Method for preparing benzimidazole derivative or salt thereof

Abstract

The present disclosure relates to a method for preparing a benzimidazole derivative or a salt thereof. Specifically, the present disclosure relates to a method for preparing methyl (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, which exhibits an excellent selectivity and yield.

Description

Preparation method of benzimidazole derivatives or their salts Technical Field

[0001] This disclosure belongs to the field of pharmaceutical technology and relates to a method for preparing benzimidazole derivatives. Background Technology

[0002] Glucagon-like peptide-1 (GLP-1) is an intestinal hypoglycemic hormone secreted by L-cells in the lower digestive tract. GLP-1 exerts its effects by binding to its widely distributed specific receptors. Organs where GLP-1 receptors are known to exist include pancreatic islet cells, gastrointestinal tract, lungs, brain, kidneys, hypothalamus, and cardiovascular system. GLP-1 receptors may also be present in the liver, adipose tissue, and skeletal muscle. GLP-1 not only acts on β-cells to promote insulin secretion but also acts on α-cells to inhibit glucagon secretion. Serum GLP-1 levels generally do not differ significantly among patients with normal glucose tolerance, impaired glucose tolerance, and type II diabetes. However, the β-cell response to GLP-1 after eating is defective, and under certain conditions, this response is significantly enhanced after continuous GLP-1 infusion. Because the duration of action of the body's own GLP-1 is very short (t1 / 2 < 1.5 minutes after intravenous injection), the body's own GLP-1 is not suitable for the clinical treatment of diabetes.

[0003] (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester Because the (S)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazol-6-carboxylic acid obtained after its hydrolysis is widely used as a key pharmacophore in small molecule GLP-1 receptor agonists. For example, WO2022007979A1 discloses a small molecule GLP-1 receptor agonist with the formula AA. Other existing technologies, such as WO2018109607A1, WO2019239319A1, and WO2022078152A1, all disclose small-molecule GLP1 receptor agonists containing the same pharmacophore. WO2018109607A1 discloses a method for preparing (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester.

[0004] This method requires an azide reaction to prepare (S)-oxetane-2-ylmethylamine, which poses high safety risks for industrial production. It also requires a precious metal catalyst to reduce the nitro group, resulting in poor performance in terms of cost control, environmental risk, and yield, which is not conducive to industrial production.

[0005] Another method for preparing (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester is disclosed in WO2024018395A1.

[0006] To avoid the selectivity issues associated with o-phenylenediamine alkylation, this method involves first hydrolyzing C106 to an acid, then condensing it with C105 via an amide reaction, followed by reduction of the carbonyl group to obtain C108, and finally synthesizing the final product. However, this method uses expensive raw materials, and the hydrolysis of C106 during the amidation reaction results in several low-yield steps and numerous side reactions, leading to a low overall yield. Summary of the Invention

[0007] This disclosure provides a method for preparing compound C or a salt thereof.

[0008] The method includes the step of reacting compound A with compound B in the presence of a base and a selective auxiliary to form compound C. in,

[0009] R1 is selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3;

[0010] R2 is selected from C 1-6 Alkyl group, optionally prefixed with one or more halogens, nitro groups, cyano groups, C6 groups, or C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted;

[0011] R3 is a leaving group.

[0012] In some implementations, R1 is selected from hydrogen, methyl, ethyl, methoxy, fluorine, and chlorine.

[0013] In some implementations, R1 is selected from methyl, ethyl, methoxy, fluorine, and chlorine.

[0014] In some implementations, R1 is selected from hydrogen.

[0015] In some implementations, n is 0.

[0016] In some embodiments, R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and trifluoromethyl.

[0017] In some implementations, R2 is selected from methyl.

[0018] In some implementations, R3 is selected from halogens or -OSO2R4, and R4 is selected from C. 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally converted to one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0019] In some implementations, R4 is selected from C 1-3 Alkyl, 6 to 10 aryl, said aryl group optionally coated with one or more halogens, C 1-6 Alkyl or C 1-6 Alkyl groups are substituted.

[0020] In some implementations, R4 is selected from methyl.

[0021] In some implementations, R4 is selected from trifluoromethyl.

[0022] In some embodiments, R4 is selected from phenyl, wherein the aryl group of the phenyl group is optionally substituted with one or more methyl, ethyl, isopropyl, fluorine, chlorine, bromine, or iodine groups.

[0023] In some implementations, R4 is selected from p-methylphenyl.

[0024] In some implementations, R3 is selected from bromine or iodine.

