DE1695202A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Process for the preparation of new heterocyclic compounds The present invention relates to a process for the preparation of new; heterocyclic compounds, namely of new en benzothiazepine compounds of the general formula in which R1 is hydrogen, a halogen atom or a lower alkyl group, R2 and R3 is hydrogen or lower alkyl groups, A is a carbonyl or methylene group, R4 is hydrogen, a lower alkyl group or a lower carboxyalkyl group, it is a lower alkanoyloxy group and R6 is hydrogen or a lower alkyl group represent, as well as acid addition salts of such compounds.

The lower alkyl groups denoted by the symbol R in the above formula straight-chain or branched alkyl groups, such as the methyl, Be ethyl, propyl and zsopropyl groups. Halogen is anything of the 4 halogens chlorine, bromine, iodine or fluorine.

The process according to the invention is characterized in that a compound of the general formula in which R1, R2, R3, R4, R6 and have the meaning given above, acyloxylated by treatment with the anhydride of a lower alkanecarboxylic acid with simultaneous conversion of the sulfinyl group into the thio group and, if desired, a base obtained is converted into an acid addition salt.

According to the invention, compounds of the formula I are obtained in that a compound of formula II with a lower alkanecarboxylic anhydride, e.g. B. treated with acetic anhydride.

Preferred compounds of the formula I are those in which A is the methylene group represents.

Thus, a preferred embodiment of a process according to the invention consists in the preparation of compounds of the general formula in which the symbols R1 to R6 have the above meaning.

For example, the starting compounds of Formula II can be prepared thereby that a nitrobenzyl halide of the formula III, e.g. an α-monoalkyl-2-nitrobenzyl halide, an α, α-dialkyl-2-nitro-benzyl halide or one which is substituted in the ring Reacts derivative of such a halide with a mercapto acid of the formula IV and the 2-nitrobenzyl mercapto acid of the formula V formed is reduced, a mixture consisting of the corresponding 2-aminobenzylmercapto acid of the formula VI and one cyclic compound of the formula IIa in which the sulfinyl group is replaced by the thio group is replaced, R6 is hydrogen and A is the carbonyl group, is obtained. This mixture is expediently subjected to dehydration, the im Mixture of existing 2-aminobenzyl mercapto acid cyclized. The yield of the desired Compound of formula IIa is thereby increased. The obtained compound of the formula If desired, IIa can be reduced and / or N-alkylated. By treating with an alkali iodate, the thio group can be oxidized to the sulfinyl group, as described above thus obtained compounds of the formula IIa in the desired starting compounds of formula II.

The following reaction scheme illustrates the synthesis described above. The symbols R1, R2, R3 and R4 in the formulas of this reaction scheme have the meanings given above.

The first stage (III + IV-sV) of the synthesis outlined above to prepare the starting compounds of the formula II consists in the implementation of a 2-nitrobenzyl halide of the formula III with an organic mercapto acid of formula IV in the presence of a base and an inert solvent. Preferred Mercapto acids used are those with at most 2 carboxyl groups, ie. so either monobasic lower alkanecarboxylic acids, such as, for example, α-mercaptoacetic acid and α-mercaptopropionic acid or lower dibasic alkanecarboxylic acids, such as for example α-mercsptosuccinic acid, the reaction temperature is not critical. However, a temperature between -10 ° C. and + 90 ° C., in particular, is preferred a temperature between OOC and room temperature is maintained. Organic bases can be used as bases and inorganic bases, such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, Amines such as pyridine and the like can be used. Examples of suitable solvents sine ketion such as acetone and methyl ethyl ketone, and also lower alcohols such as methanol, ethanol and propanol and ethers such as ethyl ether and dioxane. Signed Examples of 2-nitrobenzyl halides are 2-nitrobenzyl chloride, 2-nitrobenzyl bromide, 4-chloro-2-nitrobenzyl bromide, α, α-dimethyl-2-nitrobenzyl bromide and α-methyl-2-nitrobenzyl bromide.

Used as intermediates in the preparation of compounds of the Compounds of formula V occurring in formula 11 are new compounds.

