DE1770420B2 - Process for the preparation of 1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives - Google Patents

Description

in which R ₁ denotes a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms and R ₂ denotes a hydrogen or halogen atom, characterized in that a 2-aminomethylindole of the general formula II

CH ₁ -NH ₁

(Π)

in which R ₁ and R _{2 have} the above meaning, or the salt thereof is treated in an acidic medium and in a solvent with chromic acid or ozone in at least a stoichiometric amount.

The invention relates to a new process for the preparation of 1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula I.

(D

in which R ₁ denotes a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms and R ₂ denotes a hydrogen or halogen atom, which is characterized in that a 2-aminomethylindole in which R ₁ and R _{2 have} the above meaning, or its salt treated in an acidic medium in a solvent with chromic acid or ozone in at least a stoichiometric amount.

The benzodiazepines of general formula I are valuable tranquilizers, muscle stimulants, anticonvulsants and hypnotics.
Some processes for the production of these benzodiazepines are already known. According to the process of German Patent 11 45 626, these compounds are obtained in poor yield by reacting a 2-aminobenzophenone with glycine hydrochloride or glycine ethyl ester. So z. B.

crude 7-chloro-1-methyl-5-phenyl-1,3-dihydro-2 H - 1.4-benzodiazepin-2-one by heating 5-chloro-2-methylaminobenzophenone with glycine ether 1-ester hydrochloride can be obtained in a yield of at most 30%.

After that from the Dutch Offenletjungsschrift 65 00446 known method is a 2-aminobenzophenone with phthalimidoacetyl chloride condensed and the 2-Phthaliinidoücctamidobenzophenon obtained with hydrazine hydrate to the corresponding 5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one implemented. The yield in the preparation of T-chloro-1-methyl-S-phenyl-U-dihydro-2H-1,4-benzodiazepin-2-one starting from p-chloroaniline in the 7-step process about 5% of theory.

According to the in the journal "Journal of Organic Chemistry", Vol. 27 (1962), p. 3788. and the German In the process described in patent specification 11 36 709, the benzodiazepines are also obtained by reaction of a bromoacetamidobenzophenone with ammonia. This is how you get when implementing 2 - (2 - bromo - N - methylacetamido) - 5 - chlorobenzophenone with a methanol solution of ammonia the 7 - chloro - 1 - methyl - 5 - phenyl - 1,3 - dihydro-2H-1,4-benzodiazepin-2-one in 46.5% dent. When reacted with liquid ammonia obtained the same compound in 73% yield. Taking into account the production of the starting substances, starting from p-chloroaniline, the total yield in the latter process is approximately 16.3%.

The method according to the invention is characterized by its simplicity and economy, and the benzodiazepines are obtained in high yield and purity. One such method of conversion an indole compound with oxidation-sensitive substituents into a benzodiazepine compound a ring expansion reaction has neither been described nor suggested. It is however, it is known that indole and indole derivatives are involved the treatment with oxidizing agents are cleaved at the double bond of the pyrrole ring. the indole derivatives used, however, always carried sub-

substituents that are relatively resistant to oxidation, such as methyl or phenyl groups; see A. Weissberger, The Chemistry of Heterocyclic Compounds, 8, 23 (1954); Bull. Soc. Chim. France 1950 μ ' Pp. 555-561, and J. Org. Chem., 27, 3784 (1962).

On the basis of the above-described results of the oxidation of indole compounds should one would expect that the 2-aminomethylindoles of the general Formula II by oxidation to the corresponding dicarbonyl compounds, d. H. 2-glycylaminobenzophenones of the general formula III

R ₁ O

NC-CH ₂ -NH,

(III)

being transformed. It is assumed here that the glycylamino group is stable to oxidation. It is known, however, that when oxidizing agents act on amines, in most cases the amino group is changed because of its high reactivity; See HoubenWeyl, Methods of Organic Chemistry, 4th Edition, Vol. XI 2 (1958). S. 181 and 182. It is known of 2-glycylaminobenzophenones that, as free bases or at pH values of at least 7, ie in a neutral or alkaline medium, with intramolecular condensation, the corresponding 5-phenyl-1,3-dihydro Provide -2H-1,4-benzodiazepin-2-one compounds; See J. Org. Chem., Vol. 27 (1962), pp. 4675 to 4677 and pp. 3788 to 3796, U.S. Patent 32 02 699 and Belgian Patent 5 98 014. The cyclization is effectively prevented if one converts the 2-glycylaminobenzophenone into the salt of an acid: see J. Org. Chem., Vol. 27 (1962), p. 4676.

The process according to the invention proceeds according to a different, unknown reaction mechanism.

