JPH0228155A - Production of substituted vinylpyridines - Google Patents

Abstract

PURPOSE:To safely produce the subject compound in high selectivity by reacting a compound such as 3-benzolypyridine with a compound such as 5- carboxybenzyltriphenylphosphonium bromide in the presence of a specific solvent and a specific base. CONSTITUTION:The compound of formula III can be produced by reacting a compound of formula I [R<1> is pyridyl; R<2> is (substituted) aromatic group or heterocyclic group) with a compound of formula II (R<3> is lower alkyl, hydroxymethyl, nitroxymethyl, N-containing-5-membered ring-methyl, acetal- methyl, etc.; n is 1-22; X is halogen) using a tert-alcohol (e.g., tert-butanol) as a solvent and a metal hydride or an alkali metal tert-alkoxide as a base. The base is especially preferably sodium hydride or potassium tert-butoxide and the molar ratio of the base to the compound of formula II is 2.0-3.0.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a method for producing substituted vinylpyrinones having an action of specifically inhibiting thromboxane A t (T X A 2) synthase.

Prior Art and Problems A method for producing substituted vinylpyridines having TXAt synthetase inhibitory activity is already known (Japanese Patent Laid-Open No. 58-2
No. 19162). However, when this method is examined in detail, the described manufacturing conditions have various problems from a safety perspective, and there is a risk of developing into a major disaster, especially when the manufacturing scale is expanded.

That is, in JP-A No. 58-219162, the general formula % formula % [where Rlo is a pyridyl group, Rlo is a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylene Phenyl group, thienyl group, furyl group, which may have a dioxy group,
Naphthyl group, benzothienyl group or pyridyl group, Y
is a methylene group, R3' is a hydrogen atom or a lower alkyl group, and n' is not an integer of 0 to 6].
A compound represented by the general formula % formula % () [wherein Rlo and R″′ have the same meanings as above, and a compound represented by the general formula % formula % () [wherein, X represents a halogen atom, and R″ and n.

has the same meaning as above] is reacted in a solvent in the presence of a base. This base is
Examples include n-butyllithium, sodium hydride, and tertiary butquine potassium, among which n-butyllithium and sodium hydride are said to be preferably used. Examples of the solvent include ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or a mixed solvent of two or more of these solvents. It is said that this reaction is preferably carried out under a dry inert gas atmosphere (e.g. nitrogen gas, helium gas, etc.), and the reaction temperature is -10°C to 50°C, preferably 0°C to 30°C. The progress of the reaction can be determined by observing the disappearance of the characteristic color of the reaction, and it is said that the reaction usually ends in about 1 to 6 hours.

Among these methods, it has been pointed out that most of the combinations of solvents and bases are dangerous, and cases of explosions and the like have been reported. To introduce some of these, l) When an alkoxide such as sodium hydride or sodium methoxide is used in dimethylformamide, the dimethylformamide decomposes with rapid heat generation and carbon monoxide is produced as a by-product, resulting in runaway. Cases of reactions have been reported. [Chemistry and Industry (Ch.
industry and industry)
17 February 1986, 134. Chem, Eng, Ne
ws), 1982, 60(28), 5; Chemical
and Engineering News (Chem, En
g, News), 1982, 60 July 12, 5
;Chemical and Engineering News (C
hen, Eng, News), 60, September 13th,
5]. 2) When sodium hydride is used in a reaction in dimethyl sulfoxide, dimethylsulfinyl anions are produced, and there have been reports of explosions [Chemical and Engineering News (
Chem, Eng, News) 1966.44. April 11th 348. Chemical and Engineering
News (Che+++, Eng.

News), 1966.44. June 13, 7].
3) Cases of explosions have been reported when refluxing hydrides (the case of calcium hydride has been reported) in tetrahydrofuran [Chemical and Engineering News (Chem.

