DE1695203A1 - 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 benzothiazepine compounds of the general formula in which R1 is hydrogen, a halogen atom or a lower alkyl group, R2 and $ 3 are hydrogen or lower alkyl groups, 3 is a thio, sulfonyl or sulfonyl group, R4 is hydrogen, a lower alkyl group or a lower carboxyalkyl group and R5 is hydrogen or a lower alkyl group, 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 isopropyl groups. Halogen is anything represent 4 halogens to understand chlorine, bromine, iodine or fluorine.

The inventive method is characterized in that a compound of the general formula in which R1, R2, R3, R4, R5 and B have the meaning given above, reduced with the aid of a mixed ketal hydride and, if desired, converts the base obtained 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 mixed metal hydride, preferably treated with lithium aluminum hydride.

Preferred compounds of the formula I are those in which B is sulfur represents.

Thus, a preferred embodiment of the process according to the invention consists in the preparation of compounds of the general formula in which the symbols R1 to X5 have the above meaning.

The starting compounds of formula II can z.3. produced thereby be that one has a nitrobenzyl halide of the formula III, for. B. an α-monoalkyl-2-nitrobenzyl halide, an α, α-dialkyl-2-nitrobenzyl 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 formed of the formula V 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 B represents the thio group, obtained will. This mixture is expediently subjected to dehydration, with the 2-aminobenzyl mercapto acid present in the mixture is cyclized.

The yield of the desired compound of formula IIa is thereby increased elevated. The thio group of the resulting compound of formula IIa can, if desired are oxidized to the sulfinyl or sulfonyl group.

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

The first step (III + (V) V) of the synthesis outlined above for the preparation of the starting compounds of the formula III consists in the reaction of a 2-nitrobenzyl halide of the formula III with a mercapto acid of the formula IV in the presence of a 3ase and an inert solvent. Preferred used Nercapto acids are those with a maximum of 2 carboxyl groups, i.e. either monobasic lower alkanecarboxylic acids, such as, for example, α-mercaptoacetic acid and α-mercapto propionic acid or lower dibasic alkanecarboxylic acids, such as, for example, α-mercaptosuccinic acid. The reaction temperature is not critical. However, a temperature is preferred between -10 ° C and + 90 ° C, especially a temperature between 0 ° C and room temperature adhered to. Organic and inorganic bases, such as, for example, can be used as bases Sodium hydroxide, ammonium hydroxide, potassium hydroxide, amines such as pyridine and the like be used. 3 examples of suitable solvents such as ketones Acetone and Methylaeth6ylketon, also lower alcohols such as methanol, ethanol and Propanol and ethers such as ethyl ether and dioxane. Suitable 2-nitrobenzyl halides are for example 2-nitrobenzyl chloride, 2-nitrobenzyl bromide, 4-chloro-2-nitrobenzyl bromide, α, α-dimethyl-2-nitrobenzyl bromide and α-methyl-2-nitrobenzyl bromide.

The as intermediate products in the production vou. Connections of Compounds of formula V occurring in formula II 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, acetoin, methyl ethyl ketone and the like worked.

The subsequent synthesis step (VI # IIa) consists according to a Embodiment in heating 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 Ohlorderivaten of the aromatic mentioned links Be dissolved, preferably heating is under 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, this is what results from the second procedural step Mixture dissolved in a suitable organic solvent and mixed with dicyclohexylcarbodiimide 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 such as ethyl ether and halogenated hydrocarbons such as methylene chloride and fluorobenzenes are used.

According to a further embodiment, the connections of the Formula VIdirect, d. H. in the absence of a dispersing agent or solvent are heated, compounds of the formula IIa are also obtained.

The starting compounds of the formula II obtained are according to the invention reduced in such a way that the compounds with a mixed metal hydride, e.g. with lithium aluminum hydride at a temperature of -20 to + 90 ° C, preferably at a temperature of -5 to + 400C, in the presence of an inert organic Solvent, for example in the presence of detrahydrofuran or an ether such as diethyl ether, methyl ethyl ether and the like treated, whereby compounds of the general formula I is obtained.

Compounds of the formula I in which B represents the thio group can treated with an alkali metal periodate, preferably sodium periodate, the corresponding 4-oxide is obtained. Furthermore, the compounds of the formula I can also be treated with hydrogen peroxide, the corresponding 4,4-dioxides can be obtained.

The compounds of the formula I have a basic character and can accordingly form acid addition salts with inorganic or organic acids. Suitable acids for this purpose are, for example, hydrohalic acids, such as hydrochloric acid, uromic acid and the like, nitric acid, sulfuric acid, phosphoric acid etc. and methanesulfonic acid, succinic acid, maleic acid and the like.

Particularly preferred ones obtainable by the process according to the invention Compounds are 1,2,3,5-tetrahydro-4,1-benzothiazepine, 8-halo-1,2,3,5-tetrahydro-4,1-benzothiazepine like 8-chloro-1,2,3,5-tetrahydro-4,1-benzothiazepine.

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

The process products can therefore be used as a remedy for. B. in shape find pharmaceutical preparations use.

