JPS59196844A - Manufacture of aromatic amine - 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 The present invention relates to a method for producing cyanoalkyl-substituted aromatic amines and a method for producing O.aminoalkyl-substituted aromatic amines.

European Soba Patent Specification No. 0068833 is based on the formula: [wherein R1 is halogen, 2 is alkyl having 1 to 4 carbon atoms, 1 (3 is alkylene having 1 to 3 carbon atoms, and R4 is a certain substituted or unsubstituted pyridine group], which is useful as a histamine+1□-115 anti-histamine agent.

An important intermediate in the production of the compound of formula [■] is a compound represented by the formula: [wherein k2 and R3 are the same as above].

The compound of formula [11T] is obtained by hydrogenating a compound represented by the formula: [wherein, 2 and 1 (3 are the same as above]), It is prepared by reducing the compound with aluminum hydride.

Next, a compound of formula [11] is produced from a compound of formula [■ old] under mild conditions, and a compound of chain formula [11J is obtained in a relatively high yield and with relatively high purity. We have discovered a manufacturing method that can do this.

The production method of the present invention is not limited solely to the production of compounds of the formula [1l1, but is rather a production method that can be applied to a wide range of applications.

Thus, the present invention provides a compound of the formula (I): % formula % ([in the formula, A and O-X are the same as below] The following reaction is carried out to form a compound of the formula: %Formula%[] [In the formula, A and X are the same as below] (1)) The obtained compound of the formula [■] , further reacting with hydrazine and trivalent nickel: % formula % [wherein A is 1 or less, oxygen or sulfur and 1 to 3]
a 5-membered heteroaromatic group containing up to 3 nitrogen heteroatoms, optionally a 6-membered monocyclic aromatic group containing up to 3 nitrogen heteroatoms, or optionally a 6-membered monocyclic aromatic group containing up to 3 nitrogen heteroatoms A 9- or 10-membered bicyclic aromatic group (A
The group is optionally one, 1-, which is inert under the reaction conditions.
); X is alkylene having 1 to 5 carbon atoms;
Provided is a method for producing compound G, which refers to an alkenylene.

Groups that are inert under the reaction conditions are groups that are not reduced during the reaction or do not interfere with the reduction process. Examples of such groups include alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, halogen, amino or hydroxy.

Examples of 5-membered monocyclic aromatic groups containing one heteroatom include pyrrolyl, chenyl, furanyl, and the like. Examples of 5-membered aromatic groups containing two heteroatoms include pyranolyl, imitazolyl, thiazolyl, isothiazolyl, oxanolyl, and quinolyl.

Examples of 5-membered monocyclic aromatic groups containing three heterologous radicals include furazanyl, oxadiazolyl, and chinonfu'solyl.

Up to 3 nitrogen games from 5 qji! Examples of 6-membered jlt cyclic aromatic groups containing ) atoms include phenyl, pyridyl, pyrazinyl, pyrimidinyl and pyritanyl.

Examples of 9-membered bicyclic aromatic groups optionally containing up to 4 heteroatoms include indenyl, indolyl, inquinolyl, intridinyl and purinyl.

l optionally containing up to 4 heteroatoms.

Examples of membered bicyclic aromatic groups include naphthyl, kylyl,
Mention may be made of inquinolyl, phthalazinyl, naphthyridinyl, quinoxalininopequinazolinyl, cinnolinyl and ptericinyl.

In the compounds of formulas [V] and J, when 8 is a 5-membered ring, preferably A is imitazolyl, especially:
NO2-Am is 5-21-rho-4-imitazolyl.

In the compound of formula [■]], when 8 is a 6-membered monomer aromatic group, A is particularly unsubstituted or alkyl having 1 to 6 carbon atoms, alkoxyn having J to 6 carbon atoms Or phenyl or pyridyl with a halogen device.

Thus, in particular, NO2A- can be expressed as
2-pyridyl, 3-methyl-5-nitro-2-pyridyl, 5-methyl-3-nitro-2-pyridyl or 5-bromo-3-dil-o-2-hy+)dyl, preferably , N O2''-A= is 3-methyl-5-nitro2
-pyridyl or 5-bromo-3-nitro-2-pyridyl.

