PREPARATION OF GEM-DIHALOALKANES

Abstract: This invention relates to a method of preparing and purifying gem-dihaloalkanes in high yield and with minimal decomposition. The preparation consists essentially of halogenating a ketone with a halogenating agent and then purifying the resulting gem-dihaloalkane by vacuum distillation from the reaction mixture. In one preferred embodiment, 1,1-dichloro-1-cyclopropylethane is prepared and purified in good yield. Certain gem-dihaloalkanes are used as intermediates for the synthesis of novel HIV reverse transcription inhibitors.

Description: PREPARATION OF GEM-DIHALOALKANES CROSS-REFERENCE TO RELATED APPLICATION The present application claims the benefit of United States Provisional Application Serial No. 60/055,328 filed on August 12, 1997. FIELD OF THE INVENTION This invention is directed to a method of preparing and purifying gem- dihaloalkanes. More specifically, this invention relates to a method of halogenating a ketone with a halogenating agent and isolating the resulting gem-dihaloalkane with minimal decomposition by distillation under reduced pressure directly from the reaction mixture. BACKGROUND OF THE INVENTION Gem-dihaloalkanes are useful intermediates for a wide variety of organic compounds; they are particularly useful for providing alkynes via a dehydrohalogenati on reaction. Importantly, 1,1-dihalo-l-cyclopropylethane is useful for preparing cyclopropylethyne, which is a key intermediate in the synthesis of a novel, potent HIV reverse transcription inhibitor. (See U.S. Patent No. 5,698,741 to Thompson, et al.) Many of the drugs and drug therapies used to combat the devastating effects of acquired immune deficiency syndrome (AIDS) and the retro virus that causes AIDS (HIV) are extremely expensive often due to the difficulty of synthesizing the drugs that make up the treatment regimes. The preparation of cyclopropylethyne is but one example of the problems associated with preparing these drugs. This key intermediate is difficult to obtain in sufficiently high yield and purity because of its instability; specifically, the cyclopropyl ring readily opens under a variety of reaction conditions and purification methods to provide halo-substituted pentenes as decomposition products. Typically, gem-dihaloalkanes are obtained by the halogenation of the corresponding ketone with phosphorus pentachloride (PC1 5 ) (See: Hanack and Bassler, J. Amer. Chem. Soc. 91, 2117 (1969); Fitjer and Conia, Angew. Chem. Intemat. Ed., 12, 332 (1973); Schoberth and Hanack, Synthesis, 703 (1972) and Thompson et al. Td Lett. 36, 8937 (1995)). These synthetic procedures prescribe quenching the resulting acidic and/or the phosphorus by-products, such as P(O)Cl 3 , with a quenching agent, for example an amine base or ice water, before attempting to isolate the desired gem-dihaloalkane from the reaction mixture. Use of the described syntheses provides gem-dihaloalkanes albeit with varying results and in low yield due to acid promoted decomposition. Furthermore, the gem-dihaloalkane must be sufficiently pure for the subsequent dehydrohalogenation reaction to provide the alkyne in high yield. Impurities contaminating the gem-dihaloalkane inhibit the dehydrohalogenation reaction, decrease the yield of the alkyne and promote further decomposition. Thus, while the gem-dihaloalkanes are highly desired intermediates particularly in the synthesis of potent HIV drugs, their instability during the synthesis and purification procedures greatly inhibits their utility and increases the difficulty and costs associated with producing these important drugs. SUMMARY OF THE INVENTION There is provided in one embodiment of the present invention a method for preparing gem-dihaloalkanes in high yield and purity. The gem-dihaloalkanes are synthesized by halogenating a corresponding ketone with a halogenating agent in a suitable solvent. After the gem-dihaloalkane is formed in situ, it can be isolated directly from the reaction mixture by distillation under reduced pressure. In another embodiment of the present invention there is provided a method of purifying gem-dihaloalkanes from a reaction mixture that includes halogenated byproducts. The halogenated by-products include halo acids, phosphorus oxyhalides, and halogenated alkenes. The gem-dihaloalkanes are purified by fractionating the components in the reaction medium via distillation at reduced pressure. DETAILED