liquid.
  • the 4-cyanonotehydropyran-4-carboxylic acid ester, 4-cyanonotetrahydropyran, and tetrahydropyran-4-carboxylic acid amide obtained by the present invention are useful, for example, as raw materials for pharmaceuticals, agricultural chemicals, and synthetic intermediates.

Abstract

Disclosed is a method for producing a 4-cyanotetrahydropyran-4-carboxylic acid ester represented by the general formula (4a) or (4b) below, which is characterized in that a bis(2-halogenoethyl) ether represented by the general formula (1) below, a cyanoacetic acid ester represented by the general formula (2) below and an alkali metal alkoxide represented by the general formula (3) below are reacted in an organic solvent. (1) (In the formula, X represents a halogen atom.) (2) (In the formula, R1 represents an alkyl group having 2-6 carbon atoms.) (3) (In the formula, R2 may be the same as or different from R1 and represents an alkyl group having 1-6 carbon atoms, and M represents an alkali metal atom.) (4a) (4b) (In the formulae, R1 and R2 are as defined above.) Also disclosed is a method for producing 4-cyanotetrahydropyran represented by the formula (5), which is characterized in that at least one 4-cyanotetrahydropyran-4-carboxylic acid ester is reacted in a solvent. Further disclosed is a method for producing tetrahydropyran-4-carboxylic acid amide represented by the general formula (6), which is characterized in that the 4-cyanotetrahydropyran and a base are reacted in a solvent.

Description

明 細 書  Specification
テトラヒドロピラン化合物の製造方法  Method for producing tetrahydropyran compound
技術分野  Technical field
[0001] 本発明は、ビス (2-ハロゲノエチル)エーテルとシァノ酢酸エステルとから、 4-シァノ テトラヒドロピラン- 4-カルボン酸エステルを製造する方法、 4-シァノテトラヒドロピラン- 4-カルボン酸エステルカゝら 4-シァノテトラヒドロピランを製造する方法及び 4-シァノテ トラヒドロピランカもテトラヒドロピラン- 4-カルボン酸アミドを製造する方法に関する。 4- シァノテトラヒドロピラン- 4-カルボン酸エステル、 4-シァノテトラヒドロピラン及びテトラ ヒドロピラン- 4-カルボン酸アミドは、例えば、医薬 ·農薬等の原料や合成中間体とし て有用な化合物である（例えば、特許文献 1及び 2参照)。  [0001] The present invention relates to a process for producing 4-cyananotetrahydropyran-4-carboxylic acid ester from bis (2-halogenoethyl) ether and cyanoacetic acid ester, 4-cyananotetrahydropyran-4-carboxylic acid ester Furthermore, the present invention relates to a method for producing 4-cianotetrahydropyran and 4-cyanotetrahydropyranca also relates to a method for producing tetrahydropyran-4-carboxylic acid amide. 4-cianotetrahydropyran-4-carboxylic acid ester, 4-cianotetrahydropyran and tetrahydropyran-4-carboxylic acid amide are useful compounds as raw materials and synthetic intermediates for pharmaceuticals and agricultural chemicals, for example ( For example, see Patent Documents 1 and 2.)
背景技術  Background art
[0002] 従来、ビス (2-ハロゲノエチル)エーテルとシァノ酢酸エステルとから、 4-シァノテトラ ヒドロピラン- 4-カルボン酸エステルを製造する方法としては、例えば、金属ナトリウム の存在下、ビス (2-クロロェチル)エーテルとシァノ酢酸ェチルとをエタノール中で反応 させて、収率 33%で 4-シァノテトラヒドロピラン- 4-カルボン酸ェチルを製造する方法 が知られている（例えば、非特許文献 1参照)。し力しながら、この方法では、反応中 に水素が発生する上に、収率が低 、と 、う問題点があった。  [0002] Conventionally, as a method for producing 4-cianotetrahydropyran-4-carboxylic acid ester from bis (2-halogenoethyl) ether and cyanoacetate, for example, bis (2-chloroethyl) can be used in the presence of sodium metal. ) A method is known in which ether and cyanoacetate are reacted in ethanol to produce 4-cyantetrahydropyran-4-carboxylate ethyl in a yield of 33% (see, for example, Non-Patent Document 1). . However, this method has problems in that hydrogen is generated during the reaction and the yield is low.
又、ビス (2-クロロェチル)エーテルとシァノ酢酸メチルとを反応させた場合には、 4- シァノテトラヒドロピラン- 4-カルボン酸メチルに加え、 4-シァノテトラヒドロピラン- 4-力 ルボン酸が大量に副生することが知られている（例えば、特許文献 3参照)。そのため 、 4-シァノテトラヒドロピラン- 4-カルボン酸エステルを得るためには、 4-シァノテトラヒ ドロピラン- 4-カルボン酸を再びエステル化しなければならな!/、と!/、う問題点があった  In addition, when bis (2-chloroethyl) ether and methyl cyanoacetate are reacted, in addition to methyl 4-cyantetrahydropyran-4-carboxylate, 4-cianotetrahydropyran-4-power rubonic acid is added. It is known that a large amount of by-product is produced (for example, see Patent Document 3). Therefore, in order to obtain 4-cianotetrahydropyran-4-carboxylic acid ester, 4-cianotetrahydropyran-4-carboxylic acid had to be esterified again!
[0003] 更に、 4-シァノテトラヒドロピラン- 4-カルボン酸エステルから 4-シァノテトラヒドロビラ ンを製造する方法としては、例えば、 4-シァノテトラヒドロピラン- 4-カルボン酸エステ ルを加水分解させて得られた 4-シァノテトラヒドロピラン- 4-カルボン酸を、 180〜200 °Cに加熱して、単離収率 66%で 4-シァノテトラヒドロピランを得る方法が知られて 、る (例えば、非特許文献 1参照)。し力しながら、この方法では高い反応温度が必要で あり、 4-シァノテトラヒドロピランの工業的な製法としては満足するものではな力つた。 [0003] Further, as a method for producing 4-cianotetrahydropyran from 4-cianotetrahydropyran-4-carboxylic acid ester, for example, 4-cianotetrahydropyran-4-carboxylic acid ester is hydrolyzed. 4-cianotetrahydropyran-4-carboxylic acid obtained by heating to 180-200 ° C. is known to obtain 4-cianotetrahydropyran in an isolated yield of 66%. (For example, refer nonpatent literature 1). However, this method requires a high reaction temperature, which is not satisfactory as an industrial production method of 4-cianotetrahydropyran.
[0004] 又、テトラヒドロピラン- 4-カルボン酸アミドを製造する方法としては、例えば、テトラヒ ドロピラン- 4-カルボン酸メチルを、アンモニア水 Zメタノールの混合溶液中で反応さ せて、テトラヒドロピラン- 4-カルボン酸アミドを製造する方法が知られている（例えば、 特許文献 2参照)。し力しながら、この方法では、刺激の強いアンモニア水を用いなけ ればならな 、と 、う問題点があった。 [0004] Further, as a method for producing tetrahydropyran-4-carboxylic acid amide, for example, tetrahydropyran-4-carboxylic acid methyl is reacted in a mixed solution of ammonia water Z methanol to give tetrahydropyran-4. A method for producing a carboxylic acid amide is known (for example, see Patent Document 2). However, this method has a problem in that it is necessary to use a strong ammonia water.
更に、テトラヒドロピラン- 4-カルボン酸クロリドとアンモニア水とを反応させて、テトラ ヒドロピラン- 4-カルボン酸アミドを製造する方法が知られている（例えば、特許文献 2 参照)。し力しながら、収率の記載はなぐ刺激の強いアンモニア水を用いなければ ならず、テトラヒドロピラン- 4-カルボン酸アミドの工業的な製法としては満足するもの ではなかった。  Furthermore, a method for producing tetrahydropyran-4-carboxylic acid amide by reacting tetrahydropyran-4-carboxylic acid chloride with aqueous ammonia is known (for example, see Patent Document 2). However, the yield must be described using a strong ammonia water, which is not satisfactory for the industrial production of tetrahydropyran-4-carboxylic acid amide.
[0005] 特許文献 1：国際公開第 2005/514389号パンフレット  [0005] Patent Document 1: Pamphlet of International Publication No. 2005/514389
特許文献 2：国際公開第 2005/032848号パンフレット  Patent Document 2: International Publication No. 2005/032848 Pamphlet
特許文献 3：国際公開第 2005/028410号パンフレット  Patent Document 3: International Publication No. 2005/028410 Pamphlet
非特許文献 1： J.Chem.Soc, 1930,2525  Non-patent document 1: J. Chem. Soc, 1930, 2525
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0006] 本発明の第 1の課題は、即ち、上記問題点を解決し、温和な条件下、簡便な方法 によって、ビス (2-ハロゲノエチル)エーテルとシァノ酢酸エステルとから、 4-シァノテト ラヒドロピラン- 4-カルボン酸エステルを高収率で製造出来る、工業的に好適な 4-シ ァノテトラヒドロピラン- 4-カルボン酸エステルの製造方法を提供することである。 本発明の第 2の課題は、即ち、上記問題点を解決し、温和な条件下、簡便な方法 によって、 4-シァノテトラヒドロピラン- 4-カルボン酸エステル力も 4-シァノテトラヒドロピ ランを高収率で製造出来る、工業的に好適な 4-シァノテトラヒドロピランの製法を提供 することである。 [0006] The first problem of the present invention is to solve the above-mentioned problems and from 4-bisnotetrahydropyran from bis (2-halogenoethyl) ether and cyanate ester by a simple method under mild conditions. -To provide an industrially suitable method for producing 4-cyanotetrahydropyran-4-carboxylic acid ester capable of producing 4-carboxylic acid ester in high yield. The second problem of the present invention is to solve the above-mentioned problems, and to increase 4-cyantetrahydropyran 4-carboxylic acid ester strength by a simple method under mild conditions. An industrially suitable process for producing 4-cianotetrahydropyran, which can be produced in a yield, is provided.
本発明の第 3の課題は、即ち、上記問題点を解決し、温和な条件下、簡便な方法 によって、 4-シァノテトラヒドロピランカもテトラヒドロピラン- 4-カルボン酸アミドを高収 率で製造出来る、工業的に好適なテトラヒドロピラン- 4-カルボン酸アミドの製造方法 を提供することである。 The third object of the present invention is to solve the above-mentioned problems and to give high yields of 4-cyantetrahydropyranca and tetrahydropyran-4-carboxylic acid amide by a simple method under mild conditions. An industrially suitable method for producing tetrahydropyran-4-carboxylic acid amide, which can be produced at a high rate, is provided.
