Process for manufacturing baloxavir marboxil

Abstract

The invention relates to a novel process for making baloxavir marboxil (1) and baloxavir (1a), as well as to an integrated continuous manufacturing (ICM) implementation thereof. Formulae (1) and (1a), (1) and (1a).

Description

[0001] PROCESS FOR MANUFACTURING BALOXAVIR MARBOXIL

[0002] Field of the Invention

[0003] The present invention relates to a novel process for making baloxavir marboxil (1) and baloxavir (la), as well as to an integrated continuous manufacturing (ICM) implementation thereof.

[0004] Background of the Invention

[0005] Baloxavir (la) is a compound that exerts antiviral effects against influenza. In order to improve its oral bioavailability, baloxavir (la) is administered in the form of a prodrug, baloxavir marboxil (1), which is converted to the active form baloxavir (la) in the blood, liver, and small intestine. Baloxavir (la) is also a synthetic intermediate in the known processes for manufacturing baloxavir marboxil (1) (see for example WO2016 / 175224 and WO20 17 / 221869). Baloxavir marboxil (1) is marketed under the trade name Xofluza®.

[0006] The manufacturing process for baloxavir marboxil (1) disclosed in WO2016 / 175224 is shown in Scheme 1.

[0007]

[0008] Scheme 1

[0009] The condensation of compound 2 with compound 3 in the presence of T3P and MsOH proceeds with a poor diastereoselectivity of about 3: 1, which necessitates a subsequent purification by crystallization. Furthermore, in said condensation reaction, about 50% of the molecules lose their benzyl protective group. Since the benzyl protective group is crucial for the diastereoselective crystallization, it has to be reintroduced prior to the crystallization. What is more, the reaction of baloxavir (la) with chloromethyl methyl carbonate (4) to afford baloxavir marboxil (1) that is described in WO2016 / 175224 is conducted in DMA as a solvent, which is considered a substances of very high concern in the EU. Over all, this process is inefficient and not well suited for industrial scale manufacturing of baloxavir marboxil (1).

[0010] The issues outlined above are partly addressed by the process disclosed in WO20 17 / 221869, which is shown in Scheme 2.

[0011] Scheme 2

[0012] Thus, the hexyl protective group in compound 6 has been found to be significantly more stable than the benzyl protective group in compound 2, in that it is not cleaved under the reaction conditions that are used for the condensation reaction with compound 3. With the more stable hexyl protective group in place, a reactive crystallization could be realized. In solution, there is an equilibrium between the starting materials compound 6 and compound 3 and the product compound 7 and its diastereomer. However, in the chosen solvent, the desired product compound 7 is poorly soluble, precitipates and is thus conveniently removed from the equilibrium. Over time (approx. 20h), almost all of the starting materials are converted into compound 7. As a result, both the yield and the stereoselectivity of the process disclosed in WO2017 / 221869 (Scheme 2) are greatly improved compared to yield and stereoselectivity of the process disclosed in WO2016 / 175224 (Scheme 1). Nevertheless, the process disclosed in WO2017 / 221869 requires a tedious additional step to exchange the benzyl protective group for a hexyl protective group and has further drawbacks that are discussed below.

[0013] In summary, there is still a pressing need for a new, more efficient synthesis of baloxavir marboxil. This is particularly true in a potential scenario where large amounts of the API are needed in case of an influenza epidemic or pandemic.

[0014] Summary of the Invention

[0015] The present invention provides an improved process for manufacturing baloxavir marboxil (1), which relies on reacting compound 2 with compound 3 in the presence of a chiral acid, such as (-)-CSA, as illustrated in Scheme 3.

[0016] Scheme 3

[0017] Surprisingly, exchanging the acid MsOH as disclosed in the prior art by a chiral acid, such as (-)-CSA leads to excellent diastereoselectivity of the condensation raction. Yet more surprisingly, the benzyl protective group is completely removed under the reaction conditions, obviating the deprotection step with LiCl described in the prior art. Thus, according to the new process of the invention, baloxavir (la) can be obtained in a single step starting from compounds 2 and 3. The inventive process avoids 2 reaction steps involving hazardous and expensive chemicals and also significantly shortens the leadtime to supply the API, which is crucial in case of an influenza epidemic or pandemic where large quantities of API are needed as quickly as possible. Moreover, the process of the invention is more cost effective than the known processes for manufacturing baloxavir marboxil (1), and reduces the ecological footprint due to reduced expenditure of materials and energy etc. In addition to the above, it has surprisingly been found that the reaction of baloxavir (la) with chloromethyl methyl carbonate (4) to afford baloxavir marboxil (1) can be conducted in a mixture of acetonitrile and water, avoiding the use of toxic DMA that is described in the prior art.