[0025] In some implementations, R3 is selected from methanesulfonic acid group, trifluoromethanesulfonic acid group, and p-toluenesulfonic acid group.

[0026] In some embodiments, the selective auxiliaries are selected from NaBr, NaI, LiBr, LiI, KBr, KI, tetrabutylammonium iodide, and tetrabutylammonium bromide.

[0027] In some embodiments, the selective additive is selected from LiI.

[0028] In some embodiments, the selective auxiliary is selected from NaI.

[0029] In some embodiments, the base is selected from organic bases.

[0030] In some embodiments, the organic base is selected from triethylamine and N,N-diisopropylethylamine.

[0031] In some embodiments, the base is selected from inorganic bases.

[0032] In some embodiments, the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, magnesium carbonate, and cesium carbonate.

[0033] In some embodiments, the base is selected from potassium carbonate.

[0034] In some embodiments, the base is selected from sodium carbonate.

[0035] In some embodiments, the molar ratio of compound A to compound B is 1:1 to 1:2, including but not limited to 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, or any value between any two numbers. In other embodiments, the molar ratio of compound A to compound B is 1:1 to 1:1.5.

[0036] In some embodiments, the molar ratio of compound A to compound B is 1:1.2.

[0037] In some embodiments, the molar ratio of compound A to the base is 1:2 to 1:4, including but not limited to 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, or any value between any two numbers. In some embodiments, the molar ratio of compound A to the base is 1:3 to 1:4. In other embodiments, the molar ratio of compound A to the base is 1:3.6.

[0038] In some embodiments, the molar ratio of compound A to potassium carbonate is 1:3.6. In some embodiments, the molar ratio of compound A to sodium carbonate is 1:3.6.

[0039] In some embodiments, the molar ratio of compound A to the selective adjuvant is 1:0.1 to 1:1, including but not limited to 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or any value between any two numbers. In other embodiments, the molar ratio of compound A to the selective adjuvant is 1:0.2.

[0040] In some embodiments, the molar ratio of compound A to LiI is 1:0.2. In some embodiments, the molar ratio of compound A to NaI is 1:0.2.

[0041] In some embodiments, the solvent used for the reaction of compound B is selected from dichloromethane, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0042] In some embodiments, the solvent used for the reaction of compound B is selected from N,N-dimethylformamide.

[0043] In some embodiments, the method for preparing compound C or a salt thereof includes the step of reacting compound A with compound B in the presence of a base to form compound C. R3 is selected from halogens, and R1, R2, and n are as defined above.

[0044] In some implementations, R3 is selected from bromine or iodine.

[0045] In some embodiments, the base is selected from sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, magnesium carbonate, and cesium carbonate.

[0046] In some embodiments, the alkali is selected from potassium carbonate and sodium carbonate.

[0047] In some embodiments, the molar ratio of compound A to the base is 1:2 to 1:4, including but not limited to 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, or any value between any two numbers. In some embodiments, the molar ratio of compound A to the base is 1:3 to 1:4. In other embodiments, the molar ratio of compound A to the base is 1:3.6.

[0048] In some embodiments, the molar ratio of compound A to sodium carbonate is 1:3.6.

[0049] In some embodiments, compound C is compound C-1, and the method for preparing compound C-1 or a salt thereof includes the step of reacting compound A-1 with compound B in the presence of a base and a selective auxiliary to generate compound C-1. R2 and R3 are defined as described above.

[0050] In some embodiments, compound B is compound B-1. The method for preparing compound C-1 or its salt includes the step of reacting compound A-1 and compound B-1 in the presence of a base and a selective auxiliary to generate compound C-1.

[0051] R2, alkali, and selective additives are defined as described above.

[0052] In some embodiments, compound C is compound C-2, and the method for preparing compound C-2 or a salt thereof includes the step of reacting compound A-2 with compound B in the presence of a base and a selective auxiliary to generate compound C-2.

[0053] Among them, R3, alkali, and selective additives are defined as described above.

[0054] In some embodiments, compound C is compound C-3, and the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 and compound B-2 in the presence of a base and a selective auxiliary to generate compound C-3.

[0055] Among them, R3, alkali, and selective additives are defined as described above.

[0056] In some embodiments, the method for preparing compound C-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in the presence of potassium carbonate and lithium iodide to generate compound C-3.

[0057] In some embodiments, the method for preparing compound C-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in the presence of sodium carbonate and sodium iodide to generate compound C-3.

[0058] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in a base to generate compound C-3.

[0059] R3 is selected from bromine or iodine, and the base is selected from potassium carbonate or sodium carbonate.

