CH342559A

CH342559A - Process for the preparation of phenylcarbamates

Info

Publication number: CH342559A
Authority: CH
Original assignee: Rech Et Tech Appliquees
Priority date: 1955-02-05
Filing date: 1956-02-03
Publication date: 1959-11-30

Description

Procede de preparation de phenylcarbamates 0n connait un certain nombre de ph6nylcarba- mates comportant un hydroxyle ph6nolique en position ortho ou en position para sur 1e noyau ben- zenique. En particulier, an a dejä decrit 1e para-hydr- oxyphenylcarbamate (ou para-hydroxycarbanilate) d'6thy1e et fait mention, sans en d6crire la prepara- tion ni les proprietes, des esters methylique, propy- lique, butylique, isobutylique et iso-amylique cor- respondants. Process for the preparation of phenylcarbamates A certain number of phenylcarbamates are known comprising a phenolic hydroxyl in the ortho position or in the para position on the benzene nucleus. In particular, an has already described ethyl para-hydroxyphenylcarbamate (or para-hydroxycarbanilate) and mentions, without describing the preparation or the properties, methyl, propyl, butyl, isobutyl and isobutyl esters. -amyl compounds.

0r, an a trouv6 que certains carbamates consti- tuent des anesthesiques locaux de valeur. Ces nou- veaux compos6s repondent ä la formule generale Or, an has found that certain carbamates are valuable local anaesthetics. These new compounds correspond to the general formula

dans laquelle R est un radical alcoyle de 1 ä 14 atomes de carbone ou un radical benzyle ou ph6nyl- 6thyle, n est egal ä 2 ou 3, et 1e groupe amino ter- tiaire repr6sent6 par wherein R is an alkyl radical of 1 to 14 carbon atoms or a benzyl or phenylethyl radical, n is 2 or 3, and the tertiary amino group represented by

est un groupe di6thylamino, morpholino ou pip6ri- dino. is diethylamino, morpholino or piperidino.

Ces ph6nylcarbamates possedent, sous forme de leurs chlorhydrates, une activite 10 ä 40 fois sup6- rieure et une toxicit6 2,5 fois plus faible que la cocaine. These phenylcarbamates have, in the form of their hydrochlorides, an activity 10 to 40 times higher and a toxicity 2.5 times lower than cocaine.

Parmi les composes qui viennent d'etre d6finis, les chlorhydrates des carbamates, dont 1e radical alcoylique R possede 6 ä 8 atomes de carbone en chaine droite, sont particulierement importants, car ils offrent 1e maximum d'activite, en tant qu'anesth6- siques locaux de surface. L'activite est particuliere- ment elev6e dans. 1e cas dune chaine de 7 atomes de carbone ; ainsi 1e chlorhydrate du para-ss-morpho- linoethoxyph6nylcarbamate de n-heptyle presente un pouvoir anesth6sique local de surface environ 30 ä 40 fois plus grand que celui de la cocäine et deux fois plus grand que celui de la cinehocaine (chlor- hydrate de la ss-di6thylamino6thylamide de 1'acide quinol6ine butoxy-2 carboxylique-4) alors que sa toxicit6 (dose lethale moyenne 45 mg par kg) est environ 4,5 fois moindre que celle de la cinchocdine et 2,5 fois moindre que celle de la cocäine ; 1e compose correspondant ä groupe diethylamino (au lieu du groupe morpholino) est lui aussi important. Among the compounds which have just been defined, the hydrochlorides of the carbamates, whose alkyl radical R has 6 to 8 carbon atoms in a straight chain, are particularly important, since they offer the maximum activity as anesthetics. surface premises. Activity is particularly high in. 1st case of a chain of 7 carbon atoms; thus n-heptyl para-morpholinoethoxyphenylcarbamate hydrochloride has a local surface anesthetic power about 30 to 40 times greater than that of cocaine and twice as great as that of cinehocaine (hydrochloride of ss-di6thylaminoethylamide of quinolino-2-butoxy-4-carboxylic acid) whereas its toxicity (mean lethal dose 45 mg per kg) is approximately 4.5 times less than that of cinchocdine and 2.5 times less than that of cocaine; The compound corresponding to the diethylamino group (instead of the morpholino group) is also important.

