Flow synthesis method for producing oseltamivir

Abstract

The present invention provides a flow synthesis method for producing oseltamivir and pharmaceutically acceptable salts thereof from shikimic acid, and particularly but not exclusively provides a flow synthesis method for producing oseltamivir phosphate from shikimic acid in a nine-step flow synthesis, which provides better reaction time and product yield compared with known methods.

Description

Technical Field

[0001] The present invention relates to a method for producing oseltamivir and its pharmaceutically acceptable salts, in particular to a flow synthesis method for producing the compound. Background Art

[0002] Influenza is a serious viral infection of the respiratory system that causes significant morbidity and mortality due to annual epidemics and predictable pandemics. In the United States alone, 200,000 hospitalizations and 36,000 deaths are recorded each year. In addition, the virus affects approximately 20% of the world's population and causes approximately 500,000 deaths each year.

[0003] Oseltamivir phosphate is a compound in a class of compounds called neuraminidase inhibitors (NAIs) used to treat and prevent influenza. It is effective against influenza caused by influenza A and influenza B viruses.

[0004] Many methods and synthetic routes for preparing oseltamivir phosphate are described in the prior art.

[0005] However, existing synthetic methods for producing these compounds are essentially based on standard stirred batch reactor type processes, in which large amounts of organic solvents are used. In addition, most known methods either employ azide chemistry or protecting group chemistry, both of which introduce inherent limitations, particularly in batch processes.

[0006] EP 2 193 116 describes this batch method for the method for producing oseltamivir phosphate from shikimic acid. The method adopted is a typical batch method, and there is no suggestion that it may be desirable to try to develop a flow synthesis method based on the methods, reagents and reaction conditions disclosed therein. In addition, there is no description of how the steps disclosed in the application can be adjusted and improved to achieve a flow synthesis method that is excellent in both reaction time and reaction yield.

[0007] Azide chemistry raises many safety issues because of its dangerous and highly exothermic nature, which becomes even more apparent on an industrial scale. Due to these inherent dangers, process chemists are limited in the reaction parameters that can be used to maximize reaction efficiency and reaction yield. On the other hand, protecting group chemistry typically increases reaction time while reducing overall yield, thereby increasing final product cost.

[0008] Microreactor Technology (MRT), recently referred to as "flow chemistry", is an emerging technology that enables researchers and developers to rapidly screen reactions using continuous flow to identify reaction conditions suitable for use at a production level. Furthermore, in addition to using traditional reaction methods, the inherent safety associated with the use of small reactor volumes enables the user to employ reaction conditions that were previously considered too dangerous to use in a production environment; such as extreme reaction conditions or the use / generation of "hazardous" compounds. Thus, the types of reactions available to chemists are increased by using this technology.

[0009] Furthermore, in the case of oseltamivir phosphate, continuous flow synthesis may provide a technology efficient enough to enable rapid local manufacturing in a pandemic situation, particularly in developing countries.

[0010] The present invention seeks to address some of the shortcomings of the prior art by providing a novel flow chemistry process for the production of oseltamivir. Summary of the invention

[0011] According to a first aspect of the present invention, there is provided a flow synthesis method for producing a compound of formula 33 and a pharmaceutically acceptable salt thereof,

[0012]

[0013] The method comprises the following steps:

[0014] a) preparing ethyl shikimate of formula 39 by reacting shikimic acid with a reagent selected from the group consisting of (COCl)2, SOCl2, benzenesulfonic acid (BSA), p-toluenesulfonic acid (PTSA) and Amberlyst 15

[0015]

[0016] b) reacting ethyl shikimate of formula 39 with methanesulfonyl chloride in the presence of a base selected from trimethylamine (TEA), 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), imidazole and trihexylamine (THA) to produce O-trimethanesulfonate of formula 40

[0017]

[0018] c) reacting the O-trimethanesulfonate of formula 40 with a suitable azidating agent in an azidation reaction to produce the azide of formula 41

[0019]

[0020] d) reacting the azide of formula 41 with a trialkyl phosphite in an aziridination reaction to produce the aziridine of formula 42

[0021]

[0022] e) reacting an aziridine of formula 42 with 3-pentanol in the presence of a Lewis acid catalyst to produce a 3-pentyl ether of formula 43

[0023]

[0024] f) reacting the 3-pentyl ether of formula 43 with H2SO4 in an acetylation reaction and then with Ac2O in the presence of a suitable base to produce the acetamide of formula 44

[0025]

[0026] g) reacting the acetamide of formula 44 with a suitable azidating agent in an azidation reaction to produce the azide of formula 32

[0027] and

[0028] h) reacting the azide of formula 32 to produce a compound of formula 33 by mixing the azide with CoCl2 and reacting the mixture with NaBH4.

[0029] Preferably, the method further comprises reacting the compound of formula 33 with phosphoric acid to produce a compound of formula 3

[0030]

[0031] Preferably, in step (a), shikimic acid is reacted with (COCl)2 or Amberlyst 15.

[0032] In one embodiment, in step (a), shikimic acid is reacted with COCl2 at a temperature between about 120°C to about 170°C.

[0033] In another embodiment, in step (a), shikimic acid is reacted with Amberlyst 15 at a temperature between about 100°C to about 145°C.

[0034] In one embodiment, the reaction in step (b) is carried out at room temperature.

[0035] In a preferred embodiment, the reaction in step (b) is carried out under ultrasonic treatment.

[0036] Preferably, in step (b), the base is present in a concentration of about 8 to about 20 molar equivalents relative to ethyl shikimate.

[0037] In one embodiment, in step (c), the azidation reaction is carried out with a concentration of about 1.1 molar equivalents of NaN 3 relative to the O-trimethanesulfonate of formula 40.

[0038] In a preferred embodiment, in step (c), the azidation reaction is carried out using NaN3 at a temperature of about 50°C.

[0039] Preferably, in step (d), the trialkyl phosphite is selected from triethyl phosphite and trimethyl phosphite.

[0040] In a preferred embodiment, in step (d), the reaction is carried out in acetonitrile at a temperature between about 150°C to about 190°C.

[0041] In a preferred embodiment, in step (e), the reaction is carried out at a temperature between about 60°C and about 100°C.

[0042] Preferably, wherein in step (f), the reaction of 3-pentyl ether with H2SO4 is carried out at a temperature between about 140°C and about 180°C.

[0043] Preferably, in step (g), the reaction is carried out at a temperature between about 140°C and about 200°C.

[0044] In one embodiment, in step (h), the reaction is carried out at room temperature.

