Process for preparation of toltinib

Abstract

Disclosed herein are improved synthetic pathways for the preparation of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one (toltinib). Also disclosed herein are novel compounds for use in the synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo [4, 5-c] pyridine-2 (3H)-one.

Description

[Technical field]

[0001] Disclosed herein is a method for preparing (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one free base (tolebrutinib), also referred to herein as a compound of formula (I), having the following structure: And salt forms of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one and methods for preparing the same. Compound (1) and its salts and solid forms thereof are potent Bruton's tyrosine kinase (BTK) inhibitors and are therefore useful for treating diseases or disorders caused by excessive BTK signaling, such as diseases selected from autoimmune diseases, inflammatory diseases or cancer. [Background technology]

[0002] Compound (1) and its preparation method are disclosed in Example 3 of U.S. Pat. No. 9,688,676 B2, columns 62, line 8 to 65, line 32 and 67, lines 28 to 69. The disclosed synthesis provides 100 mg of crude compound (1), which must be purified by column chromatography to produce 54.5 mg of purified compound (1), which loses nearly 50% of the yield. The disclosed synthesis contains 10 steps, several of which involve undesirable solvents and may result in large-scale additional waste.

[0003] One factor in the suitability of a compound as a therapeutic agent is a compound synthesis that is amenable to large-scale manufacturing and isolation with minimal product waste and impurities. This factor is often considered when reviewing whether a laboratory-scale process is suitable for preparing the larger quantities required for commercial production. In addition, the environmental impact of the various reagents and conditions required for large-scale manufacturing is an increasingly important factor. [Summary of the invention]

[0004] The present disclosure relates to methods for preparing compounds of formula (I): The method comprises: The compound of formula A-oxalate is reacted: To form a compound of formula (I), wherein the reaction conditions are selected from: (i) reacting a compound of formula A-oxalate with acryloyl chloride in the presence of diisopropylethylamine in toluene; or (ii) The compound of formula A-oxalate is reacted with 3-chloropropionic acid in the presence of potassium carbonate, diisopropylethylamine and propylphosphonic anhydride in dichloromethane, then with 1,8-diazabicyclo[5.4.0]undec-7-ene in hydrochloric acid and finally with sodium bicarbonate.

[0005] The present disclosure also relates to methods of preparing compounds of formula A: In some embodiments, the compound of formula A is prepared by: making a compound of formula 1-f: and reacting with Pd / C and methanesulfonic acid in ethanol. In some embodiments, the compound of formula A is prepared by: making a compound of formula 2-d: In some embodiments, the compound of formula A is prepared by reacting the compound of formula 3-h with trifluoroacetic acid in dichloromethane. Reaction with trifluoroacetic acid.

[0006] The present disclosure still further relates to compounds selected from the group consisting of: or a salt thereof.

Brief Description of the Drawings

[0008] Figure 1 The NMR spectrum of compound 1-c is shown.

[0009] Figure 2 The NMR spectrum of compound 1-d is shown.

[0010] Figure 3 The NMR spectrum of compound 1-e is shown.

[0011] Figure 4 The NMR spectrum of compound 1-f is shown.

[0012] Figure 5 The NMR spectrum of compound 2-b is shown.

[0013] Figure 6 The NMR spectrum of compound 2-c is shown.

[0014] Figure 7 The NMR spectrum of Compound A is shown.

[0015] Figure 8A 10-step linear synthetic route for the synthesis of 2,3,4-aminopyridine ring systems based on the synthetic route disclosed in US 9,688,676 is shown.

[0016] Fig. 9 A retrosynthetic scheme for developing improved synthetic routes is shown.

[0017] Figure 10 shows a comparison of the current synthetic pathway with the second generation synthetic pathway.

[0018] Fig.11 An alternative synthetic strategy is shown, in which alternative pathways to the Chan Lam coupling step were explored.

[0019] Fig.12 The proof of feasibility (POF) process of the Buchwald reaction is shown.

[0020] Fig.13 The proof-of-feasibility (POF) process of the cyclization reaction is shown.

[0021] Fig.14 The proof of feasibility (POF) process of the deprotection reaction is shown.

[0022] Fig.15 An eco-friendly design approach for new synthetic pathways is shown.

[0023] FIG16 shows a comparison of the current synthetic pathway with another second generation synthetic pathway.

[0024] Fig.17 A new synthetic route avoiding the Chan-Lam coupling via late NHBoc introduction is shown.

[0025] Fig.18 The CH amination step of the late NHBoc-introducing synthetic pathway is shown.

[0026] Additional objects and advantages will be explained in part in the following description, and in part will be understood from the description, or may be learned through practice. Said objects and advantages will be realized and obtained by means of the elements and combinations particularly pointed out in the appended claims.

[0027] It should be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the scope of the patent claims.

[0028] The accompanying drawings and appendices, which are incorporated in and constitute a part of this specification, illustrate several embodiments and, together with the description, serve to explain the principles described herein. [Specific implementation method] definition

[0029] Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this disclosure and have the following meanings:

[0030] As used herein, "BTK inhibitor", "BTK inhibitor compound", "compound of formula (1)", "Compound 1" and "compound" refer to (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure: It is also known as 4-amino-3-(4-phenoxyphenyl)-1-[(3R)-1-(prop-2-enoyl)piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one and has the following structure: or a pharmaceutically acceptable salt thereof.

