JP2592732B2 - Method for producing phenoxyethylamines - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel method for producing phenoxyethylamines which are useful as raw materials for producing medicinal and agricultural chemicals.

[0002]

2. Description of the Prior Art Heretofore, phenoxyethylamines have been known to be important as a raw material for the production of medical and agricultural chemicals, particularly as a raw material for the production of insecticides (JP-A-59-3666).
No. 7, JP-A-62-67 and the like, and it is known that they can be produced by the methods represented by the following reaction formulas (where Ar represents an aryl group; R and R ′ are X represents an alkyl group; X represents a halogen atom).

(1) ArOCH ₂ CH ₂ Br + NH
₃ → ArOCH ₂ CH ₂ NH ₂ .Chem. B
er. , 70 (1937) p. 979 (2) ArOK + ClCH ₂ CH ₂ NH ₂ →
ArOCH ₂ CH ₂ NH ₂ .J. Pharm. Soc.
Japan, 63 (1943), p. 546 (3) ArOCH ₂ CONH ₂ + LiAlH ₄ →
ArOCH ₂ CH ₂ NH ₂ Helv. Chemica
Acta. , 31 (1948) p. 1397 (4) ArOCH ₂ CH ₂ Br + potassium phthalimide →→→ ArOCH ₂ CH ₂ NH ₂ .J. Chem. Soc. U.S. Pat. No. 3,474,134 (5) ArOH + ethyleneimine → ArO
CH ₂ CH ₂ NH ₂ · J. Amer. Chem, So
c. , 73 (1951), p. 2584 (6) ArOCH ₂ CH ₂ Br + hexamethylenetetramine → ArOCH ₂ CH ₂ NH ₂ · Roczniki Chem. , 661 (1958)
Year) ・ C. A. (1961) 2537 pages

(7) ArX + NH ₂ CH ₂ CH ₂ O
K → ArOCH ₂ CH ₂ NH ₂ .Khim. Prom-St. , Ser; Reakt.
Osobo Chist. Ves Chestva
(2) 1-3 C.I. A. 92 (3) 22184q (8) RCH ₂ NHOH + R′X → RCH ₂
NHOR ′ → RCH = NR ′ → R′NH ₂ · Chem. Letter, 10, 1057 (9) ArSO ₂ NHCH ₂ CH ₂ OH + NaOH
→ ArOCH ₂ CH ₂ NH _2. Tetrahedron Lett. , 26 vol. 228
Page 9 (10) ArOCH ₂ CN + LiAlH ₄ →
ArOCH ₂ CH ₂ NH ₂ .J. Amer. Chem.
Soc. , 109 (1987) p. 4036 (11) A method for producing ArOCH ₂ CH ₂ NH ₂ by reducing ArOCH ₂ CH ＝ NOH in the presence of a catalyst. JP-A-2-62841 (12) A method for producing secondary alkylamines by reducing ArOCH ₂ CR = NOH in the presence of a catalyst.・ DE-A-1,934,014

However, these (1) to (12)
Has the following problems. In (1), (4) and (6), ArOCH ₂ CH ₂ B
There are many by-products during the synthesis of r and the yield is poor. In addition, the method of introducing a substituent into Ar has many restrictions due to the presence of a halogen substituent, and it is very difficult to produce a target compound. In (2) and (5), the yield is very poor. In (3) and (10), since the production raw material LiAlH ₄ is expensive, there is a problem in terms of cost for industrial production. In (7), metal potassium as a raw material for production is expensive, and there is a danger in handling the metal potassium. In the case of (8), since the production raw material is very expensive, there is a problem in cost for industrial production. In (9), there is a problem that the reaction does not proceed unless the substituent is such as p-nitro. In (11) and (12), since the reduction reaction is a high-pressure reaction, there are great restrictions on the apparatus and there is a problem in cost as an industrial production method.

[0006] Therefore, from the above-mentioned problems, it has been desired to develop a method for easily and inexpensively industrially producing a target compound using milder production raw materials under mild conditions. .

[0007]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel method for producing phenoxyethylamines which are useful as raw materials for producing pharmaceuticals and agricultural chemicals.

[0008]

Means for Solving the Problems The present inventors have made intensive studies to solve the above-mentioned problems, and as a result, by reacting phenols and 2-oxazolidones in the presence of a base, mild conditions can be obtained. The present inventors have found a novel method for producing phenoxyethylamines in a high yield, and have completed the present invention.

