Patent Application
20100022804
The invention relates generally to a method for fluorinating organic compounds, and more particularly to a fluorination process which uses microwave energy with simultaneous cooling.
Several functional groups contribute to the bioactivity of pharmaceutical ingredients. However, the unique properties of fluoroaromatic organic compounds have increasingly proven useful in applications related to life sciences, particularly in pharmaceutical and crop-protection fields. In the $60 billion pharmaceutical industry, about 20 percent of all drugs manufactured today contain at least one fluorine atom, and thus the efficient manufacture of fluoroaromatic organic compounds is commercially important. These include highly profitable drugs like ARTOVASTATIN (PROZAC) (cholesterol medication), LANSOPRAZOLE (PREVACID) (ulcer and acid reflux treatment), FLUTICASONE PROPIONATE (FLONASE) (anti-asthma agent), and FLUXETINE (an antidepressant agent), FLUVOXAMINE (an antidepressant), EFFAVIRENZ (antiretroviral therapy for HIV), MEFLOQUINE (anti-malarial). Other drugs made from fluoroaromatics feedstocks include the fluoroquinolones, like CIPROFLOXACIN, MOXIFLOXACIN, and GATIFLOXACIN. Fluoro substitution typically improve the metabolic stability, acidity or basicity, lipophilicity, and enzyme inhibitors properties of new clinically valuable compounds, and are highly desired properties in new drugs.
New formulations are continuously being evaluated and it is predicted that over 33 percent of pharmaceuticals drugs would be fluorinated in the near future. There is obviously potential for growth of this sector of the pharmaceutical industry. Therefore, producers of the active pharmaceutical ingredients continue to build their capacity to produce the largest number of potential feedstock for short notice supply at the lowest price. As a result of this development, U.S. fine chemical companies are expanding by acquiring new chemistries that offer cheaper production costs and access to large scale manufacturing of new drugs. Since the proportion of fluorinated drugs has continued to increase, it is understandable that researches into new fluorination technologies are very high on the priorities of these businesses. It is believed that the process of the invention will be useful in this field. Table 1 presents the scale of global production of some fluoroaromatics by Halex processes in 2005.
Also, over the past 15 years, the number of fluorine-containing agrochemicals has grown from 4 percent to about 9 percent of the overall agrochemical production and sales. The trifluoromethyl (CF3) group is perhaps the most significant fluoro functional constituent among the new agrochemicals. About 48 percent of them are employed as herbicides, 23 percent as insecticides, and 18 percent as fungicides.13 These include NORFLURAZON and FLURIDONE (herbicides), FLURPRIMIDOL (plant regulator), FLUOTRIMAZOLE and FLUTRIAFOL (fungicides).
Citing research performed by IVA, a German agrochemical industry association, Agrow, a major business publication of the agrochemical industry reported global sales of agrochemicals in 2005 at US $32.2 billion, were 12.6% higher than the year before. A growth of this trend was predicted to continue. The 2001-2002 sales records of the six largest agrochemicals producers are shown in Table 2.
The purpose of the foregoing Abstract is to enable the public, and especially the scientists, engineers, and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection, the nature and essence of the technical disclosure of the application. The Abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way.
The invention is an improved method of adding fluorine atoms into aromatic rings. The method of the invention uses microwave energy application and simultaneous cooling to enhance the fluorination process. The result is an energy efficient method of microwave-assisted halogen exchange (HALEX) reactions involving chloroaromatics and fluorinating agents, with the result being the addition of fluorine atoms into aromatic rings. The process is particularly useful for adding a pentafluorosulfanyl (SF5) group to a benzene ring. Other fluorination reactions and products are clearly possible with the process of the invention, and are within the scope of the invention.
Points of Novelty of the Claimed Process:
In the electromagnetic spectrum, microwaves (0.3-300 GHz, i.e. wavelengths range of 90 cm and 1 mm) lie between the radiowave frequency (RF) and infrared (IR) frequency and have relatively large wavelengths. In the everyday application of its properties, a microwave oven (see
Microwave radiation is non-ionizing and therefore, incapable of breaking bonds. Microwaves are manifested as heat through their interaction with a medium or material. They can be reflected (by non polar metals, and compounds with no dipole moment, such as CCl4, SbF3 and AlF3), transmitted (by good insulators, which will not heat, such as glass), or absorbed (by organic materials) resulting in decreased available microwave energy. Absorption of microwave energy results in rapid heating of the material.