In the compound of formula (VI3), when 8 is a 9-membered bicyclic aromatic group, N02-A- is 5-nitro-
3-indolyl.

When X is alkyl having a carbon number of ~5, for example, X is ethane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl or pentane-1 ,5
-It's Jiyl. In particular, the X is propane-1,3-
It's Jill. When X is alkenylene having 2 to 5 carbon atoms, it is, for example, ]-]tyrene-1,2-diy or propane-]-7-1,3-diyl. In particular, dX is ethylene-1,2-diyl.

Preferably, the first step of the reaction is carried out under moderate conditions. That is, 1fuj sum hydrogenation/'l'l
Catalysts are used at low to slightly elevated temperatures, or more powerful catalysts are used at low to moderate temperatures.

7 for the first king of the reaction! Examples of A a'il catalysts include palladium (particularly palladium on solids) on an inert support F. 6 ■ The reaction with a moderate catalyst is 5
It can be carried out at a temperature of ~70°C. In practice, the temperature is usually between room temperature (about 20°C) and 55°C.

Examples of more powerful catalysts include nickel. This catalyst can be used at 70"C,
Preferably, reaction 7: il' is heated to 25° C. or below, e.g. 10-b. Preferably, the catalyst is palladium on carbon.

Step (1)) is carried out using nickel.

The reaction can be carried out at low temperatures to high temperatures, for example from 5'C to above room temperature, for example from 50'C to above, particularly at about 70'C.

If the A group is a group that tends to be substituted with hydrogen under stronger conditions, such as a halokene substituted -C, then the
In a) and step [1]), low 7:ii'+ is preferred.

] After performing step (a), remove the catalyst. For example, r
]b), the compound of formula [~j11'' can be recovered by evaporating the solvent. The resulting compound of formula [VllJ can then be redissolved in the same or different solvent and reacted with Raney nickel and further with hydrazine to carry out step (1)).

Preferably, the reactions are carried out in one step.

That is, the compound of formula [■1] is reacted with sufficient hydrazine and a catalyst to form the compound of formula [■11] in the system, and if the catalyst of step (a) is not a mononickel, the catalyst is removed. For example, r per
] is converted into the compound of 1] to the corresponding formula.

The reactions in step (a) and step (1)) can be carried out in the presence of a solvent. The choice of solvent is not particularly limited as long as it is inert to the reagents and products. .

Reaction 11' in l) or step (1)) above
j is the property of the reagent, the degree of reaction lii+V, and the step (
Based on the catalyst used in a). The reaction proceeded using standard techniques;
For example, if the reaction is completed, it can be monitored by 17-layer chromatography using standard techniques, e.g.
The catalyst can be removed by filtration and the product separated by evaporation of the solvent.

The present invention will now be described in more detail with reference to Examples.

Example 1 (a) Palladium on carbon 1. , Og, methanol 1
00, 4-(3-methyl-5-21・rho2 in rl
A solution of 9.6 g of (pyridyl)butyronitrile was suspended overnight, and the mixture was heated with stirring in a nitrogen atmosphere at 35'C. Aqueous hydrazine hydrate 4.0 rnl (64
96 w/v) was added dropwise to the stirred suspension, and 7:
Turn the temperature down to 52°C. The temperature is maintained at 500 °C until thin layer chromatography or reaction completion (approximately 1 hour). Exterminates fleas by passing through carbon-1 palladium. Removal of the solvent at this stage yields 4-('5-amino-3-
Methyl-2-pyridyl)butyronitrile is obtained. In this example, the ρ is used in the direct attaching process.

(1)) Add wet nickel 2y to the ρ solution obtained in Example] (a). The resulting mixture is heated to 50 DEG C. and 37 ml of aqueous hydrazine hydrate (64% W/V) are added dropwise with stirring while maintaining the temperature between 48 DEG and 54 DEG C. The temperature of the reaction mixture is maintained within this range and the progress of the reaction is followed by thin layer chromatography.

