JPH013170A - New method for producing pyridine derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Application of the Invention] The present invention relates to a novel method for producing pyrinone derivatives, which can be expected to be used as various synthetic intermediates, including pharmaceutical intermediates and agricultural chemical intermediates.

[Prior art]

As for the reaction between pyrinone or gyridine derivatives and Grignard reagents, for example, alkyl or aryl borizines are synthesized by directly reacting pyridine and Grignard reagents (for example, J, A
m, Chem, Soc, 52.2845 (1930
): J,Prakt,Chem,, [2],
135.267 (1932): Chem, Abstr.
,, 30.3420 (1936); Certain magazine, 69.5
1 (1949) etc.).

On the other hand, some of the present inventors have proposed that 2-(or 6-) or 4-substituted IJ resins can be obtained in a short time and in high yield under milder conditions. He discovered a method for synthesizing 2-(or 6-) or 4-alkyl (or aryl) pyridines by reacting a sulfonylpyridine derivative with a Grignard reagent, and previously filed a patent application (Japanese Unexamined Patent Application Publication No. 1989-1988). -280474). There is also an example of synthesizing bipyridines by reacting 2-sulfinylpyrinones with a Grignard reagent (Japanese Patent Laid-Open No. 188370/1983).

[Purpose of the invention]

An object of the present invention is to provide a method for producing a new IJ gin derivative by adding a pyridyl group to a pyridine derivative and a Grignard reagent bond.

[Structure of the invention]

The present invention comprises 2-. 3-also 1U4-iodopyridine,-
Numerical formula [I] RMgX CI ] (wherein, R represents an alkyl group or an alkenyl group, and
represents a haloke 8 atom. ) to produce a 2-23-su1-4-birinol Grignard reagent, which is then used to react with ketones, aldehydes (α, β-unsaturated ketones (or aldehydes)). This is a method for producing pyridine derivatives, which is characterized by adding a pyrinol group to a ketone group, aldehyde group, ester group, or conjugated double bond by reacting the pyridine derivative with a pyridine compound (including pyridine) or an ester.

Examples of R in the Grignard reagent represented by the general formula RMgX used in the present invention include a methyl group, an ethyl group,
Alkyl groups (which may be linear or branched) such as furoyl group, butyl group, anthyl group, hexyl group, octyl group, decyl group, or for example, vinyl group, 1-propenyl group, 2-zorobenyl group group (allyl group), 2-zotenyl group,
Isopro42/14:, 1,3-butadienyl group, 2-
Examples include alkenyl groups such as pentenyl group and 1-hexenyl group, and examples of X include location atoms such as chlorine, bromine, and iodine.

When R in RMgX is, for example, an aryl group or a substituted aryl group such as a phenyl group, tolyl group, xylyl group, biphenyl group, or naphthyl group, a pyridyl Grignard reagent is not generated and the object of the present invention cannot be achieved. do not have. In fact, instead of the 2-,3-Iff 4-iodopyridine used in the present invention, 2-23- or IJ4-chloropyridine 2-. ，
3. Even if -nur;r4-bromopyridine is used, a pyridyl Grignard reagent is not produced, and the object of the present invention cannot be achieved.

The amount of Grignard reagent used in the present invention is:
2-; usually 1 to 1 for 3-M+J4-iodopyridine
Two equivalents is sufficient.

In the present invention, the ketone to which the pyridyl group is added is represented by the formula -II2[n] (wherein RIR-C-
R R2 each independently represents an alkyl group, an aryl group, or an alkoxy-substituted aryl group. Moreover, R and R may form a ring. ) are listed. formula〔
(ii) R 1 and R2 include, for example, a methyl group, an ethyl group, a propyl group, a butyl group, an ethyl group,
Alkyl groups such as hexyl, octyl, and decyl groups (which may be linear or branched); for example, aryl groups such as phenyl, tolyl, xylyl, biphenyl, and naphthyl groups; Examples include alkoxy-substituted aryl groups substituted with a methoxy group, a methoxy group, an ethoxy group, etc., and R1,! : R
2, l! : It may form a ring such as canclohexane, cyclohexene, cyclopentane, cycloRnotene, etc., but is not particularly limited to these, and all ketones commonly used in Grignard reactions can be used. It is possible.