Example 1 A suspension of 4 g of lithium aluminum hydride in 400 ml of anhydrous tetrahydrofuran cooled to 0 ° slowly became a solution of 4.5 g of 3,5-dihydro-4,1-benzothiazepin-2 (1H) -one in 350 ml of anhydrous tetrahydrofuran added. The mixture was then stirred for 24 hours at room temperature.

After cooling briefly in an ice bath, the mixture slowly became saturated Solution of sodium sulfate was then added until hydrogen evolved added crystalline anhydrous sodium sulfate and filtered. The hydrate was evaporated and the crystalline evaporation residue recrystallized from methanol, 1,2,3,5-tetrahydro-4,1-benzothiazepine with a melting point of 85.5-87.5Q Obtained0 after adding an ethereal solution of hydrogen chloride to a solution Evaporation of the base in acetone to dry and recrystallization from an ethanol-ether mixture became 1,2,3,5-tetrahydro-4,1-benzothiazepine hydrochloride, with a melting point from 193-197 ° C.

The 3,5-dihydro-4,1-benzothiazepin-2 (1H) -one used in Example 1 can e.g. be produced as follows: To a solution of 69 g of o-nitrotoluene in 300 ml of carbon xetrachloride were 90 g of N-bromosuccinimide and 2 g of benzoyl peroxide added, whereupon the suspension obtained in this way for 3 hours was heated to reflux. After cooling, excess succinimide was filtered off and the solution evaporated to dryness. The crude o-nitrobenzyl bromide thus obtained was dissolved in 200 ml of acetone and the resulting solution was carefully and under Stir to a solution of 46 g of mercaptoacetic acid and 40 g of sodium hydroxide in 300 ml of water added. The reaction mixture was then left for 24 hours at room temperature stirred, diluted with water, extracted with methylene chloride, acidified with acetic acid and extracted again with methylene chloride. The extract thus obtained was with Water, washed9, dried over anhydrous sodium sulphate and evaporated. Of the Evaporation residue gave (2-nitrobenzylmercapto) acetic acid after recrystallization from acetone-hexane with a melting point of 99-103 ° C.

22.7 g of the (2-nitrobenzylmercapto) acetic acid thus obtained were obtained Dissolved in 1200 ml of methanol, whereupon 3.8 g of 10% palladium carbon were added to this solution were added 0 The suspension thus formed was at room temperature and a Pressures of about 4.7-7 atmospheres to complete theoretical hydrogen uptake hydrogenated, the catalyst was then filtered off and the solution was evaporated. The evaporation residue was taken up in 2 2 liters of xylene and the resulting Killing for 2 hours land heated under reflux 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 of 218-223 ° C was obtained.

Example 2 A solution of 1.65 g of 1,2,3,5-tetrahydro-4,1-benzothiazepinine 125 ml of methanol were added to 21 ml of a 0.5 molar sodium peripdate solution, the temperature was kept at 0 ° The mixture was then 4 hours stirred for a long time at room temperature and then filtered. The filtrate was evaporated and the evaporation residue was recrystallized twice from acetone, 1,2,3,5-tetrahydro-4,1-benzothiazepine-4-oxide with a melting point of 158-160.5 ° C.

Example 3 To a suspension of 4 g of lithium aluminum hydride in 400 ml of anhydrous tetrahydrofuran slowly became a solution of 5.35 g at Oo 8-chloro -3,5-dihydro-4,1-benzothiazepin-2 (1H) -one in 350 ml anhydrous tetrahydrofuran added.

The resulting mixture was stirred at room temperature for 3 hours. After brief cooling in an ice bath, this mixture slowly became a solution of Sodium sulfate added until evolution of hydrogen occurred. Then anhydrous, added crystalline sodium sulfate and the mixture filtered. The filtrate was evaporated and the crystalline evaporation residue from methanol recrystallized: wherein 8-Ohlor-19 2 3 5-tetrahydro-4,1-benzothiazepine with a melting point of 109-111 ° C was obtained The 8-chloro-3,5-dihydro-4,1-benzothiazepine-2 used in Example 3 (1H) -one can e.g. be prepared as follows: 90 g of N-bromosuccinimide were obtained and 2 g of benzoyl peroxide to a solution of 4-chloro-2-nitro-toLuene in 600 ml of carbon tetrachloride added and the reaction mixture was refluxed for 24 hours. After cooling, the excess succinimide was filtered off and the filtrate evaporated to dryness. The crude 4-chloro-2-nitrobenzyl bromide thus obtained was dissolved in 200 ml of acetone and slowly a solution of 46 g of mercaptoacetic acid at 0 ° and 40 g of sodium hydroxide in 500 ml of water were added. The mixture was at room temperature Stirred for 3 days, then diluted with water, extracted with methylene chloride, with Acetic acid acidified and extracted again with methylene chloride. The final extract was washed with water, dried and evaporated. The evaporation residue was recrystallized from a mixture of acetone and hexane, (4-chloro-2-nitrobenzylmercapto) acetic acid with a melting point of 107-111 ° C was obtained.

