Upadatinib preparation process

Abstract

The object of the present invention is the preparation of an upadatinib active pharmaceutical ingredient of formula (I) by a novel process that is novel, environmentally friendly, has a favorable pollution profile, and can be realized on an industrial scale, using a novel intermediate not yet known from the literature. JPEG2026517034000044.jpg23128

Description

[Technical Field]

[0001] The objective of the present invention is to provide a novel process for preparing upadatinib active pharmaceutical ingredient using a novel intermediate not yet known from the literature, which is novel, environmentally friendly, has a favorable pollution profile, and can be implemented on an industrial scale.

[0002] Conventional technology Developed by Abbott Laboratories (AbbVie), chemically known as (3S,4R)-3-ethyl-4-{l,5,7,10-tetraazatricyclo[7.3.0.0 2,6 The formula for the active substance known as upadatinib or ABT-494, also known as ]dodeca-2(6),3,7,9,11-pentaen-12-yl}-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxamide, is as follows:

[0003] [ka]

[0004] Upadatinib, marketed as RINVOQ, is a JAK1 selective inhibitor. RINVOQ is indicated for the treatment of moderate to severe active rheumatoid arthritis and psoriatic arthritis in adult patients who have had an inadequate response to or intolerance to one or more disease-modifying antirheumatic drugs. RINVOQ can be used as monotherapy or in combination with methotrexate. It is also indicated for the treatment of psoriatic arthritis (arthritis with psoriasis), axial spondyloarthritis, atopic dermatitis, and ulcerative colitis.

[0005] The active substance and the method for producing the same were first described in international patent application WO2011068881 by Abbott Laboratories (AbbVie).

[0006] In the synthesis of Y described in International Patent Application WO2011068881, during the preparation of two important intermediates in a common branch of the synthesis, the tert-butyl carbamate intermediate of formula (II) is N-alkylated with the α-bromo ketone of formula (III), and then the protecting Boc group is removed from the resulting adduct, and the secondary amine is subjected to a ring-closing reaction with Lawesson's reagent. The Cbz protecting group is removed from the tricyclic compound containing a tosyl group, and the N-tosyl protected pyrrolidine compound is N-carbamoylated with the imidazolide of formula (VIIa) prepared from CDI and 2,2,2-trifluoroethylamine. Finally, the tosyl protecting group is removed from the sulfamate thus prepared under alkaline conditions to obtain upadacitinib of the base of formula (I). The steps of the process described in International Patent Application WO2011068881 are summarized in Figure 1.

[0007] [Chemical formula]

[0008] In International Patent Application WO2017066775, the inventors make a number of important changes to the synthetic route, as shown in Figure 2.

[0009] [Chemical formula]

[0010] Instead of the previously preferred intermediate of tert-butyl carbamate of formula (II), a compound of formula (VIII) which is more crystallizable and thus sufficiently purifiable ethyl carbamate derivative is used, and its N-alkylation is achieved using an α-bromoketone of formula (III) and t-BuOLi. The cyclization of the α-ketocarbamate of formula (IX) is carried out using trifluoroacetic anhydride and pyridine, followed by removal of the tosyl protecting group by alkali treatment to obtain a compound of formula (X). The Cbz protecting group of the latter compound is removed by catalytic reduction to obtain a compound of formula (XI), which is isolated as the dihydrochloride of formula (XI). The pyrrolidinyl ring is selectively N-carbamoylated with the imidazolid compound of formula (VIIa) already discussed above. Also, the L-(+)-tartrate of upadacitinib is prepared from the obtained upadacitinib base.

[0011] The hydrochloride salt of the base of formula (XI) obtained by catalytic reduction of the protecting group from the compound of formula (X) in Figure 2 is a sufficiently purifiable entity due to its production method, but is severely contaminated with palladium, and its removal (and reduction to levels below its regulatory limit) causes serious problems not only at this point but also in the contamination profile of the final product.

[0012] In the final step, the carbamoylation of the dihydrochloride of the compound of formula (XI) with the compound of formula (VIIa) also slightly carbamoylates the 3H-imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at the 3-position, generating characteristic dicarbamoyl impurities, which are difficult to remove.

[0013] One of the objectives of the procedure of the present invention is to eliminate these above-mentioned drawbacks.

[0014] The process described in Figure 2 is discussed in the paper entitled "Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib" (Organic Process Research & Development 2022, 26, 949-962), which investigates the possibility of achieving optimal coupling and ring closure of the intermediates of formula (VIII) and formula (III), as well as achieving the most desirable impurity profile.

[0015] In Mankind's international patent application WO2021005484, a key intermediate of formula (XII) is reacted with a novel derivative of the α-bromoketone of formula (III), namely the compound containing the 2,2,2-trifluoroethylamine group of formula (XIII). The resulting compound of formula (XIV) is subjected to a ring-closing reaction using Lawson's reagent, and then converted to upadatinib of formula (I) by removal of the protecting group. The synthesis described in international patent application WO2021005484 is shown in Figure 3.

[0016] [ka]

[0017] The drawback of this process is that the preparation of the starting compounds of formulas (XII) and (XIII) can only be achieved through an extremely lengthy synthesis, because commercially available intermediates are not available, which would be a deviation from the inventors' process. In contrast, the inventors' process according to the present invention starts from a known compound of formula (IX), which itself is a commercially available intermediate and can be prepared in one step from readily available starting materials for the compounds of formulas (VIII and III).

[0018] In the final step of this process, the cleavage of the 2,2,2-trifluoroethyl-carbamoyl group of the final product can be achieved more easily than in the solution according to the present invention, during the removal of the acetyl group protecting the 3H-imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at position 3. In our process, milder reaction conditions used to remove the tosyl protecting group, which has remarkably good leaving group properties, eliminate the risk of cleavage of the 2,2,2-trifluoroethylcarbamoyl group, whereas in Mankind's process, cleavage of the carbamoyl group of the final product results in further significant impurities.

[0019] The object of the present invention is to overcome the shortcomings of state-of-the-art upadatinib(I) production processes by providing a final isolated product with high purity, a better contamination profile than that of state-of-the-art processes, and yields equivalent to or better than those in known literature, while simultaneously being environmentally friendly, cost-effective, reproducible, and applicable on an industrial scale, through a novel, preferably shorter, process. Prior art has not been able to provide such a solution.

[0020] Embodiment of the Invention The object of the present invention is a novel preparation process for upadatinib of formula (I), starting from two important commercially available intermediates of formulas (VIII) and (III) of the Y synthesis described in the inventors' international patent application WO2017066775, as shown in Figure 2. In the first step, the carbamate compound of formula (VIII) is N-alkylated with an α-bromoketone compound as described by the inventors. The Cbz protecting group is selectively removed from the intermediate of formula (IX), and the resulting pyrrolidine derivative of formula (XVI) is N-carbamoylated with the compound of formula (VIIa), and the intermediate of formula (XVII) is subjected to a ring-closing reaction with TFAA. The tosyl protecting group is then removed by alkaline hydrolysis to obtain the final product of upadatinib of formula (I). The process according to the present invention is summarized in Figure 4.

[0021] [ka]

[0022] The objective of the process developed by the inventors is to eliminate the shortcomings of previous solutions by obtaining a final product with higher chemical and diastereomer purity, which is achieved in such a way that the amount of trans impurities formed during the inventors' process is reduced and carbamoylation on the pyrrole N atom of the final product can be completely eliminated.

[0023] The object of the present invention is a process for preparing upadatinib of formula (I) or a salt thereof, wherein the compound of formula (XVII)

[0024] [ka] A process characterized by forming a compound of formula (I), and then converting it to a pharmaceutically acceptable form of formula (I) by crystallization or salt formation, as appropriate.

[0025] The present invention further relates to compounds of formula (XVI) or general formula (XVIxH n This relates to a preparation process for upadatinib of formula (I), comprising converting the acid addition salts of A) (wherein n is 1, 2, or 3) to the compound of formula (XVII) according to the meaning of A, then converting the compound of formula (XVII) to the compound of formula (I), and optionally converting this to a pharmaceutically acceptable form of the compound of formula (I) by crystallization or salt formation.

[0026] A further subject of the present invention is a process for preparing formula (I) upadatinib, wherein the Cbz protection is selectively cleaved from a general formula (IX) known from the literature, and the resulting compound of formula (XVI) or general formula (XVIxH n A) is a process in which the acid addition salts of (A) (wherein n is 1, 2, or 3) are reacted with the compound of formula (VIII) to obtain the compound of formula (XVII) according to the meaning of A, and then the compound of formula (XVII) is optionally converted to the compound of formula (I), and this is optionally converted to a pharmaceutically acceptable form of the compound of formula (I) by crystallization or salt formation.

