JPH02134364A - Production of 3-(4-ethoxy-2-aminophenyl)pyridine - Google Patents

Abstract

PURPOSE:To produce the title compound in high yield, industrially and advantageously by using one of 4-mesyloxy-2-nitrotoluene, 3-(2,4-dinitrophenyl)pyridine and 3-(4-ethoxyphenyl)pyridine as a raw material. CONSTITUTION:A compound shown by formula II is made into an ethyl ether compound, which is then reacted with pyrrolidine and N, N-dimethylformamide and then subjected to pyridine ring formation reaction to give a compound shown by formula V, which is reduced to give the title compound shown by formula I. A compound shown by formula VI is partially reduced to give a compound shown by formula VII, which is subjected to diazo hydrolysis reaction to give a compound shown by formula VIII. This compound is further ethyl etherified to give a compound shown by formula V, which is reduced to give the compound shown by formula I. A compound shown by formula IX is brominated to give a compound shown by formula X, which is further reacted with benzylamine to give a compound shown by formula XI, which is finally debenzylated to give the compound shown by formula I.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention provides 6-(4-ethoxy-2-aminophenyl)
This article relates to a new method for producing pyridine.

The target compound of the present invention is a compound useful as an intermediate for manufacturing pharmaceuticals, pharmaceuticals, liquid crystals, and the like.

[Conventional technology]

5-(4-Ethoxy-2-aminophenyl)pyridine is produced by using 4-methoxy-2-nitroaniline as a raw material, bonding pyridine through a pseudo bombardment reaction, and converting the methoxy group into an ethoxy group. It can be produced by converting the compound into 2-nitrophenyl)pyridine and then reducing it. (J, Chem, Sac, 194L
406-415). However, this method is not suitable for industrial production because positional isomers of pyridine are produced and separation is difficult, resinous substances are produced, and the yield is low. 5-(4-Ethoxy-2-nitrophenyl)pyridine can be produced in a very short process, for example, by reacting diethyl-(6-pyridyl)borane in the presence of a 4-bromo-6-nitrophenitol halide catalyst. However, this method has problems such as the raw materials and catalyst are expensive, the catalyst must be handled carefully under a nitrogen or argon stream, and the conditions can greatly affect the yield, making it difficult to use as an industrial method. It is difficult to apply it as

[Problem that the invention seeks to solve]

The present invention provides 6-(4-ethoxy-2-aminophenyl)
An object of the present invention is to provide an industrially advantageous method for producing pyridine.

[Means for solving problems]

The present inventors investigated various methods for producing 3-(4-ethoxy-2-aminophenyl)pyridine, and as a result, discovered a method that can be produced advantageously with a higher yield than known methods,
The invention has been completed.

This invention +! , 4-mesyloxy-2-nitrotoluene (
II) is ethyl etherified followed by pyrrolidine and N
, N-dimethylformamide dimethyl acetal, and the resulting 1-(4-ethoxy-2-nitrostyryl)pyrrolidine GV) oviridine ring-forming reaction is performed to form 6
-(4-ethoxy-2-nitrophenyl)pyridine (V
L and pear, characterized by reducing this,! l −
(4-ethoxy-2-aminophenyl)pyridine (Il
This is the manufacturing method.

The present invention also provides a method for partially reducing 5-(2,4-dinitrophenyl)pyridine (V
3-(4-hydroxy-2-
Nitropheni/l/)? This is a method for producing compound (1) by ethyl etherifying 'lysine to form a compound ('i'l), which is then reduced.

The present invention further provides bromination of 6-(4-ethoxyphenyl)pyridine (2) to give (6-bromo-4-ethoxyphenyl)pyridine (2)), which is reacted with benzylamine in the presence of sodium amide. 3-(2-pe/dylamino-4) undergoes regioselective KI via benzyne
-Ethoxyphenyl)pyridine (5) is dehensylated to produce compound (1).

The reaction formulas for these methods are as follows.

[Production method 1] [Production method 2] [Production method 6] The method of the present invention will be explained below.

Production method 1: 4-mesyloxy-2-nitrotoluene (It) (J,
Med, Chem, 502216 (1987)
) is demesylated and ethyl etherified.

For the demesylation reaction, ordinary alkaline hydrolysis is applied, and ethyl etherification reaction can also be carried out at the same time. Ethyl etherification proceeds by using, for example, diethyl sulfate, ethyl iodide, etc., and stirring with heating. The reaction is quantitative and the ethyl ether (Ill) is obtained.

