MXPA96000651A - Procedure for the preparation of p-fenetid - Google Patents

Abstract

The present invention relates to a process for the preparation of p-phenetidine, characterized in that it comprises the steps of: a) diazotizing p-phenetidine and coupling the resulting compound with phenol in a phenol / diazo molar ratio of 1.3-1, 0, b) ethylate the compound obtained in step (a) at a temperature comprised between 130 and 200 ° C, and c) catalytically hydrogenate the ethyl compound obtained in step (b), whereby 2 moles of p-2 are obtained. phenetidine, one of which is recycled as a starting reagent to the stage (

Description

nnnnpm ?? tn? tmo mm? The present invention relates to a new pirseßsa pa ** 1 * pvapax > aaión do p fanotidina. In particular, the invention relates to an improved process for the preparation of p-phenetidine of high purity and without the co-production of large quantities of by-products. BACKGROUND OF THE INVENTION P-phenetidine is an important compound used as an intermediate in the dye industry as well as for many other uses. Thus, for example, it is used in the preparation of p-ethoxyacetenyl-da and Ethoxyqüin. Due to the large quantities required of p-phenetidine, there are many patents and publics that describe different methods, the purpose of all of them being to improve the yield and purity of the product, thus reducing its cost. The general scheme for the preparation of p-phenetidine Includes three main stages; (a) Chlorobenzene nltraclon with a mixture of sulfuric acid and nitric acid. The product obtained is a T t uell of chloronitrobenzene. The o-nitrochlorobenzene obtained as a by-product has to be recovered ad, (b) Ethoxylation of p-chloronylbenzene using a base and ethyl alcohol in the presence of a catalyst. The reaction is carried out for several hours, the chlorine being replaced by the β-toxy group. It is said that yields of the order of 80 to? 0% are obtained. (c) Catalytic reduction of the nitro group at 100 * C approximately under pressure and in the presence of a catalyst selected from nickel and a noble metal. This reduction is effected in the presence of a solvent which, at the end of the period, is required? ? c evaporated, and the p-phenetidine is removed by distillation under vacuum. Several improvements have been suggested in relation to the previous scheme, all claiming that they improve the overall performance or cost of the final product. Some typical examples of a-i? I? DT according to the German Offense 2,649,741, ßß prp.pnrp? P nlppwlnnp 1pnñ pnr rn nmip.nto d «the aniline tooth-coil with RX, where X is Cl or Br, in an aprotic organic solvent and in the presence of an alkali metal alcoholate or hydride. The reaction is carried out in an autoclave at 80 ° C for 5 hours, to W- Ll «_- > J- & * • * • * - -? - I 1A * L. J? Ab-? L A * lJ < & L¿ > UJ • According to Russian Patent 514,811, p-phenetidine is obtained by reduction of p-nitrophenol in absolute aleßhßl and a concentrated pfizer of "ulfurinr" acid, using platinum oxide as a catalyst and di-fluorophosphate as a prnntnnt Fl flp nhf.lfinñ finally heating the mixture under a nitrogen medium. In addition to the Kok ^ i Ji ^ cui *** 53 849? ^ (78 / ß4923), are alkoxyanilines prepared by reduction of D-nitrophenol Q? Hydrogen is dissolved in an alcohol and in the presence of: organosulfonic acids or alkyl esters and sulfuric acid, platinum or palladium and sulfuric acid. The reaction is carried out under pressure for about 7 hours at 70-80 ° C, to give a yield of 69% p-alkoxykyliniline. According to Romanian Patent 54273, p-phenetidine is obtained by reduction of p-nitrofenetol with iron in an aqueous solution of ammonium chloride using a permanent excess of iron in the free acid-free reaction medium, the precipitate of Fe 304 thus obtained was filtered under pressure and washing with water vapor. The filtrate was further treated with sodium chloride to give p-phenetidine. an interesting process is the one described in the Czechoslovak patent 146.650 where part of phenol. In a first stage, the phenol is condensed with aniline lcu.wl.sJ. i ßa a * ila are aloruro do otilo The resulting product is dissociated at 30-60 ° C under hydrogen pressure over a paladin-on-carbon catalyst. The claimed yield to obtain is only about 90%. The previous brief exposition illustrates the importance attributed to the preparation of p-fnetnetidine, oionflo ol nhjnflun al mnjnrar alopnn lni rtftpnñ involved in the process, in order to increase the yield or purity of the final product. An object of the present invention is to provide a simple process for the preparation of p-phenetidine. Another object of the present invention is to provide a simple process for the preparation of? -fpnpt1ri1na pn altn rendímlRntins. It is an object of the present invention to provide a simple process for the preparation of p-phenetidine which is substantially free of the undesired α-phenetidine isomers and of chloro-amino aromatic compounds. BRIEF DESCRIPTION OF THE INVENTION The invention consists of an improved process for the preparation rif? n-fpnpfiriiriñ. i niial nnmprpnriPi the stages of: (a) diazotar p-phenetidine and copulate the p.omp? i? «n result nnn phenol p, n nnn GP, 1 anion mnl nr phenol / diazo of 1.3-1.0; (b) ethylating the compound obtained in step (a) at a temperature comprised between 130 and 200nC > and (c) hydrogenating the ethylated compound obtained in step (b), thereby obtaining 1 mol of p-phenetidine, one of which is reagent as starting reagent to step (a). It has been proven that, under specific critical conditions, yields greater than 97% are obtained. In addition, since the main peak