[0027] A further object of the present invention is the intermediate compound of formula (XVI) or its acid-doped salt (XVI x H n A) and the compound of formula (XVII).

[0028] Furthermore, compounds of formula (XVI) or general formula (XVIxH n The preparation of the acid addition salt A) is the subject of this invention. Detailed description of the invention

[0029] Abbreviation: ACN-acetonitrile AcOH - Acetic Acid Boc-tert-butoxycarbonyl Cbz-Benzyloxycarbonyl CDI-1,1'-Carbonyldiimidazole DCM-Dichloromethane DIPE-Diisopropyl Ether DIPEA-Diisopropylethylamine DMA-dimethylacetamide DMF-N,N-dimethylformamide HBr (hydrogen bromide) HC1 - Hydrogen Chloride K2CO3 - Potassium Carbonate K2HPO4-Dipotassium Hydrogen Phosphate KI - Potassium Iodide KOH (potassium hydroxide) Lawson's Reagent - 2,4-bis(4-methoxyphenyl)-l,3,2,4-dithiadiphosphetan-2,4-disulfide MgSO4 - Magnesium Sulfate MTBE - Methyl terc-butyl ether 2-MeTHF-2-methyltetrahydrofuran NaH - Sodium hydride NaH2BO4 - Sodium Perborate NaOH - Sodium hydroxide Pd / C-Palladium catalyst with bone. Py-pyridine rt - room temperature t-BuOLi-lithium terc-butoxide TEA-triethylamine TFA-trifluoroacetic acid TFAA-trifluoroacetic anhydride THF-tetrahydrofuran

[0030] The process developed by the inventors begins with the steps described in the inventors' international patent application WO2017066775. Thus, two commercially available intermediates are reacted with each other, namely, the urethane of formula (VIII) is N-alkylated with the α-bromoketone of formula (III) in the presence of t-BuOLi. The resulting compound (IX) is then moved to the next synthesis step without purification, or after purification as necessary.

[0031] Next, an intermediate (XVI) and its salt, which are not known from the prior art, are prepared from the compound of formula (IX) by removing the Cbz protecting group. Surprisingly, the inventors found that the removal of the benzyloxycarbonyl group with acid is a highly selective reaction, and that the other two protecting groups of the molecule, as well as the chirality center and pyrrolopyrazine ring system, remain undamaged.

[0032] In the basic process of Abbvie application WO2017066775, trans-contaminants are generated at several points, which are important for the quality of the final product. Although this is not mentioned by the inventors in the application, the paper entitled "Development of a Scalable Enantioselective Synthesis of JAK Inhibitor Upadacitinib" (Org..Process Res.Dev.2022,26,949-962) explores this phenomenon in detail. Surprisingly to chemistry experts, the inventors found that the rate of trans-impurity formation in their process is significantly reduced, and therefore their process yields a final product with overall higher diastereomer purity and chemical purity than their other process. This advantage is entirely attributable to the favorable chemical properties of the novel intermediates (XVI) and (XVII) generated by the inventors.

[0033] A further advantage of the inventors' process is (XVI x H n A) The intermediate can be isolated as a salt with good crystallinity and is recyclable, which makes it possible to remove impurities that are important to the properties of the final product at a much earlier stage than in the present inventor's process.

[0034] Furthermore, to the surprise of those skilled in the art of chemistry, the inventors have developed their intermediate XVI x H n During the preparation of A), it was found that no cleavage of the N-ethoxycarbonyl or tosyl protecting group, or any other significant decomposition or isomerization process, was observed. In contrast to the prior art, in our synthesis, ring closure occurs only in the final step. However, the open ring system remains stable for substantial parts of the process in a manner not apparent to those skilled in the art, and the Cbz protecting group can be selectively removed without cleavage or partial cleavage of other protecting groups, without significant isomerization, and without other damage to the ring system.

[0035] Surprisingly, the inventors used TFA, sulfuric acid, phosphoric acid, or aqueous HBr to produce their intermediate XVI x H n When preparing A), it was found that only the Cbz protecting group is hydrolyzed, while other structural elements of the molecule remain unaffected. In this step of the reaction for the preparation of upadatinib according to the present invention, other structural units and protecting groups of the open-chain molecule are not decomposed or cleaved by the use of acid over a relatively high temperature range, and as a result, the Cbz group is selectively removed.

[0036] Therefore, the removal of the Cbz group of the compound of general formula (IX) is carried out in or without an organic solvent, using an inorganic or organic acid absorbed or dissolved in aqueous or organic solvent, an alcohol such as water, MeOH, EtOH, IPA, acetic acid, or an ether-type solvent such as diethyl ether, DIPE, MTBE, dioxane, absorbed HCl, or HBr gas, stirred at room temperature or under warm conditions until the benzyloxycarbonyl protecting group is completely cleaved. Preferably, one or more acetic acid derivatives substituted with halogens such as trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or CCl3-COOH or CH3-COOH are used, more preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, or hydrogen bromide, and most preferably an aqueous solution of trifluoroacetic acid, sulfuric acid, phosphoric acid, or HBr. In a very preferred embodiment of the present invention, trifluoroacetic acid is used to remove the Cbz group of the compound of general formula (IX).

[0037] Therefore, the subject of the present invention is a preparation process for upadatinib, wherein the compound of formula (XVII)

[0038] [ka] In an aprotic solvent, in an inert atmosphere, in the presence of an organic base, at a temperature close to the boiling point of the solvent used, react with TFAA or another perfluorocarboxylic anhydride, and from the thus obtained compound, without optional isolation, in an aprotic solvent, in the presence of an organic or inorganic base, preferably an alkali metal base, prepare the crude compound of formula (I), and then obtain the pharmaceutically acceptable form of the compound of formula (I) by crystallization or salt formation.

[0039] According to the present invention, the aprotic solvent in which the compound of formula (XVII) reacts in the above process is dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably acetonitrile; the organic base is TEA, DIPEA, DMAP, dimethylaniline, preferably pyridine.

[0040] The subject of the inventors' research is also the preparation procedure of upadacitinib of the following formula (I),

[0041]

Chemical formula

[0042]

Chemical formula

[0043]

Chemical formula

[0044] (XVI x HnA) (where n is 1, 2, or 3 depending on the meaning of A), (A is an anion, preferably trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or an acetic acid derivative substituted by one or more halogens, such as CCl3-COO - or CH3-COO -Preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions or bromide ions, more preferably trifluoroacetic acid ions or sulfate ions, most preferably trifluoroacetic acid ions), and, if applicable, a carbamoylating agent of formula (VII) prepared in situ,

[0045] [ka] (wherein R may be chlorine, bromine, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl), reacted in an aqueous-organic solvent mixture using an aqueous buffer, preferably a phosphate buffer, in a basic medium at 10-30°C, or in an organic solvent at 10-40°C using an organic base.

[0046] Compounds of the following formula (XVII)

[0047] [ka] The compound is reacted with TFAA or other perfluorocarboxylic acid anhydride in an inert atmosphere, in a non-protic solvent, in the presence of an organic base, at a temperature up to the boiling point of the solvent used. From the resulting compound, without any optional isolation, the crude compound of formula (I) is prepared in a non-protic solvent, in the presence of an organic or inorganic base, preferably an alkali metal base, and thereafter, a pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallization or salt formation.

[0048] In the above process according to the present invention for the preparation of the compound of formula (XVII), the reaction is carried out as follows: a.) The process is carried out in a water-organic solvent mixture, preferably a water-aprotic organic solvent mixture, at a pH range of 8.5 to 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane, or DMF, preferably THF, and the volume ratio of water to organic solvent in the mixture is 1:0, 5 to 1:5, preferably 1:2, or b.) The process is carried out in water-miscible and water-immiscible solvents, such as THF, 2-MeTHF, ACN, dioxane, DCM, Ã, IPAc, and water, preferably in 2-MeTHF or THF, in the presence of an organic base, preferably TEA, DIPEA, pyridine, DMAP, DBU, preferably DIPEA or TEA, such that the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

[0049] In the preparation of the compound of formula (XVII), the reaction is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C.

[0050] In a more preferred embodiment of our invention, the preparation process for upadatinib of formula (I) is carried out using a compound of formula (XVI) or a general formula (XVI * H n The process is carried out in such a manner that compound (XVII) is prepared by reacting compound (IX) with an acid using the salt of A) (wherein n and A are as defined above).

[0051] [ka]

[0052] Therefore, in the most preferred embodiment of our method, upadatinib of formula (I) is prepared from a known compound of formula (IX) by first selectively cleaving the Cbz protecting group of formula (IX) using an acid, and then the compound of formula (XVI) or a salt thereof thus obtained is reacted with the compound of formula (VII) to obtain the compound of formula (XVII), which is converted to upadatinib of the compound of formula (I) or a salt thereof by a ring-closing reaction. Preferred embodiments of each step of this process are described in detail in the following description and examples.