That is, the present invention is as follows. The following formula (I):

[0010]

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(Wherein R ^{1 to} R ⁵ may be the same or different and represent a hydrogen atom, an alkyl group, an aralkyl group, an alkoxy group, an alkoxyalkyl group, a halogen atom, or a dialkylamino group). Phenols and the following formula (II):

[0012]

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(Wherein, R ^{6 to} R ⁹ may be the same or different and each represent a hydrogen atom or an alkyl group; R ¹⁰ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group). Reacting a 2-oxazolidone with a base in the presence of a base:

[0014]

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(Wherein R ^{1 to} R ¹⁰ have the same meanings as described above). Hereinafter, the present invention will be described in detail. Each compound represented by the above formulas (I) to (III) [hereinafter referred to as compounds (I) to (III), respectively]. ], The symbol (A) used in the target compound [Compound (III)] and its production raw material [(I), (II)]
r, R ^{1 to} R ¹⁰ ) are as follows.

Examples of R ^{1 to} R ⁵ include a hydrogen atom, which may be the same or different, an alkyl group, an aralkyl group, an alkoxy group, an alkoxyalkyl group, a halogen atom, a dialkylamino group, and the like; Is preferably a linear or branched alkyl group having 1 to 5 carbon atoms; an aralkyl group is preferably a straight or branched aralkyl group having 7 to 10 carbon atoms; as the alkoxy group A straight-chain or branched alkoxy group having 1 to 5 carbon atoms is preferable; As the alkoxyalkyl group, a straight-chain or branched alkoxy group having 1 to 5 carbon atoms, a straight-chain or branched alkoxy group having 1 to 5 carbon atoms is preferable. A substituent which is a chain or branched alkyl is preferable; a halogen atom is preferably a chlorine atom or a fluorine atom; and a dialkylamino group is Preferred substituents are straight-chain or branched alkyl having 1 to 5 carbon atoms.

Examples of R ^{6 to} R ⁹ include a hydrogen atom and an alkyl group which may be the same or different. Examples of the alkyl group include a linear or branched alkyl group having 1 to 5 carbon atoms. Alkyl groups are preferred.

R ¹⁰ is a hydrogen atom, an alkyl group,
Aryl groups, aralkyl groups and the like can be mentioned;
As the alkyl group, a linear or branched alkyl group having 1 to 5 carbon atoms is preferable; As the aralkyl group,
A linear or branched aralkyl group having 7 to 10 carbon atoms is preferred.

Compound (III) can be obtained in high yield by reacting compound (I) with compound (II) in the presence of a base, in the presence or absence of a solvent. Examples of the base include alkali metal lower alkoxides (for example, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide,
Potassium propoxide, sodium isopropoxide,
Potassium isopropoxide, sodium butoxide, potassium butoxide, etc., alkali hydroxides (eg, sodium hydroxide, potassium hydroxide, etc.) can be mentioned; when alkali hydroxide is used, it reacts with phenols. In order to avoid the influence of water generated by the reaction, it is preferable to previously react an alkali metal phenoxide obtained by reacting a phenol with an alkali hydroxide and a 2-oxazolidone.

The solvent is not particularly limited as long as it does not directly participate in the reaction. For example, alcohols (methanol, ethanol, isopropanol, butanol, cyclohexanol, amyl alcohol, ethylene glycol, ethylene glycol monomethyl ether,
Ethylene glycol monoethyl ether, diethylene glycol, propylene glycol, etc.), ethers (dioxane, tetrahydrofuran, diethyl ether, dibutyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, dimethoxyethane, etc.), aprotic polar solvents (dimethylformamide, dimethylacetamide, etc.) Examples thereof include dimethyl sulfoxide, N, N-dimethylimidazolidone, acetonitrile, etc.) and aromatic compounds (benzene, toluene, xylene, methylnaphthalene, petroleum ether, ligroin, hexane, chlorobenzene, dichlorobenzene, etc.). Preferably alcohols, ethers, aprotic polar solvents; more preferably The points 80 ° C. good at is one or more [e.g., alcohols having a boiling point above butanol, ethers (diethylene glycol dimethyl ether, diethylene glycol diethyl ether), such as a non-protonic polar solvents].

