DK161886B - PROCEDURE FOR THE PREPARATION OF ALFA-CHLORMETHYL CHLOROFORMATE FROM FORMALDEHYDE AND PHOSGEN - Google Patents

Description

in

DK 161886 B

The present invention relates to a particular process for preparing chloromethyl chloroformate from formaldehyde and phosgene. Chloromethyl chloroformate is a material which is poorly useful for numerous organic syntheses, but which is not readily available on an industrial scale.

The synthesis of α-chlorinated chloroformates of the general formula R - CHCl - O - C - Cl where R is an aliphatic or aromatic

II

0 substituent is very difficult if one wishes to avoid the introduction of additional chlorine atoms into the radical R during synthesis. In Liebig's Annalen der Chemie, 1890, vol. 257, pp. 50 et seq., Muller has proposed a method that is still the only known and used in our time. This process consists in photolytic chlorination of the corresponding chloroformate which is not substituted at the α-position. In addition to the desired product, unfortunately, numerous by-products are obtained which are more chlorinated than intended. Muller has counted no less than five of these by-products in the case of ethyl chloroformate, which he investigated. The presence of these by-products is very disruptive due to the main subsequent use of the chloroformates, which is their conversion to carbonates, especially used for the synthesis of fine pharmaceutical compounds such as penicillic acid acylals. A distillation of the reaction product is therefore indispensable, although it is difficult to perform due to the presence of numerous by-products.

Another old publication, German Patent No. 121,223, issued in 1901, discloses the synthesis of 1,2,2,2-tetrachloroethyl chloroformate and α-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, under the same conditions, one attempts to phosgenate other aldehydes in addition to the chloral and benzaldehyde mentioned, e.g. acetaldehyde, formation of numerous 2 is observed

DK 161886 B

complexes and by-products in addition to the a-chloroethyl formate, the latter being obtained in poor yield which renders the process unsuitable on an industrial scale. Furthermore, if one tries to carry out this phosgenation with an aliphatic tertiary amine such as triethylamine, destruction of this amine is mainly observed to produce a very small amount of the chloroformate.

Thus, there is a need for a process for preparing pure α-chlorinated chloroformates in yields which will allow the complete use of these α-chlorinated chloroformates, compounds of simple chemical structure, and substantial value as intermediates.

A process for preparing α-chlorinated chloroformates free of the by-products resulting from substitution of chlorine instead of hydrogen has recently been proposed from cheap raw materials in excellent yield. This process, described in Irish Patent Application No. 869/81, consists in phosgenation of an aldehyde of the formula RCHO in the presence of catalysts to obtain α-chlorinated RCHC10CO1 chloroformate. However, this process cannot be used for formaldehyde itself, HCHO, and does not allow the preparation of α-chloromethyl chloroformate, CH2C10CO1.

In the case of chloromethyl chloroformate, it is known that it can be obtained by chlorination of methyl chloroformate or 25 methylformate. Matzner et al. in Chemical Review 64, p. 646 (1964), refers to several known methods, but these methods are always sensitive syntheses leading to numerous by-products which are difficult to separate from the desired product.

An object of the present invention is to provide a process for the preparation of α-chloromethyl chloroformate in high yield.

3

DK 161886 B

The essence of the present invention lies in introducing pre-dried gaseous formaldehyde in monomeric form into a phosgene-containing reactor and a catalyst selected from a tetrasubstituted urea, a quaternary 5 ammonium halide whose substituents contain at least 16 carbon atoms, an alkali or alkaline earth halide in conjunction with a sequestering agent for its cation and the reaction product of a tetrasubstituted urea with phosgene, and by performing the reaction in total absence of water and hydrochloric acid at a temperature between -10 ° C and + 60 ° C. The quaternary ammonium halides are preferably those wherein each substituent contains at least 4 carbon atoms. According to a particular embodiment of the invention, the reaction of formaldehyde and phosgene is carried out in the presence of a catalyst in a solvent which is toluene, methylene chloride or chloroform or tetrachloro carbon.

In a preferred embodiment of the invention, the catalyst is benzyltributylammonium chloride, potassium chloride in conjunction with a crown ether or cryptate capable of complexing its cation, or phosgenated tetrabutylurea in substance.

The process of the invention consists in carrying out the reaction of dry gaseous formaldehyde in its monomeric form with phosgene in a reactor having a temperature between -10 ° C and + 60 ° C in the presence of a catalyst and in the total absence of water and hydrochloric acid. .