DESCRIPTION OF THE INVENTION Generally this invention is related to a method of preparing gem-dihaloalkanes. Examples of preferred gem-dihaloalkanes prepared according to the present invention have the general formula 1 shown below: (CH 2 ) n CHCX 2 CH 2 R wherein R is hydrogen or C 2 to C 7 alkyl, X is a halogen and n is an integer from 2 to 5. Preparation of the compounds having the general formula shown above is complicated because compounds of this formula, particularly where n is 2 or 3, are highly unstable during both the preparation and the purification procedures. These compounds decompose via a variety of routes or side reactions including dehydrohalogenation and ring opening with a concomitant 1 ,3 halogen shift to form di- and monohalogenated alkenes and/or dienes. The preparation according to the present invention consists essentially of halogenating the corresponding ketone with a halogenating agent and then isolating the resulting gem-dihaloalkane directly from the reaction mixture by distillation under reduced pressure. This preparation and purification scheme consistently provides the desired compound in high yield in high purity and with minimal decomposition. The preferable compounds having the general formula 1 shown above are prepared according to the present invention. In formula 1 , R is hydrogen or a C 2 to C 7 alkyl. It is understood for the purposes of the present invention that the term alkyl includes linear, branched and cyclic hydrocarbons. Specific examples of hydrocarbon groups useful in this invention include: methyl, ethyl, isopropyl, n-butyl, sec-butyl, tert-butyl, neopentyl, n-hexyl, dimethylhexyl, n-octyl, cyclobutyl, cyclopentyl, cyclooctyl and cyclohexyl. In the above formula, X is a halogen either chlorine or bromine. Finally, n in the above formula is an integer from 2 to 5. Thus, the compound of formula 1 includes a cycloalkane such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. This invention is particularly useful for preparing 1,1- dichloro-1 -cyclopropylethane (DCCP). The gem-dihaloalkanes of the formula 1 are prepared via halogenation of the corresponding ketones having the formula 2: (CH 2 ) n CHC(O)CH 2 R wherein R and n are defined as described above. Halogenating agents useful for the present invention include phosphorus halides such as, PC1 5 , PBr 5 , and PCl 3 Br 2 , and mixtures thereof. Preferably, freshly prepared anhydrous PC1 5 is used as the halogenating agent. Use of pure anhydrous halogenating agent provides the highest yield with minimal decomposition and inhibits generation or inadvertent introduction of HC1 into the reaction mixture. Phosphorus pentachloride can be prepared by adding one equivalent (based on PC1 ) of chlorine to a solution containing PC1 3 . The halogenation reaction can be performed in a variety of organic solvents. Importantly, the solvent should be non-reactive to the reactants and reaction products, e.g. the ketone, the halogenating agent, halogens, phosphorus oxyhalide and gem- dihaloalkanes. The organic solvents include C 5 to C 20 hydrocarbons, C 6 to C 20 aromatic hydrocarbons, C to C 20 halogenated hydrocarbons and C 6 to C 20 halogenated aromatic hydrocarbons. Preferably a C 12 to C 14 linear hydrocarbon such as Norpar™ sold by Exxon Chemical Corp. is used as the reaction solvent. This solvent is substantially inert under the reaction conditions and is sufficiently low boiling to be recovered and recycled in subsequent halogenation reactions. Furthermore, use of Norpar™ provides a solvent that is sufficiently high boiling to allow recovery of the gem-dihaloalkane via vacuum distillation without co-distillation of the solvent or, alternatively, distillation of the solvent in preference to the gem- dihaloalkane, which would concentrate the gem-dihaloalkane in the distillation still. Concentrating the gem-dihaloalkane in the pot still potentially can promote thermal decomposition. In the preferred synthetic procedure, the halogenating agent is suspended in the solvent to provide a uniform slurry. This slurry is cooled to about 0° C, and the ketone is added to the cooled slurry at a rate sufficient to maintain the temperature of the reaction mixture below about 20° C. After the addition of the ketone is complete, the reaction mixture can be warmed to ambient temperatures or above. Preferably, the reaction mixture is warmed to about 85°, more preferably to about 65° C. The slurry