Direct microwave heating can reduce chemical reaction times from hours to minutes, and it is also known to reduce side reactions, increase yields and improve reproducibility. Therefore, academic and industrial research groups are using microwave assisted organic synthesis as a forefront technology for rapid reaction optimization, for the efficient synthesis of new chemical entities, or for discovering and probing new chemical reactivity.
Microwave heating can have effects that are different from conventional heating techniques. There is focus on what in the reaction mixture is actually absorbing the microwave energy. Materials or components of a reaction mixture can differ in their ability to absorb microwaves. Reaction rates can be increased by increasing the temperature of the reactants, delivering microwave energy faster than the heat can be transferred to the bulk solvent and radiated to the environment. For this effect to be sustainable, careful attention must be paid to vessel design and vessel cooling. This effect can be achieved using microwave reflux techniques.
Microwave irradiation does not affect the activation energy, but provides the momentum to overcome this barrier and complete the reaction more quickly than conventional heating methods. Microwave energy is related to the temperature parameter in the Arrhenius equation that describes kinetic reaction rates for chemical reactions.
K=Ae−
Ea/RT
Where K=Rate constant; Ea=Activation energy; R=Gas constant; T=Reaction temperature
An increase in temperature causes molecules to move about more rapidly, which leads to a greater number of more energetic collisions. This occurs much faster with microwave energy, due to the high instantaneous heating of the substance(s) above the normal bulk temperature, and is the primary factor for the observed rate enhancements. The level of instantaneous heating will be dependent on the amount of microwave energy that is used to irradiate the reactants. The higher the level of microwave energy, the higher the instantaneous temperature will be relative to the bulk temperature. One method for increasing the microwave energy that is delivered is to use simultaneous cooling during the microwave irradiation. This allows a higher level of microwave power to be directly administered, but will prevent overheating by continuously removing latent heat. This technique has proven to be very effective in further enhancing of reaction rates and will be discussed in greater detail throughout the book.
Many chloroaromatic reagents have dipole moments, and are expected to absorb microwave radiations to heat up rapidly up to slightly above their boiling points. Earlier work on microwave-assisted Halex reactions demonstrated that the phase transfer catalysts were microwave safe up to 200° C. for brief periods. When the thermosensor for the reaction measures the temperature of the liquid reagent (in this case the chlorocarbon), it is possible to control the temperature of reaction by regulating the microwave energy required to achieve a set temperature. Some broad potential benefits of this research proposal are highlighted in the following discussions on the pharmaceutical drugs and agrochemicals production.
The process of the invention has been demonstrated to achieve energy efficient microwave-assisted halogen exchange (MAHE) reactions of haloaromatics and solid inorganic fluorinating agents for introducing fluorine atoms into aromatic rings. Fluorinated aromatics are huge synthetic ingredients for the production of fine pharmaceuticals and agrochemicals, and have annual market worth estimated at more than US $4 billion. As an example of haloaromatics in general, the conventional endothermic halogen exchange (HALEX) process currently used in industry for production of fluoroaromatic compounds that do not contain pentafluorosulfanyl (SF5) group, expends significant amount of energy estimated at several trillion BTU/year.
Those processes involve the reaction of a solid inorganic fluoride, such as KF, CsF and RbF, with a haloaromatic reagent, and a phase transfer catalyst (PTC) at 140-260° C. As a result of low solubility of these hygroscopic fluorides in aromatic substrates, aprotic solvents, rigorous pre-reaction drying of all components, high temperature reaction conditions, and long reaction periods, as much as 9-28 h, are required to increase the concentration of fluoride in solution and reaction efficiency. This provides opportunity for many side reactions and the formation of decomposition products. By employing energy-efficient microwave process, shorter reaction periods are envisaged for the production of these fluorinated pharmaceutical ingredients, and decomposition and side reactions can be reduced significantly.
