PREPARING 7-HALO-7-DEOXYLINCOMYCINS

Abstract: A process for preparing a 7-halodeoxylincomycin or an analogue thereof, which comprises reacting lincomycin or an analogue thereof with a thionyl halide and dimethylforma­ mide, under mild conditions.

Description: PREPARING 7-HALO-7-DE0XYLINCOMYCINS The present invention is an improved process for preparing 7 ha.o-7-deoxyllncomycins, including clindamycin, and pharmaceutically acceptable forms thereof from lincomycin and analogs thereof. Cl ",damycin is a well-known antibiotic that has pharmacologically useful properties. Processes for preparing 7-halo-7-deoxylincomycins are known. U.S. Patents 3,435,025, 3,496,163 and 3,509,127 disclose a process in which the 7-hydroxyl group of lincomycin and analogous compounds are replaced with a halogen group by reacting said compounds with a Rydon reagent and heating the resulting product. The use of thionyl chloride to convert lincomycin and analogous compounds to 7-chloro-7deoxy canpounds is described in U.S. Patents 3,496,163, 3,509,127 and 3,574,186. The temperature needed to effect the transition described in these patents in neutral solvents, are well above room temperature. In this regard, all of the examples disclose the reaction being conducted by refluxing in carbon tetrachloride (about 770C). A process for preparing 7-halo-7--deoxylincomycin by the use of a sulfite-protected lincomycin and Rydon reagents is described in U.S. Patent 3,714,141. The use of a Vilsmeier reagent to substitute a halo atom for a hydroxyl group has been described. Eilingsfield et al, Angew. Chem. 72, 836 (1960) and Eilengsfield et al, Chem. Ber. 96 2671 (1963). Evans et al, JOC 33, 1074 (1968) discloses on page 1075 that while a Vilsmeier reagent prepared from methanesulfonyl chloride and dimethylformamide was successfully used to replace a primary hydroxyl group, it was not in attempts to replace a secondary hydroxyl group. The structure of the adduct formed between dimethylformamide and thionyl chloride from which sulfur dioxide has not been removed has been investigated by Ferre et al, Tet. Lett. 2161 (1969) and the conditions for converting the dimethylfonamide thionyl chloride adduct to the corresponding amide chloride has been described; Kikagawa et al, Chem. Pharm, Bull. 19, 2629 (1971). Bosshard et al, Helv. Chim. Acta. 42, 16153 (1959) discloses the use of dimethyl formamide as a catalyst in the conversion of carboxylic acids to acid chlorides. Hepburn et al, J. Chem. Soc. Perkin I, 754 (1976), and Hepburn et al, Chem. h Ind. 664 (1974), describe the use of amide chlorides obtained from Vilsmeier reagents to replace hydroxyl groups by chlorine or bromine groups. However, the hydroxyl containing compounds were relatively simple alcohols and did not approach the complexity of the lincomycin molecule. The use of a mixture of mesyl chloride and N,N-dlmethylformamide to replace primary groups of hexopyranosides by chlorine is described by edward et al, Tetrahedron Letters, 2369 (1973). The halogenation of nucleosides by amide chlorides is described by Dobs et al, Tetrahedron Letters, 165 (1969). While the prior art describes the use of both Vilsmeier reagents and amide chlorides obtained therefrom in reactions similar to that of the process of this instant invention, the prior art is confusing at best. This is particularly true with respect to whether or not it is preferred to use the Vilsmeier reagent or to remove sulfur dioxide from it and use the resulting amide chloride. To applicant's knowledge, however, none of the prior art processes can be conducted under the mild conditions used In the process claimed herein. According to the present inven ticrl, 7-halo-7-Åaeoxy lincomycin and analogs thereof are prepared by reacting lincomycin with thionyl halide and dimethyl-formamide. The reaction can be conducted by (1) allowing the product of reaction between lincomycin or one of its analogs and an excess of thionyl halide to react in a solvent that is substantially composed of dimethylfonamide or (2) by treating a mixture of lincomycin or one of its analogs and dimethylformamide with an excess of thionyl halide. In alternative (1) the solvent may contain some of the solvent used In the reaction between the i lincomycin and thionyl chloride (i.e., methylene chloride). The unusually mild conditions of the reaction coupled with the ease in which it can be performed and