Patent Application
20190330150
The present invention relates to processes for the preparation of intermediates useful in the preparation of Vilazodone, and in particular, a 3-(4-halobutyl)-5-cyanoindole.
Vilazodone hydrochloride, or 5-[4-[4-(5-cyano-1H-indol-3-yl)butyl]-1-piperazinyl]-2-benzofurancarboxamide hydrochloride, exhibits activity as a selective serotonin reuptake inhibitor (SSRI), and is marketed in the United States as VIIBRYD®, which is indicated for the treatment of patients with major depressive disorder (MDD). Vilazodone hydrochloride (A) has the following structural formula:
The compound of Formula (1), wherein X is a halide, and particularly wherein X is chloride, is reported to be useful as an intermediate in the preparation of Vilazodone hydrochloride (A):
One approach that is commonly used to prepare the compound of Formula (1) is by reductive deoxygenation of the compound of Formula (2) in the presence of a suitable reducing agent as shown in Scheme 1. This methodology is reported in, for example, U.S. Pat. Nos. 5,418,237, 5,532,241, 6,509,475, Heinrich, T., et al. J. Med. Chem. 2004, 47, 4684-4692, Heinrich, T., et al. ACS Med. Chem. Lett. 2010, 1, 199-203, CN102690224, CN102659660, WO 2014/006637 A2, CN102875440, CN103467357, WO 2013/153492 A2, CN103880729, CN104592087, CN103910668 and U.S. Pat. No. 9,533,949.
In many cases, known processes for this reduction employ hazardous reducing agents and Lewis acids such as diborane, sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al®), chlorotrimethylsilane, isobutylaluminium dichloride and titanium tetrachloride. Further, the use of highly reactive and pyrophoric reagents like diborane and isobutylaluminium dichloride raises safety concerns, particularly when used on an industrial scale, where the control of exotherms of a large volume of material is challenging. When using such reagents, the necessary thermal control is typically achieved by slow addition of the reactive agent(s) under the application of a cooling mechanism, which is inefficient on a large scale owing to the low surface area to volume ratio of the reducing agent and the compound of Formula (2), and a reduction in mixing effectiveness. Additionally, depending on the choice of reagents, over-reduction of the indole ring has been reported to occur using this approach.
Owing to the drawbacks of the existing processes for the preparation of the compound of Formula (1), there is a need for improved processes for the preparation of the compound of Formula (1) that are more amenable to scale-up and use in a commercial setting.
The present invention provides improved processes for the preparation of the compound of Formula (1) that employ continuous flow technology.
Development of the processes of the present invention followed, in part, from the industrial scaling of the batch-mode reduction using sodium borohydride/iron(III) chloride that is described in U.S. Pat. No. 9,533,949 B2 and shown in Scheme 2. When this reduction was scaled from laboratory to industrial scale, there was an increase in the amount of certain impurities, and in particular, the impurity of Formula (IMP), which occurred at levels of 2-3%, and was persistent and difficult to remove. As a result, additional purification operations were required to lower the impurity levels in the compound of Formula (1-A) to acceptable levels, resulting in a lower than desired overall yield. Methods were therefore desired to provide the compound of Formula (1), and particularly the compound of Formula (1-A), with an improved impurity profile and increased yield, goals that were achieved with the continuous flow process described herein.
Without wishing to be bound to any particular theory, it is believed that the impurity of Formula (IMP) forms as a result of the reaction shown in Scheme 3, wherein the intermediate of Formula (3-A) reacts with the product of Formula (1-A). Based on this potential mechanism, it was reasoned that lower levels of the impurity of Formula (IMP) may be attainable by limiting the exposure of the intermediate of Formula (3-A) to the product of Formula (1-A). Thus, the present invention provides a process for the preparation of the compound of Formula (1-A) that produces lower levels of impurity of Formula (IMP) than are observed in known processes, by limiting the exposure of the intermediate of Formula (3-A) to the product of Formula (1-A) through the use of a continuous flow process such that reaction materials are carried as a flowing stream, with reactants/reagents continuously streamed in and products continuously streamed out. In principle, when compared to a batch process, the continuous flow processes of the present invention provide greater separation between different phases of the reaction, such as starting materials, intermediates and products, thereby lowering the frequency of side-reactions and impurity formation. Indeed, preferred embodiments of the present invention provide the compound of Formula (1-A) having less than 0.1% of the impurity of Formula (IMP) prior to any purification operations in yields as high as 71 Scheme 3
In addition to the increased reaction selectivity provided by the processes of the present invention, the processes also provide increased safety arising from the reduced accumulation of potentially unstable and reactive intermediates associated with the use of reactive reducing agents, and to the increased ability to control exotherms that is provided by the high surface area to volume ratio in the flow system. In addition, effective heat transfer and mixing allows for enhanced temperature control, wherein cooling can be applied very briefly to control exotherms for safety reasons, for example, followed immediately by a period of heating to the optimal reaction temperature to facilitate the desired reaction.
