A preparation method of gliclazide

Abstract

The present invention relates to the field of pharmaceutical synthesis, and in particular to a preparation method of gliclazide and an intermediate thereof. The preparation method comprises Mannich reaction, amino protection reaction, Perkin reaction, epoxidation reaction, hydrolysis reaction, decarboxylation reaction and reductive amination reaction to obtain the intermediate. The preparation method has mild reaction conditions, is green and environmentally friendly, generates less three wastes, does not require the use of a high-risk reducing agent, does not require a nitrosation reaction, and successfully avoids the introduction of nitrogen nitroso impurities.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, and in particular to a new method for synthesizing gliclazide. The technology adopted by the invention has the advantages of mild route conditions, green environmental protection, low production cost and the like. Background Art

[0002] Gliclazide, English name: Gliclazide; molecular formula: C 15 H 21 N3O3S; CAS number: 21187-98-4; chemical name: 1-(hexahydrocyclopenta[c]pyrrol-2(IH)-yl)-3-(4-methylphenyl-)sulfonylurea (l-(hexahgdroeycloxpenta[c]pyrrol-2(IH)-yl)-3-[(4-methylphengl)sulphonyl]urea); chemical structure is shown in Formula I:

[0003]

[0004] Gliclazide is a second-generation sulfonylurea oral hypoglycemic drug, mainly used for the treatment of type II (non-insulin-dependent) diabetes. It can not only lower blood sugar, but also improve the coagulation function of diabetic patients, improve or delay the occurrence of vascular complications in diabetic patients, and has been widely used clinically.

[0005] The most critical process for the synthesis of gliclazide is the synthesis of octahydrocyclopenta[c]pyrrole. There have been many reports at home and abroad, and the main synthetic routes are as follows:

[0006] At present, the method reported in Japanese patents (publication numbers JP05065270 and JP06041073) is widely used in China to produce gliclazide side chains. The method uses cyclopentaneimide as a raw material and undergoes reduction, nitrosation and zinc powder reduction to obtain the target product:

[0007]

[0008] In the production method, the step of reducing cyclopentanecarboxylic acid imide to octahydrocyclopenta[c]pyrrole has the following problems: the reduction is difficult, the reducing agents used, such as lithium aluminum hydride and alkali metal hydride, are relatively expensive, are prone to explosion, and are highly dangerous during transportation and use. Therefore, a new method is needed to prepare octahydrocyclopenta[c]pyrrole.

[0009] WO2009 / 55467 reports another synthesis method: N-benzylcyclopentyl imide is first reduced with LiAlH4, and then hydrogenated with 10% palladium on carbon (Pd / C) to obtain the target compound octahydrocyclopentane [C] pyrrole in two steps with a total yield of 55%. The process of this method is as follows:

[0010]

[0011] The yield of the final product is not high, less than 55%. In addition, a large amount of aluminum hydride (LiAlH4) is required, and LiAlH4 is a chemical reagent that is very sensitive to water. When used in laboratories, the risk is tolerable because the amount used is small. However, in industrial production, due to the large amount used, the risk is very high. During the reduction reaction and the post-treatment of excess reducing agent LiAlH4, heat will be released violently. In the case of local uneven heat, it is very easy to cause safety accidents such as explosions.

[0012] A Chinese patent (CN201310627653.8) discloses a method for synthesizing octahydrocyclopentane [C] pyrrole by reducing cyclopentyl imide in a suitable solvent using NaBH4 as a reducing agent and ZnCl2 as a promoter.

[0013]

[0014] The reaction conditions of this method are relatively strict, and the NaBH4 / ZnCl2 reduction system used is prone to produce a large amount of zinc-containing industrial wastewater in actual industrial production, which does not meet the requirements of environmental protection and green chemistry.

[0015] Chinese patent (CN201710165539) discloses a method for preparing octahydrocyclopenta[c]pyrrole, an intermediate of gliclazide.

[0016]

[0017] In the method, a toluene solution of red aluminum is used as a reducing agent in the preparation of octahydrocyclopenta[c]pyrrole. The reaction conditions are mild and easy to control, which improves the reaction yield. However, red aluminum is relatively expensive as a reducing agent, the product after the reaction is difficult to handle, and the amount used is large, which is not conducive to industrial production.