課題を解決するための手段  Means for solving the problem
[0007] 本発明の第 1の課題は、一般式（1)：  [0007] The first subject of the present invention is the general formula (1):
[0008]
Figure imgf000005_0001
[0008]
Figure imgf000005_0001
[0009] 式中、 Xは、ハロゲン原子を表す、  [0009] In the formula, X represents a halogen atom,
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)
Figure imgf000005_0002
(2-Norogenoethyl) ether represented by the general formula (2)
Figure imgf000005_0002
[0011] 式中、 R1は、炭素原子数 2〜6のアルキル基を表す、 [0011] In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms,
で示されるシァノ酢酸エステル及び一般式（3)：  Cyanoacetate represented by the general formula (3):
[0012]  [0012]
MOR2 (3) MOR 2 ( 3 )
[0013] 式中、 R2は、 R1と同一又は異なっていても良い炭素原子数 1〜6のアルキル基を表 し、 Mは、アルカリ金属原子を表す、 [0013] In the formula, R 2 is the same as or different from R 1 to display the alkyl group having 1 to 6 carbon atoms also, M represents an alkali metal atom,
で示されるアルカリ金属アルコキシドを有機溶媒中にて反応させることを特徴とする、 一般式 (4a)及び (4b) :  The general formulas (4a) and (4b) are characterized by reacting an alkali metal alkoxide represented by general formula (4a):
Figure imgf000005_0003
Figure imgf000005_0003
[0015] 式中、 R1及び R2は、前記と同義である、 [0015] In the formula, R 1 and R 2 are as defined above.
からなる群より選ばれる少なくとも一種の 4-シァノテトラヒドロピラン- 4-カルボン酸エス テルの製造方法によって解決される。 At least one 4-cianotetrahydropyran-4-carboxylic acid ester selected from the group consisting of It is solved by the manufacturing method of Tell.
[0016] 本発明の第 2の課題は、前記一般式 (4a)及び (4b)で示される 4-シァノテトラヒドロ ピラン- 4-カルボン酸エステルの少なくとも 1種と、アルカリ金属アルコキシド、カルボ ン酸アルカリ金属塩又はそれらの混合物とを、カーボネート類、アミド類、アミン類、尿 素類、スルホキシド類及びスルホン類カゝらなる群より選ばれる少なくとも 1種の溶媒中 で反応させることを特徴とする、一般式 (5)： [0016] The second problem of the present invention is that at least one of the 4-cyantetrahydropyran-4-carboxylic acid esters represented by the general formulas (4a) and (4b), an alkali metal alkoxide, and a carboxylic acid. It is characterized by reacting an alkali metal salt or a mixture thereof in at least one solvent selected from the group consisting of carbonates, amides, amines, ureas, sulfoxides and sulfones. General formula (5):
Figure imgf000006_0001
Figure imgf000006_0001
[0018] で示される、 4-シァノテトラヒドロピランの製造方法によって解決される。  [0018] This is solved by the method for producing 4-cianotetrahydropyran shown by
[0019] 本発明の第 3の課題は、前記一般式 (5)で示される 4-シァノテトラヒドロピランと塩 基とを溶媒中で反応させることを特徴とする、一般式 (6)： [0019] A third object of the present invention is to react the 4-cianotetrahydropyran represented by the general formula (5) with a base group in a solvent, the general formula (6):
Figure imgf000006_0002
Figure imgf000006_0002
[0021] で示されるテトラヒドロピラン- 4-カルボン酸アミドの製造方法によって解決される。  [0021] The tetrahydropyran-4-carboxylic acid amide production method represented by
本発明においては、上記 3つの工程を連続して行ってもよぐ何れか 2つの連続す る工程を目的物を単離 ·精製することなく連続して行ってもよい。  In the present invention, the above three steps may be carried out continuously, or any two successive steps may be carried out continuously without isolating and purifying the target product.
発明の効果  The invention's effect
[0022] 第 1の発明により、温和な条件下、簡便な方法によって、ビス (2-ハロゲノエチル)ェ 一テルとシァノ酢酸エステルとから、 4-シァノテトラヒドロピラン- 4-カルボン酸エステル を高収率で製造出来る、工業的に好適な 4-シァノテトラヒドロピラン- 4-カルボン酸ェ ステルの製造方法を提供することが出来る。  [0022] According to the first invention, 4-cianotetrahydropyran-4-carboxylic acid ester is increased from bis (2-halogenoethyl) ether and cyanoacetate by a simple method under mild conditions. An industrially suitable method for producing 4-cyanotetrahydropyran-4-carboxylic acid ester that can be produced in a yield can be provided.
[0023] また、第 2の発明により、温和な条件下、簡便な方法によって、 4-シァノテトラヒドロ ピラン- 4-カルボン酸エステル力 4-シァノテトラヒドロピランを高収率で製造出来る、 工業的に好適な 4-シァノテトラヒドロピランの製造方法を提供することが出来る。  [0023] Further, according to the second invention, 4-cianotetrahydropyran-4-carboxylic acid ester 4-cianotetrahydropyran can be produced in a high yield by a simple method under mild conditions. It is possible to provide a method for producing 4-cianotetrahydropyran suitable for the above.
[0024] 更に、第 3の発明により、温和な条件下、簡便な方法によって、 4-シァノテトラヒドロ ピランカもテトラヒドロピラン- 4-カルボン酸アミドを高収率で製造出来る、工業的に好 適なテトラヒドロピラン- 4-カルボン酸アミドの製造方法を提供することが出来る。 [0024] Further, according to the third invention, 4-cianotetrahydro Pilanka can also provide an industrially preferred method for producing tetrahydropyran-4-carboxylic acid amide, which can produce tetrahydropyran-4-carboxylic acid amide in high yield.
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0025] 第 1の発明において使用するビス (2-ハロゲノエチル)エーテルは、前記の一般式（1 )で示される。その一般式（1)において、 Xは、フッ素原子、塩素原子、臭素原子又は ヨウ素原子であるが、好ましくは塩素原子又は臭素原子である。  [0025] The bis (2-halogenoethyl) ether used in the first invention is represented by the general formula (1). In the general formula (1), X is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a chlorine atom or a bromine atom.
[0026] 前記のビス (2-ハロゲノエチル)エーテルの具体例としては、例えば、ビス (2-クロロェ チル)エーテル、ビス (2-ブロモェチル)エーテル、ビス (2-ョードエチル)エーテルが使 用され、好ましくはビス (2-クロロェチル)エーテル、ビス (2-ブロモェチル)エーテルが 使用される。なお、これらのビス (2-ノヽロゲノエチル)エーテルは、単独又は二種以上 を混合して使用しても良い。  [0026] Specific examples of the bis (2-halogenoethyl) ether include bis (2-chloroethyl) ether, bis (2-bromoethyl) ether, and bis (2-iodoethyl) ether. Preferably, bis (2-chloroethyl) ether or bis (2-bromoethyl) ether is used. Note that these bis (2-nitrogenoethyl) ethers may be used alone or in admixture of two or more.
[0027] 第 1の発明において使用するシァノ酢酸エステルは、前記の一般式（2)で示される 。その一般式（2)において、 R1は、炭素原子数 2〜6のアルキル基であり、例えば、ェ チル基、プロピル基、ブチル基、ペンチル基及びへキシル基が挙げられる力 好まし くはェチル基である。なお、これらの基は、各種異性体も含む。 [0027] The cyanoacetate used in the first invention is represented by the general formula (2). In the general formula (2), R 1 is an alkyl group having 2 to 6 carbon atoms, and examples thereof include an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group. An ethyl group. These groups include various isomers.
[0028] 前記シァノ酢酸エステルの使用量は、ビス (2-ハロゲノエチル)エーテル 1モルに対し て、好ましくは 0.8〜20モル、更に好ましくは 1.0〜4.0モルである。  [0028] The amount of the cyanoacetate used is preferably 0.8 to 20 mol, more preferably 1.0 to 4.0 mol, per 1 mol of bis (2-halogenoethyl) ether.
[0029] 第 1の発明において使用するアルカリ金属アルコキシドは、前記の一般式（3)で示 される。その一般式（3)において、 R2は、 R1と同一又は異なっていても良い炭素原子 数 1〜6のアルキル基を示す力 例えば、メチル基、ェチル基、プロピル基、ブチル基 、ペンチル基及びへキシル基等が挙げられる力 好ましくはメチル基、ェチル基、ブ チル基及びペンチル基、更に好ましくはブチル基である（なお、これらの基は、各種 異性体を含む。 ) o又、 Mは、アルカリ金属原子を示すが、例えば、リチウム原子、ナト リウム原子及びカリウム原子等が挙げられる力 好ましくはナトリウム原子及びカリウム 原子、更に好ましくはナトリウム原子である。 [0029] The alkali metal alkoxide used in the first invention is represented by the general formula (3). In the general formula (3), R 2 is a force indicating an alkyl group having 1 to 6 carbon atoms which may be the same as or different from R 1. For example, methyl group, ethyl group, propyl group, butyl group, pentyl group And hexyl group and the like, preferably a methyl group, an ethyl group, a butyl group and a pentyl group, more preferably a butyl group (note that these groups include various isomers). Represents an alkali metal atom, for example, a force including a lithium atom, a sodium atom and a potassium atom, preferably a sodium atom and a potassium atom, more preferably a sodium atom.
[0030] 前記のアルカリ金属アルコキシドの具体例としては、例えば、ナトリウムメトキシド、力 リウムメトキシド、リチウムメトキシド、ナトリウムエトキシド、カリウムエトキシド、ナトリウム イソプロポキシド、カリウムイソプロポキシド、ナトリウム t-ブトキシド、カリウム t-ブトキシ ド及びナトリウム t-ペントキシド等のアルカリ金属アルコキシド、好ましくはナトリウムメト キシド、ナトリウムエトキシド、ナトリウム t-ブトキシド、ナトリウム t-ペントキシド及びカリ ゥム t-ブトキシドが使用される。なお、これらの塩基は、単独又は二種以上を混合して 使用しても良い。 [0030] Specific examples of the alkali metal alkoxide include, for example, sodium methoxide, strong methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium t- Butoxide, potassium t-butoxy Alkali metal alkoxides such as sodium and sodium t-pentoxide, preferably sodium methoxide, sodium ethoxide, sodium t-butoxide, sodium t-pentoxide and potassium t-butoxide are used. These bases may be used alone or in combination of two or more.
[0031] 前記塩基の使用量は、ビス (2-ハロゲノエチル)エーテル 1モルに対して、好ましくは 1.5〜10.0モル、更に好ましくは 1.8〜5.0モルである。  [0031] The amount of the base used is preferably 1.5-10.0 mol, more preferably 1.8-5.0 mol, per 1 mol of bis (2-halogenoethyl) ether.
[0032] 第 1の発明において使用する有機溶媒としては、反応を阻害しないものならば特に 限定されず、例えば、メタノール、エタノール、イソプロピルアルコール及び t-ブチル アルコール等のアルコール類； Ν,Ν-ジメチルホルムアミド、 Ν,Ν-ジメチルァセトアミド 及び Ν-メチルピロリドン等のアミド類； 1 ,3-ジメチル -2-イミダゾリジノン等の尿素類；ジ メチルスルホキシドのスルホキシド類；スルホラン等のスルホン類；トルエン及びキシレ ン等の芳香族炭化水素類；ァセトニトリル及びプロピオ-トリル等の-トリル類；ジェチ ルエーテル及びテトラヒドロフラン等のエーテル類が挙げられる力 S、好ましくはアミド類 及びスルホキシド類が使用される。なお、これらの有機溶媒は、単独又は二種以上を 混合して使用しても良い。  [0032] The organic solvent used in the first invention is not particularly limited as long as it does not inhibit the reaction. For example, alcohols such as methanol, ethanol, isopropyl alcohol and t-butyl alcohol; Ν, Ν-dimethyl Amides such as formamide, Ν, Ν-dimethylacetamide, and メ チ ル -methylpyrrolidone; Ureas such as 1,3-dimethyl-2-imidazolidinone; Sulfoxides of dimethyl sulfoxide; Sulfones such as sulfolane; Toluene And aromatic hydrocarbons such as xylene; -tolyls such as acetonitrile and propio-tolyl; ethers such as diethyl ether and tetrahydrofuran S, preferably amides and sulfoxides are used. In addition, you may use these organic solvents individually or in mixture of 2 or more types.
