GB2065639A - N-carbamoyl-saccharin derivatives and their use as acylating agents in the preparation of phenyl carbamate derivatives - Google Patents

Description

SPECIFICATION Process and compositions for O-acylating phenols The invention relates to a new process for O-acylating phenol and to acylating compositions suitable for this purpose. More particularly, the invention concerns a new process forthe preparation of substituted phenyl carbamate derivatives of the general formula (I)

by O-acylating phenols of the general formula (II)

In the above formulae and throughout the specification R is alkyl having 1 to 8 carbon atoms; or aryl, cycloalkyl having 5 or 6 carbon atoms, or aralkyl having 7 to 16 carbon atoms, any of which groups may optionally be substituted by one or more alkyl groups, R1 is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or acylamino, R2 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, cyano (lower alkylene) e.g. cyano-methylene, or if R1 and R2 represent alkyl and/or alkoxy, they can form together a carbocyclic ring.

When R' is acylamino it may e.g. be an alkyl carbanate or other carbamate group.

Compounds of the general formula (I) are generally used for protecting plants from plant diseases.

A well-known process for the preparation of compounds of the general formula (I), wherein R1, R2 and R are as hereinabove defined, consists in the addition of phenol derivatives of the general formula (II), wherein R1 and R2 are as defined above, to isocyanates of the general formula (III) R-N=C=O (III) Due to the toxicity and mucous membrane irritating properties of the isocyanates, this process can, however, be carried out only under very strict labour-safety regulations, and therefore its performance is rather cumbersome. A further disadvantage is the strongly exothermic character of the isocyanate addition reaction, which involves further technological problems, especially when isocyanates with a low boiling point are used, and may also lead to undesired side reactions.Moreover, certain isocyanates can be stored and transported only under special conditions, which involves further expense and their accessability is restricted.

An alternative possibility for the preparation of compounds of the general formula (I) consists in the reaction of compounds of the general formula (II) with monosubstituted carbamic acid chlorides. The monosubstituted carbamic acid chlorides are, however, unstable compounds (unlike their disubstituted analogues) and are easily transformed into isocyanates with loss of hydrochloric acid. These unstable compounds can be prepared also by the addition of hydrochloric acid to isocyanates. It cannot, however, be expected that nucleophile (for example a compound of the general formula (II) can be acylated without splitting off hydrochloric acid. Moreover, the disadvantages listed in the preceding paragraph are likewise applicable when carrying out this process.

Compounds of the general formula (I) can also be prepared by reacting compounds of the general formula (II) with phosgene and acylating an amine of the general formula R-NH2 with the chloroformate ester derivative obtained. This process is, however, due to the extreme toxicity of phosgene gas, highly disadvantageous.

It has now been found that phenyl carbamate ester derivatives of the general formula (I) can be prepared with an excellent yield, in high purity by O-acylating phenols of the general formula (II). According to this process phenols of the general formula (II) are reacted with N-carbamoyl-saccharin derivatives of the general formula (IV)

in the presence of bases.

As bases inorganic bases, preferably alkali metal hydroxides, carbonates, bicarbonates; alkaline earth metal hydroxides, carbonates, bicarbonates; and teriary amines, preferably triethylamine can for example be used.

Expediently at least one equivalent of base is used per mole of the acylating agent of the general formula (lav).

The reaction of the compounds of the general formula (II) with the compounds of the general formula (IV) is preferably carried out in an organic solvent, or in a mixture of an organic solvent and water. As organic solvents hydrocarons, lower ketones or esters (acetone, methyl ethyl ketone, ethyl acetate), ethers (dioxan, tetrahydrofuran), chlorinated solvents (chloroform, dichloroethane), lower acid amides (formamide, dimethyl formamide) can for example be employed. It is preferred to use solvents in which at least two of the starting compounds of the general formula (I) obtained is insoluble, or is soluble but can be precipitated without accompanying impurities. When an inorganic base is used, the reaction product, if desired, can be purified also by treating with water.The organic bases are more preferred, taking into account also the solubility of the salt-like adducts prepared therefrom in organic solvents, especially in solvent mixtures, in which the compound of the general formula (I) obtained is insoiuble while the organic base and its saccharin adduct are soluble.

