JPH0720935B2 - Process for producing substituted vinyl pyridines - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing substituted vinylpyridines having an action of specifically inhibiting thromboxane A ₂ (TXA ₂ ) synthase.

Prior art and problems A method for producing substituted vinylpyridines having TXA ₂ synthase inhibitory action is already known (Japanese Patent Laid-Open No. 58-219162).
issue). However, when this method is examined in detail, the described manufacturing conditions pose various problems from the viewpoint of safety, and especially when the manufacturing scale is expanded, there is a risk of developing a major disaster.

That is, in JP-A-58-219162, the general formula [In the formula, R ¹ ′ is a pyridine group, R ² ′ is a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group or a phenyl group which may have a methylenedioxy group, thienyl group, a furyl group, a naphthyl group, a benzothienyl group or a pyridine group, Y is a methylene group, 'a hydrogen atom or a lower alkyl group, n' R ³ is represented by 'an integer from 0 to 6 substituents When manufacturing vinyl pyridines,
General formula [Wherein R ¹ ′ and R ² ′ have the same meanings as defined above], and a compound of the general formula [Wherein X represents a halogen atom and R ³ ′ and n ′ have the same meanings as defined above] are reacted in a solvent in the presence of a base. Examples of this base include n-butyllithium, sodium hydride, and tertiary butoxypotassium, among which n-butyllithium and sodium hydride are said to be preferably used. Examples of the solvent include ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, and a mixed solvent of two or more kinds selected from these solvents. This reaction is said to be carried out in an atmosphere of dry inert gas (eg, nitrogen gas, helium gas, etc.), and the reaction temperature is -10 ° C to 50 ° C, preferably 0 ° C to 30 ° C.
The reaction temperature can be determined by observing the disappearance of the characteristic color of phosphorane.
The reaction is said to be completed in about 6 hours. .

Among these methods, the dangers have been pointed out and the cases such as explosion have been reported for most combinations of solvent and base. Some of these are introduced: 1) When alkoxides such as sodium hydride or sodium methoxide are used in dimethylformamide, dimethylformamide decomposes with rapid heat generation to produce carbon monoxide as a by-product. Cases have been reported that triggered a runaway reaction. [Chemistry and Industry (Chemis
try and Industry) 17 February 1986, 134; Chemical and Engineering News (Chem.Eng.News), 19
82, 60 (28), 5; Chemical and Engineering
News (Chem.Eng.News), 1982, 60 July 12th, 5; Chemical and Engineering News (Chem.Eng.N)
ews), 60 , September 13, 5]. 2) It has been reported that dimethylsulfinyl anion was generated when the reaction was carried out with sodium hydride in dimethylsulfoxide, which caused an explosion [Chem. Eng. News. ), 1966, 44 , April 11th,
48, Chemical and Engineering News (C
hem.Eng.News), 1966, 44 , June 13, 7]. 3) Explosion cases were reported when refluxing with hydride (reported for calcium hydride) in tetrahydrofuran [Chemical and Engineering.
News (Chem.Eng.News), 1987, 56 , February 6th, 3; ibid. 198
7, April 17, 68]. Also, using a large amount of hydride accompanied by generation of hydrogen in a solvent having a low flash point such as ethyl ether is dangerous as in these cases, and n-butyllithium is extremely sensitive to moisture and handled. Is disadvantageous in terms of. Therefore, the present inventors have diligently studied to improve the above method so as to make it a completed industrial manufacturing method from the viewpoint of safety. As a result, no special hazard cases have been reported so far, and if the handling precautions are not strictly observed, a special hazard is not pointed out.The objective can be achieved sufficiently by the combination of the solvent and the base. The present invention has been completed by finding reaction conditions capable of safely producing substituted vinyl pyridines having a high yield.

