JPH08127557A - Production of 3-oxy-5-oxo-6-heptenoic acid derivative - Google Patents

Abstract

PURPOSE: To enable high-yield production of 3-oxy-5-oxo-6-heptenoic acid derivative which is useful as an intermediate for a blood cholesterol depressant in a shortened time by reaction of an aromatic aldehyde and an oxyglutaric acid derivative. CONSTITUTION: An aromatic aldehyde of the formula: Ar-CHO (Ar is an aromatic group) and a compound of formula I (R<1> is an aliphatic group; R<2> is a hydroxyl-protecting group; R<3> and R<4> are each a hydrocarbon group) are allowed to react with each other in the presence of a base of the formula: MxA (M is an alkali metal, A is carbonate or bicarbonate group) such as potassium carbonate in an aliphatic alcohol solvent such as isopropyl alcohol at -30 to +50 deg.C for 0.3-24 hours to give the objective compound of formula II. The aliphatLc alcohol solvent preferably contains water in an amount of 30-20,000ppm. The amount of the compound of formula I is 0.8-1.5 mole per mole of the aromatic aldehyde and the solvent is 10-100 moles, and the base is 0.7-1.8 mole, respectively.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 3-oxy-5-oxo-6-heptenoic acid derivatives such as (3R, 6E) -3-
Methyl [(tert-butyldimethylsilyl) oxy] -5-oxo-7- (pyridin-3-yl) -6-heptenoate, (3
R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7-phenyl-6-methyl heptenoate,
(3R, 6E) -3-[(tert-butyldimethylsilyl)
Oxy] -7- (2,4-dichlorophenyl) -5-oxo-6-
The present invention relates to a novel process for producing "3-oxy-5-oxo-7-aromatic group-substituted-6-heptenic acid alkyl ester" such as methyl heptenoate. The aforementioned 3-oxy-5-oxo-6-heptenoic acid derivative is a blood cholesterol lowering agent [3-hydroxy-
3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor] is useful as an intermediate in the synthesis.

In the target compound obtained by the process of the present invention, for example, (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -7- (2,4-dichlorophenyl) -5-oxo-6- Methyl heptenoate is disclosed in JP-A 5-1.
According to the method described in Japanese Patent No. 78841, detert-butyldimethylsilylation is carried out using hydrogen fluoride,
Methyl (3R, 6E) -7- (2,4-dichlorophenyl) -3-hydroxy-5-oxo-6-heptenoate was derived, and then diethylmethoxyborane and sodium borohydride (NaBH ₄ ) were used. Perform syn reduction (3R, 5
It can be derivatized to methyl S, 6E) -7- (2,4-dichlorophenyl) -3,5-dihydroxy-6-heptenoate.

Produced as described above (3R, 5
Methyl S, 6E) -7- (2,4-dichlorophenyl) -3,5-dihydroxy-6-heptenate is a compound of the Journal of Medicinal Che
According to the method described in mistry, 1985, 28, No. 3, pp. 347-358), 3-hydroxy-3-methylglutaryl coenzyme A (HM
(+)-Tr having G-CoA) reductase inhibitory activity
ans- (E) -6- [2- (2,4-dichlorophenyl) ethenyl] 3,4,5,6-tetrahydro-4-hydroxy-2H-
Pyran-2-one can be obtained.

[0004]

2. Description of the Related Art As a method for producing a 3-oxy-5-oxo-6-heptenoic acid derivative by reacting an aromatic aldehyde with an oxyglutaric acid ester derivative, there is the following method. Bio-organic & Medicinal Chemistry
letters, 1991, Vol. 1, No. 3, pp. 161-164), benzaldehyde as an aromatic aldehyde and (R) -3-[(tert-butyldimethylsilyl) oxy]-as an oxyglutarate derivative. Methyl 6- (dimethoxyphosphinyl) -5-oxohexanoate was used as a base in an acetonitrile solution in the presence of lithium chloride.
Reaction with 8-diazabicyclo [5,4,0] undecane-7-ene (hereinafter referred to as DBU) (3R, 6E)-
A method for obtaining methyl 3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7-phenyl-6-heptenate is disclosed. However, the above method was not industrially satisfactory in that the yield was as low as 71%. There is also a problem that a special and expensive compound (DBU) is used as a base.

Journal of Medicinal Chemistry (1991,
34, No. 1, pp. 367-373), 6-fluoro-4- (4-fluorophenyl) -2- as a heterocyclic aromatic aldehyde.
(1-Methylethyl) -3-quinolinecarbaldehyde and (3R, 1 ', S) as oxyglutarate derivative
-1- (1'-naphthyl) ethyl-3-[(tert-butyldimethylsilyl) oxy] -6- (dimethylphosphinyl)-
5-oxo-hexanoate was reacted with DBU in the presence of lithium chloride in a dichloromethane solution to give [R- (R ^* , R ^* )]-1-phenylethyl-3-
[(Tert-Butyldimethylsilyl) oxy] -7- [6-fluoro-4- (4-fluorophenyl) -2- (1-methylethyl) -3-quinolinyl] -5-oxo-6-heptenoate Is disclosed. However, this method was not industrially satisfactory in that the yield was as low as 33%.