Accordingly, in a first aspect of the present invention, there is provided a continuous flow process for the preparation of the compound of Formula (1):
comprising contacting a continuous flow (F1) of the compound of Formula (2):
wherein X is a halide,
in a solvent (S1), with a continuous flow (F2) of a Lewis acid in a solvent (S2), and with a continuous flow (F3) of a hydride donor reducing agent in a solvent (S3), to provide continuous flow (F4) containing the compound of Formula (1).
In a preferred embodiment of the first aspect, continuous flow (F1) and continuous flow (F2) are combined to form combined continuous flow (F1-2) prior to contact with continuous flow (F3).
In a further preferred embodiment of the first aspect, continuous flows (F1) and (F2) are combined in a first reactor, and the combined continuous flow (F1-2) that exits the reactor is contacted with continuous flow (F3) in a second reactor downstream from the first reactor to provide the continuous flow (F4). More preferably, continuous flow (F4) passes from the second reactor to a third reactor downstream from the second reactor. Preferably, the reactors are continuous stirred tank reactors.
In a further preferred embodiment of the first aspect, continuous flows (F1) and (F2) are combined at a first intersection to provide combined continuous flow (F1-2) that is then contacted with continuous flow (F3) at a second intersection downstream from the first intersection to provide continuous flow (F4). More preferably, continuous flow (F4) passes through one or more reactors connected in series downstream from the second intersection. Preferably, the reactors are continuous stirred tank reactors.
In another preferred embodiment of the first aspect, continuous flow (F4) is contacted with a supplemental continuous flow (F3′) of the hydride reducing agent in the solvent (S3′).
In preferred embodiments of the first aspect, X is chloride.
In further preferred embodiments of the first aspect, the hydride donor reducing agent is selected from the group consisting of lithium aluminium hydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride, triethylsilane, borane, diisobutylaluminium hydride and sodium bis(2-methoxyethoxy)aluminium hydride.
In further preferred embodiments of the first aspect, the Lewis acid is selected from the group consisting of aluminium(III) chloride, iron(III) chloride, magnesium chloride, zinc chloride and boron trifluoride.
In preferred embodiments of the first aspect, the hydride donor reducing agent is selected from the group consisting of borane and sodium borohydride and the Lewis acid is iron(III) chloride.
In further preferred embodiments of the first aspect, each of the solvents (S1), (S2), (S3) and, if present, (S3′), is independently an ether solvent.
In a further preferred embodiment of the first aspect, the Lewis acid is iron(III) chloride, the hydride donor reducing agent is sodium borohydride, solvents (S1) and (S2) are both tetrahydrofuran, and solvent (S3) is tetraglyme. In another preferred embodiment, the Lewis acid is iron(III) chloride, the hydride donor reducing agent is borane, and each of the solvents (S1), (S2). (S3) and, if present, (S3′), is tetrahydrofuran.
In another preferred embodiment of the first aspect, continuous flow (F4) is quenched prior to isolation of the compound of Formula (1). Preferably, continuous flow (F4) is quenched using an aqueous solution. Most preferably, the aqueous solution comprises citric acid.
In a second aspect of the present invention, there is provided a continuous flow system for conducting the continuous flow process of the first aspect of the invention. In a preferred embodiment, the continuous flow system comprises:
In a preferred embodiment of the second aspect, the first and second conduits are merged at a first intersection to provide a fifth conduit, and the third and fifth conduits are merged at a second intersection to provide the fourth conduit, and each of the intersections comprises either one or more reactors allowing for the mixing of two continuous flows, or three-way joints allowing for the merger of two continuous flows into one continuous flow. In a further preferred embodiment, each of the first and second intersections comprises a reactor. Alternatively, each of the first and second intersections comprises a three-way joint.