[0053] The compounds of formulas (XVI) and (XVII) used in this process are unknown to the current state of affairs in the art.

[0054] Furthermore, the compound of the following formula (XVI)

[0055] [ka] and

[0056] [ka] General formula (XVIxH n Salt A) is also a subject of this invention.

[0057] In a preferred embodiment of the present invention, n is as defined above, and A is an anion, preferably a trifluoroacetate anion, sulfate ion, phosphate ion, halide ion, preferably a chloride ion or bromide ion, or one or more halogen-substituted acetyl ions, for example, CCl3-COO - Or CH3-COO - A more preferably means trifluoroacetate ion, sulfate ion, phosphate ion, chloride ion, or bromide ion, more preferably trifluoroacetate ion or sulfate ion. Most preferably, it means trifluoroacetate ion.

[0058] The scope of the present invention also includes compounds of formula (XVI).

[0059] [ka] and

[0060] [ka] General formula (XVI x H n A) comprises a process for preparing the salt thereof (wherein n is 1, 2, or 3 depending on the meaning of A) (A is an anion, preferably trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or one or more halogen-substituted acetic acid derivatives, e.g., CCl3-COO- Or CH3-COO - A compound of formula (IX), more preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions, or bromide ions, even more preferably trifluoroacetic acid or sulfate ions, and most preferably trifluoroacetic acid ions, is reacted with an acid.

[0061] [ka] In this process, the benzyloxycarbonyl protecting group is selectively removed, with or without the presence of an organic solvent, using an inorganic or organic acid absorbed in aqueous solution, an organic solvent, or a mixture thereof, preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or an aqueous solution of one or more halogen-substituted acetic acid derivatives, such as CCl3-COOH or CH3-COOH, more preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, or hydrogen bromide, even more preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, or an aqueous solution of HBr, most preferably trifluoroacetic acid.

[0062] In a very preferred embodiment of the present invention, compounds of general formula (XVI) and their salts or salts thereof can be prepared by removing the benzyloxycarbonyl protecting group of a compound of formula (IX) in trifluoroacetic acid, or in an aqueous sulfuric acid solution with a concentration of 40% to 98% by weight, preferably 80% to 98% by weight, most preferably 95% to 98% by weight, or in phosphoric acid with a concentration of 60% to 85% by weight, preferably 75% to 85% by weight, or in an aqueous HBr solution with a concentration of 20% to 48% by weight, preferably 40% to 48% by weight, most preferably 48% by weight, or in HCl or HBr gas absorbed in an alcohol, acetic acid or ether-type solvent.

[0063] In a very preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting group according to the present invention is preferably carried out in 4.5 to 5 volumes of trifluoroacetic acid, 10 to 12 volumes of concentrated or dilute sulfuric acid, or 12 to 16 volumes of phosphoric acid solution, most preferably in 4.5 to 5 volumes of trifluoroacetic acid.

[0064] The amount of acid used in accordance with the present invention is defined as 1 g of compound (IX) per 1 mL of acid volume as defined above, in mass / volume ratio. For example, 1 g of compound IX is reacted with preferably 4.5 to 5 mL of trifluoroacetic acid, or 10 to 12 mL of concentrated or dilute sulfuric acid, or 12 to 16 mL of phosphoric acid solution.

[0065] According to preferred embodiments of the present invention, or depending on the acid used, the reaction is carried out at a temperature of 0 to 80°C. The choice of preferred temperature depends on the acid and solvent used, so that those skilled in the art can determine the most advantageous temperature range. In a very preferred embodiment of the present invention for removing protecting groups using trifluoroacetic acid, sulfuric acid, or an aqueous solution of hydrogen bromide, the reaction mixture is carried out preferably at 0 to 30°C, more preferably at 20 to 25°C in TFA, 0 to 10°C in sulfuric acid, and 25 to 30°C in HBr.

[0066] In another very preferred embodiment of the present invention using phosphoric acid, the reaction is carried out at a temperature of 30-80°C, preferably 50-60°C.

[0067] The reaction time may be 0.5 to 72 hours depending on the acid. The reaction in trifluoroacetic acid takes 48 to 60 hours, preferably 24 to 60 hours; the reaction in sulfuric acid takes 30 to 120 minutes, preferably 45 to 75 minutes; and the reaction in phosphoric acid takes 2 to 10 hours, preferably 4 to 6 hours.

[0068] In a very preferred embodiment of the present invention, the selective removal of the benzyloxycarbonyl protecting group according to the present invention is preferably carried out using an aqueous sulfuric acid solution of 40% to 98% by weight, preferably 80% to 98% by weight, most preferably 95% to 98% by weight, so that the compound of formula (IX) is reacted with concentrated or dilute sulfuric acid, preferably 10 to 12 times by volume, at a temperature of 0 to 30°C, preferably 0 to 15°C, for 30 to 120 minutes, preferably 45 to 75 minutes. In another very preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting group according to the present invention is preferably carried out using trifluoroacetic acid, by reacting the compound of formula (IX) with trifluoroacetic acid, preferably 4.5 to 5 times by volume, at 0 to 30°C, preferably 20 to 25°C, for 48 to 60 hours, preferably 24 to 60 hours.

[0069] In another very preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting group according to the present invention is carried out by reacting the compound of formula (IX) with phosphoric acid at a concentration of preferably 60% to 85% by weight, preferably 75% to 85% by weight, with a volume of phosphoric acid preferably 12 to 16 times, at a temperature of 30 to 80°C, preferably 50 to 60°C, for 2 to 10 hours, preferably 4 to 6 hours.

[0070] In another very preferred embodiment of the present invention, the removal of the benzyloxycarbonyl protecting group is preferably carried out using an aqueous HBr solution of preferably 20% to 48% by weight, more preferably 40% to 48% by weight, and most preferably 48% by weight.

[0071] The Cbz group can be removed, and the resulting compound of formula (XVI) can be chlorided with a base as needed, or converted from the resulting base to another salt with another acid. The conversion of the compound of formula (XVI) from base to salt, or from salt to base, is within the scope of the general knowledge of those skilled in the art.

[0072] The resulting salt of compound (XVI) can be purified, if necessary, by crystallization, by mixing with a solvent in warm water, or by adding the salt to an aqueous solution, cooling and mixing with a carbonate such as K or Na carbonate or an aqueous solution thereof, extracting the base from the aqueous solution with a solvent that is slightly miscible or immiscible with water, and then separating the base from the resulting organic solvent solution with the acid selected as the salt. These purification methods are common practices in organic chemistry and are within the general knowledge of those skilled in the art, and the salts thus obtained are generally within the scope of the inventors' patents.

[0073] However, the salt produced according to the present invention usually does not require further purification.

[0074] Compounds of the formula

[0075] [ka] (XVII) is also an objective of the present invention.

[0076] Furthermore, another object of the present invention is

[0077] [ka] (XVII) is the preparation process for the compound of the following formula.

[0078] [ka] (XVI) or compounds of the following general formulas

[0079] [ka]

[0080] (XVI x H nA) (wherein n is 1, 2, or 3) (A is an anion of an organic or inorganic acid, preferably a trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably a chloride ion or bromide ion, or an acetic acid derivative substituted with one or more halogens, for example, CCl3-COO - Or CH3-COO - A carbamoylating agent of formula (VII) is reacted with (more preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions, or bromide ions, most preferably trifluoroacetic acid or sulfate ions), (which is prepared in situ where applicable).

[0081] [ka] In the formula, R may be chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl.

[0082] This procedure can also be performed as follows: a.) The process is carried out in a water-organic solvent mixture, preferably a water-aprotic organic solvent mixture, at a pH range of 8.5 to 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane, or DMF, preferably THF, and the volume ratio of water to organic solvent in the mixture is 1:0, 5 to 1:5, preferably 1:2, or Alternatively, you can proceed as follows: b.) The procedure is carried out in water-miscible and water-immiscible solvents, such as THF, 2-MeTHF, ACN, dioxane, DCM, Ã, IPAc, and water, preferably in 2-MeTHF or THF, in the presence of an organic base, preferably in TEA, DIPEA, pyridine, DMAP, or DBU, preferably in the presence of DIPEA or TEA, such that the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

[0083] The reaction for preparing the compound of formula (XVII) is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C.

[0084] When using an aqueous buffer solution, preferably a phosphate buffer, the reaction is carried out at a temperature of preferably 10-30°C, preferably 15-20°C.

[0085] When using organic bases, the reaction should be carried out at 10-40°C, preferably 15-25°C.