In the present invention, the aldehydes to which the pyridyl group is added include -formula R3-CHO[ll1l] (wherein R3 is an alkyl group, a cycloalkyl group, an aryl group,
Indicates an alkoxy-substituted aryl group, an aralkyl group, or a heterocyclic group. ) are listed.

R3 in formula [l11) is, for example, an alkyl group (linear or branched) such as a methyl group, an ethyl group, a propyl group, a butyl group, a takutyl group, a hexyl group, an octyl group, a decyl group, etc. ), for example, a cycloalkyl group such as a cyclopentyl group or a cyclohexyl group, for example,
Examples include, but are not limited to, phenyl groups, tolyl groups, kylkoxy-substituted aryl groups, aralkyl groups such as benzyl groups and phenethyl groups, and heterocyclic groups such as furyl groups, pyrinol groups, thiazolyl groups, and oxacylyl groups. In the present invention, the α, β-unsaturated ketones (or aldehydes) to which the pyridyl group is added can be any aldehyde commonly used in Grignard reactions. , R, R, and R each independently represent an alkyl group, an aryl group, an alkoxy-substituted aryl group, or a hydrogen atom. It's ox, R4 (or R5) and R
7 may form a ring. ) are listed. R4, R5, R6, R in formula [■]
Examples of 7 include alkyl groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, and hexyl group;
Examples include, but are not limited to, alkoxy-substituted aryl groups substituted with fecy groups, etc., or hydrogen atoms, etc., as well as α, β- All unsaturated ketones (or aldehydes) can be used.

In the present invention, the esters to which the pyrinol group is added have the following formula: R8-C00-R' [V) (wherein R8 and R9 each independently represent an alkyl group or an aryl group). Examples include compounds represented by: R8 and R9 in formula [■] are, for example, alkyl groups such as methyl group, ethyl group, propyl group, butyl group, methyl group, hexyl group, octyl group, and decyl group, for example, phenyl group, tolyl group, etc. Examples thereof include, but are not limited to, aryl groups such as a xylyl group, a biphenyl group, a naphthyl group, and the like, and all esters commonly used in Grignard reactions can be used.

The amount of these ketones, aldehydes, α, β-unsaturated ketones (or aldehydes), or esters used is: 2-. Generally, 1 to 1.5 times equivalent amount is sufficient for 3- or 4-iodopyridine.

The solvents used in the present invention include ethers such as nonprodol, glymes such as diethylene glycol diethyl ether, and diethylene glycol dimethyl ether. It may also be used as

Both the reaction to produce the xyridyl Grignard reagent and the subsequent addition reaction are usually carried out at -20°C to room temperature, but depending on the partner to be added in the addition reaction,
It may also be carried out at higher temperatures, for example 60-70°C.

The reaction time for both the pyrinol Grignard reagent production reaction and the potash addition reaction is normally several minutes to several hours, but in addition reactions, the reaction time varies depending on the target to be added and the reaction temperature. not.

In the present invention, 2-23- or 4 used as a raw material
-Iodopyridine can be prepared according to a conventional method, for example, 2-, 3-
- or 4-aminopyridine is diazotized and then decomposed with potassium iodide, or 2-93- or 4-chloropyridine is easily heated with hydroiodic acid in the presence of sodium iodide for a long period of time. Since it can be obtained in this way, it is sufficient to use the one obtained in this way.

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

That is, for example, under a nitrogen atmosphere, in an aprotic solvent in which 2-13- or 4-iodopyridine is dissolved, at room temperature,
Alternatively, under cooling if necessary, add an aprotic solvent solution containing 1 to 12 equivalents of Grignard reagent and stir for several minutes to several tens of minutes, then add ketones, aldehydes (
(including α, β-unsaturated ketones (or aldehydes))
Or have a beauty salon. After the reaction, the reaction solution is neutralized, extracted with a solvent such as dichloromethane, chloroform, benzene, or ether, and the organic layer is washed with water, dried with a desiccant such as Na 2 SO 4 , and then loaded under reduced pressure. By distilling off the solvent, the desired heterocyclic compound in which a heterocyclic group is added to a ketone group, aldehyde group, ester group, or conjugated double bond is obtained. If necessary, it may be purified and isolated by column chromatography or the like.