According to the invention, the formaldehyde is to be completely dry and completely monomeric. Thus, before the beginning of the reaction, it is necessary to dry the formaldehyde and generally depolymerize it, since formaldehyde cannot be stored in the monomeric form, but forms either the tri more trioxane or a linear polymer of the general formula -fCH 2 O - n , known as paraformaldehyde, where n is a number, usually between 4

DK 161886 B

6 and 100.

The formaldehyde is dried in a dryer in the presence of a good desiccant such as phosphorus pentoxide. The drying of the formaldehyde can be carried out before or during the depolymerization, but in any case before its introduction into the phosgeneration reactor. The drying is essential to the process of the invention and must be complete. Indeed, a trace of moisture causes re-polymerization of the monomeric formaldehyde and decreases the yield of the phosgenation, as only 10 monomeric formaldehyde reacts with the phosgene. Monomeric formaldehyde is obtained in known manner, such as by heat polymerization in the case of paraformaldehyde, or by depolymerization, in the presence of catalysts in the case of trioxane. The depolymerization can take place either during the drying of formaldehyde = 15 or after drying the polymeric formaldehyde. Dry formaldehyde in monomeric form is then introduced into a completely dry reactor containing the catalyst and the phosgene. Within the scope of the invention, the term "catalyst" is to be understood as limiting. The compound added as a catalyst is essential for the reaction but does not take part directly in the reaction and is used in relatively small amounts relative to the formaldehyde. It is, in fact, a catalyst, but contrary to the general view of catalysts, it cannot always be reused for a different reaction once the introduction of the phosgene is stopped. No theoretical explanation is given for this phenomenon.

It has been possible to find a definition common to a certain number of catalysts suitable for the invention. These catalysts are organic or inorganic substances which, in a medium containing formaldehyde, phosgene and optionally a solvent, can develop a pair of ions, one of which is a halide ion and the other a cation sufficiently separate from the halide anion, such that it has a nucleophilic activity which allows it to react with aldehyde 5

DK 161886 B

function of the formaldehyde. Catalysts of the invention which fall within this definition include the following: tetrasubstituted ureas, quaternary ammonium halides whose substituents contain a total of at least 16 carbon atoms and preferably those where each component contains at least 4 carbon atoms, and the alkali or alkaline earth halogen thereof in conjunction with a sequestering agent for their cation; the reaction product of a tetrasubstituted urea with phos gene. The preferred halide is chloride.

10

As mentioned above, certain catalysts develop a halide ion, either directly or after reaction with phosgene. In this case, a general mechanism of the catalyst is likely to be the following:

Η H

M® Cl® - * '' c = ^ 0 - »M® + Cl - C - 5j f / k / 20 H .Cl Cl /

i ft Λ I

Cl - C - O - C + .C1® M® <- C-. II (II (HO * HCOH O> C1) where M + is an organic or inorganic cation, complexed or not, found as such in the catalyst initially or formed at the beginning of the reaction by the action of phosgene on the catalyst. M + may thus be a complex-bonded metallic cation or a completely organic onium-type cation, such as, for example: 35 ° C / O ° θ N, 0X K / Oy_ / N C1 \ _ / oN_ / Ολ_ /

DK 161886B

6 or M + may be formed by the more or less advanced reaction of phosgene and the substance responsible for the catalytic action, such as e.g. in the following order:

Bu \ c \ N-C-N C = 0

Bu ^ 0> ^ Bu Cl / f 10

Bu.

Bu ^ J

-N "- C ^ Bu + Cl® + CO₂

Bu ^^ Cl - \ iC0H

Wherein M + is a large chloro-immunium cation.

It has been observed that the most interesting results have been obtained with the following catalysts: tetra-substituted urine substances, especially tetraalkylureas such as tetrabutylurea and tetramethyl urea in substance, and their reaction products with phosgene, quaternary ammonium halides containing a total of at least 16 carbon atoms, and each substituent preferably having at least 4 carbon atoms, such as tributylbenzylammonium chloride, alkali metal or alkaline earth metal having one, and in conjunction with a sequestering agent for their cation, especially potassium chloride in conjunction with a crown ether such as 18 6 or a cryptate such as (222) or diaza-1,10-hexaoxa - 4, 7, 30 13, 16, 21, 24 - bicyclo (8, 8, 8) hexacosan.

In this latter case, it is of course preferred to work in conjunction with a complex binding agent which, together with the metal chloride cation, forms a complex with a high stability constant which is very easy to obtain due to the numerous studies carried out in this field, such as the study of Kappenstein, published in Bulletin 7

DK 161886 B

de la Société Chimique de France, 1974, Nos 1-2, pp. 89-109, and J.M.Lehn's work, published in Structure and Bonding, Volume 16, pp. 2-64, Springer Verlag (1974). The term "halide" essentially means a chloride, bromide or iodide, as it is understood that a chloride is preferred so that even the first molecule of formaldehyde converted through the action of the halide coming from the catalyst is converted into chloromethyl chloroformate.

