Process for manufacturing baloxavir marboxil

Abstract

The present invention relates to a novel process for the preparation of macavir (1) and baravir (1a), as well as an integrated continuous manufacturing (ICM) embodiment of the process. Formulae (1) and (1a), (1) and (1a).

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) ™ (19) World Intellectual Property ~S Organization ; LNA AMA ACA TAA International Bureau —— (10) International Publication Number (43) International Publication Date =— WO 2025 / 073819 A2 10 April 2025 (10.04.2025) WIPO| PCT (51) International Patent Classification: TY, Rajshree; c / o Continuus Pharmaceuticals Inc., 25-R CO7D 498 / 14 (2006.01) Olympia Avenue, Woburn, Massachusetts 01801 (US). (21) International Application Number: (74) Agent: NEUHAUS, Christian; c / o F. Hoffmann-La Roche PCT / EP2024 / 077821 AG, Patent Department, Grenzacherstrasse 124, 4070 Basel (22) International Filing Date: (CH). 03 October 2024 (03.10.2024) (81) Designated States (unless otherwise indicated, for every - . . kind of national protection available); AE, AG, AL, AM, (25) Filing Language: English AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, (26) Publication Language: English CA, CH, CL, CN, CO, CR, CU, CV, CZ, DE, DJ,DK, DM, 30) Priority Data: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, “” 33001730 . 05 October 2023 (05.10.2023 EP HN, HR, HU, ID, IL, IN, 1Q, IR, IS, IT, JM, JO, JP, KE, KG, 3201730. ctober 2023 (05.10.2023) KH, KN, KP. KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, (71) Applicant (for all designated States except US): F. HOFF- MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, MANN-LA ROCHE AG [CH / CH]; Grenzacherstrasse NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, 124, 4070 Basel (CH). RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, . TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, (71) Applicant (for US only): HOFFMANN-LA ROCHE ZA. ZM. ZW INC. [US / US]; Overlook at Great Notch, 150 Clove Road, ae 8th Floor, Suite 8 - Legal Department, Little Falls, New Jer- (84) Designated States (unless otherwise indicated, for every sey 07424 (US). kind of regional protection available): ARIPO (BW, CV, — . ; . GH, GM, KE, LR, LS, MW, MZ, NA, RW, SC, SD, SL, ST, === (72) Inventors:BARBATO, Keith Steven; c / o Continuus Phar- SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, — maceuticals Inc., 25-R Olympia Avenue, Woburn, Mass- RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, =— achusetts 01801 (US). BORN, Stephen Christopher, c / DE. DK. EE. ES. FL FR. GB. GR. BR. HU. IE.IS. IT. LT — o Continuus Pharmaceuticals Inc., 25-R Olympia Avenue, LU. LV “MC. ME. MK. MT. NL NO PL. PT RO RS. SE. —— Woburn, Massachusetts 01801 (US). CHAKRABAR- 0 === (54) Title: PROCESS FOR MANUFACTURING BALOXAVIR MARBOXIL — (57) Abstract: The invention relates to a novel process for making baloxavir = 5 F marboxil (1) and baloxavir (1a), as well as to an integrated continuous manufac- — a0ed turing (ICM) implementation thereof. Formulae (1) and (1a), (1) and (1a). => ONO 0 a 1 = eee (1) _— ie) ie) (e) (e) — “ aa Ne — O = F = aoe . = WN (1a) ore) oN No = OH O la) fan —) N [Continued on next page] WO 2025 / 073819 A2 |HMITINTIMNI AYIA AN TAT AIT ATTA AEA SL SK, SM, TR), OAPI (BF, BJ, CF, CG,CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) — in black and white; the international application as filed contained color or greyscale and is available for download Jrom PATENTSCOPE WO 2025 / 073819 PCT / EP2024 / 077821 PROCESS FOR MANUFACTURING BALOXAVIR MARBOXIL Field of the Invention The present invention relates to a novel process for making baloxavir marboxil (1) and baloxavir (1a), as well as to an integrated continuous manufacturing (ICM) 5 implementation thereof. F S F F OI AY H¥: H C\ N 2 Oo N~ ar) H N H ° ae NJ O O O O 7 a Ne ' OH O O 1a Background of the Invention Baloxavir (1a) is a compound that exerts antiviral effects against influenza. In order to improve its oral bioavailability, baloxavir (1a) is administered in the form of a prodrug, 10 baloxavir marboxil (1), which is converted to the active form baloxavir (1a) in the blood, liver, and smallintestine. Baloxavir (1a) is also a synthetic intermediate in the known processes for manufacturing baloxavir marboxil (1) (see for example WO2016 / 175224 and WO2017 / 221869). Baloxavir marboxil (1) is marketed under the trade name Xofluza®. The manufacturing process for baloxavir marboxil (1) disclosed in WO2016 / 175224 is 15 shown in Scheme 1. WO 2025 / 073819 PCT / EP2024 / 077821 -2- F F Ss FE Ss F OO iN ° F T3P, MsOH @) O C) O~N7 fe) us H + ne yeee , (_\ oS EtOAc, 70 °C O nto 7 Ne Yo 0 Oo OH of NJ of rw Bn 2 3 0 Oo OH O Bn 5* 1a* 46%, dr=2.1:1 ee 46%, dr=2.1:1 K,CO, F F F OL (O. Lc F F OAT TT Oa OFS We oO , aA Licl ma A™n- bo Z vo 94% yield A noo OO. 0 oO Oo (O Ve OH O . “oT 1 4a Bn 5, 53% Oo Scheme 1 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 5 purification by crystallization. Furthermore, in said condensation reaction, about 50% of the molecules lose their benzylprotective 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 (1a) with chloromethyl methyl carbonate (4) to afford baloxavir marboxil (1) that is described in WO2016 / 175224 is 10 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). The issues outlined above are partly addressed by the process disclosed in WO02017 / 221869, which is shown in Scheme 2. WO 2025 / 073819 PCT / EP2024 / 077821 -3- r F S F S : ZN Yo HexytOMgCl Nye eo SH a OO Oo 0 Et0Ac,80°C = 9 ANA NO Bn 2 rex 6, 87% OO Hex 7, 89% dir. reaction: 15.5: 1 dr recyst 100: 1, Scheme 2 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 isnot cleaved under the 5 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 10 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 15 to exchange the benzyl protective group for a hexyl protective group and has furtherdrawbacks that are discussed below. 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. 20 Summary of the Invention 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. WO 2025 / 073819 PCT / EP2024 / 077821 -4- r F S FE S 5 pO Co Oo ~N7 O OH 3 H Ay " ee ° SAS TBP, (-)-CSA 1 6 6 EtOAc, 70 °C Of NZ Bn 2 OH O 1a, 60% d.r. up to 250 : 1 Scheme 3 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 5 surprisingly, the benzyl protective group is completely removed under the reaction conditions, obviating thedeprotection step with LiCl described in the prior art. Thus, according to the new process of the invention, baloxavir (1a) 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 10 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 15 baloxavir (1a) 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. In additionto the above, the process of the invention has also been implemented as an integrated continuous manufacturing (ICM) process, which offers further benefits, as will 20 be discussed hereinbelow. Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be WO 2025 / 073819 PCT / EP2024 / 077821 5- 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 S 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 anynovel 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. 10 Theterm “S033447” refers to compound 1a as described herein. The term “S199AW” refers to compound 1b as described herein. The term “S199AL” refers to compound 2 as described herein. The term “S199AR” refers to compound 3 as described herein. The term “S199AT” refers to compound 5 as described herein. 15 The term “T3P*” refers to propylphosphonic anhydride (CAS 68957-94-8). 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 20 chiral carboxylic acid is tartaric acid.Non-limiting examples of chiral sulfonic acids are (+)- and (-)-CSA. The term “CSA” refers to camphorsulphonic acid. 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 25 product(s) of the reaction concurrently exit(s) the vessel. WO 2025 / 073819 PCT / EP2024 / 077821 -6- 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. The term “about” as used herein when referring to a measurable value such as an amount S of acompound, 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% to0.5% of the specified amount. Brief Description of the Figures 10 Figure 1 shows the equipment setup for the continuous flow manufacturing of baloxavir (1a) described in Example 2. Figure 2 shows the equipment setup for the continuous flow manufacturing of baloxavir marboxil (1) described in Example 4. Figure 3 shows a typical HPLC chromatogram of a mixture containing the reactants 15 S199AL (2) and S199AR (3), the product S033447 (1a), the steroisomer S199A W (1b) and the associated impurity S199AT (5). The chromatogram was obtained by using the HPLC method described in Example 5. Figure 4 shows a typical HPLC chromatogram of baloxavir (1a) as obtained from the continuous manufacturing process described in Example 2. The chromatogram was 20 obtained by using the HPLC method described in Example 5. Improved Prodrug Formation In the process that is described e.g. in WO2016 / 175224, the prodrug baloxavir marboxil (1) is obtained by reacting baloxavir (1a) with chloromethyl methylcarbonate (4) in DMA as a solvent. However, DMA is on the candidate list for substances of very high concern 25 (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. WO 2025 / 073819 PCT / EP2024 / 077821 -7- Thus, in a first aspect, the present invention provides a process for manufacturing baloxavir marboxil (1), or a pharmaceutically acceptable salt thereof F ON ar) NJ of A O O O O 4 Ne nid 1 O comprising reacting baloxavir (1a) F aN No of NZ NJ OH O 5 1a with chloromethyl methyl carbonate (4) 0 0 Cl 2 aia wa ° 4 in the presence of potassium carbonate and potassium iodide in a mixture of acetonitrile and water to afford baloxavir marboxil (1). 