JP2001072666A - Production of 2-(p-alkylphenyl)pyridine compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To produce the subject compound which is useful as an intermediate for synthesizing 4-(pyrdin-2-yl)benzaldehyde that is an intermediate for an anti- HIV medicine by adding manganese dioxide and trimethylchlorosilane to an ether-based organic solvent and then reacting a specific p-alkylphenylmagnesium halide with a specified halopyridine. SOLUTION: This method for producing a 2-(p-alkylphenyl)pyridine compound of formula III comprises adding manganese dioxide and trimethylchlorosilane to an ether-based organic solvent or adding manganese chloride to the ether- based organic solvent and then reacting a p-alkylphenylmagnesium halide of formula I (R is a 1 to 4C alkyl; X is a halogen) with a 2-halopyridine of formula II (Y is a halogen). The compound of formula I is preferably used in an amount of 0.6 to 1.5 moles per mole of the compound of formula II, and the manganese dioxide is preferably used in an amount of 0.02 to 0.2 mole. The trimethylchlorosilane is preferably used in an amount of 3 to 5 moles per mole of the manganese dioxide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a method for producing a 2- (p-alkylphenyl) pyridine compound. Specifically, in the presence of a compound species obtained from manganese dioxide and trimethylchlorosilane, or in the presence of manganese chloride, in an ether-based organic solvent, reacting p-alkylphenylmagnesium halide with 2-halopyridine. To a method for producing a 2- (p-alkylphenyl) pyridine compound.

[0002]

2. Description of the Related Art A 2- (p-alkylphenyl) pyridine compound is a pharmaceutical intermediate, for example, an intermediate of an anti-HIV drug (A) represented by the following formula described in WO 97/40029, 4-(-). It is a compound useful as an intermediate in the synthesis of pyridin-2-yl) benzaldehyde.

[0003]

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JP-A-3-95157 discloses a butenoic acid derivative as a therapeutic, preventive and ameliorating agent for ischemic heart disease. The butenoic acid derivative is 4- (pyridin-2-yl) benzaldehyde. Has been synthesized through. As a method for synthesizing the above 4- (pyridin-2-yl) benzaldehyde, for example, a method of brominating 2- (p-tolyl) pyridine and reacting it with hexamine is exemplified.

A method for producing a 2-phenylpyridine compound is described in, for example, Heterocycles, vol. 1
8, 117-122 (1982) shows that the reaction of 2-bromopyridine with phenyl zinc chloride is Pd (PP
The h _{3) 4} proceeds as a catalyst, 2-phenyl-pyridine 8
It is stated that it is obtained in a yield of 9%. Also, 2
As a method for producing a-(p-alkylphenyl) pyridine compound, for example, Tetrahedron Letter
s, vol. 36, no. 50, 9085-9088
(1995) added Pd via an organotin compound.
(PPh _{3) 4} 2-aryl pyridine compound as a catalyst, for example, 2-(p-tolyl) pyridine is described to be obtained at a yield of 60%. Also, Tetrah
edron, vol. 54, 1289-1298 (19
98) also describes that a 2-arylpyridine compound can be obtained by a reaction of an electrochemically obtained aryl zinc halide with 2-halopyridine using a nickel complex catalyst. However, these known 2- (p
Since all the catalysts used in the method for producing a (-alkylphenyl) pyridine compound are expensive, the development of a method for producing a 2- (p-alkylphenyl) pyridine compound which can be produced inexpensively, simply and industrially has been developed. Was desired.

[0006]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a method for producing a 2- (p-alkylphenyl) pyridine compound at low cost, easily and industrially.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies to achieve the above object, and as a result, after adding manganese dioxide and trimethylchlorosilane to an ether-based organic solvent, or After addition, p-
By reacting an alkylphenylmagnesium halide with a 2-halopyridine, a method for inexpensively, conveniently and industrially producing a 2- (p-alkylphenyl) pyridine compound has been found, and the present invention has been completed.