In a further preferred embodiment of the second aspect, the fourth conduit comprises one or more reactors connected in series between the second intersection and the quench tank.
In another preferred embodiment of the second aspect, the continuous flow system further comprises a supplemental vessel for holding a supplemental portion of the hydride donor reducing agent in solvent (S3′), wherein the supplemental vessel is in fluid communication with a supplemental conduit at one end, and another end of the supplemental conduit merges with the fourth conduit at a third intersection comprising either a reactor or a three-way joint, and a pump causes the continuous flow of solution from the supplemental vessel through the supplemental conduit.
Embodiments of the present invention are described, by way of example only, with reference to the attached Figures.
The processes of the present invention provide improvements in the preparation of the compound of Formula (1), which is an intermediate useful in the preparation of Vilazodone (A), over known processes, including enhanced safety, efficiency and selectivity, and are therefore more amenable to industrial application.
As used herein, “room temperature” generally refers to a temperature of 20-25° C.
As used herein, the term “about” means “close to”, and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, when the term “about” is used with respect to temperature, a variation of ±5° C. is generally acceptable when carrying out the processes of the present invention. When used with respect to mole equivalents, a variation of ±0.1 moles is generally acceptable.
As used herein, the term “conduit” refers to any compatible pipe, tube, channel or similar means for conveying fluids in a continuous flow process.
As used herein, the term “residence time” refers to the time required for the subject material to traverse a specified pathway.
As used herein, the term “continuous stirred tank reactor”, abbreviated “CSTR” refers to a reactor comprising a tank, a stirring system and means to continuously introduce reactants and continuously remove products.
As used herein, the term “plug flow reactor”, abbreviated “PFR”, refers to a reactor comprising a conduit wherein reactants are continuously introduced through an inlet and products are continuously withdrawn through an outlet.
In one embodiment of the present invention, there is provided a continuous flow process for the preparation of the compound of Formula (1):
comprising contacting a continuous flow (F1) of the compound of Formula (2):
wherein X is halide,
in a solvent (S1), with a continuous flow (F2) of a Lewis acid in a solvent (S2), and with a continuous flow (F3) of a hydride donor reducing agent in a solvent (S3), to provide continuous flow (F4) containing the compound of Formula (1).
In preferred embodiments of the present invention, the continuous flow process is executed in continuous flow systems having configurations such as those shown in
In
An alternative embodiment shown in
In
In the embodiment shown in
Other alternative configurations of the continuous flow system are also suitable. Preferably, the continuous flow system comprises a combination of conduits and reactors (preferably CSTRs). Usage of a series of one or more reactors in the flow system is preferred. More preferably, three or more CSTRs are used in series as part of the continuous flow system.
Alternatively, the process of the present invention may be implemented in a continuous flow system comprising a PFR using a number of intersecting conduits without tank reactors as shown in
In the processes of the present invention, variables related to the execution of the processes are typically optimized by first determining the time required to achieve reaction completion at a given temperature. This reaction time can then be used to establish the necessary residence time, defined as the time it takes to traverse from contact of continuous flows to quench of the reaction components, in the continuous flow system. The volume of the continuous flow system and the prescribed residence time establish the necessary flow rate of (F4), and the continuous flows (F1), (F2), (F3), and, when used, (F3′). Depending upon the choice of reactants, temperatures and scale of the system, the residence time of the processes of the present invention may be in the range of from about 5 minutes to about 1 hour, and is preferably from about 5 minutes to about 40 minutes.
Preferably, reactants are provided as a stock preparation in a vessel (for example, (V1), (V2), (V3) and (V3′) in
A separate stock preparation of each reactant is preferably provided for use in the present invention. However, it is also possible to prepare a mixed stock preparation of two compatible reactants, if desired. For example, the compound of Formula (2) and the Lewis acid can be prepared as a single stock preparation, in which case, the continuous flow of (F1) and (F2) is a combined continuous flow (F1-2). Alternatively, pre-combination of two compatible reactants such as the compound of Formula (2) and the Lewis acid is provided by intersecting two distinct continuous flows (F1) and (F2) of each reactant to provide a new continuous flow (F1-2).