[0086] In the most advantageous embodiment of the procedure of the present invention, the reaction is carried out in water-miscible and immiscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, siRNA, and IPAc, and in water, preferably 2-MeTHF or THF, in the presence of an organic base, preferably TEA, DIPEA, pyridine, DMAP, or DBU, more preferably DIPEA or TEA, in an amount of 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents, and the reaction is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C.

[0087] The subject of our research is also the preparation procedure for upadatinib of the following formula (I):

[0088] [ka] Compounds of the following formula (IX)

[0089] [ka] When reacted with an acid, compound (XVI) is formed.

[0090] [ka] or its salt of the following general formula

[0091] [ka]

[0092] (XVI x H n A) is (wherein n is 1, 2, or 3 depending on the meaning of A) (A is an anion, preferably trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or an acetic acid derivative substituted with one or more halogens, for example CCl3-COO - Or CH3-COO - It is reacted with an acetylating agent of formula (VII), more preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions, or bromide ions, most preferably trifluoroacetic acid or sulfate ions (which is prepared in situ in certain cases).

[0093] [ka] In the formula, R is chlorine, bromine, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazole, and the reaction is carried out at 10-30°C using an aqueous-organic solvent mixture, an aqueous buffer, preferably a phosphate buffer in a basic medium, or at 10-40°C using an organic base in an organic solvent to obtain the compound of formula (XVII) thus.

[0094] [ka] In an inert atmosphere, in an aprotic solvent, in the presence of an organic base, in TFAA or other perfluorocarboxylic acid anhydride, at a temperature close to the boiling point of the solvent used, the compound thus obtained is reacted, optionally without isolation, in an aprotic solvent, in the presence of an organic or inorganic base, preferably an alkali metal base, to prepare the crude compound of formula (I), from which a pharmaceutically acceptable form of the compound of formula (I) is obtained by crystallization or salt formation.

[0095] The pyrrolidine nitrogen of the compound of formula (XVI) is optionally replaced with a 2,2,2-trifluoroethylcarbamoyl functional group of the final product by a carbamoylating agent of general formula (VII), which is prepared in situ.

[0096] For the reaction, a carbamoylating agent known from the literature of general formula (VII) is used.

[0097] [ka] The formula used is one in which R is chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably imidazolyl. Compounds containing imidazolyl are represented by formula (VIIa).

[0098] [ka]

[0099] The in-situ synthesis of the compound of formula (VIIa) is known from the literature: a solution of 2,2,2-trifluoroethylamine in THF is added to a suspension of CDI in THF under Ar conditions while cooling.

[0100] This procedure can also be done as follows: a.) The process is carried out in a water-organic solvent mixture, preferably a water-aprotic organic solvent mixture, at a pH range of 8.5 to 9, in the presence of a buffer, preferably K2HPO4 phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane, or DMF, preferably THF, and the volume ratio of water to organic solvent in the mixture is 1:0, 5 to 1:5, preferably 1:2, or b.) The process is carried out in water-miscible and miscible solvents, such as THF, 2-MeTHF, ACN, dioxane, DCM, Ã, IPAc, and water, preferably in 2-MeTHF or THF, in the presence of an organic base, preferably TEA, DIPEA, pyridine, DMAP, or DBU, more preferably in the presence of DIPEA or TEA, such that the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

[0101] The reaction is carried out at a temperature of 10–40°C, preferably 15–25°C, to obtain the compound of formula (XVII).

[0102] When using an aqueous buffer solution, preferably a phosphate buffer, the reaction is carried out at a temperature of preferably 10-30°C, preferably 15-20°C.

[0103] When using organic bases, the reaction should be carried out at 10-40°C, preferably 15-25°C.

[0104] In the most advantageous embodiment of the procedure of the present invention, the reaction is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C, in water, preferably 2-MeTHF or THF, in the presence of an organic base, preferably TEA, DIPEA, pyridine, DMAP, DBU, more preferably DIPEA or TEA, such that the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

[0105] Aqueous phosphate buffer systems are difficult to handle due to the need for continuous pH control and are not very suitable for scale-up; therefore, this process is preferable to aqueous buffer processes.

[0106] One advantage of the inventors' method is that the synthesis of intermediate (XVI), which is synthesized immediately before the final product of formula (I), does not contain Pd. In the inventors' process shown in Figure 2, a heavy metal catalyst is used to produce the final intermediate (XI). Removing this catalyst and reducing it to below the 10 ppm level required in the final product would cause significant technical problems and result in a substantial increase in cost.

[0107] In the final step of the inventors' synthesis, they perform ring closure and removal of the tosyl protecting group of the intermediate of formula (XVII).

[0108] According to a preferred embodiment of the inventors' method, the tosylated final product intermediate formed after ring closure is reacted without isolation, and the tosyl protecting group is removed. The synthesis can also be carried out by isolating the tosylated intermediate after ring closure and then removing the protecting group.

[0109] Ring closure is carried out in an inert atmosphere, in an aprotic solvent, dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably acetonitrile, in the presence of an organic base, TEA, DIPEA, DMAP, dimethylaniline, preferably pyridine, using TFAA or other perfluorocarboxylic anhydride coupling agent, at a temperature close to the boiling point of the solvent used. Removal of the tosyl group from the protected ring-closing intermediate is carried out in an aprotic solvent, dioxane, THF, acetonitrile, toluene, DCM, DMF, preferably 2-MeTHF, in the presence of an organic or inorganic base, preferably an alkali metal base, under basic conditions, for example with an aqueous solution of NaOH, preferably by heating at 50-55°C. The crude final product is converted to a pharmaceutically acceptable form by acid-alkali treatment, followed by crystallization or salt formation.

[0110] Cis-trans isomerization occurs to a small degree in all steps, accompanied by strongly acidic or strongly basic characteristics, and generates significant trans impurities or their precursors. Furthermore, the present inventors' process uses a basic medium in the final step, potentially leading to undesirable chemical processes. Although the final step of the process according to the present inventors is also carried out in an alkaline medium, the generation of significant impurities is reduced compared to the present inventors' method due to the favorable chemical properties of intermediate (XVII) produced by the present inventors' method, resulting in a beneficial effect on the purity of the final product.

[0111] Intermediate (XVI) and (XVIxH n A) and intermediate (XVII) can be produced by the method of the present invention with a yield of over 95% and a purity of over 99%. This allows the ring-closing step to be performed with a better impurity profile without the appearance of impurities and decomposition products that are typically generated in prior art reactions. The process described by this inventor generates a significantly large amount of impurities.

[0112] In the final step of the process shown in Figure 2, the carbamoylation of the dihydrochloride of compound (XI) by compound (VII) also slightly carbamoylates the 3H-imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at the 3-position, generating a characteristic dicarbamoyl impurity that is difficult to remove. The advantage of the process according to the present invention is that it eliminates the formation of dicarbamoyl impurities, and as a result, the 3-position remains protected by the tosyl protecting group during the carbamoylation step.

[0113] The final step of the present invention is the removal of the protecting group from the 3H-imidazo-[l,2-a]pyrrolo[2,3-e]pyrazine ring at the 3-position in an alkaline medium. Removal of the tosyl protecting group as a final step allows for the acquisition of a purer product than the final product obtained by the procedure shown in Figure 3. While the process in Figure 3 uses an acetyl protecting group, the inventors use a tosyl protecting group, which has significantly better leaving group properties. Removal of this group requires milder conditions and therefore reduces the cleavage of the 2,2,2-trifluoroethylcarbamoyl group in the final product.

[0114] The enantiomer purity of the inventors' process meets the definition of the ICH Q3 guideline. According to the ICH Q3A(R2) guideline, the entire procedure should have a maximum of 0.15% specific impurities, a maximum of 0.10% unspecified impurities, a maximum of 0.5% total impurities, and an expected purity of over 99.50%.

[0115] The process according to the present invention, namely the production of upadatinib from the active compound (XVI), can be achieved with a particularly high production yield of over 70%. [Examples]

[0116] Further details of the solutions according to the present invention are shown in the following embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0117] Example 1: Preparation of benzyl-(3R,4S)-3-{2-[(ethoxycarbonyl)[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]amino]acetyl}-4-ethylpyrrolidine-1-carboxylate of the following formula (IX) Add 10.6 g of the compound of formula (VIII) to a 500 mL four-necked flask under Ar and dissolve in 51 mL of dry DMA. To the resulting diluted suspension, simultaneously add 3.28 g of LiOtBu solution in 26.5 mL of dry DMA and 15.37 g of the compound of formula (III) in 24.5 mL of DMA under Ar at -10°C for 30 minutes. Stir the solution at -10°C for 2 hours and check the reaction by HPLC. Add 0.88 mL of acetic acid to the resulting mixture while cooling. Then stop cooling and add 87.5 mL of ethanol to the reaction mixture. Raise the temperature of the formed suspension to 20°C and add 11 mL of distilled water. Stir the suspension at 50°C for 10 minutes, then cool and repeat this procedure. Filter the suspension and wash with aqueous ethanol and diethyl ether. Dry the product until it reaches a certain weight.