To the 'solution of 26 g of the (4-chloro-2-nitrobenzylmercapto) acetic acid obtained in this way in 1200 ml of methanol, 3.5 g of 10% palladium carbon were added and the mixture was at room temperature and a hydrogen pressure of about 12.5 to 15 atmospheres hydrogenated until the theoretical hydrogen uptake is reached. Then it was filtered and the eydrate evaporated to dryness. The evaporation residue was crystallized from methanol 8-chloro-3 5-dihydro-4 1-benzothiazepin-2 (1H) -one with a melting point from 222-223 ° C.

Example 4 A suspension, cooled to 0 °, of 12 g of lithium aluminum hydride a solution of 12 g of 3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one was slowly added to 1000 ml of anhydrous tetrahydrofuran added in 400 ml of anhydrous tetrahydrofuran.

The mixture was then stirred for 24 hours at room temperature. After brief cooling in an ice bath, a saturated solution of sodium sulfate slowly became added until evolution of hydrogen occurred. Then anhydrous, crystalline Sodium sulfate was added and it was filtered. The filtrate was evaporated and the residue off. Recrystallized methanol, 3-methyl-1,2,3,5-tetrahydro-1,4-benzothiazepine with a melting point of 76-78 ° C was obtained.

The 3,5-dihydro-3-methyl-4,1-benzothiazepine-2 used in Example 4 (1H) -oW can e.g. 3. can be produced as follows: A solution from 69 g of o-nitrotoluene in 300 ml of carbon tetrachloride became 90 g of N-bromosuccinimide and 2 g of benzoyl peroxide added. The suspension thus obtained was for 3 hours refluxed. After cooling, the succinimide which separated out was filtered off and the filtrate evaporated to dryness. The crude o-nitrobenzyl bromide thus obtained was dissolved in 200 ml of acetone and the resulting solution was added dropwise and while stirring an ice-cold solution of 53 g of 2N thiopropionic acid and 40 g of sodium hydroxide in .309 ml of water added The resulting mixture was 24 hours at room temperature stirred9 then made strongly alkaline, extracted with methylene chloride9 then with Acetic acid acidified and extracted again with methylene chloride0 The last 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 with a melting point of 30-132t. A solution of 4892 g of the thus obtained 2- (2-Nitrobenzylmercapto) propionic acid in 1200 ml of methanol was added to 5 g of 10% strength palladium beads added, whereupon the suspension thus obtained at room temperature and below a Hydrogen pressure of 14-19 atmospheres was hydrogenated until the theoretical amount of hydrogen The catalyst was then filtered off and the Evaporated filtrate. The non-crystalline evaporation residue was in 2 liters' Xylene was added, the resulting solution for 2 hours with slow distillation and heated to reflux while reducing the volume to 1 liter, after cooling the crystalline precipitate was filtered off and recrystallized from acetone, being 3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one with a melting point Received from 188-1890C.

Claims (10)

Claims 1. Process for the preparation of 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, B a thio, sulfinyl or sulfonyl group, R4 hydrogen, a lower alkyl group or a lower carboxyalkyl group and R5 hydrogen or a lower one Represent alkyl group, as well as acid addition salts of such compounds, characterized in that a compound of the general formula in which R1, R2, R3, R4, R5 and B have the meaning given above, reduced with the aid of a mixed metal hydride and, if desired, the base obtained is converted into an acid addition salt. 2. The method according to claim 1, characterized in that 3,5-dihydro-4, l-benzothiazepin-2 (1H) -one or 8-chloro-3,5-dihydro-3-methyl-4,1-benzothiazepin-2 (1H) -one to 1,2,3,5-tetrahydro-4,1-benzothiazepine or to 8-chloro-1,2,3,5-tetrahydro-4,1-benzothiazepine reduced. 3. The method according to claims 1 and 2, characterized in that that the reduction is carried out with the aid of lithium aluminum hydride. 4. The method according to claim 1, characterized in that the Thio group of a compound of formula 1 with sodium periodate to form the sulfinyl group oxidized. 5. The method according to claim 1, characterized in that the Thio group of a compound of formula 1 with hydrogen peroxide to form the sulfonyl group oxidized. 6. Choleretically and / or hypotensively active agents, characterized in that they contain one or more 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, B is a thio, sulfinyl or sulfonyl group, R4 is hydrogen, a lower alkyl group or a lower carboxyalkyl group and R5 is hydrogen or a lower alkyl group , or one or more acid addition salts of these compounds. 7. 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, e.g. a thio, sulfinyl or sulfonyl group, R4 is hydrogen, a lower alkyl group or a lower carboxyalkyl group and R5 is hydrogen or a lower one Represent alkyl group, as well as acid addition salts of these compounds. 8. 1,2,3,5-tetrahydro-4, l-benzothiazepine and acid addition salts this connection. 9. 8-Halo-1, 2,3, 5-tetrahydro-4, 1-benzothiazepine and acid addition salts this connection. 10. 8-chloro-1,2,3, 5-tetrahydro-4, 1-benzothiazepine and acid addition salts this connection.