Journal of organic Chemistry, 1992, 57
Vol. 6, No. 6, pp. 1935-1937), as aliphatic aldehydes (1S, 2S, 4aR, 6S, 8S, 8aS) -1, 2, 4a,
5, 6, 7, 8, 8a-octahydro-2-methyl-8-[(2 ",
2 "-dimethyl-1" -oxo-butyl) oxy] -6-
[(E) -1-propenyl] naphthalene-1-carbaldehyde and (R) -as oxyglutarate derivative
3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester was reacted in isopropanol solution using potassium carbonate or cesium carbonate as a base. Methyl (1S, 2S, 4aR, 6S, 8S, 8aS, 3'R) -7'-
[1,2,4a, 5,6,7,8, Sa-octahydro-2-methyl-8-[(2 ", 2" -dimethyl-1 "-oxo-butyl) oxy] -6-[(E ) -1-Propenyl] naphthalenyl] -3 ′
A method for obtaining-[(tert-butyldimethylsilyl) oxy] -5'-oxo-6'-heptenoate is disclosed.

However, this method is industrially satisfactory in that the reaction rate is very slow, it takes 2-3 days until the reaction is completed, the conversion rate is as low as 25%, and the yield is also low. It wasn't the way to do it. In addition, a method is also disclosed in which cesium carbonate is used as a base and a similar reaction is carried out in a tert-butanol solution. However, this method also has a slow reaction rate, and the raw material conversion rate is 4 days after the start of the reaction. Was as low as 78% and the yield was 53%, which was not an industrially satisfactory method. Therefore, any of the known manufacturing methods 3 to
The industrial method for obtaining an oxy-5-oxo-6-heptenoic acid derivative (particularly an optically active compound) has been unsatisfactory.

[0008]

DISCLOSURE OF THE INVENTION The inventors of the present invention have made diligent studies to improve the above-mentioned problems in the known production method. As a result, an aliphatic alcohol solvent was used as a solvent, and an alkali metal was used as a base. When an aromatic aldehyde and an oxyglutaric acid derivative are reacted using the carbonate or hydrogen carbonate of, the 3-oxy-
5-oxo-6-heptenoic acid derivative (especially optically active compound)
The present invention was completed by finding out that

Accordingly, the present invention is directed to aromatic aldehyde and oxyglutarate ester derivatives (particularly optically active compounds).
An object of the present invention is to provide a method for producing a 3-oxy-5-oxo-6-heptenoic acid derivative (particularly an optically active compound) in a high yield in a short time by reacting with.

[0010]

The present invention is based on the general formula (1)
An aromatic aldehyde represented by Ar-CHO (wherein Ar represents an aromatic group), and a general formula (2)

[0011]

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(Wherein R ¹ is an aliphatic group, R ² is a hydroxy protecting group, and R ³ and R ⁴ are hydrocarbon groups) and is represented by an oxyglutaric acid derivative (eg, 6-dialkoxyphosphini). And the formula (3) Mx A (in the formula, M is an alkali metal, A is a carbonate group or a hydrogen carbonate group, and x is an integer of 1 or 2). In the presence of a base represented by
In a solvent of general formula (4)

[0013]

[Chemical 4]

A 3-oxy-5-oxo-6-heptenoic acid derivative represented by the formula (wherein R ¹ and R ² have the same meanings as described above) is formed. -Oxo-
It relates to a method for producing a 6-heptenoic acid derivative.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION

The aliphatic alcohol solvent used in the production method of the present invention is mainly a secondary or tertiary aliphatic alcohol solvent (particularly preferably 80 to 100% by volume, more preferably 90 to 100% by volume). ) It is preferable that the solvent contains. Further, in the production method of the present invention, it is preferable that the aliphatic alcohol solvent (particularly, the secondary or tertiary aliphatic alcohol solvent) contains about 30 to 20,000 ppm of water. Furthermore, in the production method of the present invention, the oxyglutarate derivative represented by the general formula (2) is an optically active compound, and the compound represented by the general formula (4) is 3-
Optimally, the oxy-5-oxo-6-heptenoic acid derivative is an optically active compound. The main reaction in the production method of the present invention is, for example, a reaction formula (1) shown below.

[0017]

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Can be represented by In the aromatic aldehyde represented by the general formula (1) used in the present invention, as the aromatic group represented by Ar, a hydrocarbon aromatic group (non-heterocyclic aromatic group), a heterocyclic group An aromatic group (monocyclic heterocyclic aromatic group or condensed heterocyclic aromatic group), or one in which each of the above aromatic groups has a substituent is preferable.

Examples of the above-mentioned hydrocarbon type aromatic group in the aromatic group represented by Ar include aryl groups such as phenyl group and naphthyl group, and the above-mentioned aryl group having various substituents. Can be mentioned. Examples of the heterocyclic aromatic group include pyridyl group (pyridyl group, quinolyl group, etc.), pyrrolyl group (pyrrolyl group, indolyl group, etc.), pyrimidyl group, pyrazolyl group, pyridazyl group, imidazolyl group, furyl. Group, a heterocyclic aromatic group such as a thienyl group, and the above-mentioned heterocyclic aromatic group having various substituents.

