JPH0959253A - Production of 2-aralkyloxypyridines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To simply produce the subject compounds useful as synthetic raw materials for hydroxypyridines or pyridones which are synthetic intermediates for medicines and agrochemicals from sulfonylpyridines in high yield. SOLUTION: (A) 2-Sulfonylpyridines of formula I (R<1> is a lower alkyl, a cycloalkyl, an aryl or an aralkyl; X is methyl or H) are reacted with (B) a salt of an aralkyl alcohol of the formula R<2> OM (R<2> is an aralkyl; M is an alkali metallic atom or ammonium group) to provide (C) 2-aralkyloxypyridines of formula II. The resultant component (C) is further simply converted into 2-hydroxypyridines or 2(1H)-pyridones which are tautomers thereof by hydrogenolysis reaction in the presence of a catalyst. For example, 2- benzyloxypyridine is obtained from a solution of 2-phenylsulfonylpyridine in tetrahydrofuran and a solution of sodium benzylate in benzyl alcohol.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing 2-aralkyloxypyridines, which are raw materials for producing 2-hydroxypyridines or 2 (1H) -pyridones useful as intermediates for producing pharmaceuticals and agricultural chemicals. .

[0002]

As a general method for producing 2-hydroxypyridines or 2 (1H) -pyridones useful as intermediates for producing pharmaceuticals and agricultural chemicals, a method of deriving from substituted pyridines and a 2-hydroxypyridine ring or 2 (1
H) -pyridone ring can be synthesized.

As a method for deriving from substituted pyridines, 2-chloropyridines are treated with alkali in a tertiary alcohol to obtain 2-hydroxypyridines or 2 (1H) -pyridones (German Patent 3). , 8
14, 358) or 2-methoxypyridines obtained from 2-chloropyridines are converted to 2-hydroxypyridines or 2 (1H) -pyridones with sodium trimethylsilanethiolate (Heterocycles, 1993). 32 years
Page 3). The 2-chloropyridines used as the raw materials in these methods are obtained by converting pyridines into tetrahedron letters (Tetrahedron Le).
terts, 1971, p. 2807) to obtain pyridine N-oxides obtained by oxidation according to the method described in Chemistry of Heterocyclic Compounds.
c Compounds, Volume 14, Supplementary Volume 2, 1974
Year) chlorinated by the method described. Therefore, 2
-Hydroxypyridines or 2 (1H) -pyridones are produced from pyridines through three steps, so the overall yield is low, and waste liquid treatment of phosphorus oxychloride used for chlorination is essential. is there.

2-aminopyridines are treated with sodium nitrite under acidic conditions and then hydrolyzed to give 2-
A method for leading to hydroxypyridines or 2 (1H) -pyridones is known, but the [Journal of Heterocyclic Chemistry (Journal o
f Heterocyclic Chemistry,
1995, p. 259)], and the 2-aminopyridines used as the raw material thereof are described in, for example, Journal of Russian Physical Chemical Society (Journal).
of Russian Physical Chemi
Cal Society, 1915, p. 835), it is synthesized by amination of pyridines, and thus the overall yield is low.

Swiss Patent 644,847 in which pyridine-2-carboxylic acid N-oxides are converted to acid anhydrides with acetic anhydride and then hydrolyzed with alkali, and JP-A-6-264.
The method described in 0-61,567 can be mentioned, but the pyridine-2-carboxylic acid as a raw material is produced by, for example, oxidizing 2-methylpyridine with an oxidizing agent such as permanganate [Journal of Organic Chemistry (Journal of Orga)
nic Chemistry, 1946, Volume 14, 1
4)], the overall yield is low, and disposal of the oxidizer is a problem. Furthermore, in the presence of copper sulfate 15
A method of introducing a hydroxyl group into the 2-position of 3-methylpyridines by heating at 0 ° C. to 700 ° C. is Tetrahedron Letters.
s, 1977, p. 2193) and Polish patent 102,246, but it is not a practical reaction.