[0045] In a preferred embodiment, in step (h), the reaction is carried out under ultrasonic treatment. BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The present invention will now be described in more detail with reference to the following non-limiting embodiments and accompanying drawings, in which:

[0047] Figure 1 An example of an optimized synthetic route for a continuous flow synthesis method for producing oseltamivir phosphate is shown;

[0048] Figure 2 The effect of SOCl2 equivalents on esterification of shikimic acid is shown;

[0049] Figure 3 The effect of residence time on the esterification of shikimic acid using excess SOCl2 is shown;

[0050] Figure 4 showed the esterification of shikimate using (COCl)2 in a continuous flow system;

[0051] Figure 5 Optimization of continuous flow shikimate esterification using BSA is shown;

[0052] Figure 6 Optimization of continuous flow shikimate esterification using PTSA is shown;

[0053] Figure 7 A continuous flow system for esterification of shikimic acid using dry Amberlyst 15 is shown;

[0054] Figure 8 The effect of residence time on the mesylation of flowing ethyl shikimate is shown;

[0055] Fig. 9 The effect of the molar equivalent of base (TEA) on the conversion of ethyl shikimate is shown;

[0056] Fig.10 The effects of various bases on continuous flow mesylation are shown;

[0057] Fig.11 The azidation conversion of mesyl shikimate using NaN3 in a continuous flow system is shown;

[0058] Fig.12 The selectivity for azide 41 using NaN3 in a continuous flow system was shown;

[0059] Fig.13 The azidation conversion of mesyl shikimate using DPPA in a continuous flow system is shown;

[0060] Fig.14 The selectivity for azide 41 using DPPA in a continuous flow system was shown;

[0061] Fig.15 The formation of aziridine 42 from azide 41 using (EtO)3P in a continuous flow system is shown;

[0062] Fig.16 The conversion of aziridine 42 to 3-pentyl ether 43 in a continuous flow system is shown;

[0063] Fig.17 Continuous flow NP bond cleavage of 3-pentyl ether 43 in a continuous flow system is shown;

[0064] Fig.18 The C-5 azidation of acetamide 44 using NaN3 in a continuous flow system is shown;

[0065] Fig.19 The synthesis of oseltamivir 33 from azide 32 using CoCl2-catalyzed NaBH4 reduction in a continuous flow system is shown; and

[0066] Fig. 20The conversion of oseltamivir 33 to oseltamivir phosphate 3 in a continuous flow system is shown. DETAILED DESCRIPTION

[0067] The present invention will now be described more fully hereinafter with reference to the accompanying drawings, in which some non-limiting embodiments of the invention are shown.

[0068] The invention as described below should not be construed as limited to the specific embodiments disclosed but rather minor modifications and other embodiments are intended to be included within the scope of the invention.

[0069] Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

[0070] As used herein, throughout the specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0071] The terms and expressions used herein are for the purpose of description and should not be regarded as limiting. As used herein, the use of the terms "including," "comprising," "having," "comprising," and variations thereof are meant to encompass the items listed thereafter and equivalents thereof as well as additional items.

[0072] The present invention provides a method for producing oseltamivir and its pharmaceutically acceptable salts, in particular a flow synthesis method for producing the compound. In a particularly preferred embodiment, the present invention provides a method for producing a pharmaceutically acceptable salt of oseltamivir: (-)-oseltamivir phosphate (commonly known as The flow synthesis method mentioned).

[0073] The present invention provides a continuous flow synthesis method for producing oseltamivir and its pharmaceutically acceptable salts, which method does not include the use of rate- and yield-limiting protecting group chemistry. Due to the avoidance of protecting group chemistry, we have developed a high-yield and extremely efficient continuous flow program. In a preferred embodiment of the present invention, a 10-step continuous flow program to oseltamivir phosphate 3 is provided, with a total residence time of 11 min and an overall yield of 80.5%.

[0074] General Experimental Procedure

[0075] Chemicals were provided by Sigma Aldrich, Merck, and Industrial Analytical and used as received. Anhydrous solvents were provided by Sigma Aldrich and maintained during use by drying over appropriately activated molecular sieves.

[0076] Column chromatography was performed using Fluka Chemie silica gel 60 as the stationary phase and mixtures of ethyl acetate and hexane of varying polarity as the mobile phase. Thin layer chromatography (TLC) was performed using Merck Kieselgel 60HF254 aluminum backed TLC plates with mixtures of ethyl acetate and hexane of varying polarity as the eluent unless otherwise stated. TLC visualization was performed by fluorescence upon exposure to short wave ultraviolet (UV) light (λ 254 nm) in a Camag UV cabinet.

[0077] Nuclear magnetic resonance (NMR) spectra were recorded at room temperature in solutions in deuterated chloroform (CDCl3) or deuterated dimethyl sulfoxide (DMSO-d6). A Bruker Avance-400 spectrometer (400 MHz) was used to record spectra, with chemical shifts reported in parts per million (ppm) and coupling constants in Hertz (Hz). The Bruker spectrometer was used to record the spectra from 4000 to 500 cm -1 Record the infrared spectrum and the peak (V max ) in wavenumber (cm -1 ) report. Using Staurt d Melting points of all compounds were determined using a melting point apparatus SMP30. High performance liquid chromatography (HPLC) data were obtained using an Agilent 1200 with UV / Vis detector and an Agilent Zorbax C18 column.

[0078] HPLC Method A

[0079] HPLC analysis was performed on an Agilent Zorbax C18 column (250 mm × 4.6 mm, id 5 μm) at ambient temperature using an isocratic system. The mobile phase consisted of 70% acetonitrile and 30% water. The injection volume was 5 μl, eluted at a flow rate of 1.5 ml / min, detected at 213 nm, and the run time was 15 min.

[0080] HPLC Method B

[0081] HPLC analysis was performed on an Agilent Zorbax C18 column (250 mm × 4.6 mm, id 5 μm) at ambient temperature using an isocratic system. The mobile phase consisted of 60% acetonitrile and 40% water. The injection volume was 5 μl, eluted at a flow rate of 1 ml / min, detected at 213 nm, and the run time was 6 min.

[0082] The continuous flow system used in the present invention is described below.

[0083] Labtrix Startup System (Chemtrix)

[0084] This is a manually operated "plug and play" continuous flow reactor system for rapid reaction screening and method optimization within a microreactor. The system has a modular setup that facilitates the replacement of components to increase chemical compatibility, number of feed lines or reactor type or volume. It can be used to perform reactions with very few reagents at a temperature range of -20°C to 195°C and a maximum operating pressure of 20 bar. The system mainly consists of a Labtrix start-up unit, a thermal controller, a syringe pump, syringes, tubing and fittings. The start-up unit houses the microreactor. It can be heated or cooled to a temperature between -20°C and +195°C, controlled by the thermal controller. A syringe pump equipped with a glass gas-tight Leur lock syringe meters the reagents into the microreactor. The system has twelve different interchangeable glass microreactor types, which vary in size and design. These glass reactors are divided into three different categories based on their design and mixing mode. T-hybrid reactors, SOR-hybrid reactors and catalyst reactors are the three different categories.

