(12) Patent Application Publication (10) Pub. No.: US 2002/0082444 A1 Bonnard Et Al
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US 20020082444A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0082444 A1 Bonnard et al. (43) Pub. Date: Jun. 27, 2002 (54) PROCESS FOR THE SYNTHESIS OF (30) Foreign Application Priority Data ALIPHATIC, CYCLOALIPHATIC OR ARALPHATIC CHLOROFORMATES Dec. 22, 2000 (FR)............................................ OO 1688O Publication Classification (76) Inventors: Hubert Bonnard, La Ferte Alais (FR); Laurence Ferruccio, Vert Le Grand (51) Int. Cl." ..................................................... C07C 68/02 (FR); Patricia Gauthier, La Ferte Alais (52) U.S. Cl. .............................................................. 560/226 (FR); Jean-Pierre Senet, Chapelle La Reine (FR) (57) ABSTRACT The invention relates to a process for the Synthesis of Correspondence Address: Substituted or unsubstituted aliphatic, cycloaliphatic or BUCKNAMAND ARCHER araliphatic chloroformates by reaction of the corresponding Joseph J. Orlando alcohol with phosgene, diphosgene and/or triphosgene. The 600 Old Country Road reaction is carried out under a pressure of less than or equal Garden City, NY 11530 (US) to 95x10 Pa, i.e. 950 mbar, and at a temperature of be tween -30° C. and +50° C. (21) Appl. No.: 10/022,963 This process is particularly well Suited to the preparation of (22) Filed: Dec. 18, 2001 menthyl chloroformate and benzyl chloroformate. US 2002/0082444 A1 Jun. 27, 2002 PROCESS FOR THE SYNTHESIS OF ALIPHATIC, 0012 A person skilled in the art is therefore constantly on CYCLOALPHATIC OR ARALIPHATIC the lookout for an inexpensive process for the Synthesis of CHLOROFORMATES aliphatic, cycloaliphatic or araliphatic chloroformates which has rapid kinetics and a high yield and which gives products 0001. The present invention relates to a process for the of Very high purity. Synthesis of Substituted or unsubstituted aliphatic, cycloaliphatic or araliphatic chloro-formates. 0013 Such a process is a subject-matter of the present 0002. It relates more particularly to a process for the invention. improved synthesis of these chloroformates by phosgenation 0014. The invention relates to a process for the synthesis of the corresponding alcohols. of Substituted or unsubstituted aliphatic, cycloaliphatic or araliphatic chloroformates by reaction of the corresponding 0.003 Chloroformates are synthetic intermediates which alcohol with phosgene, diphosgene and/or triphosgene, are very useful in the pharmaceutical, cosmetic and food characterized in that the reaction is carried out under a industries. pressure of less than or equal to 95x10 Pa, i.e. under a 0004 Mention will in particular be made of benzyl pressure of less than or equal to 950 mbar. chloroformate, one of the Starting materials in the Synthesis of Z-aspartic acid, which compound is used in the manu 0015 This process exhibits the advantage of being simple facture of aspartame. and inexpensive. The chloroformates are rapidly obtained with a very high yield, generally of greater than 97%, and 0005 Another very important chloroformate is menthyl have good purity, generally of the order of 97%, indeed even chloroformate, a compound used for its menthol taste. It is 99%. Very little in the way of by-products is obtained. This encountered as Synthetic intermediate in the tobacco indus result is all the more Surprising Since vacuum is commonly try and in the pharmaceutical industry. used to remove phosgene from the reaction medium. Degas sing during the reaction should therefore result in a shortfall 0006 Processes for the synthesis of chloroformates from in phosgene. It is known that, in this case, the alcohol reacts phosgene and the corresponding alcohol are already known with the chloroformate already formed to give a carbonate. to a perSon Skilled in the art. The problem encountered Furthermore, as the reaction rate is a function of the con during Such Syntheses is the production of hydrochloric acid, centration of phosgene, the kinetics should have become which leads to the formation of by-products. slower. 0007 A first solution to this problem is to add a base, Such as a tertiary amine, to the reaction medium. A Synthesis 0016. This process makes it possible to obtain Substituted of menthyl chloroformate is thus described in a paper in the or unsubstituted aliphatic, cycloaliphatic or araliphatic chlo Journal of Organic Chemistry of 1993 (Vol. 58, No. 8, roformates which can be prepared by phosgenation of the 2186-2195): The reaction of menthol and of phosgene is corresponding alcohols. In particular, it makes it possible to carried out in toluene, in the presence of quinoline. obtain C to Coaliphatic, C to Co cycloaliphatic or C7 to Coaraliphatic chloroformates which are Saturated or unsat 0008 Another paper in the Journal of Organic Chemistry urated and Substituted or unsubstituted, the Substituents of 1998 (Vol. 63, 