Method for producing trebranib

Abstract

An improved synthetic route for the production of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (Trebilchinib) is disclosed herein. Novel compounds used in the synthesis of (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one are also disclosed herein. 【Chemical 1】 TIFF2025520382000095.tif83170

Description

Technical Field

[0001] Structure:

Chemistry

Background Art

[0002] Compound (1) and its method of preparation are disclosed in Example 3 of U.S. Patent No. 9,688,676 B2, at columns 62, lines 8 - column 65, line 32, and column 67, lines 28 - column 69. The disclosed synthesis provides 100 mg of crude compound (1) that must be purified by column chromatography, resulting in 54.5 mg of purified compound (1), which is a loss of nearly 50% in yield. The disclosed synthesis involves 10 steps, some of which involve undesirable solvents and can result in large amounts of extra waste on a large scale.

[0003] One factor in the suitability of a compound as a therapeutic agent is whether the compound is amenable to synthesis in a manner that produces minimal waste products and impurities and is suitable for large-scale manufacture and isolation. This factor is often considered when evaluating the suitability of bench-scale processes for producing the greater amounts required for commercial production. Additionally, the environmental impact of the various reagents and conditions required for large-scale manufacture is an increasingly important factor. Summary of the Invention Means for Solving the Problems

[0004] The present disclosure is a method for preparing a compound of formula (I), comprising

Chemical formula

Chemical formula

[0005] The present disclosure also relates to a method for preparing a compound of formula A:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0006] The present disclosure further relates to

Chemical formula

Brief Description of the Drawings

[0007]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 17-1

Figure 18

Figure 18-1

Mode for Carrying Out the Invention

[0008] Additional objects and advantages will be partly apparent in the following description, partly understood from this description, or can be learned by practice. The objects and advantages will be realized and achieved by the elements and combinations specifically recited in the appended claims.

[0009] It should be understood that both the foregoing general description and the following detailed description are merely exemplary and explanatory and do not limit the scope of the claims.

[0010] The accompanying drawings and appendices incorporated herein and constituting a part of this specification illustrate several embodiments and, together with this description, serve to explain the principles described herein.

[0011] Detailed Description Definitions Unless otherwise specified, the following terms used in this specification and the claims are defined for the purposes of this disclosure and have the following meanings:

[0012] As used herein, "BTK inhibitor", "BTK inhibitor compound", "compound of formula (1)", "Compound 1", and "compound" refer to the following structure: [Chemical Formula] (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one having the following structure, which has the following structure: [Chemical Formula] 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 having the following structure or a pharmaceutically acceptable salt thereof.

[0013] The present disclosure relates to a method for preparing a compound of formula (I): [Chemical Formula] comprising reacting a compound of formula A-oxalate: Formula A-oxalate: [Chemical Formula] to form a compound of formula (I), wherein the reaction conditions are (i) reacting a compound of formula A-oxalate with acryloyl chloride in toluene in the presence of diisopropylethylamine; or (ii) React the compound of formula A-oxalate with 3-chloropropanoic acid in dichloromethane in the presence of potassium carbonate, diisopropylethylamine, and propylphosphonic anhydride, followed by reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene hydrochloride, and finally with sodium bicarbonate. Selected from.

[0014] In some embodiments, the compound of formula A-oxalate is of formula A:

Chemical formula

[0015] In some embodiments, the compound of formula A is of formula 1-f:

Chemical formula

[0016] In some embodiments, the compound of formula 1-f is of formula 1-e:

Chemical formula

[0017] In some embodiments, the compound of formula 1-e is of formula 1-d:

Chemical formula

[0018] In some embodiments, the compound of formula 1-d is of formula 1-c: [Chemistry] The compound of is prepared by reacting the compound of with 4-bromodiphenyl ether in toluene in the presence of Pd2(dba)3, DavePhos, and sodium tert-butoxide.

[0019] In some embodiments, the compound of formula 1-c is the compound of formula 1-b: [Chemistry] The compound of is prepared by reacting the compound of with iron and ammonium chloride in a mixture of ethanol and water.

[0020] In some embodiments, the compound of formula 1-b is the compound of formula 1-a: [Chemistry] The compound of is prepared by reacting the compound of with tert-butyl (3R)-3-amino-piperidine-1-carboxylate in dimethylformamide in the presence of triethylamine.

