JPS60185764A - Novel process for preparation of pyridine derivative - Google Patents

Abstract

PURPOSE:To produce the titled compound useful as a synthetic intermediate of pharmaceuticals, agricultural chemicals, etc., in high yield, by reacting 2-(or 6-) or 4-substituted sulfonyl-halopyridine derivative with an alkali metal cyanide as a nucleophilic agent. CONSTITUTION:The compound of formula III or formula IV can be produced by reacting the 2-(or 6-) or 4-substituted sulfonyl-halopyridine derivative of formula I or formula II (R<1> and R<2> are alkyl, aralkyl, aryl, or alkyl-substituted aryl; X<1>-X<4> and Y<1>-Y<4> are H, alkyl, aryl, alkoxy, aryloxy, etc.; at least one of X<1>-X<4> and at least one of Y<1>-Y<4> are halogen) with an alkali metal cyanide at 20-70 deg.C, preferably 50-60 deg.C. The alkali metal cyanide is e.g. sodium cyanide, and its amount is 1-2mol per 1mol of the starting compound of formula I or formula II.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel method for producing pyridine derivatives useful as synthetic intermediates for pharmaceuticals, agricultural chemicals, and others. Specifically, the present invention relates to a method for producing a pyridine derivative having a halogen and a cyanide group on the pyridine ring by reacting a compound having a halogen and a substituted sulfonyl group on the pyridine ring with an alkali cyanide.

In general, compounds having halogen and sulfonyl groups on the b/c/rings are used as nucleating agents, such as ami/s, CH300
, CH, S○, CNC), etc., it is known that a substitution reaction with the nucleating agent occurs on the halogen side.
Similarly, it has been confirmed that when a compound having a halogen and a sulfonyl group on the pyridine ring is reacted with a nucleating agent such as a primary amine or a secondary amine, a substitution reaction occurs on the halogen side. There is. The present inventors reacted a compound having a no-rogen and a-substituted tisulfonyl group on the pyridine ring using CN○ as a nucleating agent, and surprisingly, no substitution occurred on the no-rogen side. It was discovered that substitution of sulfonyl groups and/or ano groups occurs selectively and with good yield, and the present invention was completed.

In this way, the reaction point of the viridi/ring differs depending on the type of nucleating agent, and even if a group that easily leaves, such as a nucleating agent, exists on the ring, only another leaving group However, it is completely unexpected that such substitution can be carried out selectively and with good yield in the be/se/ring.

The present invention provides 2-(or 6-) or 4-substituted sulfonyl-
A general formula (wherein X1 to X4 and X1 to X4 are the same as above) is characterized in that a halobyridine/derivative and a shear/alkali fragment reaction can be omitted. ]
This is a novel method for producing 2-(or 6-) or 4-cyano loviridi/derivatives represented by

According to the present invention, even if a easily substituted group such as No. Roge/ is attached to the viridi/ring, the halogen is not substituted, and the sulfonyl group is selectively and in good yield replaced with the ano group. Since it can be, the pyridino ring' second halogen/
A viridi/derivative having both a cyano group and a cyano group can be produced extremely easily and with good yield.

The 2-(or 6-) or 4-1if-substituted sulfonyl- represented by the general formula [I] or [11,:] used in the present invention
In the halopyridi/derivatives, R1 or haR2 is, for example, an alkyl group such as a methyl group, an ethyl group, an isopropyl group, or an n-methyl group, an aralkyl group such as a benzyl group, a phenethyl group, or a phenylpropyl group, a phenyl group, Examples include aryl groups such as naphthyl groups, alkyl-substituted aryl groups substituted with methyl groups, ethyl groups, etc. Also, X1~
X4 and X1 to X4 are, for example, hydrogen or a methyl group, an alkokene group such as an ethyltoxy group, an aryloki/group such as a phenoxy7 group, a thioethoxy group, a naoalkokene group such as a thioethoxy group, a thioaryl such as a thiophenoki7 group, etc. 7 groups of oxy, 42 groups of N, N-methylamino group,
N-monoalkylamino group such as N-ethylamino group, N
, N-dimethylamino group, N,N-dialkylamino group such as N,N-diethylamino group, N-arylamino group such as N-phenylamino group, N,N-n such as N,N-diphenylamino group Arylamino group, N-methyl-N'
Examples include N-alkyl-N'-arylamino groups such as -phenylamino groups, halogens such as chlorine, bromine, and iodine, and any of these may be used, but at least one of X1 to X4 and X1 At least one of ~X4 is halogen.

Examples of the alkali cyanide used in the present invention include sodium cyanide, potassium cyanide, etc., and the amount used is based on the 2-(or 6-) or 4-substituted sulfonyl halobyridine/derivative. Usually 1 to 2 times the mole is sufficient.

The reaction is usually carried out at 20 to 70°C, preferably 5o to 60'
It is carried out under temperature conditions of O.