[0033] 前記有機溶媒の使用量は、反応液の均一性や攪拌性により適宜調節するが、ビス ( 2-ハロゲノエチル)エーテル lgに対して、好ましくは 0.5〜30ml、更に好ましくは 1〜20 mlである。 [0033] The amount of the organic solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 0.5 to 30 ml, more preferably 1 to 20 with respect to bis (2-halogenoethyl) ether lg. ml.
[0034] 第 1の発明は、例えば、ビス (2-ハロゲノエチル)エーテル、シァノ酢酸エステル、塩 基及び有機溶媒を混合して、攪拌させる等の方法によって行われる。その際の反応 温度は、好ましくは 10〜150°C、更に好ましくは 30〜130°Cであり、反応圧力は特に制 限されない。なお、本発明の反応の好ましい態様としては、シァノ酢酸エステルとァ ルカリ金属アルコキシドとを予め反応させてシァノ酢酸エステルのアルカリ金属塩を 生成させ、次いで、ビス (2-ハロゲノエチル)エーテルと混合して反応させる方法が挙 げられる。  [0034] The first invention is carried out, for example, by a method of mixing bis (2-halogenoethyl) ether, cyanoacetic ester, a base group and an organic solvent and stirring them. The reaction temperature at that time is preferably 10 to 150 ° C, more preferably 30 to 130 ° C, and the reaction pressure is not particularly limited. As a preferred embodiment of the reaction of the present invention, a cyanoacetate and an alkali metal alkoxide are reacted in advance to form an alkali metal salt of cyanoacetate, and then mixed with bis (2-halogenoethyl) ether. And how to react.
[0035] 第 1の発明によって、一般式 (4a)及び (4b)力もなる群より選ばれる少なくとも 1種の 4-シァノテトラヒドロピラン- 4-カルボン酸エステルが得られる力 これらは、反応終了 後、例えば、濾過、濃縮、抽出、蒸留、再結晶及びカラムクロマトグラフィー等の一般 的な方法によって単離'精製される。また、単離'精製することなぐ以下の第 2の発明 を連続して行うことも可能である。 [0035] According to the first invention, the power to obtain at least one 4-cyanotetrahydropyran-4-carboxylic acid ester selected from the group consisting of the general formulas (4a) and (4b) may be obtained after completion of the reaction. For example, filtration, concentration, extraction, distillation, recrystallization and column chromatography, etc. Isolated and purified by conventional methods. It is also possible to continuously carry out the following second invention without isolation and purification.
[0036] 第 2の発明の反応にぉ 、て使用する 4-シァノテトラヒドロピラン- 4-カルボン酸エステ ルは、前記の一般式 (4a)及び (4b)で示されるもののうちの少なくとも 1種である。そ の一般式 (4a)及び (4b)において、 R1及び R2は前記と同義である。 [0036] The 4-cyantetrahydropyran-4-carboxylic acid ester used in the reaction of the second invention is at least one of those represented by the general formulas (4a) and (4b). It is. In the general formulas (4a) and (4b), R 1 and R 2 are as defined above.
[0037] 第 2の発明の反応においてはアルカリ金属アルコキシド、カルボン酸アルカリ金属 塩を使用する。アルカリ金属アルコキシドとしては、前記式（3)で示されるアルカリ金 属アルコキシドが挙げられ、例えば、ナトリウムメトキシド、カリウムメトキシド、リチウムメ トキシド、ナトリウムエトキシド、カリウムエトキシド、ナトリウムイソプロポキシド、カリウム イソプロポキシド、ナトリウム t-ブトキシド、カリウム t-ブトキシド及びナトリウム t-ペントキ シド等が挙げられる力 好ましくはナトリウムメトキシドが使用される。カルボン酸アル カリ金属塩としては、例えば、ギ酸カリウム、ギ酸ナトリウム等のアルカリ金属ギ酸塩； 酢酸ナトリウム、酢酸カリウム等のアルカリ金属酢酸塩;プロピオン酸カリウム、プロピ オン酸ナトリウム等のアルカリ金属プロピオン酸塩；安息香酸カリウム、安息香酸ナトリ ゥム等のアルカリ金属安息香酸塩等が挙げられるが、好ましくは酢酸ナトリウム、酢酸 カリウムが使用される。なお、これらのアルカリ金属アルコキシド、カルボン酸アルカリ 金属塩は、単独又は二種以上を混合して使用しても良い。  [0037] In the reaction of the second invention, an alkali metal alkoxide or an alkali metal carboxylate is used. Examples of the alkali metal alkoxide include the alkali metal alkoxides represented by the above formula (3). For example, sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isotope. Powers including propoxide, sodium t-butoxide, potassium t-butoxide, sodium t-pentoxide and the like Preferably sodium methoxide is used. Examples of the alkali metal carboxylate include alkali metal formate such as potassium formate and sodium formate; alkali metal acetate such as sodium acetate and potassium acetate; alkali metal propionate such as potassium propionate and sodium propionate An alkali metal benzoate such as potassium benzoate and sodium benzoate, and the like, preferably sodium acetate and potassium acetate are used. In addition, you may use these alkali metal alkoxide and carboxylic acid alkali metal salt individually or in mixture of 2 or more types.
[0038] 前記アルカリ金属アルコキシドの使用量は、 4-シァノテトラヒドロピラン- 4-カルボン 酸エステル 1モルに対して、好ましくは 0.1〜50モル、更に好ましくは 0.5〜20モル、特 に好ましくは 0.8〜5.0モノレである。  [0038] The amount of the alkali metal alkoxide to be used is preferably 0.1 to 50 mol, more preferably 0.5 to 20 mol, particularly preferably 0.8 to 1 mol of 4-cyantetrahydropyran-4-carboxylic acid ester. ~ 5.0 monole.
[0039] 第 2の発明の反応は、カーボネート類、アミド類、アミン類、尿素類、スルホキシド類 及びスルホン類力 なる群より選ばれる少なくとも 1種の溶媒中で行うが、使用する溶 媒としては、例えば、ジメチルカーボネート、ジェチルカーボネート及びエチレンカー ボネート等のカーボネート類； Ν,Ν-ジメチルホルムアミド、 Ν,Ν-ジメチルァセトアミド及 び Ν-メチルピロリドン等のアミド類； 1,3-ジメチル -2-イミダゾリジノン等の尿素類；トリ- η -ブチルァミン、トリ- η-ォクチルァミン、ピリジン、 2-ピコリン、 3-ピコリン、キノリン等の アミン類；ジメチルスルホキシド等のスルホキシド類;スルホラン等のスルホン類が挙げ られる。好ましくはカーボネート類、アミド類、アミン類及び尿素類が使用される。なお 、これらの溶媒は、単独又は二種以上を混合して使用しても良い。又、本発明の反応 において、反応に関与しない溶媒として、炭化水素類 (例えば、シクロヘプタン、トル ェン、キシレン等)を入れて、操作性'攪拌性を向上させても良い。 [0039] The reaction of the second invention is carried out in at least one solvent selected from the group consisting of carbonates, amides, amines, ureas, sulfoxides and sulfones, and the solvent used is Carbonates such as dimethyl carbonate, jetyl carbonate and ethylene carbonate; amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and ア ミ ド -methylpyrrolidone; 1,3-dimethyl- Ureas such as 2-imidazolidinone; amines such as tri-η-butylamine, tri-η-octylamine, pyridine, 2-picoline, 3-picoline, quinoline; sulfoxides such as dimethyl sulfoxide; sulfones such as sulfolane Is mentioned. Preferably carbonates, amides, amines and ureas are used. In addition These solvents may be used alone or in combination of two or more. In the reaction of the present invention, hydrocarbons (for example, cycloheptane, toluene, xylene, etc.) may be added as a solvent not involved in the reaction to improve operability and agitation.
[0040] 前記溶媒の使用量は、反応液の均一性や攪拌性により適宜調節するが、 4-シァノ テトラヒドロピラン- 4-カルボン酸エステル lgに対して、好ましくは 0.1〜100ml、更に好 ましくは 0.5〜50ml、特に好ましくは 1.0〜10mlである。  [0040] The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.1 to 100 ml, more preferably 4-cyantetrahydropyran-4-carboxylic acid ester lg. Is 0.5 to 50 ml, particularly preferably 1.0 to 10 ml.
[0041] 第 2の発明の反応は、例えば、 4-シァノテトラヒドロピラン- 4-カルボン酸エステル、 アルカリ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物、並び にカーボネート類、アミド類、尿素類、アミン類、スルホキシド類及びスルホン類力もな る群より選ばれる少なくとも 1種の溶媒を混合して、攪拌しながら反応させる等の方法 によって行われる。その際の反応温度は、好ましくは 20〜170°C、更に好ましくは 50〜 160°Cであり、反応圧力は特に制限されな！、。  [0041] The reaction of the second invention is, for example, 4-cianotetrahydropyran-4-carboxylic acid ester, alkali metal alkoxide, carboxylic acid alkali metal salt, or a mixture thereof, as well as carbonates, amides, urea. And at least one solvent selected from the group that also has the ability to sulphate, amines, sulfoxides, and sulphones, and the like. The reaction temperature at that time is preferably 20 to 170 ° C, more preferably 50 to 160 ° C, and the reaction pressure is not particularly limited! ,.
[0042] なお、最終生成物である 4-シァノテトラヒドロピランは、例えば、反応終了後、濾過、 抽出、濃縮、蒸留、再結晶及びカラムクロマトグラフィー等の一般的な方法によって 単離'精製される。また、単離'精製することなぐ以下の第 3の発明を連続して行うこ とも可能である。  [0042] The final product, 4-cianotetrahydropyran, is isolated and purified by general methods such as filtration, extraction, concentration, distillation, recrystallization, and column chromatography after completion of the reaction. The It is also possible to continuously carry out the following third invention without isolation and purification.
[0043] 第 3の発明において使用する塩基は、具体的には、例えば、水酸化ナトリウム及び 水酸ィ匕カリウム等のアルカリ金属水酸ィ匕物;炭酸カリウム及び炭酸ナトリウム等のアル カリ金属炭酸塩;ナトリウムメトキシド、カリウムメトキシド、リチウムメトキシド、ナトリウム エトキシド、カリウムエトキシド、ナトリウムイソプロポキシド、カリウムイソプロポキシド、 ナトリウム t-ブトキシド、カリウム t-ブトキシド及びナトリウム t-ペントキシド等のアルカリ 金属アルコキシドが挙げられる力 好ましくはアルカリ金属水酸ィ匕物、更に好ましくは 水酸化ナトリウム及び水酸化カリウムが使用される。なお、これらの塩基は、単独又は 二種以上を混合して使用しても良 、。  [0043] Specifically, the base used in the third invention is, for example, an alkali metal hydroxide such as sodium hydroxide and potassium hydroxide; an alkali metal carbonate such as potassium carbonate and sodium carbonate; Salts; alkali metal alkoxides such as sodium methoxide, potassium methoxide, lithium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium t-butoxide, potassium t-butoxide and sodium t-pentoxide Preferably, alkali metal hydroxides are used, more preferably sodium hydroxide and potassium hydroxide. These bases may be used alone or in combination of two or more.
