PRODUCTION OF PHENYL CARBAMATES

Abstract: A method of producing a phenyl carbamate, comprises reacting a phenol with phosgene to produce a phenyl chloroformate, the phosgene being present in a non-aqueous inert solvent and the non-aqueous inert solvent being in contact with an aqueous solution of an acid acceptor to provide a two-phase system, and adding a primary or secondary amine to the two-phase system after the reaction of the phosgene and the phenol, the amine reacting with the chloroformate to form the phenyl carbamate. The initial phenol may be O-isopropoxyphenol and the amine used may be methyl amine, the phenyl carbamate produced being 2-(1-methyl ethoxy)-phenyl N-methyl carbamate, also known as propoxur.

Description: Production of Phenyl Carbamates -Che present invention relates to the production of phenyl carbamates. The invention is particularly but not exclusively concerned with the production of 2-(methyl ethoxy)-phenyl N-methyl carbamate, which is also known as propoxur. Propoxur is known to have insecticidal activity- Various methods of producing phenyl carbamates are known. It is known from U.S. patent specification no. 3,167,472 to produce a phenyl carbamate by reacting phenol with phosgene to produce a chloroformate and then reacting the chloroformate with an amine, these reactions being carried out in a single-phase system comprising toluene as a solvent. It is known from British patent specification no. 1,200,768 to produce a chloroformate by reacting phenol with phosgene, the reaction being carried out in two-phase system coπprising tetra- chloroethylene in which the phosgene is dissolved and an aqueous solution of sodium hydroxide. It is known from British patent specification no. 1583677 to react an isocyanate with phenol to produce a carbonate, the reaction being carried out in an inert solvent and in the presence of a base. It is also known from the same patent specification to react a phenol with a compound of formula HalCONR.r (where R. is alkyl and R is' alkyl or hydrogen) to produce a carbamate, the reaction also being carried out in an inert solvent and in the presence of a base. In particular, it is known to produce propoxur by reacting 2-isopropoxy phenol with methyl isocyanate. However, methyl isocyanate is difficult to synthesize. We have attempted to produce propoxur by phosgenation of 2-isopropoxy- phenol followed by a ination of the resulting chloroformate, these reactions being carried out in toluene. However, we have not found this method satisfactory because an organic base is required to remove HCl and it is difficult to recover the base, if the organic base is an N,N-dialkylaniline (.an organic base comnonly used on account of its high boiling point) the product is badly discoloured, the yield is poor and variable, and the solubility of the product in an aromatic solvent is sufficiently hign that at least part of the solvent must be distilled off to recover the product. OMPI The present invention aims to provide an improved method of producing phenyl carbamates, such as propoxur. In accordance with the present invention, there is provided a method of producing a phenyl carbamate, comprising reacting a phenol with phosgene to produce a phenyl chloroformate, the phosgene being present in non-aqueous inert solvent and the non-aqueous solvent being in contact with an aqueous solution of an acid acceptor to provide a two-phase system, and adding an amine to the two- phase system after the reaction of the phosgene and the phenol, the amine reacting with the chloroformate to form the phenyl carb¬ amate. The phenol dissolves in the aqueous solution and it is believed that the phenol reacts with the phosgene at the interface of the non-aqueous solvent. It would be expected that the phenyl chloro- formate would be hydrolysed by the water of the aqueous solvent. Surprisingly, however, this does not occur and the phenyl chloro¬ formate remains in the non-aqueous solvent. It is believed that the amine reacts with the chloroformate at the interface of the non-aqueous solution. The carbonate dissolves in the non-aqueous solvent and may be recovered therefrom. The amine used may be primary or secondary amine. In particular, the amine may be of the formula NHR'R", where each of R* and R" is a substituted or unsubstituted alkyl, aryl or aralkyl group, a hydroxy group, an alkoxy group