10 In one embodiment, the mixture of acetonitrile and water is a 49 : 1 (v / v) mixture of acetonitrile and water. Diastereoselective Condensation In a further aspect, the present invention provides a process formanufacturing baloxavir (1a), or a pharmaceutically acceptable salt thereof WO 2025 / 073819 PCT / EP2024 / 077821 -8- F S. 2H N aN No NJ AL OH O 1a comprising (a) reacting compound 2 HH 2~N7 No NJ 07 A 0 0 é 5 with compound 3 F OH 3 in the presence of: (1) about 1-2 mol. equivalents of T3P relative to compound 2; and (11) about 2-6 mol. equivalents of a chiral acid relative to compound 2; 10 to afford baloxavir (1a) as a chiral acid salt. 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. 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. 15 In one embodiment, said chiral acid is a chiral carboxylic acid or a chiral sulfonic acid. WO 2025 / 073819 PCT / EP2024 / 077821 -9- In one embodiment, said chiral acid is selected from (-)-CSA and (+)-CSA. In one embodiment, saidchiral acid is (+)-CSA. In a preferred embodiment, said chiral acid is (-)-CSA. In one embodiment, the process according to the invention is conducted in the presence of 5S about 3, 4, 5, or 6 mol. equivalents of (-)-CSA relative to compound 2. 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. 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. 10 Ina 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. In one embodiment of the process according to the invention, about 1-2 mol. equivalents of compound 3 relative to compound 2 are used. In a preferred embodiment of the process according to the invention, about 1-1.5 mol. 15 equivalents of compound 3 relative tocompound 2 are used. 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. In one embodiment, step (a) of the process according to the invention is conducted ina solvent selected from: 20 (i) ethyl acetate; (11) isopropyl acetate; and (ili) a mixture of ethyl acetate or isopropyl acetate and cyclohexane (1:1, v / v). 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 25 selected from: (i) ethyl acetate; WO 2025 / 073819 PCT / EP2024 / 077821 -10- (11) isopropyl acetate; and (ili) a mixture of ethyl acetate or isopropyl acetate and cyclohexane (1:1, v / v). In a further preferred embodiment, step (a) of the process according to the invention is conducted in ethyl acetate. S Ina further preferred embodiment, step (a) of the process according to the invention isconducted in isopropyl acetate. 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 1s 1:1, v / v. 10 Ina 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. 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 15 of compound 2. 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. In one embodiment, step (a) of the process according to the invention is conducted at an 20 internaltemperature of about 50-80 °C. In one embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 60-80 °C. In a preferred embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 70-80 °C. 25 Ina particularly preferred embodiment, step (a) of the process according to the invention is conducted at an internal temperature of about 70 °C. WO 2025 / 073819 PCT / EP2024 / 077821 -11- 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. In one embodiment, the process according to the invention further comprises: (b) seeding the reaction mixture obtained from step (a) with a chiral acid salt of 5 baloxavir (1a), preferably with baloxavir (1a)*(-)-CSA salt. In one embodiment, said seeding in step (b) is seeding with about 1-15 wt% of baloxavir (1a)*(-)-CSA salt. In a preferred embodiment, saidseeding in step (b) is seeding with about 5-10 wt% of baloxavir (1a)*(-)-CSA salt. 10 Ina particularly preferred embodiment, said seeding in step (b) is seeding with about 10 wt% of baloxavir (1a)*(-)-CSA salt. In one embodiment, the process according to the invention further comprises: (c) reacting said chiral acid salt of baloxavir (1a) obtained from steps (a) and (b) with a base, prefereably with NaOH, to afford baloxavir (1a). 15 The preparation of baloxavir marboxil (1) from baloxavir (1a) is described, e.g., in WO2016 / 175224. In one embodiment, the process according to the invention further comprises: (d) reacting said baloxavir (1a) obtained from step (c) with chloromethyl methyl carbonate (4) O O Cl 2 ‘re Ne O 20 4 in the presence of potassium carbonate and potassium iodide to afford baloxavir marboxil (1). 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) ofthe 25 EU. The inventors of the present invention have now surprisingly found that reaction step WO 2025 / 073819 PCT / EP2024 / 077821 -12- (d) can also be conducted in a mixture of acetonitrile and water, avoiding the use of toxic DMA. Thus, in a preferred embodiment, step (d) of the process according to the invention is conducted in a mixture of acetonitrile and water. S Ina particularly preferred embodiment, step (d) of the process according to the invention is conducted in acetonitrile : water (49 : 1, v / v). In one embodiment, the present invention provides a process for manufacturing baloxavir (1a)*(-)-CSA salt, or a pharmaceutically acceptable salt thereof, comprising: (a) reacting compound 2 described herein with compound 3 described herein 10 in the presence of: (1) about 1-2 mol. equivalents of T3P relative to compound 2; and (11) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; and (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir(1a)*(-)-CSA salt; 15 to afford said baloxavir (1a)*(-)-CSA salt. In one embodiment, the present invention provides a process for manufacturing baloxavir (1a), comprising: (a) reacting compound 2 described herein with compound 3 described herein in the presence of: 20 (1) about 1-2 mol. equivalents of T3P relative to compound 2; and (11) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; to afford baloxavir (1a)*(-)-CSA salt; (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir (1a)*(-)-CSA salt; and 25 (c) reacting said baloxavir (1a)*(-)-CSA salt obtained from steps (a) and (b) with a base, prefereably with NaOH. to afford said baloxavir (1a). In one embodiment, the present invention provides a process for manufacturing baloxavir marboxil (1), comprising: 30 (a) reacting compound 2 described herein with compound 3 described herein WO 2025 / 073819 PCT / EP2024 / 077821 -13- in the presence of: (1) about 1-2 mol. equivalents of T3P relative tocompound 2; and (11) about 2-6 mol. equivalents of (-)-CSA relative to compound 2; to afford baloxavir (1a)*(-)-CSA salt; 5 (b) optionally seeding the reaction mixture obtained from step (a) with baloxavir (1a)*(-)-CSA salt; (c) reacting said baloxavir (1a)*(-)-CSA salt obtained from steps (a) and (b) with a base, prefereably with NaOH; to afford baloxavir (1a); and 10 (d) reacting said baloxavir (1a) obtained from step (c) with chloromethyl methyl carbonate (4) in the presence of potassium carbonate and potassium iodide; to afford said baloxavir marboxil (1). Continuous Flow Process As mentioned above, the process according to the invention has also been implemented as 15 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 batchmanufacturing processes used in the pharmaceutical industry. In contrast to batch manufacturing, ICM’s unit operation 20 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 25 tablets from raw ingredients through a single, seamless end-to-end process (Mascia ef al., Angew. Chem. Int. Ed. 2013, 52, 12359-12363.). 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. WO 2025 / 073819 PCT / EP2024 / 077821 -14- The ICM implementation of the final synthetic step in theprocess 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: 5 1. No need for purification of the API by recrystallization. 2. Wet milling of the API, as opposed to the dry milling process that is required in batch mode. 3. Reduced physical stress on the API due to shorter drying times. Dry milling in general is a dusty process creating a health hazard for the involved 10 operators. Operational exposure limits (OEL) of 2.5 mcgr / m* need 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. In one embodiment of the ICM according to the invention, steps (a), (b) and (d) are 15 conducted in an n-stage-CSTR cascade, whereinn is an integer selected from 2 to 10. 