The reduction of the compounds of formula V is expedient catalytic route in the presence of a conventional hydrogenation catalyst, such as Palladium carbon, platinum or the like carried out. Preferably in the presence an inert organic solvent such as methanol, ethanol, acetone, methyl ethyl ketone and the like worked.

The subsequent synthesis step (VI - sIIa) consists according to a Embodiment in the heating of the mixture of a compound obtained in the reduction of formula VI and a compound of formula IIa. This mixture can be used in a suitable inert organic solvent, for example in xylene, benzene, Toluene, tetrahydrofuran, heptane, pentane and chlorine derivatives of the aromatic mentioned links be dissolved. Preferably the heating is below Reflux conditions carried out. According to the above reaction scheme, the Compounds of the formula IIa prepared in a two-step process, (V # VI # IIa), namely by reduction and subsequent heating. The compounds of the formula However, IIa can also be obtained by reducing and heating be carried out simultaneously, taking directly and in good yield from compounds the formula V contains compounds of the formula IIa.

According to another embodiment, that which results from the second method step Mixture dissolved in a suitable organic solvent and mixed with licyclohexylcarbodiimide treated, whereby the desired cyclization of the compounds of formula VI occurs. Suitable solvents are in each case inert organic solvents such as for example tetrahydrofuran, benzene, ethers, for example ethyl ether and halogenated hydrocarbons such as methylene chloride and fluorobenzenes are used.

According to a further embodiment, the compounds of Formula VI direct, d. H. in the absence of a dispersant or solvent are heated, compounds of the formula IIa also being obtained.

The resulting carbonyl compounds of the formula IIa can, if necessary be reduced to the corresponding methylene compounds of the formula IIa.

The reduction is carried out in the manner that one can the carbonyl compound of formula IIa with lithium aluminum hydride at a temperature from -20 to + 900C, preferably at a temperature of -5 to + 400C, in the presence an inert organic solvent, for example in the presence of tetrahydrofuran or an ether such as diethyl ether, methyl ethyl ether and the like treated, the corresponding methylene compound of the formula IIa being obtained.

If desired, the compounds of the formula IIa Be N-alkylated. This alkylation can take place, for example, that one the sodium derivative of a compound of formula IIa by treating with a Ntraiumalkoholat, for example with sodium methoxide in an inert organic Solvent, for example in toluene, converted into the sodium derivative and this with a dialkyl sulfate or an alkyl halide in an inert solvent, for example in a hydrocarbon or in dimethylformamide. A An example of a suitable dialkyl sulfate is dimethyl sulfate and one example of a suitable dialkyl sulfate is dimethyl sulfate and an example of a suitable one Alkyl halides methyl iodide.

The oxidation of the compounds of formula IIa obtained leads to the desired starting compounds of the formula IIa.

The oxidation of the thio group can be carried out, for example, in the manner be that you have a compound of formula IIa with sodium periodate in the presence an inert organic solvent such as an alcohol such as Methanol, ethanol or the like or a ketone such as acetone, methyl ethyl ketone, Dioxane and the like at a low temperature, that is, at a temperature in the range from -20 ° to + 600C, preferably at a temperature of -5 ° to + 400C, treated, the desired starting compounds of the formula II being obtained.

Compounds of the formula I are obtained according to the invention in that a compound of formula II with the anhydride of a lower alkanecarboxylic acid, treated for example with acetic anhydride. In this way one obtains e.g. by heating 3,5-dihydro-4,1-benzothiazepine-2 (1H) -one-4-oxide with acetic anhydride the 3-acetoxy-3,5-dihydro-4,1-benzothiazepin-2 (1H) -one.

Compounds of formula 1 in which A represents the ethylene group 9 have a basic character and can accordingly be mixed with organic or organic Acids form acid addition salts. Suitable acids for this purpose are, for example, hydrohalic acids, how Hydrochloric acid, hydrobromic acid and the like, nitric acid, sulfuric acid, phosphoric acid etc. and methanesulfonic acid, succinic acid, maleic acid and the like.

The compounds of the formula I and the acid addition salts obtainable therefrom have a choleretic and / or hypotensive effect.

The products of the process can therefore be used as medicinal products, e.g. in the form of pharmaceuticals Find preparations use.