is stirred or agitated until essentially all the ketone is consumed. The reaction can be monitored by gas chromatographic analysis to determine the rate the ketone is consumed. Similarly, the decomposition of the gem-dihaloalkane can be evaluated using the gas chromatographic analysis by monitoring the rate at which halogenated alkene decomposition products or other side products are formed. Generally when the reaction mixture clarifies to provide a clear yellow solution, the ketone essentially has been consumed. If the reaction mixture is turbid or contains solids, these solid particles can be removed using common techniques such as filtering the reaction mixture through a microporous medium. Analysis of the clear yellow solution indicates greater than about 75% non-isolated yield of the desired gem-dihaloalkane is produced based upon the amount of starting ketone. The desired products from the halogenation reaction are purified in a purification scheme that consists essentially of distilling under vacuum the desired product directly from the reaction medium. The reaction mixture containing the gem- dihaloalkane and the halogenated by-products is transferred to a vacuum distillation apparatus, preferably glass lined. Fractional distillation is performed at about 5 to about 300 torr. Preferably the reaction mixture is distilled at about 5 to about 100 tqrr, more preferably at about 5 to about 55, most preferable about 5 to about 10 torr. It has been observed that reduction of the distillation temperature also reduces the amount of decomposition. It is thought that the gem-dihaloalkane is thermally unstable and decomposes via ring opening of the cycloalkyl group, particularly when n is 2 or 3, followed by a 1,3 halide shift to provide a variety of mono and dihalo alkenes and/or dienes. Thus to minimize decomposition, the reaction mixture is distilled at a reduced pressure sufficient to distill the desired gem-dihaloalkane at about 25° to about 130°C, more preferably about 25° to about 60° most preferably about 25° to about 35°C. In the most preferred embodiment, the reaction mixture is fractionally distilled under reduced pressure to remove the more volatile components from the reaction mixture. The volatile halogenated by-products, such as HC1 and P(O)Cl 3 , are removed as distillate forecuts before the desired gem-dihaloalkane is distilled. For example, application of a mild vacuum initially removes HC1 and other dissolved gases commonly referred to as lights from the reaction mixture. The vacuum is then adjusted to about 55 torr, and the reaction mixture is heated to elevate the internal pot temperature to about 60°C. Additional lights, such as P(O)Cl 3 are removed at a distillation temperature of about 40°C and a reflux to takeoff ratio of about 5:1 to about 10:1. Under these conditions, co-distillation of the gem-dihaloalkane is maintained to below about 1 wt % of this distillate. Typically after about 90 wt % of the lights are removed, the vacuum is adjusted to about 10 torr, and a transition distillate fraction is collected at a distillation temperature of about 20° to about 24°C to remove the balance of the lights. This transition distillate fraction can be retained and charged back into subsequent distillations to recover the gem-dihaloalkane from the fraction. After the lights and the transition distillate fraction have been removed, the desired gem-dihaloalkane is isolated from the reaction mixture by vacuum distillation. Preferably, the vacuum is adjusted to about 9 to about 5 torr so the desired gem- dihaloalkane can be collected at a lower distillation temperature of about 29°C or less. Typically, the pot temperature is maintained below about 95°C or, more preferably, about 65°C to limit thermal decomposition of the gem-dihaloalkane. Under these conditions, the phosphorus oxyhalide and haloalkene by-products are maintained below about 0.5 wt % in the distillate fraction. It is understood that higher or lower vacuum can be used in the practice of this invention to optimize the yield, purity and costs associated with preparing a particular gem-dihaloalkane. Typically the desired gem-dihaloalkane recovered from the fractional distillation under vacuum is sufficiently pure to carry directly to a subsequent dehydrohalogenation reaction to afford alkyne in excellent yield. It is important to note that the distillation can be performed either in a batch process