TW200821281A - Process for production of benzaldehyde compound - Google Patents

Abstract

Disclosed is a process for the production of a benzaldehyde of the formula (II), which comprises the steps of: mixing a mixed solution (1) or (2) with water and an acid to prepare a mixed reaction solution, where the mixed solution (1) contains a salt produced by reacting a benzyl compound of the formula (I) having a leaving group (L) with hexamethylenetetramine in a solvent and a solvent and the mixed solution (2) contains the compound of the formula (I), a solvent for the compound and hexamethylenetetramine; and subjecting the mixed reaction solution to a reaction to produce the benzaldehyde compound, wherein the molar ratio of hexamethylenetetramine to the compound of the formula (I) is adjusted to a value not smaller than 0.25 and smaller than 1.00. (I) (II) wherein L represents a halogen atom or the like; x, y and z independently represent an integer of 0 or 1, provided that sum total of x, y and z ranges from 1 to 3; R1 to R3 independently represent a hydrogen atom or a hydrocarbon group which may have or have not a substituent, or any two members of R1 to R3 may together form an alkylenedioxy group and form a cyclic structure together with two contiguous carbon atoms located on the benzene ring.

Description

200821281 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a sommer (using a benzyl compound such as a halogen atom 5, etc.) and a hexamethylenetetramine. Sommelet) A method of producing a benzaldehyde compound by reaction. In particular, the present invention relates to a method for reducing a hexamethylene group by producing a benzoic acid compound by a Sommer reaction of a benzyl compound having a leaving group and a hexamethylenetetramine. The amount of the tetraamine used is industrially advantageous in terms of the yield of the desired compound, and the amount of the reaction waste can be reduced, which is industrially advantageous. The benzaldehyde compound produced by the method of the present invention is a synthetic intermediate which can be used as a pharmaceutical or agricultural drug, and a perfume, and is a useful compound. [Prior Art: J 15 Background of the Invention The background art of the method of the present invention is described in the following documents. [Patent Document 1] JP-A-54-135770 (Non-Patent Document 1) R.C_Larock, Comprehensive Organic 20 Transformations· Second edition, ppl 198 to 1620 (1999) ), John Wiley & Sons, Inc. [Non-Patent Document 2] Organic Reactions, Chapter 4, The Sommelet reaction, ppl97~217 (1954) John Wiley & Sons, Inc. 6 200821281 [Non-Patent Document 3] Food and Cosmetics Toxicology, Volume 12, Issues 7-8, December 1974, pp907~908 wherein a method for producing an aromatic aldehyde is known as a method for oxidizing or dehydrogenating a benzyl alcohol derivative; Method 5 (Rossenmond reduction, Rosenmim reduction); hydrolysis of dihaloquinone derivatives; use of anhydrous copper (j) and aluminum chloride as catalysts in aromatic hydrocarbons to effect hydrogen chloride and carbon monoxide And then hydrolyzed (Gatman Koch reaction, Gatteraiann-Koch reaction); aromatic hydrocarbons with vaporized aluminum as a catalyst to allow hydrogen cyanide and hydrogenation and Method (Guterman (Gattermann) of aldehyde synthesis) performed after hydrolysis 1〇; benzyl compound, and a method of oxidizing the like. However, such methods are as described in the non-patent literature, and it is quite irritating to synthesize a compound of the present methanol compound, benzamidine halide compound or dihalogen toluene derivative as a raw material. In the case of the Group 15 aldehydes, the use of one of the highly toxic carbon monoxide and hydrogen cyanide is also a problem of safety. Therefore, such methods cannot be said to be sufficient as an industrial production method. On the other hand, in addition to the above methods, as described in the patent documents 非 and non-patent document 2, a Sommer reaction is known, which is a benzylated 2 conjugate and a hexamethylenetetramine. The reaction is carried out in an aqueous acetic acid to thereby obtain a stinky formaldehyde compound corresponding to the aforementioned benzyl compound. It is known that in such a Sommer reaction, in order to increase the reaction yield, an excessive amount of hexamethylenetetramine is used with respect to the benzyl compound. For example, Non-Patent Document 2 has a main point: relative to benzene. Molecular Weight Motility 7 200821281 Must use more than 2 times the molar amount of hexamethylenetetramine. However, if this is done, in the treatment engineering after the end of the reaction, it is necessary to additionally carry out an operation step for treating the reaction waste generated by the excessive six-methylmethylamine, and consider the separation of the target compound. To refine, this is a irritating and inefficient manufacturing method, but a method that needs to be changed in the industry. Among the quinone aldehyde compounds, piperonal is used as a blending agent for heliotrope flower essential oil as described in Non-Patent Document 3, and is also widely used as a flavoring material in general scented cosmetics. 10 A method of producing piperonal by the Sommer reaction, and a method of using a salt of a pepper base gas and a pentamethyltetramine is disclosed in Patent Document 2. Patent Document 2 discloses that in the preparation of a salt of piperonyl chloride and hexamethylenetetramine, in order to increase the yield, piperonyl chloride and hexamethylenetetramine react in an aprotic solvent such as chloroform. And the salt formed is isolated by means of 15 filtration or the like, and then the salt provides a Sommer reaction to produce a benzoic acid compound. However, in this method, since the salt to be formed must be isolated and refined before use, the operation is irritating, and in addition, since an aqueous solution of acetic acid containing ammonia is used in the Sommer reaction Or a water-soluble solution of propionic acid 20 as a solvent, the amount of ammonia used is 0.5 to 4 moles, preferably 2 to 1 mole of salt of piperonyl chloride and hexamethylenetetramine. 3.5 Moer, but a large number, this will generate a large amount of waste derived from ammonia water' and thus increase the load on the environment, etc., the reason is that this method is also difficult to call industrial excellence. Methods. 8 200821281 Further, Citation 2 does not describe the ratio of the amount of the pepper-based chloride to the hexamethylenetetramine used in the salt production. SUMMARY OF THE INVENTION 5 In the production method for producing a benzaldehyde compound by the Sommer reaction, it is conventionally known to use an excess of hexamethylenetetramine relative to the starting phenylhydrazine compound. However, the inventors of the present invention have a nitrogen atom (>N-) having four amine groups per molecule based on the hexamethylenemethylamine, and thus it is possible to form a methyltetramine relative to one molecule. The present invention has been completed by combining benzyl compounds of 1 to 4 molecules (for example, benzoyl chloride compounds), and it is possible to form a majority of salts. The present invention provides a method for producing a benzoic acid compound, which is produced by using a benzyl compound having a debonding group and a hexamethylenetetramine to produce a paraformaldehyde compound, which is compared with the conventional technique. By using a total amount of the tetraamine, the amount of use is drastically reduced, and at the same time, a yield which satisfies the industrial demand can be obtained. The method for producing a cumulonic aldehyde compound of the present invention is to react a liberated benzyl group-containing compound represented by the formula (I) and a hexamethylenetetramine in a solvent: (R1〇) )x

[In the above formula (I), L is a cleavable group selected from the group consisting of: an atom, a methoxy group, a substituted group or a non-substituted group, and has a substitution. Or an arylsulfonyloxy group having no substituent; X, y, Z are the number of alkoxy substituents, each of which is an integer of 0 or 1, and Χ + y + z is 1 to 3 a combination of integers; R1 to r3 are each independently of each other and are a hydrogen atom or a hydrocarbon group having a substituent or a substituent; or, when the 5 x + y + Z system is an integer of 2 or 3, an alkoxy substituent: 〇 Any two of R1, 〇R2, and R3 are bonded to each other to form an alkylenedioxy group, and together with two carbon atoms adjacent to the position on the %► form an annular structure. 】, in the resulting mixture containing the benzyl compound/hexamethyltetramine salt and the solvent (1) or the liberated benzylated 10-compound, solvent and the formula (j) In the mixed solution of the hexamethylenetetramine (2), the mixed reaction solution prepared by mixing the water and the acid is provided under the heating and reflux to provide a reaction, which is characterized in that it is produced. A benzoic acid compound represented by the following general formula (Π): (R1〇)x

