JPS6169760A - (4-pyridyl)alkanedione compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is 1-7C alkyl or phenyl). EXAMPLE:3-(4-Pyridyl)-2,4-pentadione. USE:Synthetic intermediate for pharmaceuticals and agricultural chemicals. PREPARATION:The compound of formula I is prepared by reacting 4- methylpyridine with the acyl halide of formula II (X is halogen) at a molar ratio of 1-4:1 at -60-+100 deg.C. The reaction product is a mixture of the compound of formula I and a 4-picolylketone compound, and the ratio of both components depends upon the reaction condition. For example, the ratio is 98/2 in the case of reacting 1mol of 4-methylpyridine with 0.4mol of acetyl chloride at a low temperature (-10 deg.C), and is 55/45 in the case of reacting the above compounds at a molar ratio of 1:1 at 40 deg.C.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel (4-pyridyl)alkanedione compound and a method for producing the same. More specifically, (4-pyridyl) represented by the general formula (1): (wherein, R is a C1-7 alkyl group or a phenyl group, and X represents a halogen atom represented by C1 or Br) (4 -Relating to a method for producing a (pyridyl)alkanedione compound.

The (4-pyridyl)alkanedione compound represented by the general formula (1) is a new compound that has not been described in any literature, and is an intermediate for pharmaceutical synthesis. It is a useful compound that is expected to have a variety of uses as an intermediate for the synthesis of various drugs.

For example, by treating the (4-pyridyl)alkanedione compound represented by the general formula (1) with an alkali, the picolylketone compound represented by the general formula (3): (wherein R is the same as above) can be easily converted into a It will be done. This picolyl ketone compound is a compound useful as an intermediate for synthesizing cardiac therapeutic drugs. Therefore, the (4-pyridyl)alkanedione compound represented by the general formula (1) has extremely high llim as an intermediate for such a picolylketone compound.

[Prior Art] Several methods have been known for producing the picolyl ketone compound represented by the general formula (3), but all of them have poor production efficiency.

For example, a method of synthesizing picoline by reacting an alkyl lithium with a cholyl anion and an acyl halide (Collection Czechoslovakia Chemical Community '7-3)
ion Czechoslov, Cheii.

Communs, ) 26.1426 (1961),
With a yield of 45%), the alkyl lithium is sensitive to moisture and oxygen, so it must be handled under an inert gas stream, and the picolyl anion obtained from picoline and sodium is reacted with the acyl halide. The method of synthesis (Japanese Unexamined Patent Publication No. 50-129571) has a low yield of 9%. Alternatively, a method of synthesizing a quaternary salt obtained from pyridine and 2,6-cyclobenzyl bromide with acetone (Justus-Liebigs-Annallen,
Del Hemi - (Justus Liebigs
Ann, chegi,) 600, 176
, yield 57%) requires a reaction to convert the produced N-benzyl-4-pyridylacetone to free 4-pyridylacetone, which makes the process long and complicated, which is economically disadvantageous.

[Problems to be Solved by the Invention] The present invention aims to solve problems such as the low yield of picolyl ketone compounds, the long manufacturing process, and the high manufacturing cost due to the use of special chemicals. It has been done.

[Means for Solving the Problems] The present inventors have conducted extensive research in order to develop an industrially advantageous method for producing the 4-picolylketone compound represented by general formula (3), and have developed a method for producing 4-alkylpyridine. 4- when quaternized
Focusing on the fact that the hydrogen atom at the α-position of the alkyl group becomes active, we investigated acylation of 4-alkylpyridine and found that 4-alkylpyridine can be acylated under mild conditions without using special chemicals as in conventional methods. By simply mixing a pyridine compound and an acyl halide, the (4-pyridyl)alkanedione compound represented by the general formula (1) can be converted into a 4-pyridyl-alkanedione compound easily and in high yield.
He discovered the ability to synthesize picolyl ketone compounds and completed the present invention.

That is, the present invention provides a compound of general formula (1) characterized by reacting a (4-pyridyl)alkanedione compound represented by general formula (1) and 4-methylpyridine with an acyl halide represented by general formula (2). ) The present invention relates to a method for producing a (4-pyridyl)alkanedione compound represented by (4-pyridyl)alkanedione.

