Organic compounds -- part of the class 532-570 series – Organic compounds – Halocarbonate esters
Reexamination Certificate
2001-12-18
2004-02-24
Richter, Johann (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Halocarbonate esters
C558S282000
Reexamination Certificate
active
06696590
ABSTRACT:
The present invention relates to a process for the synthesis of substituted or unsubstituted aliphatic, cycloaliphatic or araliphatic chloroformates.
It relates more particularly to a process for the improved synthesis of these chloroformates by phosgenation of the corresponding alcohols.
Chloroformates are synthetic intermediates which are very useful in the pharmaceutical, cosmetic and food industries.
Mention will in particular be made of benzyl chloroformate, one of the starting materials in the synthesis of Z-aspartic acid, which compound is used in the manufacture of aspartame.
Another very important chloroformate is menthyl chloroformate, a compound used for its menthol taste. It is encountered as synthetic intermediate in the tobacco industry and in the pharmaceutical industry.
Processes for the synthesis of chloroformates from phosgene and the corresponding alcohol are already known to a person skilled in the art. The problem encountered during such syntheses is the production of hydrochloric acid, which leads to the formation of by-products.
A first solution to this problem is to add a base, such as a tertiary amine, to the reaction medium. A synthesis of menthyl chloroformate is thus described in a paper in the Journal of Organic Chemistry of 1993 (Vol. 58, No. 8, 2186-2195): The reaction of menthol and of phosgene is carried out in toluene, in the presence of quinoline.
Another paper in the Journal of Organic Chemistry of 1998 (Vol. 63, 3235-3250) describes a synthesis of menthyl chloroformate from phosgene and menthol also involving a base, pyridine. The disadvantages related to such syntheses are not only the additional cost, due to the use of a base, but also the need to remove the amine hydrochloride formed, in particular by direct filtration or by washing the organic phase with water. This results in a longer and more expensive process.
Other synthetic routes not involving a base have also been provided. Thus, U.S. Pat. No. 3,419,543 discloses a base-free process for the synthesis of menthyl chloroformate from phosgene and a solution of menthol in cyclopentane. In the reaction thus described, the constituents are introduced at −75° C. This very low temperature is a disadvantage as it is difficult to obtain industrially, requiring specific and very expensive equipment.
Another synthetic route was then proposed, at a higher temperature and not involving a base either. A paper which appeared in Volume 54 of Tetrahedron in 1998 (Tetrahedron, 54 (1998), 10537-10534) discloses such a synthesis: phosgene reacts at −10° C. with menthol in toluene. Menthyl chloroformate is obtained with a yield of only 82%.
Furthermore, these processes, at atmospheric pressure and without a base, exhibit very slow reaction kinetics, which is a disadvantage industrially.
A person skilled in the art is therefore constantly on the lookout for an inexpensive process for the synthesis of aliphatic, cycloaliphatic or araliphatic chloroformates which has rapid kinetics and a high yield and which gives products of very high purity.
Such a process is a subject-matter of the present invention.
The invention relates to a process for the synthesis of substituted or unsubstituted aliphatic, cycloaliphatic or araliphatic chloroformates by reaction of the corresponding alcohol with phosgene, diphosgene and/or triphosgene, characterized in that the reaction is carried out under a pressure of less than or equal to 95×10
3
Pa, i.e. under a pressure of less than or equal to 950 mbar.
This process exhibits the advantage of being simple and inexpensive. The chloroformates are rapidly obtained with a very high yield, generally of greater than 97%, and have good purity, generally of the order of 97%, indeed even 99%. Very little in the way of by-products is obtained. This result is all the more surprising since vacuum is commonly used to remove phosgene from the reaction medium. Degassing during the reaction should therefore result in a shortfall in phosgene. It is known that, in this case, the alcohol reacts with the chloroformate already formed to give a carbonate. Furthermore, as the reaction rate is a function of the concentration of phosgene, the kinetics should have become slower.