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. In one embodiment of the ICM according to the invention, the last CSTR of said n-stage- 20 CSTR cascade that is used for reaction steps (a) and (b) is connected to a filter. In one embodiment, said filter is a continuous rotating plate filter. In one embodiment, the baloxavir (1a)*(-)-CSA salt that is obtained from said steps (a) and (b) is collected on said filter. In one embodiment of the ICM according to the invention, step (c) comprises: 25 (cl) charging a solution of baloxavir (1a)*(-)-CSA salt into reactor 1 of a 2-stage MSMPR-crystallizer; (c2) adding a solution of NaOH to reactor | until the pH reaches about 1.15; (c3) adding seeds of baloxavir (1a) to reactor 1; WO 2025 / 073819 PCT / EP2024 / 077821 -15- (c4) adding further solution of NaOH to reactor 1 until the pHreaches about 5.6; (c5) continuously adding further solution of baloxavir (1a)*(-)-CSA salt into reactor 1 while maintaining the pH constantly at about pH 5.6 by adding further solution of NaOH; 5 (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%. In one embodiment, reactor 2 of said 2-stage MSMPR-crystallizer is connected to a filter. 10 In one embodiment, said filter is a continuous rotating plate filter. In one embodiment, the baloxavir (1a) that is obtained from said step (c) is collected on said filter. In one embodiment, the baloxavir marboxil (1) that is obtained from the n-stage-CSTR cascade that is used for reaction step (d) 1s crystallized in an n-stage MSMPR-crystallizer, 15 wherein n is an integer selected from 2 to 5. In a preferred embodiment, the MSMPR-crystallizer is a 3-stage MSMPR-crystallizer. In one embodiment, thecrystalline baloxavir marboxil (1) that continuously exits the n- stage MSMPR-crystallizer is continuously wet-milled. Examples 20 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. Example 1 Batch Synthesis of Baloxavir (1a) WO 2025 / 073819 PCT / EP2024 / 077821 -16- F HH s s F F A no C\ [ [) a NO OF 6) C\ fe) 3 H fe H : Hv lH Oo. 0 + aN So Z yo 2 of 7 NWO of N77 NO OH O OH O la 1b Step 1: Reaction 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.) S 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 (1a)*(-)-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 10 cooled to room temperature. Step 2: Filtration and Purification The precipitated crystals of baloxavir (1a)*(-)-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 15 mil). Step 3: Isolation of Baloxavir (1a) The temperature of the baloxavir (1a)*(-)-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 (1a) seed crystals (2 g, or 5 wt%) were added. The adjustment of the pH 20 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%. Step 4: Filtration and Drying WO 2025 / 073819PCT / EP2024 / 077821 -17- The precipitated crystals of baloxavir (1a) were isolated by vacuum filtration and the wet cake was washed first with acetonitrile / water (1:3) and second with isopropanol (152 mL). Baloxavir (1a) was dried in vacuum at about 40°C. The isolated yield was 36.8 g (59% of theory based on Compound 2, d.r. 1a:1b = 70:1 as S determined using the HPLC method described in Example 5). Example 2 Integrated Continuous Manufacturing of Baloxavir (1a) F S FE - HH C\ S : otis On ete OH ZA N 07 SS 3 H™: H Oo. O a ZA noo NJ 2 077 OH O 1a The setup of the equipment for the continuous manufacturing process is shown in Figure 1. 10 Step 1: Reaction A 500 ml 5-stage-CSTR cascade is heated to 70°C and stirred at approx. 200 rpm. 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 inintervals 15 of 1 hour into reactor CSTR1. 1 hour after the initial charging 9.42 g of baloxavir(1a)*(-)- 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). The mean residence time in each reactor was 4 h giving a total residence time of 20 h. The 20 diastereomeric ratio in the reaction slurry was approx. 7:1 at steady stage and the calculated yield in the slurry was 74.5%. WO 2025 / 073819 PCT / EP2024 / 077821 -18- Step 2: Isolation of Crude Baloxavir(1a)*(-)-CSA Salt 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 5 acetonitrile / water (3:1) to get a solution of approx. 20 wt% of baloxavir(1a)*(-)-CSAsalt. The isolated yield of baloxavir(1a)-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). Step 3: Crystallization of Crude Baloxavir (1a) 300 mL of the obtained solution of baloxavir (1a)*(-)-CSA salt was charged into reactor 1 10 ofa 2-stage MSMPR-crystallizer. 1 M NaOH-solution was added at 1 - 1.5 mL / min into MSMPRI1. As soon as the pH reached pH 1.15, baloxavir (1a) seed was added (4.0 g, 5 wt%). Further 1 M NaOH-solution was added until the pH reached pH 5.6. Then, baloxavir (1a)*(-)-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 15 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%. Step 4: The baloxavir (1a) slurry was sent to a continuous rotating plate filter with a feed rateof 30 mL / min. The cake was washed first with acetonitrile / water (1:3 by vol) at 6 mL / min, 20 then second with isopropanol (6 mL / min). The obtained baloxavir (1a) 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. The overall isolated yield of baloxavir (1a) was 59.3%. 25 HPLC chromatogram of Baloxavir (1a) produced according to this example (see Figure 4): SP 13.566 | 1618 2 S033447 = Baloxavir 14.857 5478437 99.23 629245 (1a) WO 2025 / 073819 PCT / EP2024 / 077821 -19- St 303131457 | 0.03 | 6 [ 2.4[23335 [0.04 [40s Diasteromeric ratio (la: 1b)=171:1 Example 3 Preparation of baloxavir marboxil (1) S F - ON ON S F : Or 8«§ Ge H™: H ————_> H™: H Z noo a noo ZAG yee NJ OH O te ona 0 S The preparation of baloxavir marboxil (1) from baloxavir (1a) is described, e.g., in WO02016 / 175224. Thus, to a suspentionof baloxavir (1a) (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 10 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 15 (1) (1.10g, 1.93 mmol, 93%). 1H-NMR (DMSO-D6) 6: 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, 20 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). WO 2025 / 073819 PCT / EP2024 / 077821 -20- Example 4 Preparation of baloxavir marboxil (1) in continuous mode F F 0 0 Cl S F 7 ma N~ S F GOT °+ Ge of A 07 A OH O 0 0 0 0 4 NY 1a ne 1 0 Step 1: Reaction of baloxavir (1a) with chloromethyl methyl carbonate (4) 5 A500 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 of baloxavir (1a) are charged into CSTRI. 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 10 materials are added in 0.5 hour intervals to CSTR1:5.86 g of baloxavir (1a), 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 (1a) feed is 11.7 g / h, and the yield of baloxavir marboxil (1) relative to (1a) is estimated to be approx. 15 93.8%. Step 2: continuous crystallization of baloxavir marboxil (1) 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 20 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 fromMSMPR2 is fed in burst mode at every 30 min into MSMPR3 while anti-solvent (isopropanol : water (4:1, v / v)) iss added continuously at WO 2025 / 073819 PCT / EP2024 / 077821 -21- 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. The mean residence time is 60 min in MSMPRI1, 30 min in MSMPR2, and 30 min MSMPR3, thus the total residence time is 120 min. The steady state yield is approx. 95.2 — 5 96.7%. Step 3: Continuous filtration and milling of baloxavir marboxil (1) Baloxavir marboxil (1)-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 10 (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. Thesuspended 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. Step 4: Continuous Drying of Baloxavir Marboxil 15 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 20 collected. The overall isolated yield of steps 1 to steps 4 is approx. 90%. Example 5 HPLC - method description: Mobile phase A: 0.2mM EDTA / 0.1% TFA buffer 25 Mobile phase B: acetonitrile Diluent: (1:1)-mixture of mobile phase A and mobile phase B Standard solution: approx. 0.1 mg / mL of Baloxavir (1a) reference standard Sanple solution: approx. 50 mgsample dissolved in 50 mL diluent Equipment: Waters Alliance HPLC or equivalent WO 2025 / 073819 PCT / EP2024 / 077821 -22- Column: Waters XSelect CSH Cis 150 x 3 mm; 3.5 um Column temperature: 45 45°C Sample temperature 542°C Flow rate: 0.6 mL / min 5 Injection volume 10 wh Detection UV at 259 nm Gradient program a WO 2025 / 073819 PCT / EP2024 / 077821 -23- Claims 1. A process for manufacturing baloxavir marboxil (1), or a pharmaceutically acceptable salt thereof F ON ar) NJ of A O O O O 4 Ne nid 1 O 5 comprising reacting baloxavir (1a) F S. 2 H N aN No NJ AL OH O 1a with chloromethyl methyl carbonate (4) 0 0 Cl 2 aia wa ° 4 in the presence of potassium carbonate and potassium iodide in a 49 : 1 (v / v) mixture 10 of acetonitrile and water to afford baloxavir marboxil (1). 