The amount of catalyst used is important but not essential to the process of the invention. When the catalyst is very effective, a catalyst amount of 0.5 - 10% in mol (preferably 2-7%) relative to the molar amount of phosgene is satisfactory. On the other hand, some catalysts according to the invention are less efficient and a greater amount, approx. 1-50% (preferably 5 - 40%).

The order of introduction of the reactants into the reactor is significant. Indeed, it is essential to introduce the monomeric gaseous formaldehyde into the reactor which already contains the catalyst and phosgene so that the form = 20 aldehyde reacts immediately with the phosgene without having time to repolymerize because the reaction rate of formaldehyde with phosgene is higher than the rate of polymerization below the operating conditions used. Thus, the reactor must contain at least the catalyst, with all the phosgene being introduced into the reactor 25 prior to the start of the reaction or introduced at the same time as the formaldehyde is introduced at the bottom of the container containing the phosgene and catalyst. On the other hand, within the scope of the invention, it is not possible to place the formaldehyde and catalyst in a container and introduce the phosgene into this container, since in this case the formaldehyde would polymerize and the phosgenation reaction would be practically impossible.

8

DK 161886 B

The phosgenation reaction is advantageously carried out with stirring. The temperature of the reaction medium is preferably maintained between -10 ° C and + 30 ° C during the introduction of formaldehyde. It is even better to keep the temperature of the reaction medium at approx. 0 ° C 5 at the beginning of the introduction of formaldehyde and towards the end of the introduction of the formaldehyde to allow the temperature to reach approx. 20 ° C. It may be advantageous to terminate the reaction by heating the reaction mixture to a temperature between 40 and 60 ° C.

10 The reaction mixture must be completely free of any trace of water or hydrochloric acid, so that all risk of formaldehyde gene polymerization is avoided. For this purpose, the reactor must be flushed with dry air or with a dry inert gas before the reaction.

Although not a preferred embodiment of the invention, it is possible to carry out the reaction in the presence of a solvent. However, solvents which react with phosgene to form hydrochloric acid, such as alcohols and amines, or solvents, which decompose to form hydrochloric acid such as ketones and tetrahydrofuran, and finally, solvents which are difficult to dry, must be avoided. such as ethers. If desired, solvents such as toluene or chlorinated aliphatic solvents such as methylene chloride, chloroform 25 and tetrachlorocarbon can be used. However, the use of a solvent can sometimes prove useful, because when the reaction takes place in the presence of a solvent, the temperature can be maintained between 30 and 60 ° C, even during the introduction of formaldehyde.

The following examples illustrate the use of the method of the invention.

9

DK 161886 B

EXAMPLE 1.

The apparatus used is a glass reactor with a capacity of 100 ml, equipped with a dry ice cooler, a thermometer, a stirrer and an input for introducing a gas type. The reactor is flushed with dry nitrogen. 0.38 mole (38 g) of phosgene containing 3.3 g (0.0106 mole) of completely dry benzyl tri = butylammonium chloride is introduced into the reactor.

While keeping the mixture temperature at approx. 0 ° C, is introduced through the gas entry tube leading into the phosgene, form = aldehyde, which is taken from a bottle containing 18 g (0.6 mole) of 10 paraformaldehyde and 10 g of phosphorus pentoxide which is flushed with dry nitrogen and heated to 150 g. ° C. The addition of formaldehyde is carried out for 30 minutes until complete disappearance of the paraformaldehyde and the reaction mixture is allowed to reach 20 ° C and kept stirring for one hour at this temperature. Remaining phosgene is removed by venting and the resulting chloromethyl chloroformate is first purified by evaporation under vacuum and then by distillation at atmospheric pressure. The boiling point is 106 ° C. 20.7 g of completely dry product is obtained which is equivalent to a yield of 42% relative to the phosgene used. By NMR spectroscopy, chloromethyl chloroformate is characterized by a singlet at 5.5 ppm.

EXAMPLE 2.

Proceed as described in Example 1 with 10 g of phosgene, 10 g of paraformaldehyde and 5 g of PgO 2 un 3 using phosgene tetra-n-butylurea as a catalyst. This catalyst is prepared by phosgenation of 1.5 g of tetra-n-butyl = urea at 50 ° C according to the following reaction scheme:

DK 161886 B

- xo ✓n-butyl / n-butyl

N N

N-Butyl N-Butyl

O = C -> cly Cl - c® + co_ \ / n-butyl COCl, \ / n-butyl 5 \ n-butyl \ n-butyl

The reaction temperature is brought to 50 ° C for one hour after the introduction of formaldehyde. .