In the compound of Formula (2), X is preferably selected from the group consisting of chloride, bromide and iodide. Most preferably, X is chloride.
Solvent (S1) is any suitable solvent capable of forming a stable suspension with the compound of Formula (2) that resists rapid settling, is easily re-dispersed, and flows through the continuous flow system at the desired operational temperature, which is typically from about −5° C. to about 60° C. Preferably, solvent (S1) is selected from the group consisting of ethers and aromatic hydrocarbons. More preferably, solvent (S1) is selected from the group consisting of tetrahydrofuran, diglyme, tetraglyme and toluene. Most preferably, solvent (S1) is tetrahydrofuran.
The concentration of the compound of Formula (2) in solvent (S1) in continuous flow (F1) is a practical concentration which maintains good flowability. Preferably, this concentration is from about 0.6 M to about 1.4 M, more preferably between about 0.90 M and about 1.05 M, even more preferably between about 0.95 M and about 1.05 M, and most preferably about 1.0 M.
The optimal flow rate of continuous flow (F1) is determined taking into consideration the desired stoichiometry of the reaction, the prescribed residence time, and the total volume of the continuous flow system. The compound of Formula (2) is the limiting material in the present invention.
The Lewis acid is any suitable Lewis acid capable of facilitating reductive deoxygenation of a 3-ketoindole in the presence of a hydride reducing agent. Preferably, the Lewis acid is selected from the group consisting of aluminium(III) chloride, iron(III) chloride, magnesium chloride, zinc chloride and boron trifluoride. More preferably, the Lewis acid is selected from the group consisting of aluminium(III) chloride and iron(III) chloride, and is most preferably iron(III) chloride.
Solvent (S2) is any suitable solvent capable of providing complete or substantial dissolution of the Lewis acid at the desired operational temperature, which is typically from about −5° C. to about 60° C. Preferably, solvent (S2) is an ether solvent. More preferably, solvent (S2) is selected from the group consisting of tetrahydrofuran, diglyme and tetraglyme, and is most preferably tetrahydrofuran.
The concentration of the Lewis acid in solvent (S2) in continuous flow (F2) is a practical concentration which maintains dissolution of the Lewis acid. Preferably, the concentration is from about 0.7 M to about 2.0 M, more preferably from about 1.0 M to about 1.25 M, even more preferably from about 1.1 M to about 1.2 M, and most preferably about 1.1 M.
The flow rate of continuous flow (F2) is determined taking into consideration the desired stoichiometry of the reaction, the prescribed residence time, and the total volume of the continuous flow system. Preferably, the molar ratio of the Lewis acid with respect to the compound of Formula (2) is from about 1:1 to about 1.4:1, more preferably from about 1:1 to about 1.3:1, and most preferably is about 1.2:1.
The hydride donor reducing agent is a suitable agent capable of donating two hydride equivalents to facilitate reductive deoxygenation of a 3-ketoindole in the presence of a Lewis acid. Preferably, the hydride donor reducing agent is selected from the group consisting of lithium aluminium hydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride, triethylsilane, borane, diisobutylaluminium hydride and sodium bis(2-methoxyethoxy)aluminium hydride. Most preferably, the hydride donor reducing agent is selected from the group consisting of borane and sodium borohydride.
Solvents (S3) and (S3′) are independently any suitable solvent capable of providing complete or substantial dissolution of the hydride donor reducing agent at the desired operational temperature, which is typically from about −5° C. to about 60° C. Preferably, the solvents (S3) and (S3′) are ethers selected from the group consisting of tetrahydrofuran, diglyme and tetraglyme, and are most preferably tetrahydrofuran or tetraglyme. Preferably, when used, solvent (S3′) is the same as solvent (S3).
The concentration of the hydride donor reducing agent in solvent (S3) or (S3′) in continuous flow (F3) or (F3′), respectively, is a practical concentration which maintains dissolution of the hydride donor reducing agent. Preferably, the concentration is from about 0.75 M to about 2.25 M, more preferably from about 1.0 M to about 2.1 M, and most preferably about 1.9 M.
