Process for preparation of quinazolinone derivatives

Abstract

The present invention relates to a novel process for the preparation of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl) oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, as well as to novel intermediates useful in the large scale synthesis of said compounds.

Description

[0001] The present invention particularly relates to a new method for preparing (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide, as well as a new method for a new intermediate 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile, which can be used for the large-scale synthesis of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide.

[0002] Rapidly accelerated fibrosarcoma (RAF) class serine-threonine kinases comprise three members (ARAF, BRAF, RAF1), which constitute the first node of the MAP kinase signaling pathway. Although the three RAF subtypes are significantly redundant in signal transduction propagation through phosphorylation of MEK1 and 2, frequent oncogenic activating mutations are typically found only for BRAF. In particular, substitution of V600 with glutamate or lysine hyperactivates the kinase, thus overstimulating the MAPK pathway independently of external stimuli (Cell. June 18, 2015; 161(7):1681–1696).

[0003] Mutant BRAF is a targetable oncogenic driver, and three BRAF inhibitors (vemurafenib, dabrafenib, and encorafenib) are currently on the market, which have shown efficacy in BRAFV600E-positive melanoma. However, rapid acquisition of drug resistance is almost universally observed, and the duration of the therapeutic benefit of targeted therapies remains limited.

[0004] In addition, the developed BRAF inhibitors have revealed an unexpected and "paradoxical" ability to inhibit MAPK signaling in BRAFV600E-driven tumors, while the same inhibitors exhibit MAPK-stimulating activity in BRAF wild-type (WT) models (N Engl J Med 2012; 366:271-273; and British Journal of Cancer Volume 111, pages 640 to 645 (2014)).

[0005] Subsequently, mechanistic studies of the RAF paradox have elucidated that oncogenic BRAFV600E phosphorylates MEK1 / 2 in its monomeric cytoplasmic form, while activation of WT BRAF and RAF1 requires a complex series of events, which includes plasma membrane translocation and homo- and / or heterodimerization promoted by activated RAS (KRAS, NRAS, HRAS) (Nature Reviews Cancer Volume 14, pages 455 to 467 (2014)).

[0006] Binding of inhibitors such as vemurafenib, dabrafenib or encorafenib to WT BRAF or RAF1 protomers rapidly induces RAF homodimerization and / or heterodimerization and membrane association of newly formed RAF dimers. In the dimer conformation, one RAF protomer allosterically induces a conformational change in the second protomer, leading to a kinase-active state and, importantly, a conformation that is unfavorable for inhibitor binding. As a result, dimers induced by drug treatment promote MEK phosphorylation through catalysis by unbound protomers and hyperactivate the pathway.

[0007] The RAF paradox leads to two clinically relevant consequences: 1) accelerated growth of secondary tumors (primarily keratoacanthomas and squamous cell carcinomas) following BRAFi monotherapy (N Engl J Med 2012; 366:271-273) and 2) in the case of BRAFi monotherapy as well as BRAFi+MEKi combination therapy, acquisition of resistance presents as gene-driven events activating dimer-mediated RAF signaling, which include RAS mutations, BRAF amplifications, expression of dimer-active BRAF splice variants (Nature Reviews Cancer Volume 14, pages 455–467 (2014)). Therefore, RAF inhibitors that can break this paradox are needed.

[0008] In addition, BRAF mutations such as V600E are common in patients with colorectal cancer and, unfortunately, patients carrying these mutations have a particularly poor prognosis.

[0009] Therefore, compounds that are effective BRAF inhibitors are needed, which show considerably less paradoxical activation of the MAPK signaling pathway while maintaining high potency. Compared to compounds that induce the RAF paradox (and which can be referred to as paradox inducers or RAF paradox inducers), such compounds can also be referred to as paradox breakers or RAF paradox breakers. (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide meets these requirements as it is a paradox-breaking BRAF inhibitor with good brain penetration properties.

[0010] Accordingly, the object of the present invention is to find an improved method that is applicable on an industrial scale and that can overcome the disadvantages known in the art.

[0011] The synthetic route to obtain (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide has been disclosed in WO2021116050A1. However, due to related safety issues, limited scalability, and moderate yields, this route relies on several steps that are considered unsuitable for large-scale production.

[0012] In the route described in WO2021116050A1, the first step of the synthesis – the formation of hydroxyquinazolinone – was run in pure N-methylformamide at 145 °C, and the product was isolated from the reaction mixture by filtration. In the first scale-up attempt, it was found that the long-term heating of N-methylformamide at 145 °C resulted in very poor product quality and yield. By reacting in 1,3-dimethyl-2-imidazolidinone (DMI), the overall product quality and yield could be significantly improved. This solvent has better stability than N-methylformamide and helps to reduce degradation and polymerization. In addition, it was found that the filtration described in WO2021116050A1 was extremely slow, and thus this method is not suitable for large-scale production. To avoid this problem, a new and faster two-step method was developed: first, the product was isolated from the reaction mixture as the sodium salt; in a subsequent step, an acidic treatment was carried out to provide the target product in excellent yield and purity.

[0013] In the route described in WO2021116050A1, the synthesis of the sulfonamide structural unit from 3-fluoropyrrolidine and sulfonamide was carried out in dioxane, a highly undesirable solvent due to its health and environmental hazards. The reaction temperature of 115 °C was found to be well above the safety temperatures of the reagents (90 - 100 °C) and the product (100 °C), and thus the process was flagged as having safety issues. In addition, competitive polymerization and compound degradation accompanied by the formation of by-products required purification via column chromatography, generally precluding large-scale production. For the first clinical supply campaign, a novel two-step continuous method from chlorosulfonyl isocyanate in an environmentally friendly solvent was developed, addressing the safety and environmental issues of the previous route. For the second clinical campaign, the original one-step synthesis was further investigated. A method using water as the solvent at a milder temperature (80 °C) was developed, successfully addressing the original safety and environmental issues and allowing for large-scale production.

[0014] In the route described in WO2021116050A1, the nucleophilic aromatic substitution (S NThe final step of the synthesis is completed by the (Ar) reaction. It requires the use of DMF (a solvent that is undesirable from a health and environmental perspective), Cs2CO3 (a hygroscopic base), and due to the high reaction temperature (100 °C), the product has low selectivity. To successfully purify the product, techniques that are not suitable for large-scale production, such as chromatography and sonication, must be employed. Additionally, the product is obtained in moderate yield. To overcome these drawbacks, a novel method has been developed in which the S N Ar reaction is thus replaced by the palladium-catalyzed coupling of a novel Cl-benzonitrile precursor with an F-pyrrolidinesulfonamide, resulting in a significant improvement in the yield and purity profiles. The novel Cl-benzonitrile precursor was synthesized via the condensation of chloro-difluorobenzonitrile and a hydroxyquinazolinone compound. The S N Ar reaction conditions on similar substrates reported previously used DMF as the solvent and Cs2CO3 as the base. In the current method, they are replaced by acetone and K2CO3, respectively, to improve the method efficiency, cost, and environmental impact.

[0015] Furthermore, seeding crystallization is introduced to ensure proper purity and control in the solid form. The final particle size is adjusted to ensure a sufficient dissolution rate for BCS class II compounds and to enable the formulation of a suitable solid dosage pharmaceutical composition. This is achieved by wet milling the suspension obtained after crystallization or alternatively by jet milling.

[0016] It has been found that the object of a new method for large-scale application of the invention can be achieved by the improved method of the present invention as described below.

[0017] Accordingly, the present invention particularly relates to a novel method having a novel intermediate for the preparation of a compound of formula (I), wherein the method is safe, provides a high yield, and is generally suitable for production on an industrial scale.