In addition, reaction time varies depending on temperature conditions, but for example,
When carried out at around 60°C, the time is 8 to 15 hours, and when carried out at room temperature, it is 1.20 to 180 hours.

When carrying out this reaction, the higher the reaction temperature, the shorter the time required for the reaction (for example, if the reaction is carried out at 100°C, the reaction will complete within an hour, but the temperature will be higher). As the reaction progresses, not only the sulfonyl group present at CN◯ but also the halogen substitution occurs, and by-products are produced thereby, which is not very favorable.

The pyridyl sulfo/s with substituents used in the present invention can generally be easily obtained as follows.

For example, 2-chloro-6-methylsulfonyl biridif V
i can be obtained as follows.

That is, 2,6-dichloropyridine and methyl mercaptan are reacted, for example, in an organic solvent such as benzene and in the presence of a phase transfer catalyst (eg, tetra-n-butyl-ammonium bromide) by heating and stirring.

After the reaction, the organic layer was separated, washed with water, dried, and the solvent was distilled off to obtain 2-chloro-6-methylsulfonylviridi/
Obtain quantitatively. Next, by oxidizing this with an oxidizing agent such as hydrogen peroxide, the desired 2-chloro-6-methylsulfonylviridi/ is quantitatively obtained.

The present invention can be easily implemented, for example, as follows.

For example, 1 to 2 equivalents of alkali cyanide are added to 1 equivalent of a halogen-substituted pyridyl sulfone derivative, and N
, N-dimethylformamide, dimethyl sulfoxide,
Add an organic solvent such as hexamethylphosphoramide, acetonate (l/l), and stir well. Keep the reaction solution at 0°C and continue stirring for 10 to 12 hours. After completion of the reaction, remove the solvent (1) by distillation under reduced pressure if necessary. After washing the residue with water, extract several times with an organic solvent such as chloroform. Combine the extracts, and if necessary under reduced pressure, By distilling off the solvent, the desired pyridine derivative is obtained.

Solvents used in the present invention [JAK include formamide, N,N-dimethylformamide (DM I”)]
, N,N-dimethylacetamide, dimethylsulfoxide (DMSO), hexamethylphosphoramide (HM
P A ), acetonitrile, and other solvents that dissolve alkali cyanide are preferred, but other organic solvents, such as alcohols such as methanol, ethanol, n-propanol, and t-butanol, diethyl ether, tetrahydrofuran, anisole, and ethylene glycol Ethers such as diethyl ether, diethyl/glycol dimethyl ether, dioxane, aromatic hydrocarbons such as be/ze/, toluene/, xyleno, acet/, methyl ethyl keto/
, keto/types such as methyl isobutyl ketone, methyl acetate,
Even in solvents in which alkali cyanide has low solubility, such as esters such as ethyl acetate, and halogenated hydrocarbons such as chloroform and dichloromethane, it can be used in combination with a phase transfer catalyst such as quaternary ammonium salts and crown ethers. be able to.

In the present invention, when forming a C-C bond in a viridi/ring, instead of using a halogen/Vi which is generally considered to be easily substituted, the C-C bond can be easily substituted by a reaction accompanying the cleavage of a C-8 bond.
It is characterized in that it can form a bond, and if necessary, it is possible to further extend this C-C bond or replace the remaining halogeno side with another substituent,
The scope of application is extremely wide, and the contribution to this industry is extremely large.

Reference examples and examples are listed below, but the present invention is not limited thereto.

Reference example 1 2.6-dichlorpyridi7 509 (0,338m
ole) and methyl mercaptan (15% aqueous solution) 2
37g (', 0.507 mole) be/ze: /15
Tetra-n-butyla/moniumbuophyto3& (0,0093 mole) was added thereto, and the mixture was refluxed for 6 hours with vigorous stirring. After the reaction is completed, the organic layer is separated, thoroughly washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. By distilling the residue under reduced pressure, colorless transparent EJAiz
=Chlor-6-methylsulfenylpyridine s2.9
g (yield 98%).

bp: 105-107℃/14nnnHgI
R'('neat): ν=2940, 1570
.

1415.1160,795σ-1°NMR (CC44)°5=247 (柘, Cl-13°3'H), 6.60-7.37pr (m, pyrl
-I, 3H).

Elemental analysis: C6H6N5et Actual value (%): C45,2; I-13,8; N 9.0
Calculated value (%): C45,1; H3,8; N 8.8 Reference example 2゜2-10-6-methylsulfonylpyridine-'5
0 g (0,313 mo, le) in acetic acid 3'QQmll'
Dissolved in H2O2 (30%
) After dropping 110 ml (0,971 mole) of an aqueous solution, the mixture was returned to room temperature and stirred overnight. After the reaction is completed, cool the mixture, carefully add saturated aqueous ammonia to make it slightly alkaline, and then extract with dichloromethane. The extracted layer was thoroughly washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By recrystallizing the residue from methanol, 2-Kuguchi-6-methylsulfonylpyridine was obtained.
519 (yield c+3%) is obtained.

m p': 108.5~109.0°C I R (K
Br) Niji = 303'0, 2940, 1570°1
420, 1310 (SO2), 1150 (5
O2).

