JPH0959254A - Production of 2-hydroxypyridines and/or 2(1h)-pyridones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject compounds which are synthetic intermediates for medicines and agrochemicals from aralkyloxypyridines prepared by reacting a sulfonylpyridine with an alkali metallic salt of an aralkyl alcohol in high yield at a low cost. SOLUTION: The hydrogenolysis reaction of (A) 2-aralkyloxypyridines of formula I (R<1> is an aralkyl; X is methyl or H) is carried out in the presence of a catalyst to provide (B) 2-hydroxypyridines of formula II and/or (C) 2(1H)- pyridones of formula III. Furthermore, the component (A) can be prepared by reacting 2-sulfonylpyridine with a salt of an aralkyl alcohol. For example, Pd-C is added to a solution of 2-benzyloxypyridine in methanol in a nitrogen atmosphere and the catalytic hydrogenolysis reaction is carried out at 25 deg.C under atmospheric pressure to synthesize 2(1H)-pyridone (2-hydroxypyridine) as the component (C).

Description

Detailed Description of the Invention

[0001]

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

[0002]

BACKGROUND OF THE INVENTION 2-Hydroxypyridines and / or 2 (1H) useful as intermediates for the production of pharmaceuticals and agricultural chemicals.
-General methods for producing pyridones include a method of deriving from substituted pyridines and a method of synthesizing a 2-hydroxypyridine ring or a 2 (1H) -pyridone ring.

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 by sodium trimethylsilanethiolate (Heterocycles).
s, 1993, p. 323).
In these methods, 2-chloropyridines, which are raw materials, are prepared by converting pyridines into tetrahedron letters (Tetra)
hedron Letters, 1971, 2807
Page) pyridine obtained by oxidation by the method described in
Oxides were added to the chemistry of Heterocyclic Compounds (Chemistry of Het).
It can be obtained by chlorination according to the method described in Erocyclic Compounds, Vol. 14, Supplementary Volume 2, 1974). Therefore, 2-hydroxypyridines or 2 (1
Since (H) -pyridones are produced from pyridines through three steps, the overall yield is low, and the waste liquid treatment of phosphorus oxychloride used for chlorination is essential.

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.

[0008]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a method for producing 2-hydroxypyridines or 2 (1H) -pyridones useful as an intermediate for producing pharmaceuticals and agricultural chemicals.

[0009]

As a result of various studies to achieve the above object, the present inventors have found that 2-hydroxypyridines and / or 2 (1H) -pyridones are They have found that they can be easily produced from aralkyloxypyridines in high yield, and completed the present invention.

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

[0011]

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(Wherein R ¹ represents an optionally substituted aralkyl group, X represents a methyl group or a hydrogen atom), and 2-aralkyloxypyridines are hydrolyzed in the presence of a catalyst. The following general formula (II), characterized in that

[0013]

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(Wherein, X is the same as above) and / or the following general formula (III):

[Chemical 6] (In the formula, X is the same as above.) 2 (1
H) -pyridones.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION

In the above general formula, examples of the aralkyl group include a benzyl group and a phenethyl 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, It may be appropriately substituted with a halogen atom such as a chlorine atom or a bromine atom, a cyano group or a nitro group.

A method for producing 2-hydroxypyridines and / or tautomers of the present invention, 2 (1H) -pyridones, is shown in the following scheme.

[0018]

[Chemical 7]

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

The catalyst may be any catalyst used in a catalytic hydrogenolysis reaction, for example, palladium-carbon,
Palladium black, a palladium catalyst such as palladium-barium sulfate, a platinum catalyst such as platinum oxide, or a transition metal catalyst such as a nickel catalyst such as Raney nickel.

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, cyclohexane, alicyclic hydrocarbons such as cyclooctane, ethers such as diethyl ether and tetrahydrofuran, toluene, Examples thereof include aromatic hydrocarbons such as xylene, lower alcohols such as methanol and propanol, and esters such as methyl acetate and ethyl butyrate.

The reaction is carried out by continuously or sequentially adding hydrogen. The hydrogen pressure is usually in the range of atmospheric pressure to 20 atm, preferably atmospheric pressure to 2 atm.

The reaction is generally carried out at 20 ° C to 100 ° C, more preferably at 20 ° C to 40 ° C.

In the production method of the present invention, 2-aralkyloxypyridines represented by the general formula (I), which are raw materials, are the Journal of Chemical Society Perkin Transaction II (Journal of C).
chemical Society Perkin Tr
action II, 1988, No. 10, 279.
It can be produced by the method described on page 1) or the following method (see Reference Examples 6 and 7).

