Europâisches Patentamt è European Patent Office @ Publication number: 0 092 998 B1 Office européen des brevets EUROPEAN PATENT SPECIFICATION © Date of publication of the patent spécification : © mt. ci.*: C 07 C 41/16, C 07 C 43/10, 12.03.86 C 07 D 307/12, C 07 D 493/04 @ Application number: 83302312.0 @ Date of f iling : 22.04.83 H> Etherification process for hexitols and anhydrohexitols. © Priority: 28.04.82 US 372623 Proprietor: ICI AMERICAS INC, Concord Pike & New Murphy Road, Wilmington Delaware 19897 (US) Date of publication of application: 02.11.83 Bulletin 83/44 Inventor: Kruse, Walter Max, 1 Woodbury Court, Wilmington Delaware 19805 (US) Inventor: Stephen, John Fergus, 200 William Penn Blvd., Publication of the grant of the patent : West Chester, PA 19380 (US) 12.03.86 Bulletin 86/11 (74) Représentative: Colens, Alain M. G. M. et al, Impérial @ Designated Contracting States: Chemical Industries PLC Légal Department: Patents AT BE CH DE FR GB IT Ll LU NL SE P.O. Box 6 Bessemer Road, Welwyn Garden City Hertfordshire AL7 1 HD (GB) (§§) Références cited: AT- B- 258 870 DE-A-3038 996 DE -C -510423 GB -A- 988 123 ^ US-A-3840605 10 00 O) 0) CI o © Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be f iled in a written reasoned A statement. It shall not be deemed to have been filed until the opposition fee has been paid (Art. 99(1) European patent JJj convention). ACTORUM AG polyol, water and alkali in excess and thereafter ad- ding all at once an alkyl halide dissolved in an organic This invention is related to an improved high solvent along with a phase transfer agent. The reac- yield/low pressure process for polyetherification of tion is carried out by agitating the entire mixture until hexitol C6H8(OH)6; hexitan C6H$(OH)4 and hexide the reaction is complete. This process however re- CεHε(OH)z by the reaction of monoalkali metal quires the formation of polyalkali metal alkoxide. It alkoxides of these compounds with low molecular has now been found that the latter feature may be weight alkyl halides in aqueous solutions dispersed in detrimental for the polyalkoxylation of hexitols. organic solvents. It includes conducting the reaction It is an object therefore of the present invention to in a mixture with organic solvents and phase transfer provide for a high yield process for the polyalkylation catalysts. of hexitols and inner ethers of hexitols such as hexi- In general the method of the invention can be con- tans and hexides or isohexides to form polyalkyl sidered an improved process for conducting the inter- ethers by displacing the hydrogen on the hydroxyl action of alkaline metal alkoxide with an alkyl halide groups of these materials with alkyl groups having which is traditionally referred to as the Williamson from 1-4 carbon atoms by (a) forming an aqueous so- ether synthesis. Completely etherified anhydro- lution of the hexitol dispersed in organic solvent (b) hexitol derivatives have been described in U.S. forming a monoalkali metal alkoxide by the addition 2 234 200 and 2 420 519. The earlier patent of substantially stoicheometric amounts of sodium describes a technique for carrying out the synthesis or potassium alkali, (c) forming a monoalkyl ether by in liquid ammonia while the latter case is directed to the addition of an alkylmonohalide having 1-4 carbon the treatment of alkali solutions of sorbide (isosor- atoms to the solution, (d) completing the polyalkyla- bide) (dianhydro-sorbitol) with dimethyl sulfate. In tion by adding more alkylmonohalide with the addi- traditional commercial procedures the polyhydroxy tion of substantially stoicheometric amounts of derivatives have been treated with excess sodium hydroxide such that no more than a monoalkali metal hydroxide and thereafter reacted with alkyl chloride at alkoxide derivative is present in the solution, and (e) temperatures of 120°C and at pressures above 5,170 separating the polyalkyl ether from the reaction mix- mm Hg (100 pounds per square inch). Such high tem- ture. It is a further object to provide for a process perature reactions require special equipment, involve wherein steps (a) thru (d) is carried out in the a sizeable amount of decomposition, form products presence of a reaction promoter such as a phase which are off color and offer poor yields because of transfer catalyst. Another object includes a process incomplete alkylation and the difficulty of separating for performing steps (a) thru (c) sequentially. pure products from the reaction mixture. The process of the invention is particularly useful The present invention is directed to the stepwise in preparing fully methylated, ethylated, propylated alkylation of hexitol and anhydrohexitol derivatives in and butylated polyethers of hexitols such as sorbitol aqueous media dispersed in organic solvent. The and mannitol. In particular it is useful in preparing description of an