Next, compound (III) is reacted with N,N-dimethylpolamide dimethyl acetal and pyrrolidine in a solvent under heating and stirring to obtain 1-(4-ethoxy-2-nitrostyryl)pyrrolidine QV). D as a solvent
MF can be mentioned.

Compound (V) is then obtained by subjecting compound y) to a pyridine ring formation reaction.

The pyridine ring-forming reaction proceeds by reacting compound (IV) with acrolein and then hydroxyamine hydrochloride in a solvent. In addition, after making it react with acrolein and isolating an intermediate product, it can also be made to react with hydroxyamine hydrochloride.

The nitro group of compound (V) is preferably reduced by a conventional method using sodium hydrogen sulfide, iron or zinc/acetic acid, tin chloride, or the like.

According to this method, the target compound (11) can be produced with a high yield of 70 to 90%, and mass production is easy.
It is extremely advantageous industrially.

Production method 2: 3-phenylpyridine (, yoMed, Chem, 24
S-(2,4-dinitrophenyl)pyridine (2) obtained by nitrating S-(2,4-dinitrophenyl)pyridine (2) (see 1475 (1981)) can be reduced to a 4-amine compound (2) by a conventional method. Reduction proceeds easily by heating and refluxing using sodium hydrogen sulfide, sodium sulfide, or the like.

Compound (2) is subjected to a diazohydrolysis reaction to form 3-(4-human 0x-2-nitrophenyl)? ” Ri,)n61D
get. The diazo hydrolysis reaction proceeds by reacting with sodium nitrite while cooling with water and stirring in the presence of concentrated sulfuric acid. Then, by acid hydrolysis, the compound HATA is quantitatively obtained.

By ethyl etherification of the compound -, the compound (
V) and then reduced in the same manner as in Production Method 1 to produce the target compound (1) in a yield of 80 to 90%. Ethyl etherification easily proceeds by a method using diethyl sulfate, ethyl iodide, or the like.

Production method 3: 6-(4-ethoxyphenyl)pyridine (J, Me
d, Chem, 24) 475CA981)) When sodium amide is reacted with 3-(6-promo-4-ethoxyphenyl)pyridine (■) obtained by the action of K bromine in the presence of benzylamine, 6-<2- Benzylamino-4-ethoxyphenyl)pyridine) is obtained.

The reaction between the compound (compounds 2) and bromine proceeds by heating and stirring in the presence of a catalyst such as iron powder. Compound (1) is then reacted with sodium amide to form benzyne, which is reacted with benzylamine to yield compound (2). The reaction proceeds by heating and stirring using benzylamine as a solvent.

Compound (1) is subjected to catalytic reduction and debenzylated to obtain the target compound (1). Catalytic reduction of palladium
This can be carried out by a conventional method using carbon or the like.

[Effects of the Invention] According to the method of the present invention, 6-(4-ethoxy2-aminophenyl)pyridine (+1) can be industrially advantageously produced.

Example 1 (1) Production of 4-nitoxy-2-nitrotoluene (In): 4-mesyloxy-2-nitrotoluene (II)
Dissolve 2059 in ethanol 21, add NaOH 55°5
A solution of No. 59 in water (460 ml) was added, and the mixture was heated under reflux for 1 to 3 hours (disappearance of compound ① was confirmed by TLC), then 1 and Q ml of diethyl sulfate were added, and the mixture was heated under reflux for 1 hour. Furthermore, diethyl sulfate 5QffiA! and NaOH1B, 59 were added, and the mixture was heated under reflux for 30 minutes and 30ml of diethyl sulfate and N
Add aOH11, Oji and heat and stir for 1 hour.
The phenol body disappeared.

Distill ethanol, add 900ml of water and 60g of glycine
was added and stirred at 60°C for 1 hour.

The reaction solution was extracted with benzene 2,31, washed with 1N-NaOH and saturated brine, dried over Glauber's salt, and then the solvent was distilled off to give the compound flID155,62 as a yellow oil.
g (96.9%) was obtained. Boiling point 140-142℃
.

(2) 1-(4-ethoxy-2-nitrostyryl)
Production of pyrrolidine OV): 150.4 g of the compound ([[l) obtained in (1) was dissolved in DMF' 4 (101), and DMF (OCHs
)2 (N,N-dimethylformamide dimethyl acetal) 133 ml and pyrrolidine 85.11 nl were added,
After heating and stirring at a bath temperature of 110°C for 3 hours, DMF (0
CHs) * 15-5nl and pyrrolidine 8°3m/
! was added, and heating and stirring was continued for 2 hours.

