FI61029B - NOW THERAPEUTIC FORM OF THERAPEUTIC THERAPEUTIC DIBENSION (B, E) (1,4) DIAZEPINER - Google Patents

Description

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W 11) UTLAGGNINQSSKRIPT BEER ^ 9 C Patent granted ΙΟ 05 1932

Patent patent

Vs "“ v ^ (51) Ky.lk.3 / h «t.ci.3 OO? D 403/04 SUOMI — FINLAND (21) Ptt« nttihikamui - Ptt «ntm6kntn (9 ^ 3/73. (22) HakamltpUv * -Aiwttknlnpdkg 27-03-73 ^ * (23) Aikuptlvt — GIMihatadag 27-03-73 (41) Tullut | ulklMk * l - Bllvlt offwttflg 05.10.73

National Board of Patents and Registration <* h rql »n <^» 29.01.82 (32) (33) (31) Requested «cuoiksus — Buglrd prior lt * t · OU -72 OU-OU-72 Switzerland-Switzerland (CH) U898 / 72, U901 / 72 (71) Wander AG, Bern, Switzerland-Switzerland (CH) (72) Josef Schneider, Minusio / Locarno, Switzerland-Switzerland (CH) (7M Oy Kolster Ab (5 * +) New method, therapeutically for the preparation of useful dibenzo / b, e7A »* i7 <iiazepines - Nyt förfarande för framställning avterapeutiskt användbara dibenzo ^ ej / l ^ d-iazepiner

The invention relates to a new process for the preparation of therapeutically useful dibenzo [b, e7 / 1,4] diazepines of formula I

I1 'τ R4 wherein R1 is hydrogen, methyl, ethyl or hydroxyethyl, R3 is hydrogen, 2,61029 methyl, methoxy, methylthio, chlorine, bromine or trifluoromethyl, R4 is hydrogen or methyl, and R2 is hydrogen, methyl, dimethylaminosulfonyl, methoxy, methylthio or chlorine.

From J, Org. Chem. 34, No. 4 (1969), 1143-1145, it is known to amidate cyclic amides in the presence of a complex of a titanium (IV) compound and ammonia, a primary or secondary amine formation. The presence of titanium tetrachloride in this process causes the lactam bond to open, resulting in re-amidation, and thus amidines are obtained only in low yields. Instead, using the titanium (IV) -piperazine complexes by the process of the present invention, cyclic amides are obtained in good yield.

The process according to the invention is characterized in that the compound of formula II

O

n * 4

wherein R 2, R 3 and R 2 are as defined above are reacted with a titanium amine complex consisting of titanium and a compound of formula III

ΛΛ

HN N-R. III

'W 1 where R 1 has the same meaning as above.

In a preferred embodiment of the process of the invention, the compounds of formula II are reacted with a titanium amine complex in the presence of an acid scavenger. As the acid-binding agent, a tertiary amine can be used, such as, for example, triethylamine, pyridine, dimethylaniline or also an excess of a compound of formula III. The acid-binding amino compound should be used in an amount of at least 1 mole (equivalent amount), preferably 2 moles (twice 3,61029 times the equivalent amount) per mole of titanium-amine complex.

The reaction is most conveniently carried out in an organic solvent, e.g. an aromatic solvent such as toluene, a halogenated aromatic solvent such as chlorobenzene, a halogenated aliphatic solvent such as dichloroethane, or an ether such as anisole. The reaction temperature must then be between room temperature and 150 ° C, preferably between 50 and 120 ° C.

The titanium amine complex used in the reaction according to the invention is obtained by reacting a titanium halide, mainly tetrachloride or tetrabromide, with a compound of formula III, most preferably in a molar ratio of 1: 4. The reaction is most conveniently carried out later in the solvent used in the main reaction. In this case, the titanium halide is used as its soluble ether tin (mono- or dietherate), mainly as the anisole dietherate.

Upon completion of the reaction, the largely insoluble titanium compounds in the reaction mixture are converted to a soluble form by the addition of an alcohol, e.g., isopropanol, followed by precipitation by the addition of aqueous ammonia. From the reaction mixture from which the titanium compounds have been removed in this way, the compounds of the formula I obtained according to the invention are isolated after concentration of the reaction mixture by crystallization in a known manner and then purified in a known manner, e.g. by recrystallization from isopropanol.