[0018] The term "pharmaceutically acceptable salts" refers to those salts of the compounds of formula (I), (C1), and (C2) as shown that retain the biological effects and properties of the free base or free acid and that are not biologically or otherwise undesirable. These salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. (especially hydrochloric acid) and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine, etc. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, etc. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins (such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins, etc.). Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, mesylate, and citrate. The terms "pharmaceutically acceptable carrier" and "pharmaceutically acceptable adjuvant" refer to carriers and adjuvants that are compatible with the other components of the formulation, such as diluents or excipients.

[0019] The term "palladium catalyst" refers to any palladium catalyst that affects the rate and conversion of a chemical substrate compound to a product compound at a commercially acceptable yield and conversion. The palladium-catalyzed reactions described herein require a zero-valent palladium species (Pd(0)). Exemplary catalytically active Pd(0) species can be applied directly or can be formed in situ from a palladium source in combination with a phosphine ligand. In some embodiments or aspects of the invention, the palladium catalyst is preformed or formed in situ. In some other aspects, the palladium catalyst is formed in situ with a suitable ligand (such as L3 and L4) as described herein. In some other aspects, the palladium source is a preformed palladium catalyst.

[0020] The term "allyl", alone or in combination, refers to a group having the structural formula -CH2-HC=CH2. It consists of a methylene bridge attached to an ethylene group.

[0021] Non-limiting examples of palladium sources for use in combination with ligand (L): bis(dibenzylideneacetone)palladium (Pd(dba)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh3)2Cl2), palladium(II) acetate (Pd(OAc)2), palladium(II) trifluoroacetate (Pd(TFA)2), palladium(II) chloride (PdCl2), palladium(II) bromide (PdBr2), palladium(II) iodide (PdI2), palladium(II) acetylacetonate (Pd(acac)2), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4), bis(acetonitrile)-palladium(II) dichloride (PdCl2(CH3CN)2), cyclopentadienylallylpalladium, allylpalladium(II) chloride dimer ((Pd(allyl)Cl)2), (2-butenyl)palladium chloride dimer, (2-methylallyl)palladium(II) chloride dimer, palladium(1-phenylallyl) chloride dimer, (p-tert-butylindene)palladium(II) chloride dimer, di-μ-chlorobis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-methanesulfonylbis[2'-(amino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-methanesulfonylbis[2'-(methylamino-N)[1,1'-biphenyl]-2-yl-C]dipalladium(II), di-μ-chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II);

[0022] Non-limiting examples of preformed palladium catalysts: [Pd(L)XCl] (L = ligand, X = allyl, 2-butenyl, 2-methylallyl, 1-phenylallyl, p-tert-butylindene); [Pd(L)X] triflate (L = ligand, X = as defined above), [Pd(L)(2-(2'-amino-1,1'-biphenyl)Cl] (L = ligand); [Pd(L)(2-(2'-amino-1,1'-biphenyl)] methanesulfonate (L = ligand), [Pd(L)(2-(2'-methylamino-1,1'-biphenyl)] methanesulfonate (L = ligand), [Pd(L)(2-(2-aminoethyl)phenyl)Cl] (L = ligand), PdL2Cl2, [PdI(L)]2

[0023] The term "pharmaceutical composition" encompasses a product containing a predetermined amount or proportion of specific ingredients, as well as any product directly or indirectly resulting from the combination of specific amounts of specific ingredients. In particular, it encompasses a product containing one or more active ingredients and optionally a carrier containing inert ingredients; and any product directly or indirectly resulting from the combination, compounding, or aggregation of two or more of these ingredients, or the dissociation of one or more of these ingredients, or other types of reactions or interactions of one or more of these ingredients.

[0024] Although the present invention has been described with reference to its specific embodiments, those skilled in the art should understand that various changes can be made and equivalents can be substituted without departing from the true essence and scope of the present invention. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, method, or one or more method steps to the objective essence and scope of the present invention. All such modifications are intended to be within the scope of the appended claims herein. All independent embodiments can be combined.

[0025] Specific numbered aspects of the present invention are:

[0026] 1. A method for preparing a compound of formula (I),

[0027]

[0028] or a pharmaceutically acceptable salt thereof, the method comprising at least one of the following steps:

[0029] (a) Reacting a compound of formula (B1)

[0030]

[0031] with a compound of formula (B2)

[0032]

[0033] in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1) or a pharmaceutically acceptable salt thereof

[0034] Or

[0035] (b) Reacting a compound of formula (C1) with a compound of formula (C2)

[0036]

[0037] in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

[0038] 2. A method for preparing a compound of formula (I),

[0039]

[0040] or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (B1)

[0041]

[0042] with a compound of formula (B2)

[0043]

[0044] React in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1)

[0045]

[0046] or a pharmaceutically acceptable salt thereof.

[0047] 3. A method for preparing a compound of formula (I)

[0048]

[0049] or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0050] (a) React a compound of formula (A1)

[0051]

[0052] with a compound of formula (A2)

[0053]

[0054] in the presence of a suitable solvent (iii) and then treat with a suitable base (iii) to obtain a compound of formula (A3) or a suitable hydrate thereof

[0055]

[0056] (b) React a compound of formula (A3) or a suitable hydrate thereof

[0057]

[0058] with a suitable acid in the presence of a suitable solvent (iv) to obtain a compound of formula (B2)

[0059] and

[0060] (c) React a compound of formula (B1)

[0061]

[0062] with a compound of formula (B2)

[0063]

[0064] in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1)

[0065]

[0066] or a pharmaceutically acceptable salt thereof.

[0067] 4. A process for preparing a compound of formula (I),

[0068]

[0069] or a pharmaceutically acceptable salt thereof, the process comprising reacting a compound of formula (C1)

[0070]

[0071] with a compound of formula (C2)

[0072]

[0073] in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

[0074] 5. A process for preparing a compound of formula (I),

[0075]

[0076] or a pharmaceutically acceptable salt thereof, the process comprising the steps of:

[0077] (a) Reacting a compound of formula (C3)

[0078] or its free base

[0079] with a compound of formula (C4)

[0080]

[0081] in the presence of a suitable base (iv) and a suitable solvent (v) to obtain a compound of formula (C2)

[0082] Or alternatively (a') Reacting a compound of formula (C3)

[0083]

[0084] with a compound of formula (C5)

[0085]

[0086] in the presence of a suitable base (v) and a suitable solvent (vi) to obtain a compound of formula (C2)

[0087] and

[0088] (b) Reacting a compound of formula (C1)

[0089]

[0090] react with a compound of formula (C2)

[0091]

[0092] in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

[0093] 6. A method for preparing a compound of formula (I),

[0094]

[0095] or a pharmaceutically acceptable salt thereof, the method comprising the following steps:

[0096] (a) React a compound of formula (B1)

[0097]

[0098] with a compound of formula (B2)

[0099]

[0100] in the presence of a suitable solvent (i) and in the presence of a suitable base (i) to obtain a compound of formula (C1),

[0101] and

[0102] (b) React the compound of formula (C1) with a compound of formula (C2)

[0103]

[0104] in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

[0105] 7. The method according to any one of aspects 1, 2, 3 or 6, wherein the solvent (i) is a polar solvent, particularly a polar solvent selected from acetone and acetonitrile, more particularly acetone.

[0106] 8. The method according to any one of aspects 1, 2, 3, 6 or 7, wherein the base (i) is an inorganic base, particularly selected from K2CO3 or Cs2CO3, more particularly K2CO3.