low energy requirements are some of the advantages of the process of this invention. For instance, the use of special equipment required for processes conducted under more extreme conditions is not required. It has been found that the order of addition of the reactants is critical to achieving this result. We have found that a useful rate of reaction is achieved at less than 400C only if these orders of addition described herein are used. Otherwise, conditions appear normal for the amide chloride or thionyl chloride tn inert solvent methods. Utilizing either route (1) or (2) of the invention,the reaction is conducted at a temperature of about OOC to 500C for a period of about 10 to about 48 hours. The preferred temperature is about 150C to 300C and the preferred reaction time is about 1 to 5 hours. It is preferred to conduct the reaction with an excess of thionyl chloride. As used herein the term Uexcess thionyl halides means about four to thirteen equivalents of halide per equivalent of lincomycin or analog thereof. The preferred ratio of thionyl halide to lincomycin or analog thereof is about four to six equivalents. Starting materials for the process are lincomycin or one of its analogs and a thionyl halide and dimethylformamide. Lincomycin is a known antibiotic and methods for preparing it and its analogs are well known in the art and illustrated in U.S. Patents 3,086,912 and 3,155,580. In addition to those described in the patents cited above, analogs of lincomycin are also exemplified in U.S. Patent 3,380,992, and by protected lincomycin and analogs such as methylthiolincosaminide, 3,4-cumylidene-lincomycin, and 3,4benzylidene-lincomycin. As used herein, lincomycin, lincomycin analogs, 7-halo-7-deoxylincomycin and analogs thereof, mean the free basesor their salts. The salts may be anhydrous or hydrated. The following Examples of the process for preparing 7halo-7-deoxylincomycin and intermediates useful therein are indicative of the scope of this invention and are not to be construed as limitative. Example 1 Into an oven-dried round-bottom flask containing a magnetic stirring bar under a nitrogen atmosphere is added methylene chloride (53 ml, 1.5 volume of thionyl chloride) and thionyl chloride (35 ml, 479 mmole). The resulting solution is cooled in an ice bath, and lincomycin hydrochloride monohydrate (35.0 g, 75.1 mmole, 3.905 H20) by Karl Fischer titration) is added via a solid addition apparatus, slowly over 30 minutes. The residual solid is rinsed in with 4 ml methylene chloride. The resulting mixture is stirred at oqc for 15 minutes to effect complete dissolution. With ice-acetone cooling, N,N-dimethylformamide (70 ml, 900 mmole) is slowly added, keeping the temperature below 50C (required -30 minutes). The cooling bath is removed and-house vacuum is applied to the yellow solution. A dry ice/acetone trap is used. Over a 2.25 hour period,the reaction temperature increased to room temperature at which time a mild exotherm to 29CCis noticed with more gas evolution. The temperature is adjusted to 25t3with a water bath and the gas evolution ceased. At this point, thin layer chromatography indicates a very clean reaction to clindamycin with very little lincomycin remaining. The water bath is removed and the reaction is allowed to stir under vacuum for another hour (total reaction time of 3.25 hours). The resulting red colored solution is cooled to near O9cand anhydrous methanol (40 ml) is added slowly. Via cannula, the reaction is quenched into 114 g of 50X sodium hydroxide in 200 g ice cooled to near -100C, keeping the temperature below 37"c. Near the end of the quench, additional 50% sodium hydroxide is used to keep the pH above 11. The resulting mixture Is stirred at 370 + 40C for 45 minutes. The mixture is cooled to room temperature and pH Is adjusted to 7 with concentrated hydrochloric acid. The solution is concentrated in vacuo to approximately one-half volume, to remove all the methanol. With ice-bath cooling, the solution is adjusted to pH 1.5 with concentrated hydrochloric acid, at which time the mixture becomes homogenous. Methylene chloride (100 ml) is added and the phases are separated. the organic phase is successively extracted through (3 x 150 ml) pH 1.5 aqueous phases (0.5 M potassium hydrogen phosphate buffer adjusted to pH 1.5 with concentrated hydrochloric acid). Any interface is retained with the aqueous phase. Each