KR890001851B1 - Process for the preparation of amine alkanolester - Google Patents

Abstract

Aminoalkanol ester derivative of formula (I), useful as antispasmodic, was prepared from the reaction of (II) with alcohol compound (III). Here, R1 is H, C1-4 alkyl, C1-4 alkoxyl, halogen, trifluoro methyl. R2 is H, C1-4 alkyl. R3-7 are same or C1-4 lower alkyl. x, y, z are 0 or 1. n is 1 to 3 of integer. R is ethyl or phenyl. X is oxygen or Sulphur atom.

Description

New preparation method of aminoalkanol esters

The present invention relates to a method for producing new and old aminoalkanol ester derivatives of formula (I), which is effective for inhibiting spasms and peristalsis of gastrointestinal muscle tissue.

In the above formula, R ¹ means hydrogen, alkyl of 1 to 4 carbon atoms, alkoxyl, halogen, trifluoromethyl group of 1 to 4 carbon atoms, R ² means hydrogen, alkyl group of 1 to 4 carbon atoms, R ³ to R ⁷ represent an alkyl group having 1 to 4 carbon atoms which are the same as or different from each other, X, Y, and Z each represent 0 or 1, and n represents an integer of 1 to 3.

Methods for preparing the compound of formula (I) have been reported in British Patent No. 1,342,547, Japanese Patent Publication No. 75-142533, Korean Patent Publication No. 85-385, and in most cases, acids of the formula (II) or derivatives thereof. An ester of formula (I) was prepared by reacting an alcohol of formula (III).

Wherein R ¹ -R ⁷ and x, y, z, n are as described above.

As used herein, halogen means chloro or bromo and derivatives of acid means esters and acid chlorides. An example of preparing the compound of formula (I) using esters of the compound of formula (II) is reported in British Patent No. 1,342,547, according to this method, in the presence of a metal alkoxide which catalyzes the alkyl ester of the compound of formula (II). The ester of formula (I) was prepared by reacting the alcohol of formula (III) at high temperature. However, this method has disadvantages of high reaction temperature and low yield.

An example of preparing the compound of formula (I) using an acid chloride of the compound of formula (II) is reported in Japanese Patent Laid-Open No. 75-142533. According to this method, an acid chloride of the compound of formula (II) An ester of formula (I) was prepared by reaction with an alcohol of formula (III). However, this method has the drawback that the reaction time is long and the acid chloride is unstable at the time of ester removal.

Next, N, N'-dicyclohexylcarbodiimide, which is a condensing agent, is used. An example of preparing an ester of the structural formula (I) by directly reacting an acid of the structural formula (II) with an alcohol of the structural formula (III) is disclosed in Korean Patent Application Publication 85. It is shown in -385. However, in this method, N, N-dicyclohexylurea produced as a by-product is always present as an impurity, and there is a disadvantage in low yield because of side reactions (production of N-acylurea).

The present invention provides a novel esterification process for preparing a compound of formula (I) using a novel reactive ester of structure (VI). Accordingly, an object of the present invention is to react 1-hydroxy benzotriazole represented by formula (IV) with dialkyl (or diaryl) chlorophosphate (or clociophosphate) of formula (V) in the presence of a tertiary amine. To prepare an intermediate of formula (VI), react the acid of formula (II) to prepare a reactive ester of formula (VII), and then react it with an alcohol of formula (III) to It is to provide a new esterification method for preparing a compound.

Wherein R ¹ -R ⁷ and x, y, z, n are as described above, R represents an ethyl or phenyl group and X represents an oxygen or sulfur atom. The solvent for preparing compound (VI), which is an intermediate in these reactions, is acetone, ethyl acetate, methylene chloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran As long as it is a polar solvent which does not inhibit the above reaction, all can be used except an alcohol kind. Tertiary amines to be used include triethylamine, trimethylamine, pyridine, N-methylmorpholine and the like, of which triethylamine is most suitable. The tertiary amine may also be used in an amount of 0.5-5 equivalents to 1 equivalent of 1-hydroxybenzotriazole, preferably 1-1.5 equivalents.