or through a continuous distillation procedure. In a continuous distillation procedure, the reaction mixture is distilled through a series of distillation stills. Typically, the reaction mixture is transferred at a desired rate into a first distillation still, which is maintained at a predetermined, reduced pressure to remove a portion of the lights. The non- volatile components of the resulting mixture are transferred to a second still at a rate that is substantially equal to the rate the original reaction mixture is transferred to the first still. Preferably, the second still is maintained at a second reduced pressure that is different from the reduced pressure in the first still. In this second still, additional lights and/or other components, such as P(O)Cl 3 , are removed. Similar to the first still, the non- volatile components are transferred to a third still at a rate that is substantially equal to the rate the mixture is added to the second still. The process can be repeated as desired to provide a the gem dihaloalkane in high yield and high purity. The typical by-products from the reaction include a variety of halogenated alkenes and phosphorus halide species. The most prominent by-product is phosphorus oxychloride (P(O)Cl 3 ), or the corresponding phosphorus oxybromide (Pr(O)Br 3 ) when PBr 5 is used as the halogenating agent. A variety of halogenated organic molecules are also produced as by-products; the most prominent are dihaloalkenes. For example, the by-products from the chlorination of cyclopropyl methyl ketone (CPMK) include cis and trans-2,5-dichloro-2-pentene (DCP) as ring- opened olefinic by-products. The amount and rate of formation of decomposition products can be monitored by evaluating the ratio of the gem-dihaloalkane to the halogenated alkenes using gas chromatographic analysis. Aliquots from the reaction mixture and distillate fractions can be analyzed to determine the relative amounts of these components. Optimally, the amount of the halogenated alkenes remains consistently low throughout the preparation and purification procedures. For example, the chlorination of DCCP with PC1 5 in a C 12 to C 14 linear hydrocarbon solvent, such as NORPAR 13™ at about 0°C provides an initial 1,1-dichloro-l -cyclopropyl ethane (DCCP) to DCP ratio of about 86:14. This ratio does not change significantly during the purification procedure. Isolation of the desired DCCP product according to the present invention by vacuum distillation directly from the reaction mixture provides DCCP in greater than 98% purity with minimal conversion or decomposition during distillation. This is in contrast to other purification procedures that require addition of a quenching agent followed by isolation of the desired product from the "quenched" reaction medium by distillation, which only provide low and variable yields of the desired gem- dihaloalkane. The following examples further illustrate the present invention and are not intended to be limiting in any matter. Example 1: Preparation of 1,1-Dichlorol-l-cyclopropylethane from Cyclopropyl methyl ketone. Norpar 13™ (Exxon Chemical Corporation), a C 12 to C 14 linear hydrocarbon solvent, (4.18 kg) was charged to a 12 liter jacketed reaction kettle fitted with a mechanical agitator, temperature probes, condenser, and nitrogen purged system. The reactor was vented through a re-circulating scrubber containing 20% NaOH solution. Phosphorus pentachloride (4.34 kg) was added to the reactor, and the mixture was agitated to provide a uniform slurry. The slurry was cooled to about 0°; then cyclopropyl methyl ketone (CPMK) (1.62 kg) was added to the slurry at a rate sufficient to maintain the internal reaction temperature below about 20° C. After the CPMK addition was complete, the thin slurry was gradually heated to about 65° C. The mixture was maintained at about 65° C for about 0.5 hr during which time the slurry clarified to provide a clear yellow solution. The solution was cooled to ambient temperature. Analysis of the reaction mixture by gas chromatography of the reaction medium indicated complete conversion of CPMK to 1,1-dichloro-l-cyclopropylethane (DCCP) and the E/Z isomers of 2,5-dichloro-2-pentene (DCP). The initial DCCP to DCP ratio was about 86:14. The solution contained about 2.03 kg of DCCP (about 20.0 wt % based upon the reaction mixture) equivalent to a non-isolated yield of about 76% based upon CPMK charged to the