KR800001312B1 - Method for preparing 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole - Google Patents

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Description

Method for preparing 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole

The present invention relates to a process for the preparation of 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] phosphorus compounds of the following structural formula (I) useful as anti-inflammatory and analgesic agents: will be.

As is well known, the methods of preparation described herein and their intermediates have not been described or suggested before.

US Pat. No. 3,878,225 to Aljan et al. Describes various synthetic methods for preparing 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] indole, but the present invention It is different from the manufacturing method of. Moreover, it is unexpected that the less nucleophilic amino group, such as the amino functional group of 5-aminosalicylic acid, reacts easily with the enamine, and the method described here is a more economical and valuable 3- (3-carboxy-4- It is preferred in that hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] phosphorus is produced.

The already mentioned patent discloses γ-diketones or γ-ketoaldehydes by condensation of enamines with α-haloketones or aldehydes in solvents such as dimethylformamide or toluene at 0 to 120 ° C., followed by hydrolysis. The preparation of various pyrroles comprising 3- (3-carboxy-4-hydroxyphenyl) -2-phenyl-4,5-dihydrobenz [e] phosphorus is described. The above describes, in part, the general process by which the novel intermediates of the present invention can be prepared, but the patent does not describe the presence or separation of the intermediates, as well as the uses described in the present invention. Not.

The prior art describes only condensation reactions for the preparation of third compounds and does not describe separable and useful intermediates produced during the preparation. It has therefore been found that en ammonium salts are now particularly suitable for the first time to be effectively prepared, recognized, separated and characterized, and particularly suitable for use in the preferred method for producing valuable compounds.

3- (3-carboxy-4-hydroxy-phenyl) -4,5-dihydro-2-phenylbenz [e] phosphorus of the present invention is a 5-ammonium salt of tautomer form having the following formula (II). Prepared by reaction with amino salicylic acid.

In the above structural formula

R ¹ and R ² are the same or different and each represent alkyl having 1 to 6 carbon atoms, or together with the nitrogen atom to which they are attached form a pyrrolidino or piperidino ring;

X is bromine or chlorine. This reaction can be carried out in a solvent such as glacial acetic acid, 2-propanol or methanol at ambient temperature to the boiling point of the solvent.

Yan ammonium salts are prepared by reacting a naphthalene compound of the formula: with a pen acyl halide.

In the above structural formula

R ¹ and R ² are as described above.

This reaction can be carried out at the advantages of ambient temperature to solvent in the presence of a solvent such as dimethylformamide or toluene.

The following examples are intended to illustrate the invention in detail.

Example 1

a. A solution of 500 g of penacyl bromide in 700 ml of dimethyl formamide was added dropwise to a solution of 505 g of 2- (1-pyrrolidino) -3,4-dihydronaphthalin dissolved in 1300 ml of diethyl formamide. do. After the addition, the reaction mixture was further stirred for 4,5 hours and 1,280 ml of ether was added thereto. The precipitate is removed by suction filtration and washed sequentially with a mixture of dimedylformamide-ether (1: 2) and ether, leaving a white solid. This solid is dried under vacuum to give 1-phenacyl-2- (1-pyrrolidino) -3,4-dihydronaphthalene hydrobromide having a melting point of 217 to 219 ° C.

b. 304 g of 5-amino salicylic acid are added to 3,800 ml of acetic acid with stirring. The stirred suspension is heated to 60 ° C. and 791 g of 1-phenacyl-2- (1-pyrrolidino) -3,4-dihydronaphthalene hydrobromide are added. Additionally 150 ml of acetic acid is added and stirred at 70 ° C. for 3-4 hours and then cooled to ambient temperature. When a solid appears, it is collected by filtration, washed sequentially with acetic acid and petroleum ether, and dried under vacuum for 16 hours to obtain 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e] phosphorus. To obtain them.

Example 2

A well-stirred mixture of 3.98 g of 1-phenacyl-2- (1-pyrrolidino) -3,4-dihydro naphthalene hydrobromide (Example 1a), 1.53 g of 5-amino salicylic acid and 10 ml of acetic acid was refluxed for 15 minutes. Under heating. The reaction mixture is left at ambient temperature and then diluted with 100 ml of acetic acid. The resulting solid was collected by suction filtration, washed with 50 ml of petroleum ether and dried under high vacuum for 72 hours to afford 3- (3-carboxy-4-hydroxyphenyl) -4,5-dihydro-2-phenylbenz [e. To obtain phosphorous.

