Heyndrickx, A.

Muller, W.

Archive of European Integration

REPRINT 
tÉiülP 
EAN A' JNITY ­ EURAT 
SYNTHESIS OF N­ALLYLSALICYLAMIDE AND 
o, (N­ALLYLCARBAMYL)­PHENOXYACETIC ACID 
Ι^ «ιι1βΡ AwSfiirørøii i l i 
A. HEYNDRICKX (State University 
I lutiti 
WM 
ig ! tí 
ifií*IE'ti;TV 
Reprinted from 
JOURNAL DE PHARMACIE DE BELGIQUE 
Nos. 9­10 ­ 1964 
This document was prepared under the sponsorship of the Commission of the European 
Atomic Energy Community ^ ^ ^ ^ ^ ^ ^ B g S S B E B E 
Neither the EURATOM Commission, its contractors nor any person acting on their behalf : : ' «li 
Ï^Make any warranty or representation, express or implied, with respect to the accuracy, 
completeness, or usefulness of the information contained in this document, or that the use 
of any information, apparatus, method, or process disclosed in this document may not infringe privately owned rights; or ë Ρ y 
by kind permission of the publisher, an article from "JOURNAL DE 
PHARMACIE DE BELGIQUE", Nos. 9-10 - 1964, 436-441. For 
further copies please apply to Journal de Pharmacie de Belgique, 
A.P.B. — 11 rue Archimede, Bruxelles (Belgique). 
Dieser Sonderdruck ist für eine beschränkte Verteilung bestimmt. Die 
Wiedergabe des vorliegenden in .JOURNAL DE PHARMACIE DE 
BELGIQUE", Nos. 9-10 - 1964, 436-441 erschienenen Aufsatzes 
erfolgt mit freundlicher Genehmigung des Herausgebers. Bestellungen 
weiterer Exemplare sind an Journal de Pharmacie de Belgique, A .P.B. — 
11 rue Archimede, Bruxelles (Belgique), zu richten. 
Ce tiré-à-part est exclusivement destiné à une diffusion restreinte. II. 
reprend, avec l'aimable autorisation de l'éditeur, un article publié dans 
« JOURNAL DE PHARMACIE DE BELGIQUE», Nos. 9-10 - 1964, 
436-441. Tout autre exemplaire de cet article doit être demandé à 
Journal de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, 
Bruxelles (Belgique). 
x\ 
Questo estratto è destinato esclusivamente ad una diffusione limitata. 
Esso è stato riprodotto, per gentile concessione dell'Editore, da 
«JOURNAL DE PHARMACIE DE BELGIQUE», Nos. 9-10 - 1964, 
436-441. Ulteriori copie dell' articolo debbono essere richieste a Journal 
de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles 
Deze overdruk is slechts voor beperkte verspreiding bestemd. Het artikel 
is met welwillende toestemming van de uitgever overgenomen uit 
„JOURNAL DE PHARMACIE DE BELGIQUE", Nos. 9-10 - 1964, 
436-441. Meer exemplaren kunnen besteld worden bij Journal de 
Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles (Belgique). ·"'/ h^MMmMAWa 
>m 
fòjjiif 
EUR 692.e 
REPRINT 
SYNTHESIS OF N-AIXYLSALICYLAMIDE AND o, (N-ALLYLCAR-
BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and 
A. HEYNDRICKX (State University of Ghent, Belgium). 
European Atomic Energy Community - EURATOM. 
Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -
pp. 436-441. 
The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-
acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. 
By a reaction analysis study, we found optimum reaction conditions for the 
synthesis of I, yielding 40 %. 
The reaction conditions for the synthesis of II also had to be changed. 
A yield of 50 % was obtained. The infra-red spectra are given. 
EUR 692.e 
REPRINT 
SYNTHESIS OF N-ALLYLSALICYLAMIDE AND o, (N-ALLYLCAR-
BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and 
A. HEYNDRICKX (State University of Ghent, Belgium). 
European Atomic Energy Community - EURATOM. 
Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -
pp. 436-441. 
The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-
acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. 
By a reaction analysis study, we found optimum reaction conditions for the 
synthesis of I, yielding 40 %. 
The reaction conditions for the synthesis of II also had to be changed. 
A yield of 50 % was obtained. The infra-red spectra are given. 
EUR 692.e 
REPRINT 
SYNTHESIS OF N-ALLYLSALICYLAMIDE AND o, (N-ALLYLCAR-
BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and 
A. HEYNDRICKX (State University of Ghent, Belgium). 
European Atomic Energy Community - EURATOM. 
Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -
pp. 436-441. 
The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-
acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. 
By a reaction analysis study, we found optimum reaction conditions for the 
synthesis of I, yielding 40 %. 
The reaction conditions for the synthesis of II also had to be changed. 
A yield of 50 % was obtained. The infra-red spectra are given. 

