JPH0350741B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for producing chloromethyl chloroformate, which is useful in many organic syntheses but is not readily available on an industrial scale.

General formula: (wherein R is an aliphatic or aromatic substituent)
The synthesis of α-chlorinated chloroformates is very difficult if one wants to avoid additional introduction of chlorine atoms into the radical R during the synthesis. Liebig's
In Annalen dei Chemie, 1890, vol. 257, p. 50 et seq., Mu¨ller proposes the only method known and used to this day. This method uses α−
It consists of photochlorination of the corresponding chloroformate which is not substituted in position. Unfortunately, in addition to the desired product, this process also yields a large number of by-products that are more chlorinated than desired.
Mueller found more than five by-products in the case of ethyl chloroformate he studied. The presence of these by-products is very disturbing considering that the main use of chloroformates is to convert them to garbonates, which are used in the synthesis of pharmaceuticals, especially acylar penicillates. Therefore,
Distillation of the reaction products is essential, and this distillation must be carried out with great care due to the presence of a large number of by-products.

Another old document, German Patent No. 1901
No. 121223 discloses that 1,2,2,2-tetrachloroethyl chloroformate and α- It describes the synthesis of chlorobenzyl chloroformate.

However, when attempting to phosgenate certain chloral and benzaldehyde other aldehydes, such as acetaldehyde, under the same conditions,
In addition to the desired α-chloroethyl chloroformate, a number of complexes and by-products were observed to form, and the yield of the desired α-chloroethyl chloroformate was low. Therefore, this method cannot be used on an industrial scale. Not suitable for implementation. Moreover, if this phosgenation is carried out with an aliphatic tertiary amine, such as triethylamine, the decomposition of said amine will mainly occur and the amount of derived chloroformate produced will be very small.

Therefore, pure α-chlorinated chloroformates can be obtained in such a yield as to allow complete application of α-chlorinated chloroformates, which are compounds of simple chemical structure and of high value as intermediates. There is a need for a manufacturing process.

A process has recently been proposed for the production of by-product-free α-chlorinated chloroformates from inexpensive starting materials in high yields by replacing hydrogen with chlorine. This process is described in Irish Patent Application No. 869/81 and consists of phosgenating an aldehyde of formula RCHO in the presence of a catalyst to give the α-chlorinated RCHClOCOCl chloroformate. However, this method cannot be applied to formaldehyde HCHO itself, and α-chloromethyl chloroformate
CH ₂ ClOCOCl cannot be produced.

In the case of chloromethyl chloroformate, it is known that it can be obtained by chlorination of methyl chloroformate or methyl formate. Chemical Review volume 64, page 646 (1964)
MATZNER et al. cite several known methods, but these are delicate synthetic methods that produce numerous by-products that are difficult to separate from the desired product.

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

According to the present invention, phosgene, a tetraalkyl-substituted urea, a quaternary ammonium halide (however,
these substituents contain in total at least 16 carbon atoms) and halides of alkali and alkaline earth metal cations in association with sequestering agents and the reaction of said catalysts with phosgene. in the absence of water and hydrochloric acid in a reactor containing a selected member of the group of products -
A process for the preparation of chloromethyl chloroformate is provided, which consists in introducing gaseous formaldehyde in pre-dried monomeric form at a temperature of 10<0>C to +60<0>C. The reaction is carried out in the absence of water and hydrochloric acid at temperatures between -10°C and +60°C. According to a particular embodiment of the invention, the reaction of formaldehyde and phosgene in the presence of a catalyst is carried out in a solvent of toluene, methylene chloride, chloroform or carbon tetrachloride.

Preferred catalysts for use in the present invention are tributylbenzylammonium chloride, potassium chloride associated with a cryptate or crown ether capable of complexing the potassium cation, or phosgenated tetrabutyl urea.

The process according to the invention involves the reaction of dry gaseous formaldehyde in monomeric form with phosgene in a reactor in the presence of a catalyst and in the total absence of water and hydrochloric acid at temperatures between -10°C and 60°C. It consists of carrying out activities within the organization.

According to the invention, the formaldehyde must be completely dry and completely monomeric. That is, before starting the reaction, the formaldehyde needs to be dried, and generally formaldehyde cannot be stored in the monomeric state and is formed by the general formula (-
CH ₂ O) − _o (where n is an integer, generally 6 and
Since it is in the form of a linear polymer of between 100% and 100%, it is necessary to depolymerize it.