[0021] In some embodiments, the compound of formula A is the compound of formula 2-d: [Chemistry] The compound of is prepared by reacting the compound of with trifluoroacetic acid in dichloromethane.

[0022] In some embodiments, the compound of formula 2-d is the compound of formula 2-c: [Chemistry] The compound of is prepared by reacting the compound of with Boc2O in dimethylformamide in the presence of 4-dimethylaminopyridine.

[0023] In some embodiments, the compound of formula 2-c is the compound of formula 2-b: [Chemical formula] The compound of is prepared by reacting with 4-bromodiphenyl ether in tert-amyl methyl ether in the presence of potassium carbonate, cesium carbonate, Pd2(dba)3, and BrettPhos.

[0024] In some embodiments, the compound of formula 2-b is the compound of formula 2-a: [Chemical formula] The compound of is prepared by reacting with Pd / C and H2 in ethyl acetate.

[0025] In some embodiments, the compound of formula 2-a is the compound of formula 1-b: [Chemical formula] The compound of is prepared by reacting with bis(4-methoxybenzyl)amine.

[0026] In some embodiments, the compound of formula 1-b is the compound of formula 1-a: [Chemical formula] The compound of is prepared by reacting with tert-butyl (R)-3-aminopiperidine-1-carboxylate in dimethylformamide in the presence of triethylamine and HOBt.

[0027] In some embodiments, the compound of formula A is the compound of formula 3-h: [Chemical formula] The compound of is prepared by reacting with trifluoroacetic acid.

[0028] In some embodiments, the compound of formula 3-h is the compound of formula 3-e: [Chemical formula] The compound of [Chemical formula] is prepared by reacting the compound of

[0029] In some embodiments, the compound of Formula 3-g is the compound of Formula 3-f: [Chemical formula] which is prepared by reacting the compound of

[0030] In some embodiments, the compound of Formula 3-e is the compound of Formula 3-d: [Chemical formula] which is prepared by reacting the compound of

[0031] In some embodiments, the compound of Formula 3-d is the compound of Formula 3-c: [Chemical formula] which is prepared by reacting the compound of

[0032] In some embodiments, the compound of Formula 3-c is the compound of Formula 3-b: [Chemical formula] which is prepared by reacting the compound of

[0033] In some embodiments, the compound of Formula 3-b is the compound of Formula 3-a: [Chemical formula] The compound of is prepared by reacting it with tert-butyl (R)-3-aminopiperidine-1-carboxylate in dimethylformamide in the presence of triethylamine.

[0034] This disclosure also relates to [Chemical formula] a compound selected from or a salt thereof.

[0035] As used herein, the terms "comprising" and "including" can be used interchangeably. The terms "comprising" and "including" should be construed as specifying the presence of the described features or components as recited, but not precluding the presence or addition of one or more features, components, or groups thereof. In addition, the terms "comprising" and "including" are intended to include examples subsumed by the term "consisting of". As a result, the term "consisting of" can be used in place of the terms "comprising" and "including" to provide more specific embodiments of the present invention.

[0036] The term "consisting of" means that the subject has at least 90%, 95%, 97%, 98% or 99% of the described features or components of which it consists. In another embodiment, the term "consisting of" excludes any other features or components from any subsequent recited scope, except those that are not essential for the technical effect to be achieved.

[0037] As used herein, the term "or" should be interpreted to mean "or" including any one or any combination. Therefore, "A, B or C" does not mean 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 the combination of elements, functions, steps or acts is mutually exclusive in some way.

[0038] In this description, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value within the recited range and, where appropriate, its fractions (such as one-tenth and one-hundredth of an integer). Also, any number range recited in this specification regarding any physical characteristic such as polymer subunit, size, or thickness should be understood to include any integer within the recited range, unless otherwise indicated. As used herein, the terms "about" and "approximately" mean ±20%, ±10%, ±5% or ±1% of the indicated range, value, or structure, unless otherwise indicated.

[0039] Regardless of the stereoisomeric composition or isotopic composition, it is understood that each compound disclosed herein can be provided in any form of a pharmaceutically acceptable salt discussed herein. Similarly, it is understood that the isotopic composition can vary independently of the stereoisomeric composition of each compound referred to herein. Further, the isotopic composition is limited to those elements present in each compound or its salt disclosed herein, but otherwise can vary independently of the selection of pharmaceutically acceptable salts of each compound.