A method for producing 2-hydroxypyridine or 2 (1H) -pyridone by treating 2-benzyloxypyridine with sodium ethoxide in ethanol using palladium on carbon as a catalyst [Journal of Indian Chemistry Section
B (Journal of Indian Chemi
story. , Section B, 1984, 295.
Page)] is known, but a more efficient production method with a low yield is required.

2-hydroxypyridine ring or 2 (1
H) -pyridone ring can be synthesized by reacting methyl 2-pentenonate with bis (N, N-dimethylamino) methoxymethane and then treating with sodium methylate and ammonia to give 2-hydroxy-
5-methylpyridine or 5-methyl-2 (1H)-
A method for producing pyridone (European Patent 592,896),
A method for producing 2-hydroxypyridine or 2 (1H) -pyridones by reacting methyl 5-oxohexanoate with ammonia and hydrogen in the presence of palladium (European Patent 123,362), and 2,4-pentadienamide as tetra 2-hydroxypyridine or 2 by treatment with lithium chloropalladate (II)
Method for producing (1H) -pyridones (JP-A-51-1
43, 672 and Chemistry and Industry, 1975, p. 745), and 2,4-
1,3-Pentadienyl isocyanate obtained by reacting hexadienoic acid with ethyl chlorocarbonate and sodium azide is heated to produce 2-hydroxy-6-methylpyridine or 6-methyl-2 (1H) -pyridone. Kimika Therapeutic
Therapeutica, 1970, Volume 5, 6
No. 4, p. 416), but none of them is a production method with low yield and practical use.

The inventors of the present invention have investigated the method for industrially and inexpensively producing 2-hydroxypyridines, and as a result, catalytic 2-hydrolyzation of 2-aralkyloxypyridines in the presence of a catalyst leads to 2-hydroxypyridine. It has been found that pyridines or 2 (1H) -pyridones are produced.

The raw material used in this new manufacturing method is 2
-A method for producing aralkyloxypyridines includes 2-
2-Benzyloxy-4 is obtained by reacting chloro-4-methylpyridine with benzyl alcohol in the presence of a base.
-Manufacturing method for conversion to methylpyridine [Journal of Chemical Society Perkin Transaction II (Journal of Chemical
l SocietyPerkin Transacti
on II, 1988, p. 2791), but as described above, since 2-chloropyridines are produced from pyridines through two steps, the yield is low as a whole process, and the pharmaceutical and 2- as an intermediate for producing pesticides
For the industrial production of aralkyloxypyridines,
Development of more efficient manufacturing methods is needed.

[0010]

The present invention is a raw material for producing 2-hydroxypyridines or tautomers of 2 (1H) -pyridones useful as intermediates for the production of pharmaceuticals and agricultural chemicals. -To provide a method for producing aralkyloxypyridines.

[0011]

As a result of various studies to achieve the above object, the present inventors have found that 2-aralkyloxypyridines can be easily obtained from 2-sulfonylpyridines in high yield. The present invention has been completed and the present invention has been completed.

That is, the present invention provides the following general formula (I)

[0013]

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(In the formula, R ¹ represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, and X represents a methyl group or a hydrogen atom.) The aralkyl alcohol represented by the general formula: R ² OM (wherein R ² represents an optionally substituted aralkyl group, and M represents an alkali metal atom or an ammonium group) in the 2-sulfonylpyridine represented by Of the following general formula (II), which is characterized by reacting a salt of

[0015]