[0031] The present disclosure relates to methods for preparing compounds of formula (I): The method comprises: The compound of formula A-oxalate is reacted: To form a compound of formula (I), wherein the reaction conditions are selected from: (i) reacting a compound of formula A-oxalate with acryloyl chloride in the presence of diisopropylethylamine in toluene; or (ii) The compound of formula A-oxalate is reacted with 3-chloropropionic acid in the presence of potassium carbonate, diisopropylethylamine and propylphosphonic anhydride in dichloromethane, then with 1,8-diazabicyclo[5.4.0]undec-7-ene in hydrochloric acid and finally with sodium bicarbonate.

[0032] In some embodiments, the compound of formula A-oxalate is prepared by: making the compound of formula A: React with oxalic acid in a mixture of ethanol and water.

[0033] In some embodiments, the compound of formula A is prepared by: making a compound of formula 1-f: Reaction with Pd / C and methanesulfonic acid in ethanol.

[0034] In some embodiments, the compound of formula 1-f is prepared by: making the compound of formula 1-e: Reaction with allylamine in the presence of RuPhos Pd G2 and sodium tert-butoxide in dioxane.

[0035] In some embodiments, the compound of formula 1-e is prepared by: making the compound of formula 1-d: Reaction with carbonyldiimidazole in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in toluene.

[0036] In some embodiments, the compound of formula 1-d is prepared by: making the compound of formula 1-c: Reaction with 4-bromobiphenyl ether in the presence of Pd2(dba)3, DavePhos and sodium tert-butoxide in toluene.

[0037] In some embodiments, the compound of formula 1-c is prepared by: making the compound of formula 1-b: React with iron and ammonium chloride in a mixture of ethanol and water.

[0038] In some embodiments, the compound of formula 1-b is prepared by: making the compound of formula 1-a: Reaction with (3R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester in the presence of triethylamine in dimethylformamide.

[0039] In some embodiments, the compound of formula A is prepared by: making a compound of formula 2-d: Reaction with trifluoroacetic acid in dichloromethane.

[0040] In some embodiments, the compound of formula 2-d is prepared by: making the compound of formula 2-c: Reaction with Boc2O in the presence of 4-dimethylaminopyridine in dimethylformamide.

[0041] In some embodiments, the compound of formula 2-c is prepared by: making the compound of formula 2-b: With 4-bromobiphenyl ether in the presence of potassium carbonate, cesium carbonate, Pd2(dba)3 and BrettPhos in tert-amyl methyl ether.

[0042] In some embodiments, the compound of formula 2-b is prepared by: making the compound of formula 2-a: Reaction with Pd / C and H2 in ethyl acetate.

[0043] In some embodiments, the compound of formula 2-a is prepared by: making the compound of formula 1-b: Reaction with bis(4-methoxybenzyl)amine.

[0044] In some embodiments, the compound of formula 1-b is prepared by: making the compound of formula 1-a: Reaction with (R)-tert-butyl 3-aminopiperidine-1-carboxylate in the presence of triethylamine and HOBt in dimethylformamide.

[0045] In some embodiments, the compound of formula A is prepared by: making a compound of formula 3-h: Reaction with trifluoroacetic acid.

[0046] In some embodiments, the compound of formula 3-h is prepared by: making the compound of formula 3-e: With the compound of formula 3-g: It is reacted with N,O-bis(trimethylsilyl)acetamide in dioxane and then with zinc in acetic acid.

[0047] In some embodiments, the compound of formula 3-g is prepared by: making a compound of formula 3-f: Reaction with N-Boc-hydroxylamine in the presence of triethylamine in tetrahydrofuran.

[0048] In some embodiments, the compound of formula 3-e is prepared by: making the compound of formula 3-d: Reaction with 4-phenoxyphenylboronic acid in the presence of copper(II) acetate, 2,2'-bipyridine and cesium carbonate in dichloromethane.

[0049] In some embodiments, the compound of formula 3-d is prepared by: making the compound of formula 3-c: Reaction with carbonyldiimidazole in dimethylformamide.

[0050] In some embodiments, the compound of formula 3-c is prepared by: making the compound of formula 3-b: Reacts with iron and ammonium chloride in ethanol.

[0051] In some embodiments, the compound of formula 3-b is prepared by: making the compound of formula 3-a: Reaction with (R)-tert-butyl 3-aminopiperidine-1-carboxylate in the presence of triethylamine in dimethylformamide.

[0052] The present disclosure also relates to compounds selected from the group consisting of: or a salt thereof.

[0053] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" are interpreted as specifying the presence of the stated features or components mentioned, but do not exclude the presence or addition of one or more features or components or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples covered by the term "consisting of". Therefore, the term "consisting of" can be used to replace the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0054] The term "consisting of" means that the subject matter has at least 90%, 95%, 97%, 98%, or 99% of the stated features or components that make up it. In another embodiment, the term "consisting of" excludes any other features or components from the scope of any subsequent representation, except those features or components that are not essential to the technical effect to be achieved.

[0055] As used herein, the term "or" should be interpreted as an inclusive "or", meaning any one or any combination. Thus, "A, B or C" means any of the following: "A; B; C; A and B; A and C; B and C; A, B and C". An exception to this definition will only occur if a combination of elements, functions, steps or acts are inherently mutually exclusive to some extent.

[0056] In this specification, unless otherwise indicated, any concentration range, percentage range, ratio range or integer range should be understood to include the value of any integer within the range, and include their fractions (such as one tenth and one hundredth of an integer) when appropriate. In addition, unless otherwise indicated, any numerical range related to any physical feature (such as polymer subunits, size or thickness) described herein should be understood to include any integer within the range. As used herein, unless otherwise indicated, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value or structure.