anhydrous procedure for conduct- hexamethyl hexitols and dimethylisosorbide. The an- ing the Williamson ether synthesis in dimethylsulf- hydrohexitols are inner ethers resulting from splitting oxide has. been described by Smith, Vanderpool and off one or two moles of water from hexitol, a six car- Culak, Canadian J. Chem., 47, 1969, pages bon straight chain hexahydric alcohol. The removal of 2015-2019. When their anhydrous technique is car- one molecule of water results in the formation of a ried out in the presence of a slight excess of solid so- hexitan such as sorbitan or mannitan which are use- dium hydroxide, a large amount of dimethylsulfoxide ful starting materials in the preparations of the and applied to hexitols and hexitol anhydrides, the tetralkyl ether of sorbitan and mannitan such as reaction is very slow and does not go to completion. tetramethyl and tetraethyl sorbitan. The tetramethyl An anhydrous synthesis of aliphatic ethers in dime- sorbitan has specific solvent. properties and can be thylsulfoxide employing potassium hydroxide and used as a solvent in the preparation of certain phar- alkyl bromide or sulfate is described by Benedict, Bi- maceutical bases. The removal of two molecules of anchi, and Cate in Synthesis, June 1979, page 428 water from a hexitol results in the formation of a and 429. Alkylation of primary alcohols has been hexide or iso-hexide which are dinnerethers such as demonstrated using potassium hydroxide powder sorbide or isosorbide, mannide or isomannide. In par- and alkyl bromides and iodides in anhydrous ticularthe process can be applied to the manufacture dimethylsulfoxide at room temperature by Johnstone of dimethyl, diethyl, dipropyl, diisopropyl, diisobutyl, and Rose in Tetrahedron, 35, (1979), pages 2169- dibutyl, isosorbide. Such derivatives are particu- 2172. Reactions conducted with bromides and io- larly useful as solvents with special attention drawn dides are too expensive for commercial synthesis. to dimethyl isosorbide which has application in A recently issued patent U.S. 4 322 359 is direct- the preparation of pharmaceutical ointment and gels. ed to adding an excess of dimethyl sulfate to inner Less common hexitol isomers such as dulcitol, ethers of sorbitol in organic solvent at low tempera- iditol, talitol and their inner ethers can be used as ture. Another process for alkylating primary alcohols starting materials in proportions similar to those in organic solvent using a phase transfer catalyst em- described for sorbitol and mannitol and their cor- ploying excess aqueous alkali, alkyl chloride in organ- responding anhydro and dianhydro inner ethers to ic solvent is described by Freedman and Dubois. provide polyalkylated derivatives. Tetrahedron Letters No. 38, pp. 3251-3254 (1975). As alkylating agent may be employed a monoalkyl German patent application 3 038 996 directed to a chloride selected from methyl, ethyl, propyl, iso- process which requires first forming a mixture of propyl, butyl, and isobutyl chloride. The equivalent bromide and iodide may also be used if economical. ratio of dimethylsulfoxide to isosorbide in the starting The term alkyl halide refers to these compounds. mixture ranges from 0.2-1. A most preferred ratio is Polar aprotic solvents such as dimethyl formamide, 0.4-0.8. dimethylacetamide, and dimethylsuloxide may be When the reaction is run in a dispersion of an aro- used as dispersing agent for carrying out the reaction matic solvent such as toluene it is advantageous to provided that the water concentration does not ex- employ a phase transfer catalyst. The use of phase ceed about 50%. transfer catalyst in promoting the Williamson synthe- For example, dimethyl sulfoxide (CH3)2S0 (DMSO) sis is known for hydrophilic alcohols at a temperature is available commerically and may be used as the sol- below 60°C. Such catalytic materials include quar- vent when aqueous alkali is added thereto or as an ternary ammonium and phosphonium salts, tertiary aqueous mixture when the mol ratio of water to amines which are transformed into quarternary am- dimethyl sulfoxide does not exceed 10/1. monium salts during the reaction, strongly basic Sodium hydroxide or potassium hydroxide may be quarternary ammonium polystyrene type ion ex- added as alkali in aqueous solution, dry powder or change resins, and polyethylene glycols or their granules. In place of the hydroxide may be used the mono and dialkyl ethers. When the reaction is carried equivalent carbonates with somewhat lower activity. out at temperatures below 85°, quarternary ammoni- In the practice of this invention it is preferred to use um salts such as tetrabutyl ammonium sulfate, tri- a concentrated aqueous solution of potassium or so- butylhexadecyl phosphonium bromide, tetraethyl dium hydroxide and most preferred is a 50% aqueous ammonium bromide, methyltrioctyl ammonium chlo- solution thereof.