JP3272170B2 - Method for producing pyridine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel method for producing a pyridine derivative useful for treating central nervous system diseases such as Alzheimer's disease and Parkinson's disease.

[0002]

2. Description of the Related Art The following formula (IV)

[0003]

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A pyridine derivative represented by the formula (V):

[0005]

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The pyridine derivative (anabaseine) represented by the formula (1) or the anabaseine derivative obtained by using the above compound (IV) or (V) as a synthetic intermediate is obtained from the British Journal of Pharmacology (Brit. J. P.).
harmacol.), 18 , 543 (1962), Agricultural and biological chemistry (Agr. Biol. Che
m.), 26 , 709 (1962), Toxicon, 9 , 23
(1971), Amer. Zoologis
t), 25 , 99 (1985), Drug Development Research, 31 , 127, (1994) or 31 , 135 (1994), International Publication No. WO 92/1530.
No. 6 and International Publication No. 94/05288, etc., and are useful as therapeutic agents for central nervous system diseases such as Alzheimer's disease and Parkinson's disease.

As a method for producing the pyridine derivative represented by the formula (III) and the analogous compound, (1) N-benzoylpipe described in Chem. Ber., 69 , 1082-1085 (1936) A method for producing lidone and nicotinic acid ester using sodium ethoxide, (2)
Acta Chem. Scan
d.), 30B , 93 (1976), a method for producing myosmin using sodium hydride with N-vinylpyrrolidone and nicotinic acid ester, (3) synthetic
Communication (Synth. Commun.), 2 (4), 187-2
00 (1972), a method for producing N-nicotinoylpiperidone using calcium oxide, (4) Tetrahedron Lett., 24 (18), 193
7-1940 (1983), a method for producing bromopyridine and cyclopentenone using n-butyllithium,
(5) Using bromopyridine and N-tert-butyloxycarbonylpiperidone described in Journal of Organic Chemistry (J. Org. Chem.), 54 (1), 228-234 (1989) using n-butyllithium. And (6) a method of condensing N-trimethylsilylpiperidone and a nicotinic acid ester derivative using lithium diisopropylamide described in WO92 / 15306.

[0008]

The inventors of the present invention have studied industrial processes for producing the compounds (IV) and (V), but the processes (1) to (6) have various problems. It became clear that they had. That is, in the production method (1), the temperature rises rapidly during the reaction, it is difficult to control the reaction temperature, and 2-phenyl-3,4,4
5,6-Tetrahydropyridine is produced, which is industrially difficult to remove, and the yield is as low as 20.5%. Therefore, it is not preferable as an industrial production method. The method (2) uses sodium hydride as a reagent, foams violently during the reaction, generates heat and generates hydrogen, which is extremely dangerous and difficult to control the reaction temperature. Requires special equipment and technology. In addition, sodium hydride is generally dispersed in liquid paraffin and is commercially available at about 60% content. However, in the production of compound (III), the number of steps for completely removing liquid paraffin increases, which is not economical.
The production method (3) is very dangerous and is not suitable for an industrial production method because it is melted by an open flame in the presence of calcium oxide.
The processes (4), (5) and (6) require an ultra-low temperature reaction of -70 ° C. or less using n-butyllithium or lithium diisopropylamide, and it is difficult to control the temperature. Therefore, there is a problem that it is not industrially preferable.

The Grignard reagent is generally represented by RMgX, but since the reagent is highly nucleophilic, an alcohol or ketone is generally produced as shown in the following reaction formula. _{R a CH 2 COOR b + RMgX} → R a CH 2 C (OH) R 2 + R a CH 2 C (= O) R ( wherein, showing R, R _a, a R _b is a lower alkyl group.). Therefore, Grignard reagents are not normally used in condensation reactions as shown in the present invention.

At present, there is a demand for the development of a method for industrially producing the pyridine derivatives represented by the formulas (IV) and (V), which is easy to control the temperature, safe and economical.