[0060] In some embodiments, compound B-2 is compound B-3. The method for preparing compound C-3 or its salt includes the step of reacting compound A-2 and compound B-3 in the presence of a base and a selective auxiliary to generate compound C-3.

[0061] In some embodiments, the method for preparing compound C-3 or a salt thereof includes the step of reacting compound A-2 and compound B-3 in the presence of potassium carbonate and lithium iodide to generate compound C-3.

[0062] In some embodiments, the method for preparing compound C-3 or a salt thereof includes the step of reacting compound A-2 with compound B-3 in the presence of sodium carbonate and sodium iodide to generate compound C-3.

[0063] In some embodiments, the method for preparing compound C-3 or its salts includes the step of reacting compound A-2 and compound B-3 in the presence of a base and a selective auxiliary to generate compounds C-3 and C'-3.

[0064] In some embodiments, the ratio of C-3 to C'-3 is generated from 6:1 to 10:1, including but not limited to 6:1, 7:1, 8:1, 9:1, 10:1, or any value between the two numbers. In some embodiments, the ratio of C-3 to C'-3 is 6:1. In some embodiments, the ratio of C-3 to C'-3 is 7:1. In some embodiments, the ratio of C-3 to C'-3 is 8:1. In some embodiments, the ratio of C-3 to C'-3 is 9:1.

[0065] In some embodiments, the method for preparing compound C-3 or its salts includes the step of reacting compound A-2 and compound B-3 in the presence of potassium carbonate and lithium iodide to generate compounds C-3 and C'-3.

[0066] In some embodiments, the method for preparing compound C-3 or its salts includes the step of reacting compound A-2 and compound B-3 in the presence of sodium carbonate and sodium iodide to generate compounds C-3 and C'-3.

[0067] This disclosure also provides a method for preparing compound E or a salt thereof.

[0068] The method includes the step of reacting compound A with compound B in the presence of a base and a selective auxiliary to form compound C. Where R1-R3, n are as described above.

[0069] In some embodiments, the method for preparing compound E or a salt thereof includes the step of reacting compound A with compound B in the presence of a base to form compound C. R3 is selected from bromine or iodine, and R1, R2, and n are as defined above.

[0070] In some embodiments, compound E is compound E-1. The method for preparing compound E-1 or its salt includes the step of reacting compound A-1 with compound B in the presence of a base and a selective auxiliary to generate compound C-1. R2 and R3 are defined as described above.

[0071] In some embodiments, the method for preparing compound E-1 or a salt thereof includes the step of reacting compound A-1 with compound B in the presence of a base to generate compound C-1. Among them, the base is selected from potassium carbonate or sodium carbonate, R3 is selected from bromine or iodine, and R2 is as defined above.

[0072] In some embodiments, compound B is compound B-1. The method for preparing compound E-1 or its salt includes the step of reacting compound A-1 and compound B-1 in the presence of a base and a selective auxiliary agent to generate compound C-1.

[0073] R2, alkali, and selective additives are defined as described above.

[0074] In some embodiments, compound E is compound E-2. The method for preparing compound E-2 or its salt includes the step of reacting compound A-2 with compound B in the presence of a base and a selective auxiliary to generate compound C-2.

[0075] Among them, R3, alkali, and selective additives are defined as described above.

[0076] In some embodiments, the method for preparing compound E-2 or a salt thereof includes the step of reacting compound A-2 with compound B in the presence of a base and a selective auxiliary to generate compound C-2, wherein the base is selected from potassium carbonate or sodium carbonate, and R3 is selected from bromine or iodine.

[0077] In some embodiments, compound E is compound E-3. The method for preparing compound E-3 or its salt includes the step of reacting compound A-2 and compound B-2 in the presence of a base and a selective auxiliary to generate compound C-3.

[0078] Among them, R3, alkali, and selective additives are defined as described above.

[0079] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in the presence of potassium carbonate and lithium iodide to generate compound C-2.

[0080] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in the presence of sodium carbonate and sodium iodide to generate compound C-2.

[0081] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 with compound B-2 in the presence of a base to generate compound C-3, wherein the base is selected from potassium carbonate or sodium carbonate, and R3 is selected from bromine or iodine.

[0082] In some embodiments, compound B-2 is compound B-3. The method for preparing compound E-3 or its salt includes the step of reacting compound A-2 and compound B-3 in the presence of a base and a selective auxiliary to generate compound C-3.

[0083] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 and compound B-3 in the presence of potassium carbonate and lithium iodide to generate compound C-3.