15 [In the above formula (Π), R1 to R3 and X, y, and z are as defined above. 〕 'The amount of the hexamethylenetetramine molar used in the above mixture (1) or the amount of the hexamethylenetetramine oxime contained in the above mixture (2) relative to the liberation of formula (I) The molar ratio of the molar amount of the benzyl group compound is adjusted to 20 or more but less than 1 〇〇. In the process of the present invention, the detachment-containing benzyl group-containing compound of the above formula (I) is preferably a compound represented by the following general formula ( melon), a hydrazine alkyldioxene 200821281 benzyl group compound:

[In the above formula (melon), L is as defined above, and R4 is an alkylene group. ]. In the process of the present invention, the 3,4-alkylenedioxybenzylmethyl compound of the above formula (Π) is preferably a 3,4-decyldioxybenzyl compound. In the method of the present invention, the pH of the reaction mixture is preferably adjusted to 6 or less in the production step of the compound of the above formula (Π). In the process of the present invention, in the production step of the compound of the above formula (Π), 10 the above acid preferably contains at least one acid selected from the group consisting of sulfuric acid, phosphoric acid, hydrochloric acid, aliphatic carboxylic acid, and trifluorocarbon. Acetic acid and aliphatic sulfonic acid, aromatic sulfonic acid, and gas aliphatic acid. In the method of the present invention, the solvent of the above formula (I) preferably contains one or more solvents selected from the group consisting of aliphatic carboxylic acids, organic sulfonic acids, aliphatic 15 alcohols, aliphatic hydrocarbons, and guanamine compounds. , a urea compound, an ether compound, an aromatic hydrocarbon, an i-aromatic hydrocarbon compound, a nitroated aromatic hydrocarbon compound, a hydrocarbon compound, an aliphatic carboxylic acid ester compound, a nitrile compound, a sulfoxide compound, And sulfonic acid compounds. In the method of the present invention, a commercially available product may be used as the compound containing the liberated phenylhydrazino group 20 of the general formula (I), but a benzyl group gas compound represented by the following formula (V) may also be used: 200821281 (R10)x (7) (R2〇)^/ck

(R3〇)2ic>-CH2-CI (R10)x, among R1 to R3 and X, 7, and Z are as defined above. ▲, Blanc-Quelet reaction, and will have a chloromethylation reaction with a benzene ring compound:

(IV)]. -z is as defined above y 10 15 = method of the invention, in the case of producing a benzene (tetra) compound with a benzyl compound having a cleavable group, and stretching methyltetramine, reducing the amount of hexamethylene:amine used, At the same time, the amount of solvent (for example, acetic acid) is used; v, the benzoic acid compound can be produced at a reaction efficiency which satisfies industrial requirements, and by this method, the amount of reaction waste can be significantly reduced. 'And can reduce the environmental load caused by reactive waste. C. EMBODIMENT 3 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS The method for producing a benzoic acid compound of the present invention, which uses a benzyl compound having a cleavable group as a starting material, is represented by the following general formula. 12 200821281 (R1〇)x