The compound of formula (V) is used in the amount of 1 to 1.5 equivalents based on 1 equivalent of 1-hydroxybenzotriazole. Representative examples of the compound of formula (V) include diethyl chlorophosphate, diphenylchlorophosphate, diethyl chlorochlorothiophosphate, Diphenylchlorothiophosphate and the like.

The reaction can be carried out in the range of 0-50 ° C, but is usually carried out at room temperature and the reaction time is 1-5 hours, preferably 2 hours. After the reaction, the by-product salts are filtered off, and the solvent in the reaction solution is distilled off under reduced pressure to obtain quantitative intermediate (VI).

Next, as a solvent for preparing the reactive ester of the formula (VII), if it is a polar solvent mixed well with water such as acetone, tetrahydrofuran, N, N-dimethylacetamide, N, N-dimethylacetamide, dimethyl sulfoxide, You can use all but the kind.

The reaction is usually carried out at room temperature and the reaction time takes 1 to 5 hours, but preferably about 2 hours. When the reaction is completed, the reaction solution is dispersed in ice water to obtain byproduct reactive ester in powder form. The amount of ice water used at this time can be used 5-50 times the reaction solution. 10-15 times is most suitable.

Next, solvents for preparing the ester of the structural formula (I) include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, acetone, tetrahydrofuran, and the like. Dimethylformamide and N, N-dimethylacetamide are most preferably reacted.

The reaction time takes 4-10 hours, usually 5-6 hours at room temperature. When the reaction is completed, the reaction solution is dispersed in 10-20 times of water, extracted with an organic solvent, and then maleic acid is added to obtain an ester of formula (I) as maleate.

The present invention has the following advantages compared to the conventional esterification method.

1. Since the reactive ester of formula (VII), which is an intermediate, is more stable than conventional acid chlorides or mixed acid anhydrides, the esterification reaction can be separated quantitatively. 2. Since the side reactions do not proceed during the esterification reaction, The yield of the compound of formula (I) is high, and 3. the reaction time is relatively short, because all the reaction proceeds at room temperature, 4. the 1-hydroxybenzotriazole used for the preparation of the intermediate can be recovered and reused, The production facilities and processes are simpler and higher yield than the method of the present invention provides a new and economical esterification method.

The following examples are intended to illustrate the method of the present invention in more detail, and these examples do not limit the present invention.

Example 1

6.75 kg (0.05 M) of 1-hydroxybenzotriazole is turbid in 50 ml of acetone, and 7.66 g (0.055 M) of triethylamine is slowly added to dissolve completely. 7.23 ml (0.05 M) of diethylchlorophosphate was added dropwise over 10 minutes while maintaining the temperature of the solution at 5-10 ° C. and stirred for 1 hour at the temperature mentioned above. The resulting insolubles are filtered off and the filtrate is used for the next reaction.

10.6 g (0.05 M) of 3,4,5-trimethoxybenzoic acid was completely dissolved in a solution of 6.97 ml (0.05 M) of triethylamine and 20 ml of N, N-dimethylformamide, followed by the acetone solution prepared above. Add dropwise over 30 minutes. The reaction temperature is preferably 15-20 ℃.

Then, the mixture was stirred for 2 hours to complete the reaction, and the reaction solution was turbid in 700 ml of ice water. After the crystals were formed, the mixture was stirred for 30 minutes, filtered, and then washed with 50 ml of ice-water twice, and when dried, 15.6 g (95%) of 1-hydroxybenzotriazole ester of the desired 3,4,5-trimethoxybenzoic acid. Get

mp (℃): 160-170 (decomposition)

) : 4.02(6H,s,

4.10 (3H, S,

, 7.57(2H,S,-

, 7.48.3(4H,m, 벤조트리아졸-H)IR (KBr, cm^-One) ; 2920 (s), 1790 (VS, estercarbonyl), 1595 (VS), 1500 (VS), 1460 (VS), 1320 (VS)^OneH-NMR (CDCl₃/ TMS,

): 4.02 (6H, s,

4.10 (3H, S,

, 7.57 (2H, S,-

, 7.48.3 (4H, m, benzotriazole-H)

Example 2

The reaction of Example 1 was carried out using 50 ml of N, N-dimethylformamide instead of acetone, and 15.3 g of 1-hydroxybenzotriazole ester of the desired 3,4,5-trimethoxybenzoic acid (93 %)

mp, IR and ¹ H-NMR data are the same as in Example 1.

