JPH01113393A - Production of n-aralkylated aminofluorane - Google Patents

Abstract

PURPOSE: To obtain a high purity N-aralkylated aminofluorane at high yield without a complicated purification process by allowing an aminofluorane to react with an aralkylaryl sulfonate.

CONSTITUTION: The objective compound is obtained by allowing 2-aminofluorane expressed by a formula (the ring A is unsubstituted or substituted by halogen, nitro or the like, each of R₁ and R₃ represents H, halogen, a lower alkyl or a lower alkoxy, R₂ represents H, a lower alkyl, a lower alkoxy, each of X₁ and X₂ represents H, a (substituted) 1-12C alkyl, a cycloalkyl, tetrahydrofurylaryl, an acyl or -NX₁X₂ and is a 5- or 6-membered heterocyclic group) to react with an aralkyl aryl sulfonate expressed by a formula, Z-SO₂-O- Y (Z represents an aryl and Y represents an aryl alkyl or an aryl oxyalkyl), preferably aryl alkyl p-toluene sulfonate or the like.

COPYRIGHT: (C)1989,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing N-aralkylated aminofluorane.

Aralkyl groups are usually introduced by reacting the amino compound with an aralkyl halide such as benzyl chloride or benzyl bromide. This reaction is then carried out in the presence of an alkaline compound in a polar medium or in a non-polar solvent. However, when using polycyclic amino compounds, this method has the disadvantage that the yield of the final product is often insufficient.

The object of the present invention is to provide an improved production process which results in increased yields and at the same time provides products suitable for industrial use of high purity without complicated purification steps.

In particular, the present invention relates to a method for preparing N-aralkyl aminofluoranes, wherein the method of the present invention comprises the formula (wherein term 8 is unsubstituted or halogen, nitro, amino, lower alkylamino Substituted with di-lower alkylamino.

R1 and R1 independently represent hydrogen, halogen, lower alkyl or lower alkoxy; R2 represents hydrogen, lower alkyl or lower alkoxy; X and x2 independently represent hydrogen, unsubstituted or alkyl containing not more than 12 carbon atoms substituted by halogen, hydroxyl, cyano or lower alkoxy, or cycloalkyl, tetrahydrofuryl, aryl or acyl, or -
NX, 5-negative or 6-membered, preferably saturated with X2,
a 2-aminofluorane of the formula % (denoting a heterocyclic group) with an aralkylaryl sulfonate of the formula %, where Z is an aryl group and Y is an arylalkyl or aryloxyalkyl group. It is characterized by causing

Halogen is, for example, fluorine, bromine, iodine or preferably chlorine.

In the definition of the substituents of fluoran, lower alkyl and lower alkoxy usually refer to groups or group components containing 1 to 5, preferably 1 to 3 carbon atoms. Examples of lower alkyl are methyl, ethyl, n-propyl, isopropyl, lobutyl, 5ee-butyl, tert-butyl or amyl, and examples of lower alkoxy are methoxy, ethoxy, impropoxy, tert-methoxy, tert-amyloxy, etc. It is.

Acyl is preferably formyl, lower alkanoyl such as acetyl or propionyl, or benzoyl. In general, lower alkylsulfonyl such as methylsulfonyl or ethylsulfonyl, and also phenylsulfonyl, come into consideration as acyl groups. Cycloalkyl is, for example, cyclopentyl or preferably cyclohexyl.

Aryl in the definitions of x1 and x2 is preferably phenyl or tolyl.

Examples of heterocyclic groups -NX, Preferred saturated heterocyclic groups -NX, X2 are pyrrolidino, piperidino or morpholino.

X, and x2 are independently of each other, preferably C, -C,
-alkyl, cycloalkyl, phenyl or tolyl, particularly preferably lower alkyl, -NX, X2
preferably means pyrrolidino.

Preferably, ring A is not further substituted. If substituents are present, zero substituents are preferably halogen or lower alkylamino.

Particularly good results are obtained with the process of the invention when using fluoranes of the above formula in which R2 is hydrogen or preferably lower alkyl, most preferably methyl.

Suitable aralkylarylsulfonates of formula (2) are those in which the aryl group Z and the arylalkyl or aryloxyalkyl group Y are unsubstituted or ring-substituted. Preferred substituents are halogen, diI,
trifluoromethyl, lower alkyl preferably methyl,
Lower alkoxy such as methoxy.

Particularly suitable sulfonates of formula (2) are those in which Y is arylalkyl, such as benzenesulfonate, p-)-luenesulfonate, p-bromobenzenesulfonate,
It means p-nitrobenzenesulfonate and the like.

Examples of suitable sulfonates for introducing aralkyl groups are: benzyl p-toluenesulfonate, phenethylbenzenesulfonate.