In the aromatic group of Ar, the substituent that the aryl group or the heterocyclic aromatic group may have is
For example, an alkyl group having 1 to 10 carbon atoms (methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, etc.), vinyl group, allyl group, alkenyl group such as isopropenyl group, ethynyl group, 2- Alkynyl group such as propynyl group, non-aromatic hydrocarbon group such as cycloalkyl group such as cyclopropyl group, cyclopentyl group and cyclohexyl group, aromatic hydrocarbon group such as phenyl group and naphthyl group, and methoxymethyl group, ethoxy "Lower alkyl group having a substituent" such as methyl group, hydroxymethyl group, aminomethyl group, dimethylaminomethyl group, benzyl group, trityl group, naphthylmethyl group, 4-fluorophenyl group, tolyl group, mesityl group, 4 A "hydrocarbon aromatic group having a substituent" such as a -methoxyphenyl group can be mentioned.

As the above-mentioned substituent, a halogen atom (fluorine atom, chlorine atom, bromine atom, etc.), an amino group,
Amino group having a substituent (methylamino group, dimethylamino group, anilino group, etc.), phenoxy group, carboxyl group, alkoxycarbonyl group (methoxycarbonyl group,
Ethoxycarbonyl group, etc.), aryloxycarbonyl group (phenoxycarbonyl group, naphthyloxycarbonyl group), acyl group (acetyl group, benzoyl group, etc.), acyloxy group (acetyloxy group, benzoyloxy group, 2,2-dimethyl) Butyroyloxy group and the like). Further, as the substituent, an indolyl group, a pyridyl group, a pyrimidyl group, a quinolyl group, a pyrazolyl group, a pyridazyl group, an imidazolyl group, a pyrrolyl group, a furyl group, a heterocyclic aromatic group such as a thienyl group, a morpholino group, Examples thereof also include saturated heterocyclic groups such as piperidino group and pyridinyl group.

As the above-mentioned aromatic group of Ar, in particular,
(A) phenyl group, and 4-tolyl group, 4-chlorophenyl group, 2,4-dichlorophenyl group, 4-methoxyphenyl group,
3,5-dichloro-6- (4-fluorophenyl) phenyl group,
A "phenyl group having a substituent" such as a 2,4-dimethyl-6- (4-fluoro-3-methylphenyl) phenyl group, and (B) a pyridyl group (an unfused pyridyl group), and 4 -Phenyl-2-methylpyridin-3-yl group, 2-isopropyl-6-phenyl-4- (4-fluorophenyl) pyridin-3-yl group, 2,5-diisopropyl-4- (4-fluorophenyl) "Pyridyl group having a substituent (non-fused pyridyl group)" such as pyridin-3-yl group, (C)
Quinolyl group (condensed pyridyl group) and 2-
(4-Fluorophenyl) -4-isopropylquinoline-3-
A “quinolyl group having a substituent (condensed pyridyl group)” such as an yl group, (D) pyrimidyl group, and 6-isopropyl-2-phenyl-4- (4-fluorophenyl) pyrimidine- 5-yl group, 6-methyl-2-phenyl-
4- (4-fluorophenyl) pyrimidin-5-yl group, 2,4-
Dimethyl-6- (4-fluorophenyl) pyrimidin-5-yl group, 2- (N-methyl-N-methanesulfonyl) amino-4-isopropyl-6- (4-fluorophenyl) pyrimidin-5-yl group Such as "pyrimidyl group having a substituent"
Can be suitably mentioned.

Further, as the aromatic group of Ar,
(E) a pyrrolyl group (an unfused pyrrolyl group), and a "pyrrolyl group having a substituent" such as a 2-isopropyl-1-phenyl-4- (4-fluorophenyl) pyrrol-3-yl group (Uncondensed pyrrolyl group) '' (F) indolyl group (condensed pyrrolyl group) and `` substitution such as 3- (4-fluorophenyl) -1-isopropylindole-2-yl group '' Group having an indolyl group (condensed pyrrolyl group) '', (G) pyrazolyl group, and 5- (4-
Fluorophenyl) -3-isopropyl-1-phenylpyrazol-4-yl group such as "pyrazolyl group having a substituent", (H) pyridazyl group, and 3,4-bis (4-fluorophenyl)- "Pyridazyl group having a substituent" such as 6-isopropylpyridazin-5-yl group, (I) imidazolyl group, and 4-isopropyl-2-phenyl-1- (4-fluorophenyl) -1H-imidazo- A “imidazolyl group having a substituent” such as a ru-5-yl group, and the like can also be mentioned.

Examples of the aromatic aldehyde represented by the general formula (1) used in the production method of the present invention include benzaldehyde, 2,4,6-trimethylbenzaldehyde, and 2,4-dichlorobenzaldehyde. A phenyl (hydrocarbon aromatic) aldehyde in which an aldehyde group is directly bonded to a carbon atom forming a benzene ring which may have a group, or nicotinaldehyde (pyridine-3-aldehyde) Such "a pyridine-based aldehyde in which an aldehyde group is directly bonded to a carbon atom forming a pyridine ring which may have a substituent (which may be condensed)" is preferable. The aromatic aldehyde represented by the general formula (1) used in the production method of the present invention is, for example, 2,6-dimethyl-4- (4-fluorophenyl)-
Pyrimidine-5-carbaldehyde is described in JP-A-1-261.
It can be manufactured according to the method described in Japanese Patent No. 377.

