Method for preparing sulfonylurea derivative

Abstract

The present disclosure relates to a method for preparing a sulfonylurea derivative. Specifically, the present disclosure relates to a method for preparing a compound represented by formula (I), comprising the step of preparing the compound represented by formula (I) from a compound represented by formula (II) in the presence of LiOtBu. The method has a high yield and mild reaction conditions and thus is suitable for industrial production.

Description

A preparation method of sulfonylurea derivatives Technical Field

[0001] The present invention belongs to the field of medicine and relates to a method for preparing a sulfonylurea derivative. Background Art

[0002] Cerebral stroke, also known as "stroke" or "cerebral vascular accident" (CVA), is an acute cerebrovascular disease. It is a group of diseases caused by the sudden rupture of a cerebral blood vessel or the inability of blood to flow to the brain due to blood vessel blockage, resulting in brain tissue damage. It includes ischemic and hemorrhagic strokes. The incidence of ischemic stroke is higher than that of hemorrhagic stroke, accounting for 60% to 70% of all strokes. Occlusion and stenosis of the internal carotid artery and vertebral artery can cause ischemic stroke. It mostly affects people over 40 years old and is more common in men than women. Severe cases can cause death. Hemorrhagic stroke has a higher mortality rate. Surveys show that stroke has become the leading cause of death in my country in both urban and rural areas combined and is the leading cause of disability among Chinese adults. Stroke is characterized by high morbidity, mortality, and disability rates.

[0003] The most common cause of stroke is a small embolus on the inner wall of a blood vessel supplying the brain, which can break off and cause arterial embolism, an ischemic stroke. It can also be caused by bleeding into a cerebral vessel or thrombosis, a hemorrhagic stroke. Patients with coronary artery disease and atrial fibrillation are prone to mural thrombosis of the heart valves. If this embolus breaks off, it can block cerebral blood vessels and cause an ischemic stroke. Other contributing factors include hypertension, diabetes, and hyperlipidemia.

[0004] In 2018, the biopharmaceutical company Biogen evaluated BIIB093 (intravenous glyburide) in a Phase III clinical study for the prevention and treatment of severe cerebral edema in patients with massive cerebral infarction (LHI). LHI is one of the most severe types of stroke. An estimated 1.7 million ischemic strokes occur annually in the three major pharmaceutical markets of the United States, the European Union, and Japan, of which approximately 15% are classified as LHI. Glyburide is a sulfonylurea antidiabetic drug that acts on the ATP-sensitive potassium channel of pancreatic beta cells, directly stimulating insulin secretion. It has a strong glucose-lowering effect and is currently one of the most widely used oral antidiabetic drugs in clinical practice. BIIB093 is a high-affinity inhibitor of the SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential ion channel protein 4) channel, which is upregulated after ischemia and trauma. Opening of these channels can lead to cerebral edema, midline shift, increased intracranial pressure, and brain herniation, resulting in permanent disability or death. BIIB093 is an investigational drug being developed for the prevention and treatment of severe cerebral edema caused by LHI.

[0005] WO2022012666 relates to a series of new sulfonylurea derivatives, among which the compound represented by formula (I) has good activity and its structure is shown below: Summary of the Invention

[0006] The purpose of the present disclosure is to provide a novel method for preparing sulfonylurea derivatives.

[0007] The present disclosure provides a method for preparing a compound represented by formula (I), comprising the steps of preparing a compound represented by formula (I) from a compound represented by formula (II) in the presence of LiOtBu.

[0008] wherein R1 is each independently selected from halogen, C1-C6 alkoxy optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, hydroxyl, carboxyl and cyano;

[0009] R2 is each independently selected from halogen, C1-C6 alkoxy optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, hydroxyl and

[0010] R3 are each independently selected from C1-C6 alkyl, phenyl,

[0011] m is an integer selected from 0 to 5;

[0012] n is an integer selected from 0-10.

[0013] In some embodiments, the reactants in the step further include a compound represented by formula (III),

[0014] Wherein R2 is as defined above, R4 is selected from -NCO or

[0015] In some embodiments, the molar ratio of the compound represented by formula (II) to LiOtBu is 1:0.5-1:5, including but not limited to 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, for example 1:1-1:3.