Phenethyl p-toluenesulfonate, phenpropyl p-toluenesulfonate, α-methylbenzyl p-toluenesulfonate, phenpropylbenzenesulfonate, phenisopropyl p-toluenesulfonate, 4-chlorobenzyl p-toluenesulfonate, 4 -Methylbenzyl p-toluenesulfonate, 2.5-dimethylbenzyl p-toluenesulfonate, 2.5-dichlorobenzyl p-toluenesulfonate, benzyl p-nitrobenzenesulfonate, benzyl p
-bromobenzenesulfonate, 2,4-dimethylbenzyl p-toluenesulfonate, 4-trifluoromethylbenzyl p-toluenesulfonate, 4-methoxybenzyl p-toluenesulfonate, 2-phenoxyethyl p-toluenesulfonate, 2-phenoxyethylbenzenesulfonate.

A preferred alkyl sulfonate is benzyl p-toluene sulfonate. 2-phenoxyethyl p-toluenesulfonate is also preferred.

Aminofluorane and sulfonate are usually used in approximately stoichiometric proportions so that one or preferably two aralkyl groups are introduced for each amino group.

However, it is also possible to use an excess of one component, for example by 10 to 15%.

The reaction is conveniently carried out at elevated temperature, preferably in the range from 80 to 120°C, and in the presence of an acid acceptor.

Examples of suitable acid acceptors are alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal heavy acid salts, alkali metal carbonates, or tertiary nitrogen bases such as pyridine, N
- Methyl and lysine or trialkylamines.

Mixtures of these compounds are also suitable. A preferred acid acceptor is sodium carbonate.

Preferably, the reaction is carried out in a non-polar, preferably aromatic solvent such as benzene, toluene, xylene, chlorobenzene such as dichlorobenzene or trichlorobenzene, or nitrobenzene, particularly preferred solvents being toluene or xylene.

After the condensation reaction, the N-aralkylated aminofluorane is isolated by a conventional method. For example, the solvent is removed by steam distillation, the product is collected by filtration, and it is dried. If necessary, the aralkylated aminofluorane can be purified, for example, by recrystallization from isopropanol.

The present invention will be explained below with reference to Examples. Percentages in the examples are on a weight basis.

2-Amino-3-methyl-6-dinithylaminofluorane [West German Patent Publication No. B 2001864]
[produced according to Example 6 of No.]] and 8 of sodium carbonate.
．． 7 g of toluene are stirred in 28 g of toluene and the mixture is heated to 100°C. Then benzyl p-toluenesulfonate in toluene [Monatshefte-Chemie 1951
Manufactured according to the description on pages 452-459 of 123.6g
solution is added dropwise over a period of 2 hours at a temperature of 100-105°C. The reaction mixture is stirred at 100° C. for 8 hours and then poured into 100 g of water. The toluene phase was separated, washed three times with 50 g of water, dried over sodium sulfate,
and filter. After removing toluene by distillation under reduced pressure,
The crude product is taken up in a small amount of isopropyl alcohol, isolated in the form of a crystalline product at a temperature of 20° C. and dried. Thus, 12 g of fluorane of the following formula is obtained.

Yield: 69% of theory.

Melting point: 154-155°C.

The product immediately develops a red color on acid-modified silica gel.

12 g of 2-lamino 3-methyl-6-dinithylaminofluorane and 12.4 g of potassium carbonate are heated to 1000C in 601 of toluene. Next, 39% of benzyl P-toluenesulfonate in 51g of toluene.
Add the 3 parts of the solution over a period of 1 hour at a temperature of 100-105°C. A sample of this reaction mixture is taken and analyzed by liquid chromatography, which shows that 68.8% of the condensation product of formula (11) is already present.
The reaction is held at reflux temperature for an additional hour. Analysis of the new sample shows the presence of 99.2% reaction product.

The reaction product is filtered to remove non-alpha salts, the filtrate is concentrated, and the residue is stirred in 75o+1 isopropanol. The crystallized condensate is isolated by filtration and dried to give 5 g of product io. The results of liquid chromatography analysis show that the filtrate contains an additional 2.1 g of dibenzylaminofluorane of formula (11), but no corresponding monobenzylaminofluorane.

Comparison 1 12 g of 2-ciminol-3-methyl-6-dinithylaminofluorane and 12.4 g of potassium carbonate were mixed with 6 g of toluene.
Heat to 100°C in 0ml. Next, toluene 5
A solution of 19 g of benzyl chloride in 1 g of 100 to 10
Add over 1 hour at a temperature of 5°C. A sample taken from this reaction mixture and analyzed by liquid chromatography shows that there is still no trace of the condensation product of formula (11).

The reaction mixture is kept at reflux temperature for 1 hour. The analysis of the new sample shows no trace of the dibenzylaminofluorane of formula (11), but only the presence of 3.2% of the corresponding N-monobenzylated aminofluorane.

The reaction mixture is filtered to remove inorganic salts, the filtrate is concentrated, and the residue is stirred in a 751 Improper Tool. 8.3 g of starting material 2-amino-3-methyl-6-dinithylaminofluorane are recovered by filtering and isolating the crystalline product.

By concentrating the filtrate, the condensation proceeds slightly further. Liquid chromatography analysis showed the production of 1.7 g of monobenzylaminofluorane and 1.1 g of dibenzylaminofluorane. .