Eng. News), 1987, 56, February 6, 3; April 17, 1987, 68]. Also, using large amounts of hydrides that generate hydrogen in solvents with low flash points such as ethyl ether is dangerous, as in these cases, and n-butyllithium is extremely sensitive to moisture and must be handled carefully. It is disadvantageous in terms of Therefore, the inventors of the present invention have conducted intensive studies to improve the above-mentioned method and make it an industrial production method that is perfect from the viewpoint of safety. As a result, we found that the combination of a solvent and a base, which has not been reported as a disaster so far, and which poses no particular danger if handling precautions are strictly followed, can sufficiently achieve the purpose. The present inventors have discovered reaction conditions that allow the safe production of substituted vinylpyridines with good yield, and have completed the present invention.

The present invention is directed to a compound represented by the general formula %() 5, in which R1 represents a pyridyl group and R' represents an aromatic group or a heterocyclic group which may have a substituent; General formula % formula % () [wherein R3 is a lower alkyl group, a hydroxymethyl group,
Nitroxymethyl group, nitrogen-containing 5-membered ring-mekyl group, acetal-methyl group, trialkylsilyloxymethyl group,
Alkyl- or aryl-sulfonyloxymethyl group, alkyl- or aryl-sulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxomethyl group, aryl-oxinemethyl group, cyano group , 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, X represents a halogen atom. [In the formula, each symbol is The present invention provides a method for producing substituted vinylpyridines represented by the same meanings as above].

In the general formulas (I), (II) and (II[), R'
The pyridyl group represented by may be any of 2-pyridyl, 3-pyridyl, and 4-pyridyl, but 3-pyrinol is preferable. Examples of aromatic groups represented by R' include aryl groups such as phenyl, naphthyl, α-naphthyl, and β-naphthyl; examples of heterocyclic groups include thienyl (
2-thienyl, 3-thienyl), furyl (2-furyl,
3-furyl), bilinol (2-pyridyl, 3-pyridyl, 4-bilinol), benzothienyl group (2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-
penzothienyl, 6-benzothienyl, 7-benzothienyl), etc. R' is preferably phenyl.

These aromatic groups and heterocyclic groups may have a substituent at any position on the ring. The substituent includes lower alkoxy (e.g. methoxy, ethoxy, n-propoxy,
i-propoxy, n-butoxy, i-butoxy, t-butoquino, etc.), lower alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, (- butyl, n-pentyl, i-pentyl, etc. having 1 to 5 carbon atoms), trifluoromethyl, lower alkenyl (e.g. vinyl, allyl, pentenyl, etc. having 2 to 5 carbon atoms), halogen (fluorine, chlorine,
(bromine, iodine), methylenedioxy, etc.