[0018] In addition to the above, the process of the invention has also been implemented as an integrated continuous manufacturing (ICM) process, which offers further benefits, as will be discussed hereinbelow.

[0019] Detailed Description of the Invention

[0020] Definitions

[0021] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims and the abstract), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims and the abstract), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0022] The term “S033447” refers to compound la as described herein.

[0023] The term “SI 99 AW” refers to compound lb as described herein.

[0024] The term “S199AL” refers to compound 2 as described herein.

[0025] The term “S199AR” refers to compound 3 as described herein.

[0026] The term “S199AT” refers to compound 5 as described herein.

[0027] The term “T3P®” refers to propylphosphonic anhydride (CAS 68957-94-8).

[0028] The term “chiral acid” as used herein refers to acids having at least one asymmetric carbon atom, preferably 1 to 3 asymmetric carbon atoms, more preferably 1 to 2 asymmetric carbon atoms, most preferably 1 asymmetric carbon atom. Preferred are organic chiral acids, such as chiral carboxylic acids or chiral sulfonic acids. A non-limiting example of a chiral carboxylic acid is tartaric acid. Non-limiting examples of chiral sulfonic acids are (+)- and (-)-CSA.

[0029] The term “CSA” refers to camphorsulphonic acid.

[0030] The term “CSTR” as used herein refers to continuous stirred tank reactor and means a reaction vessel in which reagents, reactants and solvents flow into the reactor while the product(s) of the reaction concurrently exit(s) the vessel. The term “MSMPR-crystallizer” refers to Mixed- Suspension, Mixed-Product-Removal crystallizer, a device in which a saturated solution enters a chamber already full of crystals and an equal flow exits, containing whatever crystals exist at that end of the flow chamber.

[0031] The term “about” as used herein when referring to a measurable value such as an amount of a compound, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount, preferably variations of 10% to 0.5% of the specified amount, more preferably variations of 5% to 0.5% of the specified amount.

[0032] Brief Description of the Figures

[0033] Figure 1 shows the equipment setup for the continuous flow manufacturing of baloxavir (la) described in Example 2.

[0034] Figure 2 shows the equipment setup for the continuous flow manufacturing of baloxavir marboxil (1) described in Example 4.

[0035] Figure 3 shows a typical HPLC chromatogram of a mixture containing the reactants SI 99 AL (2) and SI 99 AR (3), the product S 033447 (la), the steroisomer SI 99 AW (lb) and the associated impurity SI 99 AT (5). The chromatogram was obtained by using the HPLC method described in Example 5.

[0036] Figure 4 shows a typical HPLC chromatogram of baloxavir (la) as obtained from the continuous manufacturing process described in Example 2. The chromatogram was obtained by using the HPLC method described in Example 5.

[0037] Improved Prodrug Formation

[0038] In the process that is described e.g. in WO2016 / 175224, the prodrug baloxavir marboxil (1) is obtained by reacting baloxavir (la) with chloromethyl methyl carbonate (4) in DMA as a solvent. However, DMA is on the candidate list for substances of very high concern (SVHC) of the EU. The inventors of the present invention have now surprisingly found that this reaction also performes well in a mixture of acetonitrile and water, avoiding the use of toxic DMA. Thus, in a first aspect, the present invention provides a process for manufacturing baloxavir marboxil (1), or a pharmaceutically acceptable salt thereof comprising reacting baloxavir (la) with chloromethyl methyl carbonate (4) in the presence of potassium carbonate and potassium iodide in a mixture of acetonitrile and water to afford baloxavir marboxil (1). In one embodiment, the mixture of acetonitrile and water is a 49 : 1 (v / v) mixture of acetonitrile and water.

[0039] Diastereo selective Condensation

[0040] In a further aspect, the present invention provides a process for manufacturing baloxavir (la), or a pharmaceutically acceptable salt thereof

[0041] comprising

[0042] (a) reacting compound 2 with compound 3 in the presence of:

[0043] (i) about 1-2 mol. equivalents of T3P relative to compound 2; and

[0044] (ii) about 2-6 mol. equivalents of a chiral acid relative to compound 2; to afford baloxavir (la) as a chiral acid salt.

[0045] In one embodiment, the process according to the invention is conducted in the presence of about 3, 4, 5, or 6 mol. equivalents of chiral acid relative to compound 2.

[0046] In a preferred embodiment, the process according to the invention is conducted in the presence of about 4 mol. equivalents of chiral acid relative to compound 2. In one embodiment, said chiral acid is a chiral carboxylic acid or a chiral sulfonic acid. In one embodiment, said chiral acid is selected from (-)-CSA and (+)-CSA.

[0047] In one embodiment, said chiral acid is (+)-CSA.

[0048] In a preferred embodiment, said chiral acid is (-)-CSA.