Les chlorhydrates des para-tertio-aminopropoxy- phenylcarbamates de n-heptyle sont eux aussi des composes interessants en taut qu'anesth6siques lo- caux de surface ; 1e pouvoir anesth6sique du chlor- hydrate du para-y-morpholinopropoxy-ph6nylcarba- mate de n-heptyle est particulierement elev6. The hydrochlorides of n-heptyl para-tertio-aminopropoxyphenylcarbamates are also interesting compounds as local surface anesthetics; the anesthetic potency of n-heptyl para-y-morpholinopropoxy-phenylcarbamate hydrochloride is particularly high.

De plus, 1e chlorhydrate de p-morpholino6thoxy- (ou aussi de p-diethylaminoethoxy-) ph6nylcarbamate de propyle offre un grand interet en ce sens que, bien que faiblement actif comme anesthesique local de surface, il possede en revanche une tres grande acti- In addition, propyl p-morpholinoethoxy- (or also p-diethylaminoethoxy-) phenylcarbamate hydrochloride offers great interest in the sense that, although weakly active as a local surface anesthetic, it has on the other hand a very great activity.

vit6 anesthesique de conduction, en 1'espece double de celle de la procdine (qui etait jusqu'ici 1'un des meilleurs anesth6siques de conduction et 1e plus uti- lis6). conduction anesthetic speed, in this case double that of procdin (which was hitherto one of the best conduction anesthetics and the most widely used).

Le procede selon 1'invention est caracteris6 en ce que Fon fait r6agir du p-nitroph6nol, en pr6sence d'un alcool et d'un alcoolate de sodium, avec un halog6nure de formule The process according to the invention is characterized in that p-nitroph6nol is reacted, in the presence of an alcohol and a sodium alcoholate, with a halide of formula

dans laquelle Hal reprdsente un atome d'halogene, en ce que 1'on r6duit 1e p-tert: aminoalcoxy-nitro- benzene ainsi obtenu en p-tert.-aminoalcoxy-aniline, et en ce que Fon fait r6agir cette derniere avec un ester chloroformique de formule R-O-CO-Cl. Dans les formules ci-dessus, les differents symboles ont ]es significations donn6es precedemment. in which Hal represents a halogen atom, in that the p-tert.-aminoalkoxy-nitrobenzene thus obtained is reduced to p-tert.-aminoalkoxy-aniline, and in that the latter is reacted with a chloroform ester of formula R-O-CO-Cl. In the formulas above, the various symbols have the meanings given above.

Apres s6paration de la Base brute, il y a avantage ä la transformer en chlorhydrate, de pr6f6rence par passage de gaz chlorhydrique sec ä travers une solu- tion 6th6ree ou c6tonique de rette Base. Certaines des bases sont, en effet, des huiles qui ne cristallisent pas et que Fon ne peut pas distiller ; en revanche, les chlorhydrates sont des composes que Fon peut obtenir ä 1'etat cristallin. Ort peut neanmoins isoler les bases libres en chassant 1e solvant de la solution 6th6r6e. After separation of the crude Base, it is advantageous to transform it into hydrochloride, preferably by passing dry hydrochloric gas through an ethereal or ketone solution of rette Base. Some of the bases are, in effect, oils which do not crystallize and which Fon cannot distill; on the other hand, the hydrochlorides are compounds which can be obtained in the crystalline state. However, Ort can isolate the free bases by removing the solvent from the ether solution.

11 convient de noter que, si les chlorhydrates sont d'un emploi commode en raison de leur solu- bilit6 dans Feau, les bases dont res chlorhydrates sont les sels sont elles-memes douees des meines proprietes anesth6siques locales et, 6tant liposolubles, peuvent eire utilis & s par exemple en solution hui- leuse. It should be noted that, while the hydrochlorides are convenient to use on account of their solubility in water, the bases of which the hydrochlorides are the salts are themselves endowed with the same local anesthetic properties and, being liposoluble, can be used for example in an oily solution.