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(In the formula, R ² and X are the same as above.) The present invention relates to a method for producing 2-aralkyloxypyridines.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the above general formula, examples of the lower alkyl group include a methyl group, ethyl group and propyl group, and examples of the cycloalkyl group include a cyclopentyl group, a cyclohexyl group and a cyclooctyl group. .
Examples of the aryl group include a phenyl group and a naphthyl group. These include a lower alkyl group such as a methyl group and an ethyl group, a lower alkoxy group such as a methoxy group and a propoxy group, a fluorine atom, a chlorine atom, a bromine atom and the like. It may be appropriately substituted with a halogen atom, a cyano group, a nitro group or the like. And as the aralkyl group, a benzyl group, a phenethyl group and the like can be mentioned. These are a methyl group,
Lower alkyl group such as ethyl group, lower alkoxy group such as methoxy group and propoxy group, fluorine atom, chlorine atom,
It may be appropriately substituted with a halogen atom such as a bromine atom, a cyano group, a nitro group or the like.

The method for producing 2-aralkyloxypyridines of the present invention is shown in the following scheme.

[0019]

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(In the formula, R ¹ , R ² and X are the same as above.)

Examples of the aralkyl alcohol include benzyl alcohol, p-methylbenzyl alcohol, p-methoxybenzyl alcohol, p-nitrobenzyl alcohol, o-nitrobenzyl alcohol, p-chlorobenzyl alcohol and the like.

Examples of the alkali metal atom include lithium atom, sodium atom and potassium atom, and examples of the ammonium group include ammonium group (—NH ₄ ),
Alkyl ammonium groups such as methyl ammonium group and ethyl ammonium group, dialkyl ammonium groups such as di-n-butyl ammonium group, trialkyl ammonium groups such as trimethyl ammonium group, tetra-n
-Tetraalkylammonium group such as butylammonium group, aralkylammonium group such as benzylammonium group, diaralkylammonium group such as dibenzylammonium group, aralkylalkylammonium group such as benzylmethylammonium group, aralkyldialkyl group such as benzyldimethylammonium group Ammonium groups and aralkyltrialkylammonium groups such as benzyltrimethylammonium groups.

As the aralkyl alcohol salt, an alkali metal salt is preferably used, and a sodium salt is more preferably used. The aralkyl alcohol salt can be produced according to a conventional method, for example, by reacting the aralkyl alcohol with the corresponding alkali metal or ammonium salt, or by performing a salt exchange reaction between the aralkyl alcohol and the corresponding lower alcohol salt. Although the salt can be isolated and used, it can be conveniently used as an aralkyl alcohol solution.

A solvent may be used in the reaction. As the solvent, any solvent may be used as long as it does not participate in the reaction, for example, hydrocarbons such as hexane and octane, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, ethers such as diethyl ether and tetrahydrofuran. , And aromatic hydrocarbons such as toluene and xylene.

The reaction is generally carried out at 20 ° C to 120 ° C, more preferably 60 ° C to 80 ° C.

The 2-sulfonylpyridine represented by the general formula (I), which is the starting material in the production method of the present invention, is synthesized (Synthesis, 1989, p. 623).
It can be produced by the described method or the following reaction (see Reference Examples 1 to 5).

[0027]

[Chemical 6]

(In the formula, R ¹ , R ² and X are the same as above, and R ³ represents an acyloxy group, a lower alkylthio group, an arylthio group or a tri-lower alkylsiloxy group.)

In the above general formula, the acyloxy group includes acetoxy group, propanoyloxy group, benzoyloxy group and the like, and the lower alkylthio group includes methylthio group, propylthio group and the like. Examples of the arylthio group include a phenylthio group and 2-naphthylthio group, and examples of the tri-lower alkylsiloxy group include a trimethylsiloxy group and a t-butyldimethylsiloxy group.

The compound (III) as a starting material is prepared from the corresponding sodium sulfinate by Organic Synthesis (Vol. 57, 8).
Page 8, 1977). The other starting material, compound (IV), can be obtained, for example, from Industrial and Engineering Chemistry (Industrial and Engineering).
ng Chemistry, Volume 41, No. 12, 2920
Page, 1949).