As a method for producing the above-mentioned aromatic aldehyde,
For example, by reacting ethyl acetoacetate with 4-fluorobenzaldehyde in the presence of piperidine and acetic acid in an isopropanol solvent, (E / Z) -3-ethoxycarbonyl-4- (4-fluorophenyl) -but- 3-en-2-one is obtained, then (E / Z) -3-ethoxycarbonyl-
4- (4-fluorophenyl) -but-3-en-2-one and acetamidine hydrochloride are reacted in the presence of sodium acetate in an ethanol solvent to give 1,4-dihydro-2, After obtaining ethyl 6-dimethyl-4- (4-fluorophenyl) pyrimidine-5-carboxylate, its 1,4-dihydro-2,6-dimethyl-4- (4-fluorophenyl) in acetic acid solution was obtained. Chromium trioxide is allowed to act on ethyl pyrimidine-5-carboxylate,
Produces ethyl 2,6-dimethyl-4- (4-fluorophenyl) -pyrimidine-5-carboxylate,

Then, diisobutylaluminum hydride is allowed to act on the product of the step in a toluene solution to form 2,6-dimethyl-4- (4-fluorophenyl) -5-hydroxymethyl-pyrimidine. Finally, the product of step is treated with pyridinium chlorochromate in a dichloromethane solvent to give 2,6-dimethyl-4-
A preferable method is a method for producing (4-fluorophenyl) -pyrimidine-5-carbaldehyde.

The aliphatic group represented by R ¹ in the oxyglutarate derivative represented by the general formula (2) has a carbon number of 1 to 16 and may have a straight chain or a branched group. It may be any alkyl group. As the alkyl group having 1 to 16 carbon atoms having no substituent, a linear or branched alkyl group having 1 to 8 carbon atoms (in particular, 1 to 6 carbon atoms) is preferable, and examples thereof include methyl. Group, ethyl group, propyl group (including isomers), butyl group (including each isomer), pentyl group (including each isomer), hexyl group (including each isomer), heptyl group (each isomer) including),
Examples thereof include an octyl group (including each isomer), a nonyl group (including each isomer), a decyl group (including each isomer), and the like, and particularly preferably a methyl group, an ethyl group, a propyl group (isomers). And butyl group (including each isomer), and more preferably a methyl group and an ethyl group. Examples of the alkyl group having the above-mentioned substituent include, for example, "having 7 to 14 carbon atoms, such as phenylmethyl group, naphthylmethyl group, phenylethyl group, naphthylethyl group, and
Examples of the substituent include an alkyl group having an aryl group, and a phenylethyl group and a naphthylethyl group are preferable.

Examples of the hydroxy protecting group for R ² in the oxyglutarate derivative represented by the general formula (2) include, for example, methyl group, ethyl group, propyl group, butyl group, tert-butyl group, allyl group and benzyl group. Group, tetrahydropyranyl group, tert-butyldimethylsilyl group, tert
-Ethylene-forming protecting groups such as butyldiphenylsilyl group, ester-forming protecting groups such as acetyl group and benzoyl group are preferred, and ether-forming protecting groups are preferred, and tert-butyldimethylsilyl is more preferred. It is a base.

The hydrocarbon groups represented by R ³ and R ⁴ in the oxyglutaric acid ester derivative represented by the general formula (2) are each independently an alkyl group having 1 to 5 carbon atoms, an aralkyl group, a halogenoaralkyl group, Alternatively, it may be a phenyl group. Examples of the alkyl group having 1 to 5 carbon atoms include a methyl group, an ethyl group, a propyl group (including isomers), a butyl group (including isomers), a pentyl group (including isomers) and the like. Examples of the aralkyl group include aralkyl groups having 7 to 9 carbon atoms such as benzyl group, phenethyl group and 3-phenylpropyl group, and examples of the halogenoaralkyl group include:
Examples thereof include a halogenoaralkyl group having 7 to 9 carbon atoms such as a halogenophenylmethyl group, a halogenophenylethyl group and a halogenophenylpropyl group. R ³ , R
The hydrocarbon group of ⁴ has 1 to 5 carbon atoms (in particular, 1 to 3 carbon atoms)
Is preferably an alkyl group, specifically, a methyl group or an ethyl group is preferable, and a methyl group is particularly preferable.

The oxyglutaric acid ester derivative used in the present invention may be used in an amount such that the amount thereof is usually 0.5 to 2.0 mol per 1 mol of the aromatic aldehyde used. , Especially 0.8-1.5 mol ratio to 1 mol of aromatic aldehyde, and further 1.0-
The amount is preferably 1.3 mol.

