JP2521695B2 - Method for producing carbinol derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a carbinol derivative, and more particularly to a method for producing a carbinol derivative by reacting a ketone or aldehyde with an organic compound containing halogen. It is about.

Conventional technology and problems Conventional formula [Wherein R ¹ and R ² are hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, and a C having at least one C _{1 to} C ₂₀ side chain] _{3 to} C ₁₆ alicyclic group, C ₂ to
C _{20 represents} a linear or branched unsaturated hydrocarbon group, an aryl group, a heterocyclic group or an aralkyl group, which may be the same or different and may be a carbon chain or a carbon chain containing a hetero atom. You may form. Furthermore, these may have a substituent. As the substituent, a hydroxyl group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, a C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, an aralkyl group, Amino group, amino group substituted with C _{1 to} C ₅ linear or branched alkyl group, protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid group , A protected sulfonic acid group and a cyano group, and the number of the substituents is 1 to 5, and these may be the same or different. m and n are integers of 1 to 3 and m + n = 4, X is any one of fluorine, chlorine, bromine and iodine, Y is any one of fluorine, chlorine, bromine and iodine, and X and Y are the same. Including cases. When m is 3, Y includes hydrogen, a carboxyl group, a protected carboxyl group, an amide group, or a cyano group. The carbinol derivative represented by the above method is, for example, a method using trihalogenoacetaldehyde as disclosed in JP-A-51-125252 or Angew.Chem.Int.Ed.
Engl., 16 , 57 (1977), Tetrahedron Lett., 1521 (197
8), J. Org. Chem., 50 , 2527 (1985) and the like, and is produced by an electrolytic method. However, the former method requires special raw materials for production, and the latter method requires special equipment, and thus has the drawbacks of lacking versatility and not being easy to maintain and manage. ,
In addition, the yield is not always high and a by-product is produced, which may make it difficult to separate and purify the target substance.

OBJECT OF THE INVENTION It is an object of the present invention to provide a method for producing a carbinol derivative in a high yield by a safe and simple operation without using the above method.

SUMMARY OF THE INVENTION [Wherein R ¹ and R ² have the same meanings as described above. ] In the presence of a lead compound and a metal having a higher ionization tendency than lead, a ketone or aldehyde represented by the formula CXmYn (II) [wherein X, Y, m and n have the same meanings as described above]. ] A general formula characterized by reacting with a compound represented by [In the formula, R ¹ , R ² , X, Y, m and n have the same meanings as described above. ]
Is a method for producing a carbinol derivative. This carbinol derivative is an important compound as an intermediate raw material for medicines, agricultural chemicals and the like, and is derived from, for example, a chrysanthemic acid derivative which is a raw material of a pyrethroid insecticide or an arylacetic acid derivative which is useful as a raw material of an anti-inflammatory agent.

The inventors of the present invention did not rely on the conventional method to react a ketone or aldehyde represented by the general formula (I) with a halogen-containing compound represented by the general formula (II) to give a compound represented by the general formula (II
As a result of extensive studies on the production of the carbinol derivative represented by I), it was found that lead is an excellent reducing agent, and the present invention has been completed. That is, according to the present invention, the carbinol derivative represented by the general formula (III) is generally obtained by reacting the ketone or aldehyde represented by the general formula (I) in a polar solvent in the presence of a lead compound and a metal having a higher ionization tendency than lead. By reacting with the halogen-containing compound represented by the formula (II), a high yield and simple operation can be produced without accompanying byproducts.