[0049] In one embodiment, the process according to the invention is conducted in the presence of about 3, 4, 5, or 6 mol. equivalents of (-)-CSA relative to compound 2.

[0050] In a preferred embodiment, the process according to the invention is conducted in the presence of about 4 mol. equivalents of (-)-CSA relative to compound 2.

[0051] In a preferred embodiment, the process according to the invention is conducted in the presence of about 1-1.5 mol. equivalents of T3P relative to compound 2.

[0052] In a particularly preferred embodiment, the process according to the invention is conducted in the presence of about 1.1 mol. equivalents of T3P relative to compound 2.

[0053] In one embodiment of the process according to the invention, about 1-2 mol. equivalents of compound 3 relative to compound 2 are used.

[0054] In a preferred embodiment of the process according to the invention, about 1-1.5 mol. equivalents of compound 3 relative to compound 2 are used.

[0055] In a particularly preferred embodiment of the process according to the invention, about 1.1 mol. equivalents of compound 3 relative to compound 2 are used.

[0056] In one embodiment, step (a) of the process according to the invention is conducted in a solvent selected from:

[0057] (i) ethyl acetate;

[0058] (ii) isopropyl acetate; and

[0059] (iii) a mixture of ethyl acetate or isopropyl acetate and cyclohexane (1 : 1, v / v).

[0060] In a preferred embodiment, step (a) of the process according to the invention is conducted in about 7-10 vol. eq. relative to the weight of the used amount of compound 2 of a solvent selected from:

[0061] (i) ethyl acetate; (ii) isopropyl acetate; and

[0062] (iii) a mixture of ethyl acetate or isopropyl acetate and cyclohexane (1 : 1, v / v).

[0063] In a further preferred embodiment, step (a) of the process according to the invention is conducted in ethyl acetate.

[0064] In a further preferred embodiment, step (a) of the process according to the invention is conducted in isopropyl acetate.

[0065] In a further preferred embodiment, step (a) of the process according to the invention is conducted in a mixture of isopropyl acetate and cyclohexane. In some embodiments, the ratio of isopropyl acetate and cyclohexane is 1 : 1, v / v.

[0066] In a further preferred embodiment, step (a) of the process according to the invention is conducted in a mixture of ethyl acetate and cyclohexane. In some embodiments, the ratio of ethyl acetate and cyclohexane is 1 : 1, v / v.

[0067] In a particularly preferred embodiment, step (a) of the process according to the invention is conducted in about 7-10 vol. eq. of ethyl acetate relative to the weight of the used amount of compound 2.

[0068] In a further particularly preferred embodiment, step (a) of the process according to the invention is conducted in about 7 vol. eq. of ethyl acetate relative to the weight of the used amount of compound 2.

[0069] In one embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 50-80 °C.

[0070] In one embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 60-80 °C.

[0071] In a preferred embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 70-80 °C.

[0072] In a particularly preferred embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 70 °C. In a further particularly preferred embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 80 °C.

[0073] In one embodiment, the process according to the invention further comprises:

[0074] (b) seeding the reaction mixture obtained from step (a) with a chiral acid salt of baloxavir (la), preferably with baloxavir (la)*(-)-CSA salt.

[0075] In one embodiment, said seeding in step (b) is seeding with about 1-15 wt% of baloxavir (la)*(-)-CSA salt.

[0076] In a preferred embodiment, said seeding in step (b) is seeding with about 5-10 wt% of baloxavir (la)*(-)-CSA salt.

[0077] In a particularly preferred embodiment, said seeding in step (b) is seeding with about 10 wt% of baloxavir (la)*(-)-CSA salt.

[0078] In one embodiment, the process according to the invention further comprises:

[0079] (c) reacting said chiral acid salt of baloxavir (la) obtained from steps (a) and (b) with a base, prefereably with NaOH, to afford baloxavir (la).

[0080] The preparation of baloxavir marboxil (1) from baloxavir (la) is described, e.g., in WO20 16 / 175224.

[0081] In one embodiment, the process according to the invention further comprises:

[0082] (d) reacting said baloxavir (la) obtained from step (c) with chloromethyl methyl carbonate (4) in the presence of potassium carbonate and potassium iodide to afford baloxavir marboxil (1).

[0083] In the process that is described in WO2016 / 175224, step (d) is conducted in DMA as a solvent, which is on the candidate list for substances of very high concern (SVHC) of the EU. The inventors of the present invention have now surprisingly found that reaction step (d) can also be conducted in a mixture of acetonitrile and water, avoiding the use of toxic DMA.

[0084] Thus, in a preferred embodiment, step (d) of the process according to the invention is conducted in a mixture of acetonitrile and water.

[0085] In a particularly preferred embodiment, step (d) of the process according to the invention is conducted in acetonitrile : water (49 : 1, v / v).