Means for Solving the Problems The present invention provides a general formula [In the formula, R ¹ represents a pyridine group, R ² represents a lower alkoxy, a lower alkyl, trifluoromethyl,
A lower alkenyl, halogen or an aryl group which may have methylenedioxy], [Wherein R ³ is a lower alkyl group, a hydroxymethyl group, a nitroxymethyl group, a nitrogen-containing 5-membered ring-methyl group, an acetal-methyl group, a trialkylsilyloxymethyl group, an alkyl- or aryl-sulfonyloxymethyl group. ,
Alkyl- or aryl-sulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, aryl-oxymethyl group, cyano group,
A carbamoyl group which may be substituted, a carbamoyloxymethyl group which may be substituted, a thiocarbamoyloxymethyl group which may be substituted, a carboxyl group or an alkoxycarbonyl group, n is an integer of 1 to 22, X
Represents a halogen atom. ] The compound represented by the formula] is reacted in a tertiary alcohol in the presence of a metal hydride or an alkali metal tertiary alkoxide. The present invention provides a method for producing a substituted vinyl pyridine represented by the formula [wherein each signal has the same meaning as described above].

In the general formulas (I), (II) and (III), the pyridyl group represented by R ¹ is 2-pyridyl, 3-pyridyl, 4-
Although any of pyridyl may be used, 3-pyridyl is preferable. Examples of the aryl group represented by R ² include phenyl and naphthyl (α-naphthyl, β-naphthyl). R ² is preferably phenyl. These aryl groups have a lower alkoxy (eg, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy or the like having 1 to 4 carbon atoms) as a substituent at any position on the ring. ), Lower alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl and the like having 1 to 5 carbon atoms), trifluoromethyl ,
It may have a lower alkenyl (eg, those having 2 to 5 carbon atoms such as vinyl, allyl, and pentenyl), halogen (fluorine, chlorine, bromine, iodine), and methylenedioxy.
Examples of the lower alkyl group represented by R ³ include methyl,
Ethyl, n-propyl, i-propyl, n-butyl, i
Examples of the nitrogen-containing 5-membered ring-methyl group having 1 to 4 carbon atoms such as -butyl and t-butyl include imidazolylmethyl (1-imidazolylmethyl, 2-imidazolylmethyl) and triazolylmethyl (1- Triazolylmethyl,
3-triazolylmethyl, 5-triazolylmethyl),
Hydrogen of a methyl group such as tetrazolylmethyl (1-tetrazolylmethyl, 5-tetrazolylmethyl) has 2-4 on the ring.
Substituted with a 5-membered ring group containing 5 nitrogen atoms,
Examples of the acetal-methyl group include 2-tetrahydropyranyloxymethyl and 2-tetrahydrofuryloxymethyl, and examples of the trialkylsilyloxymethyl group include dimethyl tert-butylsilyloxymethyl, the alkyl- or Examples of the aryl-sulfonyloxymethyl group include methanesulfonyloxymethyl and p-toluenesulfonyloxymethyl,
The alkyl- or aryl-sulfonylaminocarbonyloxymethyl group is, for example, methanesulfonylaminocarbonyloxymethyl, p-toluenesulfonylaminocarbonyloxymethyl, or the like, and the acyloxymethyl group is represented by the formula R ⁴ COOCH _2- [wherein R ⁴ is hydrogen, alkyl having 1 to 6 carbon atoms (methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, n-pentyl, i-pentyl, n-hexyl and the like) or pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl) is shown. ] The group represented by] is, for example, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, n-propoxycarbonyloxymethyl, i-propoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl as the alkoxycarbonyloxymethyl group,
i-butoxycarbonyloxymethyl, n-pentyloxycarbonyloxymethyl, n-hexyloxycarbonyloxymethyl and the like having 3 to 8 carbon atoms, and the halogenomethyl group is fluoromethyl, chloromethyl, bromomethyl or iodomethyl. Examples of the methyl group include methoxymethyl, ethoxymethyl, n-
Lower alkoxymethyl having 2 to 5 carbon atoms such as propoxymethyl, i-propoxymethyl, n-butoxymethyl, i-butoxymethyl is a aryloxymethyl group such as phenyloxymethyl, 2-methylphenyloxymethyl, 3-methylphenyloxymethyl, 4-
Methylphenyloxymethyl, 2,4-dimethylphenyloxymethyl, 3,4-dimethylphenyloxymethyl and the like having 7 to 9 carbon atoms are represented by the following formulas as the optionally substituted carbamoyl group. [In the formula, R ⁵ and R ⁶ are the same or different and each is hydrogen or C 1-6.
Alkyl (eg, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, t-butyl,
n-pentyl, i-pentyl, n-hexyl, i-hexyl, etc.) or C 6-8 allyl (phenyl, 2
-Methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 3,4-dimethylphenyl and the like). ] The carbamoyloxymethyl group which may be substituted is represented by the formula: [Wherein R ⁵ and R ⁶ have the same meanings as defined above], and the thiocarbamoyloxymethyl group which may be substituted is represented by the formula [Wherein R ⁵ and R ⁶ have the same meanings as defined above], and examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, and n. −
Examples thereof include those having 2 to 5 carbon atoms such as butoxycarbonyl, i-butoxycarbonyl and t-butoxycarbonyl. R ³ is preferably a carboxyl group, a methyl group or a lower alkoxycarbonyl having 2 to 5 carbon atoms. n is preferably an integer of 3 to 8 among integers of 1 to 22, and more preferably an integer of 3 to 6.