Then, the solvent was distilled off under reduced pressure, and 280 ynt of methanol was added to the deep reddish-purple residue, which was left in a cool place overnight. Collect the precipitated crystals and add n-hexane-ethyl acetate (9:1) mixture 2.
After sequentially washing with aatrl and 100 rAt of n-hexane and air drying, compound (M) was obtained as a deep reddish-purple prism.
202.86,! ? (93°2%) was obtained.

Melting point 74-75°C3(3) 3-(4-ethoxy-
Production of 2-nitrophenyl)pyridine (V): Method A: Compound GV obtained in (2) 78791c
Add 10j of toluene (or ether) and dissolve by stirring at an external temperature of 40°C for 30 minutes, then cool by stirring for 50 minutes under water cooling, and add 400rnl of acrolein and 60ml of toluene.
0 ml of the mixed liquid was added dropwise over 20 minutes. The external temperature was set to 25° C., and the mixture was stirred for 22 hours. Next, while stirring under cooling with ice water, a cold aqueous solution 151 of 0.25N-HCI was added, the external temperature was set to 25°C, and the mixture was stirred for 26 hours. The reaction solution was extracted with ethyl acetate (61×3), the extract was washed successively with water and saturated brine, dried over Glauber's salt, and the solvent was distilled off to obtain 94Qfl of a crude pale brown oil.

940 g of this oil was dissolved in Improper Tool 121, and while cooling with ice water, a solution of 833 g of hydroxyamine hydrochloride in water (41) was added dropwise at an internal temperature of 15°C or less, and the temperature was returned to room temperature.
After stirring for 0 minutes, the mixture was heated under reflux at 100° C. for 2 hours.

After cooling, 61 parts of benzene was added to the reaction mixture, and back extraction was performed with 16.4 parts of a 2N-MCI aqueous solution, and the aqueous layer was washed with benzene.

The aqueous layer was made alkaline (pH 1) with 50% NaOH aqueous solution.
0' or more), extracted with benzene 207, washed the extract with saturated brine, dried over Glauber's salt, and distilled off the solvent to obtain 740 g of a brown oil.

Dissolve this oil in 31 g of ethyl acetate and add 460 g of silica.
was added and dried under reduced pressure. 1.3 kg of silica gel in the column
and filled with silica gel that adsorbed the above oily substance, and
Elution with hexane-ethyl acetate (2:1) mixture (approximately 181) to the same (1:1) mixture (approximately 401) yielded 547 g (74.6%) of compound (V) as pale yellow crystals. .

Melting point 61-63°C [ethyl acetate-11-hexane (3
:1)).

Method B: (Compound obtained in 2J) 10. After ON was dissolved in 160 ml of toluene by stirring at room temperature for 15 minutes, 5.1 ml of acrolein was added, and the mixture was stirred at 40° C. for 1 day. Next, the reaction solution was stirred while cooling with ice water, drained for 10 minutes, added with a solution of 10.9 J of droxyamine hydrochloride in water (40 ml), returned to room temperature, stirred for 40 minutes, and further heated to a bath temperature of 10
The mixture was heated under reflux at 0°C for 2 hours.

Thereafter, the reaction solution was back-extracted with 190rn1 of 2N-HCl, and the aqueous layer was washed with benzene. 2 of the benzene washing liquid
Back-extract with 30 ml of N-HCl, and combine the aqueous layers for 25
About 100++J% NaOH aqueous solution was added to adjust the pH to 10 or more, and the mixture was extracted with 300% benzene, washed with saturated brine, dried over Glauber's salt, and then the solvent was distilled off to obtain 8.779% of a crude brown oil. When 8.779 of this oil was dissolved in benzene and subjected to silica gel column chromatography and eluted with a mixture of n-hexane and ethyl acetate (2:1), 5.124 g (55.0%) of compound (V) was obtained. Obtained.

(4) 3- (4-ethoxy-2-aminophenyl)
Production of pyridine (1): 8 o g of compound (V) obtained in (3) was dissolved in methanol-toluene (1:1) mixed solvent 41, and heated under reflux at a bath temperature of 80°C with 70% Na5H640, ! A solution of i' in 70% methanol/water (21) was added dropwise over about 50 minutes. If raw materials remain, add 70% Na5H5
After 30 minutes, the solvent was distilled off, and the residue was suspended in 81 parts of chloroform and 41 parts of water, and diluted with 10%
An aqueous solution of 2.4 liters of Ma 02 was added dropwise over about 30 minutes, and after 20 minutes, the chloroform layer was separated, and the aqueous layer was extracted with 41 ml of chloroform. Combine the chloroform layers to form A, NaH3O3 (
After washing sequentially with 4009/121 H*O) and saturated saline and drying with Glauber's salt, it was applied to a short silica gel column and eluted with chloroform-methanol (100:1) to give a crystalline crude product 657 & (93 ,7%)
was gotten. This crude crystal bSy& was mixed with chloroform-n-
Recrystallization from hexane (1:3) gives a melting point of 126-1
Target compound (1) 579. as pale yellow crystals at 28°C. !
i! (82.6%) was obtained.