[0118] Yield: 17.9g (98.1%), white crystals Melting point: 138~138.5℃ IR(KBr):3136,1729,1707,1383,1371,1235,1176,679 1 HNMR(CDCl3,600MHz):8.98(b,1H),8.02(m,2H),7.89 / 7.87(d,J=4.1Hz,1H),7.34(m,2H),7.33(m,2H),7.29(m,1H),7.29(m ,2H),6.62 / 6.49(d,J=4.0Hz,1H),5.14 / 5.13(d,J=12.4Hz,1H),5.08 / 5.06(d,J=12.4Hz,1H),4.85(d,J=18.3Hz,1H),4.78 / 4 .77(d,J=18.3Hz,1H),4.28 / 4.27(q,J=7.0Hz,2H),3.83 / 3.75(m,1H),3.60(m,1H),2.58 / 3.55(m,1H),3.42 / 3.35(m,1H),3. 35 / 3.32(m,1H),2.40(m,1H),2.38(s,3H),1.52(m,1H),1.39(m,1H),1.29 / 1.28(t,J=7.2Hz,3H),0.97 / 0.95(t,J=7.3Hz,3H) 13CNMR(CDCl3,150MHz):204.03 / 203.60,154.72 / 154.65,154.40 / 154.37,147.07,145.78 / 154.74,37.97 / 137.87,137.13 / 137.10,136.73 / 136.67,134.87,134.76 / 134.74,130.21 / 130.18,129.89,128.37,27.89,127.85,127.80 / 127.78,105.74 / 105.50,66.79 / 66.76,62.97,55.79,50.18 / 50.15,49.84 / 48.60,47.90 / 46.73,44.02 / 42.89,21.61,21.21 / 21.18,14.29,12.85 / 12.74 COSY:8.02-7.29,7.89 / 7.87-6.62 / 6.49,7.34-7.33-7.29-2.38,(5.14 / 5.13,5.08 / 5.06),(4.85,4.78 / 4.77),4.28 / 4.27-1.29 / 1.28,(3.83 / 3.75,3.58 / 3.55)-3.35 / 3.32-2.40 * -(3.60,3.42 / 3.35),2.40 * -(1.52,1.39)-0.97 / 0.95 NOESY:3.35 / 3.32-(3.58 / 3.55,2.40),2.40-(3.60,3.35 / 3.32) HSQC(140Hz):8.98-134.87,8.02-127.89,7.89 / 7.87-130.21 / 130.18,7.34-127.80 / 127.78,7.33-128.37,7.29-127.85,7.29-129.89,6.62 / 6.49-105.74 / 105.50,(5.14 / 5.13,5.08 / 5.06)-66.79 / 66.76,(4.85,4.78 / 4.77)-55.79,4.28 / 4.27-62.97,(3.83 / 3.75,3.58 / 3.55)-47.90 / 46.73,(3.60,3.42 / 3.35)-50.18 / 50.15,3.35 / 3.32-49.84 / 48.60,2.40-44.02 / 42.89,2.38-21.61,(1.52,1.39)-21.21 / 21.18,1.29 / 1.28-14.29,0.97 / 0.95-12.85 / 12.74 HMBC (8Hz, 140Hz):8.02-(145.78 / 145.74,127.89),7.89 / 7.87-(137.97 / 137.87,137.13 / 137.10,105.24 / 105.5 0,7.34-(127.85,127.80 / 127.78,66.79 / 66.76),7.33-(136.73 / 136.67,128.37),7.29-127.80 / 127.78,7.29-( 134.76 / 134.74, 129.89, 21.61), 6.62 / 6.49-(137.13 / 137.10, 130.21 / 130.18), (5.14 / 5.13, 5.08 / 5.06)-(154.72 / 154.65, 136.73 / 136.67, 127.80 / 127.78), (4.85, 4.78 / 4.77)-(204.03 / 203.60, 154.40 / 154.37, 147.07), 4.2 8 / 4.27-(154.40 / 154.37,14.29),(3.83 / 3.75,3.58 / 3.55)-(204.03 / 203.60,50.18 / 50.15,44.02 / 42.89,49.84 / 48.60,44.02 / 42.89),(3.60,3.42 / 3.35)-(49.84 / 48.60,44.02 / 42.89),3.35 / 3.32-(204.03 / 203.60,44.02 / 42 .89,21.21 / 21.18),2.40-(204.03 / 203.60,49.84 / 48.60,21.21 / 21.18),2.38-(145.78 / 145.74,129.89),(1.52,1.39)-(49.84 / 48.60,44.02 / 42.89,12.85 / 12.74),1.29 / 1.28-62.97,0.97 / 0.95-(44.02 / 42.89,21.21 / 21.18)

[0119] Example 2: Preparation of the trifluoroacetate (XVIxTFA) of the compound (XVI) ethyl N-{2-[(3R,4S)-4-ethylpyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5J / -pyrrolo[2,3-b]pyrazine-2-yl]carbamate 17.8 g of the compound of formula (IX) is weighed into a flask under Ar and dissolved in 85 mL of anhydrous TFA. The resulting solution is stirred at room temperature for 48 hours. The reaction is checked by HPLC (Phenomenex Kinetex F5 column / NH4OAc / ACN / water=5 / 95-ACN / 235 nm). After the reaction has occurred, the reaction mixture is diluted with 510 mL of DCM, washed with water and saturated NaCl solution, dried over Na2SO4, and evaporated. The residue is suspended in 135 mL of MTBE and stirred at room temperature for 18 hours. The suspension is filtered, the product is washed with 25 mL of MTBE followed by 25 mL of DIPE, and dried at 10 mbar at 50°C until it reaches a constant weight.

[0120] Yield: 15.76g (93%), white crystals Melting point: 186.5~187℃ 1 HNMR(DMSO,600MHz):9.58(b,1H),9.29(b,1H),8.77 9s,1H),8.28(d,J=4.1Hz,1H),8.01(~d,J=8.3Hz,2H),7.46(~d,J=8.3Hz,2H),6 .84(d,J=4.1Hz,1H),4.89(d,J=19.1Hz,1H),4.88(d,J=19.1Hz,1H),4.19(q,J=7 .1Hz,2H),3.66(m,1H),3.30(m,2H),3.29(m,1H),3.00(m,1H),2.53(m,1H),2.36 (s,3H),1.47(m,1H),1.25(m,1H),1.21(t,J=7.1Hz,3H),0.91(t,.J=7.3Hz,3H). 13 CNMR (DMSO,150 MHZ):204.89,158.41(q,J=30.9Hz),154.32,147.52,146.42,137.91,136.80,135.30,134.30,131.85,130.51 ,127.76,117.44(q,J=299.7Hz),106.09,62.71,56.65,48.53,48.34,45.47,42.99,21.32,20.13,14.31,12.59 COSY:8.28-6.84,8.01-7.46,(4.89,4.88),4.19-1.21,3.66 * -3.30-(9.58,9.29)-(3.29,3.00)-2.53 * -(1.47,1.25)-0.91,3.66 * -2.53 * HSQC(140Hz):8.77-135.30,8.28-131.85,8.01-127.76,7.46-130.51,6.84-106.09,4.89-56.65,4.88-56.65,4.19-62.71,3. 66-48.53,3.30-45.47,3.29-48.34,3.00-48.34,2.53-42.99,2.36-21.32,1.47-20.13,1.25-20.13,1.21-14.31,0.91-12.59 HMBC (8Hz, 140Hz):8.77-(147.52,136.80),8.28-(137.91,136.80,106.09),8.01-(146.42,127.76),7.46- (134.30,130.51,21.32),6.84-(137.91,136.80,131.85),(4.89,4.88)-(204.89,154.32,147.52),4.19-(1 54.32, 14.31), 3.66-(204.89, 48.34, 45.47, 42.99, 20.13), (3.29, 3.00)-20.13, 2.53-(204.89, 48.34, 20.13), 2.36-(146.42, 130.51), (1.47, 1.25)-(48.53, 48.34, 142.99, 12.59), 1.21-62.71, 0.91-(42.99, 20.13)

[0121] Example 3: Preparation of the ethyl N-{2-[(3R,4S)-4-ethyl-l-[(2,2,2-trifluoroethyl)carbamoyl}pyrrolidin-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate of formula (XVII)