Examples of the lower alkyl group represented by R3 include methyl, ethyl, n-propyl, i-propyl, n-butyl,
Examples of the nitrogen-containing 5-membered ring-methyl group include those having 1 to 4 carbon atoms such as i-butyl and t-butyl, such as imidazolylmethyl (I-imidazolylmethyl, 2-imidazolylmethyl), triazolylmethyl (l- triazolylmethyl,
3-triazolylmethyl, 5-triazolylmethyl),
Tetrazolylmethyl (I-tetrazolylmethyl, 5-tetrazolylmethyl) etc. where 2 to 4 hydrogen atoms of the methyl group are on the ring.
Substituted with a 5-membered ring group containing nitrogen atoms,
Examples of the acetal-methyl group include 2-tetrahydrobilanyl ochynemethyl, 2-tetrahydrofuryloxymethyl, etc., and examples of the trialkylsilyloxymethyl group include dimethyl tert-butylsilyloxymethyl. Examples of the alkyl- or aryl-sulfonyloxymethyl group include methanesulfonyloxymethyl, p-toluenesulfonyloxymethyl, etc.
Examples of the alkyl- or aryl-sulfonylaminocarbonyloxymethyl group include methanesulfonylaminocarbonyloxymethyl, p-toluenesulfonylaminocarbonyloxymethyl, and the like; examples of the acyloxymethyl group include the formula R'coocr-rt- [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, rhohexyl, etc.) or pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl). Examples of the alkoxycarbonyloxymethyl group include methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, n
-Propoxycarbonyloxymethyl, i-propoxycarbonyloxymethyl, n-butoxycarbonyloxymethyl, i-butoxycarbonyloxymethyl, lowbentyloxycarbonyloxymethyl, n-hexyloxycarbonyloxymethyl Examples of the halogenomethyl group include fluoromethyl, chloromethyl, bromomethyl, and iodomethyl, and examples of the alkoxymethyl group include methochinomethyl, ethquinmethyl, n-propoxymethyl, i-propoxymethyl,
2 carbon atoms, such as n-butoxymethyl, i-butoquinomethyl, etc.
-5 lower alkoxymethyl groups, the aryloxymethyl group is, for example, phenyloxymethyl, 2-methylphenyloxinemethyl, 3-methylphenyloxinemethyl, 4-methylphenyloxymethyl, 2,4-dimethyl Examples of the optionally substituted carbamoyl group include those having 7 to 9 carbon atoms such as phenyloxmedel and 3.4-nomethylphenyloquinemethyl, where R5 and R6 are the same or different. hydrogen, carbon number 1
~6 alkyl (e.g. methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, n-pentyl, i-pentyl, n-hexyl, i-
hexyl, etc.) or allyl having 6 to 8 carbon atoms (phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2.4-dimethylphenyl, 3.4-tsumethylphenyl, etc.). The optionally substituted carbamoyloxymethyl group is represented by the formula % [wherein R5 and R8 have the same meanings as above, and the optionally substituted carbamoyloxymethyl group] Good thiocarbamoyloxymethyl groups include those represented by the formula [wherein R5 and R8 have the same meanings as defined above], and examples of the alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, n
-propoxycarbonyl, i-propoxycarbonyl,
n-butoxycarbonyl, i-butquincarbonyl,
Examples include those having 2 to 5 carbon atoms such as t-butoxycarbonyl.

R3 is preferably a carboxyl group, a methyl group, or a lower alkoxycarbonyl group having 2 to 5 carbon atoms. n is 1
-22 integers, preferably 3-8 integers, 3-6
An integer of is more preferred.

- As a typical example of the compound of formula (1), R' is 3
-pyridyl%R'' is phenyl, R3 is carphoquinol group,
Examples include lower alkoxycarbonyl or methyl groups having 2 to 5 carbon atoms, where 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 a tertiary alkoxide of an alkali metal is used as a base.

It was found that among alcohols, when primary alcohols were used, no production of the target product was observed, and when secondary alcohols were used, the target product could only be obtained in low yield. It was also found that when a primary alkoxide such as sodium ethoxide among metal alkoxides was used as a base, the production of the target product was confirmed, but the yield was low.

In addition, in the reaction of the present invention, two types of geometric isomers (
For example, 7phenyl-7-
In the case of (3-pyridyl)-6-heptenoic acid, the biologically active E isomer is important; in many cases, one or the other isomer is useful, and selective reaction conditions are desired. . 7-phenyl-7-(3-pyridyl)-6
- In the case of heptenoic acid, it is difficult to significantly shift the equilibrium point to either one due to the structural similarity of the two substituents at the 7-position. When synthesized under the same reaction conditions, the production of the Z-form is slightly superior to that of the E-form.

However, in the production method of the present invention, in the case of a compound of general formula (1) in which R1 is a pyridyl group and R2 is a phenyl group,
The production of E-form is clearly more than that of Z-form, and its selectivity becomes more pronounced at low temperatures below 10°C, and conversely, when acetonitrile is used as a solvent, the production of Z-form becomes more pronounced. An unexpected finding was obtained.

The manufacturing method of the present invention will be explained in more detail below.