In the above formula (I), L is a leaving group selected from the group consisting of a halogen atom, a hydroxysulfonyloxy group, an alkylsulfonyloxy group having a substituent or a substituent-free group, and a hetero-substitution group or no substitution. The arylsulfonyloxy group; 5 X, y, z are the number of alkoxy substituents, each of which is an integer of 〇 or 1, and x + y + z is a combination of integers of 1 to 3 ; Ri to R 3 are each independently of each other and are a hydrogen atom or a hydrocarbon group having a substituent or a substituent; or, when x + y + z is an integer of 2 or 3, an alkoxy substituent: 〇Ri, 〇R2 Any two of 〇R3 are bonded to each other to form an alkylenedioxy group, and form a cyclic structure together with two carbon atoms adjacent to each other on the benzene ring; in the above formula (I) In the benzyl group-containing compound, the halogen atom represented by L is fluorine, chlorine, bromine or iodine. Further, the alkyl group having no substitution group represented by L, the Si & oxy group may be, for example, a methyl fluorenyloxy group, and the alkyl sulfonyloxy group having a substituted 15 group may be, for example, a trifluoromethyl group. A haloalkylsulfonyloxy group such as a sulfonyloxy group. Further, the arylsulfonyloxy group having no substituent represented by L may, for example, be a benzenesulfonyloxy group, and the arylsulfonyloxy group having a substituent may be a toluenesulfonyloxy group. In the process of the present invention, the cleavable group L is preferably a halogen, and more preferably a chloroform or a bromine atom. In the detachment-containing methyl compound having the general formula (I), the substituent-free hydrocarbon group represented by R1 to R3 is, for example, methyl, ethyl, propyl, butyl, 13 200821281 pentyl, hexagram a straight-chain number of 1 to 9 or a ring-shaped alkyl group having a carbon number of 3 to 12, a cyclic alkyl group, a cyclohexyl group, a cycloheptyl group I having a carbon number of 3 to 12; a linear alkenyl group having 2 to 1 carbon atoms such as a propylene group or a propylene group; a carbon number of 3 to 121 parts such as an isopropenyl group, a isoprenyl group or a geranyl group; a cycloalkylene group 5; a cyclopropenyl group; a cycloalkyl group having a carbon number of 3 to 12 such as a cyclobutenyl group or a cyclopentenyl group; an aryl group such as a phenyl group, a biphenyl group or a naphthyl group; a carbon number such as a fast group or a fast propyl group; 9 alkynyl and the like. Further, these groups also include various isomers thereof. Further, the hydrocarbon group (R 1 to R 3) having a substituent group is a group having a substituent group bonded to the hydrocarbon group, and the substituent group may be an oxygen atom-containing substituent group, a nitrogen atom-containing substituent group, and the like. Sulfur-substituted groups and the like. The oxygen atom substituent is a substituent which is bonded to the aforementioned hydrocarbon group via an oxygen atom, for example, a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, a heptyloxy group, a benzene group. An alkoxy group such as a methyloxy group; an aryloxy group such as a phenoxy group, a methyl i5 phenoxy group, or a naphthyl group; but other ethyl fluorenyl groups, propyl fluorenyl groups, acrylonitrile groups, neopentyl groups, and cyclohexyl groups. An aryloxywei group such as a carbonyl group such as a carbonyl group, a benzoinyl group or a naphthoquinone group, a methoxy group such as a methoxy group or an ethoxycarbonyl group, or an aryloxywei group such as a phenoxycarbonyl group or a phenoxycarbonyl group is also contained therein. Further, these groups also include various isomers thereof. The 20 έ nitrogen atom substituent group may be, for example, a cyano group or a nitro group, and the hydrocarbon group substituted by the nitrogen atom-containing substituent group may be, for example, a cyano group having a carbon number of 1 to 8 such as a cyanomethyl group or a nitromethyl group. Or nitroalkyl; cyanophenyl, nitrophenyl and the like cyanoaryl and nitroaryl. The atomic substitution system of the squash is a group which is bonded to the aforementioned hydrocarbon group via a sulfur atom. For example, it may be an alkyl group having 1 to 8 carbon atoms such as a bowl base, an ethylthio group or a propylthio group. An arylthio group such as a thio group, a phenylthio group, a methylthio group or a naphthylthio group. Moreover, these groups also include various isomers thereof. In the general formula (I), x and y z are the number of alkoxy substituents, 5 and represent an integer of 0 or 1, and X + y + z is a combination of integers of 丨 3 . In the compound of the general formula (I), 2, if X + y + z is an integer of 2 or 3, the alkoxy substituents: OR1, 〇R2, OR3 contain a position on the ring to the nucleus. The specific limitation state, and any two alkoxy substituents may be combined to form a dialkyloxy group, and two carbon atoms adjacent to the fluorene nucleus on the benzene ring nucleate to form a ring structure. The way. In the -〇-R4-〇- group formed by the combination of two methoxy substituents, R4 is a stretching group, for example, an extended group and an extended ethyl group. Preferably, the _〇_R4_〇_ group is methyldioxy(-〇-CH2_〇_) and ethylidenedioxy(_〇-C2H4-〇-)〇15 The styrene-containing hydrazino group-containing compound represented by the general formula (I) is, for example, '(1) piperonyl fluoride, piperonyl vapor, piperonyl bromide, piperonyl iodide, 3,4-extension B Dioxybenzylidene fluoride, 3,4-extended ethyldioxybenzyl chloride, 3,4-extended ethyldioxybenzyl bromide, 3,4-extended ethyldioxybenzyl iodide Equivalent alkyl dioxybenzylidenes; (2) 4-methoxybenzene 20 methyl chloride, 4-methoxybenzyl bromide, 3,4-dimethoxybenzyl chloride, 3,4-dimethoxybenzyl bromide, 2,5-dimethoxybenzyl chloride, 2,5-dimethoxybenzyl bromide, 3,4,5-trimethoxybenzene Chlorine, 3,4,5·trimethoxybenzene T-bromo, 2,3,4-trimethoxybenzyl chloride, 2,3,4-trimethoxybenzyl bromide, 2,3,6 -trimethoxybenzyl chloride, 2,3,6·trisole 15 200821281 oxybenzyl bromide, 2,4,6-trimethoxybenzyloxy, 2,4,6-trimethoxybenzene Alkyl bromide Base halides; (3) 4-benzylidene chloride, 4-hydroxybenzyl bromide, 3,4-dihydroxybenzyl chloride, 3,4-dihydroxybenzyl bromide, 2,5 -dihydroxybenzyl gas, 2,5-di-benzoquinone, 5 3,4,5-trihydroxybenzyl chloride, 3,4,5-trihydroxybenzyl bromide, 2,3 , 4-trihydroxybenzyl chloride, 2,3,4-trihydroxybenzyl bromide, 2,3,6-di-p-benzylmethyl chloride, 2,3,6-tris-benzylmethyl 2,4,6-tris-phenylhydrazine-based gas, 2,4,6-trihydroxybenzyl bromide and other hydroxybenzyl halides, (4) 3-methoxy-4-pyrimidinyl Chlorine, 3-amino-4-methoxybenzoyl 1 yl chloride, 3-methoxy-4-perbenzylmethyl, 3-hydroxy-4-methoxybenzyl > odor , 3-ethoxy-4-p-benzylmethyl gas, 3-carbyl-4-ethoxybenzyl chloride, 3-ethoxy-4-ylphenylhydrazinyl, 3-prepared -4-Ethyl adenyl bromide, 2-methoxy-5-hydroxybenzyl chloride, 2-hydroxy-5-methoxybenzyl chloride, 2-methoxy-5-hydroxybenzyl Bromine, 2-hydroxy-5-methoxybenzyl bromide, 2-ethoxylated 15-yl-p-methyl, 2-amino-5-ethoxy a hydroxy-methoxy-benzyl halide such as methyl gas, 2-ethoxy-5-hydroxyphenylhydrazine bromide or 2-hydroxy-5-ethoxyphenylhydrazine bromide; (5) toluene Acid-3,4-extended methyldioxybenzyl ester 'toluenesulfonic acid-3,4-extended ethyldioxybenzyl ester, toluenesulfonic acid_4_methoxybenzyl ester, toluene _3,4-dimethoxybenzyl ester of taraxanthin, 20 U,5-monomethoxyphenyl hydrazine vinegar, benzoic acid, 3,4-methyl benzophenone Base ester, benzenesulfonic acid-3,4-extended ethyldioxybenzyl ester, benzene 4-sulfonate benzenesulfonate,-3,4-dimethoxybenzyl benzenesulfonate Ester, benzenesulfonic acid 2,5-dimethoxybenzyl ester and other benzyl benzenesulfonate; (6) methanesulfonic acid _3, 4-methyldioxybenzyl ester, A Acid, 4-extended ethyldioxymethyl 16 200821281 Ester, 4-methoxybenzyl methyl methanesulfonate, _3,4-dimethoxybenzyl ester methanesulfonate, methylsulfonate Acid-2,5-dimethoxymethyl ester and other benzyl sulfonic acid methacrylates; (7) trifluoromethaneic acid-3,4-methyl oxalyl methyl ester, trifluoro Phthalicotin-3,4-extended ethyldioxybenzyl ester, trifluoro Sulfonic acid _4-methoxybenzyl 5-based product, 4,4-dimethoxymethyl ester of difluoromethane, trifluoromethane, 5-methoxybenzyl S is a benzyl trifluoromethanesulfonate such as trifluoromethanesulfonic acid-3,4-methylbenzyloxybenzoate. The commercially available product of the general formula (I) used in the process of the present invention may be a desorbable benzyl group. In such compounds, the benzyl chloride 10 compound can be, for example, based on LF Fieser and M. The method described in Fieser, Advanced Organic Chemistry, p778 (New York, 1961) is obtained by, for example, a benzene ring compound represented by the following general formula (IV), a formic acid or an equivalent thereof (for example, The triamaldehydes and hydrogen chloride provide a Blanc 15-Quelet reaction as shown in the following reaction formula: (R1〇)x (R10)x (R2〇)y'〆