[0085] Uniqsis Packed Bed Flow Column Reactor System

[0086] The system consisted of a 10 mm id x 100 mm Omnifit glass column with reinforced PEEK adjustable end fittings. PTFE tubing (0.8 mm ID) was used to connect the column reactor to the HPLC pump and from the reactor to the collection vessel. Liquid reagents were metered through the packed column reactor equipped with a 10 bar back pressure regulator using a peristaltic HPLC pump series III (10 ml pump head) with a flow rate range of 0.00-10.00 ml / min. A Uniqsis heating rack was used to heat the glass column reactor.

[0087] Ultrasonic treatment of PTFE coil reactor (Coil Reactor system

[0088] The system consists of a Chemyx syringe pump equipped with two 10 ml SGE glass syringes containing reagents. Two streams of reagents are pumped into a T-mixer (Omnifit labware, aperture: 8.0 mm ID, 0.5-4 mm OD), which is connected to a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 ml tube length) with a product collection bottle downstream. The T-mixer and PTFE coil reactor are placed in a temperature-controlled ultrasonic water bath. An EINS SCI professional ultrasonic bath (40 kHz) is used for ultrasonic treatment.

[0089] Reaction 1: Continuous flow esterification of shikimic acid 8

[0090]

[0091] Esterification of shikimic acid 8 is the first step in the synthesis of (-)-oseltamivir phosphate (Scheme 1). Various esterification conditions were studied to optimize the esterification reaction in the Chemtrix Labtrix and Uniqsis packed bed column flow systems. All solution phase and solid phase esterification reactions were performed in the Chemitrix Labtrix system and Uniqsis packed bed column reactor, respectively.

[0092] A Chemtrix Labtrix system was used to conduct all solution phase esterification studies. The system was equipped with a 19.5 μl glass reactor for optimization of shikimic acid esterification in the presence of catalysts. Thionyl chloride, oxalyl chloride, thionyl chloride / DMF, oxalyl chloride / DMF, benzenesulfonic acid (BSA) and p-toluenesulfonic acid (PTSA) were the various catalysts used for the studies of shikimic acid esterification. Two syringe pumps were used to pump reagents from two 10 ml SGE Luer lock gastight glass syringes into a thermally controlled microreactor system equipped with a 10 bar back pressure regulator. Shikimic acid (0.1 M) and the catalyst were both dissolved in ethanol and pumped into the flow system separately. Samples were collected and analyzed using HPLC method A.

[0093] A Uniqsis column reactor loaded with solid catalyst was used for all solid phase esterification studies (Scheme 2).

[0094]

[0095] Amberlyst 15 or Amberlyst (3 cm bed height, 2.4 reactor volumes) was filled into a 10 mm ID x 100 mm Uniqsis glass column. The column reactor was thermally controlled using a Uniqsis heating jacket and the system was pressurized using a 10 bar back pressure regulator. An ethanol solution of shikimic acid (0.1 M) was pumped into the heated packed bed using a peristaltic HPLC pump. Samples were collected and analyzed using HPLC Method A.

[0096] This article reports the results and discussion of a detailed study using SOCl2, COCl2, BSA, PTSA, Amberlyst 15, and Amberlyst 36 in the optimization of continuous flow shikimate esterification.

[0097] Shikimic acid 8 was esterified with ethanol in the presence of SOCl2 in a 19.5 μl glass microreactor system. Shikimic acid 8 (0.1 M) in ethanol was treated with SOCl2 (0.05 M, effective 1 equivalent) at 100°C with a residence time of 8 min. Shikimic acid ethyl ester 39 (68%) was successfully formed. Doubling the residence time resulted in a 6% increase in conversion. Increasing the temperature to 140°C and maintaining the residence time at 8 min gave a 79% conversion. After the initial successful experiments, a comprehensive reaction optimization study was performed. The effects of SOCl2 equivalents, reaction temperature, and residence time were studied. Figure 2 A study of the effect of SOCl2 molar equivalents on the reaction at 100 °C and 8 min residence time is shown.

[0098] Figure 2 The conversion of shikimic acid 8 to ethyl shikimate 39 generally increases with increasing SOCl2 concentration. Constant conversion % is achieved at SOCl2 molar equivalents of 2 and above. Without wishing to be bound by any particular theory, it is believed that excess SOCl2 may be necessary because it acts as a catalyst and water scavenger. At this determined optimal SOCl2 molar equivalent, the effects of residence time and temperature were studied ( Figure 3 ).

[0099] In general, the conversion of shikimic acid 8 to ethyl shikimate 39 increases with increasing residence time and temperature ( Figure 3 ). However, further increasing the residence time had limited effect on shikimic acid conversion when the residence time exceeded 8 min. In addition, at temperatures above 140 °C, shikimic acid conversion decreased. Pressurizing the continuous flow system allowed us to study reaction temperatures above the boiling point of the solvent / reactant ethanol.

[0100] The optimal conditions for the esterification were found to be equimolar equivalents of shikimic acid and SOCl2, a reaction temperature of about 140°C, and a residence time of about 8 min to give ethyl shikimic acid (93%), compared to previously reported batch reactions of up to 3 hours. Although the reaction was adequate, the use of SOCl2 is undesirable from an environmental, health, and safety perspective.

[0101] Due to the production of greenhouse gases (SO2 and HCl) as byproducts, as well as toxicity issues associated with SOCl2, its replacement is desirable from an environmental, health and safety perspective.

[0102] To develop a greener process, the use of (COCl)2 as a catalyst for the esterification of shikimic acid was investigated. Shikimic acid 8 was esterified with ethanol in the presence of (COCl)2 to afford ethyl shikimic acid 39. The optimization of the reaction was performed in a 19.5 μl glass microreactor system. Shikimic acid (0.1 M) in ethanol was treated with (COCl)2 (0.1 M, effective 2 equivalents) in a continuous flow system.

[0103] The conversion rate of shikimic acid generally increased with the increase of residence time and temperature ( Figure 4 ). However, the shikimic acid conversion decreased at 190°C. For example, there was a 73% shikimic acid conversion at 190°C and an 8 min residence time, compared to a surprising 99% conversion at 160°C and an 8 min residence time. It was found that the optimal conditions for shikimic acid esterification in the presence of (COCl)2 were about 120°C to about 170°C, preferably about 120°C to about 160°C, most preferably about 160°C, and an unexpected 99% conversion was obtained at a residence time of about 8 min. Under these conditions, (COCl)2 was demonstrated to be a superior esterification catalyst to SOCl2 (93%, 140°C and 8 min residence time). In addition, the use of (COCl)2 is more popular because it is safer and more environmentally friendly than SOCl2.

[0104] We also investigated the use of (COCl)2 in the presence of catalytic amounts of DMF, which forms the Vilsmeier reagent, which is reported to be a better activator of carboxylic acids. However, the results showed that the DMF-catalyzed procedure resulted in unexpectedly lower shikimic acid conversion than the uncatalyzed reaction.