[0107] 9. The method according to any one of aspects 1, 2, 3, 6, 7 or 8, wherein the reaction to produce the compound of formula (C1) is carried out at a temperature between about 10 °C and about 80 °C, particularly between about 20 °C and about 70 °C, more particularly at about 55 °C.

[0108] 10. The method according to any one of aspects 1, 2, 3, 6, 7, 8 or 9, wherein the reaction to produce the compound of formula (C1) is carried out between about 1 hour and about 48 hours, particularly between about 4 hours and about 24 hours, more particularly during the period of about 19 hours to 21 hours.

[0109] 11. The method according to any one of aspects 1, 2, 5 to 10, wherein the solvent (ii) is a polar solvent, particularly a solvent selected from toluene, CPME, 2-MeTHF, EtOAc, anisole, THF, TBME, tAmylOH, iPrOAc or a mixture thereof.

[0110] 12. The method according to any one of aspects 1, 2, 5 to 10, wherein the solvent (ii) is a polar aprotic solvent, particularly a solvent selected from toluene, CPME, 2-MeTHF, EtOAc, anisole, THF and TBME, more particularly selected from toluene and CPME.

[0111] 13. The method according to any one of aspects 1, 2, 5 to 10, wherein the solvent (ii) is tAmylOH or iPrOAc.

[0112] 14. The method according to any one of aspects 1, 2, 5 to 13, wherein the base (ii) is selected from K3PO4, K2CO3, Na2CO3, Na3PO4, Cs2CO3, NaOMe, DBU and TMG.

[0113] 15. The method according to any one of aspects 1, 2, 5 to 14, wherein the base (ii) is selected from K3PO4, K2CO3, Na2CO3, Na3PO4, Cs2CO3 and NaOMe, particularly selected from K3PO4 and K2CO3.

[0114] 16. The method according to any one of aspects 1, 2, 5 to 15, wherein the base (ii) is selected from DBU and TMG.

[0115] 17. The method according to any one of aspects 1, 2, 5 to 16, wherein the catalyst is a palladium catalyst, particularly a catalyst selected from the following:

[0116] catalyst:

[0117] [Pd(allyl)(tBuXPhos)]OTf, [Pd(tBuXPhos)]G3, Pd(EPhos)G3, Pd(tBuBrettPhos)G3, Pd(RockPhos)G3, Pd(AdBrettPhos)G3, [Pd(cinnamyl)(tBuXPhos)]OTf, [Pd(cinnamyl)Cl(cataCXium POMetB)], NOVECAT G1-02;

[0118] [Pd(allyl)(L1)]OTf or [Pd(cinnamyl)(L1)]OTf (L1 = bippyPhos, RockPhos, AlPhos, tBuSPhos, tBuBrettPhos, BrettPhos, AdBippyPhos, Me4tBuXPhos, AdBrettPhos, TrixiePhos, Me3OMetBuXPhos, tBuPhCPhos, JohnPhos, cataCXium POMetB, cataCXium PtB, cataCXium PIntB or tBuMePhos);

[0119] [Pd(allyl)(L2)Cl] (L2 = BrettPhos, cBRIDP or tBuDavePhos);

[0120] [Pd(allyl)Cl]2 + L3, [Pd(cinnamyl)Cl]2 + L3, Pd-G4 dimer + L 3 or

[0121] [Pd(allyl)(Cp)] + L3 (L3 = tBuXPhos, bippyPhos, RockPhos, AlPhos, tBuSPhos, tBuBrettPhos, BrettPhos, AdBippyPhos, Me4tBuXPhos, AdBrettPhos, TrixiePhos, Me3OMetBuXPhos, tBuPhCPhos, JohnPhos, cataCXium POMetB, cataCXium PtB, cataCXiumPIntB, tBuMePhos, VincePhos, AndrewPhos, SummerPhos); and

[0122] Pd2dba3 + L4 (L4 = bippyPhos or tBuXPhos);

[0123] More particularly, it is a catalyst selected from [Pd(cinnamyl)(tBuXPhos)]OTf and Pd(allyl)(tBuXPhos)]OTf.

[0124] 18. The method according to any one of aspects 1, 2, 5 to 17, wherein the catalyst is selected from

[0125] [Pd(cinnamyl)(tBuXPhos)]OTf, Pd(allyl)(tBuXPhos)]OTf, [Pd(allyl)(RockPhos)]OTf, [Pd(allyl)(tBuBrettPhos)]OTf, [Pd(allyl)Cl]2

[0126] +L and [Pd(cinnamyl)Cl]2+L, where L is selected from tBuXPhos, tBuBrettPhos and Summer Phos.

[0127] 19. The method according to any one of aspects 1, 2, 5 to 16, wherein the catalyst is a palladium catalyst, more particularly a catalyst selected from: [Pd(allyl)(tBuXPhos)]OTf,

[0128] Pd2dba3+L (L = bippyPhos or tBuXPhos), Pd(allyl)(L)]OTf (L =

[0129] bippyPhos, RockPhos, tBuBrettPhos, BrettPhos, AdBippyPhos, Me4tBuXPhos, AdBrettPhos, TrixiePhos, Me3OMetBuXPhos, tBuPhCPhos, JohnPhos, cataCXium POMetB, cataCXium PtB, cataCXium PIntB or tBuMePhos), [Pd(allyl)(L)]Cl (L = BrettPhos, cBRIDP or tBuDavePhos), [Pd(tBuXPhos)]G3, Pd(EPhos)G3, [Pd(cinnamyl)(tBuXPhos)]OTf and [Pd(cinnamyl)Cl(cataCXium POMetB)], more particularly selected from [Pd(cinnamyl)(tBuXPhos)]OTf and Pd(allyl)(tBuXPhos)]OTf.

[0130] 20. The method according to any one of aspects 1, 2, 5 to 19, wherein a suitable additive is used together with the catalyst, preferably the additive comprises trifluoroacetate, trifluoromethanesulfonate, acetate or pivalate, particularly sodium trifluoroacetate, sodium trifluoromethanesulfonate, sodium acetate, potassium trifluoroacetate, potassium trifluoromethanesulfonate, potassium acetate, sodium pivalate or potassium pivalate, and more particularly sodium trifluoroacetate.

[0131] 21. The method according to any one of aspects 1, 2, 5 to 20, wherein the reaction of the compound of formula (C1) with the compound of formula (C2) is carried out between about 50 °C and about 90 °C, particularly between about 60 °C and about 80 °C, and more particularly at a temperature of about 70 °C.

[0132] 22. The method according to any one of aspects 1, 2, 5 to 21, wherein the reaction of the compound of formula (C1) with the compound of formula (C2) is carried out for about 2 hours to about 48 hours, particularly about 4 hours to about 19 hours.

[0133] 23. The method according to any one of aspects 3, 7 to 22, wherein the solvent (iii) is 1,3-dimethyl-2-imidazolidinone (DMI).

[0134] 24. The method according to any one of aspects 3, 7 to 23, wherein the base (iii) is an aqueous solution of sodium hydroxide.

[0135] 25. The method according to any one of aspects 3, 7 to 24, wherein the solvent (iv) is methanol.

[0136] 26. The method according to any one of aspects 3, 7 to 25, wherein the acid is acetic acid (aqueous solution).

[0137] 27. The method according to any one of aspects 3, 7 to 26, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out for about 2 hours to about 48 hours, particularly about 4 hours to about 44 hours.

[0138] 28. The method according to any one of aspects 3, 7 to 27, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at about 100 °C to about 180 °C, particularly at about 120 °C to about 160 °C, and more particularly at a temperature of about 140 °C.