[0016] The solvent used in the reaction described in the present disclosure can be a conventional solvent, such as one or more of dimethylformamide, 1-methyl-2-pyrrolidone, dimethyl sulfoxide, tetrahydrofuran, ethyl acetate, dioxane, toluene, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane, chloroform, acetone, acetonitrile, methanol, ethanol, isopropanol, water, and in some embodiments, dimethylformamide or dimethyl sulfoxide.

[0017] The reaction temperature described in the present disclosure is -10-100°C, such as 0-50°C, or 0-30°C.

[0018] In some embodiments, the compound represented by formula (II) is

[0019] The compound represented by formula (I)

[0020] In some embodiments, the compound represented by formula (II) is

[0021] The compound represented by formula (I)

[0022] In some embodiments, the compound represented by formula (III) is

[0023] In some embodiments, the residual amount of the compound of formula (II) at the end of the reaction is less than 2% of the input amount, for example, less than 1%, or less than 0.5%. The end of the reaction refers to the time when the content of the compound of formula (II) in the reaction system no longer decreases with the extension of the reaction time.

[0024] The compound represented by formula (II) has similar properties to the compound represented by formula (I), and it is difficult to completely separate the two using conventional purification methods (such as recrystallization or column chromatography). Therefore, it is undesirable to have a large amount of compound represented by formula (II) remaining at the end of the reaction. The preparation method disclosed herein allows for a more complete reaction, with minimal residual reactants, facilitating post-reaction processing and improving the quality of the final product.

[0025] The "alkyl group" described in the present disclosure is preferably a C1-C6 alkyl group.

[0026] The "alkoxy group" described in the present disclosure is preferably a C1-C6 alkoxy group.

[0027] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0028] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. 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, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0029] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, substituents are preferably one or more following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic radical, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0030] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0031] "Carboxyl protecting group" is a suitable group for protecting carboxyl group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th Ed.TWGreene & P.GMWuts) in the carboxyl protecting group, as an example, the carboxyl protecting group can be a substituted or unsubstituted C 1-10 Straight or branched alkyl, substituted or unsubstituted C 2-10 Straight-chain or branched alkenyl or alkynyl, substituted or unsubstituted C 3-8 Cyclic alkyl, substituted or unsubstituted C 5-10 aryl or heteroaryl, or (C 1-8 alkyl or aryl)3 silyl, etc.

[0032] "Amino protecting group" is a suitable amino protecting group known in the art, see the literature ("Protective Groups in Organic Synthesis", 5 Th .Ed.TWGreene & P.GMWuts) in the amino protecting group, preferably, the amino protecting group can be (C 1-10 Alkyl or aromatic) acyl, for example: formyl, acetyl, benzoyl, etc.; can be (C 1-6 Alkyl or C 6-10 aryl)sulfonyl; can also be (C 1-6 Alkoxy or C 6-10 It can also be a substituted or unsubstituted alkyl group, such as trityl (Tr), 2,4-dimethoxybenzyl (DMB), p-methoxybenzyl (PMB) or benzyl (Bn).

[0033] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0034] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, i.e. if there are configurational isomers in the chemical structure, the bond Can be or include both Two configurations. In the chemical structure of the compound disclosed in the present invention, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations. DETAILED DESCRIPTION

[0035] The present disclosure will be explained in detail below with reference to specific examples so that those skilled in the art can have a more comprehensive understanding of the present disclosure. The specific examples are only used to illustrate the technical solutions of the present disclosure and do not limit the present disclosure in any way.

[0036] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0037] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0038] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0039] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0040] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0041] The method for detecting the content of the reaction system sample can be: LCMS system, its detection column is Welch Xtimate C18 (4.6*50mm*5um), the mobile phase is FA / ACN / H2O, and the detection wavelength is 214nm.

[0042] The sample purity can be detected by Agilent 1260, with a detection column of Xtimate 3um*4.6mm*150mm, a mobile phase of TFA / ACN / H2O, and a detection wavelength of 220nm.