Example 1 A mixture of 3 g of DR5-dihydro-4R1-benzothiazepine-2 (1H) -one-4-oxide was obtained and 40 ml of acetic anhydride heated to 100 ° for 2 hours. After a weiner A clear solution was obtained for a further hour. This was filtered and that The filtrate was evaporated to dryness. -Recrystallization from, acetone gave 3-acetoxy-3,5-dihydro-4,1-benzothiazepin-2 (1H) -one, with a melting point of 172-174 °.

The 3,5-dihydro-4,1-benzothiazepine-2 (1H) -one-4-oxide used in Example 1 can i.B. be prepared as follows: To a solution of 69 g of o-nitrotoluene in 300 ml of carbon tetrachloride were 90 g of N-bromosuccinimide and 2 g of bezoyl peroxide added, whereupon the suspension thus obtained is refluxed for 3 hours became. After cooling, excess succinimide was filtered off and the solution evaporated to dryness. The crude o-nitrobenzyl bromide thus obtained was in 200 ml of acetone dissolved and the resulting solution was carefully and with stirring to a solution of 46 g of nercaptoacetic acid and 40 g of sodium hydroxide in 300 ml of water added. The reaction mixture was then stirred for 24 hours at room temperature, diluted with water, extracted with methylene chloride, acidified with acetic acid and extracted again with methylene chloride. The extract thus obtained was washed with water washed, dried over anhydrous sodium sulfate and evaporated. The evaporation residue revealed after recrystallization from acetone-hexane the (2-nitrobenzylmeroapto) acetic acid with a melting point of 99-103 ° C.

There were 22.7 g of the (2-nitrobenzylmer-, capto) acetic acid thus obtained Dissolved in 1200 ml of methanol, whereupon this solution 3.8 g of 10% palladium carbon were added. The suspension thus formed was; at room temperature and one Pressure of approximately 4.7-7 atmospheres until the theoretical hydrogen uptake is complete hydrogenated. The catalyst was then filtered off and the solution was evaporated. The evaporation residue was taken up in, 2 liters of xylene and the resulting The solution is heated under reflux for 2 hours with slow distillation of the xylene. After cooling, the precipitated crystalline precipitate was filtered off and recrystallized from acetone, 3,5-dihydro-4,1-benzothiazepin-2 (1H) -one with a Melting point, obtained from 218-223 ° C.

To an ice-cold suspension of 3.6 g of 3,5-dihydro-4,1-benzothiazepin-2 (1H) -one 42 ml of a 0> 5 molar sodium periodate solution were added in 250 ml of methanol. The mixture obtained was treated for 7 hours on an ice bath and then for a further 3 days stirred at room temperature. Then the precipitated one became Sodium iodate filtered off and the filtrate evaporated to dryness. The evaporation residue was recrystallized from acetone, 3,5-dihydro-4,1-benzothiazepine-2 (1H) -one-4-oxide with a melting point of 255.5-256 ° C.

Example 2 A mixture of 2 g of 3,5-dihydro-3-methyl-4,1-benzothiazepine-2 (1H) -one-4-oxide and 40 ml of acetic anhydride was heated to 100 ° for 5 hours. The mixture was then evaporated and the evaporation residue was chromatographed on a silica gel column and the fractions are eluted with a mixture of 2% ethyl acetate and benzene. To Recrystallization from acetone gave 3-acetoxy-3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one obtained with a melting point of 186-187t.

The 3,5-dihydro-3-methyl-4,1-benzothizqepin-2 (1H) -one-4-oxide used in Example 2 can e.g. be produced as follows: A solution of 69 g of o-nitrotoluene in 300 ml of carbon tetrachloride were 90 g: N-bromosuccinimide and 2 g of benzoyl peroxide added. The suspension thus obtained was refluxed for 3 hours. After cooling, the precipitated succinimide was filtered off and the filtrate to Troc ': ne evaporated. The crude o-nitrobenzyl bromide thus obtained was in 200 ml of acetone was dissolved and the resulting solution was added dropwise while stirring an ice-cold solution of 53 g of 2-thiopropionic acid and 40 g of sodium hydroxide in. 300 ml of water were added. The obtained mixture was allowed to stand at room temperature for 24 hours stirred, then made strongly alkaline, then extracted with methylene chloride Acetic acid acidified and extracted again with methylene chloride. The final extract was washed with water, dried over anhydrous sodium sulfate and evaporated. Recrystallization of the crystalline evaporation residue from acetone gave 2- (2-nitrobenzylmercapto) propionic acid obtained with a melting point of 130-132 ° C.