[0044] 前記塩基の使用量は、 4-シァノテトラヒドロピラン 1モルに対して、好ましくは 0.1〜10[0044] The amount of the base used is preferably 0.1 to 10 with respect to 1 mol of 4-cianotetrahydropyran.
.0モル、更に好ましくは 0.2〜5.0モルである。 0.0 mol, more preferably 0.2 to 5.0 mol.
[0045] 本発明において使用する溶媒としては、反応を阻害しないものならば特に限定され ず、例えば、水；メタノール、エタノール、イソプロピルアルコール、 n-ブチルアルコー ル及び t-ブチルアルコール等のアルコール類； Ν,Ν-ジメチルホルムアミド、 Ν,Ν-ジメ チルァセトアミド及び Ν-メチルピロリドン等のアミド類； 1,3-ジメチル -2-イミダゾリジノン 等の尿素類；ジメチルスルホキシド等のスルホキシド類；スルホラン等のスルホン類； ジェチルエーテル及びテトラヒドロフラン等のエーテル類が挙げられる力 好ましくは メタノール、エタノール、 η-ブチルアルコール及び t-ブチルアルコール等のアルコー ル類が使用される。なお、これらの溶媒は、単独又は二種以上を混合して使用しても 良い。 [0045] The solvent used in the present invention is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, n-butyl alcohol And alcohols such as t-butyl alcohol; Amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and Ν-methylpyrrolidone; Ureas such as 1,3-dimethyl-2-imidazolidinone; Sulfoxides such as dimethyl sulfoxide; Sulfones such as sulfolane; Ethers such as jetyl ether and tetrahydrofuran Preferably, alcohols such as methanol, ethanol, η-butyl alcohol and t-butyl alcohol are used. . In addition, you may use these solvents individually or in mixture of 2 or more types.
[0046] 前記溶媒の使用量は、反応液の均一性や攪拌性により適宜調節するが、 4-シァノ テトラヒドロピラン lgに対して、好ましくは 0.5〜30ml、更に好ましくは l〜20mlである。  [0046] The amount of the solvent used is appropriately adjusted depending on the uniformity and stirrability of the reaction solution, but is preferably 0.5 to 30 ml, more preferably 1 to 20 ml, relative to 4-cyantetrahydropyran lg.
[0047] 本発明は、例えば、 4-シァノテトラヒドロピラン、塩基及び溶媒を混合して、攪拌させ る等の方法によって行われる。その際の反応温度は、好ましくは 20〜150°C、更に好 ましくは 30〜130°Cであり、反応圧力は特に制限されない。また、本発明においては、 反応時に水を存在させることが望ま U、。  [0047] The present invention is carried out by a method of, for example, mixing 4-cianotetrahydropyran, a base and a solvent and stirring them. The reaction temperature at that time is preferably 20 to 150 ° C., more preferably 30 to 130 ° C., and the reaction pressure is not particularly limited. In the present invention, it is desirable that water be present during the reaction.
前記水の使用量は、 4-シァノテトラヒドロピラン 1モルに対して、好ましくは 0.01〜50. 0モル、更に好ましくは 0.1〜10.0モルである。  The amount of water used is preferably 0.01 to 50.0 mol, more preferably 0.1 to 10.0 mol, per 1 mol of 4-cyantetrahydropyran.
[0048] なお、本発明によってテトラヒドロピラン- 4-カルボン酸アミドが得られる力 これは、 反応終了後、例えば、濾過、濃縮、中和、抽出、蒸留、再結晶及びカラムクロマトダラ フィ一等の一般的な方法によって単離 ·精製される。又、本発明の反応においては、 過酸化物 (例えば、過酸ィ匕水素等)や相間移動触媒（四級アンモニゥム塩、四級ホス ホ-ゥム塩等)を存在させて反応性を調節しても良い。 実施例  [0048] It should be noted that the ability to obtain tetrahydropyran-4-carboxylic acid amide according to the present invention is obtained after completion of the reaction, such as filtration, concentration, neutralization, extraction, distillation, recrystallization, column chromatography, etc. It is isolated and purified by a general method. In the reaction of the present invention, the reactivity is adjusted by the presence of a peroxide (for example, hydrogen peroxide, etc.) or a phase transfer catalyst (quaternary ammonium salt, quaternary phosphoric salt, etc.). You may do it. Example
[0049] 次に、実施例を挙げて本発明を具体的に説明する力 本発明の範囲はこれらに限 定されるものではない。  Next, the ability to specifically describe the present invention with reference to examples The scope of the present invention is not limited to these.
[0050] 実施例 1 (4-シァノテトラヒドロピラン- 4-カルボン酸ェチルの合成）  Example 1 (Synthesis of 4-cianotetrahydropyran-4-carboxylic acid ethyl)
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 8000mlのガラス製フ ラスコに、アルゴン雰囲気下、 Ν,Ν-ジメチルァセトアミド 2700ml及び純度 95%のナトリ ゥム t-ブトキシド 976g(9.65mol)をカ卩え、攪拌しながら純度 98%のシァノ酢酸ェチル 11 14g(9.65mol)をゆるやかに滴下した。滴下終了後、 40°Cにて 1時間攪拌させて、シァ ノ酢酸ェチルのナトリウム塩を含む溶液を調製した。 In a glass flask with an internal volume of 8000 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel, under an argon atmosphere, 2700 ml of Ν, Ν-dimethylacetamide and 95% pure sodium t-butoxide 976 g (9.65 mol) was added, and 14 g (9.65 mol) of ethyl cyanoacetate with a purity of 98% was gently added dropwise with stirring. After dripping, stir at 40 ° C for 1 hour to A solution containing the sodium salt of ethyl acetate was prepared.
次いで、攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 101のガラス 製フラスコに、純度 99%のビス (2-クロロェチル)エーテル 606g(4.20mol)及びトルエン 6 00mlを加え、液温を 71.3°Cまで昇温させた後、前記シァノ酢酸ェチルのナトリウム塩 を含む溶液をゆるやかに滴下した。滴下終了後、窒素雰囲気下、 80°Cで 5.5時間反 応させた。反応終了後、反応液を 10°Cまで冷却し、攪拌しながら、酢酸 101g(1.68mol) をゆるやかに滴下した。続いて水 3000mlを加え、水層と有機層（トルエン層）を分離し 、水層をトルエン 1200mlで抽出した後、該有機層とトルエン抽出液を合わせて、 20質 量％塩ィ匕ナトリウム水溶液 1710mlで洗浄した。その後、有機層を減圧下で濃縮 (85°C 、 0.53kPa)し、濃縮液 1168gをガスクロマトグラフィーで分析（内部標準法)したところ、 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 744gが生成して!/、た（ビス (2-クロロェ チル)エーテル基準の単離収率 : 96.7%)。なお、濃縮液中には、 4-シァノテトラヒドロ ピラン- 4-カルボン酸の生成は確認されな力つた。  Next, 606 g (4.20 mol) of 99% pure bis (2-chloroethyl) ether and 600 ml of toluene were added to a glass flask having an internal volume of 101 equipped with a stirrer, thermometer, reflux condenser and dropping funnel. After the temperature was raised to 71.3 ° C., the solution containing the sodium salt of cyanoacetate was slowly added dropwise. After completion of the dropwise addition, the mixture was reacted at 80 ° C for 5.5 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to 10 ° C, and 101 g (1.68 mol) of acetic acid was slowly added dropwise with stirring. Subsequently, 3000 ml of water was added, the aqueous layer and the organic layer (toluene layer) were separated, and the aqueous layer was extracted with 1200 ml of toluene, and then the organic layer and the toluene extract were combined to obtain a 20% by weight sodium chloride aqueous solution. Washed with 1710 ml. Thereafter, the organic layer was concentrated under reduced pressure (85 ° C, 0.53 kPa), and 1168 g of the concentrated liquid was analyzed by gas chromatography (internal standard method). As a result, 744 g of 4-cyantetrahydropyran-4-carboxylate was obtained. (Isolated yield based on bis (2-chloroethyl) ether: 96.7%). In the concentrated solution, the formation of 4-cianotetrahydropyran-4-carboxylic acid was not confirmed.
実施例 2 (4-シァノテトラヒドロピラン- 4-カルボン酸メチル及び 4-シァノテトラヒドロビラ ン -4-カルボン酸ェチルの合成） Example 2 (Synthesis of methyl 4-cianotetrahydropyran-4-carboxylate and 4-cianotetrahydropyran-4-carboxylate)
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 200mlのガラス製フ ラスコに、アルゴン雰囲気下、 Ν,Ν-ジメチルホルムアミド 60ml及び純度 99%のナトリウ ムメトキシド 18.9g(346.4mmol)を加え、 0°Cまで冷却した後、純度 98%のシァノ酢酸ェ チル 39.6g(343.1mmol)をゆるやかに滴下した。滴下終了後、 30°Cにて 2時間攪拌させ て、シァノ酢酸ェチルのナトリウム塩を含む溶液を調製した。  A glass flask with an internal volume of 200 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 60 ml of Ν, Ν-dimethylformamide and 18.9 g (346.4 mmol) of sodium methoxide with a purity of 99% in an argon atmosphere. In addition, after cooling to 0 ° C., 39.6 g (343.1 mmol) of ethyl cyanoacetate having a purity of 98% was gently added dropwise. After completion of the dropwise addition, the solution was stirred at 30 ° C. for 2 hours to prepare a solution containing sodium salt of cyanoacetate.
次いで、攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 200mlのガ ラス製フラスコに、純度 99%のビス (2-クロロェチル)エーテル 20.0g(138.5mmol)をカロえ 、液温を 80°Cまで昇温させた後、前記シァノ酢酸ェチルのナトリウム塩を含む溶液を ゆるやかに滴下した。滴下終了後、窒素雰囲気下、 80°Cで 10時間環化反応させた。 反応終了後、反応液を 30°Cまで冷却した後、不溶物を濾過し、濾物をメタノール 40ml で洗浄した後、濾液と洗浄液を合わせた。この溶液 169.1gをガスクロマトグラフィーで 分析したところ、 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 12.5g (ビス (2-クロロェ チル)エーテル基準の収率： 53.3%)及び 4-シァノテトラヒドロピラン- 4-カルボン酸ェ チル 8.0g (ビス (2-クロロェチル)エーテル基準の収率: 31.5%) )が生成していた。即ち 、エステルの合計収率は 84.8%であった。 Next, 20.0 g (138.5 mmol) of bis (2-chloroethyl) ether having a purity of 99% was added to a glass flask having an internal volume of 200 ml equipped with a stirrer, a thermometer, a reflux condenser, and a dropping funnel, and the liquid temperature. After the temperature was raised to 80 ° C., the solution containing the sodium salt of cyanoacetate was slowly added dropwise. After completion of the dropwise addition, cyclization was performed at 80 ° C. for 10 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to 30 ° C., insoluble matters were filtered, and the filtrate was washed with 40 ml of methanol, and then the filtrate and the washing solution were combined. When 169.1 g of this solution was analyzed by gas chromatography, 12.5 g of methyl 4-cyanotetrahydropyran-4-carboxylate (yield based on bis (2-chloroethyl) ether: 53.3%) and 4-cyanotetrahydro Pyran-4-carboxylic acid 8.0 g (yield based on bis (2-chloroethyl) ether: 31.5%)) was produced. That is, the total yield of ester was 84.8%.