amount consists of one mole of the final product obtained in the process, the purity of the final p-phenetidine can be selected according to the specific use projected. In this way, starting from a very pure p-phenetidine, on which the diazotization and coupling reactions are carried out, the corresponding very pure product will be obtained. The first stage in very early and flñt.firmina the performance achieved of p-phenetidine. In this step, two reactions are involved: the first reaction, in which the diazonium salt is obtained using a nitrite salt, such as sodium nitrite, under acidic conditions, cooling below 104C, with the preferred temperature being on the order of 0 at 5 * C. In the subsequent reaction, the diazonis salt is coupled with phenol, in an alkaline medium, maintaining a slight excess of diazo compound relative to phenol, the most preferred molar ratio being from 1 to 1.3. The reactions involved are illustrated schematically as follows: (A) Lt? . * TQ MI • - c * G-? , "- W" W It has been surprisingly proven that the slight excess of phenol with respect to dinzo is very critical for the performance that can be achieved. Although the reaction is not favorable to a 2-mole phenol with respect to the ion, it has been found that a decrease in yield will then occur. The acidic conditions necessary for the first reaction are obtained using any mineral acid, such vvuiv auUw 3l 4-l? -t - > v * * - * _ »**! £» .. to * X > 4 'T I-J-. WM.¡ MML ?? The coupling with phenol is carried out in a low medium, being the pil from 9 to 10 and more proformonta before from 9.2 to 9.4. The basic medium can be obtained by using pnalqplarrrrniniiaßrn? Lr? Linn. f? l nnmn t? 1í1r ?? 1fln nórtinn. Sodium carbonate, sodium bicarbonate, potassium hydroxide, the first being the most preferred from an economic point of view. The second step involves the ethylation of the coupled compound obtained in the first stage, using a halide or ethyl sulfate in the presence of a solvent and a basic substance, at a temperature of 130 to 200 ° C. In general, an excess of the coupled compound should be present, preferably the main * dn r > nr in m nff 1. mnli? nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn The solvent to be used should be inert toward the "component" of the reaction and can be selected from a wide class, such as acetonitrile, xylenes, methanol, ethanol, LUIUBUU », uU. The equation that illustrated it. Oatma oagunda can be represented schematically as follows: EtCl The last step involves the catalytic reduction of the etiied coupled compound and is very critical to obtain the high yield according to the present invention. In the reaction that takes place, the azo bond (N »N) breaks down and, in the presence of hydrogen, de moles of the amino compound, ie p-alkoxyaniline, are produced. It has been proven that it is reactive dtíb < it is at a temperature above 70 ° C and under a pressure greater than 5 atmospheres of hydrogen in the presence of an inert solvent and a catalyst selected from nickel and a noble metal, such as palladium, platinum, iridium , inert, an inert, inert, inert, or inert carrier must be selected from several alcohols. Tguplmantß, it is possible to carry out the reduction reaction in the absence of said alcohol, in which case the temperature should be from 40 to I60ßc. The equation involved in the second stage can be schematically represented as follows: As follows from the previous equation, 2 moles of the required product are obtained, one of them being recycled to the first stage of the diazotization reaction. Therefore, the process according to the present invention is in fact? l? common starting reagents such as phenol, ethyl chloride, mineral acid and basic reagents, to obtain valuable end products of high purity and in high yields. The invention will be illustrated below by the following examples which should not be considered as limiting thereof. The experts on the subject, a v »; read pi a rie rrr.r, will be in a position to appreciate the scope of the invention and may conceive and incorporate mur.hfla vari nfiionßa as they are covered by the appended claims, fijgmplo 1 ELA ^ A a: pg * pagaeiAB da 4-atex-i 4 'hidroui aaobonoono In a 5-liter plastic container equipped with a stirrer, 1 liter of water, 0.5 kg of crushed ice, 145 g of concentrated sulfuric acid (98%) were added. and 137.29 of distilled p-fepetidine (obtained from a previous cycle). The reaction mixture was maintained at approximately 0 * C by the addition of more crushed ice and then 230 g of 33.3% NaN02 solution were rapidly introduced under the surface. T.ß r * »rrl An i mpl i r * aria fuá mmn s? Pia - - + Nacl This diazo solution was stirred for 1 hour, while the t.e.mpp.rft ur? fie maintained at 0 * C approximately. The product obtained was subsequently coupled with phenol as follows: In a 10 liter container, equipped with an agitator, 1 liter of water, 97 g of phenol and a sodium hydroxide solution were added, thus raising the pH to 9.3. Next, the diazo solution, obtained in step a) above, was added below the duianLe 1 l? U? A afru surface. w? Íntftd * lf? * ne, ie ie the pH value was maintained between 9.2 and 9.5 by the addition of a hydroxide solution rhodics at the same time as the RR stirred. 30 minutes more and then the pH was adjusted to 6.5-7.5 by a dilute solution of anionic acid. The reaction involved was as follows: The product was filtered, washed with water until the filter cake was free of oxygen and heated to 45-60 ° C. So obtained an amount of 236 gd »-ethoxy-4'-hydroxy-azobenzene, i.e. , a performance of 97.5% of the theoretical. The p.f. of the product was 12 $ -l2g ° c.