The amount of the solvent used is such that the concentration of compound (I) is 5
The content is preferably up to 50% by weight, preferably 10 to 40% by weight. The amount of the raw material to be used is generally 1.0 to 5.0 mol, preferably 1.0 mol, of compound (II) per 1 mol of compound (I).
It is preferred to use up to 2.0 moles. The amount of the base to be used is generally 0.8 to 2.0 mol, preferably 0.9 to 1.5 mol, per 1 mol of compound (I).
The reaction temperature is 80 ° C. or higher, but preferably 80 to 200 ° C., more preferably 90 to 150 ° C. in consideration of the thermal stability of the raw materials and products. The reaction time varies depending on the concentration, temperature and raw materials described above, but is usually 2 to 100 hours.

In the reaction, it is preferable to react the compound (I) with a base to produce phenoxide, and to add the compound (II) thereto. When an alkali hydroxide is used as the base, the phenoxide obtained by reacting the compound (I) with the base is preferably dried and reacted with the compound (II).

Compound (I) can be easily obtained by a commercially available product or by synthesis according to a usual method. Examples of the compound (I) include the compounds having a substituent of R ^{1 to} R ⁵ described above; preferably, phenols which may have a stable substituent with respect to a base (for example, , Phenol, cresol, xylenols,
Methoxyphenol, fluorophenol, chlorophenol, benzyloxyphenol, methoxyethylphenol, ethoxyethylphenol, ethoxyethyldimethylphenol, dimethylaminophenol, etc.)
Is good. Compound (I) also includes positional isomers of the substituents of R ^{1 to} R ⁵ and compounds in which the substituents overlap.

Compound (II) is described, for example, in US Pat.
473388, U.S. Pat. No. 2,437,389, U.S. Pat. No. 2,437,390, JP-A-59-222481, etc.) and can be easily obtained by reacting a carbonic acid diester with a corresponding amino alcohol. As the compound (II), the above-mentioned R
Compounds having substituents from ^{6 to} R ¹⁰ can be mentioned; preferably, 2-oxazolidone, 3-methyl-2
-Oxazolidone, 3-phenyl-2-oxazolidone, 3-ethyl-2-oxazolidone, 4-methyl-2
-Oxazolidone, 4-ethyl-2-oxazolidone,
4,4-dimethyl-2-oxazolidone, 5-methyl-
2-oxazolidone, 5-ethyl-2-oxazolidone, 4,5-dimethyl-2-oxazolidone, 3,4-
Dimethyl-2-oxazolidone, 3,5-dimethyl-2
-Oxazolidone and the like are preferable.

After completion of the reaction, the target compound (III) produced as described above can be subjected to operations such as liquid separation and filtration after addition of an acid to obtain a phenoxyamine salt. This is decomposed in an aqueous alkali metal hydroxide solution, and the compound (III) released can be isolated by performing operations such as solvent extraction and liquid separation. Then, it can be further purified by a purification operation such as distillation. As the acid used here,
Mineral acids (such as hydrochloric acid, sulfuric acid, and phosphoric acid) and organic acids (such as acetic acid, formic acid, and toluenesulfonic acid) can be used.
These acid decomposition reactions are usually completed within 0.1 to 1 hour at room temperature.

As the compound (III), the compounds having the substituents of R ^{1 to} R ¹⁰ described above corresponding to the starting compounds (I) and (II) used in the production can be exemplified. But preferably, 2-phenoxyethylamine, 2- (4-methylphenoxy) ethylamine, 2- (2,3-dimethylphenoxy) ethylamine, 2- (3-methoxyphenoxy) ethylamine, 2
-(4-fluorophenoxy) ethylamine, 2- (4
-Chlorophenoxy) ethylamine, 2- (4-bromophenoxy) ethylamine, 2- (4-benzyloxyphenoxy) ethylamine, 2- [4- (2-methoxyethyl) phenoxy] ethylamine, 2- [4- (2-
Ethoxyethyl) phenoxy] ethylamine, 2- [4
-(2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, 2- (4-dimethylaminophenoxy) ethylamine, N-methyl-2-phenoxyethylamine, N-ethyl-2-phenoxyethylamine, N
-Phenyl-2-phenoxyethylamine, N-methyl-2- (4-methylphenoxy) ethylamine, N-methyl-2- (3-methoxyphenoxy) ethylamine,
N-methyl-2- (2,3-dimethylphenoxy) ethylamine, N-phenyl-2- (2,3-dimethylphenoxy) ethylamine, N-methyl-2- (4-fluorophenoxy) ethylamine, N-methyl- 2- [4-
(2-methoxyethyl) phenoxy] ethylamine, N
-Methyl-2- [4- (2-ethoxyethyl) phenoxy] ethylamine, N-methyl-2- [4- (2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, N-ethyl-2-phenoxy Ethylamine, N-
Ethyl-2- (2,3-dimethylphenoxy) ethylamine, N-ethyl-2- [4- (2-ethoxyethyl)
Phenoxy] ethylamine, N-ethyl-2- [4-
(2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine is preferred. Further, the compound (I) also includes positional isomers of the respective substituents of R ^{1 to} R ¹⁰ and compounds in which the substituents overlap.