As a typical example of the compound of formula (I), R ¹ is 3-
Pyridyl, R ² is phenyl, R ³ is a carboxyl group, a lower alkoxycarbonyl having 2 to 5 carbon atoms or a methyl group, n
Is an integer of 3 to 8, preferably 3 to 6.

Thus, in the production method of the present invention, a tertiary alcohol is used as a reaction solvent and a metal hydride or an alkali metal tertiary alkoxide is used as a base.

It was found that when a primary alcohol was used among the alcohols, the desired product was not produced, and when a secondary alcohol was used, the desired product was obtained only in a low yield. It was also found that when a primary alkoxide such as sodium ethoxide was used as the base among the metal alkoxides, the target product was produced but the yield was low.

In addition, the reaction of the present invention usually produces two types of geometrical isomers (E-form and Z-form). For example, 7-phenyl-
In the case of 7- (3-pyridyl) -6-heptenoic acid, the E isomer having biological activity is important, so that either one of the isomers is often useful, and the reaction condition having selectivity is desired. 7-phenyl-7- (3-pyridyl)
In the case of -6-heptenoic acid, it is difficult to largely move the equilibrium point to one of the two substituents at the 7-position because of the structural similarity between them. For example, it is described in JP-A-58-219162. When synthesized under the reaction conditions described above, the formation of the Z-form is somewhat superior to that of the E-form. However, in the production method of the present invention, in the case where the compound of the general formula (I) in which R ¹ is a pyridyl group and R ² is a phenyl group, the E-form is obviously produced more than the Z-form and the E-form is 10 ° C. or less. At the low temperature, the selectivity became more remarkable, and when acetonitrile was used as a solvent, the Z-form was conspicuously conversely remarkable, and an unexpected finding was initially obtained.

Hereinafter, the manufacturing method of the present invention will be described in more detail.

The tertiary alcohol used as the reaction solvent may be any tertiary alcohol such as tertiary butanol and tertiary amyl alcohol. Tertiary alcohol is
From the viewpoint of solubility and operability of the reactants, they may be mixed with other solvents such as aromatic hydrocarbons, saturated aliphatic hydrocarbons and aliphatic ethers, if desired. Toluene, benzene, xylene, etc. are used as aromatic hydrocarbons mixed with tertiary alcohols, hexane, cyclohexane, etc. are used as aliphatic saturated hydrocarbons, and ethyl ether, isopropyl ether, diethylene glycol are used as aliphatic ethers. Examples include dimethyl ether and the like. Among these, the solvent mixed with the tertiary alcohol is toluene, benzene, isopropyl ether,
Cyclohexane is preferred. As the mixed solvent, a mixed solvent with tertiary butanol is particularly preferable. These solvents are selected in consideration of solubility, operability, etc. of the compounds represented by the general formulas (I), (II) and (III), or two or more kinds of mixed solvents selected from these solvents are selected. Used. The mixing ratio can be used at any ratio in consideration of the raw material, the solubility of the product, the operability, the economical efficiency, the production ratio of the isomers, etc., but usually 50% or less relative to the tertiary alcohol. preferable.