In the present invention, R ¹ and R ² are hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, and a C ₁ to
A C _{3 to} C ₁₆ alicyclic group having at least one C ₂₀ side chain, a C _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group,
It represents an aryl group, a heterocyclic group or an aralkyl group, which may be the same or different and may form a ring with a carbon chain or a carbon chain containing a hetero atom. Furthermore, these may have a substituent. Specific examples of the C _{1 to} C ₂₀ linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,
Examples thereof include amyl, isoamyl, hexyl, octyl, decyl and dodecyl groups. Specific examples of the C ₃ -C ₁₆ alicyclic group include cyclopropyl, cyclobutyl,
Cyclopentyl, cyclohexyl, cyclooctyl, cyclodecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl,
Examples thereof include a cyclooctadienyl group. C ₁
Specific examples of the C _{3 to} C ₁₆ alicyclic group having at least one C 1 to C ₂₀ side chain include 1-methylcyclopropyl and 2
-Methylcyclopropyl, 2,2-dimethylcyclopropyl, 3-methylcyclobutyl, 1-methylcyclopentyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 3-ethylcyclopentyl, 3-t-butylcyclopentyl, 4-isopropylcyclohexyl , 4-t
-Butylcyclohexyl group and the like can be mentioned. C
Specific examples of the _{2 to} C ₂₀ linear or branched unsaturated hydrocarbon group include vinyl, ethynyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl and 2-methyl-.
Examples include 2-propenyl, propynyl, 3-butenyl, butynyl, pentenyl, pentadienyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octynyl, 9-decenyl, prenyl, geranyl groups. The aryl group is a phenyl group or a polynuclear aromatic hydrocarbon group, and specific examples of the polynuclear aromatic hydrocarbon group include α-naphthyl, β-naphthyl, anthranyl and pyrenyl groups. Examples of the heterocyclic group include a cyclic group containing oxygen, nitrogen, sulfur atom and the like, and specific examples thereof include tetrahydrofuryl, furyl, tetrahydropyranyl, pyranyl, pyrrolyl, piperidinyl, pyridyl, oxazolyl, morpholinyl, tetrahydrothienyl. , Thienyl, thiadiazolyl, triazolyl, thiazolyl, triazolyl and tetrazolyl groups. Specific examples of the aralkyl group include benzyl, phenethyl, phenylbutyl, diphenylmethyl, triphenylmethyl, naphthylmethyl, naphthylethyl and the like. When forming a ring with a carbon chain or a carbon chain containing a hetero atom [-
(CH ₂ ) k-], k is _{2 to} 13 and a hetero atom such as oxygen, nitrogen or sulfur may be introduced in place of the —CH ₂ — group.

Further, as the substituents of these R ¹ and R ^2, a hydroxyl group,
Protected hydroxyl group, acyloxy group, halogen, C ₁ ~
Substituted with a C ₅ straight-chain or branched alkyl group, a C ₂ -C ₆ straight-chain or branched unsaturated hydrocarbon group, an aralkyl group, an amino group, a C ₁ -C ₅ straight-chain or branched alkyl group Amino group, protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid group, protected sulfonic acid group, cyano group, and the number of the substituents is 1 to 5, which may be the same or different. Examples of the hydroxyl-protecting group include lower alkyl groups such as methyl, ethyl, propyl, isopropyl, and butyl groups, or green (Th
eodora W. Greene) “Protective Groups in Organi
c Synthesis "(A Weiley-Interscience Publication, 19
The hydroxyl-protecting group described in Chapter 2 of 81) can be mentioned. Specific examples of the acyloxy group include formyloxy, acetyloxy, propionyloxy, valeryloxy, benzoyloxy, trioyloxy and furoyloxy groups. Examples of halogen include fluorine, chlorine, bromine and iodine. C ₁ -C ₅
Examples of the linear or branched alkyl group include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups. Examples of the C ₂ -C ₆ linear or branched unsaturated hydrocarbon group include vinyl, ethynyl, propenyl, butenyl, hexenyl group and the like, and examples of the aralkyl group include benzyl, phenethyl, phenylpropyl, phenylbutyl, diphenylmethyl group and the like. Can be mentioned. Examples of the C _{1 to} C ₅ linear or branched alkyl group substituted with an amino group include methyl, ethyl, propyl, isopropylate, butyl, t-butyl, amyl and isoamyl groups. Examples of the amino group protector include amino group protecting groups described in Chapter 7 of the same book. Examples of the thiol protecting group include C _{1 to} C ₅ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups, phenyl, benzyl and phenethyl groups. Examples of the carboxyl-protecting group include the carboxyl-protecting groups described in Chapter 5 of the same book. Methyl, ethyl, as a protecting group of sulfonic acid group,
Examples thereof include alkyl groups such as propyl, isopropyl, butyl, t-butyl, amyl and isoamyl groups, and aralkyl groups such as phenyl, benzyl and phenethyl groups.