[0027]

[Boiling point 150 ° C / 4mmHg: Kugelrohr]

Example 2 2-Fluorophenol (2.8 g) and sodium methoxide (28% methanol solution) (4.9 g) were mixed under a nitrogen atmosphere, stirred at 50 ° C., and then butanol (10 ml) was added. added. The reaction system was depressurized to remove methanol, and 2-oxazolidone (2.6 g) was added to the reaction system.
The mixture was stirred at 20 ° C (bath temperature) for 8 hours. The reaction mixture was cooled and 1N hydrochloric acid (50 ml) was added, which was filtered,
After liquid separation, 4N-NaOH was added to the aqueous layer until the pH became 11 or more to release organic substances. Next, the organic matter is extracted with methylene chloride, and then separated, dried and concentrated to obtain crude 2- (4-fluorophenoxy) ethylamine, which is further distilled to obtain the highly purified target compound as 0%. 9.9 g was obtained (yield 23%). [Boiling point 135 ° C./3 mmHg: Kugelrohr] ¹ H-NMR (CDCl ₃ ) (δ ppm): 1.42
_{(S, 2H, NH 2)} , 3.08 (t, 2H, C
_{H 2), 3.96 (t,} 2H, CH 2), 6.79~
7.02 (m, 4H, phenyl proton)

Example 3 4-Bromophenol (0.87 g), potassium methoxide (0.36 g) and butanol (10 ml) were mixed under a nitrogen atmosphere, and the reaction system was depressurized to remove butanol. To this, 2-oxazolidone (1.22 g) and butanol (10 ml) were added, and the mixture was heated under reflux for 3 days.
The reaction mixture was cooled, 6N-hydrochloric acid (15 ml) and methylene chloride (15 ml) were added, and the mixture was stirred for 30 minutes.
To this mixture was added 10N-NaOH (15 ml) and methylene chloride (15 ml), followed by liquid separation.
Washed with N-NaOH (10 ml), dried and concentrated. The obtained residue was subjected to column chromatography (Wakogel QC200, n-hexane: ethyl acetate = 1: 1).
1 and then elution with methylene chloride: methanol = 10: 1) to give 0.23 g of 2- (4-bromophenoxy) ethylamine (yield 21
%). ¹ H-NMR (CDCl ₃ ) (δ ppm): 1.86
(Brs, 2H, NH ₂ ), 3,07 (t, 2H, CH
_{2), 3.96 (t, 2H} , CH 2), 6.72~6.
84 (m, 4H, phenyl proton), 7.30-7.
41 (m, 4H, phenyl proton)

Example 4 2,3-xylenol (1.22 g), potassium methoxide (0.71 g) and butanol (10 ml) were mixed under a nitrogen atmosphere, and the reaction system was depressurized to remove butanol. To this, 3-methyl-2-oxazolidone (1.
52 g) and butanol (5 ml) were added, and the mixture was heated under reflux for 10 hours. The reaction mixture was cooled and 6N-hydrochloric acid (1
0 ml) and methylene chloride (15 ml) were added and stirred for 30 minutes. To this mixture was added 10N-NaOH (12 m
After l) and methylene chloride (15 ml) were added and the mixture was separated, the organic layer was washed with 1N-NaOH (10 ml), dried and concentrated. The resulting residue was subjected to column chromatography (Wakogel QC200, n-hexane: ethyl acetate = 1: 1, then methylene chloride: methanol = 1).
(Eluting at 0: 1) to give N-methyl-
1.37 g of 2- (2,3-dimethylphenoxy) ethylamine was obtained (yield: 77%). ¹ H-NMR (CDCl ₃ ) (δ ppm): 1.76
(Brs, 1H, NH), 2.14 (s, 3H, C
_{H 3), 2.27 (s,} 3H, CH 3), 2.97
_{(S, 3H, CH 3)} , 2.29 (t, 2H, C
_{H 2), 4.06 (t,} 2H, CH 2), 6.71
(D, 1H, phenyl proton), 6.77 (d, 1
H, phenyl proton), 7.03 (dd, 1H, phenyl proton)