Examples of the metal hydride used as the base include hydrides of alkali metals or alkaline earth metals such as sodium hydride, potassium hydride and calcium hydride, and examples of the tertiary alkoxides of alkali metals include tertiary Examples thereof include potassium butoxide, tertiary butoxy sodium, tertiary butoxy lithium, and tertiary aluminoxy potassium. Among these bases, sodium hydride and tertiary butoxy potassium are preferable. As the tertiary alkoxy potassium, in addition to commercially available products, a tertiary alcohol potassium-containing tertiary alcohol solution obtained by the reaction of a tertiary alcohol and metallic potassium or dehydration of the tertiary alcohol and potassium hydroxide The tertiary alcohol potassium-containing tertiary alcohol solution obtained by the above can be used as it is. The amount of the base used is preferably 2.0 to 3.0 times the molar amount of the compound represented by the general formula (III).

The reaction temperature can be used in any range from -30 ° C to the boiling point of the reaction solvent used, but it is -10 to 90 in consideration of the reaction time and, if necessary, the production ratio of the E form and the Z form. It is preferably carried out in the range of ° C. The reaction temperature is usually 1 to 3.
It is preferable to carry out the reaction in a dry inert gas (for example, nitrogen gas, helium gas, etc.) atmosphere for a certain period of time.

EXAMPLES Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

Example 1 3-Benzoylpyridine (33.0 g, 0.18 mol), 5-carboxypentyltriphenylphosphonium bromide (84.0 g, 0.184 mol) and tertiary butanol (540 m
The mixture of l) was heated to about 60 ° C., and sodium hydride (60%, oily, 15.8 g, 0.396 mol) was added thereto in small portions under stirring in a nitrogen stream. After stirring at 60 to 70 ° C for 1 hour, the tertiary butanol was distilled off under reduced pressure. Toluene (80 ml) and water (160 ml) were added to the residue and the layers were separated. (E) and (Z) -7-phenyl-7- (3- in the aqueous layer
Pyridyl) -6-heptenoic acid was quantified by high performance liquid chromatography using E-form and Z-form preparations,
E form: 24.9g, Z form: 24.7g (E: Z = 50.2: 49.8), total 49.6
It was confirmed that g (yield 98.8%, yield of E form 49.6%) was contained.

Example 2 3-Benzoylpyridine (16.5 g, 90 mmol), 5-
Carboxylpentyltriphenylphosphonium bromide (42.0 g, 92 mmol), tertiary butanol (120 m
l) and toluene (30 ml) were heated to 60 ° C. and potassium tert-butoxide (25.3 g, 198 mmol) was added thereto in several portions. Stir at 60-70 ° C for 1 hour, then cool,
Water (480 ml) was added to the reaction solution. After washing with toluene (100 ml), (E) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid in the aqueous layer were quantified by the same method as in Example 1, E form: 12.9g, Z form: 10.7g,
It was confirmed that a total of 23.6 g (yield 93.1%) was contained. (E: Z = 54.8: 45.2, yield of E form 51.0%) In addition, when the reaction was carried out at 20 to 30 ° C. on the same scale,
23.0 g (yield 95.7%, E: Z) of (E + Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid formed after a lapse of time.
= 58.3: 41.7, the yield of E form was 55.8%).

Further, when the reaction temperature was 5 to 10 ° C, the production of (E + Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid after 3 hours was 23.6 g (yield 95.2%). , E: Z
= 61.0: 39.0, yield of E form: 58.1%).