[Example] The novel (4-pyridyl)alkanedione compound of the present invention is represented by the general formula (1): (wherein R is the same as above), and specific examples thereof include, for example, 3-(4 -pyridyl)-2,4-pentadione, 2-(4-pyridyl)-1,3-diphenyl-1
, 3-7' lovandione, and the like.

The compound represented by the general formula (1) includes 4-methylpyridine and an acyl halide represented by the general formula (2J: (wherein, X is the same as above),
For example, by reacting with acetyl chloride, acetyl bromide, acetyl iodide, butyroyl chloride, caproyl chloride, etc., (4-pyridyl) represented by the general formula (1) can be produced.
It is obtained as a mixture of an alkanedione compound and a 4-picolylketone compound represented by the general formula (3).

The molar ratio of 4-methylpyridine to the acyl halide represented by the general formula ('2J) and the reaction temperature are not particularly limited, but the ratio of 4-methylpyridine to the acyl halide is 1 to
It is preferable to use 4 times the mole, and the reaction temperature is -60 to
Preferably, the temperature is 100°C. The production ratio of the mixture varies depending on the reaction conditions, for example at low temperature (approximately -1
When 0.4 times the mole of acetyl chloride is added to 4-methylpyridine at 0℃), 3-(4-pyridyl)-2,
The production ratio of 4-pentadione and 1-(4-pyridyl)-2-probanone is about 98/2, and when equal moles of acetyl chloride are added to 4-methylpyridine at about 40°C, the above-mentioned The production ratio is approximately 55/45.

The 4-alkylpyridine dooracyl compound, which is presumed to be a reaction intermediate in this reaction, is originally a solid substance. Therefore, it is preferable to dissolve this intermediate and use a solvent that is inert to the acyl chloride, such as benzene, monochlorobenzene, or chloroform. The solubility of the intermediate increases in the order of benzene, monochlorobenzene, and chloroform, and the yield is also highest in this order when chloroform is used.

The (4-pyridyl)alkanedione compound represented by the general formula (1) of the present invention was added to Na081 and Ha2C.
When treated with an alkaline aqueous solution such as 03, it can easily be reduced to 80%.
The picolyl ketone compound represented by the general formula (3) can be obtained with the above-mentioned high yield.

The alkali used is required to be at least equimolar to the compound represented by the general formula (1). There are no particular limitations on the reaction temperature or reaction time, but it is usually 0-100°C, 2-3°C.
Preferably, it is carried out within a certain period of time.

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

Example 1 4-methylpyridine 11.69 and chloroform 35
After cooling the solution consisting of SF to -20 to -10°C,
While stirring, 7.8 g of acetyl chloride was added dropwise over 1 hour. Thereafter, the temperature was returned to room temperature over 3 hours, and chloroform and unreacted 4-methylpyridine were distilled off and concentrated. Add toluene to the residue and filter it to remove the crystals (4-methylpyridine hydrochloride), then concentrate and distill the filtrate to obtain bp
7.2 g of fraction at 103°C (1a+mtlO) (ap
71-73°C, yield 81% from acetyl chloride).

The obtained distillate was subjected to NHR analysis and elemental analysis, and was confirmed to be 3-(4-pyridyl)-2,4-pentadione.

The analysis results are as follows.

IH-NHR analysis (δ value, opal): 1.91
(6H1s), 7.26 (2H,d), 8.7
0 (2H, d), 16.8 (H, s) Elemental analysis (%): Cue Hn NO2 theoretical value:
C67,7886,26N 7.90 Experimental value: C67
, 22H6, 15N 7.87 NHR analysis was conducted by CDC
Performed with TH3 internal standard method, 608H2 in I3 solvent.

Example 2 18.6 g of 4-methylpyridine and 32 g of chloroform
After the temperature of the solution consisting of g was brought to 40 to 45° C., 15.7 g of acetyl chloride was added dropwise over a period of 10 minutes while stirring. Thereafter, the mixture was heated and stirred at 60°C for 3 hours.

Then, 4-methyl and 18.6 g of lysine were added, and the reaction solution was concentrated by distilling off chloroform. Crystals from the residue (4
-Methylpyridine hydrochloride) was filtered out, and the filtrate was concentrated and distilled to obtain 3.8 g of fraction (3aall(1)) (21.5% yield from acetyl chloride) at bp 100°C, and b
p 128° C. (4.79 fractions of 3a*H(1) (yield 17.4% from acetyl chloride) were obtained.