[0040] It should be noted that if there is a conflict between the illustrated structure and the name for that structure, the illustrated structure will be given more weight.

[0041] Although the various features of the present invention may be described in connection with a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present invention may be described herein in connection with separate embodiments for clarity, the present invention may also be implemented in a single embodiment.

[0042] Compound In some embodiments, a compound selected from the compounds of Table 1 or a salt thereof is provided. The specific compounds described in this disclosure, including those of Table 1, are presented as specific stereoisomers and / or in non-stereochemical forms, but any or all stereochemical forms, including any enantiomeric or diastereomeric forms, and any tautomers or other forms of the compounds of this disclosure, including those of Table 1, are contemplated herein.

[0043]

Table 1

[0044]

Table 2

[0045]

Table 3

[0046]

Table 4

Examples

[0047] The following examples are presented for purposes of illustration and not limitation. Compounds were named using the automatic name generation tool provided in ChemBioDraw Ultra (CambridgeSoft), which supports the Cahn-Ingold-Prelog rules for stereochemistry and generates systematic names for chemical structures. Those skilled in the art can modify the procedures described in the illustrative examples to arrive at the desired products.

[0048] Salts of the compounds described herein can be prepared by standard methods such as inclusion of an acid (e.g., TFA, formic acid, or HCl) in the mobile phase during chromatographic purification, or stirring of the product after chromatographic purification with a solution of an acid (e.g., aqueous HCl).

[0049] The following abbreviations may be relevant to this application. Abbreviation 2-Me-THF: 2-Methyltetrahydrofuran ACN or MeCN: Acetonitrile AcOK: Potassium acetate aq.: Aqueous 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: Hour 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-Butyldimethylsilyl triflate TEA: Triethylamine TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin Layer Chromatography V: Volume per starting material (e.g., 10V solvent per 1 g of starting material = 10 mL)

[0050] Example 1 General Route 1

Chemical Structure

Chemical Structure

[0051] Example S1.1 tert-Butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (1-b)

Chemical Structure

[0052] The NMR and LCMS data were consistent with compound 1-b.

[0053] Example S1.2 tert-butyl (R)-3-((3-amino-2-chloropyridin-4-yl)amino)piperidine-1-carboxylate (1-c)

Chemical formula

[0054] The obtained NMR data were consistent with the spectrum shown in Figure 1.

[0055] The LCMS data were consistent with compound 1-c.

[0056] Example S1.3 tert-Butyl (R)-3-((2-chloro-3-((4-phenoxyphenyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (1-d)

Chem.

[0057] NMR data as shown in Figure 2 were obtained.

[0058] The LCMS data was consistent with compound 1-d.

[0059] Example S1.4. tert-Butyl (R)-3-(4-chloro-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (1-e)

Chem.

[0060] NMR data as shown in Figure 3 were obtained.

[0061] The LCMS data was consistent with compound 1-e.

[0062] Example S1.5. tert-Butyl (R)-3-(4-(allylamino)-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (1-f)

Chemical formula

[0063] NMR data as shown in Figure 4 were obtained.

[0064] The LCMS data was consistent with compound 1-f.

[0065] Example S1.6. tert-Butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (A)

Chemical formula

[0066] The obtained NMR data was consistent with the spectrum shown in Figure 7.

[0067] The LCMS data was consistent with compound A.

[0068] 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)) The compound of formula (I) was prepared according to the procedure described in Example A. It could also be prepared according to the procedure described in Example B.

[0069] Example 2 General route 2.

Chemical formula

[0070] Example S2.1 tert-Butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (1-b) [Chemistry] Compound 1-b can be prepared in the same manner as disclosed in U.S. Patent No. 9,688,676. For example, compound 1-b can optionally be prepared in the presence of a HOBt catalyst.

[0071] The NMR and LCMS data were consistent with compound 1-b.

[0072] Example S2.2 tert-Butyl (R)-3-((2-(bis(4-methoxybenzyl)amino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (2-a) [Chemistry] Compound 1-b can be prepared in the same manner as disclosed in U.S. Patent No. 9,688,676.

[0073] The NMR and LCMS data were consistent with compound 2-a.