[0011]

Means for Solving the Problems The present inventors have developed an industrial process for producing pyridine derivatives represented by the formulas (IV) and (V), which is easy to control the temperature, safe and economical. As a result of intensive studies, they have found that the reaction proceeds under very mild conditions with certain Grignard reagents, and have completed the present invention. That is, the present invention provides a compound represented by the general formula (I):

[0012]

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(Wherein R ₁ represents an acyl group or a trialkylsilyl group), and an N-protected piperidone represented by the general formula (II):

[0014]

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(In the formula, R ₂ represents a lower alkyl group.)
A nicotinic acid ester represented by the general formula (III)

[0016]

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(In the formula, X represents a halogen atom, R ₃ and R ₄ may be the same or different lower alkyl groups, or R ₃ and R ₄ may be bonded to each other to form a ring.) Wherein the reaction is carried out in the presence of

[0018]

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A method for producing a pyridine derivative represented by the formula: and a treatment with a base after the acid treatment described above.

[0020]

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A method for producing a pyridine derivative represented by the formula: This manufacturing method is shown in detail in the figure below.

[0022]

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In the above reaction scheme, step (a) comprises:
This is a step of obtaining a compound (VI) by reacting a conventionally known compound (I) with a compound (II) in an appropriate solvent in the presence of a compound represented by the formula (III). During this process, R
_The substituent represented by ₁ means a protecting group which does not participate in the reaction, specifically, an acyl group such as trimethylacetyl, benzoyl or toluoyl group, or a trialkyl group such as trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl group. A silyl group can be exemplified, and a trimethylsilyl group is preferable. The lower alkyl group represented by R ₂ is a linear or branched alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. ,
Examples thereof include a tert-butyl group and the like, preferably a methyl or ethyl group. The lower alkyl group represented by R ₃ and R ₄ is generally a sterically bulky substituent, and is a straight-chain, branched or cyclic alkyl group having 3 to 6 carbon atoms, for example, n-propyl, isopropyl. , N-butyl, isobutyl, sec-butyl, tert-butyl group, pentyl, hexyl, cyclopentyl, cyclohexyl group and the like, and preferably a straight-chain or branched lower alkyl group having 3 to 6 carbon atoms, Preferably it is an isopropyl group. R ₃ and R ₄ may be bonded to each other to form a ring. In this case, the corresponding amine may be, for example, 2,
2,6,6-tetramethylpiperidine and the like can be exemplified.
The halogen atom for X represents chlorine, bromine or iodine, and is preferably a bromine atom.

In this step, the solvent used is not particularly limited as long as it does not adversely affect the reaction.
For example, hydrocarbons such as benzene, toluene, xylene,
Examples thereof include ethers such as diethyl ether, tetrahydrofuran, and dimethoxyethane, and aprotic polar solvents such as N, N-dimethylformamide. Preferred is tetrahydrofuran. The reaction temperature in the reaction between compound (I) and compound (II) is usually -10C to 150C,
The temperature is preferably 0 ° C to 60 ° C, more preferably about room temperature. The reaction time is 1 to 20 hours, preferably 2 to 8 hours. The ratio of each reagent used is determined by the compound (I)
The compound (II) is used in an amount of 0.5 to 2 mol, preferably equimolar, per 1 mol, and the compound (III) is used in an amount of 1 to 2 mol,
Preferably, it proceeds advantageously when the amount is 1.0 to 1.5 mol.

The compound of formula (VI) thus obtained is used in step (b) without isolation or without isolation. When these compounds are used in step (b), usually
The solvent is removed before use, but it may be used as it is. In the above step formula, the step (b) is a step of treating the compound represented by the formula (VI) obtained in the step (a) by adding an acid thereto in a suitable aqueous solvent, followed by deprotection, hydrolysis and decarboxylation. Is a step of obtaining a compound represented by the formula (IV).

The solvent used in this step is not particularly limited as long as it does not adversely affect the reaction. Generally, hydrocarbons such as benzene, toluene and xylene, ethers such as dimethoxyethane, tetrahydrofuran and dioxane, methanol and ethanol , Propanol, isopropanol, and other alcohols and water can be used, and preferably methanol, ethanol, isopropanol, or water.

The acids used include hydrochloric acid, hydrobromic acid,
Inorganic acids such as sulfuric acid and nitric acid, and organic acids such as acetic acid, p-toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid and trifluoroacetic acid can be used, and preferred examples include hydrochloric acid, hydrobromic acid and sulfuric acid. Although the reaction temperature and reaction time are not particularly limited, they are generally 50 ° C.
The temperature is about 1 to 10 hours at about 150 ° C., preferably about 1 to 5 hours at a temperature at which the solvent is refluxed.

