HU195227B - New process for preparing 1,6-dibromo-dideoxy-d-mannitol and 1,6-dibromo-dideoxy-dulcitol - Google Patents

Abstract

1,6-diibromo-di:desoxy -D-mannitol or 1,6-di:bromo-di:dezoxy -dulcitol is prepd. from D-mannitol or from Dulcitol. - These cpds. are subjected to the action of aq. Hydrogen-bromide in an enclosed space under 4-8 bar constant pressure ast 50-90 deg. C for 5-20 hours. The molar ratio of water to hydrogen bromate is kept constant below 2.5 by continuous addition of hydrogen-bromide from an external source. - The raw product is recrystallized without drying, from a water miscible solvent.

Description

The present invention relates to a novel process for the preparation of 1,6-dibromo-dideoxy-D-mannitol and 1,6-dibromo-dideoxy-dulcite.

1,6-dibromohexites, registered and marketed as antineoplastic drugs, namely 1,6-bromo-1,6-dideoxy-D-mannitol (Myelobromor, hereinafter "dibromo-mannitol") and 1,6-dibromo-1,6 ^: The preparation of dideoxydulcite (EloGromof, hereinafter referred to as dibromodulcite) is described in U.S. Patent Nos. 149,824, 152,594 and 160,131.

According to the aforementioned patents, dibromannanite (149,824) and dibromodulcite (152,594) are prepared by the action of D-mannitol or D-mannitol. dulcite is dissolved in "more than 47% aqueous hydrobromic acid"; slurry and saturate this mixture at atmospheric pressure with hydrogen bromide gas at temperatures below 0 ° C, preferably above 69-70%, followed by "closed reaction under pressure at 60 ° C to 80 ° C for 9 hours to 1 hour. / 2 hours, according to the examples, in an autoclave, preferably at 70 ° C for 4-5 hours. The crude product obtained is dried at 25-50 [deg.] C. and then dissolved in alcohols, acetone or dimethylformamide and optionally recrystallized from halogenated hydrocarbons, ethers, ketones or alcohols.

In the above patents, the production of the crude product consists of two distinct technological steps: in the first step, an aqueous solution or slurry of the corresponding hexite is saturated to 60-70% hydrobromic acid by any means obtained under vigorous cooling at temperatures below 0 ° C. preparing and maintaining an aqueous solution containing about 70% hydrogen bromide at atmospheric pressure; in the second stage, the 70% hydrobromic acid mixture maintained at about 0 ° C is autoclaved and heated to 70 ° C in an enclosed space. The hexite then reacts with the hydrobromic acid to form dibromo, monobromo, and anhydrohexites (e.g., 1-bromo-1-deoxydoluene, 1-bromo-1-deoxy-3,6-anhydrodulcite). ;

3,6-anhydrodulcit, Vidra I. et al., Carbohydrate Research, 111, 41-57 (1982). 1,4-3,6-Dianhydro-D-mannitol: Overand et al., J.Chem.Soc. 1948, 2001-2004).

During the study of this procedure, it was found that D-mannitol and / or D-mannitol were used under the given conditions. - reaction of dulcite with hydrobromic acid gives good yield of dibromannannite or dibromodulcite, if the molar ratio of water: hydrobromic acid in the reaction mixture is less than 2.5, i.e. when the concentration of hydrobromic acid is greater than 64%. In the case of lower concentrations of hydrogen bromide, the formation of monobromine and various anhydrohexites is predominant.

According to the process described in the said patents, high concentrations - for practical reasons - ca. 70% - The reaction should be started with hydrobromic acid and can be usefully continued until the hydrobromic acid used in the reaction and the water produced in parallel develops the concentration of hydrobromic acid gradually to approx. Reduces it to 64%. At this point, the formation of by-products (monobromo and anhydrohexites) predominates and the formation of the target product (dibromo mannitol or dulc t) stops.

Thus, as the reaction proceeds, the rate of formation of the target products decreases rapidly, and consequently the yields described in the cited patents are relatively modest: yields of crude products are 40% for dibromannitol and 70% for dibromodulcite.

Further study of the process has shown that the wet crude product obtained after processing the reaction mixture undergoes significant degradation during drying, while most of the product is converted to 1-bromo-3,6-anhydrohexite. As a result, the yields of recrystallizations described in those patents are only 70 and 70%, respectively. Of 75%.

The present invention is based on the discovery that reacting D-mannitol and dulcitol with aqueous hydrobromic acid in a closed space at a temperature of 50-90 ° C results in a good yield of 1,6-dibromo-1,6-dideoxy-D-mannitol and / or dulcitol. Dulcite, if the molar ratio of water to bromine hydrogen in the reaction mixture is kept constant throughout the reaction at less than 2.5. This is achieved by continuously supplying to the aqueous solution or suspension of D-mannitol or dulcite in an aqueous solution or suspension of hydrogen bromide from outside source at constant pressure of 4-8 bar until the reaction is complete. The thus obtained prickly wet product can be recrystallized without drying, thus eliminating the loss of decomposition. This is accomplished by dissolving the wet crude product in a water-miscible solvent, preferably dimethylformamide, dimethylsulfoxide, methyl alcohol, and recovering the product from the solution by crystallization with water.