Generally, dielectric constant and dielectric loss properties of the constituent of a microwave system determine heating rate, and control of reaction conditions. The current process demonstrates the suitability and safety of traditional components of HALEX process for microwave operations (KF, haloaromatic reagents, and phase transfer catalysts).
Previously, microwave-assisted halogen exchange reactions involving KF as an agent for fluorination of basic aromatic rings was discussed in the Journal of Fluorine Chemistry (vol. 125, p. 701-704, 2004). With the application of 350 W power, the authors claimed that it was possible to achieve 90 percent yield under 3 h in small scale Halex reactions catalyzed by a polymeric phase transfer catalyst, and KF as the fluorination agent. However, the basicity of KF in the reaction medium caused the initiation of significant decomposition and formation of side products. The MAHE fluorination in this work is a careful application of this technique for novel efficient production of pentafluorosulfanyl fluoroaromatic compounds.
Still other features and advantages of the present invention will become readily apparent to those skilled in this art from the following detailed description describing preferred embodiments of the invention, simply by way of illustration of the best mode contemplated by carrying out my invention. As will be realized, the invention is capable of modification in various obvious respects all without departing from the invention. Accordingly, the drawings and description of the preferred embodiments are to be regarded as illustrative in nature, and not as restrictive in nature.
The invention is an improved method of adding fluorine atoms into aromatic rings, and is further described in
Microwave-assisted Halex reactions involving KF as fluorinating agent were discussed in a paper published in the Journal of Fluorine Chemistry in 2004. With the application of 350 W power, the authors claimed that it was possible to achieve 90 percent yield under 3 hour in small scale Halex reactions catalyzed by a polymeric phase transfer catalyst, and KF as the fluorination agent. However, the basicity of KF in the reaction medium caused the initiation of significant decomposition and formation of side products.
The conventional endothermic Halex process currently used in industry expends a significant amount of energy, estimated at several trillion BTU/year for all production. Those processes involve the reaction of a solid inorganic fluoride, such as KF, CsF and RbF, with a chloroorganic reagent, and a phase transfer catalyst (PTC) above 200° C. As a result of low solubility of these hygroscopic fluorides in chloroorganic reagents, aprotic solvents, rigorous pre-reaction drying of all components, high temperature reaction conditions (above 240° C.), and long reaction periods are required to increase the concentration of fluoride in solution and reaction efficiency. This provides opportunity for many side reactions and the formation of decomposition products. To improve on this process, the process of the invention employs acid fluorides in a microwave heating process, by which decomposition and side reactions, solvents, and PTCs are avoidable, and shorter reaction periods are envisaged and far less energy is used in the production of fluorinated pharmaceutical ingredients.
The method of the invention focuses on adding a fluorine atom to an aromatic molecule. Of particular applicability to the process is the addition of a pentafluorosulfanyl (SF5) group to an organic molecule. The impetus for creating new SF5-bearing new compounds is related to the fact that the SF5 group possesses a greater electronegativity than the trifluoromethyl group (CF3) and as a result, the SF5 addition is thought to represent an advantageous alternative to the well-established and widely used practice of creating compounds bearing the CF3 moiety. In a manner that is analogous to CF3-bearing organic compounds, SF5 has been described by an expert in the field as the “substituent of the future”. Yet to be synthesized compounds containing the “SF5” moiety may likely represent the next wave of highly useful fluorochemicals that will be further distinguished over their predecessor CF3-bearing compounds by their outstanding chemical properties. These outstanding properties may include: high to extreme chemical and thermal stability, oleophobicity, lipophilicity, high density, low polarizability and low surface tension. It is anticipated that new fluorine bearing organic compounds in general, and SF5-bearing organic compounds in particular, will be utilized as new and potent pharmaceuticals, pesticides, herbicides, antibiotics, blood substitutes, fungicides, specialty polymers, lubricants, liquid crystals, and surfactants. The difficulty of commercializing such SF5-bearing organic compounds is in part related to the difficulty of obtaining sufficient and affordable quantities of any number potentially useful SF5-bearing intermediate and end-product compounds.