That is, according to the present invention, after adding manganese dioxide and trimethylchlorosilane or adding manganese chloride to an ether organic solvent, the formula (1)

[0009]

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Wherein R represents an alkyl group having 1 to 4 carbon atoms and X represents a halogen atom, and p-alkylphenylmagnesium halide represented by the following formula:

[0011]

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Wherein Y represents a halogen atom, wherein the compound is reacted with a 2-halopyridine represented by the following formula (3):

[0013]

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(Wherein R has the same meaning as described above), and a method for producing a 2- (p-alkylphenyl) pyridine compound represented by the formula: wherein X and Y are both chlorine atoms, and R is a methyl group. The present invention relates to a method for producing the above-mentioned 2- (p-alkylphenyl) pyridine compound.

[0015]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described in detail below. The alkyl group having 1 to 4 carbon atoms in R may be linear or branched, and includes, for example, methyl, ethyl, propyl, isopropyl, butyl, and tert-butyl, and preferably methyl.

As the halogen atom for X, chlorine,
Bromine, preferably chlorine.

As the halogen atom for Y, chlorine,
Bromine, preferably chlorine.

The production of the 2- (p-alkylphenyl) pyridine compound is carried out by adding manganese dioxide and trimethylchlorosilane or adding manganese chloride to an ether organic solvent, and then adding or dividing the 2-halopyridine to the ether organic solvent. And then adding a solution of a p-alkylphenylmagnesium halide in an ether organic solvent to allow the reaction to proceed. p-
The solution of the alkylphenylmagnesium halide in the ether organic solvent is preferably added dropwise.

The 2-halopyridine includes 2-chloropyridine and 2-bromopyridine, and preferably 2-chloropyridine from the viewpoint of economy.

As the p-alkylphenyl magnesium halide, for example, p-tolyl magnesium chloride,
p-tolylmagnesium bromide, p-ethylphenylmagnesium chloride, p-ethylphenylmagnesium bromide, p-propylphenylmagnesium chloride, p-propylphenylmagnesium bromide, p-butylphenylmagnesium chloride, p
-Butylphenylmagnesium bromide and the like, and preferably p-tolylmagnesium chloride.

The preparation of the p-alkylphenylmagnesium halide can be carried out in the same manner as the preparation of a usual Grignard reagent. The alkyl and halogen atoms in the p-alkylhalobenzene used for the preparation are the same as the alkyl and halogen atoms in the p-alkylphenylmagnesium halide.

The p-alkylphenylmagnesium halide is used in an amount of 0.5 to 2.0 per mole of 2-halopyridine.
Mol, preferably 0.6 to 1.5 mol.

When manganese dioxide and trimethylchlorosilane are used as the catalyst, the amount of manganese dioxide used is 0.01 to 0.3 with respect to 1 mol of 2-halopyridine.
It is desirably about mol, preferably about 0.02 to 0.2 mol, from the viewpoint of economy and reactivity. Also,
The amount of trimethylchlorosilane used is manganese dioxide 1
It is desirable that the molar ratio be about 3 to 5 times the molar amount.

When manganese chloride is used alone as a catalyst, it is used in an amount of 0.01 to 0.1 mol per mol of 2-halopyridine.
It is desirable to use about 3 mol, preferably about 0.02 to 0.2 mol, from the viewpoint of economy and reactivity.

Examples of the ether-based organic solvent include tetrahydrofuran (THF), and a mixed solvent with another organic solvent may be used as long as the reaction is not inhibited. The other organic solvent is a solvent having no reactivity with the Grignard reagent, and examples thereof include toluene.

The amount of the ether-based organic solvent to be used is not particularly limited, but is preferably 2.5 to 10 times the weight of 2-halopyridine.

[0027] The reaction temperature is preferably from 0 ° C to the boiling point of the solvent, more preferably from 20 ° C to 75 ° C.

The atmosphere for the reaction is not particularly limited, and for example, an inert gas atmosphere such as a nitrogen gas is preferable.

The reaction time varies depending on the reaction conditions such as the reaction temperature, and is usually about 2 to 10 hours.