Extrait du Journal de Pharmacie de Belgique, n°» 9-10, sept.-oct. 1964, pp. 436-441. 
SYNTHESIS OF N-ALLYLSALICYLAMIDE AND 
o, (N-ALLYLCARBAMYL)-PHENOXYACETIC ACID 
by 
W.H. MÜLLER (*) and A. HEYNDRICKX (**) 
o, (N-Allylcarbamyl)-phenoxyacetic acid is expected to be a complexing 
agent with decontaminating effects for some transition elements. 
This compound and its precursor N-allylsalicylamide are already 
known substances but the synthetic methods given in the pertinent literature 
(4, 5, 6) are not sufficient. 
N-Allylsalicyiamide (I). 
The synthesis, which is given in Equation 1, is described by W.Q. 
FOYE, H.M. KOTAK and J.J. HEFFEREN (1), who used salicylic acid (III) 
and allylisothiocyanate (IV) and yielded 25 mole-% of I, calculated on III. 
In our experiments we could not reach this value, so the reaction 
was not always reproducible. Therefore, in order to determine the 
optimum reaction conditions, a reaction analysis study was carried out by 
volume measurement of the gaseous carbonoxysulphide (V), Equation 1. 
(1) 
//" 
C ,, , C —NH—CH 8 —CH = CH, 
/ V \0H fY 
)H 
+ S = C = N —CH,—CH=CH ! ! -> 
\ / \ OH ^ ^ OH + S = C = O 
III IV I V 
Optimum reaction conditions were found at a molar ratio of salicylic 
acid to allylisothiocyanate of 1 : 2, a bath temperature of 150°C and a 
reaction time of 30 minutes, with a yield of about 40 mole-% of V. 
The conditions given by W.Q. FOYE et al. (1) were therefore changed 
as follows : the molar ratio of III to IV was raised from 1... : 1.1 to 1 : 2, 
the reaction time reduced from 20 to 2 hours and a definite bath temperature 
of 140-150°C chosen for the original reaction. The obtained yields of 
38.7 and 39.5 mole-% of I confirmed the results of the reaction analysis. 
(*) Department of Radiobiology, Euratom, Ghent Centre. 
(**) Department of Toxicology, State University of Ghent, Belgium. 
437 JOURNAL DE PHARMACIE DE BELGIQUE 
Competition reactions are responsible for the relatively low yield 
of about 40 %. 
It is a colourless crystalline substance with a m.p. of 50°C. The 
infra-red spectrum of I in CC14 shows an NH stratching vibration at 
3460 K (w.), an amide-I-band at 1650 K (s.) and an amide-II-band at 
1525 K (s.) (Fig. 1). 
Three by-products — needles with a m.p. of 246-248°C, platelets with 
a m.p. of 250-252°C, both of them containing sulphur, and crystals with 
a m.p. of 96°, all of them containing nitrogen, were isolated. 
o, (N-Allylcarbamyl)-phenoxyacetic Acid (II). 
According to Equation 2, 0. FOYE et al. synthesized II with a yield 
of 40 mole-%. This prescription was not reproducible in our laboratory. 
Therefore, the procedure was changed as described below. 
(2 ) 
//° y/° 
Λ-^/ C — NH — CH2 — CH = CH2 ~ , C — NH — CH2 — CH = CH2 
vs °^ OH + CI — CH2— C. ^ x O — CH2 — C. 
X O H " x O H 
I II 
II was obtained in colourless needles m.p. 120°C as described (1), 
with a yield of 50-52 % calculated on reacted I. 
Alkaline degradation of II yields salicylic-O-acetic acid, m.p. 190-
192°C (2), m.p. 190°C. 
The infra-red spectrum in KBr shows an NH stretching vibration 
at 3350 K (m.), a CO stretching vibration at 1755 K (s.), belonging to 
the carboxylic acid group, the amide-I-band at 1615 K (s.), the amide-II-
band at 1555 K (s.), and an ether band at 1215 K (s.) (Fig. 2). 
EXPERIMENTAL PROCEDURE (3) 
N-Allylsalicylamide. 
138 g salicylic acid (1 mole) and 200 g allylisothiocyanate (Fluka), 