[0139] 29. The method according to any one of aspects 5 to 28, wherein the solvent (vi) is a non-polar solvent or a polar aprotic solvent, particularly the solvent (vi) is selected from tert-butanol, acetonitrile, DCM, THF, dioxane or a mixture thereof, and more particularly the solvent (vi) is a mixture of tert-butanol and acetonitrile or a mixture of tert-butanol and DCM.

[0140] 30. The method according to any one of aspects 5 to 29, wherein the base (iv) is a tertiary amine, particularly triethylamine.

[0141] 31. The method according to any one of aspects 5 to 30, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at a temperature of from about -78 °C to about 50 °C, particularly from about 0 °C to about 25 °C, more particularly from about 5 °C to about 10 °C.

[0142] 32. The method according to any one of aspects 5 to 31, wherein the solvent (v) is a polar aprotic or polar protic solvent, particularly the solvent (v) is selected from water, methanol, ethanol, n-propanol or a mixture thereof, more particularly the solvent (v) is water.

[0143] 33. The method according to any one of aspects 5 to 32, wherein the base (v) is a tertiary amine, particularly triethylamine.

[0144] 34. The method according to any one of aspects 5 to 33, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at a temperature of from about -50 °C to about 150 °C, particularly from about 60 °C to about 100 °C, more particularly at about 80 °C.

[0145] 35. The method according to any one of aspects 5 to 34, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out for about 2 hours to hours, particularly about 2 hours to about 24 hours, more particularly about 3 hours to about 18 hours.

[0146] 36. The method according to any one of aspects 5 to 35, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out in a batch reactor.

[0147] 37. The method according to any one of aspects 5 to 35, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out in a flow reactor.

[0148] 38. The method according to any one of aspects 1 to 37, wherein the compound of formula (I) is subsequently subjected to recrystallization in a suitable solvent, particularly in water, THF, acetone or a mixture thereof, more particularly in a mixture of water and acetone or a mixture of water and THF.

[0149] 39. The method according to any one of aspects 1 to 38, wherein the compound of formula (I) is subsequently subjected to jet milling.

[0150] 40. The method according to any one of aspects 1 to 38, wherein the compound of formula (I) is subsequently subjected to wet milling, particularly followed by seeded crystallization after wet milling.

[0151] 41. A compound of formula (I) produced by the method according to any one of aspects 1 to 40

[0152]

[0153] or a pharmaceutically acceptable salt thereof.

[0154] 42. A compound of formula (C1)

[0155]

[0156] or a pharmaceutically acceptable salt thereof.

[0157] 43. A method for preparing a compound of formula (C2),

[0158]

[0159] or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (C3)

[0160] or its free base

[0161] with a compound of formula (C4)

[0162]

[0163] in the presence of a suitable base (iv) and a suitable solvent (v).

[0164] 44. A method for preparing a compound of formula (C2),

[0165]

[0166] or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (C3)

[0167]

[0168] with a compound of formula (C5)

[0169]

[0170] in the presence of a suitable base (v) and a suitable solvent (vi) to obtain a compound of formula (C2)

[0171] compound

[0172]

[0173] 45. The method according to aspect 43, wherein the base (iv) is a tertiary amine, particularly triethylamine.

[0174] 46. The method according to any one of aspects 5 to 40, 43 and 45, wherein 1.0 to 4.0 equivalents of base (iv) are employed, particularly wherein 2.0 to 3.0 equivalents of base (iv) are employed.

[0175] 47. The method according to any one of aspects 5 to 40, 43, 45 and 46, wherein the solvent (v) is a polar aprotic or polar protic solvent, particularly wherein the solvent (v) is selected from water, methanol, ethanol, n-propanol or a mixture thereof, more particularly wherein the solvent (v) is water.

[0176] 48. The method according to any one of aspects 5 to 40, 43, 45, 46 and 47, wherein the product of formula (I) is further seeded with (R)-3-fluoropyrrolidine-1-sulfonamide.

[0177] 49. The method according to aspect 44, wherein the base (v) is a tertiary amine, particularly triethylamine.

[0178] 50. The method according to aspect 44 or 49, wherein the solvent (vi) is a nonpolar solvent or a polar aprotic solvent, particularly wherein the solvent (vi) is selected from tert-butanol, acetonitrile, DCM, THF, dioxane or a mixture thereof, more particularly wherein the solvent (vi) is a mixture of tert-butanol and acetonitrile or a mixture of tert-butanol and DCM.

[0179] The synthesis of the compound of formula (I) can be accomplished, for example, according to the non-exhaustive procedures in the general Scheme 1 or 2 described below.

[0180] Scheme 1:

[0181]

[0182] Scheme 2:

[0183] Experimental Section

[0184] The following experiments are provided to illustrate the present invention. They should not be construed as limiting the scope of the present invention, but merely as representative thereof.

[0185] Abbreviations:

[0186] 2-MeTHF = 2-methyltetrahydrofuran; CAS = Chemical Abstracts Service; CPME = cyclopentyl methyl ether; dba = dibenzylideneacetone; DBU = 1,8-diazabicyclo(5.4.0)undec-7-ene; DCM = dichloromethane; DIPEA = N,N-diisopropylethylamine; DMF = dimethylformamide; DMI = 1,3-dimethyl-2-imidazolidinone; DMSO = dimethyl sulfoxide; ESI = electrospray ionization; EtOAc = ethyl acetate; iPrOAc = isopropyl acetate; LC-MS / MS = liquid chromatography-MS / MS; MeCN = acetonitrile; MeOH = methanol; MS = mass spectrometry; OTf = trifluoromethanesulfonate; PhMe = toluene; RT = room temperature; tAmylOH = tert-amyl alcohol; TBME = tert-butyl methyl ether; THF = tetrahydrofuran; TMG = 1,1,3,3-tetramethylguanidine.

[0187] Catalysts and Precatalysts:

[0188] The palladium catalysts and precatalysts are commercially available or prepared according to the procedures described in J. Org. Chem. 2015, 80, 6794 - 6813.

[0189] [Pd(allyl)Cl]2 (CAS: 12012 - 95 - 2);

[0190] [Pd(cinnamyl)Cl]2 (CAS: 12131 - 44 - 1);

[0191] [Pd(cinnamyl)(tBuXPhos)] CAS 1798782 - 27 - 0;

[0192] [Pd(allyl)(tBuXPhos)]OTf (CAS: 1798782 - 25 - 8);

[0193] [Pd(tBuXPhos)]G3 (CAS: 1447963 - 75 - 8);

[0194] Pd(EPhos)G3 (no CAS number; name: Palladium(II) [2-(2'-amino-1,1'-biphenyl)] methanesulfonate (dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine), EPhos: CAS 2118959 - 55 - 8);

[0195] Pd(tBuBrettPhos)G3 (CAS: 1536473 - 72 - 9);

[0196] Pd(RockPhos)G3 (CAS: 2009020 - 38 - 4);

[0197] Pd(AdBrettPhos)G3 (CAS: 1445972 - 29 - 1);

[0198] Pd - G4 dimer (CAS: 1581285 - 85 - 9);

[0199] NOVECAT G1 - 02 (CAS: 2225985 - 82 - 8);

[0200] [Pd(allyl)(Cp)] (CAS: 1271 - 03 - 0).