or a hydrogen atom, at least one of R' and R" not being hydrogen. Preferably the alkyl group, the alkyl group of the aralkyl group or the alkoxy group contains up to 6 carbon atoms. The " amine may be passed directly as a gas into the chloroformate solution or added in aqueous solution to the chloroformate solution. The acid acceptor is preferably an alkali metal hydroxide, e.g. soidu hydroxide, and is preferably used in a high concentration e.g., at least 5M. The non-aqueous solvent is preferably one in which the pheπy ] carbamate produced is insoluble or ca π be crystallized from. The non-aqueous solvent may be toluene or, preferably cyclohexan (C 6 H 12 ). The initial phenol nay be phenol (cyyH) itself, a cresol or an alkoxyphenol. In order to produce propoxur, the initial phenol is o-iεoprσpoxy- phenol and the amine used is methyl amine. Preferably the amount of acid acceptor present in the aqueous solution, when the phenol carbamate is to be formed, is at least two moles per mole of initial phenol. Such an amount of acid acceptor is required in order to remove from the organic solution all the hydrogen chloride formed when the phosgene reacts with the phenol and the chloroformate reacts with the amine. The invention provides a route to not only propoxur . but other coπpounds which may be novel and may have insecticidal activity. The invention is illustrated by the following examples, which were carried out on 100 milliroolar scale approximately. OMPI * ■ . IPO in cyclohcxane (7i> cm' ) was prepared, to which was added rapidly the phenol (0.3 mole). Reaction did not occur until bβse (8M aqueous NaOH) hud been added when exothermic reaction began and the rate of addition of base was controlled BO that the temperature was maintained ^ 70 β C in order to avoid solvent reflux. Sodium chloride was precipitated as the chloroformate was produced and then the excess phosgene was removed by nitrogen purging. In Example 1 gaseous methyla ine was then bubbled into the mixture. 3 Examples 2 to 8, an aqueous solution of amine or amine hydro- chloride (0.1 mole) was added followed by further base (8K aqueous NaOH) to act as acid acceptor in -the case of water-soluble amine * or to act as both acid acceptor and fr •»e.e base liberator in the case of hydrochloride solution. Again reaction occurred with the evolution of heat and the formation of sodium chloride. The two-phase system was then allowed to cool and the carbamate cyrεtallized. The product was then filtered and washed with water to remove any sodium chloride and finally vacuum dried. In each example, the apparatus used comprised a 500 cm*3-necked round bottom flask, as a reaction vessel, fitted with a temperature 0K OMPI « indicator, water mil dry J ce condcnrier and a pressure-equal irrtJ dropping funnel. The flask was magnetically stirred and vented to a scrubber. In Examples 3 to B, the scrubber was a caustic scrubber. In Example A the scrubber was at sl ight negative pressure. Details of the examples are given below. EXAMPLE 1 Preparation of 2-(1-methyl-ethoxy)-Phenyl N-methyl carbamate A 15% by weight solution of phosgene in cyclohexane was prepared. An amount of this solution containing 0.11 moles of phosgene was put into a reactor. 0.1 moles of o-isopropoxyphenol was then added to the reactor. Next 0.2 moles of sodium hydroxide as an 8M aqueous solution were added slowly to the reactor. An exothermic reaction resulted from the addition of the sodium hydroxide and the rate of addition of the sodium hydroxide was controlled so as to keep the temperature in the reactor from exceeding 70°C and thereby to avoid the reflux of the solvent (b.p. of C g H 12 = 80.1°C). The phosgene reacted with the phenol to produce o-phenyl chloro¬ formate, which dissolved in the cyclohexane. After the addition of the sodium hydroxide solution had been completed, excess phosgene was purged using nitrogen until the solution was phosgene-free and water was added to the reactor to dissolve salt which had precipitated. Then methyla ine was bubbled into the mixture in the reactor to effect amination of the chloroformate dissolved in the cyclo- hexane. The reaction was exothermic and was taken to be completed when .the temperature in the reactor peaked at around 70 β C. The reactor was then cooled and crystallization of a product occurred. The product was filtered from the reaction system, thoroughly washed with water followed by cyclohexane and dried overnight at 50 to 60° in a vacuum oven. The product was identified as propoxur by comparison of its IR spectra with that of a standard sample. The product had a melting point, of 90.7°C (m.p. of standard propoxur - 91°C) and was obtained in a yield of 83% based on the initial phenol. It has been found that even if the initial c^isqpropoxyphenol has impurities, the purity of the propoxur obtained is unaffected. EXΛMPLE ? Reagents: Phosgene, o- βopropoxy phenol and methylamine Procedure: The flβsk was charged w h 75 cm' cyclohexane and llg phosgene. 