[0057] It should be understood that, independent of stereoisomer or isotopic composition, each compound disclosed herein can be provided in the form of any pharmaceutically acceptable salt discussed herein. Likewise, it should be understood that the isotopic composition can vary independently of the stereoisomer composition of each compound mentioned herein. In addition, the isotopic composition, while limited to those elements present in the respective compounds disclosed herein or their salts, can also vary independently of the selection of the pharmaceutically acceptable salt of the respective compound.

[0058] It should be noted that if there is a discrepancy between a depicted structure and the name of the structure, more weight will be given to the depicted structure.

[0059] Although various features of the present invention may be described in the context of a single embodiment, these features may also be provided separately or in any suitable combination. Conversely, although for clarity, the present invention may be described herein in the context of multiple separate embodiments, the present invention may also be implemented in a single embodiment. Compound

[0060] In some embodiments, a compound or salt thereof is provided that is selected from the compounds in Table 1. Although certain compounds described in the present disclosure (including in Table 1) are presented in specific stereoisomeric and / or non-stereochemical forms, it is understood that any or all stereochemical forms (including any enantiomeric or diastereomeric forms) as well as any tautomeric or other forms of any compound of the present disclosure (including in Table 1) are described herein. Table 1. or a salt thereof. Examples

[0061] The following examples are presented by way of non-limiting illustration. The compounds are named using the automatic name generation tool provided in ChemBiodraw Ultra (Cambridgesoft), which generates systematic names for chemical structures and supports the Cahn-Ingold-Prelog rule for stereochemistry. Those skilled in the art can modify the procedures set forth in the illustrative examples to obtain the desired products.

[0062] Salts of the compounds described herein can be prepared by standard methods such as including an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification or stirring the product with an acid solution (e.g., HCl solution) following chromatographic purification.

[0063] The following abbreviations may be relevant to the application. abbreviation 2-Me-THF: 2-methyltetrahydrofuran ACN or MeCN: acetonitrile AcOK: Potassium acetate aq.: aqueous solution BSA: bis(trimethylsilyl)acetamide CDI: Carbonyldiimidazole d: day DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DEA: Diethanolamine DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: dimethylformamide EA, EtOAc or AcOEt: ethyl acetate equiv.: equivalent ESI: Electrospray ionization EtOH: ethanol h or hr: hours Hex: Hexane HOBt: Hydroxybenzotriazole HPLC: High Performance Liquid Chromatography LCMS: Liquid chromatography mass spectrometry MeOH: Methanol MTBE: Methyl tert-butyl ether PE: Petroleum ether sat.: saturated TAME: tert-amyl methyl ether TBSOTf: tert-butyl dimethylsilyl trifluoromethanesulfonate TEA: triethylamine TFA: trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin layer chromatography V: Volume per raw material (e.g. 10V solvent for 1 g of raw material = 10 mL) Example 1 General Path 1. General Path A - Example A Example S1.1 (R)-tert-Butyl 3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (1-b)

[0064] To a solution of 2,4-dichloro-3-nitropyridine (20 g, 0.10 mol) in DMF (100 mL) was added (3R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester (20.76 g, 0.10 mol) in DMF (100 mL) at 0 ° C. The mixture was stirred at 0 ° C for 1 h and then at 20 ° C for 12 h. TLC (CH2Cl2 / ethyl acetate=8 / 2) showed that the raw material was completely converted. LCMS showed that the required mass (ET44615-8-P1A1) was detected. The aqueous phase was extracted with ethyl acetate (200 mL*2). The combined organic phases were washed with water, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, CH2Cl2 / ethyl acetate=8 / 2). Compound 1-b (24 g, 67 mmol, 65% yield) was obtained as a yellow solid.

[0065] NMR and LCMS data were consistent with compound 1-b. Example S1.2 (R)-tert-Butyl 3-((3-amino-2-chloropyridin-4-yl)amino)piperidine-1-carboxylate (1-c)

[0066] Compound 1-b (20 g, 56 mmol), NH4Cl (14.99 g, 0.28 mol) and Fe (15.65 g, 0.28 mol, 5.00 equiv) were added to a mixture of EtOH (64 mL) and H2O (16 mL). The mixture was stirred at 70 ° C for 4 h. LCMS analysis confirmed that the raw material was completely converted. The mixture was filtered on diatomaceous earth and the residue was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Compound 1-c (19.3 g, 56 mmol, 100% yield) was obtained as a light brown solid.

[0067] The NMR data obtained are Figure 1 The spectrum shown in Figure 1 To.

[0068] LCMS data were consistent with compound 1-c. Example S1.3 (R)-tert-Butyl 3-((2-chloro-3-((4-phenoxyphenyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (1-d)

[0069] Compound 1-c (6.3g, 19mmol) and 4-bromodiphenyl ether (5.07mL, 29mmol) are dissolved in toluene (126mL). DavePhos (759mg, 1.93mmol) and Pd2(dba)3 (883mg, 0.96mmol) are added to the solution, followed by sodium tert-butoxide (3.71g, 0.39mol). The mixture is stirred at 100°C for 17h. LCMS analysis confirms that the raw material is completely converted. The mixture is filtered on diatomaceous earth and the organic layer is washed with water. The solvent is removed under vacuum and the product is purified by column chromatography (SiO2, CH2Cl2 / ethyl acetate=100 / 0 to 80 / 20) to obtain compound 1-d (3.60g, 7.3mmol, 38% yield) as a light brown solid.

[0070] Get as Figure 2 NMR data described in.