The formula (IV) obtained in this step is used in step (c) without isolation.
Step (c) is a step of obtaining compound (V) by treating compound (IV) obtained in step (b) with a base in a suitable aqueous solvent. The base used is not particularly limited as long as it does not adversely affect the reaction.In general, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium carbonate, alkali metal carbonates such as potassium carbonate, sodium phosphate, Examples thereof include alkali metal phosphates such as potassium phosphate, inorganic bases such as aqueous ammonia, anionic ion exchange resins, and the like, and preferred are sodium hydroxide and potassium hydroxide. As the solvent used, the solvent shown in the step (b) can be exemplified. The reaction temperature at this time is not particularly limited.
℃ preferably about room temperature, that of compound to 9-12 of the pH (V) is obtained.

For reference, the compound obtained in step (c)
Compound (IV) shows that it is possible to produce suitable aqueous solvent as shown in step (d), as a salt of the acid used the compound (V) by treatment with an acid. Examples of the solvent and acid used in this case include the solvent and acid shown in step (b). The reaction temperature and reaction time are not particularly limited either, but are generally 0 to 100 ° C for about 1 to 17 hours, preferably 0 to 50 ° C for 1 to 4 hours.

Each compound obtained according to the present invention can be isolated and purified by generally known separation and purification means, specifically, distillation, recrystallization, silica gel column chromatography and the like.

[0031]

Next, the present invention will be described specifically with reference to examples and reference examples. Example 1: 3-nicotinoyl-N-trimethylsilyl-
Synthesis of 2-piperidone bromomagnesium enolate (compound of general formula (VI): R ₁ ; trimethylsilyl group, X; bromine atom) Under argon atmosphere, 15 ml (13.5 mmol) of a 0.9 mol ethylmagnesium bromide solution in tetrahydrofuran was added. In a flask, 1.9 m of diisopropylamine
1 (27 mmol) was added and stirred at room temperature for 24 hours to prepare bromomagnesium diisopropylamide. Then 1.71 g (10 mmol) of N-trimethylsilyl-2-piperidone was added to this solution in 3 m of tetrahydrofuran.
The solution dissolved in 1 l was added dropwise at room temperature, and after stirring for 20 minutes, 1.51 g (10 mmol) of ethyl nicotinate was added dropwise at room temperature, and the mixture was reacted at room temperature for 7 hours. After washing with 3 ml of tetrahydrofuran and drying under reduced pressure, the title compound was obtained as crystals.

IR spectrum (KBr tableting method): ν _max
2950 cm ^-1 , 1700 cm ^-1 NMR spectrum (DMSO, internal standard tetramethylsilane, δ value ppm) 0.2 to 0.4 (9H, s); 1.4 to 1.8 (2H, m); 2.1 to 2.4 (2H, m); 3 .
0-3.2 (2H, m); 7.3-7.4 (1H, m); 7.6-7.8 (1H, m); 8.4-
8.6 (2H, m). Example 2: Synthesis of 3- (5-amino-1-pentanoyl) pyridine dihydrochloride (dihydrochloride of a compound of the formula (IV)) A solution of 0.9 mol ethylmagnesium bromide in tetrahydrofuran (13 ml) under an argon stream. 1.5 mmol) in a flask and 1.9 m of diisopropylamine.
1 (27 mmol) was added and stirred at room temperature for 1 hour to prepare bromomagnesium diisopropylamide. Then 1.71 g (10 mmol) of N-trimethylsilyl-2-piperidone was added to this solution in 3 m of tetrahydrofuran.
The solution dissolved in 1 was added dropwise at room temperature, and after stirring for 20 minutes, 1.51 g (10 mmol) of ethyl nicotinate was added dropwise at room temperature and reacted at room temperature for 7 hours. 6 ml of isopropanol was added to the reaction mixture, and the mixture was stirred for 20 minutes at room temperature, and the reaction solution was concentrated to dryness. 10 ml of concentrated hydrochloric acid was added to the residue, and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and 38 ml of isopropyl alcohol was added while leaving the residue about 1/10. After stirring for 2 hours,
The precipitate was collected by filtration and dried under reduced pressure to give 1.14 g of the title compound (yield 45.4%).

