GB2108961A - Preparation of chloromethyl chloroformate from formaldehyde and phosgene - Google Patents

Description

SPECIFICATION Preparation of chloromethyl chloroformate This invention is concerned with a process for the preparation of chloromethyl chloroformate, which is a material useful in numerous organic syntheses, but not readily available on an industrial scale. The synthesis of a-chlorinated chloroformates of the general formula:

in which R is an aliphatic or aromatic substituent, is very difficult if it is desired to avoid the introduction of additional chlorine atoms in the R radial during the synthesis. Muller, in Liebig's Annalen derChemie, 1890, volume 257, pages 50 et seq., suggested a process which is still the only one known and in use to date. This process consists of photolytically chlorinating the corresponding chloroformate which is not substituted in the a-position. Unfortunately, in addition to the desired product, one obtains numerous by-products which are more chlorinate then the desired product. Muller counted not less than five such by-products in the case of the ethyl chloroformate which he studied. The presence of these by-products is very disadvantageous due to the main subsequent application of the chloroformates, that is their transformation into carbonates, particularly in the synthesis of fine pharmaceuticals, such as penicillin acids acylals. Distillation of the reaction product is thus indispensable, although difficult to carry out effectively due to the presence of so many by-products. Another old publication, German Patent 121,223, which issued in 1901, describes the synthesis of 1,2,2,2-tetrachloroethyl chloroformate and a-chlorobenzyl chloroformate, by phosgenation of chloral and benzaldehyde respectively, in the presence of a stoichiometric amount of a tertiary amine which does not belong to the pyridine series. However, if one attempts to phosgenate, under the same conditions, aldehydes other than the specifically mentioned chloral and benzaldehyde, such as acetaldehyde, numerous complexes and byproducts are formed in addition to alpha -chloroethyl chloroformate, the latter being obtained in a poor yield so that this process is not suitable for use on an industrial scale. Further, if this phosgenation is carried out with an aliphatic tertiary amine, such as triethylamine, the principal result is the destruction of the amine, with only a very small amount of the desired chloroformate being formed. A process of preparing a-chlorinated chloroformates free of the by-products resulting from the substitution of chlorine for hydrogen has recently been described in Irish Patent Application 869/81. This process comprises phosgenating an aldehyde of the formula RCHO in the presence of a catalyst so as to obtain an a-chlorinated chloroformate of the formula RCH Cl OCOCI. The process uses inexpensive starting materials and gives excellent yields. However it cannot be applied to formaldehyde, HCHO, itself and cannot, therefore, be used to make a-chloromethyl chloroformate CH2CI OCOCI. It is also known that chloromethyl chloroformate can be obtained by chlorination of methyl chloroformate or methyl formate. Matzer et al, in Chemical Review, 64, page 646 (1964), give several references of methods of this kind, but they are all difficult to carry out and give rise to numerous byproducts which are difficult to separate from the desired product. We have now developed a process for the preparation of a-chloromethyl chloroformate which gives good yields of the desired compound. This process is based upon the reaction of dry gaseous monomeric formaldehyde with phosphene in the presence of certain catalysts and under anhydrous conditions. According to the present invention, therefore, there is provided a process for the preparation of chloromethyl chloroformate, which comprises introducing dry gaseous monomeric formaldehyde into a reactor containing phosgene and a catalyst selected from substituted amides, tetrasubstituted ureas and thioureas, phosphoramides in which the nitrogen is completely substituted, quaternary ammonium halides iri which the substituents include a total of at least 16 carbon atoms, and alkali metal and alkaline earth'metal halides associated with a sequestering agent for their cations, and the reaction product of any of these catalysts with phosgene, in the absence of water and hydrochloric acid and at a temperature of from -10[deg]C to +60[deg]C. The formaldehyde used in the process according to the invention must be perfectly dry and completely monomeric. It is thus necessary, before starting the reaction, to dry the formaldehyde and, in general, to depolymerize it since formaldehyde cannot be stored in the monomeric form, but forms either the trimer trioxane or a linear polymer of the general formula CH2O n in which n is an integer, usually between 6 and 100 and which is known as paraformaldehyde. The formaldehyde is dried in a dryer in the presence of a good drying agent, such as phosphorus pentoxide. The operation of drying the formaldehyde may be performed before or during the depolymerization but, in any event, before its introduction into the phosgenation reactor. The drying operation is essential for the process according to the invention and it must be complete. Indeed, any trace of moisture causes repolymerization of the monomeric formaldehyde and reduces the yield of the phosgenation since only monomeric formaldehyde reacts with phosgene. Monomeric formaldehyde is obtained in known manner, such as by thermal depolymerization in the case of paraformaldehyde or by depolymerization in the presence of a catalyst in the case of trioxane. Depolymerization can be effected either during the drying of the formaldehyde or after drying of the polymeric formaldehyde.Dry formaldehyde, in monomeric form, is then introduced into a perfectly dry reactor containing the catalyst and the phosgene. The term "catalyst" is used in this specification in a restrictive sense, that is the compound used as a catalyst is essential to the reaction, but does not directly participate in the reaction and is used in relatively small amounts with respect to the formaldehyde. It is, indeed, a catalyst, but contrary to what is the general view of catalysts, it cannot always be reused for another reaction once the introduction of phosgene has been stopped. We are not able to suggest a theoretical explanation of this phenomenon. It has been possible to find a definition common to a certain number of the catalysts which can be used according to the invention. These catalysts are organic or inorganic compounds which can generate, in a medium containing formaldehyde, phosgene and a solvent (if applicable), a pair of ions, one of which is a halide anion and the other of which is a cation sufficiently separated from the halide anion that it possesses a nucleophilic activity allowing it to react with the aldehyde function of the formaldehyde.Catalysts used according to the invention and falling within this definition include the following as such or as their reaction products with phosgene: substituted amides, tetrasubstituted ureas and thioureas phosphoramides in which the nitrogen is completely substituted, quaternary ammonium halides in which the substituents include a total of at least 16 carbon atoms and preferably those in which each constituent has at least 4 carbon atoms, and alkali metal and alkaline earth metal halides associated to a sequestering agent for their cations. The preferred halide is chloride. As mentioned above, certain of the catalysts generate a halide ion either directly, or after reaction with phosgene. In this case, the general mechanism of the catalyst is probably as follows:

in which M+ is an organic or inorganic cation, which may or may not be complexed and which is present as such in the catalyst from the start or is formed at the beginning of the reaction by the action of phosgene on the catalyst. Thus, M+ may be a complexed metallic cation or a fully-organic cation of onium type, such as:

or M+ may be formed from the more or less advanced reaction of phosgene and the compound responsible for the catalytic action, suky as in the following sequence, for example:

in which M+ is a large chlorimonium cation. It has been noted that the most interesting results have been obtained with the following catalysts: substituted amides, particularly dimethylformamide; tetrasubstituted ureas and thioureas, particularly tetraalkyl thioureas, such as tetrabutylurea and tetramethylurea; phosphoramide in which the nitrogen is completely substituted, particularly hexamethylphosphotriamide; quaternary ammonium halides which include a total of at least 16 carbon atoms and each substituent of which preferably has at least 4 carbon atoms, such of which preferably has at least 4 carbon atoms, such as tributylbenzyl ammonium chloride; alkali metal or alkaline earth metal halides associated to a sequestering agent of their cation, particularly potassium chloride associated with a crown ether, such as 18-crown-6, or a cryptate such as (222) or diaza-1,10-hexaoxa-4,7,13,16,21,24bicyclo(8,8,8)hexacosane. In the latter case, it is preferred to use a sequestering agent which forms a complex having a high stability constant, with the metal chloride cation. Suitable sequestering agents for this purpose have been described in the literature, for example by Kappenstein in Bulletin de la Societe Chimique de France, 1974, No. 1-2, pages 89-109 and by J. M. Lehn in Structure and Bonding, volume 16, pages 2-64, Springer Verlag (1974). The term "halide" is used herein to refer to chloride, bromide, or iodide, it being understood that a chloride is preferred, so that even the first molecule of formaldehyde transformed by the action of the halide arising from the catalyst is transformed into chloromethyl chloroformate. The amount of catalyst used is important, but not critical, in the process according to the invention. When a very effective catalyst is used, a ratio of catalyst of 0.5 to 10 mol % (preferably 2 to 7 mol %) with respect to the molar quantity of phosgene used is generally satisfactory. On the other hand, some catalysts used according to the invention are less effective and a higher ratio, about 1 to 50 mol % (preferably 5 to 40 mol %) must be used. The order of introduction of the reagents into the reactor is important. It is essential to introduce the monomeric gaseous formaldehyde into a reactor which already contains the catalyst and phosgene so that the formaldehyde reacts immediately with the phosgene without having time to repolymerize, the rate of reaction of formaldehyde with phosgene being higher than its rate of polymerization under the operation conditions used. The reactor must thus contain at least the catalyst with all the phosgene being introduced into the reactor before the start of the reaction or being introduced at the same time as the formaldehyde is introduced at the bottom of the vessel containing phosgene and catalyst.On the other hand, within the present invention it is not possible to place in a vessel the formaldehyde and the catalyst in the reactor and then to introduce the phosgene since, in this case, the formaldehyde would polymerize and the phosgenation reaction would become virtually impossible. The phosgenation