[0018] This patent reports a new synthesis method of gliclazide, which has mild reaction conditions, is green and environmentally friendly, produces less three wastes, and does not require the use of high-risk reducing agents. In addition, the previous synthesis routes of gliclazide all first synthesize octahydrocyclopentane and [c] pyrrole intermediates, then carry out nitrosation reaction to introduce nitroso groups, and then reduce to hydrazine. This process will inevitably introduce nitrogen-nitroso genotoxic impurities, making the quality control of gliclazide API difficult. In contrast, this route can directly synthesize gliclazide through a simple five-step reaction, avoiding the introduction of nitrogen-nitroso genotoxic impurities, thereby greatly reducing the genotoxic risk of gliclazide API. Summary of the invention

[0019] The invention provides a novel synthesis method of gliclazide, which has mild reaction conditions, is green and environmentally friendly, generates less three wastes, does not require the use of a highly dangerous reducing agent, and is suitable for industrial production and preparation.

[0020] In order to achieve the purpose of the present invention, the present invention provides the following technical solutions:

[0021] First, the present invention provides a compound of formula 1 for preparing an intermediate of gliclazide, the structural formula of which is as follows:

[0022]

[0023] In a second aspect, the present invention provides a compound of formula 2 for preparing an intermediate of gliclazide, the structural formula of which is as follows:

[0024]

[0025] Among them, R 1 is a C1-C8 silyl group, C 2-11 The acyl group, C 4-9 The cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl group; the silyl group is tetramethylsilyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; the aryl group is phenyl, furyl, thienyl or indolyl; the substituted phenyl group is alkyl-substituted phenyl, alkoxyalkyl-substituted phenyl, nitroalkyl-substituted phenyl or halogen-substituted phenyl; the alkyl-substituted phenyl group is benzyl, diphenylmethyl, triphenylmethyl; the alkoxyalkyl-substituted phenyl group is p-methoxybenzyl; the nitroalkyl-substituted phenyl group is p-nitrobenzyl; the halogen-substituted phenyl group is p-chlorophenyl.

[0026] In a third aspect, the present invention provides a compound of the intermediate formula 2-1 for preparing gliclazide, the structural formula of which is as follows:

[0027]

[0028] In a fourth aspect, the present invention provides a compound of formula 3 for preparing an intermediate of gliclazide, the structural formula of which is as follows:

[0029]

[0030] Among them, R 1 , R 2 is a C1-C8 silyl group, C 2-11 The acyl group, C 4-9 The cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl group; the silyl group is tetramethylsilyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; the aryl group is phenyl, furyl, thienyl or indolyl; the substituted phenyl group is alkyl-substituted phenyl, alkoxyalkyl-substituted phenyl, nitroalkyl-substituted phenyl or halogen-substituted phenyl; the alkyl-substituted phenyl group is benzyl, diphenylmethyl, triphenylmethyl; the alkoxyalkyl-substituted phenyl group is p-methoxybenzyl; the nitroalkyl-substituted phenyl group is p-nitrobenzyl; the halogen-substituted phenyl group is p-chlorophenyl.

[0031] In a fifth aspect, the present invention provides a compound of the intermediate formula 3-1 for preparing gliclazide, the structural formula of which is as follows:

[0032]

[0033] In a sixth aspect, the present invention provides a compound of the intermediate formula 4 for preparing gliclazide, the structural formula of which is as follows:

[0034]

[0035] In a seventh aspect, the present invention provides a method for preparing a compound of the intermediate formula 1 for preparing gliclazide, characterized in that the compound N-tosylhydraziecarboxamide, cyclopentanone and formaldehyde are subjected to a Mannich reaction under the conditions of an acid and a reaction solvent to prepare:

[0036]

[0037] The acid is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, aluminum chloride;

[0038] The reaction solvent is ethanol, methanol, isopropanol, n-propanol, butanol, tert-butanol, tetrahydrofuran, DMF, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, and chlorobenzene.

[0039] In an eighth aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 2, characterized in that the intermediate is prepared by reacting a compound of formula 1 with an amino protecting agent in the presence of a catalyst, a base and a solvent to obtain:

[0040]

[0041] The solvent is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, and chlorobenzene;

[0042] The base is triethylamine, DIPEA, DBU, pyridine, DBN, DABCO.