The flow rate of continuous flow (F3) or (F3′) is determined taking into consideration the desired stoichiometry of the reaction, the prescribed residence time, and the total volume of the continuous flow system. Preferably, the molar ratio of the hydride donor reducing agent in continuous flow (F3) with respect to the compound of Formula (2) in continuous flow (F1) is from about 1:1 to about 1.3:1, more preferably the molar ratio is about 1:1 to about 1.2:1, and most preferably the molar ratio is about 1.1:1. Preferably, the molar ratio of the hydride donor reducing agent in continuous flow (F3′) with respect to the compound of Formula (2) in continuous flow (F1) is from about 0.1:1 to about 0.6:1, and more preferably the molar ratio is from about 0.2:1 to about 0.4:1.
In embodiments, the present invention provides passage of a continuous flow through a conduit. Suitable conduits are any compatible tubing, piping or channel for transmission of organic solutions. In some cases, lengths of conduit that are compatible for use with a peristaltic pump such as Masterflex® peristaltic tubing are used in combination with other types of conduit. Preferably, conduit is constructed of material selected from the group consisting of perfluoroalkoxy alkanes (PFA), polytetrafluoroethylene (PTFE), high density polyethylene (HDPE), Tygon® and Norprene®. Suitable inner diameter and length of conduit is selected to permit unobstructed flow of the contents.
The temperature of the flow of reactants in continuous flows (F1), (F2), (F3), (F3′) and reaction mixture in continuous flow (F4) can be modulated throughout the process as necessary to suit the particular reaction conditions. Due to the physical separation of phases of the reaction that is possible with continuous flow, the temperature is preferably adjusted at different phases to optimize reaction. For example, any exotherm that occurs upon combination of the reactants is preferably extinguished by applying a cooling means to that specific phase of the flow, whereas the temperature of a downstream phase of the flow is adjusted to the optimal reaction temperature for that phase of the process. Due to the excellent temperature control afforded by the high surface area to volume ratio in the continuous flow system, safety concerns are minimized, and reaction efficiency is greatly enhanced by this targeted temperature control. Preferably, any exotherm generated by combination of continuous flows (F1), (F2) and (F3) is controlled by cooling the continuous flow (F4) immediately following mixing to a temperature of from about 10° C. to about 20° C. Otherwise, in the absence of exotherm and/or upon dissipation of the exotherm, the temperature in the remainder of the downstream path of continuous flow (F4) is preferably from about 20° C. to about 60° C., most preferably from about 25° C. to about 40° C.
At the end of the reaction, the continuous flow (F4) is collected into a non-continuous flow quenching tank (Q). The quenching solution is any suitable agent capable of quenching hydride donor reducing agents. Preferably, the quenching solution is a dilute acid solution, preferably wherein the acid is selected from the group consisting of mineral acids and organic acids. Preferably, the quenching solution is aqueous citric acid.
The following examples are illustrative of some of the embodiments of the invention described herein. It will be apparent to the person skilled in the art that various alterations to the described processes in respect of the reactants, reagents and conditions may be made when using the processes of the present invention without departing from the scope or intent thereof. In particular, while the following examples refer to the use of a specific continual flow system design, it will be apparent to the person skilled in the art that different continual flow system designs could alternatively be used.
In the synthetic preparations described in the following Examples, all operations were conducted under a positive nitrogen pressure.
The HPLC method described in Table 1 was used to determine the purity (as area %) of the compound of Formula (1-A) in the following Examples.
The compound of Formula (2-A) (20 g, 81.09 mmol, 1.0 eq.) was combined with tetrahydrofuran (68 mL) in a 100 mL round bottomed flask (V1) and the mixture was stirred at room temperature to afford a light suspension (85 mL, 0.95 M).
Iron(III) chloride (14.47 g, 89.20 mmol, 1.1 eq.) was charged under nitrogen to a 100 mL two-necked round bottomed flask containing tetrahydrofuran (56 mL) at such a rate as to maintain the temperature of the solution during the exothermic addition at less than 30° C. The resulting green solution (78 mL, 1.14 M) was transferred via cannula to a conical flask (V2).