Since the above oxyglutarate derivative has an asymmetric carbon atom, it has optical isomers. In the production method of the present invention, it is applicable to both racemic and optical oxyglutarate derivatives. However, the optical purity of the oxyglutarate derivative is not affected by the reaction in the present invention, and the 3-oxy-5-oxo-6-heptenoic acid derivative having the corresponding optical activity is produced.

The oxyglutarate derivative represented by the general formula (2) preferably has an optical activity represented by an R-type absolute configuration.

Such an oxyglutaric acid ester derivative is a compound of journal of medicinal chemistry.
(Journal of Medicinal Chemistry, 1987, 30 volumes, N
O.10, pages 1858-1873). For example, (R) -dimethyl [[3-[(tert-butyldimethylsilyl) oxy] -4- (methoxycarbonyl) butyryl] methyl] phosphonate used in the present invention is produced by the following steps 1 to 7. it can.

Step 1: To a solution of diethyl-3-hydroxyglutarate in methylene chloride was added imidazole and tert-.
Butylchlorodimethylsilyl is added and reacted to obtain diethyl 3-[(tert-butyldimethylsilyl) oxy] pentanedioate.

Step 2: Diethyl-3-obtained in Step 1
Sodium hydroxide is added to a methanol solution of [(tert-butyldimethylsilyl) oxy] pentanedioate and reacted to obtain a reaction mixture. Methanol was removed from the reaction mixture, and benzene and acetic anhydride were added to the residue for reaction to obtain 3-[(tert-butyldimethylsilyl) oxy] pentanedioic anhydride.

Step 3: 3-[(tert-butyldimethylsilyl) oxy] pentanedioic anhydride obtained in Step 2, trimethylamine, (N, N-dimethylamino) pyridine, methylene chloride and (R) -phenyl A reaction mixture is obtained by reacting with ethanol. The obtained reaction mixture was post-treated and then reacted with a solution of diazomethane in diethyl ether to react (3R, 1′R) -methyl-1′-phenylethyl-3-[(tert-butyldimethylsilyl) oxy. ] Pentandioate is obtained.

When (S) -phenylethanol was used in place of (R) -phenylethanol and reacted in the same manner as in step 3, (3S, 1'S) -methyl-1'-phenyl was obtained. Ethyl-3-[(tert-butyldimethylsilyl) oxy] pentanedioate can be obtained. When phenylethanol (racemic) was used instead of (R) -phenylethanol and reacted in the same manner as in step 3, methyl-1′-phenylethyl-3-[(tert-butyldimethylsilyl) Oxy] pentanedioate can be obtained. Any of the obtained compounds can obtain 3-[(tert-butyldimethylsilyl) oxy] pentanedioate having a corresponding optical purity according to the following steps.

Step 4: Obtained in Step 3 (3R, 1 ')
R) -Methyl-1'-phenylethyl-3-[(tert-butyldimethylsilyl) oxy] pentanedioate was added to an acetonitrile solution of hydrogen fluoride to react, and (3
R, 1'R) -Methyl-1'-phenylethyl-3-hydroxypentanedioate can be obtained.

Step 5: The reaction solution of n-butyllithium and dimethylmethylphosphonate obtained in Step 4 (3)
R, 1'R) -Methyl-1'-phenylethyl-3-hydroxypentanedioate was added and reacted to give (R)-
Dimethyl [4-[(R) -phenylethoxycarbonyl]
-3-Hydroxybutyryl] methylphosphonate can be obtained.

Step 6: (R) -Dimethyl [4-[(R) -phenylethoxycarbonyl] -3-hydroxybutyryl] methylphosphonate obtained in Step 5, imidazole and tert-butylchlorodimethyl By reacting with silane, (R) -dimethyl [3- (tert-butyldimethylsilyloxy) -4-[(R) -phenylethoxycarbonyl] butyryl] methylphosphonate can be obtained.

Step 7: (R) -Dimethyl [3- (tert-butyldimethylsilyloxy) -4- obtained in Step 6
[(R) -Phenylethoxycarbonyl] butyryl] methylphosphonate is reacted with hydrogen in the presence of palladium supported on activated carbon to obtain a reaction mixture. The obtained reaction mixture was subjected to post-treatment, and then an ether solution of diazomethane was added and reacted to give (R) -dimethyl [3-
(tert-Butyldimethylsilyloxy) -4-methoxycarbonylbutyryl] methylphosphonate can be obtained.

The alkali metal of M in the base represented by the general formula (3) includes, for example, alkali metals such as lithium, sodium, potassium, rubidium and cesium, preferably lithium, sodium and potassium. is there. In the general formula (3), x is an integer of 1 or 2, and is preferably 2. General formula (3)
In A, A represents a carbonate group or a hydrogen carbonate group, and a carbonate group is preferable.

Specific examples of the base represented by the general formula (3) include lithium carbonate, sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and cesium hydrogen carbonate. In particular, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate are preferable.

The amount of the base represented by the general formula (3) used in the present invention is usually 0.5 to 2.0 mol per mol of the aromatic aldehyde. In particular, an amount of about 0.7 to 1.8 mol is preferable, and an amount of 0.8 to 1.5 mol is more preferable.