Example 3 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol), tertiary butanol (15 ml)
Sodium hydride (60%, oily, 0.74 g, 18.4 mmol) was added in several portions under a nitrogen stream while stirring a mixture of toluene and toluene (5 ml). After the addition was completed, the mixture was stirred at 20 to 30 ° C for 2 hours. After cooling, water (50 ml) and toluene (30 ml) were added to the reaction liquid to separate them, and (E) and (Z) in the aqueous layer were added.
-7-Phenyl-7- (3-pyridyl) -6-heptenoic acid was quantified as in Example 1. As a result, E body: 1.20
It was confirmed that the amounts were g, Z isomer 1.18 g, (E: Z = 50.3: 49.7), total 2.38 g (yield: 94.1%, E isomer yield: 47.3%).

Example 4 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Tertiary butoxy potassium (2.53 g, 1.98 mmol) was added to the mixture of carboxypentyltriphenylphosphonium bromide (4.2 g, 9.2 mmol) and tertiary amyl alcohol (15 ml) under stirring in several batches to give 20- 30
The mixture was stirred at 0 ° C for 2 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) in the aqueous layer were separated.
-7-Phenyl-7- (3-pyridyl) -6-heptenoic acid was quantified as in Example 1. As a result, E body 1.31
g, Z form 1.01 g (E: Z = 56.3: 43.7), total 2.32 g (yield: 9
1.7%, yield of E form: 51.6%).

Example 5 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol), tertiary butanol (15 ml)
Sodium hydride (60%, oily, 0.55 g, 13.5
(Mmol) was added in 3 to 4 portions, and the mixture was stirred at 20 to 30 ° C for 3 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid in the aqueous layer were used in Example. 1
It quantified similarly to. As a result, E body 1.14g, Z body 1.12g
(E: Z = 50.5: 49.5), and the total amount was 2.26 g (yield: 89.5%, yield of E form: 45.2%).

Example 6 3-Benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol), tertiary butanol (15 ml)
Sodium hydride (60%, oily, 0.55
g, 13.5 mmol) in 3 to 4 portions and added at 20 to 30 ° C.
And stirred for 3 hours. Water (50 ml) and toluene (30
ml) was added and the layers were separated, and (E) and (Z) -7 in the aqueous layer were added.
-Phenyl-7- (3-pyridyl) -6-heptenoic acid was quantified as in Example 1. As a result, E body 1.11g, Z
Body 1.09g (E: Z = 50.7: 49.3), total 2.20g (Yield: 87.1
%, Yield of E form: 44.2%) was confirmed.

Comparative Example 1 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol) and tetrahydrofuran (1
To the mixture (5 ml) was added sodium hydride (60%, oily, 0.55 g, 13.5 mmol) in 3 to 4 portions under stirring in a nitrogen stream, and the mixture was stirred at 20 to 30 ° C for 3 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid in the aqueous layer were used in Example. Quantification was performed in the same manner as 1. As a result, it was confirmed that the amount of the E form was 0.04 g, the Z form was 0.11 g (E: Z = 26.7: 73.3), and the total amount was 0.15 g (yield: 0.6%, yield of the E form: 0.16%).

When tertiary potassium butoxide is used as the base, the yield
77.8%, E: Z = 35.8: 64.2 (yield of E form: 27.9%).

Comparative Example 2 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol) and isopropanol (15 m
Sodium hydride (60%, oily, 0.55 g, 13.5 mmol) was added to the mixture of 1) under stirring in a nitrogen stream in 3 to 4 portions, and the mixture was heated with stirring at about 80 ° C. for 3 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid in the aqueous layer were used in Example. Quantification was performed in the same manner as 1. As a result, it was confirmed that the E form was 0.18 g, the Z form was 0.17 g (E: Z = 51.0: 49.0), and the total amount was 0.35 g (yield: 13.9%, E form yield: 7.1%).