[0052] 比較例 1 (4-シァノテトラヒドロピラン- 4-カルボン酸メチルの合成） [0052] Comparative Example 1 (Synthesis of methyl 4-cianotetrahydropyran-4-carboxylate)
攪拌装置、温度計及び滴下漏斗を備えた内容積 50mlのガラス製フラスコに、ァルゴ ン雰囲気下、 Ν,Ν-ジメチルホルムアミド 30ml及びナトリウムメトキシド 9.44g(174.8mmol )を加え、内温を 0°Cまで冷却した後、攪拌しながら純度 99%のシァノ酢酸メチル 17.5g (174.8mmol)をゆるやかに滴下した。滴下終了後、室温にて 3時間攪拌させて、シァノ 酢酸メチルのナトリウム塩を含む溶液を合成した。  Under an argon atmosphere, 30 ml of Ν, Ν-dimethylformamide and 9.44 g (174.8 mmol) of sodium methoxide were added to a 50 ml glass flask equipped with a stirrer, thermometer and dropping funnel. After cooling to C, 17.5 g (174.8 mmol) of methyl cyanoacetate having a purity of 99% was slowly added dropwise with stirring. After completion of the dropwise addition, the solution was stirred at room temperature for 3 hours to synthesize a solution containing methyl cyanoacetate sodium salt.
次いで、攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 100mlのガ ラス製フラスコに、純度 99%のビス (2-クロロェチル)エーテル 10. lg(69.9mmol)をカロえ、 液温を 80°Cまで昇温させた後、前記シァノ酢酸メチルのナトリウム塩を含む溶液をゆ るやかに滴下した。滴下終了後、窒素雰囲気下、 80°Cで 20時間反応させた。反応終 了後、反応液を室温まで冷却してガスクロマトグラフィーで分析（内部標準法)したと ころ、 4-シァノテトラヒドロピラン- 4-カルボン酸メチルが 8.30g生成して!/、た (ビス (2-ク ロロェチル)エーテル基準の反応収率： 70.2%)。  Next, in a glass flask with an internal volume of 100 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 10. lg (69.9 mmol) of 99% pure bis (2-chloroethyl) ether, and the liquid After the temperature was raised to 80 ° C., the solution containing the sodium salt of methyl cyanoacetate was slowly added dropwise. After completion of the dropwise addition, the mixture was reacted at 80 ° C for 20 hours in a nitrogen atmosphere. After completion of the reaction, the reaction solution was cooled to room temperature and analyzed by gas chromatography (internal standard method). As a result, 8.30 g of methyl 4-cyantetrahydropyran-4-carboxylate was formed! Reaction yield based on bis (2-chloroethyl) ether: 70.2%).
続いて、反応液を 0°Cまで冷却し、純度 95%の硫酸ジメチル 23.2g(174.7mmol)をゆ るやかに滴下した。滴下終了後、室温にて 1時間反応させて、副生した 4-シァノテトラ ヒドロピラン- 4-カルボン酸をメチルエステルへと誘導して、その存在量を確認した。そ の結果、 4-シァノテトラヒドロピラン- 4-カルボン酸メチルの生成量力 算出される 4-シ ァノテトラヒドロピラン- 4-カルボン酸の生成量は 2.05gであった。（ビス (2-クロ口ェチル )エーテル基準で 18.9%であった。 )  Subsequently, the reaction solution was cooled to 0 ° C., and 23.2 g (174.7 mmol) of dimethyl sulfate having a purity of 95% was slowly added dropwise. After completion of the dropwise addition, the mixture was reacted at room temperature for 1 hour to induce by-produced 4-cianotetrahydropyran-4-carboxylic acid to a methyl ester, and the abundance thereof was confirmed. As a result, the amount of 4-cyantetrahydropyran-4-carboxylic acid produced was calculated to be 2.05 g. (It was 18.9% based on bis (2-chloroethyl) ether.)
即ち、本反応系では 4-シァノテトラヒドロピラン- 4-カルボン酸が大量に副生すること が分かる。  That is, it can be seen that a large amount of 4-cyantetrahydropyran-4-carboxylic acid is by-produced in this reaction system.
[0053] 実施例 3 (4-シァノテトラヒドロピランの合成）  Example 3 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 100%の 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 507mg(3.0mmol)、ナトリウム メトキシド 432mg(8.0mmol)及び 1,3-ジメチル- 2-イミダゾリジノン 5mlをカ卩え、攪拌しな がら 130°Cにて 4時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより 分析（内部標準法)したところ、 4-シァノテトラヒドロピラン力 S315mg生成していた (反応 収率； 94.5%)。 To a glass flask with an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser, 507 mg (3.0 mmol) of methyl 4-cyanotetrahydropyran-4-carboxylate with a purity of 100%, 432 mg (8.0 mmol) of sodium methoxide ) And 1,3-dimethyl-2-imidazolidinone (5 ml) were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution is purified by gas chromatography. Analysis (internal standard method) revealed that 4-cianotetrahydropyran force S315 mg was produced (reaction yield; 94.5%).
[0054] 実施例 4 (4-シァノテトラヒドロピランの合成）  Example 4 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 100%の 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 507mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)及び 1,3-ジメチル- 2-イミダゾリジノン 5mlをカ卩え、攪拌しな がら 130°Cにて 4時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより 分析（内部標準法)したところ、 4-シァノテトラヒドロピラン力 S312mg生成していた (反応 収率； 93.6%)。  To a glass flask equipped with a stirrer, thermometer and reflux condenser with an internal volume of 30 ml, 100% pure methyl 4-cyanotetrahydropyran-4-carboxylate 507 mg (3.0 mmol), sodium methoxide 216 mg (4.0 mmol) ) And 1,3-dimethyl-2-imidazolidinone (5 ml) were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, S312 mg of 4-cianotetrahydropyran force was produced (reaction yield; 93.6%).
[0055] 実施例 5 (4-シァノテトラヒドロピランの合成）  [0055] Example 5 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 100%の 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 507mg(3.0mmol)、ナトリウム メトキシド 432mg(8.0mmol)及び炭酸ジェチル 5mlをカ卩え、攪拌しながら 130°Cにて 4時 間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（内部標準法 )したところ、 4-シァノテトラヒドロピランが 237mg生成していた (反応収率; 71.1%)。  To a glass flask with an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser, 507 mg (3.0 mmol) of methyl 4-cyanotetrahydropyran-4-carboxylate with a purity of 100%, 432 mg (8.0 mmol) of sodium methoxide ) And 5 ml of jetty carbonate were added and reacted for 4 hours at 130 ° C with stirring. After completion of the reaction, the reaction mixture was analyzed by gas chromatography (internal standard method). As a result, 237 mg of 4-cyantetrahydropyran was formed (reaction yield; 71.1%).
[0056] 実施例 6 (4-シァノテトラヒドロピランの合成）  Example 6 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 100%の 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 507mg(3.0mmol)、ナトリウム メトキシド 1.08g(20mmol)及び炭酸ジェチル 10mlをカ卩え、攪拌しながら 130°Cにて 4時 間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（内部標準法 )したところ、 4-シァノテトラヒドロピランが 241mg生成して 、た (反応収率； 72.3%)。  Into a 30 ml glass flask equipped with a stirrer, thermometer and reflux condenser, 100% pure methyl 4-cyantetrahydropyran-4-carboxylate 507 mg (3.0 mmol), sodium methoxide 1.08 g (20 mmol) ) And 10 ml of jetyl carbonate were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction mixture was analyzed by gas chromatography (internal standard method). As a result, 241 mg of 4-cyantetrahydropyran was formed (reaction yield; 72.3%).
[0057] 実施例 7 (テトラヒドロピラン- 4-カルボン酸アミドの合成）  Example 7 (Synthesis of tetrahydropyran-4-carboxylic acid amide)
攪拌装置、滴下漏斗及び温度計を備えた内容積 500mlのガラス製フラスコに、純度 99%の 4-シァノテトラヒドロピラン 56.13g(0.5mol)、 t-ブチルアルコール 281ml及び純度 85%の水酸ィ匕カリウム 39.61g(0.6mol)をカ卩え、攪拌しながら 100°Cにて 2時間反応を行 なった。反応終了後、トルエン 112ml及び水 112mlを加えた後、液温を 25°C以下に保 ちながら 35%塩酸 50mlを滴下して pH7.5に調整した。次いで、室温にて水層を分液し た後、水層を酢酸ェチル 281mlで抽出した。得られた有機層と抽出液を合わせ、減圧 下で濃縮 (60°C、 2.0kPa)し、純度 92.5質量％(ガスクロマトグラフィーによる内部標準 法)のテトラヒドロピラン- 4-カルボン酸アミド 43.47gを得た (単離収率; 62.3%)。又、前 記の水層をガスクロマトグラフィーで分析（内部標準法)したところ、テトラヒドロピラン- 4-カルボン酸アミドカ^ 2.45g含まれていた（19.3%)。なお、テトラヒドロピラン- 4-カル ボン酸アミドの物性値は以下の通りであった。 A glass flask equipped with a stirrer, a dropping funnel and a thermometer with an internal volume of 500 ml was charged with 56.13 g (0.5 mol) of 4-cyantetrahydropyran with a purity of 99%, 281 ml of t-butyl alcohol and a hydroxide with 85% purity. Potassium 39.61 g (0.6 mol) was added, and the reaction was carried out at 100 ° C for 2 hours with stirring. After completion of the reaction, 112 ml of toluene and 112 ml of water were added, and 50 ml of 35% hydrochloric acid was added dropwise while maintaining the liquid temperature at 25 ° C. or lower to adjust the pH to 7.5. Next, the aqueous layer was separated at room temperature, and the aqueous layer was extracted with 281 ml of ethyl acetate. Combine the resulting organic layer and the extract, and reduce the pressure. The mixture was concentrated (60 ° C, 2.0 kPa) to obtain 43.47 g of tetrahydropyran-4-carboxylic acid amide having a purity of 92.5% by mass (internal standard method by gas chromatography) (isolated yield; 62.3%). Further, the aqueous layer was analyzed by gas chromatography (internal standard method) and found to contain 2.45 g of tetrahydropyran-4-carboxylic acid amide carbonate (19.3%). The physical properties of tetrahydropyran-4-carboxylic acid amide were as follows.