The aliphatic alcohol solvent used in the production method of the present invention has 1 to 10 carbon atoms (particularly 1 carbon atom).
To 6) a solvent mainly containing an aliphatic alcohol, for example, methyl alcohol (methanol), ethyl alcohol (ethanol), propyl alcohol, isopropyl alcohol, butanol, isobutanol at least 40% by volume, particularly 50% by volume. %, And more preferably 80 to 100% by volume can be suitably mentioned. In the present invention, the aliphatic alcohol is most preferably propyl alcohol or isopropyl alcohol.

As the aliphatic alcohol solvent used in the present invention, a commercially available aliphatic alcohol solvent may be used in the reaction as it is, or a small amount of water may be added and used in the reaction in the present invention. Good. In the present invention, when a secondary or tertiary aliphatic alcohol solvent is used, the reaction time is shortened by adding a small amount of water to the reaction. The water added in this case has a water content of, for example, 30 to 20,000 p with respect to the aliphatic alcohol solvent.
pm, preferably 50 to 16,000
0 ppm, more preferably 100 to 15,000
A ratio of ppm is preferable.

In the present invention, the amount of the aliphatic alcohol solvent used is usually 7.5 to 1 mol of the aromatic aldehyde.
The amount may be about 300 mol, particularly preferably about 10 to 100 mol, and further preferably 15 to 80 mol, relative to 1 mol of the aromatic aldehyde.

Some of the aromatic aldehydes and oxyglutarate ester derivatives used in the production method of the present invention have low solubility in an aliphatic alcohol solvent and may not be dissolved to a degree sufficient for the reaction to proceed. In such a case, such a raw material compound may be dissolved in another organic solvent and added to the aliphatic alcohol solvent to carry out the reaction. The organic solvent is dissolved in an aliphatic alcohol solvent,
Organic solvents that do not hinder the progress of the reaction in the present invention are preferred. Examples of such other organic solvent include cyclic ether solvents such as tetrahydrofuran, ether solvents such as diethyl ether and diisopropyl ether, and nitrile solvents such as acetonitrile and propionitrile. Examples thereof include halogenated hydrocarbon solvents such as dichloromethane and chloroform, and aprotic solvents such as dimethyl sulfoxide, dimethylformamide and 1,3-dimethyl-2-imidazolidone.

In the production method of the present invention, the aliphatic alcohol solvent may be a solvent consisting of only aliphatic alcohol (100% by volume), but as described above, when the starting compound is difficult to dissolve in the aliphatic alcohol. In the aliphatic alcohol solvent used in the present invention, the above-mentioned aliphatic alcohol is at least 40% by volume, particularly 50% by volume.
In addition to containing the above, the balance of the solvent may be "a mixed solvent of an aliphatic alcohol and another organic solvent" which is the other organic solvent described above.

3-oxy-5-oxo- represented by the general formula (4), which is the target compound produced by the production method of the present invention
In the 6-heptenoic acid derivative, R ¹ , R ² and Ar have the same meanings as described above. That is, such R ¹ , R ² and Ar
As the “derivative represented by the general formula (4)” having
It is determined by the aromatic aldehyde and the oxyglutarate derivative which are the starting compounds in the production method of the present invention. Further, as described above, the ratio of isomers in the 3-oxy-5-oxo-6-heptenoic acid derivative is substantially the same as the ratio of the isomers of the aromatic aldehyde and oxyglutarate derivative before the reaction. The reaction in the present invention does not change the ratio of isomers.

The reaction temperature in the present invention is generally -3.
0 to 50 ° C, preferably -25 to 40 ° C,
More preferably, it is -20 to 30 ° C.

In the present invention, the reaction time is the reaction temperature,
Depending on the amount of raw materials charged, etc., usually 0.25 to 30
Time, preferably 0.3 to 24 hours, 0.5 to 2
0 hours is more preferred.

In the production method of the present invention, the desired compound can be obtained from the reaction mixture containing the 3-oxy-5-oxo-6-heptenoic acid derivative formed by a combination of ordinary washing operation and separation operation. For example, it is preferable to obtain an objective compound by a method of diluting the reaction solution by adding an organic solvent, removing the inorganic base by washing with water, and then using solvent extraction, concentration under reduced pressure, or column chromatography.

Examples of the diluting organic solvent used for obtaining the target compound include aromatic hydrocarbon solvents such as benzene, toluene and xylene, ester solvents such as ethyl acetate and propyl acetate, methylene chloride and chloroform. Halogenated hydrocarbon solvents can be mentioned.
In addition, after washing the reaction solution with water, the 3-oxy-5-oxo-6-heptenoic acid derivative can be directly subjected to the above-mentioned deprotection and subsequent steps.

In the present invention, the aromatic aldehyde represented by the general formula (1) as the starting compound, the oxyglutarate derivative represented by the general formula (2) and the general formula (4) as the target compound are used. The 3-oxy-5-oxo-6-heptenoic acid derivative represented may have optical isomers or geometric isomers. In such a case, the optical isomers or geometric isomers of the corresponding target compound can be obtained by using the starting compound optically resolved or separated as desired. Further, the optical isomers or the mixture of geometrical isomers can be processed by a usual optical resolution method or separation method to obtain each isomer. The present invention can be applied to any of geometric isomers, racemates and optical isomers,
The ratio of the isomers of the aromatic aldehyde and oxyglutarate derivative is not substantially affected by the reaction,
A 3-oxy-5-oxo-6-heptenoic acid derivative with each corresponding isomer is prepared.

