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. Bismenthyl carbonate is not detected. mate, obtained respectively by reaction of menthol and benzyl alcohol with phosgene. EXAMPLE 2 0027. The phosgene is introduced into the reactor pref Synthesis of Menthyl Chloroformate Under 500 erably at a temperature of less than 8 C. and under a mbar and at a Temperature of Between 8 C. and pressure of between 35x10 Pa and 75x10 Pa, i.e. between 19° C. 350 mbar and 750 mbar. 0038. The assembled apparatus used is the same as that in 0028. When all the phosgene has been introduced, the Example 1. reactants are left in contact, preferably for a period of time 0039) 93.4 g of toluene and 315.8g of menthol, i.e. 2 mol, of between 2 and 8 hours, at a temperature preferably of are introduced into the reactor. 308 g of phosgene, i.e. 3.1 between -10° C. and 20° C. mol, i.e. 1.55 molar equivalents with respect to the menthol, 0029 Menthyl chloroformate of very high purity, of the are gradually added under a pressure of 500 mbar and at a order of 99%, and with a yield of greater than 97% is temperature of between 8 C. and 15 C. obtained. Less than 0.5% by weight of menthol and only 0040. At the end of the introduction, the reaction is traces of menthyl chloride and of bismenthyl carbonate are continued for a further 6.5 hours at a temperature of between found in it. 12 C. and 19 C. and under a pressure of 500 mbar. 0030 Benzyl chloroformate is also obtained with good purity of greater than 97%. Thus, benzyl chloride is only 0041. 435 g of menthyl chloroformate, i.e. 1.99 mol, are present therein in a proportion of 0.5% by weight or less and obtained, which corresponds to a yield of 99%. dibenzyl carbonate is only present therein in an amount of 0042. The product obtained is analysed by gas chroma less than 0.3% by weight. tography. The purity of the chloroformate is 99.7%, and less 0031. The low level of these impurities, and in particular than 0.3% of menthol and less than 150 ppm of menthyl of benzyl chloride, is highly advantageous. This is because chloride are found. Bismenthyl carbonate is not detected. benzyl chloride is a highly reactive compound and is con EXAMPLE 3 Sequently a nuisance in Some applications of benzyl chlo roformate and in particular in Syntheses of amino acids. Synthesis of Benzyl Chloroformate Under 500 0.032 The following examples illustrate, without implied mbar. limitation, alternative embodiments of the invention. 0043. The assembled apparatus used is the same as that in Example 1. EXAMPLE 1. 0044) 217 g of alcohol, i.e. 1.99 mol, are introduced into Synthesis of Menthyl Chloroformate Under 500 the reactor. The medium is cooled to approximately 0° C. mbar and at a Temperature of Between -3 C. and 0045 250 g of phosgene, i.e. 2.52 mol, are then gradually 20° C. introduced under a pressure of 500 mbar and at a tempera 0033. The reaction is carried out in a 500 ml jacketed ture of between 0° C. and 6 C. The amount of phosgene reactor. This reactor is equipped with a reflux condenser used is 1.27 molar equivalents with respect to the alcohol. surmounted by a dry ice trap. Two columns, filled with 0046) The total duration of the reaction is 6.5 hours. US 2002/0082444 A1 Jun. 27, 2002

0047 275 g of benzyl chloroformate, i.e. 1.61 mol, are reaction is continued for a further period of just over 4 hours obtained, which corresponds to a yield of 81%. at a temperature of between -5 C. and +5 C. 0.048. The product obtained is analysed by gas chroma 0060 93.4 g of menthyl chloroformate, i.e. 0.427 mol, tography. The purity of the chloroformate is 98.4%. The final are obtained, which corresponds to a yield of 68%. The main product comprises 0.4% of benzyl alcohol, 0.51% of benzyl impurity present in this product is unreacted Starting men chloride and 0.26% of dibenzyl carbonate. thol; it is present in a proportion of 33% by weight. EXAMPLE 4 In the claims Synthesis of Benzyl Chloroformate Under 250 1. Process for the synthesis of substituted or unsubstituted mbar. aliphatic, cycloaliphatic or araliphatic chloroformates by 0049. The synthesis is carried out in the same way as in reaction of the corresponding alcohol with phosgene, Example 3. It is carried out under a pressure of 250 mbar. diphosgene and/or triphosgene, characterized in that the reaction is carried out under a pressure of less than or equal 0050. The amounts of reactants used are as follows: to 95x1OPa. 0051 223 g of benzyl alcohol, i.e. 2.06 mol, and 2. Process according to claim 1, characterized in that the reaction is carried out at a temperature of between -30° C. 0052) 275 g of phosgene, i.e. 2.77 mol. and +50 C. 0.053 At the end of the introduction of phosgene, the 3. Process according claim 1, characterized in that the reaction is continued for a further 2 hours. temperature is between -10° C. and +20 C. 4. Process according to claim 1, characterized in that the 0.054 263 g of benzyl chloroformate, i.e. 1.54 mol, are pressure is between 35x10 Pa and 75x10 Pa. obtained, which corresponds to a yield of 75%. 5. Process according to claim 1, characterized in that the 0.055 The product obtained is analysed by gas chroma reaction is carried out in the presence of an inert Solvent tography. The purity of the chloroformate is 97.1%. chosen from the group consisting of chlorinated or non 0056. The final product comprises 0.02% of benzyl alco chlorinated aliphatic hydrocarbons, chlorinated or non-chlo hol, 0.27% of benzyl chloride and 0.29% of dibenzyl car rinated aromatic hydrocarbons, esters and ethers. bonate. 6. Process according to claim 1, characterized in that phosgene is used. TESTATATMOSPHERIC PRESSURE 7. Process according to claim 1, characterized in that the amount of phosgene, diphosgene and/or triphosgene used is Synthesis of Menthyl Chloroformate. such that there is between 1 and 10 molar equivalents of 0057 This test does not form part of the invention; it was phosgene with respect to the alcohol. carried out for the purpose of showing that the fact of 8. Process according to claim 7, characterized in that the operating under reduced preSSure does not correspond to an amount of phosgene, diphosgene and/or triphosgene used is arbitrary choice but corresponds to a Selection necessary in such that there are between 1.5 and 2.5 molar equivalents of order to obtain the desired technical effect. phosgene with respect to the alcohol. 9. Process according to claim 1, characterized in that the 0.058 108 g of toluene and 100 g of menthol, i.e. 0.63 mol chloroformate obtained is a Secondary or tertiary aliphatic or of menthol, are introduced into the reactor. 89 g of phosgene, cycloaliphatic chloroformate. i.e. 0.9 mol, i.e. 1.4 molar equivalents with respect to the 10. ProceSS according to claim 1, characterized in that the menthol, are introduced into the reactor. chloroformate obtained is menthyl chloroformate. 0059. The phosgene is introduced at atmospheric pres sure and at a temperature of between -8 C. and +8°C. The