Sodium borohydride (4.60 g, 121.64 mmol, 1.5 eq.) was combined with tetraglyme (60 mL) in a 100 mL round bottomed flask and the mixture was stirred at room temperature to afford a solution (65 mL, 1.87 M). One portion of the solution (47.7 mL, 89.20 mmol, 1.1 eq. NaBH4) was transferred to a first conical flask (V3). The remainder of the solution (17.3 mL, 32.44 mmol, 0.4 eq. NaBH4) was transferred to a second conical flask (V3′).
A continous flow process was conducted in a Coflore® ACR (‘Agitated Cell Reactor’) system by AM Technologies (Runcorn, England) comprising a Digital ACR Agitating Platform (ACR-P200) and a Hastelloy® Reactor Block Assembly (ACR-100-Ha). As depicted in
The stock preparations were pumped by passing a section of the feed conduit through a peristaltic pump. Each conduit (C1), (C2), (C3) and (C3′), carrying continuous flows (F1), (F2), (F3) and (F3′), respectively, and the conduit (C13) leading to the quenching flask (Q), consisted of PFA tubing, other than a short section passing through the corresponding peristaltic pump, which was Masterflex® Chem-Durance Bio Pump L/S 14 peristaltic tubing connected in line with the PFA tubing. The conduits joining the CSTR units were provided as channels within the Reactor Block.
The stock preparations of the compound of Formula (2-A), iron(III) chloride, and sodium borohydride were connected to the Reactor Block as follows: (V1) was connected to (CSTR1) via conduit (C1), (V2) was connected to (CSTR1) via conduit (C2), (V3) was connected to (CSTR2) via conduit (C3), and (V3′) was connected to (CSTR6) via conduit (C3′). Each of conduits (C1), (C2), (C3) and (C3′) was then primed with the respective stock solution. The Reactor Block was heated to 40° C. via circulation of silicon oil from a heating unit.
Stock preparation of the compound of Formula (2-A) from (V1) was pumped as continuous flow (F1) at a flow rate of 0.514 mL/min into (CSTR1) along with the stock preparation of iron(III) chloride from (V2), which was pumped into (CSTR1) as continuous flow (F2) at a flow rate of 0.472 mL/min. When the combined continuous flow (F1-2) began to enter (CSTR2), the primary stock preparation of sodium borohydride in (V3) was pumped into (CSTR2) as continuous flow (F3) at a flow rate of 0.289 mL/min, at which point hydrogen gas evolution began, and the reaction mixture became an orange/green solution, which passed from (CSTR2) as continuous flow (F4) through (CSTR3), (CSTR4) and (CSTR5) into (CSTR6). When continuous flow (F4) started to enter (CSTR6), the stock preparation of sodium borohydride in (V3′) was pumped into (CSTR6) as supplemental continuous flow (F3′) at a flow rate of 0.105 mL/min.
After passing through (CSTR6) through (CSTR10), continuous flow (F4) passed out of (CSTR10) into quench flask (Q) containing an aqueous citric acid solution (0.67 M, 60 mL). At the set flow rates and working volume, the residence time of the process was about 30 minutes. Following consumption of the stock preparations, flasks (V1), (V2) and (V3) were replenished with tetrahydrofuran, which was pumped through the system from each respective flask for 30 minutes at the established flow rates. The combined rinses were collected in quench flask (Q) together with the reaction mixture.
The resulting biphasic solution was concentrated in vacuo to remove tetrahydrofuran, and diluted with n-butanol (60 mL) and water (40 mL) prior to phase separation. The organic phase was washed three times with water (40 mL), diluted with n-butanol (40 mL), and concentrated in vacuo to 40 mL. After concentration, the solution was diluted once more with n-butanol (60 mL) and re-concentrated in vacuo to 40 mL, at which time some solids precipitated. To the resulting suspension was charged concentrated (34-37%) HCl (8.19 g, 81.09 mmol, 1.0 eq.), and the mixture was heated to 65° C. for 3 hours, then slowly cooled to room temperature and maintained at this temperature for 14 hours. After this time, the suspension was filtered, washed with 10 mL cold (−10 to −5° C.) n-butanol and dried in vacuo to provide the compound of Formula (1-A) (6.80 g, 45.6% yield) having HPLC purity of 99.64%.