both of commercial grade, are placed in a 500 ml round-bottom flask, 
which is equipped with a long reflux condenser. The flask is placed in 
an oil bath, which is heated to 150°C and kept at that temperature, after 
the reaction starts, for two hours. The start of the reaction manifests 
itself in a kind of boiling, caused by an intensive gas development (outlet). 
ïnnn itnn ™nn nnn 3000 7A0 3000 2800 2600 2400 2200 2000 1900 T8Õ0 1700 Î600 1500 1400 
Fig. 1. — N-AUylsalicylamide in CC14 
3800 3600 3400 3200 3000 2800 _3j>0 2800 2600 2400 2200 2000 1900 1800 1700 1600 1500 1400 1300 
Fig. 2. — o, (N-Allylcarbamyl)-phenoxyacetic Acid in KBr 
439 JOURNAL DE PHARMACIE DE BELGIQUE 
After this time the flask is cooled directly at room temperature. 
Further gas development is ignored and the content is mixed with 200 ml 
of ether. The solution is cooled in a refrigerator for two hours. The 
crystalline precipitate (13.3-15.0 g) is separated off by suction. The 
filtrate is evaporated under reduced pressure and the residual oil distilled. 
After the first fraction (33.8-39.0 g; b.p. 40-100°C; 15 mm Hg; water jet 
suction) containing allylisothiocyanate, the Liebig condenser is removed 
and the Claisen stillhead connected directly to the vacuum receiver adaptor. 
Distillation is recommenced with the aid of a mechanical oil vacuum pump 
connected to a refrigerating trap. 
The fraction between 100 and 160°C, 0.3 mm Hg, is collected (156.3-
164.3 g of a yellow oil), and the residue (53.8-54.1 g) discarded. The yellow 
oil is poured in a cold solution containing 60 g of sodium hydroxide in 
400 ml of water. This mixture is extracted five times with 100 ml of ether. 
The ether layer is rejected. 
The alkaline water layer is subsequently mixed, in portions, with 
160 ml of a 36 % hydrochloric acid (gas development; outlet) and 200 ml 
of ether added. This mixture is neutralized with sodium bicarbonate 
(40-50 g); after intensive shaking the ether layer is separated, combined 
with two more 200 ml ether extracts, dried over sodium sulphate for eight 
hours, and double-distilled under reduced pressure as described above. 
Should any crystalline salicylic acid appear at the beginning, the 
distillation process should be interrupted, all the oil absorbed in ether, 
washed with sodium bicarbonate water solution, and, after drying, the 
ether solution again distilled. 
Yield : 68-70 g; 38.7-39.5 mole-%, calculated on salicylic acid. b.p. 
134-136°C; 1.0 mm Hg. Yellow oil with crystallizing tendency. 
In this condition, N-allylsalicylamide is clean enough for further 
synthetic work. From di-n-butyl ether, long, firm, obtuse, colourless 
needles are obtained, m.p. 50°C. 
Analysis : 
Calculated N : 7.90 %. 
Found N : 7.92 %. 
o, (IM-Allylcarbamyl)-phenoxyacetic Acid. 
In a 250 ml three-necked round-bottom flask, fitted with a mechanical 
stirrer and a tap funnel, 10.4 g of monochloroacetic acid and 8.0 g of dry 
potassium carbonate react at room temperature in 20 ml of water. As 
soon as the carbon dioxide development is finished, 17.7 g (0.1 mole) of 
N-allylsalicylamide are placed in the flask, which is then heated on a boiling 
water bath. To the stirred hot mixture a fresh solution of 5.0 g sodium 
hydroxide in 20 ml of water is added dropwise for a period of 10 minutes. 
JOURNAL DE PHARMACIE DE BELGIQUE 440 