2. A process for manufacturing baloxavir (1a), or a pharmaceutically acceptable salt thereof WO 2025 / 073819 PCT / EP2024 / 077821 -24- F S. 2 H N ZNO No NJ AL OH O 1a comprising (a) reacting compound 2 HH 2~N7 No NJ 07 A 0 0 é 5 withcompound 3 F OH 3 in the presence of: (1) about 1-2 mol. equivalents of T3P relative to compound 2; and (11) about 2-6 mol. equivalents of (-)-CSA or (+)-CSA relative to compound 10 2; to afford baloxavir (1a) 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 15 in the presence of about 1-1.5 mol. equivalents of T3P relative to compound 2. WO 2025 / 073819 PCT / EP2024 / 077821 -25- 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: 5 (1) ethyl acetate; (11) isopropyl acetate; and (iii) a mixture of ethyl acetate or isopropyl acetate and cyclohexane. 7. The processaccording 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 10 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 (1a), preferably with baloxavir (1a)*(-)-CSA salt. 9. The process according to any one of claims 2 to 8, further comprising: 15 (c) reacting said (-)-CSA or (+)-CSA salt of baloxavir (1a) obtained from steps (a) and (b) with a base, prefereably with NaOH, to afford baloxavir (1a). 10. The process according to claim 9, further comprising: (d) reacting said baloxavir (1a) obtained from step (c) with chloromethyl methyl carbonate (4) 0 0 Cl 2 aia wa 0 20 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 acetonitrileand water. 25 12. The process according to any one of claims 2 to 11, wherein the process is a continuous flow process. WO 2025 / 073819 PCT / EP2024 / 077821 -26- 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. 5 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 (1a) 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: 10 (cl) charging a solution of said (-)-CSA or (+)-CSA salt of baloxavir (1a) into reactor 1 of a 2-stage MSMPR-crystallizer; (c2) adding a solution of NaOH to reactor | until the pH reaches about 1.15; (c3)adding seeds of baloxavir (1a) to reactor 1; (c4) adding further solution of NaOH to reactor 1 until the pH reaches about 5.6; 15 (c5) continuously adding further solution of (-)-CSA or (+)-CSA salt of baloxavir (1a), preferably baloxavir (1a)*(-)-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 20 (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 25 filter. 20. The process according to claims 18 or 19, wherein the baloxavir (1a) 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 flowprocess. WO 2025 / 073819 PCT / EP2024 / 077821 -27- 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, 5 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. WO 2025 / 073819 PCT / EP2024 / 077821 1 / 3 Figure 1 5 Oe seaVk : Sx _ S & OCD: os § , ich % : iat Se | "Sao, Sa | : 1m SE | int H i Elgg ee eye WO 2025 / 073819 PCT / EP2024 / 077821 2 / 3 Figure 2 cs G 5 | Ss &. ros a = 2 Che E “ Ns = On Las \ is 2 . oe = ° ra ges i g| © = i fy Bn ty Se = Baad 5 J ae ee S ro Ses & $82 ao ro af Py at i wv = : LP nnn ©) — § Th = € E o ej fs Ll cnmenne anch a 5 yj fs ©) Essence Bx ial 3 Ri ifs s o- 4 @ ae Pa ia ol read : & Sead 0, fod a ee i ke wa ] WO 2025 / 073819 PCT / EP2024 / 077821 3 / 3 Figure 3 oe i = | 0.18 _ <q i a A 8 < 0.08 | ia y i | 0.00 5.00 40,00 18.00 20.00 25.00 30.00 35.00 40.00 Minutes Figure 4 0.60 Al ose B 0.40- ; = y Z 030 020 | | sz o40 u s & : — ® ee mt hp oe ee 0.00 5.00 16.00 15.00 20.06 25.00 30.00 35.00 40.00 Minutes (19) State Intellectual Property Office of the People's Republic of China (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 202480062823.9 (22) Application Date Oct. 3, 2024 (30) Priority Data 23201730.1 Oct. 5, 2023 EP (85) Date of Entry of PCT International Application into the National Phase Mar. 30, 2026 (86) Application Data of PCT International Application PCT / EP2024 / 077821 Oct. 3, 2024 (87) Publication Data of PCT International Application WO2025 / 073819 EN Apr. 10, 2025 (71) Applicant Hoffmann-La Roche Ltd. Address Switzerland (72) Inventors K.S. Barbato; S.C. Born; R. Chakrabarti (74) Patent Agency ZhongZi Law Firm, Beijing (11247) Patent Attorney An Peidong; Huang Gesheng (51) Int.Cl. C07D 498 / 14(2006.01) (54) Invention Title Method for Manufacturing Marboxavir (57) Abstract The present invention relates to a novel method for preparing marboxavir (1) and baloxavir (1a), and an integrated continuous manufacturing (ICM) embodiment of the method. Formulas (1) and (1a), (1) and (1a). Claims 3 pages, Specification 15 pages, Drawings 3 pages CN 121925422 A 2026.04.24 CN 1 21 92 54 22 A 1. A method for manufacturing marboxavir (1) or a pharmaceutically acceptable salt thereof, the method comprising: reacting baloxavir (1a)1. Reaction of compound 2 with chloromethyl carbonate (4) in a 49:1 (v / v) mixture of acetonitrile and water in the presence of potassium carbonate and potassium iodide to obtain baloxavir (1). 2. A method for manufacturing baloxavir (1a) or a pharmaceutically acceptable salt thereof, the method comprising (a) reacting compound 2 with compound 3 in the presence of: (i) about 1 to 2 molar equivalents of T3P relative to compound 2; and (ii) about 2 to 6 molar equivalents of (-)-CSA or (+)-CSA relative to compound 2; to obtain baloxavir (1a) in the form of (-)-CSA or (+)-CSA salt. 3. The method according to claim 2, wherein the method is carried out in the presence of about 4 molar equivalents of (-)-CSA or (+)-CSA relative to compound 2. 4. The method according to any one of claims 2 or 3, wherein the method is carried out in the presence of about 1 to 1.5 molar equivalents of T3P relative to compound 2. 5. The method according to any one of claims 2 to 4, wherein about 1 to 2 molar equivalents of compound 3 are used relative to compound 2. 6. The method according to any one of claims 2 to 5, wherein the method is carried out in a solvent selected from: (i) ethyl acetate; (ii) isopropyl acetate; and (iii) ethyl acetate or a mixture of isopropyl acetate and cyclohexane. 7. The method according to any one of claims 2 to 6, wherein the method is carried out at an internal temperature of about 50°C to 80°C, preferably at an internal temperature of about 70°C. 8. The method according to any one of claims 2 to 7, further comprising: (b) inoculating the reaction mixture obtained from step (a) with a (-)-CSA or (+)-CSA salt of baloxavir (1a), preferably with a baloxavir (1a)*(-)-CSA salt. 9. The method according to any one of claims 2 to 8, further comprising: (c) reacting the (-)-CSA or (+)-CSA salt of the baloxavir (1a) obtained from steps (a) and (b) with a base, preferably with NaOH, to obtain baloxavir (1a). 10. The method according to claim 9, further comprising: (d) reacting the baloxavir (1a) obtained from step (c) with methyl chloromethyl carbonate (4) Claims 2 / 3 pages 3 CN 121925422 A10. The method of claim 10, wherein step (d) is carried out in a mixture of acetonitrile and water. 12. The method of any one of claims 2 to 11, wherein the method is a continuous flow process. 13. The method of claim 12, wherein steps (a) and (b) are carried out in an n-stage CSTR cascade, wherein n is an integer selected from 2 to 10. 14. The method of claim 13, wherein the last CSTR in the n-stage CSTR cascade is connected to a filter. 15. The method of claim 14, wherein the filter is a continuous rotary plate filter. 16. The method of claim 14 or 15, wherein the (-)-CSA or (+)-CSA salt of the baloxavir (1a) obtained from steps (a) and (b) is collected on the filter. 17. The method according to any one of claims 12 to 16, wherein step (c) comprises: (c1) adding a solution of the (-)-CSA or (+)-CSA salt of baloxavir (1a) to reactor 1 of a 2-stage MSMPR crystallizer; (c2) adding a NaOH solution to reactor 1 until the pH reaches about 1.15; (c3) adding seed crystals of baloxavir (1a) to reactor 1; (c4) adding additional NaOH solution to reactor 1 until the pH reaches about 5.6; (c5) continuously adding a solution of additional (-)-CSA or (+)-CSA salt of baloxavir (1a), preferably an additional solution of baloxavir (1a)*(-)-CSA salt, while maintaining the pH constant at about pH 5.6 by adding additional NaOH solution; (c6) transferring a given portion 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 approximately 65%. 18. The method of claim 17, wherein reactor 2 of the 2-stage MSMPR crystallizer is connected to a filter. 19. The method of claim 18, wherein the filter is a continuous rotary plate filter. 20. The method of claim 18 or 19, wherein the baloxavir (1a) obtained from step (c) is collected on the filter. 21. The method of claim 1, wherein the method is a continuous flow process. 22. The method of claim 21The method, wherein the method is carried out in an n-stage CSTR cascade, wherein n is an integer selected from 2 to 10. 23. The method according to claims 21 and 22, wherein the baloxavir marboxil (1) obtained from the method is crystallized in an n-stage MSMPR crystallizer, wherein n is an integer selected from 2 to 5. 24. The method according to claim 23, wherein the crystalline baloxavir (1) continuously exiting the n-stage MSMPR crystallizer is continuously wet-milled. 25. The invention as described above. Claims 3 / 3 Page 4 CN 121925422 A Method for Manufacturing Baloxavir Technical Field