, the magnetic field (insert correct H shaped symbol here), the wavelength (insert correct symbol here), and the speed of light c, to illustrate the type of energy the microwave heater 24 directs at the reaction vessel 12.
This in contrast to the conductive heating mechanism shown in
Several functional groups contribute to the bioactivity of pharmaceutical ingredients. However, the unique properties of fluoroaromatic organic compounds have increasingly endeared them to application in life sciences, particularly in pharmaceutical and crop-protection fields. To the extent that about twenty percent of all drugs manufactured today contain at least one fluorine atom in the $60 billion pharmaceutical industry. Fluoro substitution (
The process of the invention has applicability to attachment of all fluorine groups to organic molecules, but attachment of the pentafluorosulfanyl (SF5) group is a particular focus of the process of the invention. The pentafluorosulfanyl is more sterically demanding, more lipophilic, and more electronegative than the trifluoromethyl (CF3) group on many current fluorinated drugs, the SF5 group is virtually stable on any kind of benzene ring. Since the first synthesis of the first organic derivatives in 1960, the problem was in putting SF5 groups onto organic structures. The rationale for creating new SF5-bearing compounds is related to the fact that the SF5 group possesses a greater electronegativity than the CF3 group, and as a result, the SF5 substitution is thought to be an advantageous alternative to the well-recognized and widely used CF3 substituted bioactive compounds. In a manner that is analogous to CF3-bearing organic compounds, SF5 has been described by experts in the field as the substituent of the future. New compounds containing the SF5 moiety represent the next wave of highly useful fluorochemicals that will be further distinguished by their superior chemical properties over the CF3-bearing predecessor compounds first known in the 1920s. The pentafluorosulfanyl fluoroaromatics are excellent starting materials for custom synthesis of novel SF5-compounds with outstanding properties like high to extreme chemical and thermal stability, lipophilicity, unique combination of high-density and low boiling point. They are likely to find application as pharmaceuticals, agrochemicals, advanced materials, lubricants, liquid crystals, surfactants, and specialty polymers.
In 2008, researchers at Sanofi-Aventis Deutschland GmbH published Ortho-substituted pentafluorosulfanylbenzenes, process for their preparation and their use as valuable synthetic intermediates in U.S. Pat. No. 7,317,124 B2 (authors: Kleeman, H. W., and Week, R). Some of these reactions are illustrated in
Some other derivative compounds were prepared in the published work of Dr. W. A. Sheppard (1960) in
The first report of preparation of pentafluorosulfanyl nitrobenzene and its derivatives was in 1960.
By combining microwave processes and halogen exchange, the process of the invention enables large scale production of specialty fluoroaromatic compounds with the same cost and efficiency benefits that large pharmaceutical players are currently experiencing with the production of other compounds via microwave chemistry. This microwave assisted halogen exchange (MAHE) fluorination technology will not only help to reduce energy consumption by up to 50% verse conventional heating processes, but will reduce the overall carbon footprint and overall production cost. Additionally the process of the invention allows current conventional production reactors to be retrofitted with the microwave process, thereby reducing costs associated with retooling or new facility development.
Pentafluorosulfanyl aromatic compounds can be produced by as many as five different methods, but other processes are not able to prepare pentafluorosulfanyl chloroaromatic compounds in a single step. The process of the invention achieves single step production of pentafluorosulfanyl chloroaromatic compounds. Adding elemental fluorine directly to bis(chloroaromatic) disulfide or bis(polychloroaromatic) disulfide at subzero temperatures produced the respective pentafluorosulfanyl chloroaromatic or polychloroaromatic compound in high yield, in a single step.