[0122] 1. Suspend 4.35 g of CDI in 30 mL of dry THF under argon. Cool the suspension to 8-10°C and add it dropwise to 1.8 mL of trifluoroethylamine solution prepared in 5 mL of dry THF. Stir the reaction mixture at room temperature for 1 hour. 2. Mix 16 mL of dist with water and 36 mL of THF, 9.20 g (XVI x The pH of TFA) and 4.0 g K2HPO4 is measured under Ar at room temperature. The pH of the mixture is adjusted to 8.5-9 by adding a 10% KOH solution. To the resulting two-phase mixture, a solution of compound N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (VIIa), prepared according to 1, is added at 15-20°C. During the addition, the pH of the aqueous phase is checked several times and maintained at 8.5-9 by adding a 10% KOH solution. The reaction mixture is stirred at room temperature for a further 3 hours at its pH. The reaction is checked by HPLC (Phenomenex Kinetex F5 column / NH4OAc / ACN / water=5 / 95-ACN / 235nm). The resulting suspension is cooled to 0-4°C, stirred at this temperature for a further 1 hour, filtered, and washed with DIPE. The filtrate is concentrated, stirred at 0-4°C for 1 hour, and 16 mL of cold water is added. Filter the suspension and wash with cold water and DIPE. Combine the two solid fractions, suspend them in a mixture of MTBE and toluene, stir overnight, filter, wash with MTBE, and finally dry until a uniform weight is reached. Add 22 mL of DMA to the crude product and heat to 60-70°C. After complete dissolution, add 30 mL of warm ethanol. Stir the resulting suspension under warm conditions for several minutes and allow to cool slowly. Then heat to 55-60°C, cool slowly to 20-22°C, filter, wash with cold ethanol and MTBE, and dry until a uniform weight is reached.

[0123] Yield: 6.70 g (73%), pale yellowish-white crystals Melting point: 206.5~207℃ 1HNMR(DMSO,600MHz):8.79(s,1H),8.25(d,.J =4.0)Hz,1H),8.00(~d,J=8.3Hz,2H),7.45(~d,J=8.1Hz,2H),6.84(b,1H),6.83(d,J=4.1Hz,1H),4.82(s,2H),4.18(q,J=7 1Hz,2H),3.78(m,2H),3.55(m,1H),3.50(m,1H),3.40(m,1H),3.38(m,1H),3.16(m,1H),2.43(m,1H),2.35(s,3H),1.45(m,1H),1.22(m,1H),1.20(t,J=7 1Hz,3H),0.90(t,. / 7.3Hz,3H) 13 CNMR(DMSO,150MHz):204.96,155.89,154.40,147.61,146.39,137.88,136.70,134.94,134.32,131.75,130.50,127.72,125.32(q,J=279.2Hz),106.14,62.63,56.08,49.75,47.18,42.84,41.20(q,J=33.3Hz),21.32,20.96,14.27,12.74 COSY:8.25-6.83,8.00-7.45,6.84-3.78,4.18-1.20,(3.55,3.38)-3.50-2.43 * -(3.40,3.16),2.43 * -(1.45,1.22)-0.90 ROESY:2.43-(3.50,3.40) HSQC(140Hz):8.79-134.94,8.25-131.75,8.00-127.72,7.45-130.50,6.83-106.14,4.82-56.08,4.18-62.63,3.78-41.20,3.55-47.18,3.50-49.75,3.40-49.75,3.38-47.18,3.16-49.75,2.453-42.84,2.35-21.32,1.45-20.96,1.22-20.96,1.20-14.27,0.90-12.74 HMBC(8Hz,140Hz):8.79-(147.61,136.70),8.25-(137.88,136.70,106.14),8.0-(146.39,127.72) ,7.45-(134.32,130.53,21.32),6.84-155.89,6.83-(137.88,136.70,131.75),4.82-(204.96,154. 40,147.61),4.18-(154.40,14.27),3.78-155.89,(3.55,3.38)-204.96,(3.40,3.16)-(204.96,20.96),2.43-204.96,2.35-(146.39,130.50),(1.45,1.22)-49.75,1.20-62.63,0.90-(42.84,20.96)

[0124] Example 4: (I) Formula (3S,4R)-3-ethyl-4-{l,5,7,10-tetraazatricyclo[7.3.0.0 2,6 Preparation of the final product Ix1 / 2 H2O of dodeca-2(6),3,7,9,11-pentaen-12-yl}-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide) hemihydrate In a 100 mL flask, 4.0 g of the compound of formula (XVII) was suspended in 60 mL of ACN under an inert atmosphere. 1.57 mL of pyridine was added to the suspension, followed by the dropwise addition of 5.50 mL of TFAA while cooling the mixture on ice. The mixture was then heated to 75-80°C and stirred at this temperature for 5 hours, followed by a further 16 hours at room temperature. The reaction was checked by HPLC (X-Bridge BEH C18 column / ACN / water / HCOOH = 5 / 95 / 0, 05-95 / 5 / 0, 05 / 235 nm).

[0125] The resulting mixture is filtered, the filtrate is evaporated, and the residue is dissolved in 40 mL of 2-MeTHF. 11 mL of 20% NaOH solution is added to the mixture and stirred at 55°C for 2 hours. The reaction mixture is then cooled and the phases are separated. The organic phase is washed with saturated NaCl solution, dried over MgSO4, filtered on a Celite bed, washed with 2-MeTHF, and evaporated. n-heptane is evaporated from the evaporation residue. The resulting substance is dissolved in siRNA, extracted with phosphoric acid, and recycled back into the organic phase by alkalization. The organic phase is washed with saturated NaCl solution, dried on MgSCU, filtered, and evaporated to dryness.

[0126] The obtained 2.20 g of crude product is dissolved in a 3% aqueous HCl solution, upadatinib of form C is inoculated, a few drops of n-heptane are added to the resulting suspension, and the mixture is stirred for 1 hour. The suspension is filtered, washed with the mixture of aqueous HCl solution and n-heptane, and dried under vacuum at 45°C until a constant weight is reached.

[0127] Yield: 1.55 g (62.7%), pale yellowish-white crystals Melting point: 163-164°C IR(KBr):3431,3177,1656,1616,1548,1399,1147,890 'HNMR(DMSO,600MHz):12.31(b,1H),8.56(s,1H),7.49(s,1H),7.46(d,J=3.1Hz,1H),7.02(d,.J=3.3Hz,1H),7.00(bt,J=6.1Hz,1H),4. 37(m,1H),3.89(m,1H),3.83(m,1H),3.79(m,1H),3.70(m,1H),3.28(m,1H),2.57(m,1H),1.11(m,1H),0.82(m,1H),0.64(t,J=7.4Hz,3H) 13 CNMR(DMSO,150MHz):156.10,139.13,134.55,134.03,131.65,125.51,125.42(q,J=279.4 Hz),121.97,114.82,95.01,49.97,49.37,43.28,41.29(q,J=33.2Hz),37.42,21.69,12.3 COSY:12.31-7.46-7.02,7.00-3.89,(3.83,3.79)-4.37-2.57 * -(3.70,3.28),2.57 * -(1.11,0.82)-0.64. NOESY: 4.37-2.57 HSQC(140Hz):8.56-134.55,7.49-131.65,7.46-121.97,7.02-95.01,4.37-37.42,3.89-41.29,3.8 3-49.97,3.79-49.97,3.70-49.37,3.28-49.37,2.57-43.28,1.11-21.69,0.82-21.69,0.64-12.36 HMBC(8Hz,140Hz):12.31-(134.03,121.97,114.82,95.01),8.56-(139.13,134.03),7.49-139.13,7.46-(134.03 ,114.82,95.01),7.02-(134.02,121.97,114.82),7.00-(156.10,41.29),4.37-(131.65,125.51,49.97,21.69),3 89-(l 56.10,125.42),(3.83,3.79)-125.51,49.37,43.28,37.42),(3.70,3.28)-(49.97,43.28,37.42,21.69),(1.11,0.82)-(49.37,43.28,37.42,12.36),0.64-(43.28,21.69)

[0128] Example 5: Ethyl N-{2-[(3R,4S)-4-ethylpyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate acetate Measure 250 mL (96%) cc of sulfuric acid into a 500 mL three-necked flask and cool to 0-10°C. Gradually add 25 g of the benzyl(3R,4S)-3-{2-[(ethoxycarbonyl)[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]amino]acetyl}-4-ethylpyrrolidine-1-carboxylate compound of formula (IX) to the concentrated acid with vigorous stirring, then stir for 30-60 minutes while cooling, and then proceed with the treatment. Check the reaction by HPLC. Slowly pour cc of the sulfuric acid solution into 3 kg of ice water with vigorous stirring, stir for 2-4 hours, and filter the suspension. Wash the filtered product with water, dry, and wash with MTBE. Dissolve the obtained crude product in 290 mL of IPA and stir at 60-70°C for 2-4 hours, then at room temperature for 6-10 hours. Next, it was filtered, washed with IPA, then MTBE, and dried.