[R1 to R3 and X, y, and z in the above formula are as defined above], and the present compound of the formula (IV) is subjected to a chloromethylation reaction, thereby producing the awkwardness of the above formula (V). Base gas compound. 20 The reaction mixture containing the benzyl chloride compound produced by the above reaction may be supplied to the method of the present invention in its original state, but the benzene 17 200821281 sulfhydryl compound is first purified and supplied to the method of the present invention. Also. A commercially available product can be used as the hexamethylenetetramine used in the method of the present invention. In the process of the present invention, the abbreviated thiol compound/hexamethylenemethyltetramine obtained by the salt formation reaction of the ruthenium-containing fluorenyl sulfhydryl compound of the formula (I) and the hexamethylenetetramine in a solvent is contained. Water and acid in a mixed solution of a salt and the above solvent or in a mixed liquid (2) composed of the liberated benzyl group-containing compound of the above formula (I), a solvent thereof and/or methyltetramine Mixing with it, mixing the reaction mixture, and then supplying the mixed reaction solution under heating and reflux to carry out the reaction (Sommer reaction), and producing a benzene represented by the above general formula 1 (Π) Formaldehyde compound. In the method of the present invention, the amount of the hexamethylenetetramine molar used in the mixing of the mixture (1) or the amount of the hexamethylenetetramine in the mixture (2) is relative to The molar ratio of the molar amount of the benzyl group-containing compound of formula U) is adjusted to 0.25 or more, but less than 1.00, preferably 0.30 to 〇·95, more preferably 〇·35~〇_ 9〇. 15 20 仏 The mixture (1) or the mixture (2) in the formation reaction of the benzophenone compound having the formula (JJ) may contain any (10) agent, and the above-mentioned benzophenone compound formation reaction (Nule reaction) The solvent containing the de-based compound of the formula (1), which is a starting material, can also be reacted, and the benzene which is formed as a starting solvent can also be used as a solvent solvent. The organic acid used in the method of the present invention is an organic acid such as an ammonium hydride such as a cesium (tetra)-acid, a methyl pin or a trifluoromethyl group; , isopropanol, t-butanol, ethylene glycol, di-acetic acid and other aliphatic alcohols, n_pentane, n_hexane, n_g-burn, ring 18 200821281 hexane and other monthly aliphatic hydrocarbons a class of N,N-dimethylformamide, N, xylamine, methylpyrrolidine, etc., N,N,_dimethylimidazole, ketone and other ureas, B, and II Halogenated aromatics such as isopropyl ether, tetrahydrogen M, diwei, etc., aromatic hydrocarbons such as stupid, toluene, and dimethyl benzene, gas benzene, i, 2-diqi, and 1,4-monochlorobenzene Family Classes, nitrobenzene, etc., such as chlorobenzene, sulphuric hydrocarbons, methylene chloride, chloroform, etc., carboxylic acid esters such as ethyl acetate, propyl acetate, butyl acetate, acetonitrile, propionitrile, styronitrile, etc. An organic solvent such as a sulfoxide such as a nitrile or a monosulfoxide or an anthracene such as an anthracene or the like, preferably an aromatic hydrocarbon, an alcohol or an aliphatic carboxylic acid, more preferably 10 is used. Methanol, ethanol, acid and acetic acid (glacial acetic acid), particularly preferably acetic acid (ice from a. Further, these solvents may be used alone or in combination of two or more. If an organic acid is used as the solvent, The organic acid is a 15 acid which can be used as a benzaldehyde compound formation reaction (Sommer reaction) of the formula (。). In the method of the present invention, the amount of the solvent used and the kind thereof are such that the solvent is contained. The uniformity of the reaction liquid and the stirring conditions are appropriately set, and it is preferably 1 to 5000 ml, more preferably 10 to i, with respect to 1 mol of the detachment-based methyl compound of the formula (1). 〇〇〇mi, the best is 5〇20~500ml 〇 mixed liquid (1) is better for presenting a reaction mixture containing a benzyl compound/hexamethyltetramine salt formed by reacting a detachment-containing benzyl group-containing compound of the formula (I) with hexamethylenetetramine in the presence of an agent In the state, the salt solution of the salt formed in the solvent of 19 200821281 may be separated from the reaction mixture, or the salt may be isolated from the reaction mixture, and then dissolved in the solvent to form a solvent. a solution for preparing a salt-forming reaction of the mixed liquid (1) (which is a reaction of a self-contained formula (1) containing a fluorenyl benzyl compound and a hexamethylenetetramine in a solvent) 20~15〇. It is better to 〇~14 (rc, preferably in 1〇O~13 (r, and if necessary, perform the reflux of the vapor generated by cooling and liquefying), reacting, reacting The time is preferably 1 () hours, more preferably 2 to 5 hours. The reaction pressure is not particularly limited and may be carried out under normal pressure. The reaction gas pressure may also be air, but an inert gas such as nitrogen or gas may also be used. 10 The mixed liquid (2) is prepared by mixing the benzyl group-containing compound of the formula (I) with the gluten and the hexamethylenetetramine in any order or simultaneously, preferably in the form of a mixture. The detachment-containing methyl compound of (I) is first mixed in a solvent and dissolved, and then hexamethylenetetramine is mixed in the solution. In the method of the present invention, the acid used in the mixed liquid (1) or (2) to react with water and acid may be, for example, a mineral acid such as sulfuric acid, phosphoric acid, hydrochloric acid or the like; an aliphatic carboxylic acid such as, for example, Formic acid, acetic acid, propionic acid, nitric acid, trifluoroacetic acid, etc.; and organic sulfonic acids, for example, methyllithic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, and toluenesulfonic acid, etc., preferably using minerals The class, 20 organic sulfonic acids and trifluoroacetic acid, more preferably sulfuric acid, phosphoric acid, hydrochloric acid, and preferably aqueous hydrochloric acid. The above-mentioned acids may be used singly or in combination of two or more kinds. The above acid and water may be separately mixed into the mixed liquid (1) or (2), or may be previously mixed into an aqueous acid solution and mixed into the mixed liquid (1) or (2). Alternatively, the acid is previously dissolved in an organic solvent, and the 20 200821281 solution is mixed with water or separately from water to the mixed solution (1) or (2). The mixing of the combined liquid (1) or (2) with water and acid is preferably carried out in the mixed liquid (1) or by the method of dropping human water and acid. In this case, it is preferred that the mixing is heated to 20~ 130 under it, preferably to 4 〇 ~ 12 〇 under it, more preferably 5 to 60 ~ 110 CT 'to carry out the formation of steam cooling liquefaction and return flow. The pH of the mixed reaction solution prepared in the above manner is preferably adjusted to 6 or less by the acid, more preferably 0.01 to 6.0, more preferably 〇〇5 to 3.0. Further, the water contained in the mixed reaction liquid is preferably 0 to 10 ml, more preferably 0.3 to 5 ml, more preferably 0.3 to 5 ml, based on 10 parts of the benzyl group-containing compound of the formula (I). .5~2ml. If the pH of the mixed reaction solution is higher than 6, since the salt will decompose, when the desired aldehyde compound is produced, the desired reaction intermediate product cannot be obtained, and the reaction from the reaction intermediate product to the target disk compound cannot be sufficiently performed. 15 should be. Further, if the value is lower than the force 0 of 0, a bad side reaction occurs, for example, a case where the alkoxy substituent is broken or the like occurs. Further, the content of water in the mixed reaction liquid is such that the detachment-containing benzyl group-containing compound lg of the formula (I) is less than O.ltnl, and the desired reaction intermediate product cannot be obtained as described above. Alternatively, the reaction of converting the intermediate product from the reaction to the desired aldehyde compound may not be sufficiently performed, or if the amount exceeds 10 ml, the reaction rate becomes slow, and for example, the required reaction time becomes remarkably long. The mixed reaction solution thus prepared is preferably 20 to 13 Torr. (3, more preferably at 40 to 120 ° C, preferably at 60 to 11 (TC is preferably 丨 ~ (7) time, more 21 200821281 better 2 ~ = between and under the heating effect, thereby, The benzaldehyde compound formation reaction (Sommer reaction) of the formula () is carried out. The reaction pressure of the reaction of X 4 is not particularly limited, and is preferably carried out under normal pressure, and the reaction gas pressure is not particularly limited, in the air. It can be carried out, or it can be carried out in an inert gas such as nitrogen or argon. The benzoic acid compound formed by the method of the present invention can be extracted and passed through an appropriate liberation and purification method* after the end of the reaction. Purification by distillation, distillation, distillation/recrystallization, recrystallization, crystallization, column chromatography and/or high-speed liquid chromatography. 1〇I method of the invention, the six-methyl group contained in the mixed solution (1) The tetraamine molar is the amount of the hexamethylenetetramine molar used in the preparation of the mixed solution (1) or the amount of the hexamethylenemethylamine in the oral solution (2) relative to the above formula (1) The molar ratio of the molar amount of the benzyl group-containing compound, as described above, is preferably adjusted to 〇·25 or more but less than 1〇〇, more 15 〇·95 ' More preferably 〇35~〇9〇. By modulating the molar ratio as described above, compared with the conventional method, it can be In particular, the amount of methyltetramine used is relatively small, and thus the amount of solvent (e.g., acetic acid) used is reduced, and the desired reaction efficiency can be satisfied to produce the desired benzene road compound. The method of the present invention is as follows The 2〇 method is used to determine the reaction efficiency by measuring and calculating the multiplied average reaction yield. (1) Calculating the target compound from the target benzene by the yield of the compound (mol) and the starting benzyl compound Moer. Moule yield (%. This molar yield (%) is reported as the yield a (%) of the starting stupid compound. 22 200821281 (2) The yield of the desired benzene (tetra) compound ( The molar yield of the target compound was calculated by using the molar amount of the target compound (9). The molar yield of 0 Μ is the yield b (〇/〇) of the hexamethylenetetramine standard. (3) Calculating the multiplication average reaction yield from the yield y % of the starting benzyl compound and the (4) b% of the six-extension methyl group basis (1) l( X)) 〇C(%)=(axb)1/2(%) (1) ▲ $ it multiplied by the average reaction yield c (%) is used to show the yield of the target compound 'this yield is The method of the present invention is based on the molar yield of the starting benzyl compound of formula (1) and the molar yield of the hexamethylenetetramine standard. The method of the invention comprises the mixture (1) or (2) And the molar content of the methyltetramine molar relative to the molar content of the benzylic compound containing the formula (1) is more than 25, but less than 1 〇〇, compared with In the conventional technique, the molar ratio of the molar ratio of the present invention is 1.0 or more, and the multiplication average reaction yield (i.e., c値) of the present invention is clearly increased by 15. If the aforementioned molar ratio is less than 2, the target compound is The yield is insufficient, and the multiplicative average reaction yield C is also insufficient. If the ratio is above 1 Torr, the molar yield of the hexamethylenetetramine standard is insufficient, and the multiplication average reaction yield C is also insufficient. And the amount of the reaction effluent increases, and the environmental load becomes large. 20 EXAMPLES The present invention is illustrated by the following examples. The reaction products of the following examples and comparative examples were carried out by gas chromatography or high-speed liquid chromatography under the following analysis conditions. (1) Gas Chromatography Analysis Conditions: 23 200821281 Column: TC-WAXcp0.53mmX3〇mm, film thickness j 〇 ( (( GL Science Co., Ltd.) Column temperature: 80 ° C (5 minutes) _23(rc(1〇分保持)