[0058] CI-MS(m/e)； 130(M+1) [0058] CI-MS (m / e); 130 (M + 1)
^-NMRCDMSO-d , δ (ppm)) ; 1.36〜1.63(4H,m)、 2.26〜2.50(lH,m)、 3.24〜3.36(2H  ^ -NMRCDMSO-d, δ (ppm)); 1.36 ~ 1.63 (4H, m), 2.26 ~ 2.50 (lH, m), 3.24 ~ 3.36 (2H
6  6
,m)、 3.81〜3.87(2H,m)、 6.77~7.25(2H,d,J=48.4Hz)  , m), 3.81 to 3.87 (2H, m), 6.77 to 7.25 (2H, d, J = 48.4Hz)
[0059] 実施例 8 (4-シァノテトラヒドロピランの合成） [0059] Example 8 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)及び Ν,Ν-ジメチルホルムアミド 5mlをカ卩え、攪拌しながら 110 °Cにて 6時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（ 内部標準法)したところ、 4-シァノテトラヒドロピランが 222mg生成して 、た (反応収率； 66.6%) o  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ) And 5 ml of Ν, Ν-dimethylformamide were added and reacted at 110 ° C for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 222 mg of 4-cyantetrahydropyran was formed (reaction yield; 66.6%).
[0060] 実施例 9 (4-シァノテトラヒドロピランの合成）  Example 9 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)、 1,3-ジメチル- 2-イミダゾリジノン lml及びトルエン 4mlをカロ え、攪拌しながら 130°Cにて 4時間反応させた。反応終了後、反応液をガスクロマトグ ラフィーにより分析（内部標準法)したところ、 4-シァノテトラヒドロピランが 189mg生成 していた (反応収率; 56.7%)。  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ), Lml of 1,3-dimethyl-2-imidazolidinone and 4ml of toluene were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 189 mg of 4-cyantetrahydropyran was formed (reaction yield; 56.7%).
[0061] 実施例 10 (4-シァノテトラヒドロピランの合成）  Example 10 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)、 Ν,Ν-ジメチルホルムアミド lml及びトルエン 4mlを加え、攪 拌しながら 110°Cにて 4時間反応させた。反応終了後、反応液をガスクロマトグラフィ 一により分析（内部標準法)したところ、 4-シァノテトラヒドロピランが 224mg生成してい た (反応収率; 67.2%)。 A glass flask with an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyanotetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ), L, Ν-dimethylformamide (1 ml) and toluene (4 ml) were added, and the mixture was reacted at 110 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 224 mg of 4-cianotetrahydropyran was formed. (Reaction yield; 67.2%).
[0062] 実施例 11 (4-シァノテトラヒドロピランの合成） Example 11 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、 97%酢酸 カリウム 607mg(6.0mmol)及び Ν,Ν-ジメチルホルムアミド 5mlをカ卩え、攪拌しながら 150 °Cにて 6時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（ 内部標準法)したところ、 4-シァノテトラヒドロピランが 308mg生成して 、た (反応収率； 92.4%) o  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1%, 607 mg of 97% potassium acetate ( 6.0 mmol) and 5 ml of Ν, Ν-dimethylformamide were added and reacted at 150 ° C for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 308 mg of 4-cyantetrahydropyran was formed (reaction yield; 92.4%).
[0063] 実施例 12 (4-シァノテトラヒドロピランの合成）  Example 12 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、 97%酢酸 カリウム 607mg(6.0mmol)及び Ν,Ν-ジメチルァセトアミド 5mlをカ卩え、攪拌しながら 150°C にて 6時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（内 部標準法)したところ、 4-シァノテトラヒドロピランが 276mg生成して 、た (反応収率； 82 .8%)。  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1%, 607 mg of 97% potassium acetate ( 6.0 mmol) and 5 ml of Ν-dimethylacetamide were added and reacted at 150 ° C for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 276 mg of 4-cyantetrahydropyran was formed (reaction yield; 82.8%).
[0064] 実施例 13 (4-シァノテトラヒドロピランの合成）  Example 13 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、 97%酢酸 カリウム 607mg(6.0mmol)及び 1,3-ジメチル -2-イミダゾリジノン 5mlをカ卩え、攪拌しなが ら 150°Cにて 6時間反応させた。反応終了後、反応液をガスクロマトグラフィーにより分 析（内部標準法)したところ、 4-シァノテトラヒドロピランが 288mg生成して 、た (反応収 率； 86.4%)。  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1%, 607 mg of 97% potassium acetate ( 6.0 mmol) and 5 ml of 1,3-dimethyl-2-imidazolidinone were added and reacted at 150 ° C. for 6 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 288 mg of 4-cyantetrahydropyran was formed (reaction yield; 86.4%).
[0065] 実施例 14 (4-シァノテトラヒドロピランの合成）  Example 14 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)及び DMF5mlをカ卩え、攪拌しながら 130°Cにて 4時間反応さ せた。反応終了後、反応液をガスクロマトグラフィーにより分析（内部標準法)したとこ ろ、 4-シァノテトラヒドロピランが 325mg生成して 、た (反応収率； 97.5%)。 [0066] 実施例 15 (4-シァノテトラヒドロピランの合成） A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ) And 5 ml of DMF were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 325 mg of 4-cyantetrahydropyran was formed (reaction yield; 97.5%). Example 15 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)及びキノリン 5mlを加え、攪拌しながら 130°Cにて 4時間反応 させた。反応終了後、反応液をガスクロマトグラフィーにより分析（内部標準法)したと ころ、 4-シァノテトラヒドロピラン力 21 lmg生成して 、た (反応収率； 63.3%)。  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ) And 5 ml of quinoline were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 21 lmg of 4-cyantetrahydropyran force was produced (reaction yield; 63.3%).
[0067] 実施例 16 (4-シァノテトラヒドロピランの合成） Example 16 (Synthesis of 4-cianotetrahydropyran)
攪拌装置、温度計及び還流冷却器を備えた内容積 30mlのガラス製フラスコに、純 度 92.1%の 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 597mg(3.0mmol)、ナトリウム メトキシド 216mg(4.0mmol)及び 2-ピコリン 5mlをカ卩え、攪拌しながら 130°Cにて 4時間 反応させた。反応終了後、反応液をガスクロマトグラフィーにより分析（内部標準法)し たところ、 4-シァノテトラヒドロピラン力 ¾40mg生成して 、た (反応収率； 72.0%)。  A glass flask having an internal volume of 30 ml equipped with a stirrer, a thermometer and a reflux condenser was charged with 597 mg (3.0 mmol) of 4-cyantetrahydropyran-4-carboxylate having a purity of 92.1% and 216 mg (4.0 mmol) of sodium methoxide. ) And 5 ml of 2-picoline were added and reacted at 130 ° C for 4 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 40 mg of 4-cyanotetrahydropyran force was produced (reaction yield; 72.0%).
[0068] 実施例 17 (テトラヒドロピラン- 4-カルボン酸アミドの合成） Example 17 (Synthesis of tetrahydropyran-4-carboxylic acid amide)
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 500mlのガラス製フ ラスコに、アルゴン雰囲気下、 Ν,Ν-ジメチルホルムアミド 289ml及び純度 99%のナトリ ゥムメトキシド 68.2g(1.25mol)を加え、 0°Cまで冷却した後、純度 98%のシァノ酢酸ェチ ル 144.3g(1.25mmol)をゆるやかに滴下した。滴下終了後、 20°Cにて 1時間攪拌させて 、シァノ酢酸ェチルのナトリウム塩を含む溶液を調製した。  A glass flask with an internal volume of 500 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 289 ml of Ν, Ν-dimethylformamide and 68.2 g (1.25 mol) of sodium methoxide with a purity of 99% under an argon atmosphere. In addition, after cooling to 0 ° C., 144.3 g (1.25 mmol) of 98% pure ethyl cyanoacetate was gently added dropwise. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 1 hour to prepare a solution containing sodium salt of cyanoacetate.
攪拌装置、温度計、還流冷却器及び滴下漏斗を備えた内容積 1000mlのガラス製フ ラスコに、純度 99%のビス (2-クロロェチル)エーテル 72.2 g(0.50mol)をカ卩え、液温を 80 °Cまで昇温させた後、前記シァノ酢酸ェチルのナトリウム塩を含む溶液をゆるやかに 滴下した。  A glass flask with an internal volume of 1000 ml equipped with a stirrer, thermometer, reflux condenser and dropping funnel was charged with 72.2 g (0.50 mol) of 99% pure bis (2-chloroethyl) ether, and the liquid temperature was adjusted. After the temperature was raised to 80 ° C., the solution containing the sodium salt of cyanoacetate was slowly added dropwise.
[0069] 反応終了後、反応液を 10°Cまで冷却し、攪拌しながら、酢酸 18.2g(0.30mol)をゆる やかに滴下し、続いて水 361mlを加えた。水層と有機層（トルエン層）を分離し、水層 をトルエン 144mlで 1回抽出した後、該有機層とトルエン抽出液を合わせて、 20重量％ 食塩水 217mlで 3回洗浄し、有機層を減圧下で濃縮した (85°C、 0.53kPa) o得られた 赤紫色液体をガスクロマトグラフィーで分析（内部標準法)したところ 4-シァノテトラヒド 口ピラン- 4-カルボン酸メチル 43. lg (ビス (2-クロロェチル)エーテル基準の収率： 51.0 %)、 4-シァノテトラヒドロピラン- 4-カルボン酸ェチル 25.9g (ビス (2-クロロェチル)エー テル基準の収率： 28.3%)を含んで 、た。この赤紫色液体を減圧蒸留し (92〜101°C、 0.71〜1.08kPa)、無色透明液体 57.4gを得た。この無色透明液体をガスクロマトグラフ ィ一で分析（内部標準法)したところ 4-シァノテトラヒドロピラン- 4-カルボン酸メチル 37 .8g (ビス (2-クロロェチル)エーテル基準の収率： 44.7%)、 4-シァノテトラヒドロピラン- 4 -カルボン酸ェチル 19.5g (ビス (2-クロロェチル)エーテル基準の収率： 21.3%)を含ん でいた。 [0069] After completion of the reaction, the reaction solution was cooled to 10 ° C, and with stirring, 18.2 g (0.30 mol) of acetic acid was slowly added dropwise, followed by addition of 361 ml of water. The aqueous layer and the organic layer (toluene layer) are separated, and the aqueous layer is extracted once with 144 ml of toluene, and then the organic layer and the toluene extract are combined and washed three times with 217 ml of 20 wt% brine. Was concentrated under reduced pressure (85 ° C, 0.53 kPa). O The obtained reddish purple liquid was analyzed by gas chromatography (internal standard method), and methyl 4-cyantetrahydride pyran-4-carboxylate 43.lg (bis Yield based on (2-chloroethyl) ether: 51.0 %), And 25.9 g of 4-cianotetrahydropyran-4-carboxylate (yield based on bis (2-chloroethyl) ether: 28.3%). This reddish purple liquid was distilled under reduced pressure (92 to 101 ° C, 0.71 to 1.08 kPa) to obtain 57.4 g of a colorless transparent liquid. When this colorless transparent liquid was analyzed by gas chromatography (internal standard method), 37.8 g of methyl 4-cyantetrahydropyran-4-carboxylate (yield based on bis (2-chloroethyl) ether: 44.7%) It contained 19.5 g of ethyl 4-cyanotetrahydropyran-4-carboxylate (yield based on bis (2-chloroethyl) ether: 21.3%).
