SU420180A3 - METHOD FOR OBTAINING ACYLOXYLKYL HETEROCYCLIC COMPOUNDS - Google Patents

Description

one

The invention relates to the production of new heterocyclic compounds that can be used in the pharmaceutical industry.

A known method for producing acyloxyalkyl compounds of the general formula

/ ъ

A —CO — H,

“Kj,

where Z is sulfur or lower al.kylimino, RI is hydrogen, halogen, lower alkyl or alkoxy, trifluoromethyl, R2, Ra is hydrogen, "izyl 1 alkyl, AI, A2 is lower alkylene, R is lower alkyl, consisting of what is the general formula

I / L-

A {-CO-: t

where RI, Z, AB AO, Ro, RS have the indicated values, they are subjected to the acylation of the acylated HUIM agent, aanp iiMep acid chloride: M Acid C1COR, where R has the indicated values. Products are isolated in a known manner.

Using the well-known reaction of acidification of the oxo compounds, according to the proposed

The new acyloalkyalkyl-heterocyclic compounds have been obtained with improved pharmaceutical pharmaceutical properties compared with the known analogous compounds.

The described proposed method was obtained and acyloxyalkyl-heterocyclic compounds of general formula I

"

one

7 / (CH2) h

A, -CO - N ,, K-Ao-OR-2 AI II AO is lower alkylene or lower alkylidees, RI is hydrogen, halogen, trifluoromethyl, R2-acyl, selected from the group consisting of IPD alps) aticotic acyl, having 10-20 carbon atoms, phenyl - lower alkanoyl or bsnosoyl, in which the benzene nucleus can have no more than three halogen atoms, no more than three lower alkyls and / or no more than three alkoxy, n 2 3 or 3; or their salt, is that a compound of a general formula of the formula I (A-CO-K. N-A2-OK where Z, AB A2, Ri, n have the indicated meanings, or its salt, is subjected to acylation of the connected R2OH {III), where Rj has the indicated values, or its reactive derivative, predominantly chlorine nhydride | acid acid. The resulting product is isolated in free form or in the form of a salt by known methods. The hydrochloride, hydrobromnd, sulfate, acetate, picrate, citrate, tartrate are used as a sore used as the starting product of the compound R2-OH. Reaction-capable derivatives of the compound R2-OH can be haloanhydride acid, acid anhydride, amggda, esters, acid azides. When using Compound III, a condenser agent is usually required. The reaction is usually carried out in an inert medium, n (acetone, dioxane, acetone, di methyl form, amide, di methyl acetone, 1D, dimethyl sulfoxide, chloroform, ethnlendechlorde, tetrahydrofuran, tetacetate, pyridine). The reaction temperature is derived from the use of my source, 1x compounds, condeusing agent and the solvent used. Example 1. A solution of 3- 4- (2-hydroxyethyl) 1-piperazinyl-carbonylmethyl-5-chloro-2-benzotnazolinone {15.0 g) n triethylamine (16.6 g) in dry chloroform (330 cm) is maintained at 20 ° C and a solution of palmitoyl chloride (34.7 g) in dry chloroforme (60 cm) is added dropwise to it; the addition is carried out by stirring, for 2 hours. Next, the mixture is mixed for about 3 hours and, after the end of the reaction, 10% aqueous solution of caustic soda (100 cm) and water (100 cm) is added to it. The chloroform layer is separated, washed with water three times, and then dried over anhydrous magnesium sulphate. The solvent was distilled off, and the residue thus obtained was recrystallized from a mixture of benzene and petroleum gasoline to give (2-palmitoyloxyethyl) -1-piperazinyl carbonylmethyl-5-chloro-2-beisothiazolium (14.0 g) as colorless flaky-like h; Stitz with m. Pl. 84--86 ° C. Example 2. A solution of 3- 4- (2-hydroxypropyl) -1-piperazinyl-carbonylmethyl-5-chloro-2-b. Isoisothiazolium (2.0 g) and trIethylamine (1.1 g) in dry chloroform (20 cm) incubated at 15 - 20 ° C with stirring. A solution of palmitoyl chloride (5.9 g) in dry chloroform (10 cm) is added dropwise to it over 40 minutes, and then the mixture is stirred for another 4.5 hours. After completion of the reaction, water is added to the reaction mixture. The chloroform layer is separated, washed with an aqueous solution of sodium carbonate three times, and then with water and dried over anhydrous magnesium sulfate. The solvent is distilled off and the residue is chromatographed on alumina, using ethyl acetate as the developer. The resulting solution is evaporated and 3- 4- (2-palmitoyloxypropyl) -1-eperazivyl-carbonyl-5-chloro-2-benzothiazoleINO (0.9 g) is obtained. This substance is recrystallized from a mixture of petroleum gas and benzo, 1a, to obtain a colorless powder, with tl. 94-95 ° C. Example 3. A solution of 3- 4- (2- hydroxyethyl) -1-P: iper. Aeonyl - "arbonylmethyl-5-chloro-2benzothiazolinone (5.0 g); and anhydrous" potassium arbonate (3.89 g) in dry; m chloroform (100 cm) is kept at 20–23 ° C with stirring and a solution of stearoyl chloride (17.1 g) in dry chloroform (20 cm) is added dropwise to it within 55 minutes. The mixture is stirred for an additional 7 hours and after the end of the reaction, the chloroform layer is separated, washed with water, and then dried with anhydrous sulfate. Magnesium. The solvent is distilled off under reduced pressure to give an oil (8.3 g). The benzoate solution of the oil is chromatographed to give: crude oil (5.9). The oil obtained in this way is recrystallized from petroleum gas 4 times to obtain (2-stearo: iloxyethyl) -1-piperaznyl-carboylmethyl-5-chloro-2-benzothiazole; 1g, in the form of colorless cristae; 74-76 ° C. Pr 1I. M er 4. A solution of 3- 4- (2-hydroxyethyl) - I-inerase - carboiylmethyl-5-chloro-2-benzothiazolium (20.0 g) and pyridine (8.85 g) in dry chlorofor. IU (250 cm) is maintained at 15-20 ° C with stirring. A solution of phenylacetyl chloride (34.7 g) in dry chloroform (30 cm) is added dropwise to i.i for 1 hour, and then the solution is mixed again for 3.1 hours at room temperature. After completion of the reaction, an aqueous solution of sodium carbonate was added to the reaction mixture. The chloroform layer is separated, washed with sodium carbonate and extracted with 10% hydrochloric acid. The hydrochloric acid layer is left od, and then the precipitated crystals are filtered and recrystallized from ethanol to give 3- 4- (2-phenylacetoxyethyl) -1-piperazinyl-carbonylmethyl-5-chloro-2-benzothiazo hydrochloride. chlorine in the form of colorless flaky particles with m. pl. 206 - 207 ° С.