Example 3

A mixture of 1.92 g of 5-amino salicylic acid and 5.0 g of 1-phenacyl-2- (1-pyrrolidino) -3,4-dihydronaphthalene hydrobromide (Example 1a) was dissolved in 75 ml of methanol and 9 hours under nitrogen. Reflux for a while. The solution is brought to ambient temperature and filtered. Methanol is removed under vacuum to dissolve in acet natryl to give a viscous oil.

The solution was crystallized to give a yellow crystalline solid which was collected by filtration and washed with acetonitrile to give 3- (3-carboxy-4-hydroxy phenyl) -4,5-dihydro-2-phenylbenz [e]. Obtain phosphorous.

Example 4

a. A mixture of 25 g of β-tettalone and 100 g of 4a molecular sieve is dissolved in 400 ml of toluene, cooled in an ice-bath and saturated with dimethyl amine. The reaction mixture is stirred at 100 ° C. for 4 hours, cooled and filtered. The toluene was evaporated off to distill off the remaining red oil in vacuo to afford 3,4-dihydro-2-naphthyl) -dimethyl amine as a yellow oil.

b. A solution of 22 g of penacylbromide dissolved in 50 ml of dimethyl formamide was dissolved in 2-ml amino-3,4-dihydronaphthalene in 70 ml of dimethylformamide, and added dropwise to the stirred solution.After the addition, the reaction mixture was further stirred for 5 hours. And 400 ml of ether. The white precipitate is collected, washed with ether and dried. Recrystallization with acetonitrile gives 1-phenacyl-2-dimethyl amino-3,4-dihydronaphthalene hydrobromide having a melting point of 145 to 147 ° C as a white solid.

c. A mixture of 10.0 g of 1-phenacyl-2-dimethylamino-3,4-dihydronaphthalene hydrobromide and 4.1 g of 5-amino salicylic acid is dissolved in 50 ml of acetic acid and stirred vigorously at 75 ° C. for 4.5 hours. The reaction mixture was cooled to 20 ° C., filtered, and the precipitate was collected, washed 21 times with 20 ml of acetic acid and 5 times with 20 ml of hexane, and then dried under vacuum for 20 hours to obtain 3- (3-carboxy-4-hydroxyphenyl. ) -4,5-dihydro-2-phenylbenz [e] phosphoruss are obtained.

By the method of Example 1a, 2-di-n-butylamino-3,4-didihydro-naphthalene, 2-dimyl amino-3,4-di-hydro naphthalene, 2- (1-piperidino)- 3,4-dihydronaphthalene to phenacyl-2-di-n-butylamino-3,4-dihydro naphthalene hydrobromide, 1-phenacyl-2-dimyl amino-3,4-dihydro naphthalene hydrobromide And 1-phenacyl-2- (1-piperidino) -3,4-dihydro naphthalene hydrobromide.

Example 1b, 2, 3 or 4, wherein the 3- (3-carboxy-4-hydroxy phenyl) -4,5-dihydro-2-phenylbenz [e] phosphorus is 1-phenacyl-2- It can be prepared from di-n-butylamino-3,4-dihydro naphthalene hydro bromide or 1-phenacyl-2- (1-piperidino) -3,4-dihydro naphthalene hydro bromide.

By the method of Example 4a, the β-tetralone can be reacted with an amine to prepare the naphthaleno compounds necessary to prepare the corresponding enammonium salts.

Claims (1)

3- (3-carboxy-4-hydroxyphenyl) -4,5-di of the following formula (I), characterized by reacting an enammonium salt in tautomeric form having the formula (I) with 5-aminosalicylic acid Process for preparing hydro-2-phenylbenz [e] phosphorus.

R ¹ and R ² in the above formula are the same or different and each is alkyl having 1 to 6 carbon atoms or together with the nitrogen to which they are attached form a pyrrolidino or piperidino ring and X is bromine or chlorine.