One of many potential products of the current process is exemplified by the preparation of active pharmaceutical ingredients, e.g. levofloxacin, containing SF5 group is illustrated in
The preferred application of the process of the invention is shown in
An activating substituent, like CN (nitrite), NO2 (nitro), CF3 (trifluoromethyl) and F (fluoro) substitution on the benzene ring, enhances the efficiency of Halex substitution, and can be converted to other functional groups. While chlorobenezonitriles and chloronitrobenzenes have high boiling points, between 200 and 300° C., the F and CF3 substituted analogs have lower boiling points between 100-200° C., and are being used for the experiments. Pentafluorosulfanyl-4-chlorobenzene has proven to be an acceptable and preferred first reactant 22. The reaction assembly 66 includes a stirring feature 14, in the form of a magnetic stir bar 16, and a magnetic stir motor 18. Other reaction assemblies could have other forms of stirring, such as an impeller, or other stirring means known in the chemical field.
The reaction assembly 66 includes a cooling system 20, in the form of a flow of cooled air 50 which flows around the outside of the reaction vessel 12. Other cooling systems known in the chemical field would also be suitable for use in the process of the invention.
The second reactant 26 is selected from the group comprising basic fluorides like KF, and acidic fluorides like SbF3 and AlF3, for introducing fluorine atoms into organic compounds. Fluorinated organics are huge synthetic ingredients for the production of fine pharmaceuticals and agrochemicals, and have market worth estimated at more US $5 billion.
Although basic KF is widely applied in conventional industrial HALEX processes, acidic AlF3 and SbF3 have no dipoles and may be better suited for potentially energy efficient microwave-assisted Halex processes of the future.
The reaction assembly 66 of
A solvent 30 is optional and may be selected from the group comprising dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), sulfolane, dimethylformamide, and N,N-dimethylacetamide (DMAC), chlorobenzene, dichlorobenzene, trichlorobenzene, xylene, and toluene. The halogen exchange reaction of the invention can be performed in a dipolar aprotic solvent, in a non-polar solvent in the presence of a phase transfer catalyst, or in the absence of a solvent. The process of the invention is applicable for the production of fluoroorganic compounds, including, but not limited to fluoroaliphatics, fluorinated cyclic-aliphatics, fluoroaromatics, and fluorinated heterocyclic rings.
If the characteristics of a dipolar non-polar solvent are required to achieve a higher yield and easy isolation of the product, such may be utilized with the process of the invention. Examples of dipolar solvents include dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), sulfolane, dimethylformamide, and N,N-dimethylacetamide (DMAC). The preferred dipolar solvent is sulfolane because it is inexpensive and is stable and its boiling point is above the reaction temperature. Examples of non-polar solvents include chlorobenzene, dichlorobenzene, trichlorobenzene, xylene, and toluene. Trichlorobenzene is preferred as a non-polar solvent, as its boiling point is above the reaction temperature. If an aprotic solvent is used, sulfone is suitable, as is methylpyrrolidinone, which are high and medium microwave absorbers, respectively.
The phase transfer catalyst 28, for instance (C18H37)3(Me)N+Cl−, is miscible with the first reactant 22, (chloroaromatic reagent), and together they form a homogenous liquid. The halide exchange between basic fluorides, like KF, CsF, or RbF and chloroaromatic reagents is expected to rapidly produce the analogous chloride products as stable side products.
The cooling of the reactants simultaneously with application of highest possible microwave power (50 W-600 W), which forces the system to rapidly attempt to attain the set temperature. The set-temperature is the temperature at which the reaction occurs. The heat doesn't do the magic of reducing the process time as does the unique application of microwave power. Microwave irradiation heats the system, and energizes individual bonds to reaction. The cooling allows continuous application of the beneficial MW power while keeping the solution within the optimum temperature bounds.
After the reaction has proceeded a sufficient time, the reactants are allowed to cool, and the reaction assembly is purged with inert gas 32. After the reactants have cooled, the liquid product 34 is recovered from the reaction vessel 12.
A preferred microwave heater is the Discover BenchMate System microwave fabricated by CEM Instruments of Matthews, N.C. Current commercially available laboratory microwaves can operate up to 400° C. with a glass or quartz reactor. However, fluoride-corrosion resistant reactors are currently operable up to 200° C. (Teflon) and 260° C. (Teflon-PEEK polymer). Many halogen exchange reactions of KF, CsF or RbF were previously performed in glass vessels, taking necessary precautions to prevent moisture in the system. These fluorides will react with trace moisture leading to production of hydrogen fluoride gas that etches glass.