Further, specific examples of the above-mentioned substituents substituted with these groups include general formulas A group represented by the formula [wherein R ³ is hydrogen or the above-mentioned carboxylic acid-protecting group] can be given as an example.

X in the general formula CXmYn (II) is fluorine, chlorine, bromine or iodine, and Y
Is fluorine, chlorine, bromine, or iodine, and specific examples thereof include CCl ₄ , CBr ₄ , CCl ₃ Br, CCl ₂ Br ₂ , CClBr ₃ , and CCl.
₃ F, CCl ₂ F ₂ , CClF ₃ , CBr ₃ F, CBr ₂ F ₂ , CBrF ₃ , CCl ₃
I and the like. When m is 3, Y is hydrogen, a carboxyl group, a protected carboxyl group, an amide group or a cyano group, and specific examples thereof include
CHCl ₃ , CCl ₃ COOH, CBr ₃ COOH, CCl ₃ COOCH ₃ , CF ₃ COOCH ₃ ,
_{CCl 3 COOPh, CCl 3 COOCH 2} Ph, CCl 3 CONH 2, CCl 3 CON (CH 3)
₂ , CCl ₃ CN and the like.

In the present invention, the compound of the general formula (II) is a compound of the general formula (I)
It may be used in an equivalent amount with respect to the ketone or aldehyde represented by the formula (1), but a slight excess may be used to obtain better results, and the preferred range of use is 1 to 4 equivalents relative to 1 equivalent of the ketone or aldehyde.

Next, the solvent used in the present invention is preferably a polar solvent, for example, alcohols, ethers, nitriles, amides, and the like, specifically, methanol, tetrahydrofuran, sioxane, acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone. , 1,3-dimethyl-2
-Imidazolidinone, dimethyl sulfoxide and the like, which may be used alone or as a mixture. Water may be contained as needed. Particularly preferred is dimethylformamide, and its use amount is not particularly limited, but is preferably at least an amount in which the raw material is completely dissolved. However, even if it is less than that, there is no problem because the reaction proceeds, but it may be difficult to perform the operation, or there may be problems such as a decrease in yield.

The lead compound used in the present invention may have a lead valence of 0, 2, or 4, and these compounds may be in the form of a hydrate. For example, lead fluoride, lead chloride, lead bromide,
Lead halide such as lead iodide, lead nitrate, lead sulfate, lead perchlorate, lead borate, lead carbonate, lead phosphate and other inorganic acid lead, lead acetate, lead oxalate, lead stearate and other fatty acid lead , Lead oxide, lead hydroxide and various lead complexes composed of these lead compounds and a chelating agent such as ethylenediaminetetraacetic acid or nitrilotriacetic acid can be used. These lead compounds may be used alone or in combination of two or more, and particularly preferred are lead halides such as lead fluoride, lead chloride, lead bromide and lead iodide. The amount of these lead compounds used is preferably 0.01 to 0.5 equivalent to 1 equivalent of the starting material ketone or aldehyde, and less than 0.01 equivalent is less effective. If the amount is more than 0.5 equivalent, the effect is the same, but it is not economical.

The metal having a greater ionization tendency than lead used in the present invention includes any one of aluminum, iron, nickel, tin, cobalt, magnesium and zinc, or a mixture thereof, with aluminum being particularly preferred. There is no particular limitation on the shape of these metals in use, and they can be used in various shapes such as powder, plate, foil, lump, and needle. The amount used is preferably in the range of 0.3 to 4 equivalents relative to 1 equivalent of the starting material ketone or aldehyde. If it is less than 0.3 equivalents, the reaction progresses slowly or the reaction stops, and if it is 4 equivalents or more, it is economical. In addition, it causes side reactions and reduces the yield.