The stage of 2-glycylaminobenzophenone becomes not go through.

The 2-aminomethylindoles of the general formula II used in the process of the invention are new compounds that are in a known manner, for. B. by reducing the corresponding Indole-2-carboxamides can be produced. the Indole-2-carboxamides can be z. B. by amidation of the indole-2-carboxylic acid chlorides, which are obtainable from the! ndol-2-carboxylic acids with thionyl chloride. The indole-2-carboxylic acids can e.g. B. from a benzene diazonium salt and a u-benzyl - ^ - ketocarboxylic acid ester and then Saponification of the 3-phenylindolcarboxylic acid (2) ester obtained getting produced; See Chemical Abstracts, Volume 33 (1939), columns 587 'and 588'.

In practice, the process according to the invention is carried out in such a way that the 2-aminomethylindoles of the general formula II or their salts, for example the hydrochloride, hydrobromide. SuI-fat, Nitrate or acetate, in acidic medium and in a solvent with ozone or chromic acid in stoichiometric amount or oxidized in excess at room temperature. Working at higher levels however, lower temperatures sometimes give better results. The reaction temperature hanging on the type of oxidizing agent used. Chromic acid is the preferred oxidizing agent. The type of solvent depends on the type of oxidizing agent used. Examples of solvents are water, acetone, carbon tetrachloride. Acetic acid, sulfuric acid. During execution Chromic acid is preferably used in oxidation with chromic acid in the presence of acetic acid the 2 to 3 times the stoichiometric amount is used and the reaction is carried out at room temperature.

The 2-aminomethylindole is in a solvent dissolved or suspended and the oxidizing agent added with stirring. The implementation is generally finished within 24 hours. From the reaction mixture, which may be neutralized is, the resulting benzodiazepine derivative can either be extracted, or the reaction mixture is evaporated to dryness, and the product is isolated from the residue. The product Can be further purified by recrystallization from solvents such as ethanol or isopropanol will

The examples illustrate the invention.

example 1

A suspension of 10.0 g of l-methyl-2-aminometh \ l-3-phenyl-5-chloroindole hydrochloride in 100 ml of acetic acid is added dropwise with a solution of 10 g of chromic anhydride in 10 ml of water Cooling offset. The mixture is then stirred at room temperature for 15 hours. The reaction mixture is added dropwise to a solution of 200 ml of 28% aqueous ammonia and 2 (K) ml of water are added with cooling and stirring. Of the The pH of the solution is adjusted to about 9. Fine crystals precipitate here. The mixture is with Carbon tetrachloride extracted, the carbon tetrachloride extract Wipe over with a little water dried anhydrous sodium sulfate and decolorized with 0.5 g activated charcoal. The mixture is filtered and the filter residue was washed out with a little carbon tetrachloride. The filtrate and wash solutions are combined and distilled under reduced pressure. An oily residue remains, the crystallized after treatment with 8 ml of alcohol. After cooling, the crystals precipitated filtered off, washed with a little cold isopropanol and dried. There are 7.05 g (74.5% of theory) 1 -Methyl-S-phenyl ^ -chloro-1.3-dihydro-2 H-1.4-benzodiazepin-2-one obtain.

The filtrate and the washing solutions are combined and evaporated under reduced pressure. The residue is taken up in 20 ml of carbon tetrachloride and extracted with 20 ml of 4N hydrochloric acid and the extract washed with a little carbon tetrachloride. The extract is made with 10n sodium hydroxide solution adjusted to a pH of about 9 with cooling. The solution is again made with 20 ml of carbon tetrachloride extracted. The extract is washed with water and dried over anhydrous sodium sulfate. The solution is decolorized with 0.1 g of activated charcoal, filtered and the filter residue with a little Washed carbon tetrachloride. The filtrate and the

Wash solutions are combined and concentrated under reduced pressure. The residue crystallizes after treatment with 2 ml of isopropanol. There are another 0.7 g (7.4% of theory) of 1-methyl-5-phenyI-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-one of m.p. 126 to 129 ° C.

The I-Metlul-2-amiiiomethyi-3-phenyl-5-chlorinilol-h used according to the process > Hrochlopd is made as follows:

A mixture of 131g p-chloroaniline. 255 ml more concentrated Hydrochloric acid and 250 ml of water are heated and then cooled to below 0.degree. Into the reaction mixture 222 g of a 32.3% aqueous solution of sodium nitrite at a temperature below 10 C added dropwise with stirring. Then 115 g of sodium acetate are added. The resulting mixture is in proportions to a cooled mixture of 220 g of u-Benzylacetessigsäureäth / lester in 1000 ml Mefhanol and 200 l of anhydrous potassium acetate given below! 0 C with stirring. After finished The reaction mixture is stirred at below 10 ° C. for 2 hours. The resulting precipitation is filtered off, washed thoroughly with water and methanol and dried. 343 g n-Ben / vl- «- (p-Chlorophenylazol-acetacetic acid ethyl ester obtained. After recrystallization from ethanol 61 to 62.5 C. Yield: 95.7% of theory.