[0070] 次に、攪拌装置、温度計及び還流冷却器を備えた内容積 500mlのガラス製フラスコ に、先に得られた 4-シァノテトラヒドロピラン- 4-カルボン酸メチル及び 4-シァノテトラヒ ドロピラン- 4-カルボン酸ェチルの混合物 50.0g (4-シァノテトラヒドロピラン- 4-カルボ ン酸エステルとして 288mmol相当）、ナトリウムメトキシド 20.66g(382mmol)及び Ν,Ν-ジ メチルホルムアミド 250mlを攪拌しながら 130°Cにて 6時間反応させた。反応終了後、 反応液をガスクロマトグラフィーにより分析（内部標準法)したところ、 4-シァノテトラヒド 口ピランが 24.29g生成して!/、た（4-シァノテトラヒドロピラン- 4-カルボン酸メチル及び 4 -シァノテトラヒドロピラン- 4-カルボン酸ェチルの混合物基準の反応収率； 75.9%)。 続いて酢酸 24.18g(403mmol)をカ卩え、室温で 2時間攪拌後、不要物を濾過し、濾物を トルエン 50mlで洗浄した。  [0070] Next, in a glass flask having an internal volume of 500 ml equipped with a stirrer, a thermometer and a reflux condenser, methyl 4-cyantetrahydropyran-4-carboxylate and 4-cyantetrahydropyran- A mixture of ethyl 4-carboxylate 50.0 g (corresponding to 288 mmol as 4-cyanotetrahydropyran-4-carbonate), 20.66 g (382 mmol) sodium methoxide and 250 ml of Ν, Ν-dimethylformamide with stirring The reaction was performed at ° C for 6 hours. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 24.29 g of 4-cyantetrahydridopyran was produced! /, (Methyl 4-cyantetrahydropyran-4-carboxylate and 4 -Reaction yield based on a mixture of -cyantetrahydropyran-4-ethyl carboxylic acid; 75.9%). Subsequently, 24.18 g (403 mmol) of acetic acid was added, and the mixture was stirred at room temperature for 2 hours. Unnecessary substances were filtered off, and the residue was washed with 50 ml of toluene.
その後、濾液と洗浄液を合わせて減圧蒸留し (71〜74°C、 1.60〜2.00kPa)、無色透 明液体 18.13gを得た。この無色透明液体をガスクロマトグラフィーで分析（内部標準 法）したところ 4-シァノテトラヒドロピランを 17.88g (4-シァノテトラヒドロピラン- 4-カルボ ン酸メチル及び 4-シァノテトラヒドロピラン- 4-カルボン酸ェチルの混合物基準の収率 : 55.9%)を含んでいた。  Thereafter, the filtrate and the washing solution were combined and distilled under reduced pressure (71 to 74 ° C, 1.60 to 2.00 kPa) to obtain 18.13 g of a colorless transparent liquid. This colorless transparent liquid was analyzed by gas chromatography (internal standard method). As a result, 17.88 g (methyl 4-canotetrahydropyran-4-carboxylate and 4-cianotetrahydropyran-4- Yield based on the mixture of ethyl carboxylic acid: 55.9%).
[0071] 次に、攪拌装置、滴下漏斗及び温度計を備えた内容積 200mlのガラス製フラスコに 、先に得られた純度 98.7%の 4-シァノテトラヒドロピラン 14.0g(124mmol)、 t-ブチルァ ルコール 70ml及び純度 85%の水酸化カリウム 9.84g(149mmol)を加え、攪拌しながら 1 00°Cにて 2時間反応を行なった。反応終了後、反応液をガスクロマトグラフィーにより 分析（内部標準法)したところ、テトラヒドロピラン- 4-カルボン酸アミドが 15.80g生成し て 、た (4-シァノテトラヒドロピラン基準の収率： 98.6%)。 産業上の利用可能性 Next, in a glass flask having an internal volume of 200 ml equipped with a stirrer, a dropping funnel and a thermometer, 14.0 g (124 mmol) of 4-cyantetrahydropyran having a purity of 98.7% obtained above, t-butyla was obtained. 70 ml of rucol and 9.84 g (149 mmol) of potassium hydroxide having a purity of 85% were added, and the reaction was carried out at 100 ° C. for 2 hours with stirring. After completion of the reaction, the reaction solution was analyzed by gas chromatography (internal standard method). As a result, 15.80 g of tetrahydropyran-4-carboxylic acid amide was produced (yield based on 4-cyantetrahydropyran: 98.6%) ). Industrial applicability
本発明によれば、ビス (2-ハロゲノエチル)エーテルとシァノ酢酸エステルとから、 4- シァノテトラヒドロピラン- 4-カルボン酸エステルを、温和な条件下、簡便な方法によつ て製造する方法が提供される。  According to the present invention, a process for producing 4-cianotetrahydropyran-4-carboxylic acid ester from bis (2-halogenoethyl) ether and cyanoacetate by a simple method under mild conditions. Is provided.
本発明によれば、また、 4-シァノテトラヒドロピラン- 4-カルボン酸エステルカゝら 4-シ ァノテトラヒドロピランを、温和な条件下、簡便な方法によって製造する方法が提供さ れる。  According to the present invention, there is also provided a method for producing 4-cianotetrahydropyran-4-carboxylic acid ester carbonate et al. 4-cianotetrahydropyran by a simple method under mild conditions.
本発明によれば、更に、 4-シァノテトラヒドロピランカもテトラヒドロピラン- 4-カルボン 酸アミドを、温和な条件下、簡便な方法によって製造する方法が提供される。  According to the present invention, there is further provided a process for producing 4-cianotetrahydropyranca by a simple method under the mild conditions of tetrahydropyran-4-carboxylic acid amide.
本発明により得られる 4-シァノテトラヒドロピラン- 4-カルボン酸エステル、 4-シァノテ トラヒドロピラン及びテトラヒドロピラン- 4-カルボン酸アミドは、例えば、医薬.農薬等の 原料や合成中間体として有用な化合物である。  The 4-cyanonotehydropyran-4-carboxylic acid ester, 4-cyanonotetrahydropyran, and tetrahydropyran-4-carboxylic acid amide obtained by the present invention are useful, for example, as raw materials for pharmaceuticals, agricultural chemicals, and synthetic intermediates. A compound.

Claims

請求の範囲 The scope of the claims
[1] -般式 (1)
Figure imgf000020_0001
[1]-General formula (1)
Figure imgf000020_0001
式中、 Xは、ハロゲン原子を表す、  In the formula, X represents a halogen atom.
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)
Figure imgf000020_0002
(2-Norogenoethyl) ether represented by the general formula (2)
Figure imgf000020_0002
式中、 R1は、炭素原子数 2〜6のアルキル基を表す、 In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms,
で示されるシァノ酢酸エステル及び一般式（3)：  Cyanoacetate represented by the general formula (3):
MOR2 (3) 式中、 R2は、 R1と同一又は異なっていても良い炭素原子数 1〜6のアルキル基を表 し、 Mは、アルカリ金属原子を表す、 MOR 2 ( 3 ) In the formula, R 2 represents an alkyl group having 1 to 6 carbon atoms which may be the same as or different from R 1 , M represents an alkali metal atom,
で示されるアルカリ金属アルコキシドを有機溶媒中にて反応させることを特徴とする、 一般式 (4a)及び (4b) :  The general formulas (4a) and (4b) are characterized by reacting an alkali metal alkoxide represented by general formula (4a):
Figure imgf000020_0003
Figure imgf000020_0003
式中、 R1及び R2は、前記と同義である、 In the formula, R 1 and R 2 are as defined above.
力もなる群より選ばれる少なくとも一種の 4-シァノテトラヒドロピラン- 4-カルボン酸エス テルの製造方法。  A process for producing at least one 4-cyantetrahydropyran-4-carboxylic acid ester selected from the group consisting of forces.
[2] アルカリ金属アルコキシド力 ナトリウムメトキシド、ナトリウムエトキシド、ナトリウム t— ブトキシド、ナトリウム t—ペントキシド、カリウム t—ブトキシド又はそれらの混合物であ る請求の範囲第 1項記載の 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの製造 方法。 [2] Alkali metal alkoxide strength Sodium methoxide, sodium ethoxide, sodium t— The method for producing 4-cyantetrahydropyran-4-carboxylic acid ester according to claim 1, which is butoxide, sodium t-pentoxide, potassium t-butoxide or a mixture thereof.
[3] 一般式 (4a)及び (4b) :  [3] General formulas (4a) and (4b):
Figure imgf000021_0001
Figure imgf000021_0001
式中、 R1は、炭素原子数 2〜6のアルキル基を表し、 R2は、 R1と同一又は異なって Vヽても良 、炭素原子数 1〜6のアルキル基を表す、 In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms, R 2 may be the same as or different from R 1 and may be V, and represents an alkyl group having 1 to 6 carbon atoms.
で示される 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの少なくとも 1種とアル力 リ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物とを、カーボネ ート類、アミド類、アミン類、尿素類、スルホキシド類及びスルホン類カゝらなる群より選 ばれる少なくとも 1種の溶媒中で反応させること特徴とする、式 (5)：  At least one 4-cyanotetrahydropyran-4-carboxylic acid ester represented by the following formula: a metal alkoxide, a carboxylic acid alkali metal salt, or a mixture thereof; and carbonates, amides, amines, Formula (5) is characterized by reacting in at least one solvent selected from the group consisting of ureas, sulfoxides and sulfones.
Figure imgf000021_0002
Figure imgf000021_0002
で示される 4-シァノテトラヒドロピランの製造方法。  A method for producing 4-cianotetrahydropyran represented by the formula:
[4] 一般式 (4a)及び (4b)で示される 4-シァノテトラヒドロピラン- 4-カルボン酸エステル が、一般式 (1) :
Figure imgf000021_0003
[4] The 4-cianotetrahydropyran-4-carboxylic acid ester represented by the general formulas (4a) and (4b) is represented by the general formula (1):
Figure imgf000021_0003
式中、 Xは、ハロゲン原子を表す、  In the formula, X represents a halogen atom.
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)
Figure imgf000022_0001
式中、 R1は前記と同義である、 (2-Norogenoethyl) ether represented by the general formula (2)
Figure imgf000022_0001
Wherein R 1 is as defined above.
で示されるシァノ酢酸エステル及び一般式（3)：  Cyanoacetate represented by the general formula (3):
MOR2 (3) 式中、 R2は前記と同義であり、 Mは、アルカリ金属原子を表す、 MOR 2 ( 3 ) wherein R 2 is as defined above, M represents an alkali metal atom,
で示されるアルカリ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合 物とを有機溶媒中にて反応させて得られるものである請求の範囲第 3項記載の 4-シ ァノテトラヒドロピランの製造方法。  4. The 4-cyantetrahydropyran according to claim 3, which is obtained by reacting an alkali metal alkoxide represented by the formula (1) with a carboxylic acid alkali metal salt or a mixture thereof in an organic solvent. Method.
[5] 一般式 (5) :  [5] General formula (5):
Figure imgf000022_0002
Figure imgf000022_0002
で示される 4-シァノテトラヒドロピランと塩基とを溶媒中で反応させることを特徴とする 、一般式 (6) :  General formula (6), characterized by reacting 4-cyantetrahydropyran represented by the following formula with a base:
CONH
Figure imgf000022_0003
CONH
Figure imgf000022_0003
、0ノ  , 0
で示されるテトラヒドロピラン- 4-カルボン酸アミドの製造方法。  A process for producing tetrahydropyran-4-carboxylic acid amide represented by the formula:
[6] 塩基がアルカリ金属水酸ィ匕物である請求の範囲第 5項記載のテトラヒドロピラン- 4- カルボン酸アミドの製造方法。  6. The method for producing tetrahydropyran-4-carboxylic acid amide according to claim 5, wherein the base is an alkali metal hydroxide.