[0043] In a ninth aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 2-1, characterized in that the intermediate is prepared by reacting a compound of formula 1 with acetic anhydride in the presence of a catalyst, a base and a solvent through an amino protection reaction:

[0044]

[0045] The solvent is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, and chlorobenzene;

[0046] The base is triethylamine, DIPEA, DBU, pyridine, DBN, DABCO.

[0047] In a tenth aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 3, characterized in that the intermediate is prepared by reacting a compound of formula 2 with an alkyl chloroacetate in the presence of a base and a solvent through a Perkin reaction and an epoxidation reaction:

[0048]

[0049] The solvent is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butyl alcohol, toluene and chlorobenzene;

[0050] The base is potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide.

[0051] In the eleventh aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 3-1, characterized in that the intermediate is prepared by reacting a compound of formula 2-1 with ethyl chloroacetate in the presence of a base and a solvent through a Perkin reaction and an epoxidation reaction:

[0052]

[0053] The solvent is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butyl alcohol, toluene and chlorobenzene;

[0054] The base is potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide.

[0055] In a twelfth aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 4, characterized in that the compound of formula 3 is subjected to a hydrolysis reaction in a base and a solvent, and then subjected to a decarboxylation reaction in an acid and a solvent to obtain:

[0056]

[0057] The solvent is an alcohol having less than or equal to five carbon atoms;

[0058] The base is sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, potassium ethoxide, sodium ethoxide;

[0059] The acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.

[0060] In a thirteenth aspect, the present invention provides a method for preparing a gliclazide intermediate of formula 4, characterized in that the compound of formula 3-1 is subjected to a hydrolysis reaction in a base and a solvent, and then subjected to a decarboxylation reaction in an acid and a solvent to prepare:

[0061]

[0062] The solvent is an alcohol having less than or equal to five carbon atoms;

[0063] The base is sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, potassium ethoxide, sodium ethoxide;

[0064] The acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.

[0065] In a fourteenth aspect, the present invention provides a method for preparing gliclazide, characterized in that it is prepared by reductive amination reaction of a compound of formula 4 in the presence of a metal reducing agent, an acidic activator and a solvent:

[0066]

[0067] The activator is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid;

[0068] The metal reducing agent is sodium trimethoxyborohydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride;

[0069] The solvent is an alcohol having less than or equal to five carbon atoms.

[0070] In a fifteenth aspect, the present invention provides a method for preparing gliclazide, characterized in that the compound N-tosylhydraziecarboxamide, cyclopentanone and formaldehyde are subjected to a Mannich reaction under the conditions of an acid and a reaction solvent to obtain a compound of formula 1; the compound of formula 1 and an amino protecting agent are subjected to an amino protecting reaction under the conditions of a catalyst, a base and a solvent to obtain a compound of formula 2; the compound of formula 2 and an alkyl chloroacetate are subjected to a Perkin reaction and an epoxidation reaction under the conditions of a base and a solvent to obtain a compound of formula 3; the compound of formula 3 is subjected to a hydrolysis reaction under alkaline conditions, and then to a decarboxylation reaction under acidic conditions to obtain a compound of formula 4; and then the compound of formula 4 is subjected to a reductive amination reaction under the conditions of a metal reducing agent, an acidic activator and a solvent to obtain:

[0071]

[0072] Among them, R 1 , R 2 is a C1-C8 silyl group, C 2-11 The acyl group, C 4-9 The cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl group; the silyl group is tetramethylsilyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; the aryl group is phenyl, furyl, thienyl or indolyl; the substituted phenyl group is alkyl-substituted phenyl, alkoxyalkyl-substituted phenyl, nitroalkyl-substituted phenyl or halogen-substituted phenyl; the alkyl-substituted phenyl group is benzyl, diphenylmethyl, triphenylmethyl; the alkoxyalkyl-substituted phenyl group is p-methoxybenzyl; the nitroalkyl-substituted phenyl group is p-nitrobenzyl; the halogen-substituted phenyl group is p-chlorophenyl.

[0073] The acid in the Mannich reaction step is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, and aluminum chloride; the reaction solvent is ethanol, methanol, isopropanol, n-propanol, butanol, tert-butanol, tetrahydrofuran, DMF, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, and chlorobenzene.