In the preparation of compounds of formula I in which R1 corresponds to a hydroxyalkyl group, the reaction product may precipitate as a gel, since the hydroxyalkyl group also reacts with the titanium halide to form an ester. In order to prevent excessive gelation which interferes with the reaction, it is expedient to use a larger amount of solvent, e.g. chlorobenzene or anisole and an excess (10-20 times excess) of a tertiary amine, e.g. triethylamine.

The compounds of formula I prepared according to the invention can be converted into their acid addition salts and vice versa. Suitable salts include hydrochlorides, hydrobromides, sulfates, fumarates, maleinates, p-toluenesulfonates, etc.

The compounds of formula II used as starting compounds in the process described above are for the most part known, or can be prepared in a known manner from known starting compounds. Compounds of formula III are also generally already known, or can be prepared in a known manner from known starting compounds.

The compounds of the formula I prepared according to the invention are for the most part already known and, like these compounds, can be used for therapeutic purposes in a known manner. purposes. For example, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b, e] [1,4] diazepine is known as a very effective sedative called "Clozaril".

In the general formula I, the substituent is preferably in position 2 or 3, the substituent preferably in position 7 or 8.

In the following examples, temperatures are expressed in degrees Celsius and room temperature means a temperature between 20-30 ° C, unless otherwise indicated.

Example 1 8-Chloro-11 (4-methyl-1-piperazinyl) -5H-dibenzo [b] e7 / 1,47 diazepine

At a temperature of 840 ml of toluene, 90 ml of anisole and 79.2 g of titanium tetrachloride are placed in a 2.5-liter beaker equipped with a dropping funnel, a reflux condenser and a thermometer to give a dark brown clear solution. To this is added externally, with water cooling, a mixture of 167 g of N-methylpiperazine and 100 ml of toluene, the temperature rising to 50-55 ° and the amine complex forming a finely divided beige-dark brown suspension. 102 g of 8-chloro-10,11-dihydro-11-oxo-5H-dibenzo [b, f] [1,4] diazepine and 83 g of N-methylpiperazine are then added and the reaction mixture is boiled under stirring for 3 hours ( 110-112 °). After cooling to 60-70 °, 125 ml of isopropanol are added, whereby the insoluble titanium compound formed in the reaction is redissolved. After adding 8 g of diatomaceous earth followed by 115 ml of concentrated ammonia (about 27%), the mixture is cooled with stirring to about 30 ° and the precipitate formed is filtered off. The filter cake is washed 2-3 times with 330 ml portions of toluene.

The filtrate is then shaken with water and the organic phase is extracted with dilute hydrochloric acid, about 10%. The base is mixed separately by dropping the hydrochloric acid extract into excess dilute ammonia. The product is then dissolved in ether, the ether solution is washed with water and dried over sodium sulfate. After evaporation of the ether and recrystallization from isopropanol, 8-chloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b] e7 / 1,47diazepine with a mp of 184-185 ° is obtained. , the yield being 90% of the theoretical yield based on the lactam used.

Example 2 2,8-Dichloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo-Zb, e7H, 47diazepine

Mix 2.2 ml of titanium tetrachloride, 4.4 ml of anisole and 40 ml of toluene in a beaker equipped with a dropping funnel, reflux condenser and thermometer until a reddish solution is obtained. 8.9 ml of N-methylpiperazine dissolved in 5 ml of toluene are added dropwise with stirring and cooling to give a greenish suspension. To the suspension are added 5.6 g of 2,8-dichloro-10,11-dihydro-5H-dibenzo [b, e] [1,4] diazepin-11-one and 4.5 ml of N-methylpiperazine, and the resulting mixture is heated boiling for 3 hours to form a dark, homogeneous solution. 3 ml of water are added, the precipitate formed is filtered off and washed with methanol. The filtrate is evaporated to dryness, the residue is dissolved in acetic acid, the solution is clarified with activated carbon and made alkaline by adding concentrated ammonia solution. The separated base is dissolved in chloroform, the chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is dissolved in ether and the solution is clarified by filtration through a pad of alumina. Recrystallization from acetone / ether / petroleum ether gives 2,8-dichloro-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b] e7 / 1,47diazepine in 77.6% yield relative to the lactam used in the reaction. mp. 192-195 ° (yellow prisms).