The alkaline mixture is stirred and heated for one hour and then extracted 
twice with 50 ml of ether. About 4.3 g of N-allylsalicylamide are recovered 
from the ether layer. 
A solution of 11 ml of 36 % hydrochloric acid in 10 ml of water is 
now added dropwise to the alkaline water layer. The acid solution is 
extracted rapidly three times with 50 ml of ether. A yellow white crystal-
line precipitate appears very soon in the separated ether layer. 150 ml 
of petroleum ether are added. After three hours the precipitate is removed 
by suction (15.3-16.0 g), washed with petroleum ether and recrystallized 
from a water-alcohol mixture (7 + 3). 
Colourless needles of o, (N-allylcarbamyl)-phenoxyacetic acid are 
obtained, m.p. 120°C. 
Yield : 9.0-9.4 g; 50-52 mole-% calculated on reacted N-allylsalicylamide. 
Analysis : 
Calculated N : 5.96 %. 
Found N : 6.07 %. 
Summary 
The synthesis of N-allylsalicylamide (I) and o, (N-allyicarbamyl)-
phenoxyacetic acid (II), described by W.Q. Foye et al. (1) were not suffi-
ciently reproducible. 
By a reaction analysis study, we found optimum reaction conditions 
for the synthesis of I, yielding 40%. 
The reaction conditions for the synthesis of II also had to be changed. 
A yield of 50 % was obtained. The infra-red spectra are given. 
Zusammenfassung 
Die Darstellungen von N-Allylsalicylamid (I) und o, (N-Allyl-carbamyl)-
phenoxiessigsãure (II) nach W.Q. Foye und Mitarbeitern (1), waren nicht 
befriedigend reproduzierbar. 
Durch eine Reaktionsanalyse wurden optimale Reaktionsbedingungen 
für die Darstellung von I mit einer Ausbeute von 40 % gefunden. 
Die Reaktionsbedingungen für die Darstellung von II mussten eben-
alls verändert werden, wobei eine Ausbeute von 50 % erzielt werden konnte. 
Die Infra-rot-Spektren wurden aufgenommen. 
441 JOURNAL DE PHARMACIE DE BELGIQUE 
Samenvatting 
De bereiding van N­allylsalicylamide (I) en o, (N­allylcarbamyl)­phe­
noxiazijnzuur (II) volgens W.G. Foye en medewerkers (1) waren niet voldoende 
reproduceerbaar. 
Door de studie van de reaktie, vonden we de optimale voorwaarden 
voor de bereiding van I met een opbrengst van 40 %. 
De reaktievoorwaarden voor de bereiding van II, moesten eveneens 
veranderd worden, waarbij wij een rendement van 50 % konden verkrijgen. 
De infra­rood spektra zijn weergegeven. 
Résumé 
La préparation de la N­allylsalicylamide (I) et de l'acide o, (N­allyl­
carbamyl)­phénoxyacétique (II) selon la méthode de W.Q. Foye et ses colla­
borateurs (1) ne donna pas entière satisfaction en ce qui concerne la repro­
duction de la technique. 
En changeant la préparation, nous avons pu obtenir, par une étude 
approfondie de la réaction, un rendement de 40 % pour la synthèse du 
composé I. 
Pour la préparation du produit II , nous avons pu obtenir un rendement 
de 50 % en modifiant les conditions de la réaction. 
Les spectres infrarouges de ces produits ont été enregistrés. 
References 
(1) J. Amer. Pharmac. Ass., 41 , 273 (1952). 
(2) R. MEYER and DUCZMAL, Ber., 46, 3370 (1913). 
(3) "We are indebted to Prof. Dr. VERZELE of the Department, of Organic Chemistry of the State University of Ghent (Belgium), for the nitrogen analyses which were carried out in his laboratories. 
(4) E.A. TZOFIN and K.A. CHKHIKVADZE, J. Gen. Chem. U.S.S.R., 3, 17 (1933). 
(5) BOCKMÜHL M. and SCHWARZ Α., United States Patent 1.693, 432, German Pat. 
423.031 (1924). 
(6) W.H. FEINSTONE, United States Patent 2.581.397. 