aqueous phase is reextracted with (4 x 150 ml) methylene chloride. All four aqueous phases are combined and adjusted to pH 10.2 with 50% sodium hydroxide and then to pH 8.2 with concentrated hydrochloric acid (ice is added to keep temperature -250C). Methylene chloride (100 ml) is added and the phases are separated. The organic phase is extracted through (2 x 100 ml) pM 6.2 (0.5 M) phosphate buffer. The pH 8.2 and pH 6.2 aqueous phases are sequentially reextracted with (4 x 5 ml) methylene chloride. The combined organics are dried over sodium sulfate and evaporated to an oil. Residual methylene chloride is removed by two ethyl acetate azeotropes. The oil is dissolved in ethyl acetate (158 ml) and absolute ethanol (47 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding the solution with clindamycin hydrochloride ethanol solvate while simultaneously adjusting -the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring at room temperature for one hour, then Ooh for 45 minutes, the slurry is filtered and rinsed with ethyl acetate. After drying for 3 hours under vacuum, the product weighs 17.04 g, which corresponds to 68.1X yield of clindamycin hydrochloride ethanol solvate. Example 2 Into an oven-dried round-bottom flask containing a magnetic stirring bar under a nitrogen atmosphere is added lincomycin hydrochloride (35.0 g, 79 mmole, 0.9745 water by Karl Fischer titration) and N,N-dimethylformamide (125 ml). The slurry is cooled to near OOC and thionyl chloride (35 ml, 474 mmole) is added over one hour. After two hours at room temperature the reaction is complete. Following cooling to near 0 C, anhydrous methanol (75 ml) is^added slowly. The solution is stirred for one hour at room temperature. Via cannula, the reaction is quenched into 114 g of 50% sodium hydroxide in 200 g ice and 200 ml methylene chloride, precooled to near -100C,keeping the temperature below 160C. Near the end of the quench, additional 50% sodium hydroxide is used to maintain a pH of 10.5. Additional (100 ml) methylene chloride is added while stirring at room temperature for 3 hours at pH 10.5. The pH is adjusted to 7 and the reaction is left at room temperature overnight. The mixture is concentrated in vacuo to approximately one-half volume. Methylene chloride (100 ml) is added, and with ice-bath cooling, the pH is adjusted to 1.5 with concentrated hydrochloric acid. The layers are separated and the organic phase is successively extracted through (3 x 150 ml) pH 1.5 aqueous phases (0.5 M potassium hydrogen phosphate adjusted to pH 1.5 with concentrated hydrochloric acid). Any interface layer is retained with the aqueous phase. Each aqueous phase is reextracted with (4 x 50 ml) methylene chloride. The last two aqueous phases are extracted with additional (2 x 100 ml) methylene chloride. All four aqueous phases are combined and the pH adjusted to 10.5 with 50X sodium hydroxide. Ice is used to maintain the solution at room temperature. Methylene chloride (100 ml) is added and the phases are separated. The organic phase is extracted through (2 x 130 ml) pH 6.2 phosphate buffer (0.5M). The pH 10.5 and two pH 6.2 aqueous phases are reextracted with (4 x 50 ml) methylene chloride. The organics are dried over sodium sulfate and concentrated in vacuo to an oil. Residual methylene chloride is removed by two ethyl acetate azeotropes. The oil is dissolved in ethyl acetate (157 ml) and absolute ethanol solvate (45 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding the solution with the solvate while simultaneously adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring at room temperature for one hour, then OOC for 45 minutes, the slurry is filtered and rinsed with ethanol acetate. After drying the filter cake under vacuum for one hour, 26.65 g (66.55 yield) of clindamycin hydrochloride ethanol solvate is recovered. Clindamycin hydrochloride hydrate is recovered from the ethanol solvate by conventional means. Example 3 Into an oven-dried round bottom flask containing a magnetic stirring bar under nitrogen atmosphere is added methylene chloride (12.5 ml, 1.5 volume of thionyl chloride) and thionyl chloride (8.25 ml, 113 mmole). The solution is cooled in an ice bath and lincomycin hydrochloride (10 g, 22.6 mmole, by Karl Fischer titration 0.974 weight X water) is added via solid addition apparatus slowly over 25 minutes. The resulting pale-pink mixture is allowed