The tertiary alcohol used as the reaction solvent may be any tertiary alcohol such as tertiary butanol and tertiary amyl alcohol.

The tertiary alcohol may be aromatic hydrocarbon, aliphatic saturated hydrocarbon,
It can also be used in combination with other solvents such as aliphatic ethers. Aromatic hydrocarbons used in combination with tertiary alcohol include toluene, benzene, xylene, etc., aliphatic saturated hydrocarbons include hexane, cyclohexane, etc., and aliphatic ethers include ethyl ether,
Examples include isopropyl ether and diethylene glycol dimethyl ether. Among these, toluene, benzene, isopropyl ether, and cyclohexane are preferable as the solvent to be mixed with the tertiary alcohol. As the mixed solvent, a mixed solvent with tertiary butanol is particularly preferred. The selection of these solvents is based on the general formula m, (II), (II
Taking into account the solubility or operability of the compound represented by I), a single solvent or a mixture of two or more of these solvents may be used. Any mixing ratio can be used taking into consideration the solubility of raw materials and products, operability, economic efficiency, isomer production ratio, etc., but usually it is 50% or less based on the tertiary alcohol. preferable.

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

The reaction temperature can be used in any range from -30°C to the boiling point of the reaction solvent used, but the reaction temperature can be adjusted between -1O and -9 by taking into account the reaction time and the production ratio of E form and Z form if necessary.
It is preferable to carry out the reaction in the range of 0°C.

Yes. The reaction temperature is usually 1 to 3 hours, and the reaction is preferably carried out under a dry inert gas (eg, nitrogen gas, helium gas, etc.) atmosphere.

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

Example 1 3-benzoylpyridine (33,09,0,18 mol)
, 5-carboxypentyltriphenylphosphonium bromide (84,09,0,184 mol) and tertiary butanol (540 ffC) was heated to about 60°C and dissolved in sodium hydride (60% ,
Oil, l 5.89.0.396 mol) was added in small portions in several portions. After stirring at 60-700C for 1 hour, tertiary butanol was distilled off under reduced pressure. Toluene (80ffQ) and water (160d) were added to the residue to separate the layers.

(E) and (Z)-7-phenyl-7-(3
-Pyridyl)-6hebutenoic acid was quantified by high performance liquid chromatography using E-form and two-form preparations, and the results were as follows:
E body: 24.9g, 2 body: 24.7g (E:Z=50.
2:49.8), total 49.6g (yield 98.8%, E
It was confirmed that the product contained 49.6% of the product.

Example 2 3-benzo1'ruviridine (16,59,90 mmol), 5-carboquinlepentyltriphenylphosponium bromide (42,0 g, 92 mmol), tert-butanol (120 m□ and toluene (30 mmol) ,v!2)
was heated to 60°C, and tertiary butquin potassium <2
5.39.198 mmol) was added in several portions. 6
Stir at 0 to 70°C for 1 hour, cool, and add water (
480xC) was added. Results of quantifying (E) and (Z)-7-phenyl-7-(3-pyridyl)6-heptenoic acid in the aqueous layer after washing with toluene (100x (J)) in the same manner as in Example f. , E body: 12.99.2 body: 1
It was confirmed that the product contained 7 g of 23.0 g (yield: 93.1%). (E:Z=54.8・45,
(2, Yield of E form 51.0%) Note that (E+Z)-7-phenyl-7-(3-pyridyl)-6- after 1 hour when the reaction was carried out at 20 to 30°C on the same scale. The production of heptenoic acid is 23.09C yield 9
57%, E:Z=58.3:41.7, yield of E form 55
．． 8%).

In addition, when the reaction temperature was similarly carried out at 5 to IO'C, the production of (E+Z)-7-phenylene-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: 5
8.1%).