[0071] LCMS data were consistent with compound 1-d. Example S1.4. (R)-tert-Butyl 3-(4-chloro-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (1-e)

[0072] 1,8-diazabicyclo [5,4,0] undec-7-ene (1.09 mL, 7.27 mmol) was added to a mixture of compound 1-d (3.60 g, 7.27 mmol) and 1,1'-carbonyldiimidazole (2.36 g, 14.55 mmol) in toluene (36 mL). The mixture was stirred at 100 ° C for 4 h. TLC analysis (CH2Cl2 / ethyl acetate=8 / 2) confirmed that the raw material was completely converted. The residue was poured into water (40 mL) and the organic layer was separated and washed with water until pH=7. The solvent was removed under vacuum and compound 1-e (3.2 g, 6.1 mmol, 84.5% yield) was obtained as a light brown solid.

[0073] Get as Figure 3 NMR data as described in.

[0074] LCMS data were consistent with compound 1-e. Example S1.5. (R)-tert-Butyl 3-(4-(allylamino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (1-f)

[0075] To a mixture of compound 1-e (1g, 1.92mmol) and allylamine (6.49mL, 86.4mmol) in 1,4-dioxane (20V), RuPhosG2 (149mg, 0.19mmol) and sodium tert-butoxide (276.7mg, 2.88mmol) were added. The solution was sealed in a tube and stirred at 80°C for 24h. The mixture was filtered on diatomaceous earth and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and water, the organic layer was separated, and the crude solid was purified by column chromatography (SiO2, CH2Cl2 / ethyl acetate=100 / 0 to 80 / 20) and the compound 1-f (630mg, 1.2mmol, 61% yield) was separated as a yellow oil.

[0076] Get as Figure 4 NMR data as described in.

[0077] LCMS data were consistent with compound 1-f. Example S1.6. (R)-tert-Butyl 3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (A)

[0078] Methanesulfonic acid (84 μL, 1.29 mmol) was added to a mixture of compound 1-f (700 mg, 1.3 mmol) and Pd / C 10% (60 mg) in ethanol (35 mL). The solution was stirred at 80 ° C for 17 h. LCMS analysis (λ = 220 nm) confirmed that the raw material was completely converted. The mixture was filtered on diatomaceous earth and the solvent was removed under vacuum. The residue was dissolved in ethyl acetate and water, and after alkalization with NaOH, the organic layer was separated. The crude product was purified by column chromatography (SiO2, CH2Cl2 / ethyl acetate = 100 / 0 to 80 / 20) and the compound A (200 mg, 0.5 mmol, 38% yield) was separated as a beige solid.

[0079] The NMR data obtained are Figure 7 The spectrum shown in .

[0080] LCMS data were consistent with compound A. Example S1.7. (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((I))

[0081] The compound of formula (I) was prepared according to the procedure described in Example A. It can also be prepared according to the procedure described in Example B. Example 2 General Pathway 2. General Path B - Example B. Example S2.1 (R)-tert-Butyl 3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (1-b)

[0082] Compound 1-b can be prepared similarly as disclosed in US Pat. No. 9,688, 676. For example, compound 1-b can be prepared optionally in the presence of a HOBt catalyst.

[0083] NMR and LCMS data were consistent with compound 1-b. Example S2.2(R)-tert-Butyl 3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (2-a)

[0084] Compound 1-b can be prepared similarly as disclosed in US Pat. No. 9,688,676.

[0085] NMR and LCMS data were consistent with compound 2-a. Example S2.3(R)-tert-Butyl 3-((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (2-b)

[0086] Compound 2-b can be prepared similarly as disclosed in U.S. Pat. No. 9,688,676. For example, compound 2-b can be prepared as disclosed in U.S. Pat. No. 9,688,676, optionally using Pd / C and H2 in AcOEt instead of Fe in AcOH / MeOH.

[0087] Get as Figure 5 NMR data as described in.

[0088] LCMS data were consistent with compound 2-b. Example S2. tert-Butyl 4(R)-3-((2-(bis(4-methoxybenzyl)amino)-3-((4-phenoxyphenyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (2-c)

[0089] To a solution of compound 2-b (8.0 g, 14.6 mmol) in degassed tert-amyl methyl ether (TAME, 5 V) was added 4-bromobiphenyl ether (3.07 mL, 1.2 eq.), Pd2dba3 (669 mg, 5 mol%), BrettPhos (784 mg, 10 mol%), Cs2CO3 (1.43 g, 0.3 eq.) and K2CO3 (5.45 g, 2.7 eq.) under an inert nitrogen atmosphere. The mixture was stirred at reflux for 64 h to reach 96.5% conversion as measured by HPLC, then cooled to ambient temperature. Aqueous K2CO3 solution was added and the mixture was extracted by 3*10 V AcOEt. The organic phases were combined and washed with 2*10 V aqueous K2CO3 solution, 2*10 V H2O and 1*10 V brine, dried over Na2SO4 and concentrated under reduced pressure to give 13.4 g of compound 2-c, which was directly used in the next step.

[0090] Get as Figure 6 NMR data as described in.

[0091] LCMS data were consistent with compound 2-c. Example S2.5 (R)-tert-butyl 3-(4-(bis(4-methoxybenzyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (2-d)

[0092] After purification by silica gel chromatography, the desired compound was obtained using (Boc)2O in ACN; further laboratory experiments enabled its isolation from DMF by precipitation after addition of water. Prior to potential kilogram-scale synthesis, the choice of reagents and solvents, as well as the separation conditions, should be optimized. Protocol: To a solution of compound 2-c (14.6 mmol) in DMF (31.4 mL, 3V), (Boc)2O (7.02 g, 2.2 eq.) and DMAP (178.5 mg, 10 mol%) were added. When TLC indicated complete conversion, the mixture was stirred at 45°C for 4h. The mixture was cooled to 0°C and 6V H2O was added; the solid was filtered, redissolved in 3V DMF; 6V H2O was added at 0°C, the solid was filtered and dried under vacuum, redissolved in 5V DMF, and added to 15V H2O at 0°C. The solid was filtered, rinsed with 2*5V H2O and dried under vacuum to give 11 g of compound 2-d (70.8% purity, 71% corrected yield), which was directly used in the next step.