Comparative Example 3 3-benzoylpyridine (16.5 g, 90 mmol), 5-
Sodium hydride (60%, oily, 8.0 g, 135 mmol) in a mixture of carboxypentyltriphenylphosphonium bromide (42.0 g, 92 mmol) and dimethylformamide (90 ml) at 30-35 ° C under nitrogen flow with stirring.
Was added little by little and then stirred at the same temperature for 3 hours. Example 2
Treated as in (E) and (Z) -7-phenyl-
The amount of 7- (3-pyridyl) -6-heptenoic acid produced was quantified by high performance liquid chromatography. As a result, E form: 9.6 g,
Z form: 12.2 g (E: Z = 44.2: 55.8), total 21.8 g (yield: 86.0
%, Yield of E form: 38.0%).

When dimethylsulfoxide was used instead of dimethylformamide under the same conditions, the amount produced was E form: 9.6 g,
Z form: 10.8 g (E: Z = 47.0: 53.0), total 20.4 g (yield: 80.8
%, Yield of E form: 38.0%).

Comparative Example 4 3-benzoylpyridine (1.65 g, 9 mmol), 5-
A mixture of carboxypentyltriphenylphosphonium bromide (4.2 g, 9.2 mmol) and dimethylformamide (15 ml) was stirred under anhydrous potassium carbonate (1.5 g,
(11 mmol) was added, and the mixture was heated with stirring at 30 to 35 ° C. for 3 hours.
Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) -7-phenyl-7- in the aqueous layer were separated.
(3-Pyridyl) -6-heptenoic acid was quantified as in Example 1. As a result, formation of the desired product was not observed at all.

The same experiment was carried out by substituting the solvent with dimethyl sulfoxide or tetrahydrofuran, but in this case as well, the formation of the desired product was not observed.

Example 7 3-Benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol), tertiary butanol (12 ml)
Under stirring, potassium tertiary butoxide (2.53 g, 1.98 mmol) was added to the mixture of toluene and toluene (12 ml) in several portions, and the mixture was stirred at 20 to 30 ° C. for 2 hours. Water (50 ml) in the reaction solution
And toluene (30 ml) were added for liquid separation, and (E) and (Z) -7-phenyl-7- (3-pyridyl) -6 in the aqueous layer were separated.
-Heptenoic acid was quantified as in Example 1. as a result,
E body 1.18g, Z body 0.94g (E: Z = 56.3: 43.7), total 2.12g
(Yield: 90.2%, Y-form yield: 50.8%).

Example 8 3-Benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol), tertiary butanol (15 ml)
With stirring to a mixture of potassium tertiary butoxy potassium (2.53 g,
1.98 mmol) was added in several portions and the mixture was stirred at 20 to 30 ° for 2 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) -7-phenyl-7- (3-pyridyl) -6-heptenoic acid in the aqueous layer were used in Example. 1
It quantified similarly to. As a result, E body 1.29g, Z body 0.97g
(E: Z = 57.0: 43.0), the total amount was 2.26 g (yield: 92.6%, yield of E form: 52.8%).

Comparative Example 5 3-benzoylpyridine (1.65 g, 9 mmol), 5-
Carboxypentyl triphenylphosphonium bromide (4.2 g, 9.2 mmol) and tetrahydrofuran (1
(0 ml) to the mixture under stirring in a nitrogen stream, n-butyllithium (13.8 ml, 1.6 mol hexane solution) was added dropwise 20 to 30.
The mixture was stirred at 0 ° C for 2 hours. Water (50 ml) and toluene (30 ml) were added to the reaction solution to separate the layers, and (E) and (Z) in the aqueous layer were separated.
-7-Phenyl-7- (3-pyridyl) -6-heptenoic acid was quantified as in Example 1. As a result, E body 2.5m
It was confirmed that the amount was g, Z isomer 22.8 mg (E: Z = 9.8: 90.2), total 25.3 mg (yield: 1%, E isomer yield: 0.1%).