[0043] LiOtBu is lithium tert-butoxide, CAS: 1907-33-1

[0044] t BuOK is potassium tert-butoxide, CAS: 865-47-4

[0045] Example 1

[0046] Step 1: Preparation of 5-cyano-2-methoxy-N-(4-sulfamoylphenethyl)benzamide (1-3)

[0047] In a reaction flask, under a nitrogen atmosphere, 5-cyano-2-methoxybenzoic acid (1-1) (5 g, 28.2 mmol), 4-(2-aminoethyl)benzenesulfonamide (1-2) (5.66 g, 28.3 mmol), HOBt (3.82 g, 28.3 mmol), and MeCN (40 mL) were added. The reaction mixture was cooled in an ice-water bath and stirred. Pyridine (6.92 g, 87.5 mmol) and EDCI (5.46 g, 2.85 mmol) were added and stirred in the ice-water bath for 30 minutes. The ice bath was removed, the mixture was allowed to warm to room temperature, and stirred overnight. The reaction solution was concentrated under reduced pressure, water (25 mL) was added, and the mixture was stirred for 30 minutes. The solid was collected by filtration and dried to obtain compound 1-3 (9.7 g) with a reaction yield of 95.5%.

[0048] Step 2: Preparation of 5-cyano-N-(4-(N-(cyclohexylcarbamoyl)sulfamoyl)phenethyl)-2-methoxybenzamide (1)

[0049] At room temperature, 1-3 (5 g, 13.91 mmol) and DMF (25 mL) were added to the reaction flask under nitrogen balloon protection; LiOtBu (1.11 g, 13.9 mmol) was added, and 1-4 (1.8 g, 14.38 mmol) was added dropwise, and the reaction was kept warm until completion; the reaction solution was cooled with an ice-water bath, 1N HCl (25 mL) was added dropwise to adjust the pH of the solution to about 2 to 3, MTBE (10 mL) was added, water (50 mL) was added dropwise, and stirred at room temperature for 1 h-2 h; filtered, and the solid was washed with water (20 mL) and MTBE (20 mL) in sequence; the solid was collected, then slurried with EtOAc (50 mL), filtered, washed with EtOAc (10 mL) and petroleum ether (30 mL), respectively, and the solid was collected and dried in vacuo at 45 ° C to obtain compound 1 (6.49 g) with a yield of 96.1% and a purity of 99.4%, wherein the content of 1-3 was less than 0.3% as determined by HPLC.

[0050] Example 2

[0051] The same method as in Example 1 was used, except that the alkaline substance in the reactants of step 2 was replaced. The reaction conditions are shown in the following table.

[0052] While the disclosure has been described in terms of specific embodiments thereof, certain modifications and equivalents will be apparent to one skilled in the art and are intended to be included within the scope of this disclosure.

Claims

1. A method for preparing a compound of formula (I), comprising the steps of preparing a compound of formula (I) from a compound of formula (II) in the presence of LiOtBu, in, R1 is each independently selected from halogen, C1-C6 alkoxy optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, hydroxy, carboxyl and cyano; R2 is each independently selected from halogen, C1-C6 alkoxy optionally substituted by halogen, C1-C6 alkyl optionally substituted by halogen, hydroxyl and R3 are each independently selected from C1-C6 alkyl, phenyl, m is an integer selected from 0 to 5; n is an integer selected from 0-10.

2. The preparation method according to claim 1, wherein the molar ratio of the compound represented by formula (II) to LiOtBu is 1:0.5-1:5, preferably 1:1-1:

3.

3. The preparation method according to claim 1 or 2, wherein the compound shown in formula (II) is The compound represented by formula (I) is 4. The preparation method according to claim 1 or 2, wherein the compound shown in formula (II) is The compound represented by formula (I) is 5. The preparation method according to any one of claims 1 to 4, wherein the reactants in the step further comprise a compound represented by formula (III), Wherein R2 is defined as in claim 1, R4 is selected from -NCO or 6. The preparation method according to any one of claims 1 to 5, wherein the compound represented by formula (III) is 7. The preparation method according to any one of claims 1 to 6, wherein the residual content of the compound represented by formula (II) at the end of the reaction is less than 2% of the input amount, preferably less than 1%, and more preferably less than 0.5%.

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