The obtained R'tB product was subjected to NHR analysis and elemental analysis, and the fraction with a bp of 128°C (3sHQ) was found to be 3-(
4-pyridyl)-2,4-pentadione, bp 101
℃ (3 ml 1 g) fraction is 1-(4-pyridyl)-2-
It was confirmed that it was propanone.

The analysis results are as follows.

bp 128℃ (3#I+1Ill) fraction 11-
NHR analysis (δ value, ppg+): 1.91 (6N,
S), 7.26 (211, d), 8.70 (2H1d
), 16.8 (H, s) Elemental analysis (%): CIOH
ll NO2 theoretical value 2G67.78 86.26N7.
90 Experimental value: C67, 39H6, 24N 7.91b9
Fraction Ill-NOR analysis at 128°C (3 days) (δ value, I) Elm): 2.
05 (3H, s), 3.60 (28SS),
6.95 (2H, d), 8.35 (2H, d) Original 1 g analysis (%): C8H9N.

Theory 1i1: C71,06H6,71N10.36
Experimental value: C71,54H6,68N10.48 NH
R analysis was conducted under the same conditions as in Example 1.

Example 3 11.6 g of 4-methylpyridine and 36 g of chloroform
The solution consisting of iJ was heated to 10° C., and 14.19 g of benzoyl chloride was added dropwise over 1 hour while stirring, followed by stirring at room temperature (25° C.) for 3 hours. Then add 20% to the reaction solution.
After adding 200 g of %NaOH and stirring at room temperature for 2 hours, the reaction solution was separated, the oil layer was concentrated to obtain crystals, and benzene-
Recrystallized from a solvent of 273 m with a volume ratio of 〇-hexane.
8 g of crystals (yield 26.6% from benzoyl chloride) with a temperature of 123 DEG -125 DEG C. were obtained.

The obtained crystals were subjected to NHR analysis and elemental analysis, and 2-(4-pyridyl)-1,3-diphenyl-1,
It was confirmed that it was 3-propanedione.

The analysis results are as follows.

11T NHR analysis (δ value, DI) II): 6.7
(H,S), 1.1~8.4(1211,1,8,5(
2M, d) In the NHR analysis, the solvent was (CD3)
The experiment was carried out under the same conditions as in Example 1 except that 2SO2 was used.

Reference example 1 3-(4-pyridyl)-2,4-pentanedione 1
20% sodium hydroxide (209 g) was added to 7.7 g and 120 g of chloroform, and the mixture was stirred at 30 to 40°C for 3 hours. After that, the oil layer is separated and distilled to give b p 1 (24 to b
12.2 SF (yield 90.4%) was obtained.

[Effects of the Invention] According to the production method of the present invention, a novel (4-pyridyl) alkanedione compound can be obtained efficiently and easily using industrially easily available starting materials.

Furthermore, 4-picolylketone compounds can be easily synthesized from the obtained (4-pyridyl)alkanedione compounds, and 4-picolylketone compounds can be easily synthesized using conventional methods using raw materials that are complicated to handle or methods that are extremely inefficient. Compared to picolyl ketone compounds, 4-picolyl ketone compounds can be obtained at lower cost.

Claims (1)

[Claims] 1 General formula (1): ▲There are numerical formulas, chemical formulas, tables, etc.▼ (1) (In the formula, R represents an alkyl group of C_1_ to_7 or a phenyl group) (4- pyridyl) alkanedione compounds. 2. The compound according to claim 1, which is 3-(4-pyridyl)-2,4-pentadione. 3 2-(4-pyridyl)-1,3-diphenyl-1,
The compound according to claim 1, which is 3-propanedione. 4 4-Methylpyridine and general formula (2): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (2) (In the formula, R is an alkyl group or phenyl group of C_1_-_7, and X represents a halogen atom) The general formula (
1): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(1) (4-pyridyl) (in the formula, R is the same as above)
A method for producing alkanedione compounds. 5. The manufacturing method according to claim 4, wherein X in general formula (2) is a chlorine atom or a bromine atom.