[0025]

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(In the formula, R ² represents a lower alkyl group, a cycloalkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, and R ¹ and X are the same as defined above. is there.)

In the above general formula, the lower alkyl group is
Examples thereof 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. Examples of the aralkyl group include benzyl group and phenethyl group.

The 2-aralkyloxypyridine represented by the above general formula (I) can be produced by reacting the salt of aralkyl alcohol with the 2-sulfonylpyridine represented by the above general formula (IV).

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 alcohol salt include an alkali metal salt, an alkaline earth metal salt, or an ammonium salt,
An alkali metal salt is preferably used, and a sodium salt is more preferably used.

Examples of the alkali metal salt include lithium salt, sodium salt and potassium salt, and examples of the alkaline earth metal salt include magnesium salt and calcium salt. As the ammonium salt, an ammonium salt, an alkylammonium salt such as an ethylammonium salt, a dialkylammonium salt such as a di-n-butylammonium salt, a trialkylammonium salt such as a trimethylammonium salt, and a tetra-n-butylammonium salt. Tetraalkylammonium salt, aralkylammonium salt such as benzylammonium salt, diaralkylammonium salt such as dibenzylammonium salt, aralkylalkylammonium salt such as benzylmethylammonium salt, aralkyldialkylammonium salt such as benzyldimethylammonium salt, and Aralkyltrialkylammonium salts such as benzyltrimethylammonium salts are mentioned.

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 starting material (IV) is a synthesis (S
Synthesis, 1989, p. 623) or the following reaction (see Reference Examples 1 to 5).

[0033]

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(In the formula, R ¹ , R ² , and X are the same as above, and R ³ is an acyloxy group, a lower alkylthio group,
It represents 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 (V) which is a starting material is prepared from the corresponding sodium sulfinate by Organic Synthesis (Vol. 57, 88).
Page, 1977). The other starting material, compound (VI), can be obtained, for example, from Industrial and Engineering Chemistry (I).
ndustrial and Engineering
Chemistry, Vol. 41, No. 12, page 2920,
1949).

The reaction between the sulfonyl cyanide represented by the general formula (V) and the diene represented by the general formula (VI) 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 can be converted into 2-hydroxypyridines and / or 2 (1) by a hydrogenolysis reaction in the presence of a catalyst.
H) -Pyridones are easily converted.

[0040]

INDUSTRIAL APPLICABILITY By the method of the present invention, 2-hydroxypyridines and / or 2 (1H) -pyridones, which are intermediates for producing pharmaceuticals and agricultural chemicals, can be produced from 2-aralkyloxypyridines in high yield and at low cost. It can be manufactured. The 2-aralkyloxypyridines, which are the starting material for this method, can be easily produced by reacting 2-sulfonylpyridine with an alkali metal salt of aralkyl alcohol.

[0041]

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

[0043]

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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

[0047]

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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-4), 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

[0051]

[Chemical 12]

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

[0055]

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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 to give 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

[0059]

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By using 1-acetoxy-1,3-butadiene in place 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

Reference Example 6 Synthesis of 2-benzyloxypyridine

[0063]

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At room temperature, a solution of 2-phenylsulfonylpyridine (5.0 g, 22.8 mmol) in tetrahydrofuran (300 ml) was added to a solution of sodium benzylate in benzyl alcohol (1.5 M, 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

Reference Example 7 Synthesis of 4-methyl-2-benzyloxypyridine

[0067]

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By using 4-methyl-2-methylsulfonylpyridine instead of 2-phenylsulfonylpyridine in Reference Example 6, 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

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

[0071]

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Under a nitrogen atmosphere, 2-benzyloxypyridine (4.4 g, 23.8 mmol) in methanol (50 g) was added.
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 normal pressure. After replacing the reactor with nitrogen, the catalyst was filtered off, and the filtrate was concentrated to give 2 (1H) -pyridone (1.64 g, 19.3 m) having the following physical properties.
mol, 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

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

[0075]

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By using 4-methyl-2-benzyloxypyridine instead of 2-benzyloxypyridine in Example 1, 4-methyl-2 having the following physical properties is 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 represents an optionally substituted aralkyl group.
X represents a methyl group or a hydrogen atom. 2-)
A general formula (II) below, characterized in that aralkyloxypyridines are subjected to a hydrogenolysis reaction in the presence of a catalyst. (In the formula, X is the same as above.) And / or a 2-hydroxypyridine compound represented by the following general formula (III): (In the formula, X is the same as above.) 2 (1
H) -Method for producing pyridones.