[0074] The solvent for the amino protection reaction step is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, chlorobenzene; the base is triethylamine, DIPEA, DBU, pyridine, DBN, DABCO.

[0075] The solvent of the Perkin reaction step is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butanol, toluene and chlorobenzene; the base is potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide.

[0076] The solvent for the hydrolysis and decarboxylation reaction steps is an alcohol with less than or equal to five carbon atoms; the base is sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, potassium ethoxide, sodium ethoxide; and the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.

[0077] The activator in the reduction amination reaction step is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid; the metal reducing agent is sodium trimethoxyborohydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride; and the solvent is an alcohol with less than or equal to five carbon atoms.

[0078] In a sixteenth aspect, the present invention provides a method for preparing gliclazide, characterized in that the compound N-tosylhydraziecarboxamide, cyclopentanone and formaldehyde are subjected to a Mannich reaction under the conditions of an acid and a reaction solvent to obtain a compound of formula 1, the compound of formula 1 and acetic anhydride are subjected to an amino protection reaction under the conditions of a catalyst, a base and a solvent to obtain a compound of formula 2-1, the compound of formula 2-1 and ethyl chloroacetate are subjected to a Perkin reaction and an epoxidation reaction under the conditions of a base and a solvent to obtain a compound of formula 3-1, the compound of formula 3-1 is subjected to a hydrolysis reaction under alkaline conditions, and then to a decarboxylation reaction under acidic conditions to obtain a compound of formula 4, and then the compound of formula 4 is subjected to a reductive amination reaction under the conditions of a metal reducing agent, an acidic activator and a solvent to obtain:

[0079]

[0080] The acid in the Mannich reaction step is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, and aluminum chloride; the reaction solvent is ethanol, methanol, isopropanol, n-propanol, butanol, tert-butanol, tetrahydrofuran, DMF, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, and chlorobenzene.

[0081] The solvent for the amino protection reaction step is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, chlorobenzene; the base is triethylamine, DIPEA, DBU, pyridine, DBN, DABCO.

[0082] The solvent of the Perkin reaction step is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butanol, toluene and chlorobenzene; the base is potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide.

[0083] The solvent for the hydrolysis and decarboxylation reaction steps is an alcohol with less than or equal to five carbon atoms; the base is sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, potassium ethoxide, sodium ethoxide; and the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.

[0084] The activator in the reduction amination reaction step is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid; the metal reducing agent is sodium trimethoxyborohydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride; and the solvent is an alcohol with less than or equal to five carbon atoms.

[0085] The method for preparing gliclazide has mild reaction conditions, is green and environmentally friendly, generates less three wastes, does not require the use of highly dangerous reducing agents, and is suitable for industrial production and preparation. DETAILED DESCRIPTION

[0086] The present invention is further defined in the following examples. It should be understood that these examples, while indicating preferred embodiments of the present invention, are given by way of illustration only and do not limit the present invention as claimed.

[0087] Example 1: Synthesis of Compound 1

[0088]

[0089] Place N-tosylhydraziecarboxamide (5 g, 0.0218 mol), cyclopentanone (1.83 g, 0.0218 mol), paraformaldehyde (0.5 g) and ethanol (50 mL) in a 250 ml four-necked flask. Turn on magnetic stirring and stir to dissolve at 0-5 °C. Add concentrated hydrochloric acid (5 mL) at 0-5 °C. Heat to reflux for 6 hours until the raw materials are completely converted. The reaction solution was concentrated to dryness under reduced pressure at 35-40°C, ethyl acetate (30 g) and water (30 g) were added, the organic phase was separated, ethyl acetate (30 g) was added to the aqueous phase, the organic phases were combined, washed once with 15 g of saturated sodium bicarbonate aqueous solution, the organic phase was separated, and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow viscous substance, 7 g of isopropanol was added, and the mixture was heated to 75-80°C to dissolve, the heating was stopped, and the mixture was cooled naturally to crystallize to obtain a white solid (5.3 g), i.e., the target compound 1, with a yield of 75%.