Example 2 tl) Production of 3-(2,4-dinitrophenyl)pyridine (2): 6.4 g of 6-phenylpyridine was cooled with concentrated sulfuric acid 251
After adding the mixture to Rt with stirring, 7 ml of fuming nitric acid was added dropwise, and the mixture was stirred overnight at a bath temperature of 50°C. The reaction solution was poured into ice water, made alkaline with NaOH, and extracted with benzene. This extract was washed with water, dried, and concentrated, and the residue was
-When recrystallized from hexane, the compound appears as yellow needles! X17.97p (78.8%) was obtained. melting point 12
8-130℃.

+2> Production of 5-(4-amino-2-nitrophenyl)pyridine G: Add the compound (~i) 4.3.9 obtained in (1) to 170 ml of methanol-)ruey (2: 1). dissolve,
70% Na5H2,4,! Add i' and 1 at a bath temperature of 80℃.
The mixture was heated under reflux for 3 hours. From now on, methanol will be distilled off, the residue will be dissolved in a mixture of 65 Iit of chloroform and 45 ml of water, and 10%
25.7 ml of H2O2 aqueous solution was added dropwise over about 20 minutes,
Stirring was continued for an additional hour. The chloroform layer was separated from the reaction solution and further extracted with 60 ml of chloroform.

The organic layers were combined, washed successively with water, 2.7% NaH3O1 aqueous solution, and saturated brine, dried over Glauber's salt, and then the solvent was distilled off to obtain 3.6 pieces of crude crystals. When 3.6 g of this crude crystal was dissolved in chloroform-n-hexane (1:1) and recrystallization was repeated, an orange-yellow powder was obtained with a compound concentration of 113.4%.
59 (95.6%) were obtained. Melting point 140-143
°C (decomposition).

+3) 5-(4-hydroxy-2-nitrophenyl)
Production of pyridine cap: Compound ()l 7.70.9 obtained in (1) was mixed with concentrated sulfuric acid 6. Of3ml, water 16.94ml and ice 16.17ml
A solution of 2.969 g of sodium nitrite in water (10,7117 g. tl! 38,3 ral-water 19.2
It was added dropwise to the 5me mixture over 36 minutes. After dropping, react at the same temperature for 60 minutes, then adjust the pH with 50% NaOH solution.
6, extracted with ethyl acetate, dried the extract with Glauber's salt, concentrated, and washed the precipitated crystals with chloroform to obtain the compound ('47.67,!i') as yellow crystals.
(99.1%) was obtained.

Melting point: 194-195°C.

+4) Production of 3-(4-ethoxy-2-nitrophenyl)pyridine fV): Compound fi4.89. obtained by method A = (6). ! i+ and potassium carbonate 6,61N in acetonitrile 206m
1 and DMF 341R1, 6.14 g of diethyl sulfate was added, and the mixture was heated and stirred at 70° C. for 4 to 3 hours. After the reaction, acetonitrile was distilled off, 7 Qml of a saturated aqueous glycine solution was added, and the mixture was heated and stirred at a bath temperature of 60°C for 1 hour.

The reaction solution was extracted with benzene, washed successively with IN-NaOH, brine, and Na2SO4 solution, concentrated, and the residue was separated and purified using a silica gel column (solvent chloroform). -hexane (2
: Recrystallization from 1) gives compound (V)S as yellow crystals.

629 (72.2%) was obtained.

Method B: Dissolve the compound-1,99 obtained in (3) in DMF, add 1.4 g of potassium carbonate and 0.73 m of ethyl iodide.
After adding 0.1 of ethyl iodide and leaving it at room temperature overnight, add 0.1 of ethyl iodide.
After adding 4 ml and stirring for 4 hours, add 7 Qml of ice water.
The reaction solution was poured into a solution, extracted with ethanol, and washed successively with water and saturated brine. After drying the extract with Glauber's salt, the solvent was distilled off to obtain 2.04% of a brown oil. This was recrystallized from ethyl acetate-n-hexane (1:2.) to obtain compound tV) 1.8049 (84%).

Hereinafter, in the same manner as in Example 1, 6-(4-ethoxy-2-
Aminophenyl)pyridine (1) was produced.