Formaldehyde is dried in a dryer in the presence of a good drying agent, such as phosphorus pentoxide. The formaldehyde drying operation can be carried out during or before depolymerization, but in any case must be carried out before introduction into the phosgenation reaction group. This drying operation is essential to the method according to the invention and must be complete.
In fact, trace amounts of water cause repolymerization of the monomeric formaldehyde, reducing the phosgenation yield since only the monomeric formaldehyde reacts with phosgene. Monomeric formaldehyde is obtained in known manner, for example by thermal depolymerization in the case of paraformaldehyde or by depolymerization in the presence of a catalyst in the case of tritoxane. Depolymerization may be carried out either during drying of formaldehyde or after drying of polymeric formaldehyde. The monomeric dry formaldehyde is then introduced into a completely dry reactor containing the catalyst and phosgene. Within the scope of the present invention, the term "catalyst" must be understood strictly. Although the compound added as a catalyst is essential to this reaction, it does not directly participate in the reaction and is therefore used in a relatively small amount relative to formaldehyde. It is therefore a true catalyst in this sense, but unlike what is commonly referred to as a catalyst, it cannot be reused in another reaction once the introduction of phosgene has stopped. A theoretical explanation for this phenomenon is not possible at this stage.

It is possible to find a common definition for a certain number of catalysts suitable for the present invention. These catalysts include formaldehyde, phosgene and, if used,
an organic or inorganic substance capable of generating a pair of ions in a medium containing a solvent, one of said pair of ions being a halide anion, and the other one being a halide anion, and one of said ions being an aldehyde functional group of formaldehyde. A cation that is sufficiently separated from the halide anion to have nucleophilic activity capable of reacting with the halide anion. Catalysts according to the invention and falling within the above definition include, among other things, the following substances themselves or their reaction products with phosgene: i.e., tetraalkyl substituted ureas, quaternary ammonium halides (provided that these substituents have a total of at least 16 and preferably each substituent has at least 4 carbon atoms), alkali and alkaline earth metals. A halide of the metal associated with a cationic sequestering agent. A preferred halide is chloride.

As mentioned above, some catalysts generate halide ions either directly or after reaction with phosgene. In this case, the general mechanism of the catalyst is probably as follows.

In the above formula, M ⁺ is a complexed or uncomplexed organic or inorganic cation present in the catalyst from the beginning or formed at the beginning of the reaction by the action of phosgene on the catalyst. Thus, M ⁺ can be a complexed metal cation or a fully organic cation of the onium type, for example as shown below.

M ⁺ may also be formed from a further reaction of phosgene with a substance capable of responding to the action of a catalyst, for example as shown in the reaction below.

(In the formula M ⁺ is a large chlorimonium cation.) It is noteworthy that the most interesting results were obtained using the following catalysts.

i.e., tetraalkyl substituted ureas such as, for example, tetrabutyl urea and tetramethyl urea; quaternary ammonium halides (containing at least 16 carbon atoms in total and preferably each substituent having at least 4 carbon atoms); , for example tributylbenzylammonium chloride: halides of alkali and alkaline earth metal cations associated with sequestering agents, especially crown ethers or cryptates (2,2,2), such as for example 18-crown-6. (i.e. 1, 10
-diaza-4,7,13,16,21,24-hexaoxabicyclo-[8,8,8]-hexacosane).

Naturally, in the latter case it is preferred to associate with sequestering agents which form complexes with high stability constants with metal chloride ions. This is the Bulletin de la Societe.
Chimique de France, 1974, No. 1-2, 89-
Kappenstein's research described on page 109 and
Structure and Bonding, vol. 16, pp. 2-64.
JM as described in Springer Verlag (1974)
This can be easily achieved based on the numerous studies done in this field, such as the work of LEHN. The term "halide or halide" means
Practically means chloride, bromide or iodide, with chloride being preferred since even the first molecule of formaldehyde converted by the action of the halide originating from the catalyst is converted to chloromethyl chloroformate. You get the idea.

The proportion of catalyst used is important, but not essential in the process according to the invention. In fact, if the catalyst is very effective, it can contain from 0.5 to 10 mol % (preferably 2
A catalyst ratio of ~7 mol %) is sufficient. On the other hand, certain catalysts according to the invention are less effective and therefore higher proportions of about 1 to 50 mole % (preferably 4 to 40 mole %) must be used.