[0201] Ligand (L):

[0202] tBuXPhos (CAS: 564483 - 19 - 8); bippyPhos (CAS: 894086 - 00 - 1); RockPhos (CAS: 1262046 - 34 - 3); AlPhos (CAS: 1805783 - 60 - 1); tBuPhCPhos (CAS: 1660153 - 91 - 2); tBuSPhos (CAS: 819867 - 21 - 5); tBuBrettPhos (CAS: 1160861 - 53 - 9); BrettPhos (CAS: 1070663 - 78 - 3); AdBippyPhos (CAS: 1239478 - 87 - 5); Me4tBuXPhos (CAS: 857356 - 94 - 6); AdBrettPhos (CAS: 1160861 - 59 - 5); TrixiePhos (CAS: 255836 - 67 - 0); Me3OMetBuXPhos (CAS: 1359986 - 21 - 2); JohnPhos (CAS: 224311 - 51 - 7); cataCXium POMetB (CAS: 1053658 - 91 - 5); cataCXium PtB (CAS: 672937 - 61 - 0); cataCXium PIntB (CAS: 740815 - 37 - 6); tBuMePhos (CAS: 255837 - 19 - 5); VincePhos (CAS: 1355318 - 22 - 7); AndrewPhos (CAS: 2380310 - 03 - 0); SummerPhos (CAS: 2380310 - 07 - 4); cBRIDP (CAS: 742103 - 27 - 1); tBuDavePhos (CAS: 224311 - 49 - 3).

[0203] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide - Route 1 as described in Scheme 1

[0204] Step 1A: Sodium 3-methyl-4-oxoquinazoline-6-carboxylate

[0205]

[0206] 2-Amino-5-hydroxybenzoic acid (150 g, 980 mmol, Eq: 1.0, CAS: 394-31-0) and N-methylformamide (150 g, 2540 mmol, Eq: 2.6, CAS: 123-39-7) were heated in 300 ml of 1,3-dimethyl-2-imidazolidinone (DMI) at 140 °C for 23 hours, then cooled to 80 - 90 °C. 28% Aqueous sodium hydroxide solution (140 g, 980 mmol, Eq: 1.0, CAS: 1310-73-2) was added. The mixture was cooled to room temperature. Then the solid was filtered, washed and dried in vacuo to give the title compound as a light brown solid (209 g, 79% yield). MS (ESI) m / z: 177.06 [M + H - Na] +

[0207] Step 1B: 6-Hydroxy-3-methylquinazolin-4-one

[0208]

[0209] Sodium oleate of 3-methyl-4-oxo-quinazoline-6 (200 g, 740 mmol, Eq: 1) and MeOH (600 ml) were heated at 50 - 55 °C. Aqueous acetic acid solution (44.4 g, 740 mmol, Eq: 1) in water (300 g, Eq: 22.5) was added dropwise. The mixture was cooled to room temperature. Then the solid was filtered, washed and dried in vacuo to give the title compound as a light brown solid (125.8 g, 96% yield). MS (ESI) m / z: 177.06 [M + H] + .

[0210] Step 2: 6-Chloro-3-fluoro-2-(3-methyl-4-oxoquinazolin-6-yl)oxybenzonitrile

[0211]

[0212] Potassium carbonate (54.13 g, 392 mmol, Eq: 1.15) was added to a solution of 6-hydroxy-3-methylquinazolin-4-one (60 g, 341 mmol, Eq: 1) in acetone (1200 mL). Dichlorobenzyl cyanide (65.0 g, 375 mmol, Eq: 1.1, CAS [157647-02-4]) was added at room temperature and the mixture was heated to 55 - 60 °C. After 19 h, the reaction mixture was cooled to room temperature and diluted with water (1200 mL). The resulting solid was collected by filtration, washed with acetone / water (360 ml; 1:2) and dried in vacuo to give the title compound as an off-white solid, and dried overnight in vacuo to give the title compound as a light brown solid (108.3 g, 96% yield). MS (ESI) m / z: 330.04 [M+H]+.

[0213] Step 3: (3R)-3-Fluoropyrrolidine-1-sulfonamide

[0214]

[0215] A solution of tert-butanol (17.9 kg, 241 mol, Eq: 1.15) dissolved in acetonitrile (77.0 kg) was added continuously to a stream of chlorosulfonyl isocyanate (29.8 kg, 210 mmol, Eq: 1.1; CAS [1189-71-5]). A solution of triethylamine (46.8 kg) in acetonitrile (131.1 kg) was added continuously to the resulting mixture stream, followed by continuous addition of (3R)-3-fluoropyrrolidine hydrochloride (24.5 kg, 195 mol, Eq: 1; CAS [136725-55-8]) diluted in water (44.4 kg) and 28% aqueous sodium hydroxide solution (27.8 kg).

[0216] The resulting organic phase was diluted with toluene and hydrochloric acid 2.5 M (117 kg) was added. After phase separation, the organic phase was washed with an aqueous solution of sodium chloride (1.3 kg) in water (24 kg) and with water at 20 °C. The solution was concentrated and heated to 50 °C. Then a solution of acetyl chloride (22.5 kg, 587 mol, Eq: 1.5) in n-propanol (55 kg) was added slowly. The mixture was concentrated and n-propanol was exchanged with toluene. Then the mixture was heated to 50 °C and cooled to 0 °C. The resulting solid was collected by filtration, washed with a cold solution of toluene / n-heptane (1 / 1 V) and dried in vacuo to give the title compound as a solid, which was recrystallized in THF and CPME. The resulting solid was collected by filtration, washed with CPME and dried in vacuo to give the title compound as a white solid (25.9 kg, 79% yield). MS (ESI) m / z: 169.04 [M+H] + .

[0217] Step 4: [2-Cyano-4-fluoro-3-(3-methyl-4-oxoquinazolin-6-yl)oxy-phenyl]-[racemic- (3R)-3-fluoropyrrolidin-1-yl]sulfonimide potassium

[0218]

[0219] A mixture of (R)-3-fluoropyrrolidine-1-sulfonamide (5.1 g, 30 mmol, Eq: 1.0), 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (10 g, 30 mmol, Eq: 1.0) and potassium carbonate (12.6 g, 91 mmol, Eq: 3.0) was heated in CPME (200 mL) at 65 °C. Pd(allyl)(tBuXPhos)]OTf (0.657 g, 0.91 mmol, Eq: 0.03) was added and the mixture was heated to 70 °C. The reaction mixture was stirred at 70 °C for 4 h and then cooled to 50 °C. Then MeOH (500 mL) was added. After filtering off the salts, the solution was concentrated and the methanol was exchanged with CPME (200 mL). The resulting solid was collected by filtration, washed with CPME (100 ml) and dried in vacuo to give the title compound as a white solid (13.6 g, 84% yield). MS(ESI) m / z: 462.1 [M+H] + 。

[0220] Step 5: (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxoquinazolin-6-yl)oxy-phenyl]- 3-fluoropyrrolidine-1-sulfonamide

[0221]

[0222] Potassium; [2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-[rac-(3R)-3-fluoropyrrolidin-1-yl]sulfonimide (19 g, 38 mmol, Eq: 1.0) was dissolved in acetone (153 ml) and water (38 ml) at 47 °C and acetylcysteine (2.2 g, 13.4 mmol, Eq: 0.35) was added to the solution. The pH of the mixture was adjusted by adding acetic acid (7.9 g, 131 mmol, Eq: 3.5). The solution was concentrated and ethanol (265 ml) was added. The resulting solid was collected by filtration, washed with a mixture of ethanol (65 ml) and water (100 ml), then washed with ethanol (80 ml) and dried in vacuo to give the title compound as a white solid (9.1 g, 51% yield). MS(ESI) m / z: 462.1 [M+H] + 。

[0223] Step 6: Jet milling

[0224] The title compound was further micronized by jet milling to obtain the desired final particle size distribution.