Example 9 3-benzoylpyridine (22.0 g, 0.12 mol), 5-pentyltriphenylphosphonium bromide (49.6 g,
0.12 mol), tert-butanol (210 ml) and toluene (70 ml) were added to a mixture of tertiary butoxypotassium (26.9 g, 0.24 mol) in a nitrogen stream while maintaining the temperature at 3 to 10 ° C under stirring. After stirring at 3 to 10 ° C for 1 hour and at 24 to 25 ° C for 1 hour, 2 ml was added and the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (200 ml), the organic layer washed with water (200 ml x 4) was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to measure the ratio of E form to Z form. / Z = 58: 42
Met. Normal hexane (150 ml) was added to the concentrated residue and the mixture was allowed to stand overnight, and the precipitated triphenylphosphine oxide was filtered off. The mother liquor was concentrated under reduced pressure, and the residue was separated into E form and Z form by silica gel column chromatography (developing solvent: carbon tetrachloride: ethyl acetate = 10: 0.5). First, the Z form was eluted, and then the E form was eluted. Fractions containing Z-form and E-form were distilled under reduced pressure to obtain Z-form (136
~ 138 ℃ / 0.3mmHg) 6.5g, E body (136 ~ 138 ℃ / 0.3mmHg)
g) and 9.8 g of a mixture of E-form and Z-form.

Z-form: (Z) -6-phenyl-6- (3-pyridyl)-
5-hexene E form: (E) -6-phenyl-6- (3-pyridyl)-
5-Hexene Nuclear Magnetic Resonance Spectra: Z Form: 8.47 (2H, m), 7.22 (7H, m), 6.18 (1H, t), 2.12
(2H, m), 1.39 (4H, m), 0.85 (3H, t) E form: 8.53 (1H, d), 8.44 (1H, dd), 7.30 (4H, m), 7.15
(3H, m), 6.12 (1H, t), 2.15 (2H, m), 1.38 (4H, m), 0.
86 (3H, t) Example 10 3- (3,4-Methylenedioxybenzoyl) pyridine (3.0 g, 13.2 mmol), 5-carboxypentyltriphenylphosphonium bromide (6.2 g, 13.6 mmol), tertiary butanol (42 ml) and toluene (18 m
Tertiary potassium butoxide (3.3 g, 29 mmol) was added to the mixture of (1) in a nitrogen stream while stirring at 3 to 10 ° C. After stirring at 3-10 ° C for 1 hour and 20-30 ° C for 1 hour, the mixture was concentrated under reduced pressure and water (60 ml) was added. Toluene (30 ml x
After washing in 2), the pH of the aqueous layer was adjusted to 5.5. It was extracted with ethyl acetate (60 ml), the organic layer was concentrated under reduced pressure, the concentrated residue was subjected to high performance liquid chromatography, and the ratio of E form to Z form was measured. E / Z = 52: 48 there were. The concentrated residue was subjected to silica gel column chromatography and eluted with ethyl acetate to collect fractions containing Z-form and concentrated. The residue was treated with ethyl acetate-isopropyl ether to give Z-form crystals (0.65 g, 14.7%). Fractions containing a large amount of E form were collected and concentrated by silica gel column chromatography, and part of the residue (100 mg) was subjected to high performance liquid chromatography (column: YMC, ODS column 20 × 250 mm, mobile phase: methanol: 0.05 M phosphoric acid). It was attached to potassium dihydrogen = 3: 2), and the E form (55 mg, oily substance) was separated.