Examples and reference examples are listed below, but the present invention is not limited by these examples and reference examples.

〔Example〕

Reference Example 1. Synthesis of 2-Iodopyrinone Hydroiodic acid aqueous solution (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd., content 57
φ) 60ml? 10g (67m) of sodium iodide
A solution of 20 me of mol) dissolved in water was added, and 2-chloropyrinone 209 (176 mm
ol) was added dropwise. After dropping and refluxing for 12 hours,
This was neutralized under water cooling, and the liberated iodine was reduced with acidic sodium sulfite. Extracted 3 times with 70 rnl of ether,
The ether layer was washed with water, dried over magnesium sulfate, the ether was distilled off, and the residue was distilled under reduced pressure to obtain 2-iodopyridine 78.
I got g. Yield 22v.

b, p, 76-77℃ 15.5 Brain Hg 0 Reference Example 2
．． Synthesis of 3-yo1pyridine 3-aminopyrinone4. OE/ (43 m mol) was dissolved in 13 m/ of water, and 19.
4rnl was injected. A solution of 3.0 g (43 mmol) of sodium nitrite dissolved in 10 ml of water was added little by little into the tube at 0 to 4° C. under water cooling, and the mixture was stirred at the same temperature for 10 minutes after the dropwise addition. To this, potassium iodide 8.5.
! A solution of i' (51 mmol) dissolved in 10 ml of water was added dropwise, stirred for 2 hours under water cooling, and further stirred for 12 hours at room temperature. The reaction solution was neutralized with an aqueous solution of caustic soda, and the liberated iodine was decomposed with acidic thorium sulfite, followed by extraction with dichloromethane. The dichloromethane layer was washed with water, dried with magnesium sulfate/rum, and the dichloromethane was distilled off. The residue was separated using a silica gel column [Wako Kelle C-200 (Wako Tsumugi Pharmaceutical Co., Ltd.), eluent: dichloromethane].
Purification yielded 5.99 g of 3-iodopyrinone. Yield 67
%.

m, p, 53°C.

Reference Example 3 Synthesis of 4-iodopyrinone In place of 3-aminopyrinone 10I in Reference Example 2, 4
- Using 40 g of aminogeridine, the reaction and post-treatment were carried out in exactly the same manner as in Reference Example 2, except that 4-iodopyridine was obtained in a yield of 18.

m, p, 99.5°C (decomposition).

Example 1 2-iodopyridine 0.75,! 9 (3,66m
mol) was stirred and dissolved in 35 m, l of THF under a nitrogen stream, and to this was added 8.8 m/! of a THF solution (0.5 M) of C5F12MgBr at room temperature. (1.2 times equivalent) was added and further stirred for 25 minutes. After adding 0.51.9 (1.3 times equivalent) of benzaldehyde to this reaction solution and stirring at room temperature for 3 hours, the reaction solution was neutralized with IN-HCA and extracted with dichloromethane. The dichloromethane layer was washed with water, and the Na
After drying with 2SO4, it was separated and purified using a silica gel column (Wako Kele C-200 (manufactured by Wako Tsumugi Pharmaceutical Co., Ltd.), eluent: dichloromethane) to obtain 0.6:l of phenyl-2-pyridylcarbinol. . Yield 91%.

m, p, 74-75°C.

"H-NMRδppm (CDCt3): 4.64
(IH, broad, OH), 5.74 (I
H, s, CH), 7.01-7.80 (8H, m,
3,4.5-PyrH.

ArH), 8.44-8.70 (IH,m, 6-
PyrH).

Examples 2 to 7゜The benzaldehyde in Example 1 was exposed to the following light 1(a).
, Replaced with each compound in column A of (b), and in the same manner as in Example 1 except for that Table 1 f&) , B of (b)
Each product in the column was obtained as shown in Table 1 (a) and (b).