Example 3 3-benzoylpyridine (1,659,9 mmol),
Sodium hydride (60%, oily, 0.74 g, 18.4 mmol) was added in several portions. After the addition was completed, the mixture was stirred at 20 to 30°C for 2 hours. After cooling, water (50 mσ) and toluene (30 mf2) were added to the reaction solution and separated, and (E) and (Z)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid in the aqueous layer was separated. was determined in the same manner as in Example 1.

As a result, E body 1.20g, 2 bodies 1.18g, (E:
Z=50.3:49.7), total, 2.38g (yield 9
4.1%, yield of E form: 47.3%).

Example 4 3-benzoylpyridine (1,659,9 mmol),
Potassium tert-butoxy (2.53 g, 198 mmol) was added to a mixture of 5-carboxypentyltriphenylphosphonium bromide (4,29,9,2 mmol) and tertiary amyl alcohol (15 Wr:l) under stirring. The mixture was added in portions and stirred at 20-30°C for 2 hours. Water (50z0.) and toluene (30zf2) 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 was extracted. Example I
It was quantified in the same manner. As a result, 8 bodies 1.3 + 9.2 bodies 1
．． 019 (E:Z=563:43.7), total 2.32
9 (yield: 91.7%, yield of E form: 51.6%).

Example 5 3-benzoylpyridine (] , 659.9 mmol)
, 5-carboxypentyltriphenylphosphonium bromide (4.2 g, 92 mmol), tert-butanol (15z (7) and cyclohexane (5 ff) were added to a mixture of sodium hydride, (6
0%, oil-based, 0.55g, 13.5mm
The mixture was added in four portions and stirred at 20 to 30°C for 3 hours. Water (50RQ) and toluene (30d) were added to the reaction solution to branch, and (E) and (Z) 7-phenyl-7-
(3-bilinol)-6-heptenoic acid was quantified in the same manner as in Example 1. As a result, E body 1.149.4 body 1.12g
(E:Z=50.5:49.5), total 2.26! ? (
Yield: 89.5%, yield of E form: 45.2%).

Example 6 3-benzoylpyridine (1.65 g, 9 mmol),
To a mixture of 5-carboxypentyltriphenylphosphonium bromide (4,2y, 9,2 mmol), tertiary butanol (15i) and isopropyl ether (5 moles) was added sodium hydride (60
%, oily, 0.559.13゜5 mmol) from 3 to 1
The mixture was added in portions and stirred at 20-30°C for 3 hours. Water (50y &) and toluene (30Tσ) were added to the reaction solution to separate the liquid, and (E) and (Zl-7-phenyl-7-(3-bilinol)6-heptenoic acid in 1 m of water were prepared as in Example 1. It was quantified in the same way7.As a result, E body 1.1'g, 4 body 1
．． 09! ? (E:Z=507:49.3), total 2.2
0y (yield: 87.1%, yield of E form: 44.2%).

Comparative Example 1 3-benzoylpyridine (1,65y, 9 mmol),
A mixture of 5-carboxypentyltriphenylphosphonium bromide (4,2y, 9.2 mmol) and tetrahydrofuran (+5xQ) was stirred in a nitrogen stream.
Sodium hydride (60%, oily, 0.557.13.
Add 5 mmol) in 3 to 4 times and heat at 20 to 30℃.
The mixture was stirred for 3 hours. Water (soxg) and toluene (30T!0) were added to the reaction solution to separate the layers, and (E) and (
Z)-7-phenyl-7-(3-pyridyl)-6-heptenoic acid was determined in the same manner as in Example 1. As a result, 8 bodies and 0
．． 049.2 bodies 0.119 (E:Z=26.7:73.
3), total 0.15g (yield: 0.6%, yield of E form:
0.16%).

When tertiary butoxypotassium was used as a salt weir, the yield was 77.8%, E:Z=35.8:64.2 (yield of E form 27.9%).