[0084] In some embodiments, the method for preparing compound E-3 or a salt thereof includes the step of reacting compound A-2 with compound B-3 in the presence of sodium carbonate and sodium iodide to generate compound C-3.

[0085] In some embodiments, the method for preparing compound E or a salt thereof further includes the step of reacting compound C with compound D in the presence of an acid to generate compound E. R1, R2, and n are as defined above.

[0086] In some embodiments, the acid is selected from p-toluenesulfonic acid, methanesulfonic acid, and trifluoroacetic acid.

[0087] In some embodiments, the acid is selected from trifluoroacetic acid.

[0088] In some embodiments, the molar ratio of compound C to acid is 1:0.1 to 1:1, including but not limited to 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, or any value between any two numbers. In other embodiments, the molar ratio of compound C to acid is 1:0.2.

[0089] In some embodiments, the molar ratio of compound C to trifluoroacetic acid is 1:0.2.

[0090] In some embodiments, the molar ratio of compound C to compound D is 1:0.8 to 1:2, including but not limited to 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1.2, or any value between the two. In some embodiments, the molar ratio of compound C to compound D is 1:1.5.

[0091] In some implementations, the solvent used for the reaction of compound C is selected from dichloromethane and tetrahydrofuran.

[0092] In some embodiments, the solvent used for the reaction of compound C is selected from tetrahydrofuran.

[0093] In some embodiments, compound E is compound E-1. The method for preparing compound E-1 or its salt also includes the step of reacting compound C-1 with compound D in the presence of an acid to generate compound E-1.

[0094] R2 is defined as described above.

[0095] In some embodiments, the method for preparing compound E-1 or a salt thereof further includes the step of reacting compound C-1 with compound D in the presence of trifluoroacetic acid to generate compound E-1.

[0096] In some embodiments, compound E is compound E-2. The method for preparing compound E-2 or its salt also includes the step of reacting compound C-2 with compound D in the presence of an acid to generate compound E-2.

[0097] In some embodiments, the method for preparing compound E-2 or a salt thereof further includes the step of reacting compound C-2 with compound D in the presence of trifluoroacetic acid to generate compound E-2.

[0098] In some embodiments, compound E is compound E-3. The method for preparing compound E-3 or its salt also includes the step of reacting compound C-3 with compound D in the presence of an acid to generate compound E-3.

[0099] In some embodiments, the method for preparing compound E-3 or a salt thereof further includes the step of reacting compound C-3 with compound D in the presence of trifluoroacetic acid to generate compound E-3.

[0100] Some implementation schemes provide methods for preparing compound E or its salts, including:

[0101] Step 1: Compound A reacts with compound B in the presence of a base and a selective auxiliary agent to produce compound C;

[0102] Step 2: Compound C reacts with compound D in the presence of acid to form compound E;

[0103] R1, R2, R3 and n are as defined above.

[0104] Some implementation schemes provide methods for preparing compound E or its salts, including:

[0105] Step 1: Compound A reacts with compound B in the presence of a base to produce compound C;

[0106] Step 2: Compound C reacts with compound D in the presence of acid to form compound E;

[0107] R3 is selected from bromine or iodine, and R1, R2 and n are as defined above.

[0108] Some implementations provide methods for preparing compound E-1 or its salts, including:

[0109] Step 1: Compound A-1 reacts with compound B-1 in the presence of a base and a selective auxiliary agent to generate compound C-1;

[0110] Step 2: Compound C-1 reacts with compound D in the presence of acid to form compound E-1;

[0111] R2 is defined as described above.

[0112] Some implementations provide methods for preparing compound E-2 or its salts, including:

[0113] Step 1: Compound A-2 reacts with compound B in the presence of a base and a selective auxiliary agent to produce compound C-2;

[0114] Step 2: Compound C-2 reacts with compound D in the presence of acid to form compound E-2;

[0115] R3 is defined as described above.

[0116] Some implementations provide methods for preparing compound E-2 or its salts, including:

[0117] Step 1: Compound A-2 reacts with compound B in the presence of a base to produce compound C-2;

[0118] Step 2: Compound C-2 reacts with compound D in the presence of acid to form compound E-2;

[0119] R3 is selected from bromine or iodine.