Z-form: (Z) -7- (3,4-methylenedioxyphenyl) -7- (3-pyridyl) -6-heptenoic acid E-form: (E) -7- (3,4-methylenedioxyphenyl) ) -7- (3-Pyridyl) -6-heptenoic acid Melting point Z-form: 89-91 ° C Nuclear magnetic resonance spectrum Z-form: 9.20 (COOH), 8.46 (2H, m), 7.50 (1H, m), 7.30
(1H, m), 6.86 (1H, d), 6.68 (1H, d), 6.53 (1H, dd),
6.05 (1H, t), 5.92 (2H, s), 2.28 (2H, m), 1.57 (4H,
m) E form: 10.30 (COOH), 8.50 (2H, m), 7.47 (2H, m), 6.80
(1H, d), 6.60 (1H, dd), 6.57 (1H, d), 6.06 (1H, t),
5.96 (2H, s), 2.31 (2H, m), 2.16 (2H, m), 1.58 (4H,
m) Example 11 3-Benzoylpyridine (3.9 g, 10 mmol), 5-ethoxycarbonylpentyltriphenylphosphonium bromide (10.0 g, 10 mmol), tertiary butanol (7
0 ml) and toluene (30 ml) in a nitrogen stream,
Tertiary potassium butoxide (2.3 g, 10 mmol) was added while maintaining the temperature at 0 to 5 ° C. with stirring. 1 hour at 0-5 ℃, 20
After stirring at -25 ° C for 1 hour, the mixture was concentrated under reduced pressure. The residue was dissolved in toluene (100 ml), washed with water (100 ml × 2), and the organic layer was concentrated under reduced pressure. The concentrated residue is (E) -7-
(3-pyridyl) -6-heptenoic acid and (E, Z) -7
-Ethyl ester derivative derived from -phenyl-7- (3-pyridyl) -6-heptenoic acid was used as a standard and was subjected to high performance liquid chromatography to measure the ratio of E form to Z form. / Z = 62: 38.

E form: (E) -7-phenyl-7- (3-pyridyl)-
Magnetic resonance spectrum of E-form of 6-ethyl heptenoate: 8.51 (1H, d), 8.43
(1H, q), 7.20 (7H, m), 6.10 (1H, t), 4.11 (2H, q), 2.
15 (2H, m), 1.60 (2H, m), 1.23 (3H, t) Example 12 A mixture of potassium hydroxide (1.0 g, 18.4 mmol) and tertiary butanol (50 ml) was heated to 85-90 ° C. By heating, about 35 ml of a mixture of tertiary butanol and water was distilled off.

Toluene (5 ml) was added to the residue, and 3-benzoylpyridine (1.65 g, 8 mmol) and 5-carboxypentyltriphenylphosphonium bromide (4.2
g, 9.2 mmol) was added in several portions. After the addition is complete
After stirring at 5-10 ° C for additional 2 hours, water (50m
l) and toluene (30 ml) were added for liquid separation. (E) and (Z) -7-phenyl-7- (3-pyridyl) -heptenoic acid in the aqueous layer were quantified by high performance liquid chromatography using E-form and Z-form preparations. : 1.36
g, Z-form: 0.89 g (E: Z = 60.5: 39.5), total 2.25 g (yield 8
It was confirmed that the yield was 9.0% and the E-form yield was 53.8%.

EFFECTS OF THE INVENTION According to the present invention, the desired substituted vinylpyridines can be produced in good yield on an industrial scale without the risk of danger as in conventional methods.

 ─────────────────────────────────────────────────── --- Continuation of the front page (56) References JP-A-58-219162 (JP, A) L.S. F. Fieser & M.S. Fie ser, "Reagents for Organic Synthesis," Vol. 1, P. 911-927, JOHN WI LEY & SONS, Inc. (1967)

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ is a pyridyl group, and R ² is a lower alkoxy, lower alkyl, trifluoromethyl,
A lower alkenyl, halogen or an aryl group which may have methylenedioxy], [In the formula, R ³ is a lower alkyl group, a hydroxylmethyl group,
Nitroxymethyl group, nitrogen-containing 5-membered ring-methyl group, acetal-methyl group, trialkylsilyloxymethyl group,
Alkyl- or aryl-sulfonyloxymethyl group, alkyl- or aryl-sulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group, aryl-oxymethyl group, cyano group, substituted An optionally substituted carbamoyl group, an optionally substituted carbamoyloxymethyl group, an optionally substituted thiocarbamoyloxymethyl group, a carboxyl group or an alkoxycarbonyl group, n is an integer of 1 to 22, and X is A compound represented by a halogen atom] is reacted in a tertiary alcohol in the presence of a metal hydride or a tertiary alkoxide of an alkali metal. [Wherein each signal has the same meaning as defined above] A method for producing a substituted vinylpyridine.