[0093] NMR and LCMS data were consistent with compound 2-d. Example S2.6 (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (A)

[0094] A solution of compound 2-d (6.0 g, purity 70.8%, 5.7 mmol) in trifluoroacetic acid (12 mL, 27.4 equiv) was stirred at ambient temperature under an inert nitrogen atmosphere for 36 h to achieve complete conversion as measured by HPLC. 10 V of saturated NaHCO3 aqueous solution was added. The reaction mixture was extracted with 3*10 V of DCM. The organic phases were combined and washed with 2*10 V of saturated NaHCO3 aqueous solution, then washed with 10 V of deionized water and concentrated by rotary evaporation to give compound A as a brown oil.

[0095] Get as Figure 7 NMR data as described in.

[0096] LCMS data were consistent with compound A. Example S2.7 (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((I))

[0097] The compound of formula (I) was prepared according to the procedure described in Example B. It can also be prepared according to the procedure described in Example A.

[0098] NMR and LCMS data were consistent with compound (I). Example 3 General Pathway 3. General Path B - Example B Example S3.1 (R)-tert-Butyl 3-((3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (3-b)

[0099] To a solution of compound 3-a (40.0 g, 252 mmol, 1.00 equiv) in DMF (250 mL) was added Et3N (38.3 g, 378 mmol, 52.7 mL, 1.50 equiv) at 0°C under N2. The reaction was stirred at 0°C for 10 min. A solution of (R)-tert-butyl 3-aminopiperidine-1-carboxylate (50.5 g, 252 mmol, 1.00 equiv) in DMF (250 mL) was added dropwise to the above solution at 0°C. The reaction was stirred at 20°C for 16 h. LC-MS showed that the starting material was completely consumed and a peak with the desired m / z was detected. The two reactions were combined for subsequent processing. The residue was poured into water (800 mL). The aqueous phase was extracted with ethyl acetate (300 mL*2). The combined organic phase was washed with brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. Compound 3-b (120 g, 349 mmol, 69.2% yield, 93.8% purity) was obtained as a yellow oil.

[0100] LCMS: RT=0.715min, M+1=323.2.

[0101] 1H NMR (400MHz, CDCl3) δ9.22(s,1H),8.30(d,J=6.0Hz,1H),8.20(d,J=6.8Hz,1H),6.81(s,2H),3.91.(s,1H), 3.61-3.66(m,2H),3.04-3.25(m,2H),2.05-2.07(m,1H),1.74-1.84(m,2H),1.45-1.47(m,1H),1.43(s,9H). Example S3.2 (R)-tert-Butyl 3-((3-aminopyridin-4-yl)amino)piperidine-1-carboxylate (3-c)

[0102] To a solution of compound 3-b (60.0 g, 186 mmol, 1.00 equiv) in EtOH (350 mL) was added Fe (51.9 g, 930 mmol, 5.00 equiv) at 35°C under N2. The reaction was stirred at 35°C for 10 min. Then, a solution of NH4Cl (49.8 g, 930 mmol, 5.00 equiv) in H2O (100 mL) was poured into the above solution at 35°C, and the mixture was heated at 60°C for 13 h. TLC (dichloromethane / methanol=5 / 1, R f =0.50) indicates that the raw material is completely consumed. The two reactions are combined for subsequent treatment. The residue is filtered on diatomaceous earth and washed with EtOH (3000mL). The filtrate is concentrated under vacuum. The solution is poured into water (1000mL). The aqueous phase is extracted with DCM (500mL*3). The combined organic phases are washed with brine (300mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by column chromatography (SiO2, dichloromethane / methanol=50 / 1 to 0 / 1). Compound 3-c (40.0g, 135mmol, 36.3% yield, 98.9% purity) is obtained as a light brown solid.

[0103] LCMS: RT=1.775min, M+1=293.1.

[0104] 1 H NMR (400MHz, CDCl3) δ9.22(s,1H),8.30(d,J=6.0Hz,1H),8.20(d,J=6.8Hz,1H),6.81(s,2H),3.91.(s,1H), 3.61-3.66(m,2H),3.04-3.25(m,2H),2.05-2.07(m,1H),1.74-1.84(m,2H),1.45-1.47(m,1H),1.43(s,9H). Example S3.3(R)-tert-Butyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (3-d)

[0105] To a solution of compound 3-c (20.0 g, 68.4 mmol, 1.00 equiv) in DMF (100 mL) was added CDI (13.3 g, 82.1 mmol, 1.20 equiv) at 20°C. The mixture was stirred at 20°C for 2 h. TLC (dichloromethane / methanol=5 / 1, R f =0.05) indicates that the raw material is completely consumed. The solution is poured into water (500mL). The aqueous phase is extracted with DCM (80.0mL*3). The combined organic phase is washed with brine (50.0mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue is purified by column chromatography (SiO2, dichloromethane / methanol=50 / 1 to 0 / 1). Compound 3-d (12.0g, 37.7mmol, 55.1% yield, 100% purity) is obtained as a light yellow solid.