m ¡il 
i'i'Wsliá 
I" " 
j To disseminate knowledge is to disseminate prosperity — 1 mean 
I B general prosperity and not individual riches — and with prosperity 
l | | disappears the greater part of the evil which is our heritage from 
• 
I darker times. 
jBNMif ΙΙΒΒβΒ 
Alfred Nobel 
m 



SYNTHESIS OF N­ALLYLSALICYLAMIDE AND o, (N­ALLYLCARBAMYL)­PHENOXYACETIC ACID. EUR 692.e

REPRINT tÉiülP EAN A' JNITY ­ EURAT SYNTHESIS OF N­ALLYLSALICYLAMIDE AND o, (N­ALLYLCARBAMYL)­PHENOXYACETIC ACID Ι^ «ιι1βΡ AwSfiirørøii i l i A. HEYNDRICKX (State University I lutiti WM ig ! tí ifií*IE'ti;TV Reprinted from JOURNAL DE PHARMACIE DE BELGIQUE Nos. 9­10 ­ 1964 This document was prepared under the sponsorship of the Commission of the European Atomic Energy Community ^ ^ ^ ^ ^ ^ ^ B g S S B E B E Neither the EURATOM Commission, its contractors nor any person acting on their behalf : : ' «li Ï^Make any warranty or representation, express or implied, with respect to the accuracy, completeness, or usefulness of the information contained in this document, or that the use of any information, apparatus, method, or process disclosed in this document may not infringe privately owned rights; or ë Ρ y by kind permission of the publisher, an article from "JOURNAL DE PHARMACIE DE BELGIQUE", Nos. 9-10 - 1964, 436-441. For further copies please apply to Journal de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles (Belgique). Dieser Sonderdruck ist für eine beschränkte Verteilung bestimmt. Die Wiedergabe des vorliegenden in .JOURNAL DE PHARMACIE DE BELGIQUE", Nos. 9-10 - 1964, 436-441 erschienenen Aufsatzes erfolgt mit freundlicher Genehmigung des Herausgebers. Bestellungen weiterer Exemplare sind an Journal de Pharmacie de Belgique, A .P.B. — 11 rue Archimede, Bruxelles (Belgique), zu richten. Ce tiré-à-part est exclusivement destiné à une diffusion restreinte. II. reprend, avec l'aimable autorisation de l'éditeur, un article publié dans « JOURNAL DE PHARMACIE DE BELGIQUE», Nos. 9-10 - 1964, 436-441. Tout autre exemplaire de cet article doit être demandé à Journal de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles (Belgique). x\ Questo estratto è destinato esclusivamente ad una diffusione limitata. Esso è stato riprodotto, per gentile concessione dell'Editore, da «JOURNAL DE PHARMACIE DE BELGIQUE», Nos. 9-10 - 1964, 436-441. Ulteriori copie dell' articolo debbono essere richieste a Journal de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles Deze overdruk is slechts voor beperkte verspreiding bestemd. Het artikel is met welwillende toestemming van de uitgever overgenomen uit „JOURNAL DE PHARMACIE DE BELGIQUE", Nos. 9-10 - 1964, 436-441. Meer exemplaren kunnen besteld worden bij Journal de Pharmacie de Belgique, A.P.B. — 11 rue Archimede, Bruxelles (Belgique). ·"'/ h^MMmMAWa >m fòjjiif EUR 692.e REPRINT SYNTHESIS OF N-AIXYLSALICYLAMIDE AND o, (N-ALLYLCAR-BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and A. HEYNDRICKX (State University of Ghent, Belgium). European Atomic Energy Community - EURATOM. Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -pp. 436-441. The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. By a reaction analysis study, we found optimum reaction conditions for the synthesis of I, yielding 40 %. The reaction conditions for the synthesis of II also had to be changed. A yield of 50 % was obtained. The infra-red spectra are given. EUR 692.e REPRINT SYNTHESIS OF N-ALLYLSALICYLAMIDE AND o, (N-ALLYLCAR-BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and A. HEYNDRICKX (State University of Ghent, Belgium). European Atomic Energy Community - EURATOM. Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -pp. 436-441. The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. By a reaction analysis study, we found optimum reaction conditions for the synthesis of I, yielding 40 %. The reaction conditions for the synthesis of II also had to be changed. A yield of 50 % was obtained. The infra-red spectra are given. EUR 692.e REPRINT SYNTHESIS OF N-ALLYLSALICYLAMIDE AND o, (N-ALLYLCAR-BAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (Euratom) and A. HEYNDRICKX (State University of Ghent, Belgium). European Atomic Energy Community - EURATOM. Reprinted from "Journal de Pharmacie de Belgique", Nos 9-10 - 1964 -pp. 436-441. The synthesis of N-allylsalicylamide (I) and o, (N-allylcarbamyl)-phenoxy-acetic acid (II), described by W.Q. Foye et al. were not sufficiently reproducible. By a reaction analysis study, we found optimum reaction conditions for the synthesis of I, yielding 40 %. The reaction conditions for the synthesis of II also had to be changed. A yield of 50 % was obtained. The infra-red spectra are given. Extrait du Journal de Pharmacie de Belgique, n°» 9-10, sept.-oct. 1964, pp. 436-441. SYNTHESIS OF N-ALLYLSALICYLAMIDE AND o, (N-ALLYLCARBAMYL)-PHENOXYACETIC ACID by W.H. MÜLLER (*) and A. HEYNDRICKX (**) o, (N-Allylcarbamyl)-phenoxyacetic acid is expected to be a complexing agent with decontaminating effects for some transition elements. This compound and its precursor N-allylsalicylamide are already known substances but the synthetic methods given in the pertinent literature (4, 5, 6) are not sufficient. N-Allylsalicyiamide (I). The synthesis, which is given in Equation 1, is described by W.Q. FOYE, H.M. KOTAK and J.J. HEFFEREN (1), who used salicylic acid (III) and allylisothiocyanate (IV) and yielded 25 mole-% of I, calculated on III. In our experiments we could not reach this value, so the reaction was not always reproducible. Therefore, in order to determine the optimum reaction conditions, a reaction analysis study was carried out by volume measurement of the gaseous carbonoxysulphide (V), Equation 1. (1) //" C ,, , C —NH—CH 8 —CH = CH, / V \0H fY )H + S = C = N —CH,—CH=CH ! ! -> \ / \ OH ^ ^ OH + S = C = O III IV I V Optimum reaction conditions were found at a molar ratio of salicylic acid to allylisothiocyanate of 1 : 2, a bath temperature of 150°C and a reaction time of 30 minutes, with a yield of about 40 mole-% of V. The conditions given by W.Q. FOYE et al. (1) were therefore changed as follows : the molar ratio of III to IV was raised from 1... : 1.1 to 1 : 2, the reaction time reduced from 20 to 2 hours and a definite bath temperature of 140-150°C chosen for the original reaction. The obtained yields of 38.7 and 39.5 mole-% of I confirmed the results of the reaction analysis. (*) Department of Radiobiology, Euratom, Ghent Centre. (**) Department of Toxicology, State University of Ghent, Belgium. 437 JOURNAL DE PHARMACIE DE BELGIQUE Competition reactions are responsible for the relatively low yield of about 40 %. It is a colourless crystalline substance with a m.p. of 50°C. The infra-red spectrum of I in CC14 shows an NH stratching vibration at 3460 K (w.), an amide-I-band at 1650 K (s.) and an amide-II-band at 1525 K (s.) (Fig. 1). Three by-products — needles with a m.p. of 246-248°C, platelets with a m.p. of 250-252°C, both of them containing sulphur, and crystals with a m.p. of 96°, all of them containing nitrogen, were isolated. o, (N-Allylcarbamyl)-phenoxyacetic Acid (II). According to Equation 2, 0. FOYE et al. synthesized II with a yield of 40 mole-%. This prescription was not reproducible in our laboratory. Therefore, the procedure was changed as described below. (2 ) //° y/° Λ-^/ C — NH — CH2 — CH = CH2 ~ , C — NH — CH2 — CH = CH2 vs °^ OH + CI — CH2— C. ^ x O — CH2 — C. X O H " x O H I II II was obtained in colourless needles m.p. 120°C as described (1), with a yield of 50-52 % calculated on reacted I. Alkaline degradation of II yields salicylic-O-acetic acid, m.p. 190-192°C (2), m.p. 190°C. The infra-red spectrum in KBr shows an NH stretching vibration at 3350 K (m.), a CO stretching vibration at 1755 K (s.), belonging to the carboxylic acid group, the amide-I-band at 1615 K (s.), the amide-II-band at 1555 K (s.), and an ether band at 1215 K (s.) (Fig. 2). EXPERIMENTAL PROCEDURE (3) N-Allylsalicylamide. 