3235-3250) describes a synthesis of being groups which are unreactive with respect to phosgene menthyl chloroformate from phosgene and menthol also and to hydrochloric acid. This process is particularly well involving a base, pyridine. The disadvantages related to Such Suited to the preparation of Secondary or tertiary aliphatic or Syntheses are not only the additional cost, due to the use of cycloaliphatic chloroformates and of araliphatic chlorofor a base, but also the need to remove the amine hydrochloride mates. In a particularly preferred way, this proceSS makes it formed, in particular by direct filtration or by Washing the possible to obtain menthyl chloroformate and benzyl chlo organic phase with water. This results in a longer and more roformate. expensive process. 0017. The reaction is carried out at a temperature of 0009. Other synthetic routes not involving a base have between -30° C. and +50° C. and preferably between -10° also been provided. Thus, U.S. Pat. No. 3 419543 discloses C. and +20 C. a base-free proceSS for the Synthesis of menthyl chlorofor mate from phosgene and a Solution of menthol in cyclopen 0018. According to a preferred alternative form of the tane. In the reaction thus described, the constituents are invention, the reaction is carried out under a pressure of introduced at -75 C. This very low temperature is a between 5x10 Pa and 95x10 Pa, i.e. between 50 mbar and disadvantage as it is difficult to obtain industrially, requiring 950 mbar, and better still under a pressure of between Specific and very expensive equipment. 15x10 Pa and 8.5x10 Pa, i.e. between 150 mbar and 850 mbar. 0.010 Another synthetic route was then proposed, at a higher temperature and not involving a base either. A paper 0019. In a particularly preferred way, the reaction is which appeared in Volume 54 of Tetrahedron in 1998 carried out under a pressure of between 35x10 Pa and (Tetrahedron, 54 (1998), 10537-10534) discloses such a 75x10 Pa, i.e. between 350 mbar and 750 mbar. Synthesis: phosgene reacts at -10° C. with menthol in 0020 Phosgene, diphosgene and/or triphosgene can be toluene. Menthyl chloroformate is obtained with a yield of used. Preferably, phosgene is used. The amount of phosgene, only 82%. diphosgene and/or triphosgene introduced is generally Such 0.011 Furthermore, these processes, at atmospheric pres that there is between 1 and 10 molar equivalents of phosgene Sure and without a base, exhibit very slow reaction kinetics, with respect to the alcohol and preferably between 1.5 and which is a disadvantage industrially. 2.5 molar equivalents. US 2002/0082444 A1 Jun. 27, 2002 0021 AS diphosgene and triphosgene respectively gen charcoal and connected to the assembled apparatus thus erate 2 and 3 mol of phosgene, the amount used will be formed, are used to trap the phosgene and the hydrochloric between, respectively, 0.5 and 5 mol, preferably between acid given off during the reaction. 0.75 and 1.25 mol, for diphosgene and between 0.3 and 3.3 0034) 14.9 g of toluene and 50.4 g of (L)-menthol, i.e. mol, preferably between 0.5 and 0.8 mol, for triphosgene. 0.322 mol of menthol, are introduced into the reactor. The 0022. The reaction can be carried out with or without medium is cooled to approximately -3° C.-0° C. 65 g of Solvent. One of the compounds of the reaction, the chloro phosgene, i.e. 0.650 mol, are then gradually introduced formate or the phosgene, can be used as Solvent. The under a pressure of 500 mbar. The amount of phosgene is reaction is preferably carried out in the presence of an inert thus 2 molar equivalents with respect to the menthol. Solvent chosen from the group consisting of chlorinated or 0035. After introducing all the phosgene, the reaction nonchlorinated aliphatic hydrocarbons, chlorinated or non medium is gradually reheated. This operation is carried out chlorinated aromatic hydrocarbons, esters and ethers. under a pressure of 500 mbar. The temperature changes from 0023 Mention may be made, as aliphatic hydrocarbons, -3°C. to +7° C. over 4 hours and then from 7 to 19°C. over of methylene chloride, chloroform, heptane or pentane. 50 minutes and, finally, the temperature is maintained at 19 0024 Mention may be made, as aromatic hydrocarbons, C. for 20 minutes. The product obtained is subsequently of toluene or Xylene. Use may also be made of esters, Such degassed at this temperature. as, for example, ethyl acetate or isopropyl acetate but also of 0.036 70 g of (L)-menthyl chloroformate, i.e. 0.320 mol, methyl carbonate. are obtained, which corresponds to a yield of 99%. 0.025 Ethers can also be used as inert Solvent; they are, 0037. The product obtained is analysed by gas chroma inter alia, ethyl and diisopropyl ethers. tography. The purity of the chloroformate is 99%, and less 0026. This process is particularly well Suited to the than 0.5% by weight of menthol and 250 ppm of menthyl preparation of menthyl chloroformate and benzyl chlorofor chloride are found.