Step b: Preparation of 4.4 '-dietoxy-azobenzene In a pressure vessel, equipped with an oy i LaJwi, lu L.-. t-'vl -J v--. Vil lua i cu ^ li v u ^ vi-.1- 4-1 ü -. ^ L-íLift ^ i !.

Order: (a) 150 ml of methanol; (b) 36.6 g of concentrated sodium hydroxide (46.5% by weight); (c) 98.5 g of dry 4-etho? i-4'-hydroxy-azobenzene [product obtained in step (a)]; (d) 10 g of anhydrous sodium carbonate. The reactor was cooled to about 15 * C and then 33.6 g of ethyl chloride was added. The reactor was heated to 160 ° C while maintaining vigorous stirring. After 1 hour, the reactor was cooled, the product was filtered and washed with a dilute solution of sodium hydroxide, and then with a dilute solution of sulfuric acid seyuldu μuL ayua until obtaining a pH of 6 to 8 in the rinsing water . The product was then dried at 120 ° C. An amount of 108 g of 4,4'-diethoxy-azobenzene was obtained, that is to say a yield of 98.3% with respect to the theoretical, its point of rusiún roule was-16l * C. £ t. 3 ... C. 4.4'-Dletoxy-azobombine catalytic hydrolysis In a 0.4-liter pressure vessel, or fitted with a thermometer and moanium stirrer, introduce the following reagents: (a) 200 ml of methanol; (b) 0.20 g of a catalyst, consisting of 5% palladium on carbon, in the form of a paste containing about 50% water; (c) 20 g of 4,4 '? pdietoxy-a7; obpnr,? nn [nrnrtiir. n obtained in stage (b) above]. The reactor was closed, flooded three times with -il i óy tsin-% a V CAI W / H l '? U.-! ? £ ji-; i 2? to tßmpc.JTO'te? 'C- amb-Lan ^ so.