[0120] Some implementations provide methods for preparing compound E-3 or its salts, including:

[0121] Step 1: Compound A-2 reacts with compound B-3 in the presence of a base and a selective auxiliary agent to produce compound C-3;

[0122] Step 2: Compound C-3 reacts with compound D in the presence of acid to form compound E-3;

[0123] Some implementations provide methods for preparing compound E-3 or its salts, including:

[0124] Step 1: Compound A-2 and compound B-3 react in the presence of sodium carbonate and sodium iodide to produce compound C-3;

[0125] Step 2: Compound C-3 reacts with compound D in the presence of trifluoroacetic acid to generate compound E-3;

[0126] Some implementations provide methods for preparing compound E-3 or its salts, including:

[0127] Step 1: Compound A-2 reacts with compound B-2 in the presence of a base to produce compound C-3;

[0128] Step 2: Compound C-2 reacts with compound D in the presence of trifluoroacetic acid to generate compound E-2;

[0129] Among them, R 3 The base is selected from bromine or iodine, and the alkali is selected from potassium carbonate or sodium carbonate.

[0130] Some implementations provide methods for preparing compound E-3 or its salts, including:

[0131] Step 1: Compound A-2 and compound B-3 react in the presence of sodium carbonate and sodium iodide to produce compounds C-3 and C'-3;

[0132] Step 2: Compound C-3 reacts with compound D in the presence of trifluoroacetic acid to generate compound E-3.

[0133] In step 1, the ratio of C-3:C'-3 generated is greater than 90%.

[0134] Some implementations provide methods for preparing compound E-3 or its salts, including:

[0135] Step 1: Compound A-2 and compound B-3 react in the presence of potassium carbonate and lithium iodide to produce compounds C-3 and C'-3;

[0136] Step 2: Compound C-3 reacts with compound D in the presence of trifluoroacetic acid to generate compound E-3; wherein, the ratio of C-3:C'-3 generated in step 1 is greater than 90%.

[0137] This disclosure provides the use of the aforementioned method for preparing compound C and the aforementioned method for preparing compound E in the preparation of GLP-1 receptor agonists.

[0138] In some implementations, the GLP-1 receptor agonist is selected from, but is not limited to:

[0139] On the other hand, this disclosure also provides a method for preparing compound AA or a salt thereof, the method comprising the steps of the aforementioned method for preparing compound E.

[0140] In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound C described above. In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound C-2 described above. In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound C-3 described above. In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound E described above. In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound E-2 described above. In some embodiments, the method for preparing compound AA includes the steps of the method for preparing compound E-3 described above.

[0141] In some embodiments, the method for preparing the AA compound or a salt thereof includes the step of reacting compound h-2 with compound E-3 to form the AA compound. The reaction conditions and procedures are in accordance with WO2022007979, and the relevant content is incorporated herein for illustrative purposes.

[0142] The preparation method described in this disclosure further includes one or more steps of filtration, washing, drying, concentration or recrystallization.

[0143] Salts of the compounds / intermediates disclosed herein include, but are not limited to, addition salts of the free compounds / intermediates with acids or bases, wherein the acid used for salt formation includes, but is not limited to, hydrochloric acid or methanesulfonic acid. In some embodiments, the salts of the compounds / intermediates include, but are not limited to, hydrochloride salts, p-toluenesulfonate salts, methanesulfonate salts, or oxalate salts.

[0144] Terminology Definition

[0145] The terms "to form" and "to transform" do not specifically refer to a single-step transformation reaction between two substrates; they can be single-step or multi-step reactions between two substrates. If the intermediate contains a protecting group, the intermediate undergoes a step of deprotection before reacting with the corresponding substrate to obtain the target product.

[0146] The values ​​in this disclosure are instrument measurements and are subject to a certain degree of error. Generally, ±10% is within the reasonable error range. Of course, the context in which the value is used must be considered. For example, in the case of particle size of the active ingredient, where the measurement error variation does not exceed ±10%, the value can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, preferably ±5%.

[0147] In the chemical structure of the compounds described in this disclosure, the bonds... This indicates that the configuration is not specified; that is, if chiral isomers exist in the chemical structure, the bond... It can be Or simultaneously include Two configurations. For example, formula... Compounds can be represented by the formula or Or it may contain both of the aforementioned configurations.

[0148] "Alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms are also included. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and their various branched isomers. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be replaced at any usable connection point, preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C4 groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 6-membered cycloalkyl, or 3- to 6-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0149] The term "alkoxy" refers to -O- (alkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, and butoxy. Alkoxy groups can be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, oxo groups, cyano groups, amino groups, and C- groups. 1-6 Alkyl, C 1-6 Alkoxy, 3- to 7-membered cycloalkyl, or 3- to 7-membered heterocycloalkyl, wherein the alkyl, alkoxy, cycloalkyl, or heterocycloalkyl may optionally be substituted with halogen, hydroxyl, nitro, cyano, or amino.