965.800.750crrL-1°NMR (CDC
13):Σ=3.25 (S, CH3゜3H)
, 7. 3 4 ~8. 0%Jm, 3H,p
YrH).

Elemental analysis: C6I-(6NO2SC/l.

Actual value (%): C37,65; H3,14; N 7.2
9th division value (%): C37,60; H3,15; N 7.
30 Example 1゜, 2-chloro-6-mersulfonyl IJ,) 71
0 g (0,052 n'+ole) and NaCN 5.
Put 12 jJ (0,104 mole) into a reaction container,
Add DMFlooml to this and stir well at 60°C. After stirring for 12 hours, the solvent was distilled off under reduced pressure. Water was added to the residue, extracted three times with chloroform, and chloroform was distilled off from the extract to obtain the desired 2-chloro-6.
-cyanoviridiy 5.5'O,! 9 (yield 76%).

+ np 85-88°C (lit, 86-88°C) Example 2 In Example 1, 2-chloro-6-methylsulfonyl pyridine was substituted for 2-chloro-6-methylsulfonyl pyridine 7 10jj. :/ 10,! i'(0,0486
Example 1. except that mole) was used. In exactly the same manner as above, 5.53 g (yield: 82%) of 2-chloro-6-diatubiridine was obtained.

Example 3 Example 1. In place of 10g of 2-chloro-6-methylsulfonylpyridine, 10g (0,0428 mole of 2-n-butylsulfonyl-6-chlorohyridine)
) in exactly the same manner as in Example 1 except that 2-
Chlor-6-diatubirin 74.33g (yield 73%)
get.

Example 4 Example 1. Example 1 except that 10 g (0,052 mole) of 3-chloro-6-methylsulfonylpyridi was used instead of 710 g of 2-chloro-6-methylsulfonylpyridi. In exactly the same manner as above, 15.78 g (yield: 80%) of 3-chloro-6-diatupyridi was obtained.

m p 82-84°C (lit, 83-84°C)
Example 5 Example 1. 2-chloro-6-methyls/l'
E,,=-ruhiridi 7 10.9, 4-chloro-2-methylsulfonylviridiy 10g (0,052
5.69 g of 4-chloro-2-one anobi, lysine (
Yield: 79%).

++1p 85~86°C (lit, 85~86°C
) Example 6゜2-chloro-6-methylsulfonylpyridine 10 gK
15 g (0,059'mole) of 2-10-6-phenylsulfonylpyridine were used, and N
'aCN 5.12. j? Instead of KCN 7.70
．． ! Using i' (0,118 mole), IA is:
Example 1. The reaction and treatment are carried out in the same manner as above to obtain 2-chloro-6-cyanoviridine 7.79.9 (yield 72%).

Example 7゜2-chloro-6-methylsulfonylhyricine 109K
Example 1 Using 15 g (0.0!56 mole) of ester, 2-hydylsulfonyl-6-ri-ruviridi7
．． The reaction and treatment are carried out in the same manner as above to obtain 2-chloro-6-cyanopyridine 5.74.9 (yield 74%).

Example 8 In place of 10 g of 2-chloro-6-methylsulfonylpyridine, 3,5-dibromo-2-methylsulfonylpyridine l 09 (0,0318 mole) was used, and Example 1. React and treat in the same manner as 2-cyano-3,5-dibromoviridi: / 4.99. Obtain li' (60%).

mp 117-118°C (lit, 117-117
．． 5°C) Example 9゜2-chloro-6-)sulfonylhyricine"Og'
(0,052 mo16) and NaCN 5.12 g (0
, 104 mole) into a reaction vessel, and add DMF1 to this.
00'ml was added, and the mixture was stirred and reacted at room temperature for 162 hours. After the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted three times with chloroform. By distilling off chloroform from the extraction chamber, 6.80 g (yield: 94%) of the desired 2-chloro-6-cyanoviridine is obtained.

Patent applicant: Wako Pure Chemical Industries, Ltd.

Claims (1)

[Claims] (1) General formula [wherein R1 and R2 represent an alkyl group, an alanyl group, an aryl group, an alkyl-substituted aryl group, X1 to X4
, and Y1 to Y4 each represent hydrogen, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, a thioalkoxy group, a thioaryloxy group, an amino group, or a halogen, and at least one of X1 to X4 and Y1
At least one of ~Y4 represents halogen. 2-(or 6-) or 4-substituted sulfonyl-halopyridine derivative represented by the general formula [wherein XI, , X4, and Y1 to Y4 is the same as above. ] 2-(some Vi6-) or 4-cyano-
Method for producing halopyridine derivatives.