The compounds of the general formula (I) are reacted with the compounds of the general formula (IV) at 0 to 100 C, preferably at room temperature, expediently under stirring. The compounds obtained are preferably isolated by crystallization or precipitation with a suitable solvent, while saccharin liberated during the reaction remains in the solution as a salt formed with the base employed. From this salt saccharin can easily be isolated and repeatedly recycled for the preparation of an acylating agent of the general formula (lav).

While according to the methods known in the art compounds of the general formula (I) could be prepared only by an addition or a two-step substitution reaction, according to the invention these compounds are obtained by a one-step substitution reaction. Accordingly, the compounds of the general formula (I) can be prepared in an aqueous medium.

A further advantage of the process according to the invention consists in the fact that no toxic, gaseous or liquid acylating agents are used. The N-carbamoyl-saccharin derivatives are crystalline solids, which are easy to handle and can be stored without precautions. Since the acylation carried out by using these agents is far less exothermic than for example acylation performed with isocyanates, the undesired side-reactions can often be avoided and frequently compounds of the general formula (I) can be prepared in a high purity, with excellent yield.

According to a further feature of the invention there is provided an acylating composition suitable for acylating phenolic hydroxyls, which contains 5 to 50 % by weight of a compound of the general formula (IV), wherein R is an hereinbefore defined, in admixture with 0.20 to 30 % by weight but at least equivalent amount of a base and 10 to 80% by weight of a solvent.

The preferred acylating compositions contain as an acylating agent N-phenyl-carbamoyl-benzoic acid sulfimide, N-methyl-carbamoyl-benzoic acid sulfimide, N-butyl-carbamoyl-benzoic acid sulfimide, N (methylphenyl)-carbamoyl-benzoic acid sulfimide, in admixture with triethyl amine as a base and acetone as a sovent.

Further details of our invention are illustrated by the following Examples. It is to be understood that these Examples are illustrative only.

Example 1 4.3 g (0.025 mole) of methyl-(N-3-hydroxyphenyl)-carbamate are reacted with 7.3 g (0.025 mole) of N-phenyl-carbamoylbenzoic acid sulfimide (m.p.: 184-186 C) in 15 ml of acetone, in the presence of 2.56 g (0.025 mole) of triethylamine at 40"C for 15 minutes. To the reaction mixture 40 ml of water are added and it is cooled to 5 to 1Q C. The mixture is allowed to stand for 30 minutes, filtered, washed and dried. 5.5 g of 3-methoxycarbonylaminophenyl-phenyi carbamate are obtained, melting at 150 to 152 "C.

Benzoic acid sulfimide can be precipitated from the mother liquor by hydrochloric acid.

Example 2 3.35 g (0.025 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-ol are reacted with 6 g (0.025 mole) N-methylcarbamo,'l-benzoic acid sulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 mole) of triethylamine at 50 oc for 15 minutes. The reaction mixture is then cooled to room temperature, diluted with 100 ml of water, the precipitate is filtered off, washed with water and dried.

3.1 g of 2,3-dihydro-2,2-dimethyl-benzofuran-7-yl methylcarbamate are obtained, melting at 150 to 152 "C.

Benzoic acid sulfimide can be recovered by precipitation from the mother liquor with an acid.

Example 3 1.5 g of N-methylcarbamoyl-benzoic acid sulfimide are suspended in a mixture of 1 g of 2,3-dihydro-2,2 dimethylbenzofuran-7-oi in 5 ml of acetone and 5 ml of water, whereupon a solution of 0.6 g of triethylamine mixture of 2 ml of acetone and 1 ml of water is added dropwise, at room temperature with stirring, in 20 minutes. 20 ml of water are then added dropwise in 30 minutes, and the mixture is stirred for further 1.5 hours. The precipitated crystals are filtered off, washed with water and dried. 0.745 g of 2,3-dihydro-2,2dimethylbenzofuran-7-yl methylcarbamate are obtained, melting at 150 to 152 C.