The reaction between the sulfonyl cyanide represented by the above general formula (III) and the diene represented by the above general formula (IV) can be carried out under Diels-Alder reaction conditions, and the presence of a solvent and a polymerization inhibitor. In general, in the absence or in the absence, it is carried out at 20 ° C to 120 ° C, more preferably at 60 ° C to 100 ° C.

As the polymerization inhibitor, phenols such as 4-methoxyphenol and 2,6-di-t-butyl-4-methylphenol, hydroquinones such as hydroquinone and di-tert-butylhydroquinone, 1-naphthol, Examples thereof include naphthols such as 2-naphthol, and catechols such as catechol and p-tert-butylcatechol. The amount of the polymerization inhibitor added is 10 ppm to 1,000 ppm, preferably 100 ppm to 500 ppm, based on the weight of the diene. As the solvent, any solvent may be used as long as it does not participate in the reaction, for example, hydrocarbons such as hexane and octane, halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane, ethers such as diethyl ether and tetrahydrofuran. , Aromatic hydrocarbons such as toluene and xylene.

The 2-aralkyloxypyridines obtained by the production method of the present invention are hydrolyzed in the presence of a catalyst to give 2-hydroxypyridines or tautomers thereof, 2 (1H) -pyridones. It is easily converted (see Reference Examples 6 and 7).

[0034]

INDUSTRIAL APPLICABILITY By the method of the present invention, 2-aralkyloxypyridines can be produced from 2-sulfonylpyridines at high yield and at low cost. The 2-aralkyloxypyridines obtained by this production method are subjected to a hydrogenolysis reaction in the presence of a catalyst to give 2-hydroxypyridines or 2 (1
H) -Pyridones can be easily converted.

[0035]

EXAMPLES The present invention will be described in more detail with reference to Examples and Reference Examples. The present invention is not limited to these.

Reference Example 1 Synthesis of 5-methyl-2-phenylsulfonylpyridine

[0037]

[Chemical 7]

At room temperature, 4-methoxyphenol (5.2
mg, 0.04 mmol) to 1-acetoxyisoprene (17.3 g, 137.1 mmol) and benzenesulfonyl cyanide (14.4 g, 85.7 mmol).
Was added and the mixture was stirred at 80 ° C. for 1 hour. After adding saturated aqueous sodium hydrogen carbonate solution to the reaction solution to make the solution alkaline and allowed to cool to room temperature, the resulting solid was washed twice with water (200 ml), followed by washing with diethyl ether (200 ml) and under reduced pressure. By distilling off the solvent, 5-methyl-2-phenylsulfonylpyridine having the following physical properties was obtained as a white solid (19.0 g, yield 95.2%).

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.40 (s, 3H, -CH 3), 7.52-
7.60 (m, 3H, Ar-H), 7.70 (dd, 1
H, J = 1.8, 8.6 Hz, H-4), 8.03-
8.07 (m, 2H, Ar-H), 8.09 (d, 1
H, J = 8.6 Hz, H-3), 8.49 (d, 1H,
J = 1.8 Hz, H-6) CIMS (m / z): 234 (M ⁺ +1), 169 (M ⁺ )
-SO ₂ ) Melting point: 118 ° C to 120 ° C

Reference Example 2 Synthesis of 5-methyl-2-methylsulfonylpyridine

[0041]

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By using methanesulfonyl cyanide instead of benzenesulfonyl cyanide in Reference Example 1, 5-methyl-2-methylsulfonylpyridine having the following physical properties was obtained as a white solid (yield 69.3%). .

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.47 (s, 3H, —CH ₃ ), 3.21
_{(S, 3H, -SO 2 -CH} 3), 7.75 (dd, 1
H, J = 1.9, 8.0 Hz, H-3), 7.99
(D, 1H, J = 8.0 Hz, H-3), 8.56
(D, 1H, J = 1.9 Hz, H-6) Melting point: 85.5 ° C to 86.5 ° C

Reference Example 3 Synthesis of 4-methyl-2-phenylsulfonylpyridine

[0045]

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By replacing 1-acetoxyisoprene with 1-acetoxy-3-methyl-1,3-butadiene in Reference Example 1, 4-methyl-2-phenylsulfonylpyridine having the following physical properties was obtained as a white solid (yield: Rate 85.0%).