[0225] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide - alternative synthesis as described in Scheme 2

[0226] Step I-A: Sodium 3-methyl-4-oxoquinazoline-6-carboxylate

[0227]

[0228] 2-Amino-5-hydroxybenzoic acid (26.5 kg, 173 mol, Eq: 1.0, CAS: 394-31-0) and N-methylformamide (26.5 kg, 449 mol, Eq: 2.6, CAS: 123-39-7) were heated at 140 °C in 55 l (2.9 eq.) of 1,3-dimethyl-2-imidazolidinone (DMI) for 44 h and then cooled to 75 °C. An aqueous solution of sodium hydroxide (28%, 27.2 kg, 190 mol, Eq: 1.1, CAS: 1310-73-2) was added and then cooled to room temperature. The solid was filtered, washed and dried in vacuo to give the title compound as an off-white solid (40 kg, 85% yield). MS (ESI) m / z: 175.05 [M-H] - 。

[0229] Step I-B: 6-Hydroxy-3-methylquinazolin-4-one

[0230]

[0231] Sodium 3-methyl-4-oxo-quinazoline-6-carboxylate (78.5 kg, 290 mol, Eq: 1.0) and MeOH (235 l) were heated at 55 °C. An aqueous acetic acid solution was added. The solid was filtered, washed and dried in vacuo to give the title compound as an off-white solid (49 kg, 96% yield). MS (ESI) m / z: 177.1 [M+H] + 。

[0232] Step II: 6-Chloro-3-difluoro-2-(3-methyl-4-oxoquinazolin-6-yl)oxybenzonitrile

[0233]

[0234] Potassium carbonate (22 kg, 159 mol, Eq: 1.15) was added to a solution of 6-hydroxy-3-methylquinazolin-4-one (24.4 kg, 138.5 mol, Eq: 1.0) in acetone (470 L). Dichlorobenzyl cyanide (26.4 kg, 152 mol, Eq: 1.10, CAS [157647-02-4]) was added at room temperature and the mixture was heated to 55 °C. After 19 h, the reaction mixture was cooled to room temperature and diluted with water (490 L). The resulting solid was collected by filtration, washed with acetone / water (150 L) and dried in vacuo to give the title compound as an off-white solid. (44 kg, 95% yield). MS (ESI) m / z: 330.04 [M+H]+.

[0235] Step III: (3R)-3-Fluoropyrrolidine-1-sulfonamide

[0236]

[0237] Synthesis in a batch reactor:

[0238] Option 1:

[0239] (R)-3-Fluoropyrrolidine hydrochloride (22.0 kg, 175 mol, Eq: 1.0, CAS [136725-55-8]) was dissolved in 100 L of water at 60 °C, sulfuric diamide (42.1 kg, 438 mol, Eq: 2.5, CAS [7803-58-9]) and triethylamine (23.0 kg, 227 mol, Eq: 1.3) were added and the mixture was heated to 80 °C for 5 h. Aqueous NaHSO4 was added at 65 °C, the mixture was cooled to 0 °C, filtered, washed with water and dried in vacuo to give the title compound as a white crystalline solid (23.7 kg, 80% yield). MS (ESI) m / z: 169.04 [M+H]+.

[0240] Option 2:

[0241] (3R)-3-Fluoropyrrolidine hydrochloride (30 g, 0.24 mol, 1.0 eq.) and sulfonamide (57.4 g, 0.60 mol, 2.5 eq., CAS [7803-58-9]) were dissolved in water (120 mL) at ambient temperature, and then triethylamine (60.4 g, 83.2 mL, 0.60 mol, 2.5 eq.) was added. The resulting pale yellow emulsion was heated to reflux (75 °C) and stirred for 4 h. Subsequently, the reaction mixture was cooled to 60 °C, and the pH was adjusted to pH = 6.6–7.2 with aqueous sulfuric acid solution (30%, ca. 30 mL). The pale yellow solution was seeded with (R)-3-fluoropyrrolidine-1-sulfonamide (20 mg, 0.12 mmol, 0.05 mol%) at 60 °C, cooled to 0 °C for at least 2 h, and stirred at this temperature for at least 30 min. The resulting white suspension was filtered, and the filter cake was washed twice with ice-cold water (30 mL). The wet product (37.9 g) was dried in a cabinet at 45 °C for 18 h to give (R)-3-fluoropyrrolidine-1-sulfonamide (32.8 g, 0.20 mmol, 82%) as off-white, shiny crystals.

[0242] Synthesis in a plug flow reactor:

[0243] (R)-3-Fluoropyrrolidine hydrochloride (60.0 g, 0.478 mol, Eq: 1.0, CAS [136725-55-8]) was dissolved in 0.24 L of water at 25 °C, and sulfuric diamide (114.81 g, 1.19 mol, Eq: 2.5, CAS 7803-58-9) and triethylamine (62.86 g, 0.621 mol, Eq: 1.3) were added. The clear single-phase solution was pumped through a heated plug flow reactor (jacket temperature 135 °C, back pressure 6 bar, residence time ca. 5 min) and collected in a receiving tank within 180 min. The product suspension was heated to 65 °C and cooled to -5 °C over 3 h. The formed suspension was filtered, the solid was washed with water and dried in vacuo to give the title compound (48.42 g, 72% yield) as a white crystalline solid. MS (ESI) m / z: 169.04 [M+H]+.

[0244] Step IV: (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxoquinazolin-6-yl)oxy-phenyl]- 3-fluoropyrrolidine-1-sulfonamide

[0245]

[0246] (R)-3-Fluoropyrrolidine-1-sulfonamide (14.9 kg, 89.2 mol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (26.8 kg, 80.2 mol, Eq: 1.0), potassium phosphate (34.0 kg, 162 mol, Eq: 2.0) were suspended in toluene (590 L) and heated to 55 °C. [Pd(allyl)(tBuXPhos)]OTf (1.75 kg, 2.4 mol, Eq: 0.03) was added and the mixture was heated to 70 °C for 19 h. Acetone (110 L) was added and the mixture was extracted with water at 50 °C. Acetylcysteine (5.4 kg) and acetic acid (32.6 L) were added to the aqueous phase and the mixture was extracted with Me-THF at 50 °C. The organic phase was collected and the solvent was exchanged to iProAc (1000 L). After filtration, the title compound as a colorless solid was isolated (32.1 kg, 85% yield). MS (ESI) m / z: 462.1 [M+H] + .

[0247] Alternative catalysts for the reaction of Step IV are summarized in Table 1 (P1 (area %) refers to the yield of the product (compound of formula (I), as determined by HPLC in area %).

[0248] Table 1:

[0249]

[0250] The following conditions were used in the reaction, as summarized in Table 1: (R)-3-Fluoropyrrolidine-1-sulfonamide (0.056 g, 0.334 mmol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (0.100 g, 0.303 mmol, Eq: 1.0), catalyst (6.06 nmol, Eq: 0.020), potassium phosphate (0.090 g, 0.424 mmol, Eq: 1.4), CPME (1 mL), 60 °C, 21 h.

[0251] Alternative conditions for the reaction of Step IV are summarized in Table 2 (P1 (area %) refers to the yield of the product (compound of formula (I), as determined by HPLC in area %).

[0252] Table 2:

[0253]

[0254]

[0255] The following conditions were used in the reaction, as summarized in Table 2: (R)-3-fluoropyrrolidine-1-sulfonamide (0.056 g, 0.334 mmol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (0.100 g, 0.303 mmol, Eq: 1.0), catalyst (Eq: 0.01 - 0.03), base (0.424 mmol, Eq: 1.4), solvent (1 mL or 2 mL, as shown by the concentration [ml / g] solvent / gram of 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile).