[0106] LCMS: RT=1.753min, M+1=319.1.

[0107] 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),8.30(d,J=5.2Hz,1H),7.07(d,J=5.6Hz,1H),4.10-4.22(m,3H),3.40-3.46 (m,1H),2.77(s,1H),2.33-2.41(m,1H),2.00-2.03(m,1H),1.86-1.90(m,1H),1.62-1.70(m,1H),1.46(s,9H)

[0108] As shown in the Appendix, this step can also be achieved using H2 and Pd / C in ethyl acetate followed by (Boc)2O and DMAP. Example S3. tert-Butyl 4(R)-3-(2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (3-e)

[0109] Compound 3-d (9.80 g, 30.78 mmol, 1.00 equiv), copper (II) acetate (2.8 g, 15.39 mmol, 0.5 equiv), 2,2'-bipyridine (2.4 g, 15.39 mmol, 0.5 equiv), cesium carbonate (20.06 g, 61.56 mmol, 2 equiv) were added to DCM (196 mL). The mixture was stirred at 20 ° C under atmosphere and air flow for 1 h. Then, 4-phenoxyphenylboronic acid (14.82 g, 69.26 mmol, 2.25 equiv) was added. After one night, LCMS indicated that 13.8% of the starting material remained. Two days later, 34 g (117.7 mmol, 3.4 equiv) of 4-phenoxyphenylboronic acid was added to the mixture portionwise with copper (II) acetate (0,7 g, 3,85 mmol, 0.125 equiv) to complete the reaction. DCM (196mL) and water (98mL) are added to the mixture, and the organic layer is then extracted and washed with water (98mL). The organic layer is concentrated under reduced pressure to give a residue (40g). The residue is purified by column chromatography (SiO2, DCM / MeOH=100 / 0 to 98 / 2). Compound 3-e (9g, 18,49mmol, 60% yield) is obtained as a transparent brown solid.

[0110] NMR and LCMS data were consistent with compound 3-e. Example S3.5 tert-Butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate (3-g)

[0111] To a solution of compound 3-f (220.8 g, 1.66 mol, 1.1 eq.) and N-Boc-hydroxylamine (300.0 g, 1.51 mol, 1.0 eq.) in THF (3.0 L) was added dropwise Et3N (153.0 g, 1.51 mol, 1.0 eq.) at -20°C over 30 min. The mixture was stirred at -20°C for 10 min. TLC (petroleum ether / ethyl acetate=3 / 1, R fThe mixture was stirred for 2 hours at room temperature for 1 000 ℃ for 2 hours.Then, 4-nitropropene was added to 1% ethyl acetate (500 g, 1.42 mol, 47.11% yield, 84% purity) to obtain compound 3-g (500 g, 1.42 mol, 47.11% yield, 84% purity) as a yellow solid. The solid was purified by silica gel column chromatography (100-200 mesh, petroleum ether / ethyl acetate=50 / 1 to 0 / 1). The crude product was purified by recrystallization from a solution of ethyl acetate and petroleum ether (3V, 1 / 5) at 50 ° C to obtain compound 3-g (205 g, 682 mmol, 40.3% yield, 98.3% purity) as a white solid.

[0112] LCMS: RT=3.358min, M+23=318.0.

[0113] 1 H NMR (400MHz, CDCl3) δ8.19 (s, 1H), 1.54 (s, 9H). Example S3.6 (R)-tert-butyl 3-(4-((tert-butoxycarbonyl)amino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (3-h)

[0114] Anhydrous 1,4-dioxane (90 ml) was added to compound 3-e (3 g, 6.17 mmol, 1 eq.) and N, O-bis(trimethylsilyl)acetamide (3.76 g, 18.5 mmol, 3 eq.). The mixture was stirred at RT under an N2 atmosphere, and compound 3-g (2.73 g, 9.25 mmol, 1.5 eq.) was then added. The mixture was warmed at 80 °C for 8 h, during which compound 3-g (2.08 g, 7.05 mmol, 0.875 eq.) was added portionwise. After one night, LCMS indicated that 4.7% of the starting material remained. The reaction mixture was cooled at RT, and Zn (2.02 g, 30.83 mmol, 5 eq.) and glacial acetic acid (90 ml) were then added. After 2 h at RT, the mixture was filtered through diatomaceous earth.

[0115] NMR and LCMS data were consistent with compound 3-h. Example S3.7 (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (A)

[0116] TFA (15mL) was added to the obtained filtrate to complete the partial deprotection that had begun to occur. The reaction mixture was warmed at 80°C during 10h. LCMS indicated that acetamide derivatives were generated together with the desired product. Therefore, KOH / EtOH (1M, 45mL) was added to the mixture and warmed at 70°C (overnight, 8h) to recover the 2-amino function from the corresponding acetamide impurities. In order to eliminate some tarry substances, the mixture was filtered through diatomaceous earth. The obtained solution was concentrated. DCM (90mL) and water (60mL) were poured on the dry residue and the obtained organic layer was separated. The water layer was re-extracted with DCM (30mL) and the combined organic layer was washed twice with water (2*30mL). The HPLC title was able to estimate a yield of 17% in the organic layer. The organic layer was concentrated under reduced pressure to obtain a residue. The residue was purified twice by column chromatography (SiO2, DCM / MeOH=100 / 0 to 75 / 25). Compound A (60 mg, p=87%, 0.13 mmol, 2.4% yield) was obtained as a transparent brown solid.

[0117] LCMS data were consistent with compound A.