When the chromatography indicates completion of the reaction, the catalyst is removed by filtration and the solvent is evaporated to give 4-(5-amino/-
3-Methyl-2-pyridyl)butylamine 6.879(
8296) is obtained.

Example 2 t;, j 3 J ml of sulfuric acid and 35 ml of concentrated nitric acid
dropwise into a stirred cold (5°C) solution of 50.39 minol of 5-bromopyridine in 1 ml of acid 24. During the addition, the reaction mixture temperature of 5
Incubate J-4i at ~6°C. After the addition is complete, the reaction mixture is
Stir for additional J at 5-8°C for 0 hours, warm to 30°C,
Leave it for about 18++, 1] time.

Further, 35 ml of 413 nitric acid was added to the reaction lIN compound, and the mixture was cooled for 11 hours while stirring and maintaining the temperature at 30 to 40°C.

A portion of 50 ml of this solution was poured into 100 ml of hot water at about 70°C.
The mixture was heated to 120°C with rapid stirring.
Heat to. Gas is generated. Once this gas evolution has stopped, is there still some part of the reaction mixture? , 5ynl, temperature 1
Add while maintaining the temperature at 20°C. After completion of JII, the resulting solution is poured over 111 g of ice I Ky and cooled in a salt/ice bath. Fine orange crystals form, which are collected and recrystallized from dimethylformamide/water to give 23.59% of 2-hydroxy-3-nitro-5-bromopyridine. Melting point: 24.0-243°C.

(1)) 2-Hydroquine- in 16 ml of phosphoryl chloride
A solution of 23.49 ml of 3-nitro-5-bromopyridine was added to 2
Heat to reflux for 5 hours. Pour the reaction mixture into ice/water,
A brown solid forms, which is collected in lJ'i.

The solid is dissolved in chloroform, dried over sodium sulfate, and decolorized by heating with carbon for 30 minutes.

The common medium was removed from the liquid and 240 g of yellow periphery was obtained.
194 g of 2-chloro-3-21.rho-5-bromopyridine was obtained by recrystallization from . Melting point 66-68°C ((:) A solution of 24.2y of 2-(2-thia/ethyl)malonic acid diethyl ester in 15ml of tetrahydrofuran was mixed with 245g of hydrogenated sodium chloride in 30ml of tetrahydrofuran. 22 g of 2-chloro-3-25U:J-5-pro(pyridine) was added to the mixture under a nitrogen atmosphere at 20°C.
Heat to 5°C. A subtotal of tetrahydrofuran is distilled off. The mixture was heated to reflux for 2.5 hours IJ [1]. The reaction mixture was poured into water and neutralized to pH 7 with a'3 hydrochloric acid. The aqueous layer is extracted with chloroporum, dried over magnesium sulfate, decolorized with carbon, and filtered through a solitnose gel column. Evaporation of the chloroform 9 eluate yields /111. This crystallizes slowly.Turn the crystal to the right ether (40~6
0C)-C611 was purified and dried to give 4-(5-bromo-3
-21.IJpyridin-2-yl)-4,4-bis(l
28 g of butyronitrile are obtained.

Ni:1!1. ', I, 58-62 = C1 ((113M sodium hydroxide aqueous solution lf 263.6n+7
-buo'e-3-nitropyridin-2-yl)-4,
4bis(carboetquin)butyronitrile 2], 8g
Add to the solution. The resulting mixture is stirred for 18 hours. Concentrated hydrochloric acid was added to the mixture to give a pIt of 1.5, and the mixture was heated at 50°C.
Heat for 4.75 hours. The solution is neutralized to PTL 7 with sodium hydroxide solution and methanol is distilled off. The remaining water m7& was extracted with chloroform-C and purified by Ura 11. ．． 2
! i' was obtained, and this was subjected to chromatography on a polymer column-1-1 and eluted with chloroform to obtain 96 g of 4-[5-bromo-3-21-rho-2-pyridyl]butyronitrile as a yellow solid. obtain.