Example 5 N-methyl-2- (3-methoxyphenoxy) ethylamine was replaced by 1 in the same manner as in Example 4 except that m-methoxyphenol (1.24 g) was used instead of 2,3-xylenol. .26 g was obtained (yield: 75%). ¹ H-NMR (CDCl ₃ ) (δ ppm): 1.76
(Brs, 1H, NH), 2.50 (s, 3H, C
_{H 3), 2.97 (s,} 3H, CH 3), 3.78
_{(S, 3H, OCH 3)} , 4.05 (t, 2H, C
_{H 2), 6.46~6.66 (m,} 3H, phenyl protons), 7.12~7.28 (m, 1H, phenyl protons)

Example 6 2,3-xylenol (1.22 g), potassium methoxide (0.71 g) and butanol (10 ml) were mixed and stirred under a nitrogen atmosphere to obtain a homogeneous solution. Was reduced to remove butanol. Butanol (5 ml) was added to the obtained potassium-2,3-xylenoxide.
And further added 3-phenyl-2-oxazolidone [Ber. Deutsch Chem. GeS. , 55
Page (produced according to 1966. Melting point: 120 ° C.) (2.4
5 g) was added and the mixture was heated under reflux for 15 hours. The reaction mixture was cooled, 6N hydrochloric acid (20 ml) and methylene chloride (20 ml) were added, and the mixture was stirred for 1 hour. 1 to this mixture
0N-NaOH (20 ml) and methylene chloride (20 m
1) and liquid separation was performed, and then the organic layer was separated with 1N-NaOH.
(20 ml), dried and concentrated. The resulting concentrate is subjected to column chromatography (Wakogel Q
C200, eluted with n-hexane: ethyl acetate = 3: 1)
By purifying with N-phenyl-2- (2,3
2.27 g of (-dimethylphenoxy) ethylamine was obtained (yield: 94%). ¹ H-NMR (CDCl ₃ ) (δ ppm): 2.15
_{(S, 3H, CH 3)} , 2.27 (s, 3H, C
_{H 3), 3.53 (t,} 2H, CH 2), 4.14
_{(T, 2H, CH 2)} , 6.60~7.27 (m, 8
H, phenyl proton)

Example 7 4- (2-ethoxyethyl) -2,3-dimethylphenol (1.9 g) and sodium methoxide (28% methanol solution) (2 g) were mixed under a nitrogen atmosphere.
Stirred at ° C. After a homogeneous solution was obtained, the reaction system was depressurized to remove methanol to obtain sodium 4- (2-ethoxyethyl) -2,3-dimethylphenoxide. Butanol (10 ml) was added thereto, and 2-oxazolidone (1 g) was further added. The mixture was stirred at 120 ° C. (bath temperature) for 4 hours to precipitate a colorless solid. The reaction mixture was cooled, 1N-hydrochloric acid (40 ml) was added, and the mixture was filtered. The obtained solid and an aqueous layer were mixed, and 4N-Na was added.
OH was added until the pH was above 11 to liberate organics. Next, the organic matter was extracted with methylene chloride, separated, dried and concentrated to obtain crude 2- [4- (2-ethoxyethyl) -2,3-dimethylphenoxy] ethylamine, which was further distilled. Thus, 1.1 g of the target compound purified to a high purity was obtained (yield: 47%). [Boiling point 210 ° C / 4mmHg: Kugelrohr]

[0034]

According to the novel production method of the present invention, it is possible to produce phenoxyethylamines useful as raw materials for the production of medicinal and agricultural chemicals in high yields using mild starting compounds under mild reaction conditions. it can.

Claims (1)

(57) [Claims] (1) The following formula: (Wherein, R ^{1 to} R ⁵ may be the same or different and represent a hydrogen atom, an alkyl group, an aralkyl group, an alkoxy group, an alkoxyalkyl group, a halogen atom, or a dialkylamino group). The following formula: (Wherein, R ^{6 to} R ⁹ may be the same or different and represent a hydrogen atom or an alkyl group; R ¹⁰ represents a hydrogen atom, an alkyl group, an aryl group, or an aralkyl group). Is reacted in the presence of a base with the following formula: (Wherein, R ^{1 to} R ¹⁰ have the same meanings as described above).