The following are some of the specifications of the Discover BenchMate System microwave which is the preferred microwave heater for the process of the invention. The Discover BenchMate system is a 300-watt laboratory microwave reactor module. The microwave applicator provides a self-tuning feature to insure optimal field tuning to all samples. The platform includes a fluoropolymer sleeved cavity with cavity access port, vacuum fluorescent display with alpha/numeric capabilities, an alpha/numeric keypad, (1) computer port, (1) Ethernet network port, and a detachable power cord. The system is capable of continuous power delivery which can be varied in 1-watt increments. It has dimensions of 14.4 W×17.2 D×8.7H with a weight of 30 lbs. The LabMate Intellivent package comes configured with the following options:
Magnetic Stirring Option
Standard Cooling Option
Infrared Temperature Feedback Control
Intellivent SafeSeal Option
Accessory Kit
This system accommodates vessels ranging in size from a 5-mL tube to a 125 mL round bottom flask −24/40 ground glass joint.
One preferred embodiment of the process of the invention is one that utilizes a software controller for controlling the microwave output over time. The Synergy Software Option is a PC-based software package that allows the user to program, monitor, and control all System functions. The software package communicates via either serial port or Ethernet connection to the various instruments. The package creates, and allows for the full management of, a database for all system reaction data. System methods can be downloaded to the Instrument Modules or uploaded from the Instrument Modules' onboard memory to the software platform. The package is Windows 2000, NT, and Vista compliant. Minimum system requirements are a Pentium P4 class processor running at 1.6 GHz, with 64 Mb of RAM and with at least 120 Mb of available disk space. An Ethernet and serial Cable is included in the option.
The reaction of the process of the invention is preferably carried out between 140-260° C. The maximum operable temperature of a Teflon reactor may restrict the maximum temperature to 200° C. The reactions of KF, CsF and RbF can occur at 200° C.
The reactor system can be conducted at pressures up to 300 PSIG, however, use of a Teflon reactor may reduce the maximum pressure to 120 PSIG.
The process of the invention is exemplified by the following example procedures.
Place 20.2 g (0.116 mol) 3,4-dinitrochlorobenzene, 0.7 g (0.002 mol) (C8H17)3N+Cl−, a phase transfer catalyst (about 6% mol chloroaromatic reagent). Freeze the chloroaromatic reagent, and pull vacuum to remove air and moisture from the system. Purge the system with nitrogen to atmospheric pressure. While maintaining inert atmosphere in the 125 mL reactor, add 6.8 g (0.117 mol) potassium fluoride—a solid fluorinating agent, a magnetic stir bar, and fit the reactor to a 24″ reflux condenser that is fitted to a source of constant purging by an inert gas. Program the software to set reaction profile and power cut off limit. Microwave power was set at 300 W, and this was accompanied by flow of dry air regulated to 20 PSIG from a compressed cylinder at 1 standard liter per minute (SLPM), power will be required. Ensure vigorous stirring of the reaction. After adequate reaction time has lapsed, cool down the system to room temperature. Purge the system with N2 or Helium. Aliquot samples were removed at 1 h, 2 h, 5 h, and 9 h process time and analyze raw product samples by GC to reveal yields of 24, 35, 44, and 92 percent yields, respectively. This result compared to 13.4 percent yield of the expected product-3-chloro-4-fluoronitrobenzene—by conventionally heating the reaction for 9 h, in U.S. Pat. No. 5,545,768 (1996).
In this work, pentafluorosulfanyl 4-chlorobenzene and pentafluorosulfanyl 4-fluorobenzene were prepared in 39-42% by direct fluorination of the respective bis(4-halophenyl) disulfide by using 10% Fluorine in nitrogen mixture at low temperatures. The products in the figure below were characterized by their boiling points.