Example 3

The reaction of Example 1 was carried out using 10.36 ml (0.05 M) of diphenylchlorophosphate instead of diethylchlorophosphate, thereby yielding 1-hydroxybenzotriazole of the desired 3,4,5-trimethoxybenzoic acid. 15.8 g (96%) of ester are obtained.

mp, IR and ¹ H-NMR data are the same as in Example 1.

Example 4

The reaction of Example 1 was carried out using 7.86 ml (0.05 M) of diethylchloroophosphate instead of diethylchlorophosphate, thereby yielding 1-hydroxybenzotria of the desired 3,4,5-trimethoxybenzoic acid. 14.8 g (90%) of sol esters are obtained.

mp, IR and ¹ H-NMR data are the same as in Example 1.

Example 5

4.66 g (0.02 M) of 2-dimethylamino-2phenylbutanol hydrochloride are turbid in 150 ml of N, N-dimethyl formamide and 6.0 ml (0.04 M) of triethylamine are added slowly. After stirring for 30 minutes, 6.69 g (0.02 M) of 1-hydroxy benzotriazole ester of 3,4,5-trimethoxybenzoic acid prepared in Example 1 was added in a solid state. The solution is stirred at 15-20 ° C. for 5 hours to complete the reaction. The reaction solution is slowly added to 21 ice water and extracted with ethyl acetate (200 ml x 3). The ethyl acetate layer was washed with ice water (100m1x2) and 2% aqueous sodium carbohydrate solution (50mlx2) to distill the solvent under reduced pressure.

40 ml of ethanol and 7.5 g of maleic acid were added to the residue, followed by complete solution and stirring. The crystals began to precipitate. After stirring for 2 hours at 0-5 ° C. at room temperature, the mixture was filtered to obtain 2-dimethylamino-2-phenylbutyl ester of 3 ', 4', 5'-trimethoxybenzoic acid as white crystals. .

Yield: 7.76 g (82%)

mp (℃): 129-130

IR (KBr, cm ^-1 ): 2950 (m), 1720 (VS, ester carbonyl), 1590 (s), 1450 (VS), 1330 (VS), 1210 (Vs)

) : 1.00(3H, t, J=8Hz,-CH₂-CH₃),2.65(2H,9,J=8Hz,-CH₂-CH₃),2.92

¹ H-NMR (CDCl ₃ / TMS,

): 1.00 (3H, t, J = 8Hz, -CH ₂ -CH ₃ ), 2.65 (2H, 9, J = 8Hz, -CH ₂ -CH ₃ ), 2.92

Example 6

Reaction was carried out by the method of Example 5 using 150 ml of N, N-dimethylacetamide instead of N, N-dimethylformamide, and 2-dimethyl of the desired 3 ', 4', and 5'-trimethoxybenzoic acid. Amino-2-phenylbutyl ester is obtained as maleic acid salt.

Yield: 7.38 g (78%)

mp, IR and H- ¹ NMR data are the same as in Example 5.

Claims (1)

Intermediate of formula (VI) was prepared by reacting 1-hydroxybenzotriazole of formula (IV) with dialkyl (or diaryl) chlorophosphate (or chlorothiophosphate) of formula (V) in the presence of a tertiary amine. And reacting an acid of formula (II) to prepare a reactive ester of formula (VII), which is then reacted with an alcohol of formula (III) to form an ester of formula (I), which is a maleate salt. Method of preparation as (VIII)

In the above formula, R ¹ means hydrogen, alkyl having 1 to 4 carbon atoms, alkoxyl having 1 to 4 carbon atoms, halogen, trifluoromethyl group, R ² is hydrogen, alkyl group having 1 to 4 carbon atoms, R ³ to R ⁷ is a lower alkyl group having 1 to 4 carbon atoms which are the same or different from each other, x, y and z are each 0 or 1, n is an integer of 1 to 3, R is an ethyl or phenyl group, and X is oxygen or a sulfur atom. .