A solution won 48.2 g of the 2- (2nitro @ enz @ mercapto) propionic acid thus obtained in 1200 ml of methanol 5 g of 10% palladium chloride were added, whereupon the so obtained suspension at room temperature and under a hydrogen pressure of 14-19 Atmospheres was hydrogenated until the theoretical amount of hydrogen was absorbed The catalyst was then filtered off and the filtrate evaporated. The non-crystalline evaporation residue was taken up in 2 liters of xylene, which solution obtained in this way for 2 hours with slow distillation and with concentration of the volume heated to 1 liter at reflux. After cooling, the crystalline The precipitate is filtered off and recrystallized from acetone, 3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one with a melting point of 188-189 ° C.

A suspension of 3.86 g of 3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one in 250 ml of methanol were 42 ml of a 0.5 normal sodium periodate solution at 0 ° added, the resulting mixture was 1 hour in an ice bath and then Stirred for 3 hours at room temperature. Then the excreted sodium iodate became filtered off and the solution evaporated to dryness. The evaporation residue was boiled in acetone. It was then filtered, the filtrate evaporated and the evaporation residue " crystallized from acetone. The obtained product was chromatographed on a silica gel column and the fractions were eluted with a mixture of 15% ethyl acetate and benzene. After recrystallization from acetone, 3,5-dihydro-3-methyl-4,1-benzothiazepine-2 (1H) -one-4-oxide was obtained obtained with a melting point of 220-223 ° C.

Claims (6)

Claims 1. Process for the preparation of new heterocyclic compounds of the general formula in which R1 represents hydrogen, a halogen atom or a lower alkyl group, R2 and R3 hydrogen or lower alkyl groups, A a carbonyl or methylene group, R4 hydrogen, a lower alkyl group or a lower carboxyalkyl group, R5 a lower alkanoyloxy group and R6 hydrogen or a lower alkyl group represent, as well as acid addition salts of such compounds, dadureh denotes that one is a compound of the general formula in which R1, R2, R3, R4, R6 and A have the meaning given above1 acyloxylated by treatment with the anhydride of a lower carboxylic acid with simultaneous conversion of the sulfinyl group into the thio group and, if desired, a base obtained is converted into an acid addition salt. 2. The method according to claim 1, characterized in that 3,5-dihydro-4,1-benzothiazepine-2 (1H) -one-4-oxide is obtained or 3,5-dihydro-3-methyl-4, 1-benzothiazepine-2 (1H) -one-4-oxide by treating with Acetic anhydride into 3-acetoxy-3,5-dihydro-4,1-benzothiazepin-2 (1H) -one or converted into 3-acetoxy-3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one. 3. Choleretic and / or hylsotensiv agents, characterized in that they contain one or more heterocyclic compounds of the general formula in which R1 represents hydrogen, a halogen atom or a lower alkyl group, R2 and R3 hydrogen or lower alkyl groups, A a carbonyl or methylene group, R4 hydrogen, a lower alkyl group or a lower carboxyalkyl group, R5 a lower alkanoyloxy group and R6 hydrogen or a lower alkyl group represent, or contain one or more acid addition salts of these compounds. 4. Heterocyclic compounds of the general formula in which R1 is hydrogen, a halogen atom or a lower alkyl group, R2 and R3 are hydrogen or lower alkyl groups, A. is a carbonyl or methylene group, R4 is hydrogen, a lower alkyl group or a lower carboxyalkyl group, R5 is a lower alkanoyioxy group and R6 is hydrogen or a lower one Represent alkyl group, as well as acid addition salts of these compounds. 5. 3-Acetoxy-3, 5-dihydro-4, 1-benzothiazepin-2 (1H) -one. 6. 3-Acetoxy-3, 5-dihydro-3-methyl-4, l-benzothiazepin-2 (1H) -one.