En outre, les sels solubles des phenylcarbamates repondant ä la formule ci-dessus et dans lesquels R comporte 5 ä 8 atomes de carbone offrent Fint6- ret de donner des solutions mousseuses et peuvent etre utilises dans diverses industries en consid6ration de leur pouvoir tensio-actif. Les esters en question peuvent, de plus, etre utilis6s pour la synthese d'au- tres composes tels que des iodomethylates. In addition, the soluble salts of the phenylcarbamates corresponding to the above formula and in which R contains 5 to 8 carbon atoms offer the interest of giving foamy solutions and can be used in various industries in consideration of their surfactant power. . The esters in question can, moreover, be used for the synthesis of other compounds such as iodomethylates.

Exemple A 139 g (1 mol6cule-gramme) de p-nitrophenol, dissous dans une solution d'alcoolate de sodium contenant 23 g (1 atome-gramme) de sodium dans 1200 cm3 d'alcool absolu, an ajoute 164 g (1 mo16- cule-gramme + 10 % d'exces) de chlorure de ss- morpholinoAhyle. 0n chauffe 1e melange ä reflux pendant une heure, an essore 1e chlorure de sodium pr6cipite, puis an 1e lave plusieurs fois ä Falcool. Le filtrat (auquel sont joints les liquides de lavage) est aban- donn6 ä la glaciere. 0n essore 1e ss-morpholino- ethoxy-l-nitro-4-benzene qui se separe ä froid, an 1e lave ä l'alcool, puis an 1e seche. 0n recueille ainsi 199 g de substance sous la forme d'un compose cristallis6 et jaune qui fond ä 890. Le chlorhydrate de ce compos6 fond ä 199 . Example A 139 g (1 gram-molecule) of p-nitrophenol, dissolved in a solution of sodium alcoholate containing 23 g (1 gram-atom) of sodium in 1200 cm3 of absolute alcohol, an adds 164 g (1 mo16 - cule-gram + 10% excess) of ss-morpholinoAhyle chloride. The mixture is heated at reflux for one hour, the sodium chloride which precipitates is filtered off, then washed several times with alcohol. The filtrate (to which the washing liquids are attached) is left in the cooler. The ss-morpholino-ethoxy-1-nitro-4-benzene, which separates in the cold, is drained, washed with alcohol, then dried. 199 g of substance are thus collected in the form of a crystallized and yellow compound which melts at 890. The hydrochloride of this compound melts at 199.

Ort met 50,4 g de ss-morpholino6thoxy-l-nitro- 4-benzene ainsi obteng en suspension dans 200 cm! d'alcool absolu, an y ajoute 10 g d'un catalyseur ä 5 1% de palladium et an hydrogene ä froid sous 80 atmospheres de pression initiale. Ort puts 50.4 g of ss-morpholino6thoxy-1-nitro-4-benzene thus obtained in suspension in 200 cm! of absolute alcohol, 10 g of a catalyst containing 51% palladium and cold hydrogen are added thereto under 80 atmospheres of initial pressure.

L'hydrog6nation termin6e (lorsque la quantite th6orique a 6t6 absorbee), an elimine 1e catalyseur par filtration, an chasse l'alcool du filtrat et an dis- tille 1e residu sous un vide pousse. 0n recueille ainsi 37,9 g de p-para-ss-morpholinoethoxy-aniline passant ä 165 -1670 sous une pression de 0,4 mm et se pr6- sentant sous la forme d'un liquide incolore, qui se solidifie ä froid en une masse cristallis6e qui est Blanche mais brunit ä Fair. Le point de fusion est de 73,1. Le point de fusion du chlorhydrate est de 176o. When the hydrogenation is complete (when the theoretical amount has been absorbed), the catalyst is removed by filtration, the alcohol is removed from the filtrate and the residue is distilled under a high vacuum. 0n thus collects 37.9 g of p-para-ss-morpholinoethoxy-aniline passing to 165 -1670 under a pressure of 0.4 mm and appearing in the form of a colorless liquid, which solidifies cold in a crystallized mass which is white but browns to Fair. The melting point is 73.1. The melting point of hydrochloride is 176o.