Heating rate: 10 ° C / min 5 INJ temperature: 160 ° C

DET temperature: 200 ° C current · · 120mV

He flow rate: 6.5~7.0ml/rnin Internal standard material: Lianqi 0 (2) High-speed liquid chromatography analysis conditions: Pipe column ·································································· Acetonitrile = 2/1 (by volume) pH: 2.5 (adjusted with trifluoroacetic acid)

Flow rate··1.0ml/min 5 Column oven temperature: 40°C Detection wavelength·· 260nm (3) Calculation method of multiplication and average reaction yield 20 (IV) Yield (mol) from the target benzene (tetra) compound Starting the benzoic acid compound molar amount to calculate the target compound material (4). The yield (%) is expressed as the yield a (%) of the starting benzyl compound. (4) The molar yield (%) of the target compound was calculated from the amount of the target of the benzene (tetra) compound. This molar yield (%) was recorded as the yield of the hexamethylenetetramine standard. (3-3) The ratio of the yield of the starting benzyl compound to the yield of b-extension 24 200821281 methyltetramine benchmark b% is calculated by the following formula (1): C (%) ). C(%) = (axb)1/2(%) (1) Example 1 (Synthesis of heliotropin: molar ratio of hexamethylenetetramamine to benzylic compound: 0.25) In a 200 ml flask with 3 ports, 17.06 g (100 mmol) of pepper-based gasification was mixed with 8.5 ml of acetic acid having a purity of 96% or more, and 3.50 g (25 mmol) of six-stretching was added thereto at a temperature of 20 to 27 °C. Methyltetramine is stirred and refluxed at a temperature of 115 to 125 ° C to carry out a reaction, and a mixture containing a piperonyl chloride/hexamethylenetetramine salt (1) is prepared. The mixed liquid (1) was refluxed at a temperature of 115 to 125 ° C, and a mixture of 8.5 ml of water and 6.3 ml of a 35 mass % aqueous hydrochloric acid solution was dropped into it by dropping, and the resulting mixed reaction liquid was obtained. (pH: 〇·8 〇) At a temperature of 90 to 100 ° C and stirring under reflux for 2 hours, a sporadic pepper 15 aldehyde was synthesized. After the completion of the above reaction, the obtained reaction solution was allowed to cool to room temperature, and 100 ml of ethyl acetate was used for layering and extraction, and the obtained organic layer was washed with water, and then washed with saturated sodium hydrogencarbonate and saturated brine. net. After washing, the organic/gluten solution was analyzed by Southern Liquid Chromatography (absolute method), and the yield of piperonal was 8.66 g. The yield based on the piperonyl chloride of the piperonal acid was 58%, and the yield of the hexamethylenetetramine standard was 231%'. The multiplied average reaction yield was 112%. Continuing, the organic solvent was removed from the above organic solution to obtain 8.4 〇g of spironic acid. The yield of the pepper-based gasification benchmark derived from pepper was 56%. 25 200821281 The physical properties of the peppers obtained are as follows. Spectrum (300MHz, CDC13) δρρηι : 9.81(1H,S), 7·42(1Η,dd,J1 = 8·0Ηζ, J2=1.6·Ηζ), 7·33(1Η,d,J二1·6Ηζ) ,6·93(1Η,d,J=8.0Hz),6_08(2H,s) 5 Mass Spectrometry (Cl, m/z) ·· 151 [M+H]+ Example 2 (heliotropin) Synthesis: molar ratio of hexamethylenetetramine to p-benzoyl chloride compound: 0.39) 114.6 g (1.0 mol) of a 35 wt% aqueous hydrochloric acid solution and 9.79 g (0-300 mol) were mixed in a 200 ml triangular flask with 3 ports. The purity of 92% by weight of 10 tripolymethyl, and then the internal temperature of the flask is cooled to 8~9 °C. In the above mixture, a solution of 12.21 g (0.10 mol) of 1,2-methyldioxybenzene disposed under 20 ml of toluene was slowly dropped while maintaining the internal temperature at 8 〜 while stirring. Reaction for 7 hours. After the completion of the reaction, the obtained reaction solution was transferred to a separatory funnel, and the aqueous layer was separated and removed. The obtained organic layer was transferred to a 200 ml triangular flask having 3 mouths, and after removing toluene under reduced pressure, the obtained concentrate was quantitatively analyzed by gas chromatography (internal standard method), and the pepper-based chloride was used. The reaction yield was 85.0% (〇.〇85 mol). Then, the concentrate of the toluene solution of the piperonyl chloride is mixed with 5.7 ml of acetic acid having a purity of 96% or more and 4.63 g (0.033 mol) of hexamethylenemethyltetradecylamine, and refluxed at a temperature of 115 to 125 ° C. In an hour, a mixture (1) containing a piperonyl chloride/hexamethylenetetramine salt was prepared. Thereafter, 5.7 mi of water and 4.2 ml of a 35 wt% aqueous hydrochloric acid solution were added dropwise to the mixed solution (1) under reflux of 115 to 1251: the pH of the mixed reaction solution was confirmed to be 2 by using pjj test paper. 4. This mixed reaction solution was at 90 to 1 Torr. (3 at a temperature of 26 200821281 reaction for 2 hours. After the reaction is finished, the obtained reaction solution is allowed to cool to room temperature, and then separated and extracted with 100 ml of ethyl acetate, the obtained organic layer is water. The mixture was washed successively with saturated sodium bicarbonate water and saturated brine. After washing, the obtained organic layer solution was subjected to high-speed liquid chromatography (absolute calibration method) for quantitative analysis, and the yield of the dispersed piperonal was 10.4g. The reaction yield of the pepper-based chloride standard is 81.5%, the reaction yield of the hexamethylenetetramine standard is 209%, and the multiplication and average reaction yield is 131%. Example 3 (heliotropin) Synthesis: molar ratio of hexamethylenetetramine to benzyl gas compound: 0.62) 10 Mix 114.6 g (li〇mol) of 35 wt% hydrochloric acid aqueous solution with 9-fold in a 200 ml flask. 79 g (0.300 mol) of 92% by weight of trimeric formic acid' and then cooled the inner temperature of the flask to 8 to 9 ° C. In the above mixture, slowly drip was placed under 20 ml of toluene 12.21 g (O.lOOmol) Bu 2-extended methyldioxybenzene solution while maintaining the internal temperature at 8 15 ～9 °C, while stirring for 16 hours. After the reaction was completed, the obtained reaction liquid was transferred to a separatory funnel, and the aqueous layer was separated. The obtained organic layer was transferred to a 200 ml triangular flask with 3 mouths, and removed under reduced pressure. After toluene, the obtained concentrate was subjected to quantitative analysis by gas chromatography (internal standard method), and the reaction yield of the pepper base gas was 80.8% (0.081 mol). 20 Then, the pepper base chloride was used. The toluene solution concentrate is mixed with 8.7 ml of 96% purity acetic acid and 7.01 g (0.050 mol) of hexamethylenetetramine and 8.7 ml of water, and stirred under reflux at a temperature of 90 to 100 ° C for 2 hours to prepare a pepper. a mixture of a base gas/hexamethyltetramine salt (1). Thereafter, 6.4 ml of a 35 wt% hydrochloric acid water 27 200821281 solution is dropped into the mixture at a reflux temperature of 115 to 125 ° C ( 1) The pH of the obtained mixed reaction liquid was confirmed to be 2 to 4 by using a pH test paper. The mixed reaction liquid was refluxed while stirring at a temperature of 9 Torr to 1 ° C for 2 hours to synthesize piperonal. After the end, the obtained reaction solution was allowed to cool to room temperature, and 10 〇 1111 was used. Ethyl acetate is separated and extracted, and the obtained organic layer is washed sequentially with water, saturated sodium bicarbonate water and saturated brine. After washing, the obtained organic layer solution is subjected to high-speed liquid chromatography (absolutely Quantitative analysis, the yield of the divergent pepper was 11.8 g. The reaction yield of the pepper-based vapor reference was 97.3%, and the reaction yield of the hexamethylenetetramine standard was 157%. The average reaction yield was 124%. 10 Example 4 (Synthesis of heliotropin: molar ratio of hexamethylenetetramine to benzyl chloride compound: 0.50) In a 200 ml triangular flask with 3 mouths, I7. 〇 6g (l〇 〇mmol) piperonyl chloride is dissolved in 8.5 ml of acetic acid, and 7 lg (50 mmol) of hexamethylenetetramine is mixed in the solution, and refluxed at 115 to 12 rc while heating. 