reaction, and the reaction mixture also contained 0.33 kg (about 3.2 wt % ) DCP. The reaction mixture was transferred to a 12 liter still fitted with a 10-tray, vacuum jacketed glass Oldershaw column (28" x 3"), distillation reflux splitter head, reflux clock, condenser and receivers. The reaction mixture analyzed at 29.1 wt % P(O)Cl 3 , 20.0 wt % DCCP; 3.2 wt % DCP; 41.2 wt % Norpar 13. The balance of the components were attributed to lights (primarily HC1), chlorinated Norpar species and unknowns. The still was purged with nitrogen, and then mild vacuum (about 100 torr) was applied to the still to remove volatiles and dissolved gases such as HC1, from the reaction mixture. The vacuum was then adjusted to about 55 torr, and reaction mixture was heated to reflux. After the reflux equilibrated, phosphorus oxychloride was removed at a distillate temperature of about 40° C and a reflux to takeoff ratio of about 5 : 1 to about 10:1. Under these conditions, the DCCP content in the P(O)Cl distillate fraction was maintained below about 1.0 wt % based on P(O)Cl 3 . After about 90 wt % of the POCl 3 was removed, the vacuum was adjusted to about 10 torr and a transitional distillate fraction comprising about 5.0 wt % of the still charge was collected to remove the balance of the P(O)Cl 3 . The typical composition of the transition distillate was about 55 to 65 wt % P(O)Cl 3 and about 40 to 45 wt % DCCP. This transition distillate can be retained and charged in a subsequent distillation to recover the included DCCP. The vacuum was adjusted to about 9 torr and the desired DCCP product was collected at a distillation temperature range of about 26° to 29° C at a reflux to takeoff ratio of about 3 : 1 to about 5:1. Under these conditions, the P(O)Cl 3 and DCP by-products in the distillate were below about 0.5 wt % based upon the distillate fraction. The DCCP composition in the distillate was typically greater than 98% pure. The DCCP recovery was equivalent to about 90% of the original DCCP produced in a halogenation reaction. This DCCP product was sufficiently pure to be carried through a dehydrohalogenation reaction without any further purification to afford cyclopropylethyne in excellent yield. A DCCP/DCP transition distillate fraction was collected at a distillation temperature range of about 90° to 125° C, an overhead temperature range of about 30° to 65° C at about 9 torr using a 3:1 reflux to takeoff ratio. The composition of this transition distillate fraction contained about 95% DCP, less than about 5% DCCP and a trace of Norpar 13. Typically recoveries retrieved from the distillation were about 98 to 101 wt % P(O)Cl 3 , 97 to 99 wt % Norpar 13, 90 to 92 wt % DCCP, and about 108 to about 110 wt % DCP. (The DCP recovery is greater than 100% based upon the original still composition analysis. This recovery is due to the minor decomposition of DCCP via ring opening, to give DCP during the distillation. The increase in DCP content is consistent with DCCP loss and services as a marker for determining the extent of DCCP decomposition.) The recovered Norpar 13 is sufficiently pure to be recycled in subsequent reaction sequences. Furthermore, the recovered P(O)Cl 3 is sufficiently pure to be used as a reagent in other chemistries that employ P(O)Cl 3 or sold to third parties. Example 2: Preparation of 1,1-Dichloro-l-cyclobutyl butane A 12 liter jacketed reaction kettle as described in Example 1 is charged with chlorobenzene (4.0 kg) followed by phosphorous pentachloride (4.0 kg). The resulting slurry is cooled to about 0°C; then cyclobutyl propyl ketone (CBPK) (2.2 kg) is added. The resulting reaction mixture is warmed to about 75°C for about 0.5 to about lhr to provide the 1,1-dichloro cyclobutylbutane (DCCB). The reaction mixture is transferred to a 12 liter still fitted with a 10 tray vacuum-jacketed Oldershaw column as described in Example 1. The lights including HC1 and other dissolved gasses are removed at a vacuum of about 100 torr. Then the vacuum is adjusted to about 50 torr, and the reaction mixture is heated to reflux to remove P(O)Cl 3 . After about 85 wt % of the theoretical weight of P(O)Cl 3 is removed, a transition distillate fraction is collected. This transition distillate fraction contains both P(O)Cl 3 and DCCB. After removing a total of about 30 to about 35 wt % of the initial reaction mixture, the vacuum is adjusted to about 5 torr and the desired DCCB is collected.