50 ml of concentrated sulfuric acid are added dropwise to a suspension of 180 g of benzyl (p-chlorophenyla / o) -acetoacetic acid ethyl ester in 500 ml of isopropanol. The mixture is _{refluxed for} 2 hours and then cooled. The precipitate is filtered off, washed with isopropanol and water and dried. Yield 114 g of 5-chloro-3-phenylindole-2-carboxylic acid ethyl ester. After recrystallization from ethanol 178 to 180 C. Yield: 75.7% of theory.

30.0 g of 5-chloro-3-phenylindole-2-carboxylic acid ethyl ester with 100 ml of acetone and with a 50% strength by weight aqueous potassium hydroxide solution is added at room temperature. The resulting solution is added dropwise below 50 C and with water cooling and stirring with 18.9 g of dimethyl sulfate and then heated under reflux for 4 hours. After the reaction has ended, the reaction mixture is 30 ml of water are added and the acetone is distilled off. The residue is dissolved in 60 ml of water and 20 g of concentrated hydrochloric acid are added to the solution while cooling with ice. The formed white precipitate is filtered off, washed with water and dried. Yield: 28.4 g of 1-methyl-3-phenyl-5-chloroindole-2-carboxylic acid of melting point 213 to 214.5 C. Yield: 99.4% of theory.

A mixture of 29 g of 1-methyl-S-phenyl-S-chloroindole-2-carboxylic acid and 56.2 g of thionyl chloride is refluxed for 2 hours. After the reaction has ended, excess thionyl chloride is distilled off. Yellowish-brown 1-methyl-3-phenyl-5-chloroindole-2-carboxylic acid chloride remains. The product is dissolved in 600 ml of anhydrous ether and treated with ammonia gas. the The resulting precipitate is filtered off, washed with water and dried. 26.5 g (91.6% of theory) I -Methyl ^ -phenyl-S-ehlorindol ^ -earboxamid obtain. The ethereal solution is evaporated under reduced pressure, with a further amount of carboxamide is obtained. The overall bulge is tuianlitative

A suspension of 1 6 g lithium aluminum hydride in 300 ml of ether is mixed with 3.0 g of 1-meth \ l-3-phen \ l-5-chloroindole-2-carboxamide added, refluxed for 4 hours, then cooled and treated with 20 ml of water dropwise. the Ether solution is treated dropwise with 44 ml of 12% hydrochloric acid while cooling. The resulting Crystals are filtered off and dried. 19 g (90% of theory) of l-methyl-2-aminometh \ l-

3-phenyl-5-chloroindole hydrochloride was obtained. After recrystallization from ethanol, the compound melts at 256.5 C (decomposition).

A suspension of 4.5 g of 1-methyl-2-aminometh \ l-3-phenyl-5-chloroindole hydrochloride 10% aqueous sodium hydroxide solution is added to 100 ml of water until the mixture has an alkaline reaction. Thereafter the reaction mixture is stirred for 1 hour at room temperature, then the crystals filtered off. Washed with water and dried.

3.8g of l-MelhyI-2-aminometh \ l-3-phen \ l-5-chloroindole are obtained obtain. After recrystallization from aqueous ethanol, the compound melts at M. to 67 "C.

Example 2

A suspension of 1 g of 2-aminomethyl-3-phenyl-5-chloroindole hydrochloride in 10 ml of acetic acid, 2 ml of an aqueous solution of 1 g of chromic anhydride are added dropwise with stirring. It takes place an exothermic reaction. The reaction mixture is stirred at room temperature and finally heated. After the reaction has ended, the reaction mixture is allowed to cool, water is added and the mixture is added insoluble substances filtered off. The filtrate is made alkaline with 28% aqueous ammonia solution and extracted with methylene chloride. The methylene chloride solution is extracted with 10% hydrochloric acid. The extract is made alkaline again with aqueous ammonia and with methylene chloride extracted. The methylene chloride extract is dried over anhydrous sodium sulfate and the solvent distilled off. An ethanol solution of hydrogen chloride is added to the residue. It is the 5 - phenyl - 7 - chloro - 1,3 - dihydro-2 H - 1,4 - benzodiazepin - 2 - one - hydrochloride from Melting point: 249 to 250 ° C. Yield: 0.72 g (70% of theory).