The starting 2,8-dichloro-10,11-dihydro-5H-di-benzo [b] 7,7,4-diazepin-11-one is obtained in a manner known per se by reacting 5-chloroanthranilic acid with 2-bromo-5-chloro-nitrobenzene. in the presence of potassium carbonate and Cu powder in boiling amyl alcohol (Ullmann condensation) and by treatment with 4,4, -dichloro-2-nitrodiphenylamine-2'-carboxylic acid (m.p. 274-276 °) in ammonia to give 4.4 * -dichloro-2-aminodiphenylamine-2'-carboxylic acid (m.p. 200-208 °), which, when heated at reflux in xylene for 40 hours, gives 2,8-dichloro-10,11-dihydro-5H-dibenzo [b, e7 / l, 4 / diazepin-11-one, m.p. 308-310 °.

Using the methods described in Examples 1 and 2 above and the corresponding starting compounds, the following compounds are obtained in an analogous manner: a) 5-methyl-11- (4-methyl-1-piperazinyl) -dibenzo [k, e] -1,4'-diazepine, mp. 122-124 ° (from ether / petroleum ether), b) 11- (4-methyl-1-piperazinyl) -dibenzo [b, e] 1,47d-diazepine, m.p. 184-185 °.

c) 5-methyl-8-methoxy-11- (4-methyl-1-piperazinyl) -dibenzo [b, e] 1,4] diazepine, m.p. 139 °, d) 3-methyl-11- (4-methyl-1-piperazinyl) -dibenzo [b] e7 / 1,47 diazepine, m.p. 168-170 °, e) 3-chloro-11- (4-methyl-1-piperazinyl) -dibenzo [b,% 7], 4J7 diazepine, m.p. 169-171 °, f) 3-methoxy-11- (4-methyl-1-piperazinyl) -dibenzo [b, e] [d], 47 diazepine, m.p. 212-214 °, g) 8-trifluoromethyl-11- (4-methyl-1-piperazinyl) -dibenzo [b, e] 1,47diazepine, m.p. 193-194 °, h) 11- [4- (β-hydroxyethyl) -1-piperazinyl] -7-dibenzo [b, e] [1,7] diazepine, m.p. 182-184 °, i) 4-methylthio-5-methyl-11- (4-methyl-1-piperazinyl) dibenzo [b] e7 / 1,47diazepine, m.p. 140 °, j) 7-methylthio-11- (4-methyl-1-piperazinyl) -dibenzo [b, e] 1,47diazepine, m.p. 120/146-150 °, k) 8-chloro-11- [4- (β-hydroxyethyl) -1-piperazinyl] dibenzo [b] e7 / 1,47diazepine, m.p. 241-244 °, 1) 8-chloro-11- (4-ethyl-1-piperazinyl) -dibenzo [b] q7 / i> 47 diazepine, m.p. 162-163 °, m) 2-dimethylaminosulfonyl-8-chloro-11- (4-methyl-1-piperazinyl) -dibenzo [b] e7 / 1,47diazepine, m.p. 198-200 °, n) 2-chloro-8-methyl-11- (4-methyl-1-piperazinyl) -dibenzo [b] e7 / 1,47diazepine, m.p. 236-237 °, o) 8-methoxy- (4-methyl-1-piperazinyl) -dibenzo [b] e7 / 1,47 diazepine, m.p. 182-184 °, p) 2,8-dichloro-11-piperazino-5H-dibenzo [b, e7], 47-diazepine, m.p. 216-219 °, q) 2-chloro-8-bromo-11- (4-methyl-1-piperazinyl) -5H-dibenzo [b] e7 / 1,47diazepine, m.p. 198-200 °.

Claims (1)

A new process for the preparation of therapeutically useful dibenzo [b, e] E, 47diazepines of the formula I I1 | I <X Xj ",! R4 wherein R1 is hydrogen, methyl, ethyl or hydroxyethyl is hydrogen, methyl, methoxy, methylthio, chlorine, bromine or trifluoromethyl, R4 is hydrogen or methyl, and R2 is hydrogen, methyl, dimethylamino- sulfonyl, methoxy, methylthio or chlorine, characterized in that a compound of formula II O II R 1 -OC R j K in which R j, R j and R 2 are as defined above is reacted with a titanium amine complex consisting of titanium and a compound having is the formula III m ^ NR III III_V 1 wherein R 1 is as defined above.