Example 4 4.3 g (0.025 mole) of methyl-(N-3-hydroxyphenyl)-carbamate are refluxed with 7.3 g (0.025 mole) of N-phenyl-carbamoyl-benzoic acid sulfimide (m.p.: 184 to 186 "C) in 15 ml of acetone, in the presence of 2 g (0.0145 mole) of potassium carbonate for 15 minutes. 40 ml of water are then added and the mixture is cooled to 5 to 10 "C. After standing for 1 hour, the precipitated crystals are filtered off, washed and dried. 5.8 g of 3-methoxycarbonylamino-phenylcarbamate are obtained, melting at 150 to 152 "C.

Example 5 4.5 g (0.025 mole) of ethyl-(N-3-hydroxyphenyl)-carbamate are reacted with 7.3 g (0.025 mole) of N-phenyl-carbamoyl-benzoic acid sulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 mole) of triethylamine at 40 "C for 15 minutes. Upon addition of 40 ml of water the reaction mixture is cooled to 5 C, allowed to stand for 30 minutes, filtered, washed and dried. 5.7 g of 3-ethoxycarbonyl-aminophenylphenylcarbamate are obtained, melting at 117 to 119 C.

Example 6 4.3 g (0.025 moles) of methyl-(N-3-hydroxyphenyl)-carbamate are reacted with 7.9 g (0.025 mole) of N-(3-methylphenyl)-carbamoyl benzoic acid sulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 mole) of triethylamine at 30 "C for 30 minutes. Upon addition of 50 ml of water the reaction mixture is cooled to 5 to 10 "C, allowed to stand for 30 minutes, filtered, washed and dried. 5.3 g of 3methoxycarbamoylphenyl-3'-methyl-phenyl-carbamate are obtained, melting at 140 to 142 "C.

By precipitation with hydrochloric acid 3.5 g (76 %) of benzoic acid sulfimide are recovered. This method can equally be employed in any of the preceding examples.

Example 7 5 g N-methyl-carbamoyl-benzoic acid sulfimide are suspended in a mixture of 2.67 g 2-chlorophenoi and 50 g acetone. The mixture is then cooled to 5"C and while stirring a solution of 2.9 ml triethylamine in 30 ml acetone is added dropwise. The temperature of the mixture during the addition (two hours) was not allowed to increase above 6"C. After standing for 12 hours and stirring at a temperature of 5"C, 240 ml distilled water was added in portions to the mixture, which was then extracted with 3 x 30 ml portions of ether. The ethereal extract was dried with sodium sulfate, then the solvent was evaporated in vacuo at a temperature not above 30"C.

3.13 g 2-Chlorophenyl N-methylcarbamate are obtained, melting at 90-91"C after recrystallization from n-pentane.

Example 8 5 g N-Methyl-carbamoyl-benzoic acid sulfimide are suspended in a mixture of 2.6 g methoxyphenol and 50 ml acetone and while stirring at room temperature, a solution of 2.9 ml triethylamine in 30 ml acetone is added dropwise, over one hour. The mixture is stirred for a further 2 hours at room temperature, then 240 ml distilled water is slowly added to the mixture and it is extracted with 3 x 30 ml portions of ether. The ethereal extract is dried with sodium sulfate, then the solvent evaporated in vacuo at a temperature not above 30"C.

2.43 g 2-Methoxyphenyl-N-methylcarbamate are obtained; recrystallized from N-pentane, the m.p. is 90-92"C.

Example 9 2.4 9 N-Methyl-carbamoyl-benzoic acid sulfimide are suspended in a mixture of 1.63 g 2-methoxy-4cyanomethylene-phenol in 15 ml acetone, and while stirring at room temperature a solution of 1.4 ml triethylamine in 5 ml acetone is added, over one hour. After standing another 2 hours at room temperature 65 ml distilled water is added to the mixture. After standing for 16 hours at 5"C the precipitated crystals are filtered off, washed with water and dried. 0.72 g product is obtained, melting at 138-139"C.

Analysis: Calculated: C% = 59.99, H% = 5.45, N% = 12.72 Found: C% = 60.05, H% = 5.52, N% = 12.65 The mother liquor from the crystallization is washed with 3 x 10 ml portions of ether, the ethereal extracts dried with sodium sulfate, then in vacuo at a temperature not above 30"C to evaporate the solvent. An additional 0.95 g 2-methoxy-4-cyano-methylenephenyl-N-methylcarbamate was obtained.