Ort dissout 44,1 g (0,2 mo16cule-gramme) de ss-morpholinoethoxy-l-amino-4-benzene ainsi obtenu dans 200 cm3 de methyl-6thyl-cetone anhydre et an les ajoute peu ä peu, en agitant, ä 35,6 g (0,2 mole- cule-gramme) de chloroformiate de n-heptyle dis- sous dann 100 cm3 de methyl-ethyl-cetone anhydre. La r6action est exothermique ; an la modere en refroidissant 1e m61ange par un bain d'eau. Le coinpos6 forme se separe imm6diatement sous la forme d'un precipite blanc. 0n abandonne 1e me- lange une nuit ä la temp6rature ambiante, an essore 1e chlorhydrate de para-ss-morpholinoethoxyph6nyl- carbamate de n-heptyle, an 1e lave trois fois ä la methyl-6thy1-c6tone anhydre, puis an 1e seche sous vide. Ort dissolves 44.1 g (0.2 gram-molecules) of ss-morpholinoethoxy-1-amino-4-benzene thus obtained in 200 cm3 of anhydrous methyl-6-thyl-ketone and adds them little by little, while stirring, to 35.6 g (0.2 mole-gram) of n-heptyl chloroformate dissolved in 100 cm3 of anhydrous methyl-ethyl-ketone. The reaction is exothermic; in moderation by cooling the mixture in a water bath. The compound formed separates immediately as a white precipitate. The mixture is left overnight at room temperature, the para-ss-morpholinoethoxyphenyl-n-heptyl carbamate hydrochloride is filtered off, washed three times with anhydrous methyl ethyl ketone, then dried under vacuum. .

Apres 1'avoir recristallise une fois dans la m6thyl- 6thy1-cetone anhydre, sur du noir animal, an re- cueille 60 g (rendement 75 b/o) d'un compos6 cris- tallis6 et blanc, fondant ä 152o. After having recrystallized it once from anhydrous methyl ethyl ketone, on animal charcoal, an collects 60 g (yield 75 b/o) of a crystallized and white compound, melting at 152°.

En op6rant comme d6crit ci-dessus, an peut preparer les chlorhydrates des divers p-(tertioamino- alcoxy) phenylcarbamates d'alcoyle et d'aralcoyle qui sont 6numeres dans 1e tableau suivant et qui repon- dent ä la formule gen6rale By operating as described above, one can prepare the hydrochlorides of the various alkyl and aralkyl p-(tertioaminoalkoxy) phenylcarbamates which are listed in the following table and which correspond to the general formula