[0105] The esterification of shikimic acid with ethanol using benzenesulfonic acid (BSA) in a continuous flow system was studied. Shikimic acid (0.1 M, 1 eq.) in ethanol was treated with BSA (0.1 eq.) in a continuous flow system. The results are shown in Figure 5 .

[0106] Depend on Figure 5 It can be seen that the increase in residence time and temperature leads to an increase in shikimic acid conversion, with a conversion plateau of 98%. In addition, the shikimic acid esterification procedure preferably uses highly anhydrous ethanol to obtain high conversion. The optimal conditions for the Fischer esterification of shikimic acid using BSA were found to be about 190°C and about 20 min residence time, resulting in 94% shikimic acid conversion. Although slightly more efficient, BSA can be considered a more favorable esterification catalyst than SOCl2 from a health, environment and safety perspective.

[0107] The use of PTSA as a catalyst for the esterification of shikimic acid with ethanol in a continuous flow system was investigated. Shikimic acid (0.1 M) in ethanol was treated with a catalytic amount of PTSA (0.1 eq) in a continuous flow system to give ethyl shikimate 39. The results are shown in Figure 6 .

[0108] In the presence of catalytic amounts of PTSA, the shikimic acid conversion increased with increasing residence time and temperature. Better conversions were achieved at 160 °C and above. The optimum conditions for PTSA-catalyzed esterification of shikimic acid were found to be about 190 °C and about 40 min residence time to obtain 96% conversion. Although better reaction efficiency was observed using SOCl2, PTSA can be considered a preferred esterification catalyst over SOCl2 from the health, environment, and safety perspective.

[0109] To avoid the generation of large amounts of acid waste, the esterification of shikimic acid with ethanol using solid acid catalyst Amberlyst 15 was investigated in a continuous flow system (Scheme 2).

[0110] In the presence of dry Amberlyst 15 as the shikimic acid esterification catalyst, the shikimic acid conversion increased with increasing temperature and residence time ( Figure 7 ). It appears that the reaction reaches a conversion plateau at about 97%. The typical recommended operating temperature for Amberlyst 15 is 120°C. However, the inventors unexpectedly discovered that shikimate esterification can be studied using Amberyst 15 at higher temperatures, including about 140°C.

[0111] To their delight, they observed better conversion at 140°C (8 min residence time, 92%) than at 120°C (8 min residence time, 79%). In the experimental setup, the optimal conditions were found to be 140°C and 8 min residence time to obtain 92% conversion of shikimic acid. This compares favorably with the optimal conditions for shikimic acid esterification using SOCl2 (93%, 140°C and 8 min residence time). Moreover, from a health, environment and safety point of view, the Amberlyst 15 procedure is preferred over the hazardous SOCl2 procedure. As an additional advantage, Amberlyst 15 can be removed at the end of the reaction and regenerated for further use. Amberlyst 36 was also evaluated. However, the results showed that Amberlyst 36 required almost twice the residence time required for Amberlyst 15 and SOCl2 to obtain the same shikimic acid conversion.

[0112] Reaction 2: Continuous flow mesylation of ethyl shikimate 39

[0113]

[0114] Mesylation of ethyl shikimate 39 was performed in a 0.8 ml PTFE coil reactor system under sonication (Scheme 4).

[0115]

[0116] The mesylation of ethyl shikimate 39 was optimized using a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 m tube length) under ultrasonication (Scheme 4) to give the trimesylate 40. Ethyl shikimate 39 (0.2 M) was premixed with methanesulfonyl chloride (0.9 M, 4.5 eq.) in ethyl acetate to prepare a first solution. Ethyl shikimate 39 is not easily soluble in ethyl acetate. Therefore, it was first dissolved in hot ethyl acetate, cooled, and then premixed with methanesulfonyl chloride. A second solution was prepared by dissolving an organic base in ethyl acetate. The following bases were screened: triethylamine (TEA), imidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), and trihexylamine (THA). The collected samples were first filtered through a PTFE syringe filter (0.45 μl pore size) to remove the ammonium salts formed during the reaction and then analyzed using HPLC Method B.

[0117] The mesylation of ethyl shikimate 39 was reported to be carried out in a batch reaction using MsCl in the presence of triethylamine (TEA) as a base at low temperature, preferably at 0°C, for about 2 to 4 hours. Although batch mesylation transformations are well established and documented, to our knowledge, there is no literature on continuous flow mesylation of ethyl shikimate, on any mesylation in the Tamiflu synthesis process, and even less on a simple model mesylation reaction.

[0118] Initial attempts at mesylation of ethyl shikimate (0.05 M) were performed in ethyl acetate using MsCl (0.23 M, effective 1.5 equiv) and TEA (5 equiv) in a 19.5 μl Chemtrix glass microreactor (300 μm channel width, 120 μm channel depth), but failed due to spontaneous blockages. These blockages were due to precipitation of ammonium salts formed between MsCl and TEA during the reaction. Experiments with lower concentrations also suffered from the same problem.

[0119] To investigate reactors with larger channel diameters, we used a LittleThings Factory (LTF) glass reactor with a 0.8 mm channel diameter. Experiments were also attempted using a simple PTFE coil reactor (1 mm ID). Disappointingly, none of these attempts resolved the problem of reactor clogging, even at very low concentrations.

[0120] However, in another experiment, we used a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 m tube length) under ultrasound treatment (Scheme 4). The ultrasound treatment appears to help the movement of the ammonium salt precipitate, thereby avoiding reactor blockage. Therefore, this development allows us to study different reaction parameters and ultimately optimize the reaction. However, it is conceivable that ultrasound treatment may not be required when the reaction is scaled up to industrial scale.

[0121] Shikimate ethyl ester b was premixed with MsCl in ethyl acetate and treated with TEA in a continuous flow system with sonication to give the trimesylate 40. Studies in this system were performed using shikimate ethyl ester (0.2 M), MsCl (0.9 M, 1.5 equiv. effectively) and TEA (1.2 M, 6 equiv.) in ethyl acetate at 0 °C. The effect of residence time on the reaction is shown in Figure 8 .

[0122] The conversion rate of ethyl shikimate increased with the increase of residence time ( Figure 8 ). However, surprisingly, the increase in residence time did not significantly increase the conversion as the conversion of ethyl shikimate. Although the reaction is reported to be preferably carried out batchwise at 0 °C, the use of higher temperatures was investigated to increase the conversion in a continuous flow system. Room temperature and 40 °C were investigated with no increase in conversion. Therefore, further studies were conducted at room temperature.

[0123] Since the increase in residence time and reaction temperature resulted in insignificant ethyl shikimate conversion, the effect of increasing the base (TEA) concentration was investigated. These experiments used ethyl shikimate (0.2 M, 1 eq.), MsCl (1.5 eq.) at room temperature and 12 s residence time while varying the TEA concentration. The results of these experiments are shown in Fig. 9 .