[0056]

According to the present invention, the aromatic aldehyde of the general formula (1) and the oxyglutaric acid ester derivative of the general formula (2) are treated with an aliphatic compound in the presence of a base of the general formula (3). By reacting in an alcohol solvent, the target compound, a 3-oxy-5-oxo-6-heptenoic acid derivative,
It can be manufactured in high yield in a short time. The optical purity of the oxyglutarate derivative is substantially the same as that of the 3-oxy-5-oxo-6-heptenoic acid derivative obtained after the reaction is completed, and the optical purity does not change due to the reaction. Absent.

[0057]

Examples are shown below. The yield in the examples is the yield of the 3-oxy-5-oxo-6-heptenoic acid derivative (mol) based on the aromatic aldehyde (mol).

Example 1 Nicotinaldehyde (pyridine-3-aldehyde) 140
mg (1.3 mmol) and (R) -3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphosphinyl) -5-oxohexanoic acid methyl ester 500 mg
(1.3 mmol, optical purity: 99% ee) and isopropanol (5 ml, water content 10,000 ppm)
To obtain an alcohol solution. To the obtained alcohol solution, 181 mg (1.3 mmol) of potassium carbonate was added, and the mixture was reacted at room temperature (22 ° C) for 3 hours with stirring. 20 ml of ethyl acetate was added to the obtained reaction liquid, and the mixture was stirred and washed with 10 ml of water. Wash 2
I went there. The organic layer obtained by performing a liquid separation operation was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 1: 1) (3R, 6E) -3-.
[(Tert-Butyldimethylsilyl) oxy] -5-oxo-7- (pyridin-3-yl) -6-heptenoic acid methyl ester 469 mg was obtained (yield: 99%).

¹ H-NMR (CDCL ₃ , 400 MH
z) δ = 0.05 (s, 1H), 0.08 (s, 1H),
0.83 (s, 9H), 2.54 (dd, 1H, J = 1
4.7 and 5.9 Hz, 2.61 (dd, 1H, J
= 14.7 and 5.9 Hz), 2.91 (dd, 1
H, J = 15.6 and 5.4 Hz), 2.99 (d
d, 1H, J = 15.6 and 6.8 Hz), 3.69
(S, 3H), 4.68 (ddt, 1H, J = 6.8,
5.9 and 5.4 Hz), 6.82 (d, 1H, J =
16.6 Hz), 7.37 (dd, 1H, J = 7.8a
nd4.9 Hz), 7.55 (d, 1H, J = 16.6)
Hz), 7.89 (ddd, 1H, J = 7.8, 2.0
and 1.5 Hz), 8.63 (dd, 1H, J = 4.
9 and 1.5 Hz), 8.78 (d, 1H, J = 2.
0Hz)

Example 2 (3R, 6E) -3-[(t) was carried out in the same manner as in Example 1 except that the water content of isopropanol was 50 ppm.
ert-Butyldimethylsilyl) oxy] -5-oxo-7-
(Pyridin-3-yl) -6-heptenoic acid methyl ester 4
01 mg was obtained (yield: 85%).

Example 3 Benzaldehyde 139 instead of nicotinaldehyde
(3R, 6E) -3-[(tert-Butyldimethylsilyl) oxy] -5-oxo-7-phenyl-6-heptene was prepared in the same manner as in Example 1 except that mg (1.3 mmol) was used. 450 mg of acid methyl ester was obtained (yield: 95
%).

¹ H-NMR (CDCL ₃ , 400 MH
z) δ = 0.04 (s, 1H), 0.08 (s, 1H),
0.84 (s, 9H), 2.53 (dd, 1H, J = 1
4.7 and 6.4 Hz, 2.61 (dd, 1H, J
= 14.7 and 5.9 Hz), 2.88 (dd, 1
H, J = 15.6 and 5.9 Hz), 2.98 (d
d, 1H, J = 15.6 and 6.4 Hz), 3.68
(S, 3H), 4.68 (tt, 1H, J = 6.4an
d5.9 Hz), 6.75 (d, 1H, J = 16.1H)
z), 7.38-7.42 (m, 3H), 7.52-
7.60 (m, 2H), 7.56 (d, 1H, J = 1
6.1 Hz)

The resulting (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7-phenyl-
The optical purity of 6-heptenoic acid methyl ester was measured under the following conditions. As a result, the optical purity was 99% ee.

Conditions for measuring optical purity Column: CHIRALCEL OD Eluent: Hexane: Ethanol: Trifluoroacetic acid = 1
00: 0.5: 0.01 (volume ratio) Flow rate; 1.0 ml / min Detector; UV (wavelength: 260 nm) Temperature; 30 ° C. Sample concentration; 10 mg / 10 ml (eluent)

Example 4 Except that methanol having a water content of 120 ppm was used,
In the same manner as in Example 3, 422 mg of (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7-phenyl-6-heptenoic acid methyl ester was obtained (yield: 89% ).