Melting point 73-76°C.

tC) 34 g of nickel moistened with ethanol and 3.50 m7 of ethanol! Finely crushed 4-5 inside
-Bromo-3-nitro-2-bilinyl]bunaroni l-U
Add Ru:゛・1 elemental atmosphere to 8.4 g of shield turbidity. The mixture was cooled to ]0°C and a solution of 2.34 ml of hydrazinohydrate in 10 ml of ethanol was added to reaction 7+'.
Add 14 JL of water at 12-15°C.

The reaction mixture was warmed to room temperature with constant stirring and 15.57 liters of hydrazine hydrate was added to 3 ml of ethanol + 1 ml of hydrazine hydrate.
．． i 2.3 d at regular intervals over a period of 46 hours. Cool the reaction mixture to 15° C. before each addition. After 23 hours, add another 6 g of Raney nickel. 4
After 7 hours, stop the reaction. The reaction mixture was passed through a pad of algae (1) to remove the medium. The solvent was evaporated to give 7.9 g of chlorine, which was chromatographed on a silica gel column and eluted with ethyl acetate/Cokenor 10.880 ammonia (15:10:2) to give a curved 4-cylindrical column. 3-Amine-5-O-2-pyridyl”
Butylamine/1. (Get 1,9.

Example: 3 In the method of Example 1, 4-(3-methyl-5-
2l-1: 4-(3-nitro-2-pyridyl)butyronitrile 8 instead of J-2-pyridyl)butyronitrile
．． Using 9 g, 4-(3-amino-2-pyridyl)butyl)'mine was obtained.

Example 4 In the same manner as in Example 1, 4-(3-methyl-5
-nitro-2-pyridyl)propytrilno instead of (2
-nitrophenyl)acetonitrile 7,69 woJ4J
2-(2-aminephenyl)ethylamine is obtained.

Example 5 In the method of Example 1, 4-(3-methyl-5-
Using 2-(5-nitro-3-indolyl)propionitrile instead of 21-2-pyridyl)butyronitrile, 2-(5-ami/-3-inodolyl)propylamine is obtained.

4? f irB, 1. llν [1 person Ms. Klein & French Waboratories Ltd. 2 people Mr. Rikiji Haga Aoyama Continuing from page 1 ■ Int, C1, 3 identification code Internal reference number C0
7D 213/73 7138-
4C Priority Claim 0 July 23, 1983 [Area] United Kingdom (GB) ■8319876 0 Inventor Maria Alexandra Wiltins, United Kingdom, England, Hertfordshire, Unilin, Garden City Moorlands, No. 16

Claims (1)

[Claims] Lll [a) Formula: % formula % [In the formula, A and % [in the formula, Δ and A formula characterized by. N112-AX-CI(2N112[■J [wherein A is 3 in which 1 or less is oxygen or sulfur and 1 to 3 are nitrogen
a 5-membered heteroaromatic group containing up to 5 heteroatoms,
6-membered monocyclic aromatic group optionally containing up to 3 nitrogen heteroatoms or optionally containing up to 4 heteroatoms of up to 1 oxygen or sulfur and 1 to 4 nitrogen The A group of the 9- or 10-membered bicyclic aromatic group may be optionally substituted with one or more H groups that are inert under the reaction conditions; X has 1 to 5 carbon atoms; A method for producing a compound shown in Table 1. (2) NO2-A-, 2-nitropheninope 3-nitro-2-pyridyl, 5-21-rho-2-pyridyl, 3
-Methyl-5-nitro-2-pyridyl, 5-methyl-3
-nitro-2-pyritur, 5-bromo-3-nitro-2
-Pyridyl if this is 5-nitro-3-indolyl. +3) No2- is 3-methyl-5-nitro-2-
The method according to item (2) above, which is pyridyl or 5-bromo-3-nitro-2-1°pyridyl. (4) Before X is propane-1,3-diyl,
The manufacturing method according to any one of items 1) to (3). (5) The method according to any one of items 11) to (4) above, wherein the catalyst for step tal is palladium on carbon. (6) Form a compound of the formula [■] in the system, and if the catalyst is other than Raney nickel, replace the catalyst with Raney nickel to form a compound of the formula (VJ).
The method according to any one of items (1) to (5) above, wherein the method is reacted with hydrazine.