5 mixing is carried out for 2 days. To prepare a mixed liquid (1) containing a pepper base gas/hexamethylenemethylamine salt. In the mixed liquid (1) containing the piperonyl chloride/hexamethylenetetramine salt and acetic acid, 8.5 ml of water and 6.3 ml of a concentration of 35 mass% of citric acid were dropped at 115 to 125 under reflux. Mix. The resulting mixed reaction solution 2 had a pH of 2 to 4 (pH test paper). Then, the mixed reaction liquid was heated and stirred at a temperature of 90 to 100 C for 2 hours, thereby producing sporadic piperonal. After the completion of the reaction, the obtained reaction liquid was cooled to room temperature, and then mixed with 100 ml of ethyl acetate for separation and extraction, and the obtained organic layer was washed with water, saturated sodium hydrogen carbonate water and saturated brine. After washing, the organic layer solution obtained in 28 200821281 was quantitatively analyzed by high-speed liquid chromatography (absolute calibration method), and the yield of the divergence of piperonal was 12.4 g. The reaction yield of the pepper-based gasification standard was 82.6%, the reaction yield of the hexamethylenetetramine standard was 165%, and the multiplied average reaction yield was i17%. 5 Example 5 (Synthesis of heliotropin: Stone molar ratio of hexamethylenetetramine to benzyl gas compound: 〇·75) In a 200 ml triangular flask with 3 mouths, 17.06 g ( 100 mmol) of piperonyl chloride was dissolved in 8.5 ml of acetic acid, and 10.51 g (75 mmol) of hexamethylenetetramine was mixed in the solution, and heated at 115 to 125 ° C while heating and stirring for 10 hours to prepare A mixture containing piperonyl chloride/hexamethylenetetramine salt (1). In the obtained mixed liquid (1) containing piperonyl chloride/hexamethylenetetramine salt and acetic acid, 8.5 ml of water and 6.3 ml of a concentration of 35 mass% of citric acid were dropped by reflux at 115 to 125 ° C. mixing. The resulting mixed reaction liquid 15 had a pH of 2 to 4 (pH test paper). Then, the mixed reaction solution was at 9 Torr to 1 Torr. Heat and stir at 温度; mix for 2 hours, thus producing a sprinkling of pepper acid: After the completion of the reaction, the obtained reaction liquid was cooled to room temperature, and then mixed with 100 ml of ethyl acetate, and separated and extracted. The obtained organic layer was washed successively with water, saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer solution was quantitatively analyzed by high-speed liquid chromatography (absolute calibration method), and the yield of the divergence of piperonal was 11.59 g. The reaction yield of the piperonyl chloride standard was 77.2%, the reaction yield of the hexamethylenetetramine standard was 103%, and the multiplied average reaction yield was 89%. Example 6 (Synthesis of heliotropin························································ (l〇〇mm〇i) piperonyl chloride, dissolved in 8.5ml of acetic acid, mixed with U 92g (SSmmol) hexamethylenetetramine in the solution, and heated under reflux at 115~ΐ25χ: 5 The mixture was stirred for 2 hours to prepare a mixed liquid (1) containing a piperonyl chloride/hexamethylenetetramine salt. Mixing 8.5 ml of water with 6.3 ml of hydrochloric acid having a concentration of 35 mass% in a mixed liquid (1) containing piperonyl chloride/hexamethylenetetramine salt and acetic acid at 115 to 125 under reflux . The resulting mixed reaction liquid 10 had a pH of 2 to 4 (pH test paper). Then, the mixed reaction liquid was heated and stirred at a temperature of 90 to 1 ° C for 2 hours, thereby producing sporadic piperonal. After the completion of the reaction, the obtained reaction liquid was cooled to room temperature, and then mixed with 100 ml of ethyl acetate, and separated and extracted. The obtained organic layer was washed successively with water, saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer solution was quantitatively analyzed by high-speed liquid chromatography (absolute calibration method), and the yield of the divergence of piperonal was 12.98 g. The reaction yield of the piperonyl chloride standard was 86.4%, the reaction yield of the hexamethylenetetramine standard was 101.7%, and the multiplication and average reaction yield was 94%. Example 7 (Synthesis of heliotropin: molar ratio of hexamethylenetetramethyleneamine to benzyl chloride compound: 0.95) 17.06 g (100 mmol) of pepper in a 200 ml triangular flask with 3 mouths The base gas is dissolved in 8.5 ml of purity 96% or more of 1 acetic acid, and 13.32 g (95 mmol) of hexamethylenetetramine is mixed in the solution, and refluxed at 115 to 125 ° C while heating and stirring for 2 hours to prepare A mixture containing sulphate-based chloride / 30 200821281 hexamethylene monoamine salt (丨). In the obtained mixed solution (1) (ρΗ: 2 to 4; pH test paper) containing piperonyl chloride/hexamethylenetetramine salt and acetic acid, 8.5 ml of water and 6.3 ml were refluxed at 115 to 125 ° C. Hydrochloric acid having a concentration of 35% by mass was dropped, and then heated at a temperature of 90 to 1 ° C. • Stirring was carried out for 2 hours and 5 hours. After the reaction is completed, the obtained reaction solution is cooled to room temperature, and then mixed with 1 ml of ethyl acetate and separated and extracted. The obtained organic layer is in the order of water, saturated sodium bicarbonate water and saturated brine. Wash. After washing, the obtained organic layer solution was quantitatively analyzed by a high-speed liquid chromatography method (absolute calibration method), and the yield of the divergent piperonal was 10 11.61 g. The reaction yield of the pepper-based gasification standard was 77.3%, the reaction yield of the six-extension methyltetramine standard was 81.3%, and the multiplication and average reaction yield was 79%. Example 8 (heliotropin) Synthesis: molar ratio of hexamethylenetetramine to benzyl chloride compound: 〇·5〇) 15 Placed in a 200ml flask with 3 mouths with 17.06 g (100 mmol) of pepper-based gasification, 7.01 g (50 mmol) hexamethylenetetramine and 8.5 ml of a mixture of acetic acid having a purity of 96% or more (7) were added with 85 ml of water and 6.3 ml of a 35 mass% aqueous hydrochloric acid solution to obtain a mixed reaction solution (pH: 2 to 4). ; pH test paper) is refluxed at a temperature of 92 to 951: for 4 hours, and 20% is sprinkled with piperonic acid. After the completion of the reaction, the obtained reaction liquid was cooled to room temperature, and separated and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with water, saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer was quantitatively analyzed by Southern Liquid Chromatography (absolute calibration method), and the yield of the disperse piperonal was 9.5 g. The inverse of the pepper-based chloride standard 31 200821281 The yield was 63.3%, the reaction yield of the six-extension methyltetramine standard was 127%, and the multiplied average reaction yield was 89%. Example 9 (Synthesis of 4-methoxybenzaldehyde: molar ratio of hexamethylenetetramine to benzyloxy compound: 0.33) 5 In a 5 〇ml two-necked flask with 2 mouths, 7.99 g (50 mmol) 4-methoxybenzyl chloride, 2.31 g (16.5 mmol) of hexamethylenetetramine, 2.9 ml of acetic acid having a purity of 96% or more as a mixture, and stirred under reflux at a temperature of 115 to 125 for 3 hours. Thus, a reaction liquid (1) containing 4·methoxybenzyl chloride/hexamethylenetetramine salt was prepared. Then, 2.9 ml of water and 2·1 ml of a 35 mass% aqueous hydrochloric acid solution were dropped into the reaction liquid (1) at a temperature of 10 to 115 ° C, and the resulting mixed reaction solution was added thereto. pH: 2 to 4; pH test paper) was stirred at a temperature of 90 to 100 QC for 3 hours to synthesize 4-methoxybenzaldehyde. After the completion of the reaction, the obtained reaction solution was cooled to room temperature, and separated and extracted with 10 ml of ethyl acetate. The obtained organic layer was washed sequentially with water, saturated sodium hydrogencarbonate, and saturated brine. After washing, the obtained organic layer solution was subjected to quantitative analysis by high-speed liquid chromatography (absolute calibration method), and the yield of the 4-methoxybenzoquinal was 6.1 g. The reaction yield of the pepper-based chloride standard was 89.6%, the reaction yield of the hexamethylenetetramine standard was 271%, and the multiplied average reaction yield was 156%. 