Next, hydrogen was introduced to obtain a pressure of 8 atmoai &xa? or tem erature environment. The reactor was then heated to 100 ° C while maintaining a continuous hydrogen feed and vigorous stirring. After 30 minutes, the reaction was completed and the reaction mixture was cooled and filtered. The solvent was evaporated and the crude p-phenethidine was distilled under vacuum. An amount of 19.7 g of product was obtained, ie a yield of 97% with respect to the theoretical, the product having a refractive index N20d = 1. 0650. EXAMPLE 2 The experiment of Example 1 was repeated wherein steps (a) and (b) were the same, using the same reagents and amounts thereof.

In step (c), the hydrogension was carried out as in Example 1, in the same pre-canned vessel and starting from the p-phenetidine obtained in Example 1, the other reagents and their amounts of the steps being ( a) and (b) the same, but the catalyst used in xa 'stage i cj consisted of 1 g of nickel phthaiiey (60% of ßólidoß). Also, in this case, the same amount of 19.7 g of p-phenetidine product having the same refractive index N20d-1.0650 was obtained. Yes bi ?? The invention has been described in connection with certain preferred embodiments, it should be understood that it does not intend to limit the invention to said particular examples. On the contrary, other modifications beyond the particular examples, such as may be included within the scope of the invention, should be included in the present invention. It should be understood that the described features are uniquely offered? by way of example without limiting the invention.

Claims (1)

REVINDICATIONS 1.- A process for the preparation of p-fepeLldiiia, uc- * cLe / izad © parque comprendo lao otapao do: (a) diazotizing p-phenetidine and coupling the resulting compound with phenol at a molar ratio fßnol / diazo e

1.3-1.0; (b) synthesizing the compound obtained in step (a) at a compressed temperature of 100 [deg.] C. and 200 [deg.] C. and (c) catalytically hydrogenating the ethylated compound obtained in step (b), whereby 2 are obtained. moles of p-phenetidine, one of which is recycled as starting reagent to step (a) 2, - A process according to claim 1, characterized in that the diazotization reaction is carried out at a temperature of 0 to 5. * C 3. A process according to claim 1, characterized in that the coupling of the compound of diat-ft * aai6n to ianol oo ofootúa at a pH of fl 4 - A process according to claim 3, characterized in that rh ' r.hn pH is maintained by a basic compound selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate and potassium hydroxide 5. A process according to claim 1, characterized in that diphn rear.r.iñn ft This is done with a reagent selected from the group. in ethyl chloride and ethyl sulfate, in the presence of an inert solvent. 6. A process according to claim 5, characterized in that the molar ratio between the coupled compound and the ethylation reagent is of the order of 1 to 1.3. 7. A process according to claim 5, characterized in that said ethylation is carried out at a temperature of 130 to 200QC. 8. A process according to claim 5, characterized in that said inert solvent is selected from the group consisting of xylenes, toluenes, methanol, ethanol and acetonitrile. 9. A process according to claim 1, characterized in that the catalytic hydrogenation of the comptaate ßtilad a * «£» ".; Id * & a temperature below 70 ° C and under a pressure of 5 atmospheres of hydrogen, in the presence of an inert solvent and a catalyst. 10. A process according to claim 9, characterized in that said solvent is an inert alcohol.