[0001] The present invention relates to a novel method for preparing baloxavir marboxil (1) and baloxavir (1a), and an integrated continuous manufacturing (ICM) implementation of the method.

[0002] Background Art

[0003] Baloxavir (1a) is a compound with an antiviral effect against influenza. To improve its oral bioavailability, baloxavir (1a) is administered as a prodrug mabaloxavir (1), which is converted into the active form baloxavir (1a) in the blood, liver, and small intestine. Baloxavir (1a) is also a synthetic intermediate in known methods for manufacturing mabaloxavir (1) (see, for example, WO2016 / 175224 and WO2017 / 221869). Mabaloxavir (1) is sold under the trade name Xofluza®.

[0004] The method for manufacturing mabaloxavir (1) disclosed in WO2016 / 175224 is shown in Scheme 1.

[0005]

[0006] Scheme 1

[0007] The condensation of compound 2 and compound 3 in the presence of T3P and MsOH proceeds with poor diastereoselectivity of about 3:1, thus requiring subsequent purification by crystallization. Furthermore, in the condensation reaction, about 50% of the molecules lose their benzyl protecting groups. Since benzyl protecting groups are crucial for diastereoselective crystallization, they must be reintroduced before crystallization. More importantly, the reaction of baloxavir (1a) with methyl chloromethyl carbonate (4) described in WO2016 / 175224 to obtain mabaloxavir (1) is carried out in DMA as a solvent, which is considered a substance of high concern in the EU. In summary, this method is inefficient and unsuitable for the industrial-scale production of mabaloxavir (1).

[0008] The above problems are addressed by WO2017 / 221869The method disclosed in [Scheme 1] partially solves the problem, as shown in Scheme 2.

[0009]

[0010] Scheme 2

[0011] Therefore, it has been found that the hexyl protecting group in compound 6 is significantly more stable than the benzyl protecting group in compound 2 because it does not cleave under the reaction conditions used for the condensation reaction with compound 3. With the more stable hexyl protecting group, reactive crystallization can be achieved. In solution, there is an equilibrium between the starting materials compound 6 and compound 3 and the product compound 7 and its diastereomers. However, in the selected solvent, the desired product compound 7 is poorly soluble, precipitates, and is therefore easily removed from the equilibrium. Over time (approximately 20 h), almost all of the starting materials are converted to compound 7. Therefore, the method disclosed in WO2017 / 221869 (Scheme 2) has significantly improved yield and stereoselectivity compared to the method disclosed in WO2016 / 175224 (Scheme 1). However, the method disclosed in WO2017 / 221869 requires a cumbersome additional step to exchange the benzyl protecting group for the hexyl protecting group, and has other disadvantages discussed below.

[0012] In summary, there remains an urgent need for a new and more efficient synthesis of mabaloxavir. This is especially true in potential scenarios where large amounts of API are required during influenza epidemics or pandemics. Summary of the Invention

[0013] The present invention provides an improved method for the manufacture of mabaloxavir (1) which relies on the reaction of compound 2 with compound 3 in the presence of a chiral acid such as (-)-CSA, as shown in Scheme 3.

[0014]

[0015] Scheme 3 Specification 2 / 15 pages 6 CN 121925422 A

[0016] Surprisingly, the exchange of the acid MsOH disclosed in the prior art by a chiral acid such as (-)-CSA results in excellent diastereoselectivity of the condensation reaction. More surprisingly, the benzyl protecting group is completely removed under the reaction conditions, thus avoiding the deprotection step with LiCl described in the prior art. Therefore, according to the novel method of the present invention, baloxavir (1a) can be obtained in a single step starting from compounds 2 and 3. The method of the present invention avoids two reaction steps involving hazardous and expensive chemicals and also significantly shortens the development cycle for supplying the API, which is crucial in the event of an influenza epidemic or pandemic, as large quantities of API are needed as quickly as possible. Furthermore, the method of the present invention is more cost-effective than known methods for manufacturing mabaloxavir (1) and reduces the ecological footprint due to reduced material and energy consumption, etc. In addition to the above, it is surprising to find that the reaction of baloxavir (1a) with methyl chloromethyl carbonate (4) yields mabaloxavir (1).The process can be carried out in a mixture of acetonitrile and water, avoiding the use of toxic DMAs described in the prior art.

[0017] In addition to the above, the method of the present invention is also implemented as an integrated continuous manufacturing (ICM) method, which provides further benefits, as will be discussed below. Detailed Description

[0018] Definitions

[0019] Features, integrals, properties, compounds, chemical parts or groups described in connection with a particular aspect, embodiment or example of the invention shall be understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All features disclosed in this specification (including any appended claims and abstract) and / or all steps of any method or process disclosed thereby may be combined in any combination except for at least some mutually exclusive combinations of these features and / or steps. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any new feature or any new combination of features disclosed in this specification (including any appended claims and abstract), or to any new step or any new combination of steps of any method or process disclosed thereby.

[0020] The term “S033447” refers to compound 1a as described herein.

[0021] The term “S199AW” refers to compound 1b as described herein.

[0022] The term “S199AL” refers to compound 2 as described herein.

[0023] The term “S199AR” refers to compound 3 as described herein.

[0024] The term “S199AT” refers to compound 5 as described herein.

[0025] The term “T3P®” refers to propylphosphonic anhydride (CAS 68957-94-8).

[0026] As used herein, the term “chiral acid” refers to an acid having at least one asymmetric carbon atom, preferably 1 to 3 asymmetric carbon atoms, more preferably 1 to 2 asymmetric carbon atoms, and 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.

[0027] The term “CSA” refers to camphor sulfonic acid.

[0028] As used herein, the term “CSTR” refers to a continuous stirred tank reactor and means a reaction vessel in which reagents, reactants, and solvents flow into the reactor while the products of the reaction simultaneously exit the vessel.

[0029] The term “MSMPR – crystallizer” refers to a mixed suspension, mixed product – remove crystallizer, in which a saturated solution enters a chamber already filled with crystals, and an equal volume of fluid exits, the exiting fluid containing any crystals present at the end of the flow chamber.

[0030] As used herein, when referring to measurable values ​​such as the amount of compound, dosage, time, temperature, etc., the terminology specification refers to…Page 3 / 15 7 CN 121925422 A “about” means covering a variation of 20%, 10%, 5%, 1%, 0.5% or even 0.1% of the specified amount, preferably a variation of 10% to 0.5% of the specified amount, more preferably a variation of 5% to 0.5% of the specified amount. Brief Description of the Drawings

[0031] Figure 1 shows the apparatus setup for the continuous flow manufacturing of baloxavir (1a) described in Example 2.

[0032] Figure 2 shows the apparatus setup for the continuous flow manufacturing of mabaloxavir (1) described in Example 4.

[0033] Figure 3 shows a typical HPLC chromatogram of a mixture containing reactants S199AL (2) and S199AR (3), product SO33447 (1a), stereoisomer S199AW (1b), and related impurity S199AT (5). The chromatogram was obtained using the HPLC method described in Example 5.

[0034] Figure 4 shows a typical HPLC chromatogram of baloxavir (1a) obtained by the continuous manufacturing method described in Example 2. The chromatogram was obtained by using the HPLC method described in Example 5.

[0035] Improved Prodrug Formation

[0036] In the method described, for example, in WO2016 / 175224, the prodrug mabaloxavir (1) is obtained by reacting baloxavir (1a) with methyl chloromethyl carbonate (4) in DMA as a solvent. However, DMA is on the EU's list of Substances of Very High Concern (SVHC). The inventors of the present invention have now surprisingly discovered that the reaction also performs well in a mixture of acetonitrile and water, avoiding the use of toxic DMA.

[0037] Therefore, in a first aspect, the present invention provides a method for manufacturing mabaloxavir (1) or a pharmaceutically acceptable salt thereof,

[0038]

[0039] the method comprising: reacting baloxavir (1a)

[0040]

[0041] with methyl chloromethyl carbonate (4) in the presence of potassium carbonate and potassium iodide in a mixture of acetonitrile and water to obtain mabaloxavir (1).

[0044] In one embodiment, the mixture of acetonitrile and water is a 49:1 (v / v) mixture of acetonitrile and water.

[0045] Diastereoselective condensation

[0046] In another aspect, the present invention provides a method for manufacturing baloxavir (1a) or a pharmaceutically acceptable salt thereof,

[0047]

[0048] the method comprising

[0049] (a) reacting compound 2

[0050]

[0051] with compound 3

[0052]

[0053] The reaction is carried out in the presence of:

[0054] (i) about 1 to 2 molar equivalents of T3P relative to compound 2; and

[0055] (ii) about 2 to 6 molar equivalents of a chiral acid relative to compound 2;

[0056] to obtain baloxavir (1a) in the form of a chiral acid salt.

[0057] In one embodiment, the method according to the invention is carried out in the presence of about 3, 4, 5 or 6 molar equivalents of a chiral acid relative to compound 2. Specification 5 / 15 pages 9 CN 121925422 A

[0058] In a preferred embodiment, the method according to the invention is carried out in the presence of about 4 molar equivalents of a chiral acid relative to compound 2.

[0059] In one embodiment, the chiral acid is a chiral carboxylic acid or a chiral sulfonic acid.

[0060] In one embodiment, the chiral acid is selected from (-)-CSA and (+)-CSA.

[0061] In one embodiment, the chiral acid is (+)-CSA.

[0062] In a preferred embodiment, the chiral acid is (-)-CSA.

[0063] In one embodiment, the method according to the invention is carried out in the presence of about 3, 4, 5 or 6 molar equivalents of (-)-CSA relative to compound 2.

[0064] In a preferred embodiment, the method according to the invention is carried out in the presence of about 4 molar equivalents of (-)-CSA relative to compound 2.