Example 10 5 g N-Butyl-carbamoyl benzoic acid sulfimide are suspended in the mixture of 1.67 g phenol and 50 ml water, then while stirring for 5 hours a solution of 0.71 g sodium hydroxide in 50 ml water is added. After stirring another 3 hours, the mixture is extracted with 3 x 30 ml portions of ether, the ethereal extracts are dried with sodium sulfate, then the solvent evaporated in vacuo at a temperature not above 30"C. 2.15 g Phenyl N-butylcarbamate are obtained, which can be distilled at 146-148"C at 2mmHg.

Example 17 5 g N-Tert.butyl-carbamoyl-benzoic acid sulfimide and 1.9 g 4-methylphenol in 50 ml chloroform are heated to boiling point, then while stirring a mixture of 2.5 ml triethylamine and 30 chloroform is added, over one hour. After boiling an hour the solvent is evaporated in vacuo and the oily residue is mixed with ether.

The precipitated benzoic acid sulfimide triethylamine salt is filtered, then the ethereal solution is evaporated in vacuo at a temperature not above 30"C.

2.4 g 4-Methylphenyl N-tertiary butylcarbamate is obtained, melting at 130-132"C after crystallization from petrol ether.

Claims (15)

1. A process for preparing a phenyl carbamate derivative of the general formula (I)

wherein R is alkyl having 1 to 8 carbon atoms; or aryl, cycloalkyl having 5 or 6 carbon atoms, aralkyl having 7 to 16 carbon atoms, any of which groups may optionally be substituted by one or more alkyl groups, R1 is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms or acylamino, R2 is hydrogen, halogen, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms, or cyano (lower alkylene), or if R1 and R2 represent alkyl and/or alkoxy, they can form together a carbocyclic ring, which comprises acylating a phenol of the general formula (II)

wherein R1 and R2 are as defined above, with an N-carbamoyl-saccharin derivative of the general formula (IV)

wherein R has the same meaning as defined above, in the presence of a base.

2. A process as claimed in claim 1, wherein at least one molar equivalent of base is used, per mole of compound of the general formula IV.

3. A process as claimed in claim 2, wherein said base is an alkali metal hydroxide, carbonate, or bicarbonate; an alkaline earth metal hydroxide, carbonate or bicarbonate; or tertiary amine base.

4. A process as claimed in claim 3 wherein said base is triethylamine.

5. A process as claimed in any of the preceding claims wherein the reaction is performed in a liquid reaction medium selected from organic solvents, aqueous organic solvents and water.

6. A process as claimed in any of the preceding claims wherein the reaction is performed at a temperature in the range of 0 to 100 C.

7. A process as claimed in claim 6 wherein the reaction is performed at room temperature.

8. A process as claimed in any of the preceding claims wherein 2,3-dihydro-2,2-dimethyl-benzofuran-7 ol, a n an alkyl-(N-3-hydroxyphenyl)-carbamate or 2-(1,3-dioxan-2-yl)-phenol is employed as said phenol.

9. A process as claimed in any of the preceding claims wherein said compound of general formula IV is N-phenyl-carbamoyl-benzoic acid sulfimide, N-methylcarbamoyl-benzoic acid sulifmide, N-butyl-carbamoylbenzoic acid sulfimide or N-(methylphenyl)-carbamoyl-benzoic acid sulfimide.

10. A process a as claimed in claim 1, substantially as described herein.

11. A process as claimed in claim 1, substantially as illustrated in any one of the Examples.

12. An acylating composition suitable for use in the process of claim 1 which comprises as an acylating agent 5 to 50% by weight of a saccharin derivative of the general formula (IV) as defined in claim 1, in admixture with 0.2 to 30% by weight but at least an equivalent amount of a base, and 10 to 80% by weight of one or more solvents.

13. A composition as claimed in claim 12, which comprises as an acylating agent N-phenylcarbamoylbenzoic acid sulfimide, N-methylcarbamoyl-benzoic acid sulfimide, N-butyl-carbamoyl-benzoic acid sulfimide or N-(methylphenyl)-carbamoyl-benzoic acid sulfimide.

14. A composition as claimed in claim 12 or 13, which comprises triethylamine as a base, and acetone as a solvent.

15. A composition as claimed in claim 12, substantially as illustrated in any one of the Examples.