Example 6 (1) Production of 3-C6-bromo-4-ethoxyphenyl)pyridine (X): 3-(4-ethoxyphenyl)pyridine (capital) 1919
was dissolved in 4Qml of acetic acid, 223mg of iron powder was added, and while heating and stirring at an external temperature of 60°C, acetic acid containing 11.2 and 31 bromine (2O
mz) The solution was slowly added dropwise. After the dropwise addition, after heating and stirring for 1 to 3 hours, 120ml of water was added to the reaction solution, and Na2
S2O4 was added little by little, and when the color of the reaction solution changed from orange to yellow to white, it was neutralized by adding sodium carbonate, made alkaline with NaQH, and extracted with 250 ml of benzene. The benzene layer was washed with saturated brine and dried over sodium sulfate, then the solvent was distilled off, and the resulting residue was separated and purified by silica gel column chromatography [eluting with n-hexane-ethyl acetate (1:1)]. , recrystallization from ethyl acetate-n-hexane gave compound (Xj 12-249 (88%) as white needles. Melting point 95-97°C.

+2) Production of 3-(2-benzylamino-4-ethoxyphenyl)pyridine (to): Sodium amide 2.34! iK be/zylamine j4
ml was added with stirring over ice water, and after stirring for 15 minutes, the mixture was returned to room temperature and stirred for 1 to 2 hours. Compound (Xl
Dissolve 8.34 g in benzylamine 26%, add this solution dropwise to the above sodium amide solution at room temperature, and stir for 2 hours at an external temperature of 60 ° C. Confirm the disappearance of compound (X) by TLC], NH, C11゜6j! and methanol 2
0 ml was added to make the reaction solution a homogeneous solution. After methanol was distilled off under reduced pressure, excess benzylamine was recovered. Add 30 mJ of chloroform to the residue, and add 2N-hydrochloric acid 6
00 ml, the aqueous layer was washed with ethyl acetate, and N
After neutralizing with a2COs, the mixture was made alkaline by adding KOH, extracted with 200 ml of benzene, washed with saturated brine, dried over Glauber's salt, and then the solvent was distilled off. The resulting residue 9429 was subjected to silica gel column chromatography (2 ，
The compound IE 7,37N (eluted with 5% methanol/chloroform) was separated and purified as a brown oil.
83%) was obtained.

Melting point 168-172°C (hydrochloride).

+5) 3- (4-ethoxy-2-aminophenyl)
Production of pyridine (1): Add 7.37 g of compound (XI) obtained in (2) to vinegar F.
It was dissolved in 50 ml of BI, and catalytic reduction was performed at 60°C in the presence of 15 g of 10% Pd-C in a hydrogen stream. Approximately 2
After an hour, 10% Pd-C was removed, the solvent of solution F was distilled off, 100 mJ of water was added to the residue, neutralized with Na2CO3, and made alkaline with NaOH.1. Chloroform 75m/! After extraction with water, washing with saturated saline, and drying with Glauber's salt, the solvent was distilled off and the resulting residue (5 g) was subjected to silica gel column chromatography (eluted with n-hexane-acetone (5:3 to 1:1)). ] and crystallized from n-hexane, the target compound tl)2.97F
(57%) was obtained.

Claims (1)

[Claims] 1, obtained by ethyl etherifying 1,4-mesyloxy-2-nitrotoluene and then reacting it with pyrrolidine and N,N-dimethylformamide dimethyl acetal.
-(4-ethoxy-2-nitrostyryl)pyrrolidine is subjected to a pyridine ring formation reaction to form a
A method for producing 3-(4-ethoxy-2-aminophenyl)pyridine, which comprises preparing 3-(4-ethoxy-2-aminophenyl)pyridine and reducing it. Partial reduction of 2,3-(2,4-dinitrophenyl)pyridine yields 3-(4-amino-2-nitrophenyl)
3-(4-hydroxy-2-nitrophenyl)pyridine is converted into pyridine, subjected to diazohydrolysis reaction, and the resulting 3-(4-hydroxy-2-nitrophenyl)pyridine is converted into 3-(4-ethoxy-2-
A method for producing 3-(4-ethoxy-2-aminophenyl)pyridine, which comprises preparing 3-(4-ethoxy-2-aminophenyl)pyridine and reducing it. 3,3-(4-Ethoxyphenyl)pyridine is brominated to give 3-(3-bromo-4-ethoxyphenyl)pyridine, which is reacted with benzylamine in the presence of sodium amide and regioselected via benzyne. 3-(2-benzylamino-4-ethoxyphenyl)pyridine obtained by debenzylation.
Method for producing (4-ethoxy-2-aminophenyl)pyridine.