20 Comparative Example 1 (synthesis of heliotropin: molar ratio of hexamethylenetetramine to benzyl chloride compound: 2.0) 17.06 g in a 2 〇〇ml flask with 3 mouths ( 100 mmol) piperonyl vapor, 28.04 g (200 mmol) of hexamethylenetetramine, 34 ml of acetic acid, 34 ml of water, and 25 ml of a 35 wt% aqueous solution of hydrochloric acid are mixed according to the cis 32 200821281 sequence described above, and the examples 1 The mixture was heated at the same temperature and stirred at 90 to 100 ° C for 4 hours to prepare a reaction liquid containing spironolidine. The obtained reaction solution was cooled to room temperature, and separated and extracted using 100 ml of ethyl acetate. The obtained organic layer was washed with water, saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer solution was subjected to quantitative analysis by high-speed liquid chromatography (absolute calibration method), and the yield of the spanning piperonal was 12.2 g. The reaction yield of the pepper-based chloride standard was 81.4%, and the reaction yield of the hexamethylenetetramine standard was 40.6% but was rather low, and a considerable amount of hexamethylenetetramine was consumed. Therefore, the multiplied average reaction yield was 57%. 10 Comparative Example 2 (Synthesis of heliotropin) • Mohr ratio of hexamethylenetetramine to benzyl gas compound: 0.1) In a 200 ml triangular flask with 3 mouths, 17.06 g (l〇) 〇mm〇l) piperonyl chloride was mixed with 8.5 ml of acetic acid, and then uQg (10 mmol) of hexamethylenetetramine was mixed, and in the same manner as in Example 1, the mixture was refluxed for 15 hours, thereby preparing A reaction solution containing piperonyl chloride/hexamethylenemethylamine. In the same manner as in Example 1, 8.5 ml of water and 6.3 ml of a 35 wt% aqueous hydrochloric acid solution were added dropwise under reflux, and the resulting mixed reaction solution (pH: 2 to 4; pH test paper) was further stirred for 2 hours. Therefore, the synthesis of Hu 20 pepper aldehyde. The obtained reaction liquid was cooled to room temperature, and separated and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed sequentially with water, saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer solution was subjected to quantitative analysis by Southern Liquid Chromatography (absolute calibration method), and the yield of the sparged acid was 1.7 g. The reaction yield of the pepper base vapor reference was η"%, 33 200821281 The reaction yield of the hexamethylenetetramine standard was 113%, and the multiplied average reaction yield was 36%. Comparative Example 3 (Synthesis of heliotropin: molar ratio of hexamethylenetetramine to benzylic compound: 0.15) 5 In a 200 ml flask with 3 mouths, 17.06 g (lOOmmol) of pepper The base chloride was mixed with 8.5 ml of acetic acid, and then 2.10 g (i5 mmol) /, 曱 曱 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四 四A reaction solution of a chlorine/hexamethylenetetramine salt. 10 The reaction liquid was mixed with 8.5 ml of water and 6.3 ml of a 35 wt% aqueous hydrochloric acid solution under reflux in the same manner as in Example 1 to obtain a mixed reaction solution (pH · 2 to 4; pH test paper) and Example 1 The mixing was further carried out for 2 hours in the same manner, and thus the synthesis of piperonal was carried out. The obtained reaction liquid was cooled to room temperature, and separated and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with water, 15 saturated sodium hydrogen carbonate and saturated brine. After washing, the obtained organic layer solution was subjected to quantitative analysis by high-speed liquid chromatography (absolute calibration method), and the yield of the spanning piperonal was 3. 6 g. The reaction yield of the sulphate-based chloride standard was 20.3%, the reaction yield of the hexamethylenetetramine standard was 136%, and the multiplied average reaction yield was 53%. 20 Comparative Example 4 (Synthesis of heliotropin: molar ratio of hexamethylenetetramine to benzyl chloride compound: 1.05) In a 200 ml triangular flask with 3 mouths, 17 〇 6g (1〇) 〇mm〇1) Pepper-based chloride was mixed with 8.5 ml of acetic acid, and then 14 72 g (105 mmol) of hexamethylenetetramine was mixed, and heated back in the same manner as in Example 1 for the second time. Thus, a reaction liquid containing a piperonyl chloride/hexamethylenetetramine salt was prepared. In the same manner as in Example 1, 8.5 ml of water and 6.3 ml of a 35 wt% aqueous hydrochloric acid solution were added dropwise under reflux to obtain a mixed reaction solution (pH ··2 to 4; pH test paper) and Example 1 The same is repeated for another 2 hours and 5 stirrings, thus synthesizing the spar. The obtained reaction liquid was cooled to room temperature, and separated and extracted with 100 ml of ethyl acetate. The obtained organic layer was washed with water, saturated sodium hydrogen carbonate water and saturated brine. After washing, the obtained organic layer solution was quantitatively analyzed by high-speed liquid chromatography (absolute calibration method), and the yield of the spanning piperonal was 10.46 g. The reaction yield of the piperonyl chloride 10 standard was 69.7%, the reaction yield of the hexamethylenetetramine standard was 64.7%, and the multiplied average reaction yield was 68 〇/〇. Comparative Example 5 (Synthesis of 4-methoxybenzaldehyde·········································· 99 g (5〇mm〇1) 4_methoxy-15-benzylmethyl chloride is mixed with 14.2 g (l〇〇min〇l) hexamethylenetetramine and 17 ml of acetic acid, and is the same as in the first embodiment. The mixture was stirred under heating and reflux for 3 hours, thereby preparing a mixed liquid containing 4-methoxybenzyl gas/hexamethylenetetramine salt. In the mixed liquid, a mixed reaction liquid (pH: 2 to 4; pH test paper) obtained by mixing, for example, water and 13 ml of a 35% by mass aqueous hydrochloric acid solution was mixed in the same manner as in Example 1 except that the mixture was heated under reflux. Methoxybenzaldehyde. After the completion of the reaction, the obtained reaction liquid was cooled to room temperature, and the organic layer obtained by separating and extracting with 150 ml of ethyl acetate was washed successively with water, saturated sodium hydrogen carbonate water and saturated brine. After washing, the obtained organic layer solution was subjected to quantitative analysis by high-speed liquid chromatography (absolute calibration method), and the yield of the 4-methoxybenzene 35 200821281 aldehyde was 2.5 g. The reaction yield of the pepper-based chloride standard was 36.7%, the reaction yield of the hexamethylenetetramine standard was 18.3%, and the multiplied average reaction yield was 26%. In Examples 1 to 8 of the method of the present invention, the amount of acetic acid used as the solvent was 5, which is 1/4 of the amount of acetic acid used in Comparative Example 1 of the prior art, and Example 9 is also Comparative Example 5. The amount of acetic acid used is 1/5 or less. In other words, the method of the present invention can greatly reduce the amount of acetic acid used as a solvent. In Examples 1 to 9 of the method of the present invention, the objective compound was multiplied by an average reaction yield; C was 79 to 156%. On the other hand, the molar ratio is less than 10 0.25 (Comparative Example 2, 3), and the multiplied average reaction yield; C system is 36 to 53%, and the molar ratio is above 1.00 (comparison In the case of Examples 1, 4, and 5), C is 26 to 68%, and neither of them achieves the effects of the present invention. Advantages of the Invention Industry The method of the present invention can successfully reduce the use amount of hexamethylenetetramine while maintaining the requirements for industrial reaction efficiency, and in addition, reducing the amount of reaction waste, Reducing the cost of reactive waste treatment has a very high practical effect. t diagram simple description 3 (none) 20 [main component symbol description] (none) 36