Comparative example 2 3-benzoylpyridine (1,65Li, 9 mmol)
Sodium hydride (60%, oily, 0.55y, 13.5
mmol) was added in 3 to 4 portions, and the mixture was heated and stirred at about 80°C for 3 hours. Water (50z12) and toluene (301η) were added to the reaction solution to separate the layers, and (E) and (
Z)-7-phenyl-7-(3-bilinol)-6-heptenoic acid was determined in the same manner as in Example 1. As a result, 8 bodies and 0
．． +89.2 bodies 0°17! ? (E:Z=51.0:49
．． 0), and a total of 0.359 (yield: 13.9%, yield of E form: 7.1%).

Comparative example 3 3-benzoylpyridine (16,59,90 mmol)
, 5-carboxypentyltriphenylphosphonium bromide (42,09,92 mmol) and trimethylformamide (90! %
, oily, 8.07.135 mmol) was added little by little, and the mixture was stirred at the same temperature for 3 hours. Treated in the same manner as in Example 2,
The amount of (E) and (Z)-7-phenyl-7-(3-bilinol)-6-heptenoic acid produced was determined by high-performance liquid chromatography. As a result, E form: 9.69.4 form: 12.
2g (E:Z=442:55.8), total 21.89 (
Yield: 860%, yield of E form: 38.0%).

When the experiment was carried out under the same conditions using dimethylsulfoquine instead of dimethylformamide, the amount produced was E-form; 969
．． 4 bodies: I O, 8? (E:Z=4-7.0:53.0
), total 20.49 (yield 80.8%, yield of E form: 3
8.0%).

Comparative Example 4 3-benzoylpyridine (1,65y, 9 mmol),
Anhydrous potassium carbonate (1,59,11 mmol) was added to a mixture of 5-carboxypentyltriphenylphosphonium bromide (4,29,9,2 mmol) and dimethylformamide (1,511 mmol) with stirring, and 30 to 3
The mixture was heated and stirred at 5°C for 3 hours. Water (502Q) in the reaction solution
and toluene (30xC) to separate the layers, and (E
) and (Z)-7-phenyl7-(3-bilinol)-
6-heptenoic acid was determined in the same manner as in Example 1. As a result, no formation of the target product was observed.

Similar experiments were conducted by replacing the solvent with dimethyl sulfoxide or tetrahydrofuran, but no production of the target product was observed in these cases either.

Example 7 3-benzoylpyridine (1,659,9 mmol),
To a mixture of 5-carboxypentyltriphenylphosphonium bromide (4,29,9,2 mmol), tert-butanol (121) and toluene (12xC) was added tert-butoquinocpotassium (253 g, 1.98 mmol) with stirring. ) was added in several portions and stirred for 2 hours at 20-30°C.Water (50d) and toluene (30d) were added to the reaction mixture to branch, and (E) and (Z)-7 in the aqueous layer were added. -Phenyl-7-(3pyridyl)-6-heptenoic acid in Example 1
It was quantified in the same manner. As a result, 8 bodies weighed 1.18g, 2 bodies weighed 0.
．． 949 (E:Z=56.3・43.7), total 2.1
2y (yield: 90.2%, yield of E form: 50.8%).

Example 8 3-benzoylvirinone (1.65 g, 9 mmol),
Potassium tert-butoxy (2,539,1,98 mmol) was added several times to a mixture of 5-carboxypentyltriphenylphosphonium bromide C (4,29,9,2 mmol) and tert-butanol (15xC) under stirring. The mixture was added in portions and stirred at 20-30° for 2 hours. Water (5
(E) and (Z)-7-phenyl-7-(3-
(pyridyl)-6-heptenoic acid was determined in the same manner as in Example 1. As a result, 8 bodies weighed 1°29g, 2 bodies weighed 0.979g (E:
Z=57.0:43.0), total 2.269 (yield: 9
It was confirmed that the yield of isomer E was 52.8%).

Comparative Example 5 3-benzoylpyridine (1.65 g, 9 mmol),
A mixture of 5-carboxypentyltriphenylphosphonium bromide (4,29,9,2 mmol) and tetrahydrofuran (10 iN) was stirred in a nitrogen stream.
n-Butyllithium (13,8x(!.