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.47 (s, 3H, —CH ₃ ), 7.25 (d
d, 1H, J = 1.6, 4.8 Hz, H-5), 7.5
3-7.62 (m, 3H, Ar-H), 8.04-8.
08 (m, 2H, Ar-H), 8.10 (d, 1H, J
= 1.6 Hz, H-3), 8.52 (d, 1H, J =
4.8 Hz, H-6) Melting point: 128 ° C to 129 ° C

Reference Example 4 Synthesis of 6-methyl-2-phenylsulfonylpyridine

[0049]

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6-Methyl-2-phenylsulfonylpyridine having the following physical properties was obtained by using 4-acetoxy-1,3-pentadiene instead of 1-acetoxyisoprene in Reference Example 1 as a yellow semi-solid (yield 25. 8
%).

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.74 (s, 3H, —CH ₃ ), 7.35
(Dd, 1H, J = 4.6, 7.4 Hz, H-4),
7.57 (dd, 1H, J = 1.2, 7.4 Hz, H-
3), 7.61-7.64 (m, 3H, Ar-H),
8.00-8.04 (m, 2H, Ar-H), 8.40
(Dd, 1H, J = 1.2, 4.6 Hz, H-5) IR (KBr) ν _max / cm ^-1 : 3075, 1760,
1455, 1315 (SO ₂ ), 1165 (SO ₂ ), 7
30,600

Reference Example 5 Synthesis of 2-phenylsulfonylpyridine

[0053]

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By using 1-acetoxy-1,3-butadiene instead of 1-acetoxyisoprene in Reference Example 1, 2-phenylsulfonylpyridine having the following physical properties was obtained as a white solid (yield 85.5%). It was

¹ H NMR (200 MHz, CDCl ₃ )
δ: 7.48 (dt, 1H, J = 1.8, 7.7H
z, H-4), 7.54-7.62 (m, 3H, Ar
-H), 7.65 (dt, 1H, J = 1.6, 7.7H
z, H-5), 8.05-8.10 (m, 2H, Ar-
H), 8.22 (dd, 1H, J = 1.6, 7.7H
z, H-3), 8.67 (dd, 1H, J = 1.8,
7.7 Hz, H-6) Melting point: 91.5 ° C to 92.5 ° C

Example 1 Synthesis of 2-benzyloxypyridine

[0057]

[Chemical 12]

At room temperature, a solution of 2-phenylsulfonylpyridine (5.0 g, 22.8 mmol) in tetrahydrofuran (300 ml) was added with a solution of sodium benzylate in benzyl alcohol (1.5M, 16.7 ml, 2).
(5.1 mmol) was added, and the mixture was heated under reflux for 1 hr. After allowing the reaction solution to cool to room temperature, the precipitated sodium benzenesulfinate was filtered, and the filtrate was washed with water and saturated saline,
2-Benzyloxypyridine having the following physical property values (3.1 g, 16.8 mmol, yield 73.) was obtained by subjecting the residue to distillation under reduced pressure to distill off benzyl alcohol.
8%) as a colorless liquid.

¹ H NMR (200 MHz, CDCl ₃ )
δ: 5.38 (s, 2H, —CH ₂ —Ph), 6.81
(Dd, 1H, J = 1.8, 7.7 Hz, H-3),
6.92 (dt, 1H, J = 1.8, 7.7 Hz, H-
5), 7.31-7.50 (m, 5H, Ar-H),
7.59 (dt, 1H, J = 1.9, 7.7 Hz, H-
4), 8.18 (dd, 1H, J = 1.9, 7.7H)
z, H-6) EIMS (m / z): 185 (M ⁺ ), 91 (PhCH ₂
⁺ ), 79 (C ₅ H ₅ N ⁺ ) IR (KBr) ν _max / cm ⁻¹ : 3050, 1610,
1570, 1480, 1440

Example 2 Synthesis of 4-methyl-2-benzyloxypyridine

[0061]

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By using 4-methyl-2-methylsulfonylpyridine instead of 2-phenylsulfonylpyridine in Example 1, 4-methyl-2-benzyloxypyridine having the following physical properties was obtained as a colorless liquid (yield 9
1.3%).