[0086] In one embodiment, the present invention provides a process for manufacturing baloxavir (la)*(-)-CSA salt, or a pharmaceutically acceptable salt thereof, comprising:

[0087] (a) reacting compound 2 described herein with compound 3 described herein in the presence of

[0088] (i) about 1-2 mol. equivalents of T3P relative to compound 2; and

[0089] (ii) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; and

[0090] (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir (la)*(-)-CSA salt; to afford said baloxavir (la)*(-)-CSA salt.

[0091] In one embodiment, the present invention provides a process for manufacturing baloxavir (la), comprising:

[0092] (a) reacting compound 2 described herein with compound 3 described herein in the presence of:

[0093] (i) about 1-2 mol. equivalents of T3P relative to compound 2; and

[0094] (ii) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; to afford baloxavir (la)*(-)-CSA salt;

[0095] (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir (la)*(-)-CSA salt; and

[0096] (c) reacting said baloxavir (la)*(-)-CSA salt obtained from steps (a) and (b) with a base, prefereably with NaOH. to afford said baloxavir (la).

[0097] In one embodiment, the present invention provides a process for manufacturing baloxavir marboxil (1), comprising:

[0098] (a) reacting compound 2 described herein with compound 3 described herein in the presence of:

[0099] (i) about 1-2 mol. equivalents of T3P relative to compound 2; and

[0100] (ii) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; to afford baloxavir (la)*(-)-CSA salt;

[0101] (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir (la)*(-)-CSA salt;

[0102] (c) reacting said baloxavir (la)*(-)-CSA salt obtained from steps (a) and (b) with a base, prefereably with NaOH; to afford baloxavir (la); and

[0103] (d) reacting said baloxavir (la) obtained from step (c) with chloromethyl methyl carbonate (4) in the presence of potassium carbonate and potassium iodide; to afford said baloxavir marboxil (1).

[0104] Continuous Flow Process

[0105] As mentioned above, the process according to the invention has also been implemented as an integrated continuous manufacturing (ICM) process (see Examples 2 and 4, as well as Figures 1 and 2). ICM consists of a series of unit operations that operate in flow and are integrated into a seamless end-to-end (from synthesis to final product) manufacturing process. ICM represents a shift from the batch manufacturing processes used in the pharmaceutical industry. In contrast to batch manufacturing, ICM’ s unit operation integration process results in significant operational advantages. ICM significantly reduces manufacturing costs (>50% reduction) and lead times (>90% reduction), has a smaller footprint (-90% reduction) and provides higher quality drugs. These advantages were demonstrated in the first-of-its kind ICM pilot plant (capacity of 1.5 tons of Active Pharmaceutical Ingredient per year) at MIT, which was able to produce finished coated tablets from raw ingredients through a single, seamless end-to-end process (Mascia et al. , Angew. Chem. Int. Ed. 2013, 52, 12359-12363.).

[0106] In one aspect, the process of the invention is an integrated continuous manufacturing (ICM) process. The ICM process according to the invention is illustrated by Examples 2 and 4, as well as Figures 1 and 2. The ICM implementation of the final synthetic step in the process for making baloxavir marboxil (1), and the ensuing workup (see Example 4) offers several advantages over the current batch-mode process for the industrial production of baloxavir marboxil (1), including:

[0107] 1. No need for purification of the API by recrystallization.

[0108] 2. Wet milling of the API, as opposed to the dry milling process that is required in batch mode.

[0109] 3. Reduced physical stress on the API due to shorter drying times.

[0110] Dry milling in general is a dusty process creating a health hazard for the involved operators. Operational exposure limits (OEL) of 2.5 mcgr / m3need to be observed, requiring extensive technical measures to contain airborn API particles. Dry milling of baloxavir marboxil (1) is particularly cumbersome because both unmilled and milled API have a poor flowability, leading to low throughput rates and frequent line blockings.

[0111] In one embodiment of the ICM according to the invention, steps (a), (b) and (d) are conducted in an n-stage-CSTR cascade, wherein n is an integer selected from 2 to 10.

[0112] In a preferred embodiment of the ICM according to the invention, steps (a) and (b) are conducted in a 5-stage-CSTR cascade, and step (d) is conducted in a 3-stage-CSTR cascade.

[0113] In one embodiment of the ICM according to the invention, the last CSTR of said n-stage- CSTR cascade that is used for reaction steps (a) and (b) is connected to a filter.

[0114] In one embodiment, said filter is a continuous rotating plate filter.

[0115] In one embodiment, the baloxavir (la)*(-)-CSA salt that is obtained from said steps (a) and (b) is collected on said filter.