[7] 溶媒がアルコール類である請求の範囲第 5項記載のテトラヒドロピラン- 4-カルボン 酸アミドの製造方法。  [7] The process for producing tetrahydropyran-4-carboxylic acid amide according to claim 5, wherein the solvent is an alcohol.
[8] 反応時に水を存在させることを特徴とする請求の範囲第 5項記載のテトラヒドロビラ ン -4-カルボン酸アミドの製造方法。  [8] The process for producing tetrahydrobilan-4-carboxylic acid amide according to claim 5, wherein water is present during the reaction.
[9] 水の使用量が、 4-シァノテトラヒドロピラン 1モルに対して、好ましくは 0.01〜50.0モ ル、更に好ましくは 0.1〜10.0モルである請求の範囲第 8項記載のテトラヒドロピラン- 4 -力ルボン酸アミドの製造方法。 [9] The amount of water used is preferably 0.01 to 50.0 moles per mole of 4-cianotetrahydropyran. 9. The process for producing tetrahydropyran-4-strong rubonic acid amide according to claim 8, which is more preferably 0.1 to 10.0 mol.
一般式 (5)で示される化合物が、一般式 (4a)及び (4b)：  Compounds represented by general formula (5) are represented by general formulas (4a) and (4b):
Figure imgf000023_0001
Figure imgf000023_0001
式中、 R1は、炭素原子数 2〜6のアルキル基を表し、 R2は、 R1と同一又は異なって Vヽても良 、炭素原子数 1〜6のアルキル基を表す、 In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms, R 2 may be the same as or different from R 1 and may be V, and represents an alkyl group having 1 to 6 carbon atoms.
で示される 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの少なくとも 1種とアル力 リ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物とを、カーボネ ート類、アミド類、アミン類、尿素類、スルホキシド類及びスルホン類カゝらなる群より選 ばれる少なくとも 1種の溶媒中で反応させることにより得られるものである請求の範囲 第 5〜9項のいずれか一項に記載のテトラヒドロピラン- 4-カルボン酸アミドの製造方 法。 At least one 4-cyanotetrahydropyran-4-carboxylic acid ester represented by the following formula: a metal alkoxide, a carboxylic acid alkali metal salt, or a mixture thereof; and carbonates, amides, amines, 10. The tetrahydropyran according to any one of claims 5 to 9, which is obtained by reacting in at least one solvent selected from the group consisting of ureas, sulfoxides and sulfones. -Method for producing 4-carboxylic amide.
一般式 (4a)及び (4b)で示される 4-シァノテトラヒドロピラン- 4-カルボン酸エステル が、一般式 (1) :
Figure imgf000023_0002
The 4-cianotetrahydropyran-4-carboxylic acid ester represented by the general formulas (4a) and (4b) is represented by the general formula (1):
Figure imgf000023_0002
式中、 Xは、ハロゲン原子を表す、  In the formula, X represents a halogen atom.
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)：
Figure imgf000023_0003
式中、 R1は前記と同義である、 で示されるシァノ酢酸エステル及び一般式（3)： Bis (2-nitrogenoethyl) ether represented by general formula (2):
Figure imgf000023_0003
Wherein R 1 is as defined above. Cyanoacetate represented by the general formula (3):
M0R2 (3) 式中、 R2は前記と同義であり、 Mは、アルカリ金属原子を表す、 M0R 2 (3) wherein R 2 is as defined above, M represents an alkali metal atom,
で示されるアルカリ金属アルコキシドを有機溶媒中にて反応させて得られるものであ る請求の範囲第 10項記載のテトラヒドロピラン- 4-カルボン酸アミドの製造方法。  11. The process for producing tetrahydropyran-4-carboxylic acid amide according to claim 10, which is obtained by reacting the alkali metal alkoxide represented by the formula (1) in an organic solvent.
[12] 一般式 (1) :
Figure imgf000024_0001
[12] General formula (1):
Figure imgf000024_0001
式中、 Xは、ハロゲン原子を表す、  In the formula, X represents a halogen atom.
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)
Figure imgf000024_0002
(2-Norogenoethyl) ether represented by the general formula (2)
Figure imgf000024_0002
式中、 R1は、炭素原子数 2〜6のアルキル基を表す、 In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms,
で示されるシァノ酢酸エステル及び一般式（3)：  Cyanoacetate represented by the general formula (3):
MOR2 (3) 式中、 R2は、 R1と同一又は異なっていても良い炭素原子数 1〜6のアルキル基を表 し、 Mは、アルカリ金属原子を表す、 MOR 2 ( 3 ) In the formula, R 2 represents an alkyl group having 1 to 6 carbon atoms which may be the same as or different from R 1 , M represents an alkali metal atom,
で示されるアルカリ金属アルコキシドを有機溶媒中にて反応させ、一般式 (4a)及び（ 4b)：  Is reacted with an alkali metal alkoxide represented by the general formula (4a) and (4b):
Figure imgf000024_0003
式中、 R1及び R2は、前記と同義である、
Figure imgf000024_0003
In the formula, R 1 and R 2 are as defined above.
力もなる群より選ばれる少なくとも一種の 4-シァノテトラヒドロピラン- 4-カルボン酸エス テルを得、  Obtaining at least one 4-cianotetrahydropyran-4-carboxylic acid ester selected from the group of
次 、で、得られた 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの少なくとも 1種 とアルカリ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物とを、 カーボネート類、アミド類、アミン類、尿素類、スルホキシド類及びスルホン類力もなる 群より選ばれる少なくとも 1種の溶媒中で反応させ、式 (5)：  Next, at least one of the obtained 4-cianotetrahydropyran-4-carboxylic acid ester and an alkali metal alkoxide, a carboxylic acid alkali metal salt, or a mixture thereof, carbonates, amides, amines, Reaction is carried out in at least one solvent selected from the group consisting of ureas, sulfoxides and sulfones, and the formula (5):
Figure imgf000025_0001
Figure imgf000025_0001
で示される 4-シァノテトラヒドロピランを得、  4-Cianotetrahydropyran represented by
更に、得られた 4-シァノテトラヒドロピランと塩基とを溶媒中で反応させることを特徴 とする、一般式 (6) :  Furthermore, the general formula (6), characterized by reacting the obtained 4-cianotetrahydropyran with a base in a solvent:
CONH
Figure imgf000025_0002
CONH
Figure imgf000025_0002
、0ノ  , 0
で示されるテトラヒドロピラン- 4-カルボン酸アミドの製造方法。  A process for producing tetrahydropyran-4-carboxylic acid amide represented by the formula:
[13] 一般式 (1) :
Figure imgf000025_0003
[13] General formula (1):
Figure imgf000025_0003
式中、 Xは、ハロゲン原子を表す、  In the formula, X represents a halogen atom.
で示されるビス (2-ノヽロゲノエチル)エーテル、一般式（2)
Figure imgf000025_0004
式中、 R1は、炭素原子数 2〜6のアルキル基を表す、 (2-Norogenoethyl) ether represented by the general formula (2)
Figure imgf000025_0004
In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms,
で示されるシァノ酢酸エステル及び一般式（3)： MOR2 (3) 式中、 R2は、 R1と同一又は異なっていても良い炭素原子数 1〜6のアルキル基を表 し、 Mは、アルカリ金属原子を表す、 Cyanoacetate represented by the general formula (3): MOR 2 ( 3 ) In the formula, R 2 represents an alkyl group having 1 to 6 carbon atoms which may be the same as or different from R 1 , M represents an alkali metal atom,
で示されるアルカリ金属アルコキシドを有機溶媒中にて反応させ、一般式 (4a)及び（ 4b)：  Is reacted with an alkali metal alkoxide represented by the general formula (4a) and (4b):
Figure imgf000026_0001
Figure imgf000026_0001
式中、 R1及び R2は、前記と同義である、 In the formula, R 1 and R 2 are as defined above.
力もなる群より選ばれる少なくとも一種の 4-シァノテトラヒドロピラン- 4-カルボン酸エス テルを得、  Obtaining at least one 4-cianotetrahydropyran-4-carboxylic acid ester selected from the group of
次 、で、得られた 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの少なくとも 1種 とアルカリ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物とを、 カーボネート類、アミド類、アミン類、尿素類、スルホキシド類及びスルホン類力もなる 群より選ばれる少なくとも 1種の溶媒中で反応させることを特徴とする式 (5) :  Next, at least one of the obtained 4-cianotetrahydropyran-4-carboxylic acid ester and an alkali metal alkoxide, a carboxylic acid alkali metal salt, or a mixture thereof, carbonates, amides, amines, Formula (5) characterized by reacting in at least one solvent selected from the group consisting of ureas, sulfoxides and sulfones.
Figure imgf000026_0002
Figure imgf000026_0002
で示される 4-シァノテトラヒドロピランの製造方法。  A method for producing 4-cianotetrahydropyran represented by the formula:
[14] 一般式 (4a)及び (4b) :
Figure imgf000027_0001
[14] General formulas (4a) and (4b):
Figure imgf000027_0001
式中、 R1は、炭素原子数 2〜6のアルキル基を表し、 R2は、 R1と同一又は異なって Vヽても良 、炭素原子数 1〜6のアルキル基を表す、 In the formula, R 1 represents an alkyl group having 2 to 6 carbon atoms, R 2 may be the same as or different from R 1 and may be V, and represents an alkyl group having 1 to 6 carbon atoms.
力もなる群より選ばれる少なくとも一種の 4-シァノテトラヒドロピラン- 4-カルボン酸エス テルを得、 Obtaining at least one 4-cianotetrahydropyran-4-carboxylic acid ester selected from the group of
次 、で、得られた 4-シァノテトラヒドロピラン- 4-カルボン酸エステルの少なくとも 1種 とアルカリ金属アルコキシド、カルボン酸アルカリ金属塩、又はそれらの混合物とを、 カーボネート類、アミド類、アミン類、尿素類、スルホキシド類及びスルホン類力もなる 群より選ばれる少なくとも 1種の溶媒中で反応させ、式 (5)：  Next, at least one of the obtained 4-cianotetrahydropyran-4-carboxylic acid ester and an alkali metal alkoxide, a carboxylic acid alkali metal salt, or a mixture thereof, carbonates, amides, amines, Reaction is carried out in at least one solvent selected from the group consisting of ureas, sulfoxides and sulfones, and the formula (5):
Figure imgf000027_0002
Figure imgf000027_0002
で示される 4-シァノテトラヒドロピランを得、 4-Cianotetrahydropyran represented by
更に、得られた 4-シァノテトラヒドロピランと塩基とを溶媒中で反応させることを特徴 とする、一般式 (6) :  Furthermore, the general formula (6), characterized by reacting the obtained 4-cianotetrahydropyran with a base in a solvent:
CONHCONH
Figure imgf000027_0003
Figure imgf000027_0003
、0ノ  , 0
で示されるテトラヒドロピラン- 4-カルボン酸アミドの製造方法。 A process for producing tetrahydropyran-4-carboxylic acid amide represented by the formula:
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