[0256] Further alternative conditions for the reaction of Step IV are summarized in Table 3 (P1 (area %) refers to the yield of the product (compound of formula (I), as determined by HPLC in area %).

[0257] Table 3:

[0258]

[0259] The following conditions were used in the reaction, as summarized in Table 3: (R)-3-fluoropyrrolidine-1-sulfonamide (0.112 g, 0.667 mmol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (0.200 g, 0.606 mmol, Eq: 1.0), catalyst (Eq: 0.030 - 0.050), base (0.848 mmol, Eq: 1.4), solvent (1 mL or 2 mL, as shown by the concentration [ml / g] solvent / gram of 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile).

[0260] Further alternative conditions for the reaction of Step IV are summarized in Table 4 (P1 (area %) refers to the yield of the product (compound of formula (I), as determined by HPLC in area %).

[0261] Table 4:

[0262]

[0263]

[0264] The following conditions were used in the reaction, as summarized in Table 4: (R)-3-fluoropyrrolidine-1-sulfonamide (1.12 g, 6.67 mmol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (2.00 g, 6.06 mmol, Eq: 1.0), catalyst (Eq: 0.010), base (8.48 mmol, Eq: 1.4), solvent (40 mL).

[0265] Further alternative conditions for the Step IV reaction are summarized in Table 5 (conversion % and product % (P%) determined by LC-MS).

[0266] Table 5:

[0267]

[0268]

[0269] The following conditions were used in the reaction, as summarized in Table 5: (R)-3-fluoropyrrolidine-1-sulfonamide (28.1 mg, 0.17 mmol, Eq: 1.1) and 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile (50.0 mg, 0.15 mmol, Eq: 1.0), catalyst (Eq: 0.0075 to 0.03; as shown in the table), base (0.30 mmol, Eq: 2.0), solvent (10 to 20 mL of solvent per gram of 6-chloro-3-fluoro-2-(3-methyl-4-oxo-quinazolin-6-yl)oxy-benzonitrile), indicated ligand (if catalyst 0.75eq, ligand 2.25eq; if catalyst 2.0eq, ligand 5.0eq) and indicated additive (Eq: 2.0; no additive is used in combination with inorganic base, but the additive is used in combination with organic base to improve the yield). In all cases, the conversion was not less than 79%. The reactions described in Table 5 were run for 20 hours and the conversion (%) was not less than 94%, except for [Pd(allyl)Cl]2 with AndrewPhos (82% conversion), [Pd(allyl)Cl]2 with tBuXPhos (89% conversion), Pd-G4 dimer with tBuXPhos (79% conversion) and [Pd(allyl)(Cp)] with tBuXPhos (89% conversion).

[0270] Step V: (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxoquinazolin-6-yl)oxy-phenyl]- 3-fluoropyrrolidine-1-sulfonamide

[0271]

[0272] Option 1a, followed by Step VI:

[0273] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (28.9 kg, 62.6 mol) was dissolved in a mixture of water (113 L) and acetone (445 L, 349 kg) at 50 °C and filtered through a 5-μm filter to remove particles. The mixture was distilled under reduced pressure and after addition of water (320 L) to a total volume of 550 L. Thereafter, the suspension was cooled to room temperature, and the title compound was separated by filtration, washed and dried in vacuo to give a white solid (27.9 kg, 97% yield).

[0274] Option 1b, followed by Step VI:

[0275] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (24 g, 52.0 mmol, 1.0 eq.) was dissolved in a mixture of tetrahydrofuran (235.8 g, 268.0 mL) and water (59.0 g, 59.0 mL). The mixture was stirred at 45 °C until dissolved. A seed crystal of (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (240 mg, 520.11 μmol, 0.010 eq) was suspended in water (1 mL) and THF (10 drops) and added to the solution. 90 mL of volume was distilled off under vacuum (500 mbar). Then water (92.8 g, 92.8 mL) was added dropwise to keep the volume constant during distillation. At the end of the addition, the mixture was stirred at 45 °C for 30 minutes, then cooled to 10 °C over 3.5 hours and stirred at this temperature for 60 minutes. Then the mixture was heated to 35 °C over 30 minutes and stirred at this temperature for 60 minutes. Then the mixture was cooled to 10 °C over 2.5 hours and stirred at this temperature overnight. The title compound was separated by filtration, washed and dried in vacuo to give a white solid (22.4 g, 92% yield).

[0276] Option 1c, followed by Step VI:

[0277] (3R)-N-[2-Cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (20 g, 43.3 mmol, 1.0 eq.) was dissolved in a mixture of acetone (221 g, 280 mL), tetrahydrofuran (79 g, 90 mL) and water (78 g, 78 mL). The mixture was stirred at 50 °C and filtered through a 5-μm filter to remove particles. The mixture was concentrated under reduced pressure until the volume was approximately 420 mL. Then water (136 g, 136 mL) was added at 45 °C, and the mixture was stirred at this temperature for 30 minutes. The mixture was concentrated under reduced pressure until the volume was approximately 460 mL. Then water (96 g, 96 mL) was added and the mixture was concentrated under reduced pressure until the volume was approximately 530 mL. The mixture was cooled to 20 °C within 60 minutes and further stirred at this temperature for 12 hours. The title compound was separated by filtration, washed and dried in vacuo to give a white solid (19.1 g, 95.4% yield).

[0278] Option 2: Crystallization and wet milling:

[0279] As an alternative to micronization by jet milling (Step VI), the desired particle size distribution of the title compound can be obtained via wet milling. In this case, (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide (110.0 g, 238.3 mmol) was dissolved in a mixture of water (430.5 mL) and acetone (1.71 L, 1.35 kg) at 30 °C. The mixture was distilled under reduced pressure to a total volume of 1.60 L, (3R)-N-[2-cyano-4-fluoro-3-(3-methyl-4-oxo-quinazolin-6-yl)oxy-phenyl]-3-fluoro-pyrrolidine-1-sulfonamide seed crystals (0.25 g) were introduced as a suspension in water (total volume 2.5 ml), and distillation was carried out until a final volume of 900 ml was reached. Thereafter, the suspension was cooled to 20 °C and circulated in a wet mill with a rotor / stator configuration until the particle size distribution was constant. The title compound was separated by filtration, washed and dried in vacuo as a white solid (103.7 g, 94% yield).

[0280] Step VI: Jet milling

[0281] After Step V (Option 1a, 1b or 1c), the title compound was further micronized by jet milling to obtain the desired final particle size distribution.

Claims

1. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising at least one of the following steps: (a) Reacting a compound of formula (B1) with a compound of formula (B2) in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1) or a pharmaceutically acceptable salt thereof or (b) Reacting the compound of formula (C1) with a compound of formula (C2) in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

2. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (B1) with a compound of formula (B2) in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1) or a pharmaceutically acceptable salt thereof.

3. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising the following steps: (a) Reacting a compound of formula (A1) with a compound of formula (A2) in the presence of a suitable solvent (iii) and subsequently treating with a suitable base (iii) to obtain a compound of formula (A3) or a suitable hydrate thereof (b) Reacting the compound of formula (A3) or a suitable hydrate thereof with a suitable acid in the presence of a suitable solvent (iv) to obtain a compound of formula (B2), and (c) Reacting a compound of formula (B1) with a compound of formula (B2) in the presence of a suitable solvent (i) and optionally in the presence of a suitable base (i) to obtain a compound of formula (C1) or a pharmaceutically acceptable salt thereof.

4. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising reacting a compound of formula (C1) with a compound of formula (C2) in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

5. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising the following steps: (a) Reacting a compound of formula (C3) or its free base with a compound of formula (C4) in the presence of a suitable base (iv) and a suitable solvent (v) to obtain a compound of formula (C2) Alternatively (a') Reacting a compound of formula (C3) with a compound of formula (C5) in the presence of a suitable base (v) and a suitable solvent (vi) to obtain a compound of formula (C2) and (b) Reacting a compound of formula (C1) with a compound of formula (C2) in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

6. A method for preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, the method comprising the following steps: (a) Reacting a compound of formula (B1) with a compound of formula (B2) in the presence of a suitable solvent (i) and in the presence of a suitable base (i) to obtain a compound of formula (C1), and (b) Reacting the compound of formula (C1) with a compound of formula (C2) in the presence of a suitable catalyst and in the presence of a suitable base (ii) and a suitable solvent (ii).

7. The method according to any one of claims 1, 2, 3 or 6, wherein the solvent (i) is a polar solvent, particularly a polar solvent selected from acetone and acetonitrile, more particularly acetone.

8. The method according to any one of claims 1, 2, 3, 6 or 7, wherein the base (i) is an inorganic base, particularly selected from K2CO3 or Cs2CO3, more particularly K2CO3.

9. The method according to any one of claims 1, 2, 3, 6, 7 or 8, wherein the reaction for producing the compound of formula (C1) is carried out at a temperature between about 10 °C and about 80 °C, particularly between about 20 °C and about 70 °C, more particularly at about 55 °C.

10. The method according to any one of claims 1, 2, 3, 6, 7, 8 or 9, wherein the reaction for producing the compound of formula (C1) is carried out for a period between about 1 hour and about 48 hours, particularly between about 4 hours and about 24 hours, more particularly for about 19 hours.

11. The method according to any one of claims 1, 2, 5 to 10, wherein the solvent (ii) is an aprotic polar solvent, particularly a solvent selected from toluene, CPME, 2-MeTHF, EtOAc, anisole, THF and TBME, more particularly selected from toluene and CPME.

12. The method according to any one of claims 1, 2, 5 to 11, wherein the base (ii) is selected from K3PO4, K2CO3, Na2CO3, Na3PO4, Cs2CO3 and NaOMe, particularly selected from K3PO4 and K2CO3.

13. The method according to any one of claims 1, 2, 5 to 12, wherein the catalyst is a palladium catalyst, particularly a catalyst selected from the following: [Pd(allyl)(tBuXPhos)]OTf, [Pd(tBuXPhos)]G3, Pd(EPhos)G3, Pd(tBuBrettPhos)G3, Pd(RockPhos)G3, Pd(AdBrettPhos)G3, [Pd(cinnamyl)(tBuXPhos)]OTf, [Pd(cinnamyl)Cl(cataCXiumPOMetB)], NOVECAT G1-02; [Pd(allyl)(L1)]OTf or [Pd(cinnamyl)(L1)]OTf (L1 = bippyPhos, RockPhos, AlPhos, tBuSPhos, tBuBrettPhos, BrettPhos, AdBippyPhos, Me4tBuXPhos, AdBrettPhos, TrixiePhos, Me3OMetBuXPhos, tBuPhCPhos, JohnPhos, cataCXiumPOMetB, cataCXium PtB, cataCXium PIntB or tBuMePhos); [Pd(allyl)(L2)Cl] (L2 = BrettPhos, cBRIDP or tBuDavePhos); [Pd(allyl)Cl]2 + L3, [Pd(cinnamyl)Cl]2 + L3, Pd - G4 dimer + L 3 or [Pd(allyl)(Cp)] + L3 (L3 = tBuXPhos, bippyPhos, RockPhos, AlPhos, tBuSPhos, tBuBrettPhos, BrettPhos, AdBippyPhos, Me4tBuXPhos, AdBrettPhos, TrixiePhos, Me3OMetBuXPhos, tBuPhCPhos, JohnPhos, cataCXium POMetB, cataCXium PtB, cataCXium PIntB, tBuMePhos, VincePhos, AndrewPhos, SummerPhos); and Pd2dba3 + L4 (L4 = bippyPhos or tBuXPhos); More particularly, a catalyst selected from [Pd(cinnamyl)(tBuXPhos)]OTf and [Pd(allyl)(tBuXPhos)]OTf.

14. The method according to any one of claims 1, 2, 5 to 13, wherein the reaction of the compound of formula (C1) with the compound of formula (C2) is carried out at a temperature between about 50 °C and about 90 °C, particularly between about 60 °C and about 80 °C, more particularly at about 70 °C.

15. The method according to any one of claims 1, 2, 5 to 14, wherein the reaction of the compound of formula (C1) with the compound of formula (C2) is carried out for about 2 hours to about 48 hours, particularly about 4 hours to about 19 hours.

16. The method according to any one of claims 3, 7 to 15, wherein the solvent (iii) is 1,3-dimethyl-2-imidazolidinone (DMI).

17. The method according to any one of claims 3, 7 to 16, wherein the base (iii) is an aqueous solution of sodium hydroxide.

18. The method according to any one of claims 3, 7 to 17, wherein the solvent (iv) is methanol.

19. The method according to any one of claims 3, 7 to 18, wherein the acid is acetic acid (aqueous solution).

20. The method according to any one of claims 3, 7 to 19, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out for about 2 hours to about 48 hours, particularly about 4 hours to about 44 hours.

21. The method according to any one of claims 3, 7 to 20, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at a temperature between about 100 °C and about 180 °C, particularly between about 120 °C and about 160 °C, more particularly at about 140 °C.

22. The method according to any one of claims 5 to 21, wherein the solvent (vi) is a non-polar solvent or a polar aprotic solvent, particularly the solvent (vi) is selected from tert-butanol, acetonitrile, DCM, THF, dioxane or a mixture thereof, more particularly the solvent (vi) is a mixture of tert-butanol and acetonitrile or a mixture of tert-butanol and DCM.

23. The method according to any one of claims 5 to 22, wherein the base (iv) is a tertiary amine, particularly triethylamine.

24. The method according to any one of claims 5 to 23, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at a temperature between about -78 °C and about 50 °C, particularly between about 0 °C and about 25 °C, more particularly at about 5 °C to about 10 °C.

25. The method according to any one of claims 5 to 24, wherein the solvent (v) is a polar aprotic solvent or a polar protic solvent, in particular the solvent (v) is selected from water, methanol, ethanol, n-propanol or a mixture thereof, and more particularly the solvent (v) is water.

26. The method according to any one of claims 5 to 25, wherein the base (v) is a tertiary amine, in particular triethylamine.

27. The method according to any one of claims 5 to 26, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out at a temperature of about -50 °C to about 150 °C, in particular at about 60 °C to about 100 °C, and more particularly at about 80 °C.

28. The method according to any one of claims 5 to 27, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out for about 2 hours to hours, in particular about 2 hours to about 24 hours, and more particularly about 3 hours to about 18 hours.

29. The method according to any one of claims 5 to 28, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out in a batch reactor.

30. The method according to any one of claims 5 to 28, wherein the reaction of the compound of formula (A1) with the compound of formula (A2) is carried out in a flow reactor.

31. The method according to any one of claims 1 to 30, wherein the compound of formula (I) is subsequently subjected to jet milling.

32. The method according to any one of claims 1 to 30, wherein the compound of formula (I) is subsequently subjected to wet milling, in particular seeded crystallization is carried out after wet milling.

33. The compound of formula (I) produced by the method according to any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof.

34. A compound of formula (C1) or a pharmaceutically acceptable salt thereof.

35. The present invention as described in this specification.

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