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.30 (s, 3H, —CH ₃ ), 5.36 (s,
_{2H, -CH 2 -Ph), 6.63} (d, 1H, J =
0.9 Hz, H-3), 6.72 (dd, 1H, J =
0.9, 5.3 Hz, H-5), 7.30-7.48
(M, 5H, Ar-H), 8.03 (d, 1H, J =
5.3 Hz, H-6) EIMS (m / z): 199 (M ⁺ ), 91 (Ph-C)
H ₂ ⁺ ), 79 (C ₅ H ₅ N ⁺ ) IR (KBr) ν _max / cm ⁻¹ : 3075, 1750,
1620, 1570, 1460, 1425

Reference Example 6 Synthesis of 2 (1H) -pyridone (2-hydroxypyridine)

[0065]

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Under a nitrogen atmosphere, 2-benzyloxypyridine (4.4 g, 23.8 mmol) in methanol (50
ml) solution to palladium-carbon (10% w / w, 440
mg, 10 wt%) was added, and the catalytic hydrogenolysis reaction was carried out at 25 ° C. under 1 atm of hydrogen. After purging the reactor with nitrogen, the catalyst was filtered off and the filtrate was concentrated to give 2 (1H) -pyridone (1.64 g, 1) having the following physical properties.
9.3 mmol, yield 81.1%) was obtained as a white solid.

¹ H NMR (200 MHz, CDCl ₃ )
δ: 6.29 (dt, 1H, J = 1.0, 7.7 Hz,
H-5), 6.59 (dd, 1H, J = 1.0, 7.7)
Hz, H-3), 7.38 (dt, 1H, J = 2.1,
7.7 Hz, H-4), 7.48 (dd, 1H, J =
2.1, 7.7 Hz, H-6), 13.09 (br-
s, 1H, -NH-CO) EIMS (m / z): 95 (M ⁺ ) Melting point: 103 ° C to 105 ° C

Reference Example 7 4-Methyl-2 (1H) -pyridone (2-hydroxy-
4-Methylpyridine)

[0069]

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By using 4-methyl-2-benzyloxypyridine in place of 2-benzyloxypyridine in Reference Example 6, 4-methyl-2 having the following physical properties was obtained.
(1H) -Pyridone was obtained as a white solid (yield 89.8%).

¹ H NMR (200 MHz, CDCl ₃ )
δ: 2.22 (s, 3H, —CH ₃ ), 6.12 (d
d, 1H, J = 1.6, 6.8 Hz, H-5), 6.3
7 (d, 1H, J = 1.6 Hz, H-3), 7.24
(D, 1H, J = 6.8 Hz, H-6), 13.10
(Br-s, 1H, -NH-CO) EIMS (m / z): 109 (M ⁺ ) Melting point: 127 ° C to 131 ° C

Claims (1)

[Claims] 1. The following general formula (I): (In the formula, R ¹ is a lower alkyl group, a cycloalkyl group,
It represents an optionally substituted aryl group or an optionally substituted aralkyl group, and X represents a methyl group or a hydrogen atom. The aralkyl represented by the general formula: R ² OM (in the formula, R ² represents an optionally substituted aralkyl group, and M represents an alkali metal atom or an ammonium group). Characterized by the action of an alcohol salt, the following general formula (II): (Wherein, R ² and X are as defined above.) The preparation of 2-aralkyloxy pyridines represented by.