[0116] In one embodiment of the ICM according to the invention, step (c) comprises:

[0117] (cl) charging a solution of baloxavir (la)*(-)-CSA salt into reactor 1 of a 2-stage MSMPR-crystallizer;

[0118] (c2) adding a solution of NaOH to reactor 1 until the pH reaches about 1.15;

[0119] (c3) adding seeds of baloxavir (la) to reactor 1; (c4) adding further solution of NaOH to reactor 1 until the pH reaches about 5.6;

[0120] (c5) continuously adding further solution of baloxavir (la)*(-)-CSA salt into reactor 1 while maintaining the pH constantly at about pH 5.6 by adding further solution of NaOH;

[0121] (c6) transferring given portions of the mixture from reactor 1 to reactor 2 at given time intervals; and

[0122] (c7) feeding water into reactor 2 to achieve a final water volume fraction of about 65%.

[0123] In one embodiment, reactor 2 of said 2-stage MSMPR-crystallizer is connected to a filter.

[0124] In one embodiment, said filter is a continuous rotating plate filter.

[0125] In one embodiment, the baloxavir (la) that is obtained from said step (c) is collected on said filter.

[0126] In one embodiment, the baloxavir marboxil (1) that is obtained from the n-stage-CSTR cascade that is used for reaction step (d) is crystallized in an n-stage MSMPR-crystallizer, wherein n is an integer selected from 2 to 5.

[0127] In a preferred embodiment, the MSMPR-crystallizer is a 3-stage MSMPR-crystallizer.

[0128] In one embodiment, the crystalline baloxavir marboxil (1) that continuously exits the n- stage MSMPR-crystallizer is continuously wet-milled.

[0129] Examples

[0130] The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples.

[0131] Example 1

[0132] Batch Synthesis of Baloxavir (la)

[0133] Step 1 : Reaction

[0134] Ethyl acetate (300.5 ml, 7.1 vol. eq) was charged into a 500 ml jacketed stirred tank reactor, stirred at approx. 200 rpm and heated to 70°C. Compound 2 (42.3 g, 1.0 mol. eq.) was added, followed by Compound 3 (37.5 g, 1.1 mol. eq.), T3P (83.7 ml of a 50 wt%- solution in ethyl acetate, 1.1 mol. eq.) and finally (-)-camphor sulfonic acid (CSA) (120.0 g, 4.0 mol. eq.). The addition of (-)-CSA starts the reaction. After 1 h of stirring at 70°C, baloxavir (la)*(-)-CSA salt (9.2 g, 10 wt%) were added as seed. Stirring was continued at 70°C for a total reaction time of approx. 20 hours, and then the reaction mixture was cooled to room temperature.

[0135] Step 2: Filtration and Purification

[0136] The precipitated crystals of baloxavir (la)*(-)-CSA salt were isolated by vacuum filtration. The wet cake was washed first with ethyl acetate and second with acetone (130 mL and 260 mL), respectively. The washed crystals were dissolved in acetonitrile / water (3: 1, 300 ml).

[0137] Step 3: Isolation of Baloxavir (la)

[0138] The temperature of the baloxavir (la)*(-)-CSA salt solution was adjusted to 20°C, and afterwards 1 M aqueous NaOH-solution was added. As soon as the pH had increased to pH 0.9-1.0, baloxavir (la) seed crystals (2 g, or 5 wt%) were added. The adjustment of the pH was continued until the pH reached pH 5.6. The total time for pH adjustment was approx. 1.5 h. Afterwards, water (202 ml) was added until the water fraction reached 65%.

[0139] Step 4: Filtration and Drying The precipitated crystals of baloxavir (la) were isolated by vacuum filtration and the wet cake was washed first with acetonitrile / water (1 :3) and second with isopropanol (152 mL). Baloxavir (la) was dried in vacuum at about 40°C.

[0140] The isolated yield was 36.8 g (59% of theory based on Compound 2, d.r. la:lb = 70: l as determined using the HPLC method described in Example 5).

[0141] Example 2

[0142] Integrated Continuous Manufacturing of Baloxavir (la)

[0143] The setup of the equipment for the continuous manufacturing process is shown in Figure 1.

[0144] Step 1 : Reaction

[0145] A 500 ml 5-stage-CSTR cascade is heated to 70°C and stirred at approx. 200 rpm.

[0146] 75.1 ml of ethyl acetate is charged into CSTR1 followed by 10.6 g of S199AL 2, 9.4 g of S199AR 3 (1.1 mol. eq.), 20.9 ml of a T3P-solution (50 wt% in ethyl acetate) (1.1 mol. eq.) and 30.0 g of (-)-CSA (4.0 mol. eq.). The same amounts were then added in intervals of 1 hour into reactor CSTR1. 1 hour after the initial charging 9.42 g of baloxavir(la)*(-)- CSA salt seed (10 wt%) was added to CSTR1. Slurry materials were transferred between the reactors and to a collection vessel in a burst pump mode in 1 hour intervals as soon as the reactors had reached their target volume (4 portions).