Point R Ren- de I Point deR I n -N < R- , de fusion m@nt fdella base C2H5 . . . . . . . `2 diethylamino 151-152 68 i n-C3H7 . . . . . . I 154-155 71 n-C4H9 . . . . . . I 162-163 70 t-C4H9 . . . . . . 155 58 @ n-C5H11 . . . . . I 146 68 n-C6Hls . . . . . i 148 78 n-C7H15 . . . . . 132 55 59 n-C8H17 . . . . . I 135 81 61 n-C1oH21 . . . . . 110 53 48 n-C14H29 . . . . . 117 64 61 CBH5-CH2 . . . . 196 85 C6H5. CH2. CH2 123 1 56 ` CH3 . . . . . . . 2 morpholino ! 225 C2H5 . . . . . . . 174 I 64I 92 n-C3H7 . . . . . . , 178 - 104 n-C4H9 . . . . . . ( y > 146 ' 78 ( 94 i-C4H8 . . . . . . 12 morpholino 175 69 n-C5H11 . . . . . I 145 86 n-C6H13 . . . . . 147 76 64 n-C7H15 . . . . . 5 > 153 67 n-C8H17 . . . . . i 155 77I 68 n-C19H21 . . . . . 1591 29 78 C6H5. C H2 . . . I 190 63 103 C2H5 . . . . . . . 13 220 58 121 n-C3H7 . . . . . . 1 219 - 107 n-C4H9 . . . . . . I 204 I 82 ( 90 n-C5H11 . . . . . I 190 52 80 n-CGH13 . . . . . I 186 54 n-C7H15 . . . . . i 180 45 88 C6H5 . CH2 . . . 222 39 i C2H5 . . . . . . . 2 pipdridino 182 65 n-C4H8 . . . . . . 146-147' 47 n-C5H11 . . . . . I 144 47 n-C6H13 . . . . . I 160 46 n-C7H15 . . . . . I 157 58 n-C8H17 . . . . . I 159 56 58 n-C19H21 . . . . . I D 143 82 , n-C14H29 . . . . . 144 69I 78 C6H5-CH2 . . . . ' 182 73 C6H5. CH2. CH2 I 178 I 49 I 106 I Melting point R Ren- de I Point deR I n -N < R- , m@nt fdella base C2H5 . . . . . . . `2 diethylamino 151-152 68 i n-C3H7 . . . . . . I 154-155 71 n-C4H9 . . . . . . I 162-163 70 t-C4H9 . . . . . . 155 58@n-C5H11 . . . . . I 146 68 n-C6Hls. . . . . i 148 78 n-C7H15 . . . . . 132 55 59 n-C8H17 . . . . . I 135 81 61 n-C1oH21 . . . . . 110 53 48 n-C14H29. . . . . 117 64 61 CBH5-CH2 . . . . 196 85 C6H5. CH2. CH2 123 1 56 ` CH3 . . . . . . . 2 morpholinos! 225 C2H5. . . . . . . 174I64I92n-C3H7. . . . . . , 178 - 104 n-C4H9 . . . . . . ( y > 146 ' 78 ( 94 i-C4H8 . . . . . . . 12 morpholino 175 69 n-C5H11 . . . . . I 145 86 n-C6H13 . . . . . . 147 76 64 n-C7H15 . . . . . 5 > 153 67 n-C8H17 . . . . i 155 77I 68 n-C19H21 . . . . . 1591 29 78 C6H5.C H2 . . . I 190 63 103 C2H5 . . . . . . 13 220 58 I 186 54 n-C7H15 . . . . . i 180 45 88 C6H5 . CH2 . . . 222 39 i C2H5 . . . . . . . 2 pipdridino 182 65 n-C4H8 . . . . . . 146-147' 47 n -C5H11 . . . . . I 144 47 n-C6H13 . . . . . I 160 46 n-C7H15 . . . . . I 157 58 n-C8H17 . . . . . 143 82 , n-C14H29 . . . . 144 69I 78 C6H5-CH2 . . . ' 182 73 C6H5.CH2.CH2 I 178 I 49 I 106 I

Claims

CLAIM Process for the preparation of phenylcarbamates, characterized in that p-nitrophenol is reacted, in the presence of an alcohol and (a sodium alcoholate, with a halide of formula

in which Hal represents a halogen atom, n is equal to 2 or 3, and

represents a didthylamino, morpholino or piperidino group, in that the p-tert.-amino-alkoxy-nitrobenzene thus obtained is reduced to p-tert.-amino-alkoxy-aniline, and in that the p-tert.-amino-alkoxy-aniline is reacted the latter with a chloroform ester of formula R-O-CO-Cl, in which R represents an alkyl radical of 1 to 14 carbon atoms, or a benzyl or phenylethyl radical. SUB-CLAIMS 1. Process according to claim, characterized in that Fon converts the phenylcarbamate obtained into an acid addition salt.

2. Process according to claim, characterized in that the reduction is carried out by cold catalytic hydrogenation.

3. Process according to claim, characterized in that Fon carries out the reaction of p-tert.-amino-alkoxy-anüine with chloroform ester. Jans an anhydrous organic solvent.