Example 5. A mixture of 3- 4- (2- oxnpropi.) - 1-piperazinyl-carb0: nilmethyl-5-chloro-2-benzothiazolion (2.0 g) .and triethylamine (0.55 g) in total. Chloroform (20 cm) is maintained at 20 - 25 ° C under stirring. 1 solution of feium acetyl chloride (1.01 g) in dry chloroform (10 cm) was added dropwise to the mixture and the mixture was stirred for another 4 hours at room temperature. After the end of the reaction, water is added to the reaction mixture. The chloroform layer is separated, washed with sodium hydroxide solution, water, dilute hydrochloric acid, and again with WATER, then dried over anhydrous magnesium sulfate. The solvent is distilled off, and the remaining oil is chromatographed on alumina with benzene. The eluent is copulated to give an oil (0.4 g) and an ethanol solution of hydrochloric acid is added to it. The precipitated crystals are collected by filtration and recrystallized from an aqueous solution of ethanol to give 3- 4- (2-phenyl-aceto-ipropyl) -1-piperazine Il-Carbopnlmethyl-5-chloro-2-benzotnazolinone hydro / legal as a colorless rind. 250 ° C (with decomposition).

Example 6. C. a mixture of 3- 4- (2-okoiethyl) -1-lipezinyl-carbonylmethyl-5-chloro-2-benzothiazolinone (1.0 g), 3, 4, 5- trimethoxybenzoyl chloride (0.7 g) 1I anhydrous carbonate calc. And (0.2 g in dimethylformamides (20 cm) are stirred at room temperature for 17 hours. After the reaction is complete, the reaction mixture is washed with water and extracted with chloroform. The extract is dried and the solvent is distilled off, the residue is chromatographed with ethyl acetate using ethyl acetate as the solvent. The resulting stream is evaporated and the residue is dissolved in m a scrap of dry ethanol and precipitated by adding an ethereal solution of maleic acid. The precipitated crystals are recrystallized from dry ethanol to give 3- 4- (2- (3, 4, 5-trimethoxybe "zoyloxy) -ethyl-1-piner. vinyl-carbonylmethyl- 5-chloro-2-benzotriazolinone, maleate (0.3 g) with mp 123-130 ° C (with decomposition).