[0074] Example S2.3 tert-Butyl (R)-3-((3-amino-2-(bis(4-methoxybenzyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (2-b) [Chemistry] Compound 2-b can be prepared in the same manner as disclosed in U.S. Patent No. 9,688,676. For example, compound 2-b can be prepared by optionally using Pd / C and H2 in AcOEt instead of Fe in AcOH / MeOH as described in U.S. Patent No. 9,688,676.

[0075] NMR data as shown in Figure 5 were obtained.

[0076] The LCMS data were consistent with compound 2-b.

[0077] Example S2.4 tert-Butyl (R)-3-((2-(Bis(4-methoxybenzyl)amino)-3-((4-phenoxyphenyl)amino)pyridin-4-yl)amino)piperidine-1-carboxylate (2-c) [Chemical formula] To a solution of compound 2-b (8.0 g, 14.6 mmol) in degassed tert-amyl methyl ether (TAME, 5V) under an inert nitrogen atmosphere were added 4-bromodiphenyl ether (3.07 mL, 1.2 equiv), Pd2dba3 (669 mg, 5 mol%), BretPhos (784 mg, 10 mol%), Cs2CO3 (1.43 g, 0.3 equiv), and K2CO3 (5.45 g, 2.7 equiv). The mixture was stirred at reflux for 64 h to reach a conversion of 96.5% by HPLC and then cooled to ambient temperature. Aqueous K2CO3 solution was added, and the mixture was extracted with 3 × 10V of AcOEt. The organic phases were combined, washed with 2 × 10V of aqueous K2CO3, 2 × 10V of H2O, and 1 × 10V of brine, dried over Na2SO4, and concentrated under reduced pressure to give 13.4 g of compound 2-c, which was directly involved in the next step.

[0078] NMR data as shown in Figure 6 were obtained.

[0079] The LCMS data were consistent with compound 2-c.

[0080] Example S2.5 tert-Butyl (R)-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) [Chemical Formula] Using (Boc)2O in ACN, the expected compound was obtained after purification by silica gel chromatography; further laboratory attempts enabled its isolation from DMF by precipitation after water addition. The choice of reagents and solvents, along with the isolation conditions, should be optimized prior to potential multi-kilogram synthesis. Protocol: To a solution of compound 2-c (14.6 mmol) in DMF (31.4 mL, 3V) were added (Boc)2O (7.02 g, 2.2 eq) and DMAP (178.5 mg, 10 mol%). The mixture was stirred at 45 °C for 4 h, at which point TLC indicated complete conversion. The mixture was cooled to 0 °C and 6V of H2O was added; the solid was filtered, redissolved in 3V of DMF; 6V of H2O was added at 0 °C, the solid was filtered, dried under vacuum, redissolved in 5V of DMF, and added to 15V of H2O at 0 °C. The solid was filtered, washed with 2 × 5V of H2O, and dried under vacuum to give 11 g of compound 2-d (purity 70.8%, corrected yield 71%) which was used directly in the next step.

[0081] The NMR and LCMS data were consistent with compound 2-d.

[0082] 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) [Chemical Formula] A solution of compound 2-d (6.0 g, purity 70.8%, 5.7 mmol) in trifluoroacetic acid (12 mL, 27.4 eq) under an inert nitrogen atmosphere was stirred at ambient temperature for 36 h to reach complete conversion by HPLC. 10 V of saturated aqueous NaHCO3 was added. The reaction mixture was extracted with 3 × 10 V of DCM. The organic phases were combined, washed with 2 × 10 V of saturated aqueous NaHCO3, then washed with 10 V of deionized water, and concentrated by rotary evaporation to obtain compound A as a brown oil.

[0083] NMR data as shown in Figure 7 were obtained.

[0084] The LCMS data was consistent with compound A.

[0085] 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)) The compound of formula (I) was prepared according to the procedure described in Example B. It could also have been prepared according to the procedure described in Example A.

[0086] The NMR and LCMS data were consistent with compound (I).

[0087] Example 3 General route 3.

Chemical formula

Chemical formula

[0088] Example S3.1 tert-Butyl (R)-3-((3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (3-b)

Chemical formula

[0089] LCMS: RT = 0.715 min, M+1 = 323.2.

[0090] 1 H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 6.8 Hz, 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).