[0150] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0151] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6- to 12-membered, such as phenyl and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl, or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, and non-limiting examples include:

[0152] The aryl group can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogen, hydroxyl, oxo, nitro, cyano, C 1-6Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 Alkyne group, 3- to 6-membered cycloalkoxy group, 3- to 6-membered heterocycloalkoxy group, C 3-8 Cycloalkenyloxy, 5- to 6-membered aryl or heteroaryl, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyloxy group, C 2-6 The alkynyl group, 3 to 6 cycloalkoxy group, 3 to 6 heterocycloalkoxy group, 3 to 8 cycloalkenyl group, 5 to 6 aryl group, or heteroaryl group may be selected from one or more halogens, hydroxyl groups, cyano groups, amino groups, C6 groups, etc. 1-6 Alkyl or C 1-6 Alkyl-substituted.

[0153] The term "heteroaryl" refers to a heteroaryl system comprising 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furanyl, thiophene, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrole, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazole, pyrazinyl, triazolyl, indazole, benzimidazolyl, etc. wait.

[0154] The heteroaryl ring may be fused to an aryl, heterocyclic alkyl, or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

[0155] The heteroaryl group can be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, independently selected from halogens, hydroxyl groups, cyano groups, amino groups, C4 groups, etc. 1-6 Alkyl or C 1-6 Alkyl group.

[0156] "Substitution" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms that are independently substituted by the corresponding number of substituents. Detailed Implementation

[0157] The present disclosure will be explained in more detail below with reference to embodiments or experimental examples. The embodiments or experimental examples in the present disclosure are only used to illustrate the technical solutions in the present disclosure and are not intended to limit the substance and scope of the present disclosure.

[0158] Test conditions of the instruments used in the experiment:

[0159] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ ohms. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), with tetramethylsilane (TMS) as the internal standard.

[0160] MS measurements were performed using an Agilent 1200 / 1290 DAD-6110 / 6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS), a waters ACQuity UPLC-QD / SQD system (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0161] High-performance liquid chromatography (HPLC) analysis was performed using an Agilent HPLC 1200DAD, an Agilent HPLC 1200VWD, and a Waters HPLC e2695-2489 HPLC system.

[0162] High performance liquid chromatography (HPLC) was performed using Waters 2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP, and Gilson-281 preparative chromatographs.

[0163] Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0164] Unless otherwise specified in the examples, all reactions can be carried out under an argon or nitrogen atmosphere.

[0165] Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.

[0166] In the examples, the reaction process was monitored using thin-layer chromatography (TLC). The volume ratio of the developing solvent used in the reaction, the eluent system used for column chromatography to purify the compound, and the developing solvent system for TLC were adjusted according to the different polarities of the compounds. Small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.

[0167] Example 1

[0168] first step

[0169] (S)-4-amino-3-((oxetane-2-ylmethyl)amino)methyl benzoate compound 1b

[0170] Methyl 3,4-diaminobenzoate (20 g, 120 mmol, 1.0 eq.) was dissolved in DMF (1 L, 0.12 M), and sodium carbonate (46 g, 434 mmol, 3.6 eq.) and sodium iodide (3.6 g, 24 mmol, 0.2 eq.) were added at room temperature. After heating the reaction to 60 °C, (S)-oxetane-2-ylmethyl-4-methylbenzenesulfonate (34.8 g, 144 mmol, 1.2 eq.) was slowly added. The reaction was stopped after the starting material disappeared as detected by TLC. HPLC results showed that the peak areas of 1b:1b' were 51.8%:5.6%. The reaction was quenched with 1 L of water, and the resulting mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to give compound 1b 19.8 g (70% yield, HLPC purity 97.8%).

[0171] Compound 1b 1 H NMR (400MHz, DMSO-d6) δ7.17(dd,J=8.1,1.9Hz,1H),7.04(d,J=1.9Hz,1H),6.56(d,J=8.1Hz,1H),5.46(s,2H),4.94–4.90(m,1H),4.69(t,J=5.7 Hz,1H),4.57-4.51(m,1H),4.50-4.46(m,1H),3.73(s,3H),3.37-3.25(m ,2H),2.70-2.63(m,1H),2.48-2.43(m,1H).LC-MS(ESI):[M+H]*=237.1.