[0147] The mean residence time in each reactor was 4 h giving a total residence time of 20 h. The diastereomeric ratio in the reaction slurry was approx. 7 : 1 at steady stage and the calculated yield in the slurry was 74.5%. Step 2: Isolation of Crude Baloxavir(la)*(-)-CSA Salt

[0148] The slurry was sent to a continuous rotating plate filter with a feed rate of 25 mL / min. The cake was washed first with ethyl acetate (6 mL / min) and second with acetone (12 mL / min). The washed filter cake was collected and dissolved at room temperature in acetonitrile / water (3: 1) to get a solution of approx. 20 wt% of baloxavir(la)*(-)-CSA salt. The isolated yield of baloxavir(la)-CSA salt was approx. 62.6% with a diasteromeric ratio of approx. 16.5 : 1 (as assessed using the HPLC method described in Example 5).

[0149] Step 3: Crystallization of Crude Baloxavir (la)

[0150] 300 mL of the obtained solution of baloxavir (la)*(-)-CSA salt was charged into reactor 1 of a 2-stage MSMPR-crystallizer. 1 M NaOH-solution was added at 1 - 1.5 mL / min into MSMPR1. As soon as the pH reached pH 1. 15, baloxavir (la) seed was added (4.0 g, 5 wt%). Further 1 M NaOH-solution was added until the pH reached pH 5.6. Then, baloxavir (la)*(-)-CSA salt solution was added to MSMPR1 at 5 mL / min while the pH was maintained constantly at pH 5.6 by adding 1 M NaOH-solution. Slurry product was transferred to MSMPS2 in a burst pump mode (128.5 mL at 20 min intervals). Water was fed into stage-2 MSMPR at 3.32 mL / min to achieve a final water volume fraction of 65%.

[0151] Step 4:

[0152] The baloxavir (la) slurry was sent to a continuous rotating plate filter with a feed rate of 30 mL / min. The cake was washed first with acetonitrile / water (1 :3 by vol) at 6 mL / min, then second with isopropanol (6 mL / min). The obtained baloxavir (la) had an assay of 98.8%, a purity of 99.5% and a distereomeric ratio of 171 : 1 at steady state (see Figure 4, assessed using the HPLC method described in Example 5). Notably, the dr was often >200 : 1, and in some instances even up to 900 : 1.

[0153] The overall isolated yield of baloxavir (la) was 59.3%.

[0154] HPLC chromatogram of Baloxavir (la) produced according to this example (see Figure 4):

[0155] Diasteromeric ratio (la : lb) = 171 : 1

[0156] Example 3

[0157] Preparation of baloxavir marboxil (1)

[0158] The preparation of baloxavir marboxil (1) from baloxavir (la) is described, e.g., in WO2016 / 175224. Thus, to a suspention of baloxavir (la) (1.00 g, 2.07 mmol) in DMA (5 ml) were added chloromethyl methyl carbonate (4) (0.483 g, 3.10 mmol), potassium carbonate (0.572 g, 4. 14 mmol) and potassium iodide (0.343 g, 2.07 mmol) and the mixture was stirred at 50°C for 6 hours. To the mixture was added DMA (1 ml) and the mixture was stirred for 6 hours. The mixture was cooled to room temperature, DMA (6 ml) was added thereto, and the mixture was stirred at 50°C for 5 minutes. The mixture was filtered. To the obtained filtrate were added 1 mol / L aqueous solution of hydrochloric acid (10 ml) and water (4 ml) and the mixture was stirred for 1 hour. The precipitated solid was filtered and dried under reduced pressure at 60°C for 3 hours to obtain baloxavir marboxil (1) (1.10g, 1.93 mmol, 93%).

[0159] 1H-NMR (DMS0-D6) 5: 2.91-2.98 (1H, m), 3.24-3.31 (1H, m), 3.44 (1H, t, J = 10.4 Hz), 3.69 (1H, dd, J = 11.5, 2.8 Hz), 3.73 (3H, s), 4.00 (1H, dd, J = 10.8, 2.9 Hz), 4.06 (1H, d, J = 14.3 Hz), 4.40 (1H, d, J = 11.8 Hz), 4.45 (1H, dd, J = 9.9, 2.9 Hz), 5.42 (1H, dd, J = 14.4, 1.8 Hz), 5.67 (1H, d, J = 6.5 Hz), 5.72-5.75 (3H, m), 6.83-6.87 (1H, m), 7.01 (1H, d, J = 6.9 Hz), 7.09 (1H, dd, J = 8.0, 1. 1 Hz), 7. 14-7.18 (1H, m), 7.23 (1H, d, J = 7.8 Hz), 7.37-7.44 (2H, m). Example 4