Example 7. C. a mixture of 3- 4- (2-hydroxyethyl) - 1-piperazyl or carbonylmethyl-5-chloro-2-bb-oxoxazolinone (1.0 g), palmitoyl chloride (0.89 g), potassium carbonate (0, 41 g of dry dimethylformamide (0.5 cm) stirred

within 3 hours After completion of the reaction, ethyl acetate and water were added to the reaction mixture. The ethyl acetate fraction is washed with water and dried over anhydrous magnesium sulphate. After distillation of the solvent, (2-palmitoyloxyethyl) -1-piperazivyl-carbonallmethyl-5-chloro-2-benzoxazolinone (1.2 g) was obtained. This substance is recrystallized from petroleum gas and a colorless powder with a melting point is obtained. 72 - 74 ° C

Example 8. To a solution of 3-methyl-6 -chloro-4- (2-hydroxyethyl) -1-piperazinyl-carbonylmethyl-2-bé; 1 zimidazolium non (0.35 g) in dimethyl acetamide (7 cm), potassium carbonate ( 0.3 g). Next, a solution of ilmitoyl chloride (0.3 g) in dimethylformamides (3 cm) is added to the mixture. The mixture obtained in such a way is alternated for another 2 hours at room temperature. After completion of the reaction, the reaction mixture is washed with ice water and extracted; ethyl acetate is added several times. The extract is well washed with water and dried. The solvent is distilled off, and the remainder of the 1 stalls 130 is taken from a mixture of benzene and m-hydroxy, to obtain 3-methyl-6-chloro-1- 4- (2-palmitoyloxyethyl) -1-piperazinyl-carboylmethyl-2-benzimidazolinone (0.25 g with t. pl. 97-98 ° C.

Example 9. 3- 4- (2-lauroyoyloxyethyl) -1-piperazinyl-carboni, tmethyl-5-chloro-2-benzothiazolino} (0.5 s) is prepared in much the same way as described above, by the reaction of 3-4 ( hydroxyethyl) -1-piperazipyl-carbopylmethyl-5-chloro-2-benzothiazolinium (0.72 s) with lauroyl chloride (0.44 s. This substance is converted by the usual method into maleate and colorless crystals are obtained with mp 168-171 ° WITH.

Example 10. (2-L11NOLOILOXYETHYL) -1-P1sherasil-carbopolylmethyl-5-chloro-2-benzothiazolino (0.5 g) is obtained in the same manner as described above, by reaction of 3- 4- (2-hydroxyethyl) - 1-piperazyl-carbonyiomethyl-5-chloro-2-benzothiazolipon (0.74 g) with l) P10loyl chloride (0.8 g). Colorless 1C maleate crystals have m. Pl. 150-152 ° C (decomposition).

Example 11.3- 4- (2-lauroploxypropyl) -1-piperazinyl-carbopropylmethyl-5-chloro-2-benzothiazolium (0.8 g, prepared in the same manner as described above, by the reaction of 3- 4- (2-ox -propyl) -1-piperazyl-carboplmethyl-5-chloro-2-benzothiazolinone (0.9 g with lauroyl chloride (0.64 g). Maleate has a melting point of 162-165 ° C.

Prpmer 12. 3- 4- (2-lioloilokoshopropil) - 1-piperazinyl - carbonylmethyl-5-chloro-2-benzothiazolium, and get the same way, which is described above, by reaction of 3- 4- (2-hydroxypropyl) -1 - piperazinyl - carbonylmethyl - 5 - chlorothiazolium with lino, 10yl chloride.

Subject invention

1. The method of producing acyloxyalkyl-heterocyclic compounds of the common

/ (eNo)

rt

: G-Ao-OB.7

And, - CO-,

where Z is sulfur, sour yud,

lower alkylimpio group A and A2-inisuiHfl alkylene or lower A.chylnden,

RI is hydrogen, halogen or trifluoro-methyl, R2-acyl, selected from the group consisting of aliphatic acyl, IM 10 10-20 carbon atoms, fpl-izshego alkayoyl or benzoyl,. in which there are 13 solids, it can have more than three halo atoms, no more than three iz x alkyl and / or no more than three lower alkoxyls, n 2 or 3; 1 or their salts, characterized in that the compounds and general formulas

(CH, 1

|

/

CO-N

where Z, A, A2, RI, and p have the indicated values, or its salt, is acylated with an Ro OH acylating agent, where R2 has the indicated values, not all of its reactants are ion-producing organisms, after which the compound is isolated and converted into salt by lime. tricks.

2. The method according to and. 1, characterized in that. that acid chlorine is used as the 5th acylating agent.