According to the invention, D-mannitol and / or D-mannitol are used. dulcite is reacted with hydrobromic acid in an aqueous solution of hydrobromic acid at a pressure of 4-8 bar at a temperature of 50-90 ° C for 5-20 hours so that the molar ratio of water to hydrobromic acid in the reaction mixture is less than 2.5 with continuously fed external hydrogen bromide, is kept constant until the reaction is complete.

The above procedure has several advantages with respect to U.S. Patent No. 149,824. and U.S. Patent No. 152,593. against the procedures described in Hungarian patents.

By maintaining constant reaction parameters favorable to the formation of the target product, on the one hand, the formation of by-products can be eliminated, thereby improving the quality of the product and, on the other hand, significantly increasing the yield. The yield of crude dibromo-2195227 mannitol increased from 40% to 61% and the yield of dibromo-dulcite from 70% to 94%.

The recrystallization method of the present invention also increases the yield of the crystalline product by at least 15-20% relative to the yield of the crystalline product obtained by the known process.

And with a significant reduction in the amount of unutilized hydrobromic acid, the need for equipment and working time will be reduced.

The invention is illustrated by the following non-limiting examples.

EXAMPLES

1. Preparation of 1,6-dibromo-1,6-dideoxy-D-mannitol: In an enameled autoclave, 40 kg (71 kg = 570 mol) of 65% room temperature hydrobromic acid are dissolved in 20 kg (109.8 mol) of D-manfitol. By heating the solution to 45-50 ° C, a hydrobromic gas is introduced from the gas bottle at a pressure of 1.96.10® Pa through a bottom tube at a rate such that the pressure is constant from 3.92.10® to 4.90.10® Pa and the temperature is 65-70 ° C. . The total amount of introduced hydrogen bromide gas was 24 kg (297 moles) and the reaction time was 16 hours. After the completion of the reaction, the pressure of the autoclave was reduced to 1.96.10.Pa.s. and the reaction mixture was pressed into 115 L of ice water. The crystallized product was stirred at -5 ° C for 8 hours, then centrifuged and washed with water to remove acid.

Weight: 20.3 kg (61%) m.p. 175-176 ° C

The crude product can be further purified by recrystallization.

2. Preparation of 1,6-dibromo-1,6-dideoxydulcite: In an enamel autoclave, 20 kg (109.8 mole) of dulcite was suspended in 40 L (71 kg = 570 mol) of 65% room temperature hydrobromic acid. The slurry is heated to 45-50 ° C and hydrogen bromide gas is introduced from the gas bottle (1.96.10® Pa) through a bottom tube at a rate such that the pressure is constant from 4.9.10® to 5.9.10® Pa (75-80 ° C). be. The total amount of introduced hydrogen bromide gas was 24 kg (297 mol) and the reaction time was 12 hours. After the completion of the reaction, the pressure of the autoclave was lowered to 1.96.10.Pa.s. and the reaction mixture was pressed into 115 L of ice water. The crystallized product was stirred at -5 ° C for 8 hours, then centrifuged and washed with water to remove acid.

Yield: 31.8 kg (94%), m.p. 184-186 ° C

The crude product can be further purified by recrystallization.

3. Recrystallization of crude 1,6-dibromo-1,6-dideoxy-D-mannitol:

The crude product (kg), 50% water and 20 kg dry matter was dissolved in enameled autoclave in 50 l of dimethyl sulfoxide. The solution was filtered, then added slowly to 150 1 of ice water while stirring _{to 15} were repeated, the resulting crystal suspension was cooled, centrifuged, washed with water and then with methanol below 0 ° C.

Weight of recrystallized product: 17.0 kg, 85% melting point 178-180 ° C.

4. Recrystallization of crude product of 1,6-dibromo-1,6-dideoxydulcite: 43 kg ca. The crude product with 25% water content and 32.0 kg dry matter was dissolved in 450 L dimethylformamide in an enameled autoclave. The solution is filtered and the filtrate is stirred with 225 mL of ice water.

The crystal suspension was cooled to below 0 ° C, centrifuged, and washed with water and methanol.

Claims (1)

A process for the preparation of 1,6-dibromo-1,6-dideoxy-D-mannitol and 1,6-dibromo-1,6-dideoxydulcite, characterized in that D-mannitol and dulcite are dissolved in an aqueous solution of hydrobromic acid for 4-8 hours. bar at constant pressure, The reaction is carried out at a temperature of 50 to 90 ° C for 5 to 20 hours with hydrobromic acid in such a manner that the molar ratio of water: hydrobromic acid in the reaction mixture is continuously pressurized with hydrobromic acid from external sources until the reaction is complete. and the crude product obtained after filtration is recrystallized from a water-miscible solvent without drying.