reaction is preferably carried out with stirring. The temperature of the reaction medium is preferably kept at from -10[deg]C to +30[deg]C during the introduction of formaldehyde. It is still better to keep the temperature of the reaction medium at about 0[deg]C at the beginning of the introduction of the formaldehyde and by the end of the introduction of the formaldehyde, the temperature is allowed to reach about 20[deg]C. It may be advantageous to end the reaction by heating the reaction mixture to a temperature of from 40[deg] to 60[deg]C. The reaction mixture must be totally free of any trace of water or hydrochloric acid so as to avoid any risk of formaldehyde repolymerization. For this purpose, the reactor must be flushed with dry air or , with a dry inert gas befory the reaction. Although this is not a preferred embodiment of the invention, it is possible to carry out the reaction in the presence of a solvent. One must, however, avoid using solvents which react with halogens to form hydrochloric acid, such as alcohols and amines, or solvents which break down to form hydrochloric acid, such as ketones and tetrahydrofuran and, finally, solvents which are difficult to dry, such as ethers. Suitable solvents are, for example, toluene and chlorinated aliphatic solvents, such as methylene chloride, chloroform and carbon tetrachloride. The use of a solvent may sometimes prove useful since, when the reaction takes place in the presence of a solvent, the temperature is preferably maintained at from 30 to 60[deg]C even during the introduction of the formaldehyde. In order that the invention may be more fully understood, the following examples are given by ! way of illustration:

Example 1 The apparatus used was a 100 ml capacity glass reactor fitted with a dry ice cooler, a thermometer, a stirrer and an inlet for the introduction of a gas. The reactor was flushed with dry nitrogen. Phosgene 38 g (0.38 mol) in which was dissolved 3.3 g (0.0106 mol) of perfectly dry benzyl tributylammonium chloride, was introduced into the reactor. While the temperature of the mixture was kept at about 0[deg]C, there was introduced through a gas inlet tube which dipped into the phosgene, formaldehyde taken from a bottle containing 18 g (0.6 mole) paraformaldehyde and 10 g phosphorus pentoxide (P2O5), this bottle being flushed with dry nitrogen and being heated at 150[deg]C. The addition of formaldehyde was continued for 30 minutes until the paraformaldehyde had completely disappeared from the supply bottle and the reaction mixture was allowed to reach 20[deg]C and was stirred for one hour at this temperature. The residual phosgene was removed by deaeration and the chloromethyl chloroformate obtained was purified first by evaporation under vacuum and then by distillation at 106[deg]C at atmospheric pressure. There were obtained 20.7 g of perfectly dry product, equivalent to a yield of 42% with respect to the phosgene used.In NMR spectrography, chloromethyl chloroformate is characterized by a singlet at 5.5 ppm.

Example 2 The process of Example 1 was repeated, but using 10 g phosgene, 10 g paraformaldehyde, and 5 g P2O5, and using phosgenated tetra n-butyl urea as catalyst. This catalyst was prepared by phosgenating 1.5 g tetra n-butyl urea at 50[deg]C according to the following reaction scheme:

The reaction temperature was raised to 50[deg]C for one hour after the end of the introduction of the formaldehyde. Chloromethyl chloroformate was obtained in a yield of 91.5% with respect to the phosgene used. This yield was determined by NMR dosing, using toluene as internal standard.