The compound of Formula (2-A) (20 g, 81.09 mmol, 1.0 eq.) was combined with tetrahydrofuran (73 mL) in a 100 mL round bottomed flask (V1) and the mixture was stirred at room temperature to afford a light suspension (90 mL, 0.90 M).
Iron(III) chloride (13.15 g, 81.09 mmol, 1.0 eq.) was charged to a 100 mL two-necked round bottomed flask containing tetrahydrofuran (68 mL) at such a rate as to maintain the temperature of the solution during the exothermic addition at less than 30° C. The resulting green solution (70 mL, 1.16 M) was transferred via cannula to a conical flask (V2).
A commercial solution of borane in tetrahydrofuran (1 M) was used. One portion of this solution (81 mL, 81 mmol, 1.0 eq. BH3) was transferred to a conical flask (V3). A second portion of this solution (16 mL, 16 mmol, 0.2 eq.) was transferred to a separate conical flask (V3′).
The continous flow process of this example was conducted using the same reactor system as described in Example 1.
The stock preparations of the compound of Formula (2-A), iron(III) chloride, and borane were connected to the Reactor Block as follows: (V1) was connected to (CSTR1) via conduit (C1), (V2) was connected to (CSTR1) via conduit (C2), (V3) was connected to (CSTR2) via conduit (C3), and (V3′) was connected to (CSTR6) via conduit (C3′). Each of conduits (C1), (C2), (C3) and (C3′) was then primed with the respective stock solution. The reactor block was maintained at 20° C. via circulation of silicon oil from a heating unit.
Stock preparation of the compound of Formula (2-A) from (V1) was pumped as continuous flow (F1) at a flow rate of 2.451 mL/min into (CSTR1) along with the stock preparation of iron(III) chloride from (V2), which was pumped into (CSTR1) as continuous flow (F2) at a flow rate of 1.907 mL/min. When the combined continuous flow (F1-2) began to enter (CSTR2), the primary stock preparation of borane in (V3) was pumped into (CSTR2) as continuous flow (F3) at a flow rate of 2.206 mL/min, at which point hydrogen gas evolution began, and the reaction mixture became a yellow/green solution, which passed from (CSTR2) as continuous flow (F4) through (CSTR3), (CSTR4) and (CSTR5) into (CSTR6). When the continuous flow (F4) started to enter (CSTR6), the stock preparation of borane in (V3′) was pumped into (CSTR6) as supplemental continuous flow (F3′) at a flow rate of 0.436 mL/min.
After passing through the remaining CSTRs ((CSTR6) through (CSTR10)), continuous flow (F4) passed out of (CSTR10) into quench flask (Q) containing an aqueous citric acid solution (0.67 M, 60 mL). At the set flow rates and working volume, the residence time of the process was about 5 minutes. Following consumption of the stock preparations, flasks (V1), (V2) and (V3) were replenished with tetrahydrofuran, which was pumped through the system from each respective flask for 5 minutes at the established flow rates. The combined rinses were collected in quench flask (Q) together with the reaction mixture.
The resulting biphasic solution was separated and the organic phase was concentrated in vacuo to 150 mL. The solution was diluted with n-butanol (20 mL) and water (40 mL) prior to phase separation. The organic phase was washed twice with water (40 mL) and then concentrated in vacuo to 40 mL. After concentration, the solution was diluted with n-butanol twice (40 mL, 60 mL) and re-concentrated in vacuo to 40 mL after each dilution, by which time some solids had precipitated. To the resulting suspension was charged concentrated (34-37%) HCl (8.19 g, 81.09 mmol, 1.0 eq.), and the mixture was heated to 65° C. for 3 hours, then slowly cooled to room temperature and maintained at this temperature for 14 hours. After this time, the suspension was filtered, washed with 10 mL cold (−10 to −5° C.) n-butanol and dried in vacuo to provide the compound of Formula (1-A) (12.54 g, 66.5% yield) having HPLC purity of 99.62%.
The compound of Formula (2-A) (30 g, 121.61 mmol, 1.0 eq.) was combined with tetrahydrofuran (105 mL) in a 100 mL round bottomed flask (V1) and the mixture was stirred at room temperature to afford a light suspension (135 mL, 0.90 M).