NMR spectrum (DMSO, internal standard tetramethylsilane, δ value ppm) 1.6 to 1.8 (4H, m); 2.7 to 2.9 (2H, m); 3.1 to 3.3 (2H, m);
9-8.0 (1H, m); 8.0-8.3 (2H, b); 8.7-9.4 (3H, m); 9.4-
10.4 (2H, b). Example 3: Synthesis of 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine (compound of formula (V)) In a stream of argon, 15 ml of a 0.9 mol ethylmagnesium bromide solution in tetrahydrofuran (13. 5 mmol) into a flask and 1.9 m of diisopropylamine.
1 (27 mmol) was added and stirred at room temperature for 1 hour to prepare bromomagnesium diisopropylamide. Then 1.71 g (10 mmol) of N-trimethylsilyl-2-piperidone was added to this solution in 3 m of tetrahydrofuran.
The solution dissolved in 1 was added dropwise at room temperature, and after stirring for 20 minutes, 1.51 g (10 mmol) of ethyl nicotinate was added dropwise at room temperature and reacted at room temperature for 7 hours. 6 ml of isopropanol was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 20 minutes, and then concentrated to dryness. 28.5 ml of concentrated hydrochloric acid was added to the residue, and after heating under reflux for 2 hours, the mixture was cooled, and a 10 mol aqueous sodium hydroxide solution was added dropwise at room temperature to adjust the pH to about 10. This aqueous solution was extracted twice with ethyl acetate and dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain 0.9 g (yield: 56.3%) of the title compound.

NMR spectrum (CDCl ₃ , internal standard tetramethylsilane, δ value ppm) 1.5 to 2.0 (4H, m); 2.5 to 2.7 (2H, m); 3.8 to 3.9 (2H, m);
2 to 9.0 (4H, m). Reference Example Synthesis of 3- (5-amino-1-pentanoyl) pyridine dihydrochloride 0.84 g (5.3 mmol) of 2- (3-pyridyl) -3,4,5,6-tetrahydropyridine was added to 18 ml of isopropanol. After dissolving, 0.9 ml of concentrated hydrochloric acid was added, the mixture was stirred at room temperature for 3 hours, and further stirred at 5 ° C. or lower for 2 hours, and the precipitate was collected by filtration and dried under reduced pressure. Yield 0.98 g (73.6% yield).

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ identification code FI A61P 25/00 A61P 25/00 C07B 61/00 300 C07B 61/00 300 (58) Investigated field (Int. Cl. ⁷ , DB Name) C07D 213/00-213/90 B01J 31/00-31/02 C07D 401/00-401/14 A61K 31/44-31/4545 A61P 1/00-43/00 C07B 61/00 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (6)

(57) [Claims] 1. A compound of the general formula (I) (Wherein R ₁ represents an acyl group or a trialkylsilyl group) and an N-protected piperidone represented by the general formula (II): (Wherein R ₂ represents a lower alkyl group), and a nicotinic acid ester represented by the general formula (III): (Wherein X represents a halogen atom, R ₃ and R ₄ represent the same or different lower alkyl groups, or R ₃ and R ₄ may be bonded to each other to form a ring). Reacting and then treating with an acid.
V) A method for producing a pyridine derivative represented by the formula: 2. A compound of the formula (V), which is treated with a base after the acid treatment according to claim 1. A method for producing a pyridine derivative represented by the formula: 3. The method for producing a pyridine derivative according to claim 1, wherein R ₃ and R ₄ in the general formula (III) are a linear or branched lower alkyl group having 3 to 6 carbon atoms. 4. The method for producing a pyridine derivative according to claim 1, wherein R ₃ and R ₄ in the general formula (III) are isopropyl groups. 5. R ₁ in the general formula (I) is a trialkylsilyl group, R ₂ in the general formula (II) is an ethyl group, X in the general formula (III) is a bromine atom,
_{3. The} method for producing a pyridine derivative according to claim 1, wherein R ₃ and R ₄ are isopropyl groups. 6. R ₁ in the general formula (I) is a trimethylsilyl group, R ₂ in the general formula (II) is an ethyl group, X in the general formula (III) is a bromine atom,
_{3. The} method for producing a pyridine derivative according to claim 1, wherein ₃ and R ₄ are isopropyl groups.