[0065] In a preferred embodiment, the method according to the invention is carried out in the presence of about 1 to 1.5 molar equivalents of T3P relative to compound 2.

[0066] In a particularly preferred embodiment, the method according to the invention is carried out in the presence of about 1.1 molar equivalents of T3P relative to compound 2.

[0067] In one embodiment of the method according to the invention, about 1 to 2 molar equivalents of compound 3 relative to compound 2 are used.

[0068] In a preferred embodiment of the method according to the invention, compound 3 is used in an amount of about 1 to 1.5 molar equivalents relative to compound 2.

[0069] In a particularly preferred embodiment of the method according to the invention, compound 3 is used in an amount of about 1.1 molar equivalents relative to compound 2.

[0070] In one embodiment, step (a) of the method according to the invention is carried out in a solvent selected from:

[0071] (i) ethyl acetate;

[0072] (ii) isopropyl acetate; and

[0073] (iii) a mixture of ethyl acetate or isopropyl acetate with cyclohexane (1:1, v / v).

[0074] In a preferred embodiment, step (a) of the method according to the invention is carried out in a weight of about 7 to 10 volume equivalents relative to the amount of compound 2 used in a solvent selected from the following:

[0075] (i) ethyl acetate;

[0076] (ii) isopropyl acetate; and

[0077] (iii) a mixture of ethyl acetate or isopropyl acetate with cyclohexane (1:1, v / v).

[0078] In another preferred embodiment, step (a) of the method according to the invention is carried out in ethyl acetate.

[0079] In another preferred embodiment, step (a) of the method according to the invention is carried out in isopropyl acetate.

[0080] In another preferred embodiment, step (a) of the method according to the invention is carried out in a mixture of isopropyl acetate and cyclohexane. In some embodiments, the ratio of isopropyl acetate to cyclohexane is 1:1, v / v.

[0081] In another preferred embodiment, step (a) of the method according to the invention is carried out in a mixture of ethyl acetate and cyclohexane. In some embodiments, the ratio of ethyl acetate to cyclohexane is 1:1, v / v.

[0082] In a particularly preferred embodiment, step (a) of the method according to the invention is carried out in about 7 to 10 volume equivalents of ethyl acetate relative to the amount of compound 2 used.

[0083] In another particularly preferred embodiment, step (a) of the method according to the invention is carried out in about 7 volume equivalents of ethyl acetate relative to the amount of compound 2 used.

[0084] In one embodiment, step (a) of the method according to the invention is carried out at an internal temperature of about 50°C to 80°C.

[0085] In one embodiment, step (a) of the method according to the invention is carried out at an internal temperature of about 60°C to 80°C.

[0086] In a preferred embodiment, step (a) of the method according to the invention is carried out at an internal temperature of about 70°C to 80°C.

[0087] In a particularly preferred embodiment, step (a) of the method according to the invention is carried out at an internal temperature of about 70°C.

[0088] In another particularly preferred embodiment, step (a) of the method according to the invention is carried out at an internal temperature of about 80°C.

[0089] In one embodiment, the method according to the invention further comprises:

[0090] (b) inoculating the reaction mixture obtained from step (a) with a chiral acid salt of baloxavir (1a), preferably with a baloxavir (1a)*(-)-CSA salt.

[0091] In one embodiment, step...(b) The inoculation is performed with about 1 to 15 wt% of baloxavir (1a)*(-)-CSA salt.

[0092] In a preferred embodiment, the inoculation in step (b) is performed with about 5 to 10 wt% of baloxavir (1a)*(-)-CSA salt.

[0093] In a particularly preferred embodiment, the inoculation in step (b) is performed with about 10 wt% of baloxavir (1a)*(-)-CSA salt.

[0094] In one embodiment, the method according to the invention further comprises:

[0095] (c) reacting the chiral acid salt of baloxavir (1a) obtained from steps (a) and (b) with a base, preferably with NaOH, to obtain baloxavir (1a).

[0096] The preparation of mabaloxavir (1) from baloxavir (1a) is described, for example, in WO2016 / 175224.

[0097] In one embodiment, the method according to the invention further comprises:

[0098] (d) reacting the baloxavir (1a) obtained from step (c) with methyl chloromethyl carbonate (4)

[0099]

[0100] in the presence of potassium carbonate and potassium iodide to obtain mabaloxavir (1).

[0101] In the method described in WO2016 / 175224, step (d) is carried out in DMA as a solvent, which is on the EU's list of substances of very high concern (SVHC). The inventors of the present invention have now surprisingly discovered that reaction step (d) can also be carried out in a mixture of acetonitrile and water, avoiding the use of toxic DMA.

[0102] Therefore, in a preferred embodiment, step (d) of the method according to the invention is carried out in a mixture of acetonitrile and water.

[0103] In a particularly preferred embodiment, step (d) of the method according to the invention is carried out in acetonitrile:water (49:1, v / v).

[0104] In one embodiment, the invention provides a method for manufacturing baloxavir (1a)*(-)-CSA salt or a pharmaceutically acceptable salt thereof, as described in the specification 7 / 15 pages 11 CN 121925422 A, the method comprising:

[0105] (a) reacting compound 2 described herein with compound 3 described herein

[0106] in the presence of:

[0107] (i) about 1 to 2 molar equivalents of T3P relative to compound 2; and

[0108] (ii) about 2 to 6 molar equivalents of (-)-CSA relative to compound 2; and

[0109] (b) optionally reacting the compound from step (a) with baloxavir (1a)*(-)-CSA salt.The obtained reaction mixture was inoculated;

[0110] to obtain the baloxavir (1a)*(-)-CSA salt.

[0111] In one embodiment, the present invention provides a method for manufacturing baloxavir (1a), the method comprising:

[0112] (a) reacting compound 2 described herein with compound 3 described herein

[0113] in the presence of:

[0114] (i) about 1 to 2 molar equivalents of T3P relative to compound 2; and

[0115] (ii) about 2 to 6 molar equivalents of (-)-CSA relative to compound 2;

[0116] to obtain baloxavir (1a)*(-)-CSA salt;

[0117] (b) optionally inoculating the reaction mixture obtained from step (a) with baloxavir (1a)*(-)-CSA salt; and

[0118] (c) reacting the baloxavir (1a)*(-)-CSA salt obtained from steps (a) and (b) with a base, preferably with NaOH,

[0119] To obtain the baloxavir (1a).

[0120] In one embodiment, the present invention provides a method for manufacturing mabaloxavir (1), the method comprising:

[0121] (a) reacting compound 2 described herein with compound 3 described herein

[0122] in the presence of:

[0123] (i) about 1 to 2 molar equivalents of T3P relative to compound 2; and

[0124] (ii) about 2 to 6 molar equivalents of (-)-CSA relative to compound 2;

[0125] to obtain baloxavir (1a)*(-)-CSA salt;

[0126] (b) optionally inoculating the reaction mixture obtained from step (a) with baloxavir (1a)*(-)-CSA salt;

[0127] (c) reacting the baloxavir (1a)*(-)-CSA salt obtained from steps (a) and (b) with a base, preferably with NaOH,

[0128] To obtain baloxavir (1a); and

[0129] (d) reacting the baloxavir (1a) obtained from step (c) with chloromethyl carbonate (4) in the presence of potassium carbonate and potassium iodide,

[0130] to obtain the mabaloxavir (1).

[0131] Continuous Flow Process

[0132] As described above, the method according to the invention has also been implemented as an integrated continuous manufacturing (ICM) method (see Examples 2 and 4, and Figures 1 and 2). The ICM consists of a series of unit operations operating in a flow and is integrated into a seamless end-to-end (from synthesis to final product) manufacturing method. ICMThe specification, page 8 / 15, 12 CN 121925422 A, represents a shift in the batch manufacturing method used in the pharmaceutical industry. Compared to batch manufacturing, the unit operation integration approach of ICM yields significant operational advantages. ICM significantly reduces manufacturing costs (reduction >50%) and development cycles (reduction >90%), has a smaller footprint (reduction -90%), and provides higher quality drugs. These advantages were demonstrated in MIT’s first ICM pilot plant (capacity to produce 1.5 tons of active pharmaceutical ingredient per year), which is able to produce finished coated tablets from raw materials through a single, seamless end-to-end method (Mascia et al., Angew. Chem. Int. Ed. 2013, 52, 12359-12363).

[0133] In one aspect, the method of the present invention is a synthetic continuous manufacturing (ICM) method. Examples 2 and 4, and Figures 1 and 2, illustrate the ICM method according to the present invention.

[0134] The ICM implementation of the final synthesis step in the method for preparing mabaloxavir (1) and subsequent checks (see Example 4) offer several advantages over current batch-mode methods for the industrial production of mabaloxavir (1), including:

[0135] 1. No need to purify API by recrystallization.

[0136] 2. Wet milling of API, instead of the dry milling method required in batch mode.

[0137] 3. Reduced physical stress on API due to shorter drying time.