The order of introduction of the reactants to the reactive group is important. into the reactor already containing the catalyst and phosgene so that formaldehyde reacts directly with phosgene without giving it time to repolymerize (the rate of reaction of formaldehyde with phosgene is faster than its polymerization rate under the operating conditions used). It is essential to introduce monomeric gaseous formaldehyde. In this way, the reactor will contain all the phosgene introduced into the reactor before the start of the reaction, or all the phosgene introduced at the same time as the formaldehyde is introduced into the bottom of the vessel containing the phosgene and catalyst. must include at least In contrast, in the present invention it is not possible to place formaldehyde and catalyst in a container and introduce phosgene into this container. because,
This is because in this case, formaldehyde polymerizes and the phosgenation reaction becomes virtually impossible.

The phosgenation reaction of the present invention is preferably carried out under stirring. The temperature of the reaction medium is preferably kept between -10°C and +30°C during the introduction of formaldehyde. Furthermore, it is more preferred to maintain the temperature of the reaction medium at about 0°C at the beginning of the formaldehyde introduction, and by the end of the formaldehyde introduction this temperature reaches about 20°C. reaction mixture 40
Preferably, the reaction is terminated by heating to a temperature between 60°C and 60°C.

The reaction mixture must also be completely free of trace amounts of water or hydrochloric acid, in order to completely avoid the risk of formaldehyde repolymerization. For this purpose, the reactor must be flushed with dry air or dry inert gas before the reaction.

Although not a preferred embodiment of the invention, the reaction can be carried out in the presence of a solvent. However, the use of solvents such as alcohols and amines, which react with phosgene to form hydrochloric acid, and solvents such as Kent and tetrahydrofuran, which decompose to form hydrochloric acid, must be avoided, and solvents such as ethers, which are difficult to dry, must be avoided. The use of solvents must also be avoided. If desired, solvents such as toluene or chlorinated aliphatic solvents such as methylene chloride, chloroform and carbon tetrachloride can be used. However, it is often advantageous if the reaction is carried out in the presence of a solvent, since the reaction temperature can be maintained at a temperature between 30° C. and 60° C. even during the introduction of formaldehyde.

Examples are given below to illustrate the use of the process according to the invention.

Example 1 The equipment used was a dry ice cooler, a thermometer,
It is a 100 ml glass reactor equipped with a stirrer and an inlet for gas introduction. The reactor was flushed with dry nitrogen. 0.38 moles (38 g) of phosgene containing 3.3 g (0.0106 moles) of completely dry benzyltributylammonium chloride were introduced into the reactor.

18 g (0.6 mol) of paraformaldehyde and phosphorus pentoxide were added through a gas inlet tube immersed in phosgene while maintaining the temperature of the mixture at approximately 0°C.
Formaldehyde was introduced from a bottle containing 10 g of P ₂ O ₅ . The bottle was flushed with dry nitrogen and heated to 150°C. Addition of formaldehyde was carried out for 30 minutes until complete disappearance of poraformaldehyde, and the reaction mixture was allowed to reach 20° C. and stirring was continued at this temperature for 1 hour. Residual phosgene was removed by degassing and the resulting chloromethyl chloroformate was purified first by evaporation under vacuum and then by distillation at atmospheric pressure. The boiling point was 106°C. The weight of the completely dried product obtained was 20.7 g, which was a yield of 42% based on the phosgene used. In the RMN Spectro analysis, chloromethyl chloroformate was characterized by a single line at 5.5 ppm.

Example 2 Using phosgenated tetra-n-butyl urea as a catalyst, 10 g of phosgene, 10 g of paraformaldehyde
and 5 g of P ₂ O ₂ as in Example 1 above. This catalyst was prepared by phosgenating 1.5 g of tetra-n-butyl urea at 50 DEG C. according to the following reaction formula.

The reaction temperature was determined after the introduction of formaldehyde.
The temperature rose to 50℃ in one hour.

Chloromethyl chloroformate was obtained with a yield of 9.15% based on the phosgene used. The yield was determined by RMN measurement using toluene as an internal standard.

Example 3 This process was carried out using 20 g of phosgene, 15 g of paraformaldehyde and 10 g of P ₂ O ₅ and 1.3 g of potassium chloride associated with 0.4 g of cryptate (2,2,2) as the catalyst described in Example 2 above.
It was carried out according to the method of Chloromethyl chloroformate was obtained in a yield of 63% based on the phosgene used.

Example 4 The same equipment as described in Example 1 above was used. The reactor was flushed with dry nitrogen. Already 20 g of phosgene containing 1.3 g of potassium chloride associated with 0.4 g of cryptate (2,2,2) were introduced into the reactor.