10 g of 2-amino-3-methyl-6-dinithylaminofluorane, 10.4 g of potassium carbonate and 21.9 g of 2-phenoxyethyl P-toluenesulfonate [Journal of Organic Chemistry] (J,
Org, (:hem, )dan (1944), 235
．． prepared as described on pages 238-240] in xylene (
Isomer mixture) is stirred under reflux for 11 hours at a temperature of 137 to 140° C. in 40 ml. Another 501 g of xylene was added and the reaction mixture was boiled with 100 u+1 water at a temperature of 50"C.

Extract in return. The xylene phase is concentrated until the condensate crystallizes. Then the product i! ! Overisolate, wash with isopropanol, and dry. Thus, 3.1 g of a compound of the following formula is obtained.

The product is in the form of colorless crystals, with a melting point of 18
9-191''C. A solution of this compound in toluene instantly develops a black color on acid-modified silica gel.

Shigowata A The filtrate obtained in Example 3 was subjected to column chromatography (silica gel column: toluene/ethyl acetate 2
Dissolve in a 0:1 mixture.

2.8 g of fluoran of the following formula was obtained.

The melting point after recrystallization from isopropanol/toluene (10:1) is 117-119°C.

This compound instantly develops a red color on acid-modified silica gel.

Mitate 1 9.6 g of 2-amino-6-dinithylaminofluorane
,) 6.9 g of potassium J acid and 14.6 g of 2-phenoxyethyl p-toluenesulfonate are heated in 50 ml of xylene with good stirring and the mixture is kept under reflux at a temperature of 133-137° C. for 22 hours. do. Furthermore, 501 xylene was added to this reaction mixture, and 80
Add 100 ml of water at a temperature of °C. After this, the xylene phase is separated, washed repeatedly with water, and concentrated to obtain the crude reaction mixture ioz. Equation (14) and Equation (15) below
Fluorane compounds can be separated by column chromatography using a silica gel column; 10% of toluene/ethyl acetate
:1 mixture) and each is recrystallized from isopropanol.

Melting point: 124-127°C0 Melting point: 143-146°C.

On acid-modified clay, the compound of formula (14) develops a green color, and the compound of formula (15) develops a black color.

Claims (1)

[Claims] 1. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, ring A is unsubstituted or substituted with halogen, nitro, amino, lower alkylamino or di-lower alkylamino) R_1 and R_3 independently represent hydrogen, halogen, lower alkyl or lower alkoxy, R_2 represents hydrogen, lower alkyl or lower alkoxy, X_1 and X_2 independently represent hydrogen, , unsubstituted or substituted by halogen, hydroxyl, cyano or lower alkoxy, alkyl containing not more than 12 carbon atoms, or cycloalkyl, tetrahydrofuryl, aryl or acyl, or -NX_1X_2 with 5 members or a 6-membered heterocyclic group) with the formula (2) Z-SO_2-O-Y, where Z is an aryl group and Y is an arylalkyl or aryloxyalkyl group. A method for producing N-aralkylated aminofluorane, which comprises reacting it with an aralkylaryl sulfonate (meaning ). 2. The process according to claim 1, wherein an aralkylaryl sulfonate of formula (2) is used, in which Y is an arylalkyl group. 3. The method according to claim 1, wherein the aralkyl arylsulfonate is arylalkyl p-toluenesulfonate, arylalkyl p-bromobenzenesulfonate or arylalkyl p-nitrobenzenesulfonate. 4. Aralkylaryl sulfonate is benzyl p-
The method according to claim 1, wherein the toluene sulfonate is toluene sulfonate. 5. The method according to claim 1, wherein the aralkylaryl sulfonate is 2-phenoxyethyl p-toluenesulfonate. 6. Formula (1) where R_2 is hydrogen or a lower alkyl group
2. The method according to claim 1, wherein a fluoran compound of 7. The method according to claim 1, wherein a fluoran compound of formula (1) is used, in which R_2 is methyl. 8. Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, ring A is unsubstituted or substituted with halogen, nitro, amino, lower alkylamino or di-lower alkylamino, R_3 independently of each other means hydrogen, halogen, lower alkyl or lower alkoxy group, R_2 means hydrogen, lower alkyl or lower alkoxy, X_1 and X_2 independently of each other hydrogen, unsubstituted or halogen, means alkyl containing not more than 12 carbon atoms substituted by hydroxyl, cyano or lower alkoxy, or cycloalkyl, tetrahydrofuryl, aryl or acyl, or -NX_1X_2, 5- or 6-membered heterocycle and Y_1 means an aryloxyalkyl group). 9. Claim 8, wherein Y_1 is 2-phenyloxyethyl.
Aminofluorane as described. 10. The aminofluorane according to claim 8, wherein R_2 is methyl. 11.Do X_1 and X_2 mean lower alkyl?
The aminofluorane according to claim 8, wherein -NX_1X_2 means pyrrolidino, piperidino or morpholino.