15.2g o-iεopropoxy phenol was added rapidly with negligible temperature change followed by slow addition of 25 cm' 8K NaOH giving exothermic reaction (maximum temperature 60°C) and formation of aCl and the chloroformate. Excess phosgene was removed using a nitrogen purge and then aqueous methylamine solution (3.1g of methylamine as a IK solution) again giving exothermic reaction. T = 41 0 C. On cooling crystallization occurred giving a white product which was filtered, water wash and then vacuum dried. Product: Yield * 65% m.pt = 90.9 β C 2(l-π * eth l ethoxy)phenyl N-methyl .carbamate C H. I H 3 EXAMPLE 3 The scrubber was a caustic scrubber. Reagents: Phosgene, o-isopropoxy phenol bp 0.98 *C ) and hydroxylamine hydrochloride. Procedure: The flask was charged with 75 cm' of cyclohexane and llg of phosgene, 35.2g of the o-isopropoxy phenol were added rapidly with negligible•temperature change, followed by 25 cm 3 of 8 NaOH. Addition time was 10 minutes and the temperature rose from 22 to 61°C. A sample was taken for I.R. analysis and the characteristic absorption •§> 1795 cm was observed indicating conversion to chloroformate. The excess phosgene was removed by nitrogen purge. Hydroxylamine hydrochloride (6.95g) was added as a 20% w/w solution followed by 12 at? 8K NaOH to liberate the free base. The temperature rose slowly from 17 to 36*C in seven ninutes and the reactor was allowed to cool with continued -magnetic stirring. Crystallization occurred -giving an off— hite product which was filtered, water washed and vacuum dried. Product: Yield « 61% 2—(1-me hyl ethoxy)phenyl N-hydroxy carbamate CHz 1 H.V. « 211 c rt- EXAMPLE A The scrubber wab » cnuntic βcrubber "Bt slight negative pressure. * Reagents: Gam-our, phosgene, o-isopropoxy phenol (bp__._ 198*C) — /DO and o-methyl hydroxylamine hydrochloride ' Procedure: The flask was charged with 75 cm' cyclohexane and llg of phosgene were added giving a 15.8% w/w solution, 15.2g of the o-isopropoxy phenol were added rapidly with negligible- temperature change followed by 25 en. 3 8K NaOH: addition time 10 minutes and the maximum temperature 6 °C. The excess phosgene was removed using a nitrogen purge arid the o-methyl hy-droxy amine hydrochloride (8.35g) was added as a 20% w/w solution followed by 12.5 cm 3 8K NaOH to liberate the free base. Addition took 10 minutes and the maximum temperature was 35°C. The reaction •». mixture was allowed to cool and crystallization occurred giving a white product, that was filtered, water washed and vacuum dried. Product: Yield m 69% in.pt « * = 83.7 # C 2-(methyl ethoxy)phenyl N-methoxy carbamate OMPI EXAMPLE 5 Reagents: Phosgene, o-isopropoxy phenol (bp 198 760 β C), aniline-'- 7% w/w HC1. Procedure: The flask was charged with 75 cm 3 cyclohexane .and llg phosgene followed by 15.2g o-isopropyl phenol. 12.5 cm 3 of 8M NaOH were added slowly and the temperature rose from 26 to 54°C. Excess phosgene was removed using a nitrogen purge. The solution was added rapidly with vigorous stirring to the chloro¬ formate solution followed by 25 cm 3 8M NaOH to act as acid acceptor and liberate free base. The temperature rose slowly from 22 to 37°C maximum and the solid product crystallized very suddenly giving .an off-white product which was filtered, water washed and vacuum dried. Product: Yield = 38% m.pt = 97.4 β C 2-(methyl ethoxy)phenyl N-phenyl carbamate SUBSTITUTE SHEET EXAMPLE 6 Reagents: Phosgene, o-isopropoxy phenol, £>-aminophcnol (pAP) 7% HCl. Procedure: The flask was charged with 75 cm 3 cyclohexane and llg phosgene, 15.2g o-isopropoxy phenol were added rapidly followed by 25 cm 3 8M NaOH. Temperature rose from 22 to 69°C. Excess phosgene was removed by a nitrogen purge. 