[0124] from Fig. 9 It can be seen that the conversion of ethyl shikimate increases with increasing base (TEA) concentration. The optimal conditions were found to be 100% conversion of the desired mesylate using ethyl shikimate (0.2 M), MsCl (0.9 M, effective 1.5 equiv), TEA (3 M, 15 equiv) at room temperature and 12 s residence time. The observations suggest that the reaction can even be carried out at residence times much shorter than 12 s. However, due to the limitations of the available syringe pumps, it is difficult to fully investigate lower residence times.

[0125] The use of bases other than TEA in the continuous flow mesylation of ethyl shikimate was investigated. These experiments used a continuous flow system under sonication at room temperature and a residence time of 12 s (Scheme 4). Ethyl shikimate (0.2 M, 1 eq.) premixed with MsCl (1.5 eq.) in ethyl acetate was treated with the appropriate base (6 eq.) in the continuous flow system. The results are shown in Fig.10 .

[0126] from Fig.10 It can be seen that TEA has the highest conversion among the studied bases, while DABCO performs the worst. Except for DABCO, all the studied bases gave comparable results to TEA. There is still the problem of ammonium salt precipitation. However, lighter precipitation was observed when using DBU and imidazole. Interestingly, clear solutions were obtained using THA. The absence of precipitation can be attributed to the increase in hydrophobicity of (THA), due to the increased chain length compared to TEA, making the formed ammonium salt soluble in the reaction solvent ethyl acetate.

[0127] Reaction 3: Continuous flow azidation of ethyl (3R,4S,5R)-3,4,5-tri-O-methylsulfonylshikimate 40

[0128]

[0129]

[0130] By using different azidating reagents and conditions, the OMs group at the allylic C-3 position was stereoselectively and regioselectively nucleophilically substituted with an azido group (Scheme 5).

[0131]

[0132] A continuous flow system was started using a Chemtrix Labtrix equipped with a 19.5 μl glass reactor in the presence of various azidating agents to optimize the azidation of the OMs group at the allyl C-3 position of mesyl shikimate 40 (Scheme 6). Sodium azide (NaN3), diphenylphosphoryl azide (DPPA), trimethylsilyl azide (TMSA) and tetrabutylammonium azide (TBAA) were the various azidating agents studied in this system. The reaction was quenched in the flow reactor using aqueous HCl (0.11 M, 1.1 equivalents) when necessary. Samples were collected and analyzed using HPLC method A.

[0133] In the presence of a suitable azidating agent, mesylate 40 undergoes highly regio- and stereoselective nucleophilic substitution of allyl O-mesylate at the C-3 position to afford azide compound 41 (Scheme 5).

[0134] Initial experiments have shown that the conversion rates in acetone and acetonitrile are the same as those in the mesyl shikimate solvent. However, the use of acetone is associated with the microreactor blockage caused by the precipitation produced by the acetone-NaN3 aqueous solution mixture. In addition, acetonitrile has a higher boiling point than acetone, which is welcome for exploring high temperature reactions. Therefore, acetonitrile is a preferred solvent for mesyl shikimate 40 that is further optimized in a continuous flow system.

[0135] In a thermally controlled microreactor system (Scheme 6), mesyl shikimate 40 (0.1 M) in acetonitrile was treated with aqueous NaN3 (0.11 M, 1.1 eq.). The reaction generally afforded two products, the desired azide compound 41 and the byproduct 41a (Scheme 7).

[0136]

[0137] The effects of various reaction conditions on conversion and selectivity are shown in Fig.11 and Fig.12 .

[0138] from Fig.11 It can be clearly seen that the conversion of mesyl shikimate increases with increasing residence time and temperature. At 50°C and above, complete conversion is achieved at short residence times. Complete conversion is achieved at 50°C and 3s residence time, and 71% conversion is achieved at 0°C and 3s residence time ( Fig.11 ).

[0139] The product selectivity of azide 41 is shown in Fig.12 .from Fig.12 It can be seen that the selectivity generally decreases with increasing residence time and temperature. However, at 0 °C, the selectivity to the desired azide 41 was 100% for all residence times studied. At 50 °C, 100% and 73% selectivities to azide 41 were obtained at 3 s and 300 s, respectively. Clearly, high temperatures favor the undesired aromatic azide 41a.

[0140] The effect of NaN3 concentration on the reaction was studied to determine the effect of NaN3 molar equivalents on the conversion of mesylate shikimate 40 and the selectivity of the desired azide 41 at 150°C and 12s residence time. The results showed that the selectivity for azide 41 decreased with increasing NaN3 concentration. In contrast, the conversion of mesylate shikimate 40 increased with increasing NaN3 (1 and 2 equivalents). It is believed that excess NaN3 increases the reaction basicity, resulting in a strong preference for the undesirable azide 41a.

[0141] The preferred flow conditions for this reaction were found to be 1.1 equivalents of NaN3, 50°C, and 12 s residence time, giving complete conversion to the desired azide 41. Although, as previously reported, high temperature, long reaction time, and alkalinity were detrimental to selectivity to the desired azide 41 in batches, it is evident from our experiments that the use of a microreactor significantly improves selectivity and even more significantly reduces reaction time.

[0142] An alternative non-aqueous azidation procedure in a continuous flow system was also investigated. The azidation agents investigated included diphenylphosphoryl azide (DPPA), trimethylsilyl azide (TMSA), and tetrabutylammonium azide (TBAA).

[0143] In a continuous flow system, mesyl shikimate (0.1 M) was treated with a mixture of DPPA (0.11 M, 1.1 eq.) and TEA (0.12 M, 1.2 eq.). The reaction was quenched with aqueous HCl (0.5 M, 0.5 eq.) in the flow system. The results of the conversion and selectivity of the reaction are shown in Fig.13 and Fig.14 .

[0144] from Fig.13 It can be seen that using DPPA as the azide agent, an increase in temperature and residence time leads to an increase in the conversion of mesyl shikimate in the microreactor. The selectivity of azide 41 decreases with increasing temperature and residence time ( Fig.14 ). The trend observed for DPPA is similar to that observed using NaN3 as the azidating agent.

[0145] The selectivity for azide 41 associated with DPPA was low as a result of the base used. It has been reported that basic conditions are not favorable for azide 41 selectivity. The use of base in the DPPA procedure is inevitable because the reaction will not proceed in the absence of base. The reaction was quenched using aqueous HCl in a microreactor. The effect of base (TEA) concentration on the selectivity for azide 41 was studied at room temperature and 6 s residence time to determine its role in the formation of the undesired aromatic azide 41a. The results show that the selectivity for the desired azide 41 decreases with increasing base concentration.