138 g salicylic acid (1 mole) and 200 g allylisothiocyanate (Fluka), both of commercial grade, are placed in a 500 ml round-bottom flask, which is equipped with a long reflux condenser. The flask is placed in an oil bath, which is heated to 150°C and kept at that temperature, after the reaction starts, for two hours. The start of the reaction manifests itself in a kind of boiling, caused by an intensive gas development (outlet). ïnnn itnn ™nn nnn 3000 7A0 3000 2800 2600 2400 2200 2000 1900 T8Õ0 1700 Î600 1500 1400 Fig. 1. — N-AUylsalicylamide in CC14 3800 3600 3400 3200 3000 2800 _3j>0 2800 2600 2400 2200 2000 1900 1800 1700 1600 1500 1400 1300 Fig. 2. — o, (N-Allylcarbamyl)-phenoxyacetic Acid in KBr 439 JOURNAL DE PHARMACIE DE BELGIQUE After this time the flask is cooled directly at room temperature. Further gas development is ignored and the content is mixed with 200 ml of ether. The solution is cooled in a refrigerator for two hours. The crystalline precipitate (13.3-15.0 g) is separated off by suction. The filtrate is evaporated under reduced pressure and the residual oil distilled. After the first fraction (33.8-39.0 g; b.p. 40-100°C; 15 mm Hg; water jet suction) containing allylisothiocyanate, the Liebig condenser is removed and the Claisen stillhead connected directly to the vacuum receiver adaptor. Distillation is recommenced with the aid of a mechanical oil vacuum pump connected to a refrigerating trap. The fraction between 100 and 160°C, 0.3 mm Hg, is collected (156.3-164.3 g of a yellow oil), and the residue (53.8-54.1 g) discarded. The yellow oil is poured in a cold solution containing 60 g of sodium hydroxide in 400 ml of water. This mixture is extracted five times with 100 ml of ether. The ether layer is rejected. The alkaline water layer is subsequently mixed, in portions, with 160 ml of a 36 % hydrochloric acid (gas development; outlet) and 200 ml of ether added. This mixture is neutralized with sodium bicarbonate (40-50 g); after intensive shaking the ether layer is separated, combined with two more 200 ml ether extracts, dried over sodium sulphate for eight hours, and double-distilled under reduced pressure as described above. Should any crystalline salicylic acid appear at the beginning, the distillation process should be interrupted, all the oil absorbed in ether, washed with sodium bicarbonate water solution, and, after drying, the ether solution again distilled. Yield : 68-70 g; 38.7-39.5 mole-%, calculated on salicylic acid. b.p. 134-136°C; 1.0 mm Hg. Yellow oil with crystallizing tendency. In this condition, N-allylsalicylamide is clean enough for further synthetic work. From di-n-butyl ether, long, firm, obtuse, colourless needles are obtained, m.p. 50°C. Analysis : Calculated N : 7.90 %. Found N : 7.92 %. o, (IM-Allylcarbamyl)-phenoxyacetic Acid. In a 250 ml three-necked round-bottom flask, fitted with a mechanical stirrer and a tap funnel, 10.4 g of monochloroacetic acid and 8.0 g of dry potassium carbonate react at room temperature in 20 ml of water. As soon as the carbon dioxide development is finished, 17.7 g (0.1 mole) of N-allylsalicylamide are placed in the flask, which is then heated on a boiling water bath. To the stirred hot mixture a fresh solution of 5.0 g sodium hydroxide in 20 ml of water is added dropwise for a period of 10 minutes. JOURNAL DE PHARMACIE DE BELGIQUE 440 The alkaline mixture is stirred and heated for one hour and then extracted twice with 50 ml of ether. About 4.3 g of N-allylsalicylamide are recovered from the ether layer. A solution of 11 ml of 36 % hydrochloric acid in 10 ml of water is now added dropwise to the alkaline water layer. The acid solution is extracted rapidly three times with 50 ml of ether. A yellow white crystal-line precipitate appears very soon in the separated ether layer. 