The completion of the reaction can be confirmed by analysis using, for example, high performance liquid chromatography.

The desired 2- (p-alkylphenyl)
The pyridine compound can be isolated by washing, extraction, filtration, concentration, distillation, crystallization, and other operations.
It can be isolated as a (p-alkylphenyl) pyridine compound or a salt thereof.

The 2- (p-alkylphenyl) pyridine compound obtained by the method of the present invention is described in WO 97/400.
The compound is useful as an intermediate for the synthesis of 4- (pyridin-2-yl) benzaldehyde, which is an intermediate of the anti-HIV drug (A) described in No. 29. For example, 2- (p-tolyl)
By brominating pyridine and reacting with hexamine, 4- (pyridin-2-yl) benzaldehyde is obtained.

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to only these examples.

[0034]

EXAMPLE 1 213 g of THF, 5.43 g of manganese dioxide and 27.1 g of trimethylchlorosilane were placed in a 2 liter flask.
Was added and left at room temperature for 12 hours, and 70.85 g of 2-chloropyridine was added. 98.8 p-chlorotoluene
g of p-tolyl magnesium chloride prepared from
389.5 g of the HF solution was added dropwise to the flask at 48 to 51 ° C. over 8 hours. After the completion of the reaction, a part of THF was distilled off under reduced pressure at 40 to 50 ° C., and 282 g of toluene was added.
Was added, and 550 ml of water was added dropwise.

[0035] 100 g of ammonium chloride was added to the system, and the mixture was stirred, and insoluble materials were filtered. Separate the filtrate, remove the aqueous layer,
300 ml of water and 53.0 g of concentrated hydrochloric acid were added to the organic layer, and the mixture was stirred and separated. The organic layer and the aqueous layer were separated. 150 ml of water and 4.0 g of concentrated hydrochloric acid were added to the organic layer, and the mixture was stirred and allowed to stand still. The organic layer was discarded. The aqueous layer was combined with the previous aqueous layer, and 87.7 g of toluene and 25% caustic soda water were added thereto. Was made alkaline. A part of insolubles generated was removed by filtration, and the filtrate was separated to remove the aqueous layer and concentrate the organic layer. The concentrate contained 2- (p-tolyl) pyridine corresponding to 75 mol% with respect to 2-chloropyridine based on the analysis by HPLC. The desired 2-
(P-tolyl) pyridine as a highly pure liquid in a yield of 71
%. IR (neat) cm ^-1 : 1615,1588,1563,1515,1467,1433,1299,
1185,1153,1111,989,830,773 ¹ H-NMR (CDCl ₃ ) δ: 2.40 (s, 3H), 7.19 (m, 1H), 7.28
(d, J = 8.0Hz, 2H), 7.70 (d, J = 1.6Hz, 1H), 7.72 (m, 1
H), 7.89 (d, J = 8.0Hz, 2H), 8.67 (dt, J = 2.0Hz, 1.2Hz,
1H) bp: 120-140 ℃ / 5-10mmHg

Example 2 213 g of THF, 6.3 g of manganese chloride (crushed product) and 70 g of 2-chloropyridine were placed in a 1-liter flask.
85 g were added. 330 g of a THF solution of p-tolylmagnesium chloride prepared from 104.3 g of p-chlorotoluene was added dropwise to the flask at 47 to 58 ° C. over 7 hours. After completion of the reaction, TH
After distilling off F, 282 g of toluene was added and 550 g of water was added.
ml was added dropwise.