[0118] The NMR data obtained are Figure 7 The spectrum shown in . Example S3.7 (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (I)

[0119] The compound of formula (I) was prepared according to the procedure described in Example B. It can also be prepared according to the procedure described in Example A.

[0120] NMR and LCMS data were consistent with compound (I). Final Path - Example A. General Pathway A. Example SA.1 (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (A-oxalate)

[0121] To compound A dissolved in 16V EtOH, add oxalic acid (655mg, 1.3 equivalents) in 4V EtOH. The solution is stirred at 15°C for 2h and the solid is filtered out. The filter cake is washed with 2V EtOH and then with 2V MTBE. 2.7g A-oxalate (85% purity, 81.5% corrected yield) is obtained as a gray solid. 680mg (43.5% purity, 10.4% corrected yield) is filtered out for the second time (jet).

[0122] NMR and LCMS data were consistent with Compound A-oxalate salt. Example SA.2 (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((I))

[0123] Compound (I) can be prepared similarly as disclosed in US9688676B2. For example, as described in US9688676B2, compound (I) can be prepared by reacting compound A-oxalate with acryloyl chloride, optionally using DIPEA base in toluene instead of TEA in DCM / MeOH.

[0124] NMR and LCMS data were consistent with compound (I). Final Path - Example B. General pathway B. Example SB.1 (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (A-oxalate)

[0125] To compound A dissolved in 16V EtOH, add oxalic acid (655mg, 1.3 equivalents) in 4V EtOH. The solution is stirred at 15°C for 2h and the solid is filtered out. The filter cake is washed with 2V EtOH and then with 2V MTBE. 2.7g A-oxalate (85% purity, 81.5% corrected yield) is obtained as a gray solid. 680mg (43.5% purity, 10.4% corrected yield) is filtered out for the second time.

[0126] NMR and LCMS data were consistent with Compound A-oxalate salt. Example SB.2 (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (I)

[0127] Purified water (7.5 volumes) and K2CO3 (at least 3.0 equivalents) were added to compound A-oxalate (hydrate; corresponding to 1 equivalent of compound A) in DCM (12 volumes) at 20°C, and the reaction mixture was stirred for at least 2h. Then it was allowed to stand and the reaction mixture was separated. The organic layer was collected and washed 1-2 times with water (7.5 volumes) to obtain A-oxalate in DCM solution. The solution was concentrated to 12 volumes and mixed with DIPEA (4 equivalents) at 20°C. Then, a solution of 3-chloropropionic acid (1.05 equivalents) in DCM (2.3 volumes) and T3P (50% DCM solution, 1 equivalent) was added at 20°C. Compound B was formed in situ. Then, DBU (4 equivalents) was added to the reaction mixture at 30°C for at least 30min. And the resulting mixture was kept at 30°C for at least 2h. The organic layer was washed 3-5 times with HCl (1N, 10 volumes) at 20°C. Then, the organic layer was concentrated to 2.73 volumes and the temperature was adjusted to 35°C. Compound (I)-HCl seed (0.1 kg / kg) was added to the organic layer at 35°C and the temperature was maintained for at least 1h. Ethyl acetate (2 volumes) was then added and the temperature of 35°C was maintained for at least 1h. Then, the reaction mixture was cooled to 10°C and ACN (1.07 volumes) was added. The mixture was neutralized with NaHCO3. The mixture was cooled to 0°C. The resulting suspension was loaded in a filter-dryer and re-slurried with DCM (0.72 volumes) / AcOEt (0.63 volumes) / ACN (0.45 volumes) at 0°C. The solid was filtered, washed twice with AcOEt (1.8 volumes), and washed twice with ACN (1.8 volumes). The compound of the resulting formula (I) was dried at a maximum temperature of 50°C. The following elemental analyses were performed by Galbraith Laboratories: carbon, hydrogen, and nitrogen determination using a PerkinElmer 2400 Series II CHNS / O analyzer, and total halogen or total halide determination by potentiometric titration.

[0128] NMR and LCMS data were consistent with compound (I).

[0129] Additional Research: Additional research was conducted to improve the Figure 8A 10-step linear synthesis of the 2,3,4-aminopyridine ring system described in . The 10-step linear synthesis: with an overall 20% yield, several steps containing undesirable solvents, and a Chan Lam coupling step that was a challenge for scale-up. Therefore, although developmental studies successfully validated the industrial scale of the process, improved synthetic routes are still needed. Considering the negative environmental impact of solvents such as DMF-DMA, DMF, and CH2Cl2, the goal is to develop a more efficient and environmentally friendly process.

[0130] Therefore, the Fig. 9 The retrosynthetic scheme described in was used to identify the pathway to be improved. Based on this scheme, a second generation pathway was designed that bridged the N-1 intermediate with the N-7 intermediate of the current process, resulting in a 6-step synthesis as shown in Figure 10. The second generation pathway avoids the Chan Lam coupling step and instead introduces Fig.11 The three new steps described in the previous section are: Buchwald reaction, cyclization and deprotection.

[0131] like Fig.12 As described in , the feasibility proof (POF) process of the Buchwald reaction on a 100 g scale was explored. Different reaction conditions were tested using a design of experiments (DOE) screen. Fig.13 and Fig.14 The proof-of-concept process described in explored cyclization and deprotection reactions.

[0132] Explored Fig.15 The present invention relates to an eco-friendly method for a new synthetic route described in . The three steps in the new route are allowed to be carried out continuously without the need to purify intermediates. The catalyst % and ligand % are greatly reduced in the Buchwald reaction used (each is 1 mol%), and the Pd catalyst can be replaced by a Cu catalyst. Instead of dichloromethane, the deprotection step can be carried out in anisole (a greener solvent).