[0138] Generally, dry milling is a dusty process that poses health hazards to operators. An Operational Exposure Limit (OEL) of 2.5 mcgr / m3 needs to be observed, which requires extensive technical measures to contain airborne API particles. Dry milling of mabaloxavir (1) is particularly problematic because unmilled and milled API has poor flowability, resulting in low throughput and frequent line blockages.

[0139] In one embodiment of the ICM according to the invention, steps (a), (b), and (d) are performed in an n-stage CSTR cascade, where n is an integer selected from 2 to 10.

[0140] In a preferred embodiment of the ICM according to the invention, steps (a) and (b) are performed in a 5-stage CSTR cascade, and step (d) is performed in a 3-stage CSTR cascade.

[0141] In one embodiment of the ICM according to the invention, the last CSTR in the n-stage CSTR cascade for reacting to steps (a) and (b) is connected to a filter.

[0142] In one embodiment, the filter is a continuous rotary plate filter.

[0143] In one embodiment, the baloxavir (1a)*(-)-CSA salt obtained from steps (a) and (b) is collected on the filter.

[0144] In one embodiment of the ICM according to the invention, step (c) comprises:

[0145] (c1) adding a solution of baloxavir (1a)*(-)-CSA salt to reactor 1 of a 2-stage MSMPR crystallizer;

[0146] (c2) adding a NaOH solution to reactor 1 until the pH reaches about 1.15;

[0147] (c3) adding seed crystals of baloxavir (1a) to reactor 1;

[0148] (c4) adding additional NaOH solution to reactor 1 until the pH reaches about 5.6;

[0149] (c5) continuously adding additional baloxavir (1a)*(-)-CSA salt solution to reactor 1 while maintaining the pH constant at about pH 5.6 by adding additional NaOH solution;

[0150] (c6) removing a given portion of the mixture from reactor 1 at given time intervals. The mixture is transferred to reactor 2; and

[0151] (c7) water is fed into reactor 2 to achieve a final water volume fraction of approximately 65%.

[0152] In one embodiment, reactor 2 of the 2-stage MSMPR-crystallizer is connected to a filter.

[0153] In one embodiment, the filter is a continuous rotary plate filter.

[0154] In one embodiment, baoloxavir (1a) obtained from step (c) is collected on the filter specification page 9 / 15, 13 CN 121925422 A.

[0155] In one embodiment, mabaloxavir (1) obtained from the n-stage CSTR cascade for reaction step (d) is crystallized in an n-stage MSMPR-crystallizer, where n is an integer selected from 2 to 5.

[0156] In a preferred embodiment, the MSMPR-crystallizer is a 3-stage MSMPR-crystallizer.

[0157] In one embodiment, crystalline baoloxavir (1) continuously exiting an n-stage MSMPR crystallizer is continuously wet-milled.

[0158] Examples

[0159] The invention will be more fully understood by referring to the following examples. However, the claims should not be construed as limiting the scope of the examples.

[0160] Example 1

[0161] Batch synthesis of baoloxavir (1a)

[0162]

[0163] Step 1: Reaction

[0164] Ethyl acetate (300.5 ml, 7.1 volume equivalents) was added to 500 mlIn a jacketed stirred tank reactor, the mixture was stirred at approximately 200 rpm and heated to 70°C. Compound 2 (42.3 g, 1.0 mol equivalent) was added, followed by compound 3 (37.5 g, 1.1 mol equivalent), T3P (83.7 ml of a 50 wt% solution in ethyl acetate, 1.1 mol equivalent), and finally (-)-camphorsulfonic acid (CSA) (120.0 g, 4.0 mol equivalent). The addition of (-)-CSA initiated the reaction. After stirring at 70°C for 1 h, baloxavir(1a)*(-)-CSA salt (9.2 g, 10 wt%) was added as a seed crystal. The reaction mixture was stirred at 70°C for a total reaction time of approximately 20 h, and then the reaction mixture was cooled to room temperature.

[0165] Step 2: Filtration and Purification

[0166] The precipitate of baloxavir (1a)*(-)-CSA salt was separated by vacuum filtration. The wet filter cake was first washed with ethyl acetate, and then with acetone (130 mL and 260 mL). The washed crystals were dissolved in acetonitrile / water (3:1, 300 mL).

[0167] Step 3: Separation of Baloxavir (1a)

[0168] The temperature of the baloxavir (1a)*(-)-CSA salt solution was adjusted to 20°C, and then 1 M NaOH aqueous solution was added. When the pH rose to pH 0.9 to 1.0, baloxavir (1a) seed crystals (2 g, or 5 wt%) were immediately added. The pH was adjusted until pH 5.6 was reached. The total pH adjustment time was approximately 1.5 h. Then, water (202 ml) was added until the water content reached 65%.

[0169] Step 4: Filtration and drying

[0170] The precipitate of baloxavir (1a) was separated by vacuum filtration, and the wet filter cake was first washed with acetonitrile / water (1:3) and then with isopropanol (152 mL). Baloxavir (1a) was vacuum dried at about 40°C.

[0171] The yield was 36.8 g (based on the theoretical yield of compound 2 of 59%, dr1a:1b = 70:1, as determined by the HPLC method described in Example 5 on page 14 of the specification 10 / 15, CN 121925422 A).

[0172] Example 2

[0173] Integrated continuous manufacturing of baloxavir (1a)

[0174]

[0175] The equipment setup for the continuous manufacturing method is shown in Figure 1.

[0176] Step 1: Reaction

[0177] Heat 500 ml of 5-stage-CSTR cascade to 70°C and stir at about 200 rpm.

[0178] 75.1 ml of ethyl acetate was added to CSTR1, followed by 10.6 g of S199AL 2, 9.4 g of S199AR 3 (1.1 molar equivalent), 20.9 ml of T3P solution (50 wt% in ethyl acetate) (1.1 molar equivalent), and 30.0 g of (-)-CSA (4.0 molar equivalent). The same amounts were then added to reactor CSTR1 at 1-hour intervals. One hour after the initial addition, 9.42 g of baloxavir (1a)*(-)-CSA salt seed crystals (10 wt%) were added to CSTR1. Once the reactor reached its target volume (4 portions), the slurry was immediately transferred between reactors and to a collection container at 1-hour intervals using a pulse pump.

[0179] The average residence time in each reactor was 4 h, and the total residence time was 20 h. During the steady-state phase, the diastereomeric ratio in the reaction slurry was approximately 7:1, and the calculated yield in the slurry was 74.5%.

[0180] Step 2: Separation of crude baloxavir (1a)*(-)-CSA salt

[0181] The slurry was fed to a continuous rotary plate filter at a feed rate of 25 mL / min. The filter cake was first washed with ethyl acetate (6 mL / min), followed by washing with acetone (12 mL / min). The washed filter cake was collected and dissolved in acetonitrile / water (3:1) at room temperature to obtain a solution of approximately 20 wt% baloxavir (1a)*(-)-CSA salt. The separation yield of baloxavir (1a)-CSA salt was approximately 62.6%, with a diastereomeric ratio of approximately 16.5:1 (as evaluated using the HPLC method described in Example 5).

[0182] Step 3: Crystallization of crude baloxavir (1a)

[0183] 300 mL of the obtained baloxavir (1a)*(-)-CSA salt solution was added to reactor 1 of the 2-stage MSMPR crystallizer. 1 M NaOH solution was added to MSMPR1 at a rate of 1 to 1.5 mL / min. When the pH reached pH 1.15, baloxavir (1a) seed crystals (4.0 g, 5 wt%) were immediately added. Another 1 M NaOH solution was added until the pH reached pH 5.6. Then, the baloxavir (1a)*(-)-CSA salt solution was added to MSMPR1 at a rate of 5 mL / min, while maintaining the pH constant at pH 5.6 by adding 1 M NaOH solution. The slurry product was transferred to MSMPR2 using a pulse pump (at 20 min intervals, 128.5 mL / min).Water was fed to stage-2 MSMPR at a rate of 3.32 mL / min to achieve a final water volume fraction of 65%.

[0184] Step 4:

[0185] The baloxavir (1a) slurry was fed to a continuous rotary plate filter at a feed rate of 30 mL / min. The filter cake was first washed with acetonitrile / water (1:3, by volume) at 6 mL / min, and then with isopropanol (6 mL / min). The obtained baloxavir (1a) had a determination of 98.8% at steady state, a purity of 99.5%, and an isomer ratio of 171:1 (see Figure 4, as evaluated using the HPLC method described in Example 5). It is noteworthy that dr is typically >200:1, and in some cases even up to 900:1.

[0186] The overall separation yield of baloxavir (1a) was 59.3%.