Claims (1)

200821281 X. Patent application scope: 1. A method for producing a benzaldehyde compound, characterized in that it contains a deductive benzyl group-containing compound represented by the following formula (I) and methyltetramine a mixed liquid (1) obtained by mixing a benzyl compound/hexamethyltetramine salt formed by a reaction with a solvent in a solvent or a debondable benzyl group-containing compound having the above formula (I) In a mixture of a solvent and a hexamethylenetetramine, (2), water and an acid are mixed therein: (R1〇)x [In the above formula (I), L is a leaving group selected from the group consisting of a halogen atom, a hydroxysulfonyloxy group, an alkylsulfonyloxy group having a substituent or a substituent-free group, and having a substituent group or none. The arylsulfonyloxy group of the substituent; X, y, z are the number of alkoxy substituents, each of which is an integer of 0 or 1, and X + y + z is an integer of 1 to 3 The combination '· R1 to R 3 are each independently a hydrogen atom or a hydrocarbon group having a substituent or a substituent; or, when x + y + z is an integer of 2 or 3, an alkoxy substituent; OR1, OR2 And any two of 〇R3 are combined to form a stretching oxydioxy group, and together with two carbon atoms located adjacent to the benzene ring form a ring structure], the mixed reaction liquid is prepared, and heated. The mixed reaction solution is supplied under reflux to carry out a reaction, and when a benzoic acid compound represented by the following general formula (2) is produced: 37 200821281 (R1〇)x [In the above formula (R), R1 to R3 and x, y, and z are as defined above], and the amount of the hexamethylenetetramine or the mixture of the above-mentioned mixed liquid (1) is prepared. The molar ratio of the hexamethylenetetraamine molar amount contained in the formula (I) to the molar amount of the styrene-containing hydrazino group-containing compound of the formula (I) is adjusted to be 0.25 or more but less than 1.00. 2. The method of claim 1, wherein the liberated benzyl group-containing compound of the above formula (I) is a 3,4-alkylenedioxybenzene group represented by the following general formula (m) Base compound: CH2-L (III) [In the above formula (ΠΙ), L is as defined above, and R4 is a stretching group]. 3. The method of claim 2, wherein the 3,4-alkylenedioxyphenyl fluorenyl compound of the above formula (m) is a 3,4-methyldioxybenzyl compound. 4. The method of claim 1, wherein in the step of producing the compound of the formula (Π), the pH of the reaction mixture is adjusted to 6 or less. 5. The method of claim 1, wherein in the step of producing the compound of the formula (Π), the acid comprises at least one acid selected from the group consisting of: sulfuric acid, phosphoric acid, hydrochloric acid, aliphatic A carboxylic acid, a trifluoroacetic acid, an aliphatic sulfonic acid, an aromatic sulfonic acid, and a fluoroaliphatic sulfonic acid. 6. The method of claim 1, wherein the solvent of the above formula (I) is a solvent containing one or more selected from the group consisting of aliphatic carboxylic acids, organic sulfonic acids, aliphatic alcohols, aliphatic hydrocarbons. , guanamine compounds, urea compounds, ether compounds, aromatic hydrocarbons, i-aromatic aromatic hydrocarbon compounds, nitroated aromatic hydrocarbon compounds, i-hydrocarbon compounds, aliphatic carboxylic acid ester compounds, nitriles a compound, a sulfoxide compound, and a sulfonic acid compound. 7. The method of claim 1, wherein the benzyl group-containing compound of the formula (I) is a benzoyl chloride compound represented by the following formula (V): (R'〇) x [In the above formula (V), R1 to R3 and X, y, and z are as defined above], and the compound of the formula (V) is a black-quine using formaldehyde or a polyhydric substance thereof and hydrogen chloride (Blanc) -Quelet) reaction, which is obtained by chloromethylation of a benzene compound represented by the general formula (IV): (R1〇)x I [In the above formula (IV), R1 to R3 and x, y, and z are as defined in the previous paragraph 39 200821281]. 8. The method of claim 7, wherein the benzyl chloride compound of the formula (V) is a pepper base gas. 40 200821281 VII. Designation of Representative Representatives (1) The representative representative of the case is: (). (None) (2) A brief description of the symbol of the representative figure: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: