JP4984676B2 - Preparation of aniline having benzyloxy group - Google Patents

Description

  The present invention relates to a method for producing an aniline having an aralkyloxy or heteroaralkyloxy group by reacting nitrobenzene having an aralkyloxy or heteroaralkyloxy group with hydrogen, without causing dearalkylation or deheteroaralkylation. Aniline having an aralkyloxy or heteroaralkyloxy group is a useful compound as a raw material for pharmaceuticals, agricultural chemicals, etc., or a synthetic intermediate.

Conventionally, as a method for producing aniline having an aralkyloxy or heteroaralkyloxy group by reacting nitrobenzene having an aralkyloxy or heteroaralkyloxy group with hydrogen, for example, a method using tin chloride (for example, non-patent literature) 1), a method using iron and iron chloride (for example, see Non-Patent Document 2) and a method using iron and hydrochloric acid (for example, see Non-Patent Document 3). However, in these methods, complicated operations must be performed to remove metals from the reaction solution, which is disadvantageous as an industrially suitable method for producing anilines having an aralkyloxy or heteroaralkyloxy group.
J. Org. Chem., 66 (8), 2881 (2001) J. Med. Chem., 45 (17), 3772 (2002) Tetrahedron, 51 (19), 5617 (1995)

  The object of the present invention is to solve the above-mentioned problems, by reacting nitrobenzene having an aralkyloxy or heteroaralkyloxy group with hydrogen by a simple method under mild conditions to dearalkylate or deheteroaralkylate. An object of the present invention is to provide an aniline having an aralkyloxy or heteroaralkyloxy group.

  The subject of this invention is general formula (1) in presence of a metal catalyst.

（式中、Ａｒは、置換基を有していても良いアリール基又はヘテロアリール基、Ｚは、置置換基を有していても良い二価の芳香族基を示す。）
で示されるアラルキルオキシ又はヘテロアラルキルオキシ基を有するニトロベンゼンと水素とを反応させることを特徴とする、一般式（２）

(In the formula, Ar represents an aryl group or heteroaryl group which may have a substituent, and Z represents a divalent aromatic group which may have a substituent.)
A nitrobenzene having a aralkyloxy or heteroaralkyloxy group represented by formula (2) is reacted with hydrogen.

（式中、Ａｒ及びＺは、前記と同義である。）
でアラルキルオキシ又はヘテロアラルキルオキシ基を有するアニリンの製法によって解決される。

(In the formula, Ar and Z are as defined above.)
This is solved by a process for preparing anilines having an aralkyloxy or heteroaralkyloxy group.

  According to the present invention, nitrobenzene having an aralkyloxy or heteroaralkyloxy group is reacted with hydrogen by a simple method under mild conditions, without causing aralkyloxy or heteroaralkyloxylation without dearalkylation or deheteroaralkylation. An aniline having a group can be provided.

  The nitrobenzene having an aralkyloxy or heteroaralkyloxy group used in the reaction of the present invention is represented by the general formula (1). In the general formula (1), Ar is an aryl group or heteroaryl group which may have a substituent, and examples of the aryl group include a phenyl group, a p-tolyl group, a naphthyl group, and an anthryl group. The heteroaryl group includes, for example, a furyl group, a thienyl group, a pyrrolyl group, an oxazolyl group, a pyridyl group, a quinolinyl group, and a carbazolyl group. These groups include various isomers.

  The aryl group or heteroaryl group may have a substituent. Examples of the substituent include a substituent formed through a carbon atom, a substituent formed through an oxygen atom, a substituent formed through a nitrogen atom, a substituent formed through a sulfur atom, and a halogen atom.

  Examples of the substituent formed through the carbon atom include alkyl groups such as a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, and a hexyl group; a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclo group. Cycloalkyl groups such as heptyl group; Alkenyl groups such as vinyl group, allyl group, propenyl group, cyclopropenyl group, cyclobutenyl group, cyclopentenyl group; quinolyl group, pyridyl group, pyrrolidyl group, pyrrolyl group, furyl group, thienyl group, etc. An aryl group such as phenyl group, tolyl group, fluorophenyl group, xylyl group, biphenylyl group, naphthyl group, anthryl group, phenanthryl group; acetyl group, propionyl group, acryloyl group, pivaloyl group, cyclohexylcarbonyl group, Benzoyl group, naphthoyl Group, acyl group such as toluoyl group (may be acetalized); carboxyl group; alkoxycarbonyl group such as methoxycarbonyl group and ethoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; trifluoromethyl group and the like A halogenated alkyl group; and a cyano group. These groups include various isomers.

  Examples of the substituent formed through the oxygen atom include a hydroxyl group; an alkoxyl group such as a methoxyl group, an ethoxyl group, a propoxyl group, a butoxyl group, a pentyloxyl group, a hexyloxyl group, a heptyloxyl group, and a benzyloxyl group; Aryloxyl groups such as phenoxyl group, toluyloxyl group, naphthyloxyl group and the like can be mentioned. These groups include various isomers.

Examples of the metal catalyst used in the reaction of the present invention include platinum / carbon, platinum sulfide / carbon, palladium-platinum / carbon, platinum oxide , platinum / alumina, and rhodium / carbon. Platinum / carbon (for example, platinum sulfide / carbon) is preferably used. In addition, these metal catalysts may be used individually or in mixture of 2 or more types, and may be a water-containing product or an anhydrous product.

  The amount of the metal catalyst used is preferably 0.1 to 1000 mg, more preferably 0.5 to 500 mg, based on 1 g of nitrobenzene having an aralkyloxy or heteroaralkyloxy group, in terms of metal atoms.

  The amount of hydrogen used in the reaction of the present invention is preferably 2 to 50 mol, more preferably 2 to 10 mol, per 1 mol of nitrobenzene having an aralkyloxy or heteroaralkyloxy group.

  The reaction of the present invention can be carried out in the presence or absence of a solvent, but the solvent used is not particularly limited as long as it does not inhibit the reaction. For example, water; methanol, ethanol, isopropyl alcohol, n -Alcohols such as butyl alcohol and t-butyl alcohol; carboxylic acid esters such as methyl acetate, ethyl acetate and methyl propionate; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; diethyl ether, dimethoxyethane, Ethers such as tetrahydrofuran, dioxane, diisopropyl ether and the like can be mentioned, and esters and ethers are preferably used. In addition, you may use these solvents individually or in mixture of 2 or more types.

  The amount of the solvent used is appropriately adjusted depending on the uniformity and stirring properties of the reaction solution, but is preferably 0 to 100 g, more preferably 0 to 30 g based on 1 g of nitrobenzene having an aralkyloxy or heteroaralkyloxy group. is there.

  In the reaction of the present invention, for example, nitrobenzene having an aralkyloxy or heteroaralkyloxy group, a metal catalyst and a solvent are mixed and stirred in the presence of hydrogen gas (which may be diluted with an inert gas). It is done by the method. The reaction temperature at that time is preferably 0 to 300 ° C., more preferably 20 to 200 ° C., and the reaction pressure is preferably 0.1 to 10 MPa, more preferably 0.1 to 2 MPa.

  By the reaction of the present invention, an aniline having an aralkyloxy or heteroaralkyloxy group is obtained, which can be obtained, for example, after neutralization, extraction, filtration, concentration, distillation, recrystallization, crystallization, column chromatography. It is isolated and purified by a general method such as

  Next, the present invention will be specifically described with reference to examples, but the scope of the present invention is not limited thereto.

Reference Example 1 (Synthesis of 2-benzyloxyaniline)
In a glass container with an internal volume of 100 ml equipped with a stirrer, thermometer, reflux condenser and balloon filled with hydrogen, 3.0 g (13.09 mmol) of 2-benzyloxynitrobenzene , 3 mass% platinum sulfide / carbon (50% water content) Product) 0.15 g and 30 ml of butyl acetate were added and reacted in a hydrogen atmosphere at 60 ° C. for 3 hours with stirring. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 2.46 g of 2-benzyloxyaniline as a brown liquid (isolated yield; 94.6% ).
The physical properties of 2-benzyloxyaniline were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.85 (2H, brS), 5.11 (2H, S), 6.70-6.90 (3H, m), 7.32-7.48 (4H, m)
CI-MS (m / e); 200 (M +)

Reference Example 2 (Synthesis of 3-benzyloxyaniline)
The reaction was performed in the same manner as in Reference Example 1 except that 2-benzyloxynitrobenzene was changed to 3-benzyloxynitrobenzene in Reference Example 1. As a result, 1.80 g of 3-benzyloxyaniline was obtained as a beige solid (isolation yield: 69.2%).
The physical properties of 3-benzyloxyaniline were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.66 (2H, brs), 5.04 (2H, s), 6.31 to 6.44 (3H, m), 7.05 to 7.11 (1H, m), 7.30 to 7.46 ( 5H, m)
CI-MS (m / e); 200 (M +)

Reference Example 3 (Synthesis of 4-benzyloxyaniline)
The reaction was performed in the same manner as in Reference Example 1 except that 2-benzyloxynitrobenzene was changed to 4-benzyloxynitrobenzene in Reference Example 1. As a result, 2.29 g of 4-benzyloxyaniline was obtained as a brown solid (isolation yield; 88.0%).
The physical properties of 4-benzyloxyaniline were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.44 (2H, brs), 5.01 (2H, s), 6.63 to 6.68 (2H, m), 6.81 to 6.86 (2H, m), 7.30 to 6.68 ( 5H, m)
CI-MS (m / e); 200 (M +)

Reference Example 4 (Synthesis of 4- (3-fluorobenzyloxy) -3-chloroaniline)
In a 100 ml glass container equipped with a stirrer, thermometer, reflux condenser and balloon filled with hydrogen, 3.0 g (10.65 mmol) of 4- (3-fluorobenzyloxy) -3-chloronitrobenzene, 3 mass % Platinum sulfide / carbon (50% water-containing product) 0.15 g and butyl acetate 30 ml were added, and the mixture was reacted at 60 ° C. for 3 hours in a hydrogen atmosphere with stirring. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 4: 1 (volume ratio)) to obtain 2.36 g of 4- (3-fluorobenzyloxy) -3-chloroaniline as a brown solid. (Isolated yield; 88.0%).
The physical properties of 4- (3-fluorobenzyloxy) -3-chloroaniline were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.51 (2H, brs), 5.04 (2H, s), 6.49 to 6.53 (1H, m), 6.77 to 6.80 (2H, m), 6.97 to 7.04 ( 1H, m), 7.19-7.23 (2H, m), 7.31-7.38 (1H, m)
CI-MS (m / e); 252 (M +)

Reference Example 5 (Synthesis of 3-amino-2-benzyloxypyridine)
In a glass container with an internal volume of 100 ml equipped with a stirrer, thermometer and reflux tube, 2.0 g (8.68 mmol) of 3-nitro-2-benzyloxypyridine, 3% by mass of platinum sulfide / carbon (50% water-containing product) 0.10 g and 20 ml of butyl acetate were added, and the mixture was reacted at 60 ° C. for 3 hours with stirring in a hydrogen atmosphere. After completion of the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (developing solvent; hexane: ethyl acetate = 1: 1 (volume ratio)) to obtain 0.80 g of 3-amino-2-benzyloxypyridine as a brown solid (isolated product). Rate; 46.2%).
The physical properties of 3-amino-2-benzyloxypyridine were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 4.28 (2H, brs), 5.16 (2H, s), 6.01 to 6.06 (1H, m), 6.49 to 6.52 (1H, m), 6.70 to 6.73 ( 1H, m), 7.24-7.36 (5H, m)
CI-MS (m / e); 201 (M +)

Example 6 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate)
In a glass container with an internal volume of 20 ml equipped with a stirrer, thermometer, reflux condenser and balloon filled with hydrogen, 4.0 g (12.6 mmol) of methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate, 3 0.2% by mass of platinum sulfide / carbon (60% water-containing product) and 20 ml of dimethoxyethane were added, and the mixture was reacted at room temperature for 7 hours with stirring in a hydrogen atmosphere. After completion of the reaction, the reaction solution is allowed to stand for 10 days and then filtered, and the reaction solution is concentrated under reduced pressure to obtain 3.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate as a light brown solid. (Isolation yield; 87%).
The physical properties of methyl 2-amino-4-benzyloxy-5-methoxybenzoate were as follows.

¹ H-NMR (CDCl ₃ , δ (ppm)); 3.81 (3H, s), 3.83 (3H, s), 5.09 (2H, s), 5.37 (2H, brs), 6.15 (1H, s), 7.31 ~ 7.41 (6H, m)
CI-MS (m / e); 287 (M +)

Example 7 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate)
In Example 6, the reaction was performed in the same manner as in Example 6 except that 3% by mass of platinum sulfide / carbon was changed to 5% by mass of platinum / alumina. As a result, 2.17 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate was formed (reaction yield: 54.6%).

Example 8 (Synthesis of methyl 2-amino-4-benzyloxy-5-methoxybenzoate)
In Example 6, the reaction was performed in the same manner as in Example 6 except that 3% by mass of platinum sulfide / carbon was changed to 5% by mass of rhodium / carbon. As a result, 3.15 g of methyl 2-amino-4-benzyloxy-5-methoxybenzoate was produced (reaction yield: 79.2%).

  The present invention relates to a method for producing an aniline having an aralkyloxy or heteroaralkyloxy group by reacting nitrobenzene having an aralkyloxy or heteroaralkyloxy group with hydrogen, without causing dearalkylation or deheteroaralkylation. Aniline having an aralkyloxy or heteroaralkyloxy group is a useful compound as a raw material for pharmaceuticals, agricultural chemicals, etc., or a synthetic intermediate.

Claims (3)

In the presence of at least one metal catalyst selected from the group consisting of platinum / carbon, platinum sulfide / carbon, palladium-platinum / carbon, platinum oxide, platinum / alumina and rhodium / carbon , the general formula (1)

(In the formula, R represents an alkoxycarbonyl group .)
Characterized by reacting a nitrobenzene and hydrogen with benzyl Oki sheet group represented in the general formula (2)

(Wherein, R has the same meaning as described above.)
Preparation of the aniline with benzyl Oki sheet group shown in. Wherein the metal catalyst is, preparation of aniline with benzyl Oki sheet group according to claim 1, wherein at least one selected from the group consisting of platinum sulfide / carbon, platinum / alumina and rhodium / carbon. The method for producing an aniline having a benzyloxy group according to claim 1 or 2, wherein the nitrobenzene having a benzyloxy group is methyl 4-benzyloxy-5-methoxy-2-nitrobenzoate.