Iron(III) chloride (19.73 g, 121.61 mmol, 1.0 eq.) was charged to a 100 mL two-necked round bottomed flask containing tetrahydrofuran (103 mL) at such a rate as to maintain the temperature of the solution during the exothermic addition at less than 30° C. The resulting green solution (105 mL, 1.16 M) was transferred via cannula to a conical flask (V2).
A commercial solution of borane in tetrahydrofuran (1 M) was used. One portion of this solution (121.6 mL, 121.6 mmol, 1.0 eq. BH3) was transferred to a conical flask (V3). A second portion of this solution (24.3 mL, 24.3 mmol, 0.2 eq.) was transferred to a separate conical flask (V3′).
A continous flow process was conducted in a system (depicted in
The stock preparations of the compound of Formula (2-A), iron(III) chloride) and borane were pumped through the respective conduits by passing a section of the conduit through peristaltic pumps (P1), (P2), (P3) and (P3′), respectively. The flow through the three CSTR flasks and into the quenching flask was controlled by passing each connecting conduit through peristaltic pumps (P4), (P5) and (P6), which were activated once the desired working volume in each CSTR was obtained, with the flow rates set to correspond with the incoming flow rates to maintain CSTR volume. Each conduit (C1), (C2), (C3) and (C3′), (C6), (C7) and (C8) consisted of PFA tubing, other than a short section passing through the corresponding peristaltic pump, which was Masterflex® Chem-Durance Bio Pump L/S 14 peristaltic tubing. All other conduits were PFA tubing.
Stock preparation of the compound of Formula (2-A) from (V1) was pumped as continuous flow (F1) at a flow rate of 4.898 mL/min through (C1) towards the first three-way joint (T1). At the same time, stock preparation of iron(III) chloride from (V2) was pumped as continuous flow (F2) at a flow rate of 3.809 mL/min through (C2) towards the first three-way joint (T1). At the first three-way joint (T1), continuous flows (F1) and (F2) joined to form continuous flow (F1-2), which flowed from (T1) through conduit (C4). When the combined continuous flow (F1-2) in (C4) approached the second three-way joint (T2), the primary stock preparation of borane in (V3) was pumped through conduit (C3) as continuous flow (F3) at a flow rate of 4.412 mL/min towards (T2). At the second three-way joint (T2), continuous flows (F1-2) and (F3) join to form continuous flow (F4), which flowed from (T2) through conduit (C5) towards (CSTR1). Continuous flow (F4) passed through conduit (C5), which was submerged in a water bath at 20° C. to control the temperature of the resulting exothermic reaction, and then entered into the first of the three CSTR units. When the continuous flow (F4) of the reaction mixture started to enter (CSTR2), the stock preparation of borane in (V3′) was pumped into (CSTR2) as supplemental continuous flow (F3′) at a flow rate of 0.881 mL/min through conduit (C3′).
The continuous flow (F4) passed from (CSTR2) into (CSTR3), and then out of (CSTR3) into quench flask (Q) containing an aqueous citric acid solution (0.67 M, 60 mL). At the set flow rates and working volume, the residence time of the process was about 5 minutes. Following consumption of the stock preparations in (V1), (V2) and (V3), the flasks were replenished with tetrahydrofuran, which was pumped through the system from each respective flask for 5 minutes at the established flow rates. The combined rinses were collected in quench flask (Q) together with the reaction mixture.
The resulting biphasic solution was separated and the organic phase was concentrated in vacuo to 300 mL. The concentrated organic solution was diluted with n-butanol (60 mL) and water (60 mL), and the phases were separated, with the organic phase being washed twice with water (60 mL) before being concentrated in vacuo to 60 mL, at which time some solid precipitated. After concentration, the suspension was heated to 65° C. and concentrated (34-37%) HCl (12.45 g, 121.61 mmol, 1.0 eq.) was charged, and the mixture was maintained at 65° C. for 3 hours, before being slowly cooled to room temperature and maintained at this temperature for 14 hours. After this time, the suspension was filtered, washed with 15 mL cold (−10 to −5° C.) n-butanol and dried in vacuo to provide the compound of Formula (1-A) (20.16 g, 71% yield) having HPLC purity of 99.60%.
This application claims the benefit of U.S. Provisional Patent Application No. 62/664,501, filed Apr. 30, 2018, the disclosure of which is hereby incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62664501 | Apr 2018 | US |