Chloromethyl chloroformate is obtained in a yield of 91.5% relative to the phosgene used. This yield is determined by NMR-10 analysis using toluene as the internal standard.

EXAMPLE 3.

The procedure is carried out as described in Example 2 with 20 g of phosgene, 15 g of paraformaldehyde and 10 g of use as catalyst of 1.3 g of potassium chloride in connection with 0.4 g of cryptate (2,2,2). Chloromethyl chloroformate is obtained in a yield of 63% over the phosgene used.

EXAMPLE 4.

The apparatus used is identical to the apparatus described in Example 1. The reactor is flushed with dry nitrogen. 20 g of phos = 20 gene are introduced into the reactor, which already contains 1.3 g of potassium chloride in conjunction with 0.4 g of cryptate (2,2,2).

While keeping the temperature of the mixture at approx. 0 ° C, is introduced through the bubble tube, which dips into the phosgene, formaldehyde, which comes from a bottle containing 15 g of paraformalde = 25 hyd heated to 150 ° C. This bottle was previously rinsed dry with nitrogen and the paraformaldehyde was dried over under a vacuum of 0.1 mm Hg in a dryer before incorporating it.

DK 161886 B

11 is introduced into the depolymerization bottle. The introduction of formaldehyde is carried out for 30 minutes, and then the reaction mixture is heated to 50 ° C for one hour to complete the reaction. Chloromethyl chloroformate is obtained in a yield of 73¾ relative to the phosgene used.

EXAMPLE 5.

The same apparatus is used as described in Example 1. The reactor is rinsed with dry nitrogen. 40 ml of anhydrous tetrachloro-carbon as solvent, 12 g of phosgene and, as a catalyst, phosgenated tetra-n-butyl urea in substance prepared as described in Example 2 of 1.5 g of tetra-n-butyl urea substance are introduced. .

15

After raising the temperature of the reaction mixture to 40 ° C, formaldehyde prepared as described in Example 4 is introduced from 3.8 g of paraforma 1dehyde. The reaction mixture is kept at 40 ° C for 2 hours after introduction of the formaldehyde.

20

Chloromethyl chloroformate is obtained in a yield of 65% over the formaldehyde used.

EXAMPLE 6.

25

The procedure is carried out as described in Example 2 with 20 g of phosgene, 20 g of paraformaldehyde and 12 g of P2O5 using phosgenerated tetramethylurea as a catalyst. This catalyst is prepared by phosgenation of 1.16 g of tetramethyl urea at 50 ° C according to the following reaction scheme:

Cl ©

Me ^ Me Me ^ + .Me _J> ^ NCN ^ + COCl2 -t> N-C ~ N \ + CO2

Me ^ 11 ^ Me Mex | 'xMe 0. Cl

Melting point: 112 ° C

(decomposition) 35

Claims (6)

A process for preparing chloromethyl chloroformate 30 from formaldehyde and phosgene in the presence of a catalyst, characterized by introducing gaseous formaldehyde pre-dried in monomeric form into a reactor containing phosgene and a catalyst selected from a tetrasubstituted urea. , a quaternary ammonium halide whose substituents contain a total of at least 16 carbon atoms, an alkali or alkaline earth halide in conjunction with a sequestering agent for its cation and the reaction product of a phosgene, and by reacting the reaction in total absence of water and hydrochloric acid at a temperature between -10 ° C and + 60 ° C. Process according to claim 1, characterized in that the catalyst is selected from tetrabutylurea, tetramethylurea, the reaction product of tetrabutylurea and phosgene, the reaction product of tetramethylurea and phosgene, tributylbenzylammonium chloride, potassium chloride in connection with 10 6 and ka1 iumch1 or id related to cryptate (2.2.2). Process according to claim 1 or 2, characterized in that the desiccant used to dry the formaldehyde is phosphorus pentoxide. Process according to claims 1-3, characterized in that the temperature of the reaction mixture is maintained between -10 ° C and + 30 ° C during the introduction of formaldehyde. 20 Process according to claim 4, characterized in that the temperature of the reaction mixture is kept at approx. 0 ° C at the beginning of the introduction of formaldehyde and kept at approx. 20 ° C at the end of the introduction of formaldehyde. 2 5 Process according to claim 5, characterized in that the temperature of the reaction mixture is raised to between 40 ° C and 60 ° C after the formaldehyde has been introduced into the reactor. 30 35