A 1.6M hexane solution) was added dropwise and stirred at 20 to 30°C for 2 hours. Water (50ff12) and toluene (
Add 30ff□ to separate the layers, and (E) and (Z
) 7-phenyl-7-(3-pyridyl)-6-heptenoic acid was determined in the same manner as in Example 1. As a result, E body 2,
5 tx9.2 bodies 22.8j! g(E:Z=9.8:9
o.

2), a total of 25.3J+9 (yield: 1%, yield of E form: 0.1%) was confirmed.

Example 9 3-benzoylvirinone (22,09,0,12 mol)
, 5-pentyltriphenylphosphonium bromide (
49,69,0,12 mol), tertiary butanol (21
Potassium tert-butoxy (26.9 g, 0.24 mol) was added to a mixture of 0xQ) and toluene (70++2) under nitrogen flow and stirring while maintaining the temperature at 3-10°C. 3
After stirring for 1 hour at ˜10° C. and 1 hour at 24-25° C., 2 portions were added and concentrated under reduced pressure. Dissolve the residue in toluene (200z
The organic layer dissolved in 1J) and washed with water (200y12x4) was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography to measure the ratio of E form and Z form.
=58:42. Normal hexane (
150R was added and left 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: tetrachloride). Carbon: Ethyl acetate = IO: 0.5). First, the Z-isomer was eluted, followed by the E-isomer. Both the Z-isomer and the E-isomer were distilled under reduced pressure to obtain the Z-isomer (136 to +38 °C/0,3
mxHg) 659, E form (136-138°C10,
5.9 g of 3-shoulder Hy) and 9.9 g of a mixture of E and Z forms.
I got 89.

Z-form: (Z)-6-phenyl-6-(3-pyridyl)-
5-hexene E-form (E)-6-phenyl-6-(3-pyridyl)-
5-hexene nuclear magnetic resonance spectrum: Z form: 8.47 (2H, m), 7.22 (7H, m),
6.18 (l H, t), 2.12 (21-(, m),
1.39 (4H.

m), 0.85 (3I-1, t) E body・8.53 (L H, d), 8.44 (lH, dd
), 7.30 (4H, m), 7.15 (3H, m), 6
．． 12 (I Ht), 2.15 (2H, m), 1.38
(4H, m), 0°86 (3T-1, t) Example 10 3-(3,4-methylenedioquine benzoyl)pyridine (3,0 g, 13.2 mmol), 5-carboxypentyltriphenylphosphonium Bromide (6, 29,
13,6 mmol), tertiary butanol (4231f2
) and toluene (18 sυ) in a nitrogen atmosphere with stirring while maintaining the temperature at 3-10°C. Tert-butoxypotassium (3,39,29 mmol) was added at 3-10°C for 1 hour After stirring at 20-30°C for 1 hour, the mixture was concentrated under reduced pressure and water (60C) was added.