[0133] Another second generation pathway was designed that prepared the N-1 intermediate via a novel process that was more convergent and did not require palladium, as depicted in FIG16 .

[0134] New second-generation pathways can Fig.17 The Chan Lam coupling was bypassed by late NHBoc introduction as described in . High throughput screening studies confirmed that the aryl conjugation step can be achieved in high yields in the presence of copper catalysts. Fig.18 As described in , the CH amination step can be carried out in a regioselective manner by using highly activated pyrazine residues. Various reaction conditions were considered, with NsCl or TsCl activators, acetonitrile solvents, and saccharinamine alternatives being chosen as greener, more environmentally friendly options.

[0135] Although the present disclosure has been described in considerable detail by way of illustration and example for purposes of clarity of understanding, the description and example should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific literature cited herein are expressly incorporated herein by reference in their entirety.

Claims

1. A method for preparing a compound of formula (I): The method comprises: The compound of formula A-oxalate is reacted: To form a compound of formula (I), wherein the reaction conditions are selected from: (i) reacting a compound of formula A-oxalate with acryloyl chloride in the presence of diisopropylethylamine in toluene; or (ii) The compound of formula A-oxalate is reacted with 3-chloropropionic acid in the presence of potassium carbonate, diisopropylethylamine and propylphosphonic anhydride in dichloromethane, then with 1,8-diazabicyclo[5.4.0]undec-7-ene in hydrochloric acid and finally with sodium bicarbonate.

2. The method of claim 1, wherein the compound of formula A-oxalate is prepared by: making the compound of formula A: React with oxalic acid in a mixture of ethanol and water.

3. The method according to any one of claims 1 or 2, wherein the compound of formula A is prepared by: making a compound of formula 1-f: Reaction with Pd / C and methanesulfonic acid in ethanol.

4. The method of claim 3, wherein the compound of formula 1-f is prepared by: making the compound of formula 1-e: Reaction with allylamine in the presence of RuPhos Pd G2 and sodium tert-butoxide in dioxane.

5. The method of claim 4, wherein the compound of formula 1-e is prepared by: making the compound of formula 1-d: Reaction with carbonyldiimidazole in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene in toluene.

6. The method of claim 5, wherein the compound of formula 1-d is prepared by: making the compound of formula 1-c: Reaction with 4-bromobiphenyl ether in the presence of Pd2(dba)3, DavePhos and sodium tert-butoxide in toluene.

7. The method of claim 6, wherein the compound of formula 1-c is prepared by: making the compound of formula 1-b: React with iron and ammonium chloride in a mixture of ethanol and water.

8. The method of claim 7, wherein the compound of formula 1-b is prepared by: making the compound of formula 1-a: Reaction with (3R)-3-amino-piperidine-1-carboxylic acid tert-butyl ester in the presence of triethylamine in dimethylformamide.

9. The method of claim 1 or 2, wherein the compound of formula A is prepared by: making a compound of formula 2-d: Reaction with trifluoroacetic acid in dichloromethane.

10. The method of claim 9, wherein the compound of formula 2-d is prepared by: making the compound of formula 2-c: Reaction with Boc2O in the presence of 4-dimethylaminopyridine in dimethylformamide.

11. The method of claim 10, wherein the compound of formula 2-c is prepared by: making the compound of formula 2-b: With 4-bromobiphenyl ether in the presence of potassium carbonate, cesium carbonate, Pd2(dba)3 and BrettPhos in tert-amyl methyl ether.

12. The method of claim 11, wherein the compound of formula 2-b is prepared by: making the compound of formula 2-a: Reaction with Pd / C and H2 in ethyl acetate.

13. The method of claim 12, wherein the compound of formula 2-a is prepared by: making the compound of formula 1-b: Reaction with bis(4-methoxybenzyl)amine.

14. The method of claim 13, wherein the compound of formula 1-b is prepared by: making the compound of formula 1-a: Reaction with (R)-tert-butyl 3-aminopiperidine-1-carboxylate in the presence of triethylamine and HOBt in dimethylformamide.

15. The method of claim 1 or 2, wherein the compound of formula A is prepared by: making a compound of formula 3-h: Reaction with trifluoroacetic acid.

16. The method of claim 15, wherein the compound of formula 3-h is prepared by: making the compound of formula 3-e: With the compound of formula 3-g: It is reacted with N,O-bis(trimethylsilyl)acetamide in dioxane and then with zinc in acetic acid.

17. The method of claim 16, wherein the compound of formula 3-g is prepared by: making the compound of formula 3-f: Reaction with N-Boc-hydroxylamine in the presence of triethylamine in tetrahydrofuran.

18. The method of claim 16, wherein the compound of formula 3-e is prepared by: making a compound of formula 3-d: Reaction with 4-phenoxyphenylboronic acid in the presence of copper(II) acetate, 2,2'-bipyridine and cesium carbonate in dichloromethane.

19. The method of claim 18, wherein the compound of formula 3-d is prepared by: making a compound of formula 3-c: Reaction with carbonyldiimidazole in dimethylformamide.

20. The method of claim 19, wherein the compound of formula 3-c is prepared by: making the compound of formula 3-b: Reacts with iron and ammonium chloride in ethanol.

21. The method of claim 20, wherein the compound of formula 3-b is prepared by: making the compound of formula 3-a: Reaction with (R)-tert-butyl 3-aminopiperidine-1-carboxylate in the presence of triethylamine in dimethylformamide.

22. A compound selected from the group consisting of: or a salt thereof.

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