Formaldehyde from a bottle containing 15 g of paraformaldehyde and heated to 150° C. was introduced through a bubble tube immersed in the phosgene while maintaining the temperature of the mixture at approximately 0° C. The bottle was previously flushed with dry nitrogen and the paraformaldehyde was dried over P ₂ O ₅ under a vacuum of 0.1 mmHg in a dryer before being charged into the depolymerization bottle. The introduction of formaldehyde was carried out over a period of 30 minutes, and the reaction mixture was then heated to 50° C. for 1 hour to complete the reaction. Chloromethyl chloroformate was thus obtained in a yield of 73% based on the phosgene used.

Example 5 The same equipment used in Example 1 was used. The reactor was flushed with dry nitrogen. To this reactor were introduced 40 ml of anhydrous carbon tetrachloride as solvent, 12 g of phosgene, and as catalyst phosgenated tetra-n-butyl urea prepared as described in Example 2 from 1.5 g of tetra-n-butyl urea.

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

In this way, chloromethyl chloroformate was obtained with a yield of 65% based on the formaldehyde used.

Example 6 This process uses 20 g of phosgene, 20 g of paraformaldehyde and 12 g of P ₂ O ₅ using phosgenated tetramethylurea as a catalyst.
It was carried out as described in Example 2. This catalyst converts 1.16g of tetramethylurea into 50%
Prepared by phosgenation at °C.

Chloromethyl chloroformate was obtained in a yield of 72% based on the phosgene used.

Example 7 This process uses 1.6g of tetra(n) as catalyst.
- butyl) urea, 10 g of phosgene and 10 g
of paraformaldehyde and 5 g of P ₂ O ₅ as in Example 1.

Addition of formaldehyde was carried out for 45 minutes. Then, after the formaldehyde introduction was completed, the reaction temperature was raised to 50° C. over 1 hour.

Chloromethyl chloroformate was obtained in a yield of 48% based on the phosgene used.

Example 8 This Porcess uses the same amount of compound, but instead of tetra(n-butyl)urea as catalyst.
It was carried out as described in Example 7 using 0.6 g of tetramethylurea.

Chloromethyl chloroformate was obtained in a yield of 35% based on the phosgene used.

Claims (1)

[Scope of Claims] 1. Phosgene, a tetraalkyl-substituted urea, 4.
a catalyst selected from class ammonium halides with the proviso that these substituents contain a total of at least 16 carbon atoms; and halides of alkali and alkaline earth metal cations in association with sequestering agents; In the absence of water and hydrochloric acid, in the absence of water and hydrochloric acid, the gaseous pre-dried monomeric state is introduced into a reactor containing a catalyst and a member selected from the group of reaction products of phosgene. A process for the preparation of chloromethyl chloroformate consisting of introducing formaldehyde. 2. The catalyst is a tetraalkyl-substituted urea, a quaternary ammonium halide (each of these substituents containing at least 4 carbon atoms), a halogen of said metal in association with a sequestering agent of alkali and alkaline earth metal cations. 2. A method according to claim 1, wherein the catalyst is a selected member of the group of phosgene and a reaction product of said catalyst with phosgene. 3. The catalyst is tetrabutylurea, tetramethylurea, tributylbenzylammonium chloride, potassium chloride associated with ether-18-crown-6, and 1,10 diaza-4,7,13,16,
21,24-hexakiosabicyclo-[8,8,8]-
3. A method according to claim 2, which is a selected member of the group of potassium chlorides associated with hexacosane. 4. Claim 1, wherein the desiccant used to dry formaldehyde is phosphorus pentoxide;
The method according to paragraph 2 or 3. 5. Adjust the reaction temperature to -10 during the introduction of formaldehyde.
The method according to claim 1, wherein the method is maintained between 0.degree. C. and +30.degree. 6. A process according to claim 5, wherein the temperature of the reaction mixture is maintained at about 0°C at the beginning of the introduction of formaldehyde and about 20°C at the end of the introduction of formaldehyde. 7. A process according to claim 6, in which the temperature of the reaction mixture is between 40°C and 60°C after formaldehyde is introduced into the reactor. 8. The method according to claim 1, wherein the reaction is carried out in a solvent. 9. The method of claim 8, wherein said solvent is a member selected from the group of toluene, methylene chloride, chloroform and carbon tetrachloride. 10. A process according to claim 8 or 9, wherein the reaction is carried out at a temperature between 30°C and 60°C.