[0091] Example S3.2 tert-butyl (R)-3-((3-aminopyridin-4-yl)amino)piperidine-1-carboxylate (3-c)

Chemical formula

[0092] LCMS: RT = 1.775 min, M+1 = 293.1.

[0093] 1 1H NMR (400 MHz, CDCl3) δ 9.22 (s, 1H), 8.30 (d, J = 6.0 Hz, 1H), 8.20 (d, J = 6.8 Hz, 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).

[0094] Example S3.3 tert-Butyl (R)-3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (3-d)

Chemical formula

[0095] LCMS: RT = 1.753 min, M+1 = 319.1.

[0096] 1 H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 7.07 (d, J = 5.6 Hz, 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).

[0097] As shown in the appendix, this step could also be achieved using H2 and Pd / C in ethyl acetate, followed by (Boc)2O and DMAP.

[0098] Example S3.4 tert-Butyl (R)-3-(2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (3-e)

Chemical formula

[0099] The NMR and LCMS data were consistent with compound 3-e.

[0100] Example S3.5 tert-Butyl ((3-chloro-5,6-dicyanopyrazin-2-yl)oxy)carbamate (3-g) [Chemical formula] To a solution of compound 3-f (220.8 g, 1.66 mol, 1.1 equiv) and N-Boc-hydroxylamine (300.0 g, 1.51 mol, 1.0 equiv) in THF (3.0 L), Et3N (153.0 g, 1.51 mol, 1.0 equiv) was added dropwise at -20 °C over 30 min. The mixture was stirred at -20 °C for 10 min. TLC (petroleum ether / ethyl acetate = 3 / 1, R f(Product) = 0.46) indicated that the starting materials had been completely consumed. The two suspensions were filtered, and the filtrates were concentrated under vacuum to obtain residues. The residues were purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 0 / 1). Compound 3-g (500 g, 1.42 mol, yield 47.11%, purity 84%) was obtained as a yellow solid. The solid was purified again by column chromatography on silica gel (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, yield 40.3%, purity 98.3%) as a white solid.

[0101] LCMS: RT = 3.358 min, M+23 = 318.0.

[0102] 1 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 1.54 (s, 9H).

[0103] Example S3.6 tert-Butyl (R)-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)

Chemical Structure

[0104] The NMR and LCMS data were consistent with compound 3-h.

[0105] 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)

Chemical formula

[0106] The LCMS data was consistent with Compound A.

[0107] The obtained NMR data was consistent with the spectrum shown in Figure 7.

[0108] 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) The compound of formula (I) was prepared according to the procedure described in Example B. It could also have been prepared according to the procedure described in Example A.

[0109] The NMR and LCMS data were consistent with Compound (I).

[0110] Final Route - Example A. General Route A.

Chemical Structure

[0111] 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)

Chem.

[0112] The NMR and LCMS data were consistent with compound A-oxalate.

[0113] 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))

Chem.

[0114] The NMR and LCMS data were consistent with compound (I).

[0115] Final Route - Example B. General Route B.

Chem.

[0116] 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)

Chem.

[0117] The NMR and LCMS data were consistent with compound A-oxalate.

[0118] 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)

Chem.

[0119] The NMR and LCMS data were consistent with compound (I).

[0120] Additional Research: Additional research was conducted to improve the 10-step linear synthesis for preparing the 2,3,4-aminopyridine ring system as depicted in Figure 8. This 10-step linear synthesis had a total yield of 20%, several steps containing undesirable solvents, and a Chan Lam coupling step that was challenging to scale up. Therefore, although the development research had successfully demonstrated the industrial scale of this process, an improved synthetic route was needed. The objective was to develop a more efficient and environmentally friendly process as the environmental impact of solvents such as DMF-DMA, DMF, and CH2Cl2 was considered.

[0121] Accordingly, a retrosynthetic scheme as depicted in Figure 9 was prepared to identify a route for improvement. Based on this scheme, a second-generation route was devised that bridges the N-1 intermediate to the N-7 intermediate of the current process, resulting in a 6-step synthesis as shown in Figure 10. The second-generation route eliminated the Chan Lam coupling step and instead introduced three new steps as depicted in Figure 11: Buchwald reaction, cyclization reaction, and deprotection reaction.

[0122] The proof-of-feasibility (POF) process of the Buchwald reaction was examined on a 100 g scale as depicted in Figure 12. Various reaction conditions were tested using design of experiments (DOE) screening. The cyclization reaction and deprotection reaction were also examined through proof-of-concept processes as depicted in Figures 13 and 14.