[0129] m = 23.3 g (slightly hygroscopic white powder) T~99% HPLC: 99.45% ethyl N-{2-[(3R,4S)-4-ethylpyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolyl[2,3-b]pyrazine-2-yl]carbamate sulfate + 0.39% trans-ethyl N-{2-[(3S,4R)-4-ethylpyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzene (Sulfonyl)-5H-pyrrolyl[2,3-b]pyrazine-2-yl]carbamate sulfate Imp. + 0.16% benzyl-ethyl N-{2-[(3R,4S)-4-ethyl-l-[(2,2,2-trifluoroethyl)carbamoyl]pyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolyl[2,3-b]pyrazine-2-yl]carbamate Imp.

[0130] Melting point: 157.5~158.5℃ IR(KBr):3435,1729,1376,1225,1171,1090,1063,591,574. ’HNMR(DMSO,a600):8.01(b,2H),8.76(s,1H),8.28(d,J=3.8Hz,1H),8.01(~d,J=8.0Hz,2H),7.46(~d,J=7.9Hz,2H),6.83(d,J=3.8Hz,1H),4.90(d,J=19.5Hz,1h),4.88(d,J=19.5Hz,1H),4.19(q,J=6.9Hz,2H),3.67(m,1H),3.32(m,1H),3.31(m,2H),3.00(m,1H),2.54(m,1H),2.36(s,3H),1.50(m,1H),1.24(m,1H),1.21(t,J=6.9Hz,3H),0.92(t,J=7.1Hz,3H) 13 CNMR:205.19,154.32,147.53,146.44,137.91,136.81,135.33,134.31,131.88,130.53,127.78,106.10,62.73,56.74,48.68,48.34,46.13,43.03,21.34,20.18,14.33,12.63. COSY:8.28-6.83,8.01-7.46,(4.90,4.88),4.19-1.21,3.31-3.67-3.54 * -(3.32,3.00),2.54 * -(1.50,1.24)-0.92 HSQC(140Hz):8.76-135.33,8.28-131.88,8.01-127.78,7.46-130.53,6.83-106.10,4.90-56.74,4.88-56.74,4.19-62.73,3.67-48.34,3.32-48.68,3.31-46.13,3.00-48.68,2.54-43.03,2.36-21.34,1.50-20.18,1.24-20.18,1.21-14.33,0.92-12.63 HMBC(8Hz,140Hz):8.76-(147.53,136.81),8.28-(137.91,136.81,106.10),8.01-(146.44,127.78 ),7.46-(134.31,130.53,21.34),6.83-(136.81,131.88),(4.90,4.88)-(205.19,154.32),4.19-(1 54.32, 14.33), 3.67-(205.19, 48.68, 46.13, 43.03), (3.32, 3.00)-48.34, 46.13, 43.03), 3.31-(205.19, 48.34), 2.36-(146.44, 130.53), (1.50, 1.24)-(48.68, 48.34, 43.03), 1.21-62.73, 0.92-43.09

[0131] Example 6: Preparation of the ethyl N-{2-[(3R,4S)-4-ethyl-1-[(2,2,2-trifluoroethyl)carbamoyl}pyrrolidin-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate of formula (XVII) 1. In a 250 mL flask, measure 12 g of CDI under Ar and suspend it in 85 mL of dry 2-MeTHF. Add 6.25 mL of trifluoroethylamine solution in 30 mL of 2-MeTHF to the suspension over 20-25 minutes while cooling with water (5-10°C). After addition, stir the reaction mixture at room temperature for 1-2 hours. 2. In a 1000 mL three-necked flask, add 25 g of UPAD32, 400 mL of 2-MeTHF, and 21.60 mL of DIPEA under Ar at room temperature. Stir the resulting yellow suspension at room temperature for 15 minutes, then slowly add the solution prepared in step 1 under Ar at 10-15°C, and stir the reaction mixture at room temperature for 2-4 hours. Next, add 200 mL of water and stir for 30-45 minutes, checking the reaction by HPLC. Extract the reaction mixture with DCM, and evaporate the organic phase using a rotating film evaporator. Suspend the obtained substance in MTBE, stir at room temperature for 8-12 hours, filter, wash with water and MTBE, and dry. m=24.35g (white powder) Yield: -94.1% HPLC: 99.76% ethyl-N-{2-[(3R,4S)-4-ethyl-l-[(2,2,2-trifluorethyl)carbamoyl]pyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methyl-benzolsulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate + 0.11% trans-ethyl N-{2-[(3S,4R)-4-ethyl-1-[(2,2,2-trifluorethyl)carbamoyl]pyrrolidine-3-yl]- 2-Oxoethyl}-N-[5-(4-methyl-benzol-sulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate Imp. + 0.02% benzyl-ethyl-N-{2-[(3R,4S)-4-ethyl-l-[(2,2,2trifluoretyl)carbamoyl]pyrrolidine-3-yl]-2-oxoethyl}-N-[5-(4-methyl-benzolsulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate Imp. Melting point: 191-192°C

[0132] Example 7: Form of formula (I) C compound ((3S,4R)-3-ethyl-4-{l,5,7,10-tetraazatricyclo[7.3.0.0 2,6 Dodeca-2(6),3,7,9,11-pentaen-12-yl}-N-(2,2,2-trifluoroethyl)pyrrolidine-l-carboxamide) 30.0 g of ethyl N-{2-[(3R,4S)-4-ethyl-1-[(2,2,2-trifluoroethyl)carbamoyl]pyrroridine-3-yl]-2-oxoethyl}-N-[5-(4-methylbenzenesulfonyl)-5H-pyrrolo[2,3-b]pyrazine-2-yl]carbamate of formula (XVII) is added to a 500 mL reactor under Ar and suspended in 360 mL of ACN. 12.95 mL of pyridine, followed by 45.8 mL of TFAA, are slowly added under argon while cooling on ice. The mixture is then heated to 75-80°C and stirred at this temperature for 6-8 hours, followed by stirring at room temperature for a further 8-12 hours. The reaction is checked by HPLC (X-Bridge BEH C18 column / ACN / water / HCOOH=5 / 95 / 0.05~95 / 5 / 0.05 / 235nm).

[0133] The reaction mixture is evaporated using a rotary evaporator, and the thick oily cream is dissolved in 300 mL of 2-MeTHF and stirred with 90 mL of fresh 20% NaOH at 50-60°C for 1-2 hours. The phases are then separated, the organic portion is washed with saturated NaCl, and then stirred with a mixture of Na2SO4, Celite, and silica gel, and filtered.

[0134] Add 360 mL of 0.5 MH3PO4 solution to the 2-MeTHF solution. Bubble argon over the mixture and stir for 20 minutes. Then separate the phases. Repeat extraction until the product is visible in the organic phase. Add siRNA to the combined phosphoric acid solution, then adjust the pH to 6 with 2 M NaOH, stir for 20 minutes, and then separate the phases. Add siRNA again to the aqueous phase, mix for several minutes, and then separate. Then adjust the pH of the aqueous phase to 6.5 with 2 M NaOH and extract with siRNA. Repeat extraction until the product is visible in the aqueous phase.

[0135] Wash the combined siRNA phase with saturated NaCl, dry, filter, and concentrate to 65.1 mL. Add 1.20 mL of water to the concentrated siRNA solution while stirring vigorously. Stir the resulting suspension at room temperature for 1-2 hours, then add 7.92 mL of n-heptane and stir for 2-4 hours. Filter the suspension, wash with EtAc / water / n-heptane = 90 / l / 20, and finally dry the filtrate.

[0136] m = 13.7g (gray powder) Yield: 74% HPLC: 99.96% upadatinib product + 0.04% ethyl-upadatinib imp. Form: Form C Enantiomer: 100% ee KF: 2.39% GC OVI: ACN: 18 ppm 1-Acetate: 2169 ppm Me-THF: 17ppm n-heptane: 6 ppm Pyridine: 77 ppm

[0137] Upadatinib in form C, as described in international patent application WO2017066775, was tested using the following apparatus and measurement method: Equipment: PANalytical Empyrean X-ray powder diffractometer Measurement settings: transparent

[0138] x-ray tube Type: Empyrean long narrow focus high resolution tube Anode: Cu Wavelength: Kα (1.541874Å) Focus: Line focus

[0139] Light source side optical elements Divergent gap: Fixed gap 1 / 2° Mirror: Focusing elliptical mirror Solar gap: 0.04 rad Dispersion prevention gap: Fixed gap 1 / 2°

[0140] Diffractive lateral optical elements Leakage prevention gap: Programmable gap in fixed mode: 1 / 2° Solar gap: 0.04 rad

[0141] Sample stage Type: Reflective-transmissive type with rotating sample holder Rotation speed: 1 revolution / second

[0142] Direct beam pliers ("Beam Knife"): Translucent

[0143] detector Type: PIXcel 3D 1x1 Area Detector Operating mode: Sweep line detector (ID) mode

[0144] Active detector window Dimensions: 3.3473° Sample preparation: Insert the sample between two Mylar films without pulverizing it.