[0160] Preparation ofbaloxavir marboxil (1) in continuous mode

[0161] Step 1 : Reaction ofbaloxavir (la) with chloromethyl methyl carbonate (4)

[0162] A 500 ml 3-stage-CSTR is heated to 70°C and stirred at approx. 550 rpm. To start up, 500 mL acetonitrile : water (49 : 1, v / v) and 41.0 g ofbaloxavir (la) are charged into CSTR1. Then, 5.6 g of potassium iodide, 15.2 g of potassium carbonate and 19.0 g of chloromethyl methyl carbonate (4) are added. Slurry material is transferred between the reactors and to the collection vessel in a burst pump mode at 0.5 h intervals. The following materials are added in 0.5 hour intervals to CSTR1 : 5.86 g ofbaloxavir (la), 71.4 ml of ACN : water (49 : 1), 0.8 g of potassium iodide, 2.2 g of potassium carbonate and 2.7 g of chloromethyl methyl carbonate (4). The average residence time per reactor is 3.5 h, leading to a total residence time of 10.5 h. The throughput of baloxavir (la) feed is 11.7 g / h, and the yield ofbaloxavir marboxil (1) relative to (la) is estimated to be approx. 93.8%.

[0163] Step 2: continuous crystallization ofbaloxavir marboxil (1)

[0164] The reaction slurry from step 1 is continuously crystallized in a 3 -stage MSMPR-cascade where the reactors were kept at temperatures of 35°C (MSMPR1), 25°C (MSMPR2) and 20°C (MSMPR3). 70 mL of reaction slurry is fed in burst mode into MSMPR1 every 60 min. Anti-solvent (isopropanol: water (4: 1, v / v) is fed continuously at 2.33 mL / min into MSMPR1. 70 mL slurry product from MSMPR1 is burst fed every 30 min to MSMPR2 where anti-solvent (isopropanol : water (4: 1, v / v)) is fed continuously at 3.5 mL / min. 175 mL of slurry product from MSMPR2 is fed in burst mode at every 30 min into MSMPR3 while anti-solvent (isopropanol : water (4: 1, v / v)) iss added continuously at 11.67 mL / min to attain a dilution by factor 15. Slurry product from MSMPR3 is transferred to the collection vessel in burst mode at 525 mL every 30 min.

[0165] The mean residence time is 60 min in MSMPR1, 30 min in MSMPR2, and 30 min MSMPR3, thus the total residence time is 120 min. The steady state yield is approx. 95.2 - 96.7%.

[0166] Step 3: Continuous filtration and milling of baloxavir marboxil (1)

[0167] Baloxavir marboxil (l)-slurry is fed at 80 mL / min to a rotating plate filter. The filter cake is washed on the plate first with isopopanol: water (1 :4, v / v; 6 mL / min) and second with isopropanol (6 mL / min). After cake removal, the plate is washed with acetonitrile : water (4: 1, v / v, 12 mL / min). Isolated crystals of baloxavir marboxil are suspended in n-heptane : ethyl acetate (50 : 1, v / v) to obtain a 10 wt%-slurry. The suspended baloxavir marboxil (1) is recirculated through a wet mill at 500 mL / min for 3 h. The milled wet slurry is sent downstream for drying.

[0168] Step 4: Continuous Drying of Baloxavir Marboxil

[0169] The slurry of baloxavir marboxil (1) in n-heptane : ethyl acetate (50: 1, v / v) is fed to a drum dryer at 15 mL / min and evenly distributed on the drum surfaces, forming a thin slurry film to facilitate the conductive drying process. Drying is done continuously at a drum temperature of 65°C and a vacuum pressure of 250 torr. Residence time in the dryer is approx. 1 min. The dried product is pneumatically conveyed to a cyclonic separator and collected.

[0170] The overall isolated yield of steps 1 to steps 4 is approx. 90%.

[0171] Example 5

[0172] HPLC - method description:

[0173] Mobile phase A: 0.2mM EDTA / 0. 1% TFA buffer

[0174] Mobile phase B: acetonitrile

[0175] Diluent: (1 : l)-mixture of mobile phase A and mobile phase B

[0176] Standard solution: approx. 0.1 mg / mL of Baloxavir (la) reference standard

[0177] Sanple solution: approx. 50 mg sample dissolved in 50 mL diluent

[0178] Equipment: Waters Alliance HPLC or equivalent Column: Waters XSelect CSH Cis 150 x 3 mm; 3.5 pm

[0179] Column temperature: 45 ±5°C

[0180] Sample temperature 5 ±2 °C

[0181] Flow rate: 0.6 mL / min Injection volume 10 pL

[0182] Detection UV at 259 nm

[0183] Gradient program

Claims

Claims1. A process for manufacturing baloxavir marboxil (1), or a pharmaceutically acceptable salt thereofcomprising reacting baloxavir (la)with chloromethyl methyl carbonate (4)in the presence of potassium carbonate and potassium iodide in a 49 : 1 (v / v) mixture of acetonitrile and water to afford baloxavir marboxil (1).