This process makes it possible to obtain substituted or unsubstituted aliphatic, cycloaliphatic or araliphatic chloroformates which can be prepared by phosgenation of the corresponding alcohols. In particular, it makes it possible to obtain C
1
to C
20
aliphatic, C
4
to C
20
cycloaliphatic or C
7
to C
20
araliphatic chloroformates which are saturated or unsaturated and substituted or unsubstituted, the substituents being groups which are unreactive with respect to phosgene and to hydrochloric acid. This process is particularly well suited to the preparation of secondary or tertiary aliphatic or cycloaliphatic chloroformates and of araliphatic chloroformates. In a particularly preferred way, this process makes it possible to obtain menthyl chloroformate and benzyl chloroformate.
The reaction is carried out at a temperature of between −30° C. and +50° C. and preferably between −10° C. and +20° C.
According to a preferred alternative form of the invention, the reaction is carried out under a pressure of between 5×10
3
Pa and 95×10
3
Pa, i.e. between 50 mbar and 950 mbar, and better still under a pressure of between 15×10
3
Pa and 85×10
3
Pa, i.e. between 150 mbar and 850 mbar.
In a particularly preferred way, the reaction is carried out under a pressure of between 35×10
3
Pa and 75×10
3
Pa, i.e. between 350 mbar and 750 mbar.
Phosgene, diphosgene and/or triphosgene can be used. Preferably, phosgene is used. The amount of phosgene, diphosgene and/or triphosgene introduced is generally such that there is between 1 and 10 molar equivalents of phosgene with respect to the alcohol and preferably between 1.5 and 2.5 molar equivalents.
As diphosgene and triphosgene respectively generate 2 and 3 mol of phosgene, the amount used will be between, respectively, 0.5 and 5 mol, preferably between 0.75 and 1.25 mol, for diphosgene and between 0.3 and 3.3 mol, preferably between 0.5 and 0.8 mol, for triphosgene.
The reaction can be carried out with or without solvent. One of the compounds of the reaction, the chloroformate or the phosgene, can be used as solvent. The reaction is preferably carried out in the presence of an inert solvent chosen from the group consisting of chlorinated or nonchlorinated aliphatic hydrocarbons, chlorinated or nonchlorinated aromatic hydrocarbons, esters and ethers.
Mention may be made, as aliphatic hydrocarbons, of methylene chloride, chloroform, heptane or pentane.
Mention may be made, as aromatic hydrocarbons, of toluene or xylene. Use may also be made of esters, such as, for example, ethyl acetate or isopropyl acetate but also of methyl carbonate.
Ethers can also be used as inert solvent; they are, inter alia, ethyl and diisopropyl ethers.
This process is particularly well suited to the preparation of menthyl chloroformate and benzyl chloroformate, obtained respectively by reaction of menthol and benzyl alcohol with phosgene.
The phosgene is introduced into the reactor preferably at a temperature of less than 8° C. and under a pressure of between 35×10
3
Pa and 75×10
3
Pa, i.e. between 350 mbar and 750 mbar.
When all the phosgene has been introduced, the reactants are left in contact, preferably for a period of time of between 2 and 8 hours, at a temperature preferably of between −10° C. and 20° C.
Menthyl chloroformate of very high purity, of the order of 99%, and with a yield of greater than 97% is obtained. Less than 0.5% by weight of menthol and only traces of menthyl chloride and of bismenthyl carbonate are found in it.
Benzyl chloroformate is also obtained with good purity of greater than 97%. Thus, benzyl chloride is only present therein in a proportion of 0.5% by weight or less and dibenzyl carbonate is only present therein in an amount of less than 0.3% by weight.
The low level of these impuri
Bonnard Hubert
Ferruccio Laurence
Gauthier Patricia
Senet Jean-Pierre
Buckname & Archer
Richter Johann
SNPE
Zucker Paul A.
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