The 2-aminomethyl-S-phenyl-S-chloroindole hydrochloride used according to the process is made as follows:

A mixture of 82 g of S-chloro-S-phenyl-indole-2-carboxylic acid ethyl ester and 1.2 liters of 2.7% strength potassium hydroxide solution in ethanol is refluxed for 2 hours. The ethanol is then distilled off and the residue was taken up in 300 ml of water. The solution is made with concentrated hydrochloric acid acidified with cooling. The precipitate formed is filtered off and washed thoroughly with water and dried. There are 72 g of 5-chloro-3-phenylindole-2-carboxylic acid obtained from m.p. 227-228 ° C. After recrystallization from benzene, melting point 231.degree. yield : 97.1% of theory.

A solution of 60 g of 3-phenyl-5-chloroindole-2-carboxylic acid in 1200 ml of anhydrous benzene and 150 g of thionyl chloride is refluxed for 3 hours cooked. When the reaction has ended, the solvent is distilled off under reduced pressure. It remains in practically ouanliialiver

Loot 64.2 g of 3-phenyl-5-chloroindole-2-carboxylic acid chloride. The product is dissolved in 1.5 liters of anhydrous ether and with ice-cooling with ammonia gas treated. The reaction mixture is then left to stand for 1 hour and then evaporated. The crystals formed are filtered off, washed with water and dried. yield 58 g of 3-phenyl-5-chloroindole-2-carboxamide with a melting point of 217 to 219 ° C. Yield 96.8% of theory.

A suspension of 20 g of lithium aluminum hydride in 2 l of anhydrous ether is mixed with 35 g of 3-phenyl-5-chloroindole-2-carboxamide slowly added with stirring and refluxed for 4 hours. After the reaction has ended, the reaction mixture becomes cooled and water was added dropwise to destroy excess lithium aluminum hydride. The ether solution is mixed with 10% hydrochloric acid and shaken. Here white needles fall des 2 - aminomethyl - 3 - phenyl - 5 - chloroindole hydrochloride. Yield 32 g (84% of theory). To Recrystallization from ethanol melts the compound at 231 to 232 ° C (decomposition).

Example 3

A mixture of 3 g of 1-methyl-2-aminomethyl-3-phenyl-5-chloroindole and 30 ml of acetic acid are mixed with a solution of 3 g of chromic anhydride in 3 ml of water with cooling. The reaction mixture is stirred at room temperature for 15 hours, then poured into 150 ml of water with aqueous Ammonia made alkaline and extracted with chloroform. The chloroform solution becomes over anhydrous Dried sodium sulfate and evaporated under reduced pressure. The residue is with a little ethanol added. There are 2.2 g of crystalline

1 -Methyl-S-phenyl ^ -chloro-1,3-dihydro-2 H-1,4-benzodiazepin-2-one obtained, which melts after recrystallization from methanol at 130 to 132 "C. Yield:

70% of theory.

Example 4

A suspension of 11.67 g of 1-methyl-2-aminomethyl-3-phenyl-5-chloroindole sulfate in 50 g of acetic acid is cooled with a solution of 11 g Chromic anhydride is added to 11 ml of water. The mixture is worked up as in Example 5. It 6.9 g (76% of theory) of l-methyl-5-phenyl-7 - chlorine -1,3 - dihydro - 2 H -1,4 - benzodiazepin - 2 - one of m.p. 130 to 132 "C.

The 1-methyl-2-aminomethyl-3-phenyl-5-chloroindole sulfate used according to the process is made as follows:

A suspension of lithium aluminum hydride in ether consisting of 6.7 g of lithium hydride, 1.6 g of anhydrous Aluminum bromide and anhydrous aluminum chloride in ether is produced proportionally with 22.8 g of 1-methyl-S-phenyl-S-chloroindole-2-carboxamide offset. The mixture is stirred at room temperature for 20 minutes and then Boiled under reflux for 6 hours. The reaction mixture is then cooled and added dropwise with 55 ml of water are added. The ether solution is added dropwise with 26 g of 30% sulfuric acid with cooling added and the resulting precipitate filtered off, washed with ether and dried. 1-methyl-

2-aminomethyl-3-phenyl-5-chloroindole-sulfate with a melting point of 243 to 245 ° C. (decomposition) was obtained. Yield: 23.7 g (92.5% of theory).

509 528/407

Claims (1)

Claim: Process for the preparation of 1,3-dihydro-2H-1,4-benzodiazepin-2-one derivatives of the general formula I. of the general formula II CH, - NH ₁