[0146] The use of TMSA as an azidating agent was also investigated. It was found that the conversion using TMSA was comparable to that using NaN3 and DPPA. Using TMSA, DPPA, and NaN3 as azidating agents, the conversions of mesyl shikimate were 64%, 66%, and 71%, respectively, at 25°C and a residence time of 3 s. The selectivity of azide 41 using TMSA was also comparable to that obtained using DPPA and NaN3.

[0147] Reactions performed using TBAA resulted in unacceptable selectivity towards azide 40, while use of an azide ion exchange resin (Amberlite IRN78) gave relatively poor conversion performance.

[0148] The preferred reaction conditions for the NaN3 procedure were found to be about 1.1 equivalents of NaN3, 50°C and 12 s residence time, giving complete conversion to the desired azide 41. In contrast to all published literature procedures, no byproduct 41a was produced using our procedure. The preferred conditions for the anhydrous procedure were about 1.1 equivalents of DPPA / TMSA, about 1.1 equivalents of TEA, 50°C and 12 s, giving about 81% conversion to the desired azide 41.

[0149] Reaction 4: Continuous flow aziridination of ethyl (3S,4R,5R)-3-azido-4,5-bis(methylsulfonyloxy)cyclohex-1-enecarboxylate 41

[0150]

[0151] Continuous flow aziridination of azide 41 was performed in a Chemtrix Labtrix flow system (Scheme 9).

[0152]

[0153] A continuous flow system was started using a Chemtrix Labtrix equipped with a 19.5 μl glass reactor to optimize the aziridination reaction of azidoshikimate 41 using trialkyl phosphites. Triethyl phosphite and trimethyl phosphate were the two alkyl phosphites studied. A solution of azidoshikimate in anhydrous acetonitrile (0.1 M) and a solution of trialkyl phosphite in anhydrous acetonitrile (0.11 M, 1.1 equiv) were pumped from two 10 ml SGE Luer lock gastight glass syringes into a thermally controlled microreactor system equipped with a 10 bar back pressure regulator using two syringe pumps, respectively (Scheme 9). Samples were collected and analyzed using HPLC method A.

[0154] Azide 41 undergoes aziridination in the presence of a trialkyl phosphite under anhydrous conditions (Scheme 8). In one set of experiments, azide 41 was treated with (EtO)3P under anhydrous conditions in a continuous flow system to give azide 42.

[0155] Azide 41 (0.1 M) was treated with (EtO)3P (0.11 M, 1.1 equiv.) and reacted spontaneously, resulting in complete conversion to the unwanted product. This suggests the formation of an intermediate. The experiment was then carried out using acetonitrile as a solvent, the only possible disadvantage of acetonitrile being its lower boiling point compared to toluene. This was compensated for by pressurizing the system, which allowed the reaction to overheat without the solvent boiling.

[0156] Azide 41 (0.1 M) in acetonitrile was treated with (EtO)3P (0.11 M, 1.1 equiv) to afford aziridine 42. The conversion of azide 41 to aziridine 42 under various flow conditions is shown in Fig.15 . In the presence of (EtO)3P, the conversion of azide 41 to aziridine 42 increases with increasing temperature and residence time. Good conversions were achieved at very fast residence times (<120s). It was found that temperature had the most significant effect on the successful synthesis of aziridine 42. As described above, at room temperature (toluene), in the presence of (EtO)3P, azide 41 was completely consumed, but aziridine 42 was not detected. The use of a pressurized microreactor allows very high reaction temperatures, which results in very fast reactions. In addition, microreactors allow the safe exploration of potentially explosive azide chemistry at very high temperatures. The optimal conditions were found to be about 190°C and a residence time of 12s to obtain complete conversion to the desired aziridine 42.

[0157] In another set of experiments, the aziridination reaction of azide 41 was carried out with (MeO)3P using a continuous flow system to give aziridine 42. The results show that, like (EtO)3P, the formation of aziridine increases with increasing temperature and residence time. It was demonstrated that the use of (MeO)3P in the aziridination reaction is slightly more effective than (EtO)3P. At approximately 190°C and a residence time of 3s, 93% and 98% of aziridine 42 were formed using (EtO)3P and (MeO)3P, respectively.

[0158] Importantly, our system and method allows for high temperature azide chemistry, resulting in a very rapid reaction compared to previously reported 5 h batch reactions.

[0159] Reaction 5: Continuous Flow Synthesis of Ethyl (3R,4S,5R)-4-(diethoxyphosphoramido)-5-methanesulfonyloxy-3-(pent-3-yloxy)cyclohex-1-enecarboxylate 43

[0160]

[0161] In a continuous flow system, aziridine 42 reacted with 3-pentanol and the Lewis catalyst boron trifluoride etherate complex to undergo regio- and stereoselective ring opening at the allylic position (Scheme 10).

[0162]

[0163] A continuous flow system was started using a Chemtrix Labtrix equipped with a 19.5 μl glass reactor to optimize the ring opening of aziridine 42 with 3-pentanol and boron trifluoride etherate complex (Scheme 11). Aziridine 42 (0.1 M) in acetonitrile / 3-pentanol (50:50) and boron trifluoride etherate complex (0.15 M, 1.5 eq.) in acetonitrile / 3-pentanol (50:50) were pumped from two 10 ml SGE Luer lock gastight glass syringes into a thermally controlled microreactor system equipped with a 10 bar back pressure regulator using two syringe pumps, respectively. Samples were collected and analyzed using HPLC method A.

[0164] Initial experiments were performed by treating aziridine 42 (0.1 M) in 3-pentanol with BF3.OEt2 (0.12 M, 1.2 eq.) in 3-pentanol in a continuous flow system at 60°C with a residence time of 30 s to afford 3-pentyl ether 43 with 88% conversion. The use of excess BF3.OEt2 (1.5 eq.) resulted in complete conversion to 3-pentyl ether 43. Due to the high viscosity of 3-pentanol, which resulted in increased pressure in the system at higher flow rates, residence times below 30 s could not be studied in this system. Therefore, preliminary studies with residence times less than 30 s were successfully completed using a 3-pentanol / acetonitrile (50 / 50) mixture.

[0165] The reaction was optimized in a continuous flow system by treating aziridine 42 (0.1 M) in 3-pentanol / acetonitrile (50 / 50) with BF3.OEt2 (0.15 M, 1.5 eq.) in 3-pentanol / acetonitrile (50 / 50) under various reaction conditions. The use of dilute 3-pentanol allowed us to interrogate the reaction with very fast reaction times. The results of these experiments are shown in Fig.16 .

[0166] from Fig.16 It can be seen that the conversion of aziridine 42 to 3-pentyl ether 43 increases with increasing residence time and temperature. Increased temperature leads to a significant increase in conversion. At a residence time of 12 s, 66% and 100% yields of 3-pentyl ether 43 were achieved at 25°C and 100°C, respectively. It was found that the preferred conditions were about 100°C and 12 s residence time to obtain complete conversion to 3-pentyl ether 43.