[0172] Compound 1b' 1 H NMR (400MHz, CDCl3) δ7.57(dd,J=8.4,2.0Hz,1H),7.41(d,J=2.0Hz,1H),6.62(d,J=8.4Hz,1H),5.14–5.06(m,1H),4.78–4.70 (m,1H),4.63–4.55(m,1H),3.85(s,3H),3.51–3.37(m,2H),2.79–2.69(m,1H),2.61–2.52(m,1H).LC-MS(ESI):[M+H]*=237.2.

[0173] Step 2

[0174] (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester compound 1

[0175] Compound 1b (8 g, 34 mmol, 1.0 eq.) was added to THF (80 mL), followed by the addition of 2-chloro-1,1,1-trimethoxyethane (7.85 g, 50.9 mmol, 1.5 eq.) and dropwise addition of 7.7 g of p-toluenesulfonic acid (1.16 g, 6.75 mmol, 0.2 eq.) at room temperature. The system was heated to 40 °C and stirred for 6 h. After the starting material disappeared as detected by TLC, 500 mL of water was added and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give compound 1 (7.93 g, 81% yield).

[0176] 1 H NMR (400MHz, DMSO-d6) δ8.34(d,J=1.1Hz,1H),7.86(dd,J=8.5&1.5Hz,1H),7.72(d,J=8.5Hz,1H),5.10(m,3H) ,4.75(m,1H),4.63(dd,J=15.5&2.7Hz,1H),4.45(m,1H),4.31(m,1H),3.87(s,3H),2.69(m,1H),2.37(m,1H).

[0177] Example 2

[0178] first step

[0179] Methyl 3,4-diaminobenzoate (20 g, 120 mmol, 1.0 eq.) was dissolved in DMF (1 L, 0.12 M), and potassium carbonate (60 g, 434 mmol, 3.6 eq.) and lithium iodide (3.2 g, 24 mmol, 0.2 eq.) were added at room temperature. After heating the reaction to 60 °C, (S)-oxetane-2-ylmethyl-4-methylbenzenesulfonate (34.8 g, 144 mmol, 1.2 eq.) was slowly added. After the starting material disappeared as detected by TLC, 1 L of water was added to quench the reaction. The resulting mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 1b 11.3 g, in 40% yield.

[0180] Example 3

[0181] Methyl 3,4-diaminobenzoate (20 g, 120 mmol, 1.0 eq.) was dissolved in DMF (1 L, 0.12 M), and sodium bicarbonate (40 g, 480 mmol, 4 eq.) was added at room temperature. After heating the reaction to 60 °C, (S)-oxetane-2-ylmethyl-4-methylbenzenesulfonate (34.8 g, 144 mmol, 1.2 eq.) and sodium iodide (5.4 g, 36 mmol, 0.3 eq.) were slowly added. After the starting material disappeared as detected by TLC, 1 L of water was added to quench the reaction. The resulting mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 1b 17.2 g, with a yield of 61%.

[0182] Example 4

[0183] first step

[0184] Methyl 3,4-diaminobenzoate (20 g, 120 mmol, 1.0 eq.) was dissolved in DMAc (1 L, 0.12 M), and sodium carbonate (46 g, 434 mmol, 3.6 eq.) was added at room temperature. The reaction was heated to 50 °C, and (S)-2-iodomethyl-oxetane (34.8 g, 144 mmol, 1.2 eq.) was slowly added. The reaction was stopped after the starting material disappeared as detected by TLC. The reaction was quenched with 1 L of water, and the resulting mixture was extracted with ethyl acetate (2 × 200 mL). The combined organic phases were concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography to give compound 1b 22.7 g, in 80% yield.

[0185] Step 2

[0186] (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester compound 1

[0187] Compound 1b (8 g, 34 mmol, 1.0 eq.) was added to 80 mL of THF, followed by the addition of 7.85 g, 50.9 mmol, 1.5 eq. of 2-chloro-1,1,1-trimethoxyethane and dropwise of 7.7 g of trifluoroacetic acid (0.77 g, 6.75 mmol, 0.2 eq.) at room temperature. The system was heated to 40 °C and stirred for 6 h. After the starting material disappeared as detected by TLC, 500 mL of water was added and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give 9.02 g of compound 1 (90% yield).

[0188] Example 5

[0189] first step

[0190] Methyl 3,4-diaminobenzoate (20 g, 120 mmol, 1.0 eq.) was dissolved in DMF (1 L, 0.12 M), and potassium carbonate (50 g, 360 mmol, 3 eq.) was added at room temperature. After heating the reaction to 60 °C, (S)-2-bromomethyloxetane (21.7 g, 144 mmol, 1.2 eq.) was slowly added. After the starting material disappeared as detected by TLC, 1 L of water was added to quench the reaction. The resulting mixture was extracted with ethyl acetate (2 × 200 mL), and the combined organic phases were concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography to give compound 1b 13.3 g, with a yield of 47%.