2. A process for manufacturing baloxavir (la), or a pharmaceutically acceptable salt thereofcomprising(a) reacting compound 2with compound 3in the presence of:(i) about 1-2 mol. equivalents of T3P relative to compound 2; and(ii) about 2-6 mol. equivalents of (-)-CSA or (+)-CSA relative to compound2; to afford baloxavir (la) as a (-)-CSA or (+)-CSA salt.

3. The process according to claim 2, wherein the process is conducted in the presence of about 4 mol. equivalents of (-)-CSA or (+)-CSA relative to compound 2.

4. The process according to any one of claims 2 or 3, wherein the process is conducted in the presence of about 1-1.5 mol. equivalents of T3P relative to compound 2.

5. The process according to any one of claims 2 to 4, wherein about 1-2 mol. equivalents of compound 3 relative to compound 2 are used.

6. The process according to any one of claims 2 to 5, wherein the process is conducted in a solvent selected from:(i) ethyl acetate;(ii) isopropyl acetate; and(iii) a mixture of ethyl acetate or isopropyl acetate and cyclohexane.

7. The process according to any one of claims 2 to 6, wherein the process is conducted at an internal temperature of about 50-80 °C, preferably at an internal temperature of about 70 °C.

8. The process according to any one of claims 2 to 7, further comprising:(b) seeding the reaction mixture obtained from step (a) with a (-)-CSA or (+)-CSA salt of baloxavir (la), preferably with baloxavir (la)*(-)-CSA salt.

9. The process according to any one of claims 2 to 8, further comprising:(c) reacting said (-)-CSA or (+)-CSA salt of baloxavir (la) obtained from steps (a) and (b) with a base, prefereably with NaOH, to afford baloxavir (la).

10. The process according to claim 9, further comprising:(d) reacting said baloxavir (la) obtained from step (c) with chloromethyl methyl carbonate (4)in the presence of potassium carbonate and potassium iodide to afford baloxavir marboxil (1).

11. The process according to claim 10, wherein step (d) is conducted in a mixture of acetonitrile and water.

12. The process according to any one of claims 2 to 11, wherein the process is a continuous flow process.

13. The process according to claim 12, wherein steps (a) and (b) are conducted in an n- stage-CSTR cascade, wherein n is an integer selected from 2 to 10.

14. The process according to claim 13, wherein the last CSTR of said n-stage-CSTR cascade is connected to a filter.

15. The process according to claim 14, wherein said filter is a continuous rotating plate filter.

16. The process according to claims 14 or 15, wherein the (-)-CSA or (+)-CSA salt of baloxavir (la) that is obtained from said steps (a) and (b) is collected on said filter.

17. The process according to any one of claims 12 to 16, wherein step (c) comprises: (cl) charging a solution of said (-)-CSA or (+)-CSA salt of baloxavir (la) into reactor 1 of a 2-stage MSMPR-crystallizer;(c2) adding a solution of NaOH to reactor 1 until the pH reaches about 1.15;(c3) adding seeds of baloxavir (la) to reactor 1;(c4) adding further solution of NaOH to reactor 1 until the pH reaches about 5.6;(c5) continuously adding further solution of (-)-CSA or (+)-CSA salt of baloxavir (la), preferably baloxavir (la)*(-)-CSA salt into reactor 1 while maintaining the pH constantly at about pH 5.6 by adding further solution of NaOH;(c6) transferring given portions of the mixture from reactor 1 to reactor 2 at given time intervals; and(c7) feeding water into reactor 2 to achieve a final water volume fraction of about 65%.

18. The process according to claim 17, wherein reactor 2 of said 2-stage MSMPR- crystallizer is connected to a filter.

19. The process according to claim 18, wherein said filter is a continuous rotating plate filter.

20. The process according to claims 18 or 19, wherein the baloxavir (la) that is obtained from said step (c) is collected on said filter.

21. The process according to claim 1, wherein the process is a continuous flow process.

22. The process according to claim 21, wherein the process is conducted in an n-stage- CSTR cascade, wherein n is an integer selected from 2 to 10.

23. The process according to claims 21 and 22, wherein the baloxavir marboxil (1) that is obtained from said process is crystallized in an n-stage MSMPR-crystallizer, wherein n is an integer selected from 2 to 5.

24. The process according to claim 23, wherein the crystalline baloxavir marboxil (1) that continuously exits the n-stage MSMPR-crystallizer is continuously wet-milled.

25. The invention as described hereinbefore.

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