[0167] Reaction 6: Continuous Flow Synthesis of Ethyl (3R,4S,5R)-4-Acetylamino-5-methanesulfonyloxy-3-(pent-3-yloxy)cyclohex-1-enecarboxylate 44

[0168]

[0169] Acetylation of 3-pentyl ether 43 was achieved by cleavage of the NP bond with sulfuric acid followed by acetylation under mild basic conditions (Scheme 12).

[0170]

[0171] Intermediate 43a was formed in situ in the first thermally controlled reactor by treating 3-pentyl ether 43 (0.1 M) in acetonitrile with H2SO4 (0.8 M, 8 eq.) in acetonitrile. The in situ formed intermediate 43a was treated in a second thermally controlled reactor with NaOH (1.62 M, 16.2 eq.) and then with acetic anhydride (1.6 eq.) to give acetamide 44. This system for a multi-stage continuous flow system was equipped with a 10 bar back pressure regulator. Samples were collected and analyzed using HPLC method A.

[0172] In a preliminary set of experiments, 3-pentyl ether 43 (0.1 M) in ethanol was treated with H2SO4 (0.8 M, 8 eq.) in ethanol at 75°C and a residence time of 6 s to afford compound 43a in 51% conversion. Comparable results were obtained when acetonitrile was used as solvent instead of ethanol. Since acetonitrile is a common solvent for most continuous flow steps, the reaction was subsequently optimized in acetonitrile. In a Chemtrix microreactor, 3-pentyl ether 43 in acetonitrile (0.1 M) was treated with H2SO4 in acetonitrile (0.8 M, 8 eq.) under various reaction conditions for optimization. The results of these experiments are shown in Fig.17 .

[0173] The conversion of 3-pentyl ether 43 to compound 43a increases with increasing temperature and residence time. At a residence time of 1.5 s, the conversion to compound 43a is 37% and 91% at 60° C. and 150° C., respectively. At a constant temperature of 60° C., the conversion to compound 43a is 31% and 54% at 0.7 s and 12 s, respectively. It was found that the preferred conditions for continuous flow NP bond cleavage are about 170° C. and a residence time of 3 s, using H2SO4 (8 equivalents) to obtain complete conversion of compound 43a.

[0174] After successfully demonstrating the continuous flow NP bond cleavage in 3-pentyl ether 43 to give compound 43a, the study was extended to the acetylation of compound 43a.

[0175] Acetylation of 3-pentyl ether 43 was accomplished by subsequent treatment of the in situ formed compound 43a with Ac2O under weakly basic conditions to afford acetamide 44 in a continuous flow system (Scheme 13). Based on the results of previous experiments, 3-pentyl ether 43 (0.1 M) in acetonitrile was treated with H2SO4 (8 eq) in acetonitrile at 170°C in the first microreactor for 6 s residence time to afford compound 43a in situ. Compound 43a was subsequently treated with aqueous NaOH (0.8 M, 16.2 eq) at room temperature followed by Ac2O (0.8 M, 1.6 eq) for a total residence time of 9 s to afford acetamide 44 (65%).

[0176] An increase in the total residence time for the acetylation resulted in an increase in the formation of acetamide 44. Doubling the total residence time resulted in a 12% increase in conversion. A total residence time of 30 s gave 93% of acetamide 44, and there was no improvement in conversion beyond a residence time of 30 s. As in the previous step, the alkaline reaction medium may cause side reactions, thereby reducing the yield of acetamide 44. The alkaline reaction medium is attributed to the weakly alkaline medium used to promote the acetylation and the alkalinity of the intermediate 43a formed in situ.

[0177] Reaction 7: Continuous Flow Synthesis of Ethyl (3R,4S,5S)-5-Azido-4-acetylamino-3-(1-ethyl-propoxy)-cyclohex-1-enecarboxylate 32

[0178]

[0179] Acetamide 44 is treated with a suitable azidating agent to afford azide 32. The C-5OMs group on acetamide 44 is nucleophilically displaced by the N3 group (Scheme 14).

[0180]

[0181] A continuous flow system was started using a Chemtrix Labtrix equipped with a 19.5 μl glass reactor to optimize the C-5 azidation of acetamide 44 (Scheme 15). Acetamide 44 (0.1 M) in acetonitrile and the azidating agent (0.3 M, 3 equivalents) in an appropriate solvent were pumped from two 10 ml SGE Luer lock gas-tight glass syringes into a thermally controlled microreactor system equipped with a 10 bar back pressure regulator using two syringe pumps, respectively. The use of NaN3, TBAA, DPPA, and TMSA was studied. Samples were collected and analyzed using HPLC method A.

[0182] Initial flow experiments were performed at 100°C in a 19.5 μl glass microreactor using acetamide 44 (0.1 M) and aqueous NaN3 (0.3 M, 3 eq.) in DMF for 90 s to afford azide 32 (63%). In additional experiments, we achieved 59% conversion of azide 32 in acetonitrile. The reaction was further optimized using acetonitrile as solvent for acetamide 44 (0.1 M) and aqueous NaN3 (0.1 M, 3 eq.). The results of these experiments are shown in Fig.18 .

[0183] from Fig.18 It can be seen that the formation of azide 32 is a function of temperature and residence time. The conversion of acetamide 44 to azide 32 increases with increasing temperature. At a residence time of 45 seconds, the conversion to azide 32 is 55% and 100% at 80°C and 190°C, respectively. It was found that the preferred conditions are about 190°C, 45 seconds residence time, to obtain complete conversion of azide 32.

[0184] In a 19.5 μl glass microreactor, the preferred conditions developed for NaN3 (3 eq, 190 °C, and 45 s) were used to study the use of DPPA, TMSA, and TBAA as azidating agents for acetamide 44. In these experiments, acetamide 44 was successfully converted to azide 32 with varying conversions under the action of DPPA, TMSA, and TBAA. It appears that the application of ionically bonded azides (NaN3 and TBAA) resulted in similar conversions (100% and 93%, respectively), while covalently bonded azides (DPPA and TMSA) resulted in relatively lower conversions (84% and 81%, respectively).

[0185] Reaction 8: Continuous Flow Synthesis of Oseltamivir 33

[0186]

[0187]

[0188] The reduction of azide 32 using NaBH4 and CoCl2 was optimized using a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 m tube length) under ultrasonic treatment (Scheme 17) to obtain oseltamivir. A mixture of azide 32 (0.15 M) with CoCl2 (0.1 eq) in ethanol and NaBH4 (0.30 M, 2 eq) in water (pH = 8) was pumped through a continuous flow system to obtain oseltamivir 33. The collected samples were first filtered through a PTFE syringe filter (0.45 μl pore size) to remove the cobalt boride precipitate formed in the reaction and then analyzed using HPLC method A.