to stir at 0 until it becomes homogeneous (15 minutes). LiCl (4.8 g, 113 mole, dried 7 hours at 130or and 2 mm Hg) Is added. With ice-acetone cooling, N,N-dimethylformamide (17.6 ml, 226 mmole) is slowly added, keeping the temperature below 50C. The cooling bath is removed and house vacuum is applied. Within 20 minutes the reaction mixture becomes a gel. Dimethylfornamide (10 ml) is added to facilitate stirring. After 4.25 hours, the reaction is complete by thin layer chromatography; methylene chloride (40 ml) is added, and the reaction Is cooled to near 0 C. Via cannula, the reaction is quenched into 27.2 g of 50Z sodium hydroxide and 100 g ice cooled to near -10 C, keeping the temperature below +20"C. Towards the end of the quench, additional 50% sodium hydroxide is used to keep the OH greater than 11. After stirring for 2 hours at pH 10-11 and room temperature, the pH is adjusted to 7 with concentrated hydrochloric acid and the mixture is left at room temperature overnight. The pH is readjusted to 10 with 50± sodium hydroxide and the layers are separated. The organic phase is extracted through (4 x 75 ml) pH 1.5 aqueous phases consecutively (0.5 M potassium hydrogen phosphate adjusted to pH 1.5 with concentrated hydrochloric acid). The pH 10 aqueous phase is reextracted with (4 x 50 ml) methylene chloride, carrying each wash through the four pH 1.5 phases successively. The aqueous phases are combinet and adjusted to pH 10.5 with 50X sodium hydroxide. Methylene chloride (100ml) is added and the layers are separated. The organic phase is successively extracted through (2 x 75 ml) pH 6.2 + 0.1 (0.5 molar) phosphate buffer. The pH 10.5 and the two pH 6.2 aqueous phases are reextracted with (4 x 50 ml) methylene chloride. The organics are dried over sodium sulfate and evaporated to an oil. Residual methylene chloride is removed by two ethyl acetate azeotropes. The remaining oil is dissolved in ethyl acetate (25 ml) and stirred at room temperature for 45 minutes with activated carbon (0.5 g Darco grade G-60). After filtering through Celite 545, the filtrate is evaporated to dryness. The resulting oil is dissolved in ethyl acetate (45 ml) and absolute ethanol (12.9 ml). Clindamycin hydrochloride ethanol solvate is obtained by seeding this solution with clindamycin hydrochloride ethanol solvate while simultaneously adjusting the pH to 1.0-1.5 with concentrated hydrochloric acid. After stirring at room temperature for 1 hour, then for 30 minutes, the slurry is filtered and rinsed with room temperature ethyl acetate. After drying for 1.5 hour under vacuum the product weighs 8.25 g, which corresponds to 72% yield of clindamycin hydrochloride ethanol sol vate. ("Celite" and "Darco" may be registered Trade Marks).

Claims: CLAIMS 1, A process for preparing a 7-halodeoxylincomycin or an analogue thereof, which comprises reacting lincomycin or an analogue thereof with a thionyl halide and dimethylformamide. 2. A process according to claim 1, wherein the product of reaction between the. lincomycin or its analogue and the thionyl halide is reacted with dimethylformamide. 3. A process according to claim 2, wherein the product of reaction of lincomycin and an excess of thionyl chloride is reacted with dimethylformamide, to prepare clindamycin and/or a salt thereof. 4. A process according to claim 3, wherein lincomycin hydrochloride is reacted with from four to thirteen equivalents of thionyl chloride, at less than 500C, and the reaction product is then allowed to react in a solvent/reagent system substantially composed of dimethylformamide, at 0 to 500C, to prepare clindamycin and/or clindamycin hydrochloride. 5. A process according to claim 1, wherein a mixture of lincomycin or its analogue and dimethylformamide is reacted with an excess of the thionyl halide. 6. A process according to claim 5, wherein a mixture of lincomycin and dimethylformamide is reacted with an excess of thionyl chloride, to prepare clindamycin and/or a salt thereof. 7. A process according to claim 6, wherein a mixture of lincomycin hydrochloride and dimethylformamide is treated with from four to thirteen equivalents of thionyl chloride, at 0 to 500C, to prepare clindamycin and/or clindamycin hydrochloride.

Inventors: LIVINGSTON, DOUGLAS ALAN, PETRE, JANET ELIZABETH
Applicants: THE UPJOHN COMPANY
Application year: 1985
Main classification: C07H15
IPC codes: C07H15, C07H17, C07H1