In the present method, the presence of the above solvent and catalyst is essential, and even if any of them is lacking, the object of the present invention cannot be achieved.

The reaction temperature in the present invention is preferably in the range of 0 to 100 ° C., though the preferable range varies depending on the raw material, solvent and catalyst.

As described above, the present invention provides a method for producing a carbinol derivative in good yield under mild conditions by the synergistic effect of a lead compound, a metal having a greater ionization tendency than lead, and a solvent.

[Examples] The present invention will be described more specifically with reference to Examples below.

Example 1 In a round bottom flask, take 184 mg (0.5 mmol) of lead bromide and 150 mg (5.5 mmol) of finely sliced aluminum foil, and add 10 ml of dimethylformamide and 530 mg of benzaldehyde.
(5 mmol) and 1.39 g (9 mmol) of carbon tetrachloride were added, and the reaction was carried out at room temperature for 3.5 hours with stirring. After completion of the reaction, 10 ml of water was added to the reaction solution and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give an oil 1.
2 g was obtained. This was purified using a silica gel column to obtain 1.1 g (yield 95%) of oily phenyl trichloromethyl carbinol. The NMR spectrum of this product was in good agreement with its production. ¹ H-NMR (CDCl ₃ ) δ3.50 (brs, 1H, OH), 5.10 (s, 1H, CH—O), 7.15 to 7.70
(M, 5H, Ph).

Examples 2-13 The reaction was carried out under the same conditions as in the method of Example 1 except for the conditions shown in Table 1, and the products shown in Table 1 were obtained in high yield and high selectivity.

Continuation of front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication C07C 29/38 C07C 29/38 31/36 31/36 33/42 33/42 33/46 33/46 35 / 48 35/48 69/74 9546-4H 69/74 Z 253/30 253/30 255/36 255/36 C07D 317/54 C07D 317/54 // C07B 61/00 300 C07B 61/00 300 (56) Reference Documents JP 62-5926 (JP, A) JP 61-161225 (JP, A) JP 52-106808 (JP, A)

Claims (2)

(57) [Claims] 1. A general formula [Wherein R ¹ and R ² are hydrogen, a C _{1 to} C ₂₀ linear or branched alkyl group, a C _{3 to} C ₁₆ alicyclic group, and a C having at least one C _{1 to} C ₂₀ side chain] _{3 to} C ₁₆ alicyclic group, C _{2 to} C
₂₀ straight or branched unsaturated hydrocarbon groups, aryl groups,
It represents a heterocyclic group or an aralkyl group, which may be the same or different and may form a ring with a carbon chain or a carbon chain containing a hetero atom. Furthermore, these may have a substituent. As the substituent, a hydroxyl group, a protected hydroxyl group, an acyloxy group, a halogen, a C _{1 to} C ₅ linear or branched alkyl group, a C _{2 to} C ₆ linear or branched unsaturated hydrocarbon group, an aralkyl group, Amino group, amino group substituted with C _{1 to} C ₅ linear or branched alkyl group, protected amino group, nitro group, protected thiol group, carboxyl group, protected carboxyl group, sulfonic acid group , A protected sulfonic acid group and a cyano group, and the number of the substituents is 1 to 5, and these may be the same or different. ] In the presence of a lead compound and a metal having a greater ionization tendency than lead in a polar solvent, a ketone or aldehyde represented by the following general formula CXmYn (II) [wherein m and n are integers of 1 to 3 and m + n = 4 , X is any one of fluorine, chlorine, bromine and iodine, and Y is any one of fluorine, chlorine, bromine and iodine, including the case where X and Y are the same. When m is 3, Y includes hydrogen, a carboxyl group, a protected carboxyl group, an amide group, or a cyano group. ] A general formula characterized by reacting with a compound represented by [In the formula, R ¹ , R ² , X, Y, m and n have the same meanings as described above. ] The manufacturing method of the carbinol derivative represented by these. 2. A metal having a greater ionization tendency than lead is aluminum, iron, nickel, tin, cobalt, magnesium,
The method according to claim 1, which is one of zinc and a mixture thereof.