[0145] Measurement conditions Temperature: room temperature Acceleration voltage: 45kV Anode current: 40mA Scanning method: Continuous (9 / 9) sweep Range: 2.0000~34.9964 2θ° Process interval: 0.0131 2θ° Time per process: 109.650 seconds Number of measurement cycles: 1 Measurement time: Approximately 20 minutes

Claims

1. Preparation process for upadatinib, comprising the compound of formula (XVII) 【Chemistry 1】 A preparation process characterized by reacting with TFAA or other perfluorocarboxylic acid anhydride in an inert atmosphere, in a non-protic solvent, in the presence of an organic base, at a temperature close to the boiling point of the solvent used; preparing a crude compound of formula (I) in a non-protic solvent, in the presence of an organic or inorganic base, preferably an alkali metal base, without arbitrarily isolating the compound thus obtained; and obtaining a pharmaceutically acceptable form of the compound of formula (I) from thereby by crystallization or salt formation.

2. The process according to claim 1 for the preparation of upadatinib of the following formula (I), 【Chemistry 2】 The compound of formula (XVII) and the compound of formula (XVI) 【Transformation 3】 or 【Chemistry 4】 General formula (XVI x H ｎ A) the salt of (wherein n is 1, 2, or 3 depending on the meaning of A) (A is an anion, preferably trifluoroacetate ion, sulfate ion, phosphate ion, halide ion, preferably chloride ion or bromide ion, or CCl) ３ - COO － Or CH ３ - COO － It is prepared by reacting an acetic acid derivative substituted with one or more halogens, more preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions, or bromide ions, even more preferably trifluoroacetic acid or sulfate ions, with a carbamoylating agent of formula (VII) which is prepared in situ where applicable. 【Transformation 5】 A process characterized by reacting R with an imidazolyl group, wherein R may be a chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group.

3. A process according to claim 2 for preparing upadatinib (I), comprising a compound of formula (XVI) or a compound of general formula (XVI xH ｎ A) The salt of (wherein n and A are as defined in claim 2) and the compound of formula (IX) 【Transformation 6】 A process of preparing a substance by reacting it with an acid.

4. A process according to any one of claims 1 to 3 for the preparation of upadatinib of formula (I), characterized in that the aprotic solvent in which the compound of formula (XVII) reacts is dioxane, THF, 2-MeTHF, toluene, DCM, DMF, preferably acetonitrile; and the organic base is TEA, DIPEA, DMAP, dimethylaniline, preferably pyridine.

5. A process according to any one of claims 2 to 4 for preparing upadatinib of formula (I), wherein the compound of formula (XVII) is prepared by carrying out the reaction in the following manner: a.) In a water-organic solvent mixture, preferably a water-aprotic organic solvent mixture, with a pH range of 8.5 to 9, a buffer solution, preferably K ２ HPO ４ The process is carried out in the presence of a phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane, or DMF, preferably THF, and the water-organic solvent volume ratio in the mixture is 1:0.5 to 1:5, preferably 1:2, or b.) A process characterized by being carried out in a water-miscible and immiscible solvent, such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IPAc, and water, preferably in 2-MeTHF or THF, in the presence of an organic base, preferably TEA, DIPEA, pyridine, DMAP, or DBU, more preferably in the presence of DIPEA or TEA, wherein the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

6. A process according to any one of claims 2 to 5 for the preparation of upadatinib of formula (I), characterized in that the reaction is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C, during the preparation of the compound of formula (XVII).

7. The process according to any one of claims 3 to 6 for the preparation of upadacitinib of formula (I), wherein the Cbz protecting group of the compound of formula (IX) is removed using a mineral acid or an organic acid absorbed or dissolved in an aqueous or organic solvent or a mixture thereof, in an organic solvent or without it, preferably using trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or an acetic acid derivative substituted by one or more halogens, preferably using CCl ３ -COOH or CH ３ -COOH, more preferably using trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide, most preferably using an aqueous solution of trifluoroacetic acid, sulfuric acid, phosphoric acid or HBr, and recovering the resulting compound of general formula (XVI) as the base or a salt of general formula (XVIXH ｎ A), characterized in that it is a process.

8. A process according to claim 7 for the preparation of upadatinib of formula (I), characterized in that the cleavage of the Cbz protecting group of the compound of formula (IX) is carried out in trifluoroacetic acid, or in an aqueous sulfuric acid solution at a concentration of 40% to 98% by weight, preferably 80% to 98% by weight, most preferably 95% to 98% by weight, or in phosphoric acid at a concentration of 60% to 85% by weight, preferably 75% to 85% by weight, or in an aqueous HBr solution at a concentration of 20% to 48% by weight, preferably 40% to 48% by weight, most preferably 48% by weight, or in HC1 or HBr gas absorbed in an alcohol, acetic acid or ether-type solvent.

9. Formula (XVI) 【Transformation 7】 Compounds and salts having the following general formula, 【Transformation 8】 (XVI x H ｎ A) (wherein n is 1, 2, or 3, and A is an anion of an organic or inorganic acid), and formula 【Chemistry 9】 A compound of [this].

10. A process for preparing the compound of formula (XVI) and its salt according to claim 9, wherein the Cbz protecting group of the compound of formula (IX), in or without an organic solvent, is absorbed or dissolved in aqueous solution, an organic solvent, or a mixture thereof with a mineral acid or organic acid, preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide, or an acetic acid derivative substituted with one or more halogens, preferably CCl ３ -COOH or CH ３ -COOH is reacted with more preferably trifluoroacetic acid, sulfuric acid, phosphoric acid, hydrogen chloride, or hydrogen bromide, and most preferably with an aqueous solution of trifluoroacetic acid, sulfuric acid, phosphoric acid, or HBr, and the resulting compound of general formula (XVI) is used as a base or general formula (XVIxH ｎ A preparation process characterized by recovering the salt of A).

11. A process according to claim 9 for preparing a compound of formula (XVI) and a salt thereof, characterized in that the cleavage of the Cbz protecting group of the compound of formula (IX) is carried out in trifluoroacetic acid, or in an aqueous sulfuric acid solution at a concentration of 40% to 98% by weight, preferably 80% to 98% by weight, most preferably 95% to 98% by weight, or in phosphoric acid at a concentration of 60% to 85% by weight, preferably 75% to 85% by weight, or in an aqueous HBr solution at a concentration of 20% to 48% by weight, preferably 40% to 48% by weight, most preferably 48% by weight, or in HCl or HBr gas absorbed in an alcohol, acetic acid, or ether-type solvent.

12. Compounds of the following formula 【Chemistry 10】 A preparation process for (XVII) according to claim 9, wherein the compound of formula (XVI) or a salt thereof of the general formula (XVI x HnA) (wherein n is 1, 2, or 3 depending on the meaning of A, and A is an anion, preferably a trifluoroacetate ion, a sulfate ion, a phosphate ion, a halide ion, preferably a chloride ion or a bromide ion, or CCl ３ - COO － Or CH ３ - COO － An acetic acid derivative having one or more substituted halogens, preferably trifluoroacetic acid, sulfate ions, phosphate ions, chloride ions, or bromide ions, most preferably trifluoroacetic acid or sulfate ions), is reacted with a carbamoylating agent of formula (VII) which is optionally prepared in situ. 【Chemistry 11】 A preparation process characterized in that, in the formula, R is a chloro, bromo, alkylcarbonyloxy, substituted alkylcarbonyloxy, or other carbamic acid activating group, preferably an imidazolyl group.

13. A process according to claim 12 for the preparation of a compound of formula (XVII), wherein the process comprises: a.) In a water-organic solvent mixture, preferably a water-aprotic organic solvent mixture, with a pH range of 8.5 to 9, a buffer solution, preferably K ２ HPO ４ The process is carried out in the presence of a phosphate buffer, where the aprotic organic solvent is THF, 2-MeTHF, ACN, dioxane, or DMF, preferably THF, and the water-organic solvent volume ratio in the mixture is 1:0.5 to 1:5, preferably 1:2, or b.) A preparation process characterized by being carried out in water-miscible and immiscible solvents such as THF, 2-MeTHF, ACN, dioxane, DCM, EtOAc, IPAc, and water, preferably in 2-MeTHF or THF, in the presence of an organic base, DIPEA, pyridine, DMAP, DBU, preferably in the presence of DIPEA or TEA, wherein the amount of base used is 2 to 6 molar equivalents, preferably 2.5 to 3 molar equivalents.

14. A process according to any one of claims 12 and 13 for preparing a compound of formula (XVII), characterized in that the reaction is carried out at a temperature of 10 to 40°C, preferably 15 to 25°C.

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