100 g of ammonium chloride is added to the system,
The mixture was stirred, and the insoluble matter was filtered. The filtrate was separated, the aqueous layer was removed, 300 ml of water and 53.0 g of concentrated hydrochloric acid were added to the organic layer, and the mixture was stirred and separated to separate the organic layer and the aqueous layer. 150 ml of water and 4.0 g of concentrated hydrochloric acid were added to the organic layer, and the mixture was stirred and allowed to stand still for separation. The organic layer was discarded, the aqueous layer was combined with the previous aqueous layer, and 87.7 g of toluene and 25% caustic soda water were added. The layer was made alkaline. Partially formed insolubles were removed by filtration, the filtrate was separated to remove the aqueous layer, and the organic layer was concentrated. From the analytical value by HPLC in the concentrate, 2- (p-
(Tril) pyridine. The desired 2- (p-tolyl) pyridine was obtained as a highly pure liquid at a yield of 56% by distillation under reduced pressure. The obtained 2- (p-tolyl)
Various spectral data of pyridine were the same as in Example 1.

Example 3 227.1 g of THF, 20.1 g of manganese chloride (anhydrous pulverized product) and 227.1 g of 2-chloropyridine were added into a 2 liter flask. p-chlorotoluene 15
483.4 g of a THF solution of p-tolyl magnesium chloride prepared from 1.9 g was added to the above flask in an amount of 58 to 6 g.
It was added dropwise at 2 ° C. over 4 hours.

After completion of the reaction, the reaction solution was poured into another 2 liter flask containing 1 liter of water, and the pH of the aqueous layer was adjusted to 4 with concentrated hydrochloric acid. The temperature was raised to about 55 ° C., and after standing liquid separation, the aqueous layer was discarded. The amount of 2-chloropyridine corresponding to 47.8% of the added amount was recovered as a THF solution by distilling the organic layer. Further, 174.8 g of a fraction of 2- (p-tolyl) pyridine partially containing 4,4′-dimethylbiphenyl was obtained. The 2- (p-tolyl) pyridine fraction was purified by acid-alkali (after dissolving 2- (p-tolyl) pyridine in acidic water and removing 4,4′-dimethylbiphenyl, a neutral substance, from the organic layer. And the aqueous layer was neutralized to purify 2- (p-tolyl) pyridine) to obtain 157.3 g of 2- (p-tolyl) pyridine (yield: 2-chloropyridine consumed) For 8
8.9%). Various spectral data of the obtained 2- (p-tolyl) pyridine were the same as in Example 1.

[0040]

According to the present invention, a 2- (p-alkylphenyl) pyridine compound can be produced inexpensively, easily and industrially. The obtained 2- (p-alkylphenyl) pyridine compound is useful as an intermediate for the synthesis of 4- (pyridin-2-yl) benzaldehyde, which is an intermediate of the anti-HIV drug (A) described in WO97 / 40029. For example, by brominating 2- (p-tolyl) pyridine and reacting it with hexamine, 4-
(Pyridin-2-yl) benzaldehyde is obtained.
As a result, a pharmaceutical intermediate such as an anti-HIV drug can be easily provided at low cost.

 ──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Kiyoshi Sugi 3-1-1, Utajima, Nishiyodogawa-ku, Osaka Sumitomo FineChem Co., Ltd. (72) Inventor Tetsuya Shintaku 3-1-1, Utajima, Nishiyodogawa-ku, Osaka-shi No. Sumika Finechem Co., Ltd. (72) Inventor Nobutoshi Itaya 3-1-1, Utajima, Nishiyodogawa-ku, Osaka Sumitomo Finechem Co., Ltd. F-term (reference) 4C055 AA01 BA02 BA05 BA08 CA01 DA01 FA03 FA31 FA37

Claims (2)

[Claims] After adding manganese dioxide and trimethylchlorosilane or adding manganese chloride to an ether-based organic solvent, a compound of the formula (1) is obtained. (Wherein, R represents an alkyl group having 1 to 4 carbon atoms, and X represents a halogen atom), and a p-alkylphenylmagnesium halide represented by the following formula: (Wherein, Y represents a halogen atom), characterized by reacting with 2-halopyridine represented by the following formula (3): (Wherein, R has the same meaning as described above).
-Alkylphenyl) pyridine compounds. 2. X and Y are both chlorine atoms;
Is a methyl group. 2. The method for producing a 2- (p-alkylphenyl) pyridine compound according to claim 1, wherein