After washing with toluene (30+CX2), the pH of the aqueous layer was adjusted to 5.5. Extracted with ethyl acetate (60z□), concentrated the organic layer under reduced pressure, subjected the concentrated residue to high performance liquid chromatography, and measured the ratio of E-form and Z-form, and found that E/Z = 52:48. The concentrated residue was subjected to silica gel column chromatography, eluted with ethyl acetate, and both fractions containing the Z form were collected and concentrated. When the residue was treated with ethyl acetate-isopropyl ether, crystals of the Z form were obtained as 0659 ( 14.7%) was obtained. Collect and concentrate both components containing the E-isomer by silica gel column chromatography, and a portion (100ag) of the residue was purified by high performance liquid chromatography (column: YMC1ODS column 20X250
+z, mobile phase: methanol + 0.05M potassium dihydrogen phosphate - 3:2), E form (55, W9, oil)
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 (l Hm), 7.30 (I H, m), 6.8
6(l Hd), 6.68(I H,d), 6.53(
l H, dd), 605 (I H, t), 5.92 (2
H, s), 2.28 (2H, m), 1.57 (4H,
m) E form: l O, 30 (Cool (), 8.50 (2H,
m), 747 (2H1m), 6.80 (II, d), 6
．． 60 (IHdd) 6.57 (IH,d), 6.0
6 (I H, t) 5.96 (2 H, s), 2.31 (2
H, m), 2.16 (2H, m), 1, 58 (4
H, m) Example +1 3-benzoylpyridine (3,99,1089 mol),
5-Ethoquinocarponylbentyltriphenyphosphonium bromide (l 0.Oy, IO mmol), tert-butanol (70TIQ) and toluene (30*f
Tertiary butquine potassium (2.37, 10 mmol) was added to the mixture of 2) in a nitrogen stream while stirring and maintaining the temperature at 0 to 5°C. After stirring at 0-5°C for 1 hour and at 20-25°C for 1 hour, it was concentrated under reduced pressure.

Dissolve the residue in toluene (10ml) and water (100ml).
After washing with x2), the organic layer was concentrated under reduced pressure. The concentrated residue was converted into (E)-7-(3-bilinol)-6-heptenoic acid and (E,Z)-7-phenyl-7-(3-bilinol)-
The ethyl ester derivatives derived from 6-heptenoic acid were subjected to high performance liquid chromatography as standards, and the ratio of the E and Z forms was measured; E/Z = 62:38.
Met.

E form: (E)-7-phenyl-7-(3-pyrinol)6
-Magnetic resonance spectrum of standard sample of ethyl heptenoate E: 8.51 (IH, d
), 8.43 (IH, q), 7.20 (7H, m), 6
．． 10 (eyes (, t), 4. I I (2H, Q), 2.1
5 (2H, m).

1.60 (2H, m), 1.23 (3H, t) Example 1
2 A mixture of potassium hydroxide (+, 09.18.4 mmol) and tertiary butanol (50 mQ) was heated at 85-90°C.
The mixture of tert-butanol and water is heated to about 35%
112 were distilled off.

Add toluene (50%) to the residue and incubate at 5~10°C for 3~
Benzoylpyridine (1,65g, 8mmol), 5-
Carboquinopendeltriphenylphosphonium bromide (429.92 mmol) was added in portions. After the addition was completed, the mixture was further stirred at 5 to 10°C for 2 hours, and water (50i0) and toluene (301N□) were added to the reaction mixture to separate the layers. (E) and (Z)-7-phenyl- in the aqueous layer 7
-(3-Pyridyl)-heptenoic acid was quantified by high performance liquid chromatography using preparations of the E form and the Z form. The E form: 1.36 g, the 2 form: 0.89 g (E:Z=6
0.5:39.5), total 2.259C yield 89.0%
, the yield of E form was confirmed to be 53.8%.

According to the present invention, target substituted vinylpyrinones can be produced in high yield on an industrial scale without the dangers encountered in conventional methods.

Patent applicant: Takeda Pharmaceutical Company Limited

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a pyridyl group, and R^2 represents an aromatic group or heterocyclic group that may have a substituent. ] and the general formula ▲ mathematical formula, chemical formula, table, etc. -Methyl group, trialkylsilyloxymethyl group, alkyl- or aryl-sulfonyloxymethyl group, alkyl- or aryl-sulfonylaminocarbonyloxymethyl group, acyloxymethyl group, alkoxycarbonyloxymethyl group, halogenomethyl group, alkoxymethyl group , an aryl-oxymethyl group, a cyano group, 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 from 1 to 22, and X represents a halogen atom] in a tertiary alcohol in the presence of a metal hydride or a tertiary alkoxide of an alkali metal. A method for producing substituted vinylpyridines represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, each symbol has the same meaning as above].