10.9g pAP were added to 50 cm 9 of approximately 7% HCl and the resultant hydrochloride solution was brownish. This was added rapidly followed by 12.5 cm 3 8.>. NaOH and crystallization occurred very suddenly T = 34°C. max The product was mauve coloured, it was filtered and washed with cyclohexane and water and then vacuum dried. Product: Yield = 64% β.pt «= 137.4 β C 2—(1—methyl ethoxy) phenyl N,-4-hydroxy phenyl carbamate OM EXAMPLE 7 Reagents: Phosgene, 3-methy phenol (m-cresol), methylamine Procedure: The flask was charged with 75 cm 3 cyclohexane and llg phosgene. 10.8g m—cresol were added rapidly with no temperature change. 12.5 cm* 8M NaOH were added and the temperature rose from 26 to 65°C and salt was precipitated. The excess phosgene was removed by a nitrogen purge over a period of 30 minutes. Amination was carried out by addition 75 cm 3 of a l.bK methylamine solution followed by 12.5 cπ? 8K NaOH. The temperature rose rapidly to <45°C maximum and then was allowed to cool and crystalli^j&e solid was isolated after filtration and water and cyclohexane washing. Product: Yield *- 39% β.pt = .B0.0- » C 3-methyl phenyl N—methyl carbamate OMPI Reagents: Phosgene, phenol, methylamine Procedure: The flask was charged with 75 cm 3 of cyclohexane r and llg of phosgene, 9.4g of phenol were βdded rapidly followed by 12.5 cm 3 8M NaOH. Temperature rose from 30°C to 59 β C and sodium chloride was formed. The excess phosgene was removed by a nitrogen purge and then 75 cm 3 of 1.5K methyl-amine solution were added followed by 12.5 cm 3 8K NaOH. The- temperature rose from 17°C to 45°C and crystallization occurred. The reactor was allowed to cool and finally chilled. A white crystallizinc- solid was isolated by vacuum filtration and vacuum -dried. Product: Yield = 71% m.pt * - 85.2°C •»» Phenyl N-methyl carbamate o ' 0 J M.W. m 151 8 H 9 0 2 OMP

Claims: CLAIMS 1. A method of providing a phenyl carbamate, comprising reacting a phenol with phosgene to produce a phenyl chloroformate, the phosgene being present in a non-aqueous inert solvent and 5 the non-aqueous inert solvent being in contact with an aqueous solution of an acid acceptor to provide a two-phase system, and adding a primary or secondary amine to the two-phase system after the reaction of the phosgene and the phenol, the amine reacting with the chloroformate to form the phenyl carbamate 102. A method according to claim 1, wherein the amine is of the formula NHR'R", where each of R' and R" is a substituted or unsubstituted alkyl, aryl or aralkyl group, a hydroxyl group, an alkoxy group or a hydrogen atom, at least one of R' and R" not being hydrogen. 153. A method according to claim 2, wherein the alkyl group, the alkyl group of the aralkyl group, or the alkoxy group contains up to 6 carbon atoms. 4. A method according to claim 1 or 2, wherein the amine is passed as a gas into the •chloroformate solution. 205. A method according to claim 1 or 2, wherein the amine is added in agueous solution to ' the chloroformate'solution. 6. A method according to .any preceding * claim, wherein the acid acceptor is an alkali metal hydroxide. » » 7. A method according to any preceding claim, wherein the 25 acid acceptor is present in a concentration of at least 5M in the aqueous solution thereof. 8. A method according to .any preceding claim, wherein the non-aqueous solution is one in which the phenyl carbamate is insoluble or can be crystallized from. ** 9. A method according to any preceding claim, wherein the non-aqueous solvent is toluene." 10. A method according to any of claims 1 to 8, wherein the non-aqueous solvent is cyclohexane. 11. A method according to any preceding claim, wherein the phenol is phenol itself, a cresol or an alkoxyphenol. 12. A method according to claim 11, wherein the alkoxy group of the alkoxyphenol contains up to 6 carbon atoms. 13. A method according to claim 12, wherein the alkoxyphenol is o-isopropoxyphenol. 14. A method according to any preceding claim, wherein the amine is methyl amine. 15. A method according to any preceding claim, wherein the amount of the acid acceptor is at least two moles per mole of the phenol to be reacted. ( OMP

Inventors: COTTON ALAN, FIELD PETER GRAHAM SPENCER, HARDWICK FRANK, COTTON, ALAN, FIELD, PETER, GRAHAM, SPENCER, HARDWICK, FRANK
Applicants: STAVELEY CHEM LTD, STAVELEY CHEMICALS LIMITED
Application year: 1983
Main classification: C07C125
IPC codes: C07C271