[0187] The HPLC chromatogram of baloxavir (1a) produced according to this example (see Figure 4):

[0188]

[0189] Diasteresome ratio (1a: 1b) = 171: 1

[0190] Example 3

[0191] Preparation of mabaloxavir (1)

[0192]

[0193] The preparation of mabaloxavir (1) from baloxavir (1a) is described, for example, in WO2016 / 175224. Therefore, methyl chloromethyl 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) were added to a suspension of baloxavir (1a) (1.00 g, 2.07 mmol) in DMA (5 ml), and the mixture was stirred at 50 °C for 6 hours. DMA (1 ml) was added to the mixture, and the mixture was stirred for 6 hours. The mixture was cooled to room temperature, DMA (6 ml) was added to it, and the mixture was stirred at 50 °C for 5 minutes. The mixture was filtered. A 1 mol / L aqueous solution of hydrochloric acid (10 ml) and water (4 ml) was added to the obtained filtrate, 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 mabaloxavir (1) (1.10 g, 1.93 mmol, 93%). 1H-NMR (DMSO-D6) δ: 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).

[0195] Example 4

[0196] Preparation of baoloxavir (1) in a continuous mode

[0197]

[0198] Step 1: Reaction of baoloxavir (1a) with chloromethyl carbonate (4)

[0199] 500 ml of 3-stage-CSTR was heated to 70°C and stirred at about 550 rpm. Initially, 500 mL of acetonitrile:water (49:1, v / v) and 41.0 g of baloxavir (1a) were added to CSTR1. Then, 5.6 g of potassium iodide, 15.2 g of potassium carbonate, and 19.0 g of chloromethyl carbonate (4) were added. The slurry material was transferred between reactors and to a collection vessel at 0.5 h intervals using a pulse pump. The following materials were added to CSTR1 at 0.5 h intervals: 5.86 g of baloxavir (1a), 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 carbonate (4). The average residence time per reactor was 3.5 h, and the total residence time was 10.5 h. The feed flux of baloxavir (1a) was 11.7 g / h, and the yield of mabaloxavir (1) relative to (1a) was estimated to be about 93.8%.

[0200] Step 2: Continuous crystallization of mabaloxavir (1)

[0201] The reaction slurry from step 1 was continuously crystallized in a 3-stage MSMPR cascade, wherein the reactor was maintained at 35°C (MSMPR1) and 25°C.The reaction slurry was fed into MSMPR1 at temperatures of 20°C (MSMPR2) and 20°C (MSMPR3). 70 mL of the reaction slurry was pulsed into MSMPR1 every 60 min. The antisolvent (isopropanol:water (4:1, v / v)) was continuously fed into MSMPR1 at a rate of 2.33 mL / min. 70 mL of the slurry product from MSMPR1 was pulsed into MSMPR2 every 30 min, with the antisolvent (isopropanol:water (4:1, v / v)) continuously added at a rate of 3.5 mL / min. 175 mL of the slurry product from MSMPR2 was pulsed into MSMPR3 every 30 min, while the antisolvent (isopropanol:water (4:1, v / v)) was continuously added at a rate of 11.67 mL / min to achieve a dilution factor of 15. The slurry product from MSMPR3 was transferred to a collection container in pulsed mode at a rate of 525 mL every 30 min.

[0202] The average residence time in MSMPR1 was 60 min, the average residence time in MSMPR2 was 30 min, and the average residence time in MSMPR3 was 30 min, so the total residence time was 120 min. The steady-state yield was approximately 95.2% to 96.7%.

[0203] Step 3: Continuous filtration and grinding of mabaloxavir (1)

[0204] The mabaloxavir (1) slurry was fed into a rotary plate filter at a rate of 80 mL / min. The filter cake was first washed on the plate with isoamyl alcohol:water (1:4, v / v; 6 mL / min), and then with isopropanol (6 mL / min). After removing the filter cake, the plate was washed with acetonitrile:water (4:1, v / v, 12 mL / min). The isolated crystals of mabaloxavir were suspended in n-heptane:ethyl acetate (50:1, v / v) to obtain a 10 wt% slurry. The suspended mabaloxavir (1) was recirculated by wet milling at 500 mL / min for 3 h. The milled wet slurry was sent downstream for drying.

[0205] Step 4: Continuous drying of mabaloxavir

[0206] The slurry of mabaloxavir (1) in n-heptane:ethyl acetate (50:1, v / v) was fed into a cylindrical dryer at 15 mL / min and evenly distributed on the cylindrical surface to form a thin slurry film for conductive drying. Drying was carried out continuously at a cylindrical temperature of 65°C and a vacuum pressure of 250 Torr. The residence time in the dryer was about 1 min. The dried product was pneumatically conveyed to a cyclone separator and collected.

[0207] The total separation yield of steps 1 to 4 is approximately90%.

[0208] Example 5

[0209] HPLC - Method Description:

[0210]

[0211] Gradient Program Specification 14 / 15 pages 18 CN 121925422 A

[0212] Specification 15 / 15 pages 19 CN 121925422 A Figure 1 Specification Figure 1 / 3 pages 20 CN 121925422 A Figure 2 Specification Figure 2 / 3 pages 21 CN 121925422 A Figure 3 Figure 4 Specification Figure 3 / 3 pages 22 CN 121925422 A

Claims

1. A method for manufacturing mabaloxavir (1) or a pharmaceutically acceptable salt thereof. The method includes: Baloxavir (1a) With methyl chloromethyl carbonate (4) The reaction was carried out in the presence of potassium carbonate and potassium iodide in a 49:1 (v / v) mixture of acetonitrile and water to give mabaloxavir (1).

2. A method for manufacturing baloxavir (1a) or a pharmaceutically acceptable salt thereof. The method includes (a) Make compound 2 With compound 3 Reacts in the presence of the following: (i) T3P relative to approximately 1 to 2 molar equivalents of compound 2; and (ii) Approximately 2 to 6 molar equivalents of (-)-CSA or (+)-CSA relative to compound 2; To obtain baloxavir in the form of (-)-CSA or (+)-CSA salts (1a).

3. The method according to claim 2, wherein the method is carried out in the presence of about 4 molar equivalents of (-)-CSA or (+)-CSA relative to compound 2.

4. The method according to any one of claims 2 or 3, wherein the method is carried out in the presence of about 1 to 1.5 molar equivalents of T3P relative to compound 2.

5. The method according to any one of claims 2 to 4, wherein compound 3 is used in an amount of about 1 to 2 molar equivalents relative to compound 2.

6. The method according to any one of claims 2 to 5, wherein the method is carried out in a solvent selected from the group consisting of: (i) Ethyl acetate; (ii) Isopropyl acetate; and (iii) A mixture of ethyl acetate or isopropyl acetate with cyclohexane.

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

8. The method according to any one of claims 2 to 7, the method further comprising: (b) Inoculate the reaction mixture obtained from step (a) with (-)-CSA or (+)-CSA salt of baloxavir (1a), preferably with baloxavir (1a)*(-)-CSA salt.

9. The method according to any one of claims 2 to 8, the method further comprising: (c) The (-)-CSA or (+)-CSA salt of the baloxavir (1a) obtained from steps (a) and (b) is reacted with a base, preferably with NaOH, to obtain baloxavir (1a).

10. The method according to claim 9, further comprising: (d) Mix the baloxavir (1a) obtained from step (c) with methyl chloromethyl carbonate (4). The reaction was carried out in the presence of potassium carbonate and potassium iodide to obtain mabaloxavir (1).

11. The method of claim 10, wherein step (d) is carried out in a mixture of acetonitrile and water.

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

13. The method of claim 12, wherein steps (a) and (b) are performed in an n-level CSTR cascade, wherein n is an integer selected from 2 to 10.

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

15. The method of claim 14, wherein the filter is a continuous rotary plate filter.

16. The method according to claim 14 or 15, wherein the (-)-CSA or (+)-CSA salt of the baloxavir (1a) obtained from steps (a) and (b) is collected on the filter.

17. The method according to any one of claims 12 to 16, wherein step (c) comprises: (c1) A solution of the (-)-CSA or (+)-CSA salt of the baloxavir (1a) is added to reactor 1 of the 2-stage MSMPR crystallizer; (c2) Add NaOH solution to reactor 1 until the pH reaches approximately 1.15; (c3) Add seed crystals of baloxavir (1a) to reactor 1; (c4) Add another NaOH solution to reactor 1 until the pH reaches approximately 5.6; (c5) A solution of another baloxavir (1a) salt in (-)-CSA or (+)-CSA, preferably another baloxavir (1a)*(-)-CSA salt solution, is continuously added to reactor 1 while the pH is maintained at approximately pH 5.6 by adding another NaOH solution. (c6) Transfer a given portion of the mixture from reactor 1 to reactor 2 at given time intervals; as well as (c7) Feed water into reactor 2 to achieve a final water volume fraction of approximately 65%.

18. The method of claim 17, wherein the reactor 2 of the 2-stage MSMPR crystallizer is connected to a filter.

19. The method of claim 18, wherein the filter is a continuous rotary plate filter.

20. The method according to claim 18 or 19, wherein the baloxavir (1a) obtained from step (c) is collected on the filter.

21. The method of claim 1, wherein the method is a continuous flow process.

22. The method of claim 21, wherein the method is performed in an n-level CSTR cascade, wherein n is an integer selected from 2 to 10.

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

24. The method of claim 23, wherein the crystalline mabaloxavir (1) continuously exiting the n-stage MSMPR crystallizer is continuously wet-milled.

25. The present invention as described above.

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