Their individual retention times were obtained by elution of volatile solution on a gas chromatograph, and used to calibrate the method for determination of yields of microwave-assisted halogen exchange (MAHE) fluorination process in the
0.2 g (0.000839 mol) 4-Chlorophenyl sulfurpentafluoride, (4-C1—C6H4SF5); 0.4 g (0.0069 mol) spray dried potassium fluoride; 0.05 g, (0.000129 mol) (C8H17)3N+C−; 3 mL N-methylpyrrolidinone (NMP); and a 1-cm long magnetic stirrer were placed in a 10 mL reactor in an inert atmosphere. The CEM Intellivent™ cap, a safety vent at 300 PSIG, was carefully placed as reactor cover. The mixture consisted of clear liquid solution of A in xylene or nitrobenzene over solid white potassium fluoride and magnetic stirrer. The glass reactor was then placed into the single mode microwave chamber of CEM Discover™ instrument The CEM Synergy™ software was used to control and program power, stirring, temperature, and cooling inputs of the process method. The method for this process included the following settings: power=300 W, stirring=ON, temperature=180° C.; chamber cooling=ON. The method controlled the start, stop, and program the duration of the application of microwave power. At the end of the 3 h process, and subsequent cooling, the intellivent cap was carefully opened to reveal a brown mixture. The solution was extracted with 50 mL diethyl ether. The organic content was washed twice with 20 mL water in a separating funnel, and dried by using magnesium sulfate. The crude mixture was analyzed by Gas chromatography (GC). Further, the diethyl ether solution mixture of the byproducts was evaporated under vacuum, dissolved in deuterated chloroform (CDCl3), and analyzed by 19F nuclear magnetic resonance (NMR). The spectrum shows that the sulfurpentafluoride (SF5) group, as signals at 62.6 ppm (doublet) and 82.8 ppm (quintet), was not destroyed by the MAHE fluorination process.
Preliminary recording of GC retention time for 4-chlorophenyl sulfurpentafluoride (
5 g (0.021 mol) 4-Chlorophenyl sulfurpentafluoride, (4-Cl—C6H4SF5); 10 g (0.172 mol) spray dried potassium fluoride; 0.34 g, (0.00129 mol) 18-Crown-6; 40 mL N-methylpyrrolidinone (NMP, an average absorber of microwave energy); and a 3-cm long magnetic stirrer were placed in a 125 mL reactor in an inert atmosphere. The flask was carefully fitted with a reflux condenser and constant nitrogen purge at 50 ml/min at 1 atm. At the beginning, the mixture consisted of clear liquid solution in sulfolane over solid white potassium fluoride and magnetic stirrer. The glass reactor was then placed into the single mode microwave chamber of CEM Discover™ instrument The CEM Synergy™ software was used to control and program power, stirring, temperature, and cooling inputs of the process method. The method for this process included the following settings: power=300 W, stirring=ON, temperature=180° C.; chamber cooling=ON. The method controlled the start, stop, and program the duration of the application of microwave power. At the end of the 5 h, and subsequent cooling, the condenser was carefully removed, and the flask taken out of the microwave chamber to reveal a brown mixture. The solution was extracted with 150 mL diethyl ether. The organic content was washed twice with 60 mL water in a separating funnel, and dried by using magnesium sulfate. The crude mixture was analyzed by Gas chromatography (GC), and the results are shown in
While the invention is susceptible of various modifications and alternative constructions, certain illustrated embodiments thereof have been shown in the drawings and will be described below in detail. It should be understood, however, that there is no intention to limit the invention to the specific form disclosed, but, on the contrary, the invention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the invention as defined in the claims.
While there is shown and described the present preferred embodiment of the invention, it is to be distinctly understood that this invention is not limited thereto but may be variously embodied to practice within the scope of the following claims. From the foregoing description, it will be apparent that various changes may be made without departing from the spirit and scope of the invention as defined by the following claims.
This application claims the priority date of the provisional application entitled Halex Microwave Fluorination: Energy Efficient Production of Fluorinated Active Pharmaceutical Ingredients by Halogen Exchange Processes filed by Bamidele Omotowa on Jan. 1, 2008 with application Ser. No. 61/011,210.
| Number | Date | Country | |
|---|---|---|---|
| 61011210 | Jan 2008 | US |