[0123] An environmentally friendly approach was examined for the new synthetic route as depicted in Figure 15. The three steps of the new route enabled subsequent progression without intermediate purification. The Buchwald reaction used could dramatically reduce the % of the catalyst and the % of the ligand (1 mol% each) and the Pd catalyst could be replaced with a Cu catalyst. Instead of dichloromethane, the deprotection step could be carried out in anisole (a lower-pollution solvent).

[0124] As described in Figure 16, another second-generation route was devised to prepare the N-1 intermediate by a completely novel process that is more convergent and does not require palladium.

[0125] As shown in Figure 17, the novel second-generation route was able to bypass the Chan Lam coupling by late-stage NHBoc introduction. High-throughput screening studies confirmed that the aryl conjugation step could be achieved in high yield using a copper catalyst. The CH amination step could be carried out in a regioselective manner by using highly activated pyrazine residues as shown in Figure 18. Various reaction conditions were considered, selecting NsCl or TsCl activators, an acetonitrile solvent, and a saccharin amine surrogate as a more environmentally friendly option with lower environmental impact.

[0126] Although the present disclosure has been described in some detail by way of illustration and example for clarity of understanding, the description and examples should not be construed as limiting the scope of the invention. The disclosures of all patents and scientific documents cited herein are hereby expressly incorporated by reference in their entirety.

Claims

1. Formula (I): 【Chemistry 1】 1. A method for preparing a compound of formula (I), comprising: Formula B: 【Chemistry 2】 is reacted with a first base, followed by hydrochloric acid, in a first organic solvent to produce a compound of formula (I)-HCl: 【Transformation 3】 and reacting the compound of formula (I)-HCl with a second base in a second organic solvent to form the compound of formula (I).

2. 2. The method of claim 1, wherein the first base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), 7-methyltriazabicyclo[4.4.0]dec-5-ene (MTBD), or diisopropylethylamine (DIPEA).

3. 2. The method of claim 1, wherein the first base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).

4. 10. The method of claim 1, wherein the second base is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or sodium acetate.

5. 10. The method of claim 1, wherein the second base is sodium bicarbonate.

6. 2. The method of claim 1, wherein the first organic solvent and the second organic solvent are each independently methanol, ethanol, dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, chloroform, or a mixture thereof.

7. 7. The method of claim 6, wherein the first organic solvent is dichloromethane.

8. 7. The method of claim 6, wherein the second organic solvent is dichloromethane, ethyl acetate, acetonitrile, or a mixture thereof.

9. The compound of formula B has formula A - oxalate: 【Chemistry 4】 with a third base in a third organic solvent, followed by 3-chloropropanoic acid, an amide coupling reagent, and a fourth base in a third organic solvent.

10. 10. The method of claim 9, wherein the third base is sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, or sodium acetate.

11. 10. The method of claim 9, wherein the third base is potassium carbonate.

12. 10. The method of claim 9, wherein the amide coupling reagent is propanephosphonic anhydride (T3P), diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (HATU).

13. 10. The method of claim 9, wherein the amide coupling reagent is propanephosphonic anhydride (T3P).

14. 10. The method of claim 9, wherein the fourth base is diisopropylethylamine (DIPEA), N-methylmorpholine (NMM), diethanolamine, pyridine, or triethylamine (TEA).

15. 10. The method of claim 9, wherein the fourth base is diisopropylethylamine (DIPEA).

16. 10. The method of claim 9, wherein the third organic solvent is methanol, ethanol, dichloromethane, acetonitrile, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, cyclopentyl methyl ether, chloroform, or a mixture thereof.

17. 10. The method of claim 9, wherein the third organic solvent is dichloromethane.

18. The compound of formula A - oxalate salt has formula A: 【Transformation 5】 10. The method of claim 9, wherein the compound is prepared by a process comprising reacting the compound of formula (I) with oxalic acid in a mixture of a fourth organic solvent and water.

19. 19. The method of claim 18, wherein the fourth organic solvent is methanol, ethanol, acetonitrile, ethyl acetate, tetrahydrofuran, dioxane, or a mixture thereof.

20. 19. The method of claim 18, wherein the fourth organic solvent is ethanol.

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