150 ml of petroleum ether are added. After three hours the precipitate is removed by suction (15.3-16.0 g), washed with petroleum ether and recrystallized from a water-alcohol mixture (7 + 3). Colourless needles of o, (N-allylcarbamyl)-phenoxyacetic acid are obtained, m.p. 120°C. Yield : 9.0-9.4 g; 50-52 mole-% calculated on reacted N-allylsalicylamide. Analysis : Calculated N : 5.96 %. Found N : 6.07 %. Summary The synthesis of N-allylsalicylamide (I) and o, (N-allyicarbamyl)-phenoxyacetic acid (II), described by W.Q. Foye et al. (1) were not suffi-ciently reproducible. By a reaction analysis study, we found optimum reaction conditions for the synthesis of I, yielding 40%. The reaction conditions for the synthesis of II also had to be changed. A yield of 50 % was obtained. The infra-red spectra are given. Zusammenfassung Die Darstellungen von N-Allylsalicylamid (I) und o, (N-Allyl-carbamyl)-phenoxiessigsãure (II) nach W.Q. Foye und Mitarbeitern (1), waren nicht befriedigend reproduzierbar. Durch eine Reaktionsanalyse wurden optimale Reaktionsbedingungen für die Darstellung von I mit einer Ausbeute von 40 % gefunden. Die Reaktionsbedingungen für die Darstellung von II mussten eben-alls verändert werden, wobei eine Ausbeute von 50 % erzielt werden konnte. Die Infra-rot-Spektren wurden aufgenommen. 441 JOURNAL DE PHARMACIE DE BELGIQUE Samenvatting De bereiding van N­allylsalicylamide (I) en o, (N­allylcarbamyl)­phe­noxiazijnzuur (II) volgens W.G. Foye en medewerkers (1) waren niet voldoende reproduceerbaar. Door de studie van de reaktie, vonden we de optimale voorwaarden voor de bereiding van I met een opbrengst van 40 %. De reaktievoorwaarden voor de bereiding van II, moesten eveneens veranderd worden, waarbij wij een rendement van 50 % konden verkrijgen. De infra­rood spektra zijn weergegeven. Résumé La préparation de la N­allylsalicylamide (I) et de l'acide o, (N­allyl­carbamyl)­phénoxyacétique (II) selon la méthode de W.Q. Foye et ses colla­borateurs (1) ne donna pas entière satisfaction en ce qui concerne la repro­duction de la technique. En changeant la préparation, nous avons pu obtenir, par une étude approfondie de la réaction, un rendement de 40 % pour la synthèse du composé I. Pour la préparation du produit II , nous avons pu obtenir un rendement de 50 % en modifiant les conditions de la réaction. Les spectres infrarouges de ces produits ont été enregistrés. References (1) J. Amer. Pharmac. Ass., 41 , 273 (1952). (2) R. MEYER and DUCZMAL, Ber., 46, 3370 (1913). (3) "We are indebted to Prof. Dr. VERZELE of the Department, of Organic Chemistry of the State University of Ghent (Belgium), for the nitrogen analyses which were carried out in his laboratories. (4) E.A. TZOFIN and K.A. CHKHIKVADZE, J. Gen. Chem. U.S.S.R., 3, 17 (1933). (5) BOCKMÜHL M. and SCHWARZ Α., United States Patent 1.693, 432, German Pat. 423.031 (1924). (6) W.H. FEINSTONE, United States Patent 2.581.397. m ¡il i'i'Wsliá I" " j To disseminate knowledge is to disseminate prosperity — 1 mean I B general prosperity and not individual riches — and with prosperity l | | disappears the greater part of the evil which is our heritage from • I darker times. jBNMif ΙΙΒΒβΒ Alfred Nobel m 

SYNTHESIS OF NALLYLSALICYLAMIDE AND o, (NALLYLCARBAMYL)PHENOXYACETIC ACID. EUR 692.e

Abstract

Similar works

Full text

Available Versions

Archive of European Integration

Archive of European Integration

SYNTHESIS OF N­ALLYLSALICYLAMIDE AND o, (N­ALLYLCARBAMYL)­PHENOXYACETIC ACID. EUR 692.e

Abstract

Similar works

Full text

Available Versions

Archive of European Integration

Archive of European Integration

SYNTHESIS OF NALLYLSALICYLAMIDE AND o, (NALLYLCARBAMYL)PHENOXYACETIC ACID. EUR 692.e