Example 8゜3-Yaw 1. 'Pirinone 0.75,! 9 (3,6
6 m rnoA') under nitrogen flow, THF 35 rn
Dissolve C2Hs MgB with stirring at room temperature.
8.8 me (1.2 times equivalent) of THF solution (0.5M) of r was added and stirred for further 25 minutes. After adding 0.51 g (1.3 times equivalent) of benzaldehyde to this reaction solution and stirring at room temperature for 6 hours, the reaction solution was neutralized with IN-HCt.
Extracted with dichloromethane. After washing the dichloromethane layer with water and drying with Na 2 SO
Phenyl-3-
Pyridyl carbinol 0.55.9 was obtained. Yield: 81.

'H-NMRδppm (CDCA3): 5.32 (
IH, broad 110H), 5.72 (I Hl
s, CH), 6.98-7.40 (6H, m, 5-
PyrH, ArH), 7.51-7.80 (1, H, m
, 4-PyrH), 8. o 8-8.43 (2H1
m, 2.6-PyrH).

Example 9゜Compound 0X in place of benzaldehyde in Example 8
Using CH=CHCO(O), the reaction and post-treatment were carried out in the same manner as in Example 8 (however, the reaction time was 3 hours), and the compound was obtained in a yield of 79%.

"H-NMRb ppm (cDctρ: 3.73
(2H, d, J=7.2Hz.

CH2), 4.84 (IH, t, J=7.2Hz
, CH), 703~s, o 6 (121(, m,
4.5-PyrH%ArH), 8.10-8.92 (
2H,m, 2.6-PyrH).

Example 10゜ 075 g of 3-yo P pyridine in Example 8 was replaced with 0075.9 g of 4-yo F'' pyridine, except that the reaction and post-treatment were carried out in exactly the same manner as in Example 8, 0.58.94 of phenyl-4-pyridylcarbinol was obtained. Yield: 85.

'H-NMRδ (CDC73): 3.32 (
I H, broad, OH), 5.76 pm (II(, s, CI(), 7.15-7.45 (7H
, m, 3.5-Pyre%ArH), 8.25-8
．． 55 (2H,m, 2.6-PyrH).

Examples 11 and 12゜Penzaldehy 1:'' in Example 10 was replaced with each compound in Column A of Coating 2 below, and in the same manner as in Example 10, each product in Column B in Table 2 was prepared. It's a good deal as shown in Table 2.

〔Effect of the invention〕

As described above, the present invention provides 2-13- or 4-yoP
This product provides a completely new reaction between a gyridine derivative and a Grignard reagent, in which pyridine and a Grignard reagent are reacted to produce a pyridyl Grignard reagent. (including α, β-unsaturated ketones (or aldehydes)) or esters to add a pyrinol group to a ketone group, an aldehyde group, an ester group, or a conjugated double bond. This method has an extremely remarkable effect in that it has made it possible to synthesize various pyridine derivatives that would otherwise have been impossible to synthesize.

Patent applicant: Wako Pure Chemical Industries, Ltd. Procedural strength 1) 1. Mr. F September 22, 1988 1, Indication of the case 1988 1 patent No. 15G301 Cross 2, Name of the invention New method for producing pyridine derivatives 3, Person making the amendment Relationship with the case Patent amount 1 Applicant 541 Address 3-10 Domine-cho, Higashi-ku, Osaka-shi, Osaka Contact information Patent source (Tokyo) 03-270-857] 5. Specification subject to amendment 1! Column for detailed explanation of F's invention.

6. Contents of amendment) column, r6.77 written from the first line to the second line.
(III, s, = C-Ita) J to r6.7
7 (111, s, = C-It tx )J.

) column, line 2 1] r6.80 (Ill, s,
Ilβ-C=O)J to r6.80 (l11.s, lI
β-C-)".

I”d

Claims (1)

[Claims] (1) 2-, 3- or 4-iodopyridine and general formula [
I ] RMgX [ I ] (wherein, R represents an alkyl group or an alkenyl group, and
represents a halogen atom. ) to produce a 2-, 3- or 4-pyridyl Grignard reagent, which is then reacted with ketones, aldehydes (α,β-unsaturated ketones (or aldehydes)). A method for producing a pyridine derivative, which comprises adding a pyridyl group to a ketone group, an aldehyde group, an ester group, or a conjugated double bond by reacting with a pyridine derivative (including pyridine) or an ester.