[0189] Oseltamivir 33 was synthesized by reduction of azide 32 by NaBH4 catalyzed by CoCl2 in a continuous flow system under sonication, as the formation of a black precipitate (cobalt boride) was observed in preliminary batch studies. However, the formation of this precipitate may not be a problem when the process is carried out using industrial-scale equipment.

[0190] A mixture of azide 32 (0.15 M) and CoCl2 (0.1 eq) in ethanol was treated with NaBH4 (0.3 M, 2 eq) in buffered water (pH = 8) in a 0.8 ml PTFE coil reactor system (0.8 mm ID, 1.6 m tube length) under sonication to give oseltamivir 33. The results of these experiments are shown in Fig.19 The conversion to oseltamivir 33 increased with increasing residence time. It was unexpectedly found that at only 1 s and 5 s residence time, the conversion to oseltamivir 33 was 81% and 96%, respectively. The preferred conditions were found to be about room temperature and about 5 s residence time to obtain oseltamivir 33 (96%).

[0191] We also conducted experiments to investigate the use of ethanol and methanol for NaBH4. These experiments were performed at room temperature in a continuous flow system with sonication for 1.5 s residence time. Although ethanol and methanol are known to react with NaBH4, it appears that in the presence of catalytic amounts of CoCl2, the azide reduction reaction is so fast that it masks the competing reactions of these solvents. Therefore, although water at ph>7 is preferred, it is expected that several other solvents will also be suitable.

[0192] In other experiments, as suggested by known batch methods, a phosphine-based reaction was attempted in flow by treating azide 32 (0.15 M) in THF with Ph3P (0.18 M, 1.2 eq.) in THF / water (10:1) in a continuous flow system at 50°C to give oseltamivir 33. The conversions of azide 32 to oseltamivir 33 were 25% and 78% at residence times of 5 min and 60 min, respectively, which are much lower than the conversions obtained in the preferred reaction with CoCl2 and NaBH4.

[0193] Reaction 8: Continuous Flow Synthesis of Oseltamivir Phosphate 3

[0194]

[0195] Oseltamivir 33 was treated with H2PO4 in a continuous flow system to obtain oseltamivir phosphate 3 (Scheme 18).

[0196]

[0197] In a continuous flow system, a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 m tube length) under ultrasonic treatment was used to optimize the treatment of oseltamivir 33 with H2PO4 to obtain oseltamivir phosphate 3. Oseltamivir 33 in ethanol (0.1 M) and H2PO4 in ethanol (0.12 M, 1.2 equivalents) were pumped through a thermally controlled continuous flow system to obtain oseltamivir phosphate. Samples were collected and analyzed using HPLC method A.

[0198] Oseltamivir 33 (0.1 M) in ethanol was treated with H2PO4 (0.12 M, 1.2 eq) in ethanol at different residence times for optimization in a 0.8 ml PTFE coil reactor (0.8 mm ID, 1.6 m tube length) under ultrasound at 50°C. The results of these experiments are shown in Fig. 20 .

[0199] The conversion to oseltamivir phosphate 3 increases with increasing residence time. A 98% (HPLC) conversion plateau to oseltamivir phosphate 3 was reached at a residence time of 60 s. Based on these experiments, the preferred conditions are about 50° C. and a residence time of 60 s to obtain oseltamivir phosphate 3 (98%, HPLC), which is a significant improvement over any previously reported reaction.

[0200] The above description of some illustrative embodiments of the invention is intended to indicate how the invention may be made and implemented. One of ordinary skill in the art will appreciate that various details may be modified to arrive at further embodiments, but many of these embodiments will remain within the scope of the invention.

Claims

1. A flow synthesis method for producing a compound of formula 33 and a pharmaceutically acceptable salt thereof, The method The following steps are involved: a) by reacting shikimic acid with a mixture selected from (COCl) 2 , SOCl 2 , benzenesulfonic acid, p-toluenesulfonic acid and Amberlyst 15 to prepare ethyl shikimate of formula 39 b) reacting ethyl shikimate of formula 39 with methanesulfonyl chloride in the presence of a base selected from trimethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, imidazole and trihexylamine to produce O-trimethanesulfonate of formula 40 c) reacting the O-trimethanesulfonate of formula 40 with a suitable azidating agent in an azidation reaction to produce the azide of formula 41 d) reacting the azide of formula 41 with a trialkyl phosphite in an aziridination reaction to produce the aziridine of formula 42 e) reacting an aziridine of formula 42 with 3-pentanol in the presence of a Lewis acid catalyst to produce a 3-pentyl ether of formula 43 f) reacting the 3-pentyl ether of formula 43 with H in an acetylation reaction 2 SO 4 Then react with Ac in the presence of a suitable base. 2 O to produce acetamide of formula 44 g) reacting the acetamide of formula 44 with a suitable azidating agent in an azidation reaction to produce the azide of formula 32 and h) By reacting azide with CoCl 2 Mix and add the mixture to NaBH 4 The azide of formula 32 is reacted to produce the compound of formula 33.

2. The method according to claim 1, further comprising reacting the compound of formula 33 with phosphoric acid to produce a compound of formula 3 3. The method according to claim 1, wherein in step (a), shikimic acid is reacted with (COCl) 2 or Amberlyst 15 reactions.

4. The method according to claim 1, wherein in step (a), shikimic acid is reacted with (COCl) 2 React at a temperature between 120°C and 170°C.

5. The process of claim 1, wherein in step (a), shikimic acid is reacted with Amberlyst 15 at a temperature between 100°C and 145°C.

6. The method according to claim 1, wherein the reaction in step (b) is carried out at room temperature.

7. The method according to claim 1, wherein the reaction in step (b) is carried out under ultrasonic treatment.

8. The method of claim 1, wherein in step (b), the base is present in a concentration of 8 to 20 molar equivalents relative to ethyl shikimate.

9. The method according to claim 1, wherein in step (c), the azidation reaction is carried out with a concentration of 1.1 molar equivalents of NaN relative to the O-trimethanesulfonate of formula 40. 3 conduct.

10. The method according to claim 1, wherein in step (c), the azidation reaction is carried out at a temperature of 50°C with NaN 3 conduct.

11. The method according to claim 1, wherein in step (d), the trialkyl phosphite is selected from triethyl phosphite and trimethyl phosphite.

12. The process of claim 1, wherein in step (d), the reaction is carried out in acetonitrile at a temperature between 150°C and 190°C.

13. The process of claim 1, wherein in step (e), the reaction is carried out at a temperature between 60°C and 100°C.

14. The method according to claim 1, wherein in step (f), 3-pentyl ether and H 2 SO 4 The reaction is carried out at a temperature between 140°C and 180°C.

15. The method of claim 1, wherein in step (g), the reaction is carried out at a temperature between 140°C and 200°C.

16. The method according to claim 1, wherein in step (h), the reaction is carried out at room temperature.

17. The method according to claim 1, wherein in step (h), the reaction is carried out under ultrasonic treatment.

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