Example 3 The process of Example 2 was repeated, but using 20 g phosgene, 15 g paraformaldehyde, and 10 g P2O5, and using as catalyst 1.3 g potassium chloride associated with 0.4 g cryptate (2,2,2). Chloromethyl chloroformate was obtained in a yield of 63% with respect to the phosgene used.

Example 4 The apparatus used was identical with that used in Example 1. The reactor was flushed with dry nitrogen and 1.3 g potassium chloride associated with 0.4 g cryptate (2,2,2) and phosgene 20 g were successively introduced into it. The temperature of the mixture was kept at about 0[deg]C and there was introduced through a bubbling tube which dipped into the phosgene, formaldehyde coming from a bottle containing 15 g paraformaldehyde, heated at 150[deg]C. This bottle had previously been flushed dry with nitrogen and the paraformaldehyde dried over P2O5 under a vacuum of 0.1 mm Hg in a drier before being placed in the depolymerizing bottle. The introduction of formaldehyde was carried out for 30 minutes, and the reaction mixture was then heated at 50[deg]C for one hour to allow the reaction to proceed to completion. Chloromethyl chloroformate was obtained a yield of 73% with respect to the phosgene used.

Example 5 The same apparatus as described in Example 1 was used. The reactor was flushed with dry nitrogen and 40 ml anhydrous carbon tetrachloride, 12 g of phosgene and, as catalyst, phosgenated tetra n-butyl urea, prepared as described in Example 2 from 1.5 g tetra n-butyl urea, were introduced into it. After the temperature of the mixture had been raised to 40[deg]C, formaldehyde prepared as described in Example 4 from 3.8 g paraformaldehyde, was introduced. The reaction mixture was kept at 40[deg]C for 2 hours after introduction of the formaldehyde. Chloromethyl chloroformate was obtained in a yield of 65% with respect to the formaldehyde used.

Claims (12)

Claims

1. A process for the preparation of chloromethyl chloroformate, which comprises introducing dry gaseous monomeric formaldehyde into a reactor containing phosgene and a catalyst selected from substituted amides, tetra-substituted ureas and thioureas, phosphoramides in which the nitrogen is completely substituted, quaternary ammonium halides in which the substituents include a total of at least 16 carbon atoms, and alkali metal and alkaline earth metal halides associated with a sequestering agent for their cations, and the reaction product of any of these catalysts with phosgene, in the absence of water and hydrochloric acid and at a temperature of from -10[deg]C to +60[deg]C.

2. A process according to claim 1, in which each of the substituents in the quaternary ammonium halide catalyst contains at least four carbon atoms.

3. A process according to claim 1 or 2, in which the catalyst is dimethylformamide, tetrabutylurea, tetramethylurea, hexamethylphosphotriamide, tributyl benzyl ammonium chloride, potassium chloride associated with ether 18-crown-6, or potassium chloride associated with cryptate (2,2,2).

4. A process according to any of claims 1 to 3, in which the drying agent used to dry the formaldehyde is phosphorus pentoxide.

5. A process according to any of claims 1 to 4, in which the temperature of the reaction mixture is kept at from 10[deg]C to +30[deg]C during the introduction of the formaldehyde.

6. A process according to claim 5, in which the temperature of the reaction mixture is about 0[deg]C at the beginning of the introduction of the formaldehyde and is allowed to rise to about 20[deg]C at the end of the introduction of the formaldehyde.

7. A process according to claim 6, in which the temperature of the reaction mixture is raised to from 40 to 60[deg]C after all the formaldehyde has been introduced into the reactor.

8. A process according to any of claims 1 to 4, in which the reaction is carried out in a solvent.

9. A process according to claim 8, in which the solvent is toluene, methylene chloride, chloroform, or carbon tetrachloride.

10. A process according to claim 8 or 9, in which the reaction is carried out at a temperature of from 30 to 60[deg]C.

11. A process for the preparation of chloromethyl chloroformate substantially as herein described in any of the Examples.

12. Chloromethyl chloroformate when prepared by the process claimed in any of the preceding claims.