Example 5 In the same manner as in Example 1 except that 194 mg (1.3 mmol) of 2,4,6-trimethylbenzaldehyde was used in place of nicotinaldehyde and isopropanol having a water content of 5,000 ppm was used. (3R, 6E) -3-[(t
ert-Butyldimethylsilyl) oxy] -5-oxo-7-
423 mg of (2,4,6-trimethylphenyl) -6-heptenoic acid methyl ester was obtained (yield: 80%).

¹ H-NMR (CDCL ₃ , 400 MH
z) δ = 0.06 (s, 1H), 0.08 (s, 1H),
0.84 (s, 9H), 2.29 (s, 3H), 2.3
3 (s, 6H), 2.54 (dd, 1H, J = 14.7)
and 6.4 Hz), 2.62 (dd, 1H, J = 1
4.7 and 5.9 Hz, 2.86 (dd, 1H, J
= 15.6 and 5.9 Hz), 2.96 (dd, 1)
H, J = 15.6 and 6.9 Hz, 3.68 (s,
3H), 4.71 (ddt, 1H, J = 6.9, 6.4)
and 5.9 Hz), 6.36 (d, 1H, J = 16.
6 Hz), 6.90 (s, 3H), 7.73 (d, 1)
H, J = 16.6 Hz)

The resulting (3R, 6E) -3-[(tert-butyldimethylsilyl) oxy] -5-oxo-7- (2,4,4
The optical purity of 6-trimethylphenyl) -6-heptenoic acid methyl ester was measured under the following conditions. As a result, the optical purity was 99% ee.

Conditions for measuring optical purity Column: CHIRALCEL OD Eluent: Hexane: Ethanol: Trifluoroacetic acid = 1
00: 0.5: 0.01 (volume ratio) Flow rate; 0.7 ml / min Detector; UV (wavelength: 260 nm) Temperature; 30 ° C. Sample concentration; 10 mg / 10 ml (eluent)

Example 6 2,4-Dichlorobenzaldehyde (457 mg, 2.6 m
mol) and 3-[(tert-butyldimethylsilyl) oxy] -6- (dimethoxyphenyl) -5-oxohexynoic acid methyl ester (1.0 g, 2.6 mmol) in isopropanol (10 ml, water content 9, 500 ppm) to obtain an alcohol solution. Potassium carbonate (362 mg, 2.6 mmol) was added to the obtained alcohol solution, and the mixture was reacted by stirring at room temperature (22 ° C.) for 3 hours. 40 ml of ethyl acetate was added to the obtained reaction liquid, and the mixture was stirred and washed with 20 ml of water. Wash 2
I went there. The organic layer obtained by performing a liquid separation operation was dried over anhydrous magnesium sulfate and filtered to obtain a filtrate. The obtained filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 95: 5) (E) -3-[(tert-
Butyldimethylsilyl) oxy] -7- (2,4-dichlorophenyl) -5-oxo-6-heptenoic acid methyl ester 1.
06 g was obtained (yield: 94%).

¹ H-NMR (CDCL ₃ , 400 MH
z) δ = 0.05 (s, 3H), 0.08 (s, 3H),
0.83 (s, 3H), 2.54 (dd, 1H, J = 1
4.7 and 6.4 Hz, 2.61 (dd, 1H, J
= 14.7 and 5.9 Hz), 2.90 (dd, 1
H, J = 15.6 and 5.9 Hz), 3.00 (d
d, 1H, J = 15.6 and 6.4 Hz), 3.68
(S, 3H), 4.67 (tt, 1H, J = 6.4an
d5.9 Hz), 6.68 (d, 1H, J = 16.1H)
z), 7.28 (dd, 1H, J = 8.3 and 2.0)
Hz), 7.46 (d, 1H, J = 2.0 Hz), 7.
56 (d, 1H, J = 8.3 Hz), 7.88 (d, 1
H, J = 16.1 Hz)

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Hiroshi Sasaki 5 Ube, Ube City, Yamaguchi Prefecture 5 1978, Kobeshi, Ube Ube Institute of Industrial Research Co., Ltd.

Claims (3)

[Claims] 1. The general formula (1) Ar—CHO (wherein Ar
Represents an aromatic group) and an aromatic aldehyde represented by the general formula (2): (Wherein R ¹ is an aliphatic group, R ² is a hydroxy protecting group, R
³ and R ⁴ represent a hydrocarbon group) and a oxyglutaric acid derivative represented by the general formula (3) Mx A (in the formula, M is an alkali metal, A is a carbonate group or a hydrogen carbonate group, and x is 1). Or 2
In an aliphatic alcohol solvent in the presence of a base represented by the general formula (4) 3-oxy-5-oxo-6-heptenoic acid derivative represented by the formula: wherein R ¹ and R ² have the same meanings as described above.
Process for producing 6-heptenoic acid derivative. 2. The aliphatic alcohol solvent is secondary or tertiary.
A solvent mainly containing a high-grade aliphatic alcohol.
The manufacturing method described in. 3. The aliphatic alcohol solvent absorbs about 30 to about water.
The production method according to claim 1, which contains 20,000 ppm.