[0191] Step 2

[0192] Compound 1b (8 g, 34 mmol, 1.0 eq.) was added to acetonitrile (80 mL), followed by the addition of 2-chloro-1,1,1-trimethoxyethane (7.85 g, 50.9 mmol, 1.5 eq.) and dropwise addition of 7.7 g of trifluoroacetic acid (0.77 g, 6.75 mmol, 0.2 eq.) at room temperature. The system was heated to 40 °C and stirred for 6 h. After the starting material disappeared as detected by TLC, 500 mL of water was added and the mixture was extracted with dichloromethane. The organic phase was concentrated under reduced pressure to obtain the crude product, which was then purified by column chromatography to give compound 1 (8.52 g, 85% yield).

Claims

1. A method for preparing compound C or its salt, The method includes the step of reacting compound A with compound B in the presence of a base and a selective auxiliary to form compound C. in, R1 is selected from hydrogen, halogen, amino, hydroxyl, cyano, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl or alkoxy group is optionally oxidized by one or more halogens, nitro groups, cyano groups, C6 groups, or C4 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted, and n is 0, 1, 2 or 3; R2 is selected from C 1-6 Alkyl group, optionally prefixed with one or more halogens, nitro groups, cyano groups, C6 groups, or C7 groups. 1-6 Alkyl or C 1-6 Alkyl groups are substituted; R3 is a leaving group.

2. The method according to claim 1, wherein the selective auxiliary is selected from NaBr, NaI, LiBr, LiI, KBr, KI, tetrabutylammonium iodide, tetrabutylammonium bromide, preferably NaI.

3. The method according to claim 1 or 2, wherein the base is selected from sodium bicarbonate, potassium bicarbonate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, potassium carbonate, sodium carbonate, magnesium carbonate, cesium carbonate, triethylamine, N,N-diisopropylethylamine, preferably potassium carbonate or sodium carbonate, and more preferably sodium carbonate.

4. The method according to any one of claims 1-3, wherein R1 is selected from hydrogen, halogen, C 1-6 Alkyl group, preferably hydrogen.

5. The method according to any one of claims 1-4, wherein R2 is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, and trifluoromethyl.

6. The method according to any one of claims 1-5, wherein R3 is selected from halogens or -OSO2R4, and R4 is selected from C. 1-6 Alkyl, 6- to 10-membered aryl, or 5- to 10-membered heteroaryl, wherein the alkyl, aryl, or heteroaryl group is optionally converted to one or more halogens, hydroxyl groups, nitro groups, cyano groups, or C6 groups. 1-6 Alkyl or C 1-6 Alkoxy groups are substituted, preferably halogens, -OTs, -OTf, -OMs, and more preferably iodine and -OTs.

7. The method according to any one of claims 1-6, wherein compound C is compound C-3.

8. A method for preparing compound E or its salt, The method includes the method according to any one of claims 1-7.

9. The method according to claim 8, further comprising the step of reacting compound C with compound D in the presence of an acid to generate compound E. R1, R2, and n are defined as in claim 1.

10. The method according to claim 9, wherein the acid is selected from p-toluenesulfonic acid, citric acid, methanesulfonic acid, trifluoroacetic acid, preferably trifluoroacetic acid.

11. The method according to any one of claims 8-10, wherein compound E is compound E-1.

12. A method for preparing compound E, comprising the following steps: Step 1: Compound A reacts with compound B in the presence of a base and a selective auxiliary agent to produce compound C, and; Step 2: Compound C reacts with compound D in the presence of acid to form compound E. R1, R2, R3 and n are defined as in claim 1.

13. A method for preparing (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid methyl ester, comprising the following steps: Step 1: Methyl 3,4-diaminobenzoate and (S)-oxetane-2-ylmethyl4-methylbenzenesulfonate are reacted in the presence of sodium carbonate and sodium iodide to generate methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate. Step 2: Methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate reacts with 2-chloro-1,1,1-trimethoxyethane in the presence of trifluoroacetic acid to generate methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazolium-6-carboxylic acid.

14. A method for preparing compound AA, said method comprising the steps of the method according to any one of claims 1-13.

15. Use of the preparation method according to any one of claims 1-13 in the preparation of GLP-1 receptor agonists.

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