Claims: We claim: 1. A method for preparing a compound of the formula 1 : (CH 2 ) n CHCX 2 CH 2 R wherein X is halogen, R is hydrogen or Ci to C 7 alkyl and n is an integer from 2 to 5, said method consisting essentially of: halogenating a compound of the formula 2: (CH 2 ) n CHC(O)CH 2 R with a halogenating agent in a solvent to provide 1 in a reaction mixture comprising the solvent and halogenated by-products, distilling at reduced pressure a portion of the halogenated by-products from the reaction mixture, and distilling 1 at reduced pressure from the reaction mixture. 2. The method of claim 1 wherein X is chlorine or bromine. 3. The method of claim 1 wherein n is 2. 4. The method of claim 1 wherein R is hydrogen or methyl. 5. The method of claim 1 wherein the halogenating agent selected from the group consisting of PC1 5 PBr 5 , PCl 3 Br 2 and mixtures thereof. 6. The method of claim 1 wherein 1 is distilled from the reaction mixture at about 5 to about 300 torr. 7. The method of claim 6 wherein 1 is distilled from the reaction mixture at about 5 to about 100 torr. 8. The method of claim 7 wherein 1 is distilled from the reaction mixture at about 5 to about 55 torr. 9. The method of claim 8 wherein 1 is distilled from the reaction mixture at about 5 to about 10 torr. 10. The method of claim 1 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 130°C. 11. The method of claim 10 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 60°C. 12. The method of claim 11 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 35°C. 13. The method of claim 1 wherein the portion of the halogenated by-products is continuously distilled from the reaction mixture at reduced pressure. 14. The method of claim 1 wherein 1 is continuously distilled from the reaction mixture at reduced pressure. 15. A method of purifying a compound of the formula 1 : (CH 2 ) n CHCX 2 CH 2 R wherein X is halogen, R is hydrogen or a Cj . to C alkyl and n is an integer from 2 to 5, from a reaction mixture comprising 1, a solvent and halogenated by-products, said method consisting essentially of: distilling a portion of the halogenated by-products from the reaction mixture at reduced pressure, and distilling 1 from the reaction mixture at reduced pressure. 16. The method of claim 15 wherein X is chlorine or bromine. 17. The method of claim 15 wherein n is 2. 18. The method of claim 15 wherein R is hydrogen. 19. The method of claim 15 wherein 1 is distilled from the reaction mixture at about 5 to about 300 torr. 20. The method of claim 19 wherein 1 is distilled from the reaction mixture at about 5 to about 100 torr. 21. The method of claim 20 wherein 1 is distilled from the reaction mixture at about 5 to about 55 torr. 22. The method of claim 21 wherein 1 is distilled from the reaction mixture at about 5 to about 10 torr. 23. The method of claim 15 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 130°C. 24. The method of claim 23 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 60°C. 25. The method of claim 24 wherein the reduced pressure is sufficient to distill 1 from the reaction mixture at a distillation temperature of about 25° to about 35°C.

Inventors: OWENS STEPHEN W, REINEKE KARL E, SANCHEZ IGNACIO H, SHIPPLETT REX A, TUETING DAVID R, WOLTERMANN CHRISTOPHER J, OWENS, STEPHEN, W., REINEKE, KARL, E., SANCHEZ, IGNACIO, H., SHIPPLETT, REX, A., TUETING, DAVID, R., WOLTERMANN, CHRISTOPHER, J.
Applicants: GREAT LAKES CHEMICAL CORP, GREAT LAKES CHEMICAL CORPORATION
Application year: 1998
Main classification: C07C17
IPC codes: C07C17