[0090] Example 2: Synthesis of Compound 2-1

[0091]

[0092] Compound 1 (3.25 g, 0.01 mol), DCM (30 mL), triethylamine (1.1 g), DMAP (0.12 g) and acetic anhydride (1.12 g) were placed in a 100 ml four-necked flask. The mixture was stirred with magnetic force and reacted at 20-25 °C for 3 hours. After the reaction, 20 mL of water was added, the organic phase was separated, and the mixture was washed once with 10 mL of saturated sodium bicarbonate solution. The organic phase was separated and concentrated to dryness under reduced pressure at 35-40 °C to obtain a crude product, which was then recrystallized with ethyl acetate (3 ml) and n-heptane (15 ml) to obtain a light yellow solid (2.64 g), i.e., the target product, compound 2-1, with a yield of 72%.

[0093] Example 3: Synthesis of Compound 3-1

[0094]

[0095] Compound 2-1 (4.2 g, 0.011 mol), ethyl chloroacetate (1.34 g), and THF (40 ml) were placed in a 100 ml four-necked flask. Magnetic stirring was turned on, and t-BuOK (1.85 g) was slowly added at 20-25°C. After the addition, the mixture was reacted at 20-25°C for 15 hours. After the reaction, 20 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a brown oil. The crude product was separated by column chromatography [mobile phase was n-heptane: ethyl acetate = 2: 1 (volume ratio)] to obtain a light yellow oil (2.6 g), i.e., the target product compound 3-1, with a yield of 52%.

[0096] Example 4: Synthesis of Compound 4

[0097]

[0098] Compound 3-1 (4.4 g, 0.01 mol) and MeOH (20 mL) were placed in a 100 mL four-necked flask. Magnetic stirring was turned on, sodium methoxide was added at 20-25°C, and the mixture was reacted at 20-25°C for 12 hours. After the reaction, methanol was evaporated under reduced pressure at 20-25°C, 20 mL of water and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow oil. The yellow oil was dissolved in a 10% aqueous sulfuric acid solution (40 mL) and reacted at 50-60°C for 5 hours. The mixture was cooled to 20-25°C, 20 mL of dichloromethane was added, and the mixture was stirred and allowed to stand for separation. The aqueous layer was extracted twice with dichloromethane (20 mL*2). The dichloromethane phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow solid. 5 mL of ethanol was added for pulping and a white solid (2.4 g) was obtained by filtration, i.e., the target compound 4 with a yield of 71%.

[0099] Example 5: Synthesis of Compound 5

[0100]

[0101] Compound 4 (2.3 g, 0.0067 mol), MeOH (15 mL) and hydrochloric acid (2 mL) were placed in a 100 mL single-necked flask. Magnetic stirring was turned on, and sodium triacetoxyborohydride (1.72 g) was slowly added at 20-25°C. After the addition, the mixture was reacted at 20-25°C for 2 hours. After the reaction was completed, the mixture was concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow solid. 5 mL of dichloromethane was added to the mixture for 1 hour, and the mixture was filtered to obtain an off-white solid (1.34 g), i.e., the target product, compound 5, with a yield of 62%.

[0102] Example 6: Synthesis of Compound 2-2

[0103]

[0104] Compound 1 (3.25 g, 0.01 mol), DCM (30 mL), triethylamine (1.1 g) and benzoyl chloride (2.10 g) were placed in a 100 ml four-necked flask. The mixture was stirred with magnetic force and reacted at 20-25 °C for 3 hours. After the reaction, 20 mL of water was added, the organic phase was separated, and the mixture was washed once with 10 mL of saturated sodium bicarbonate solution. The organic phase was separated and concentrated to dryness under reduced pressure at 35-40 °C to obtain a crude product, which was then recrystallized with ethyl acetate (3 ml) and n-heptane (15 ml) to obtain a light yellow solid (3.40 g), i.e., the target product, compound 2-2, with a yield of 80%.

[0105] Example 7: Synthesis of Compound 3-2

[0106]

[0107] Compound 2-2 (5.0 g, 0.012 mol), ethyl chloroacetate (1.47 g), and THF (45 ml) were placed in a 100 ml four-necked flask. Magnetic stirring was turned on, and t-BuOK (1.96 g) was slowly added at 20-25°C. After the addition, the mixture was reacted at 20-25°C for 15 hours. After the reaction was completed, 20 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a brown oil. The crude product was separated by column chromatography [mobile phase was n-heptane: ethyl acetate = 1:1 (volume ratio)] to obtain a light yellow oil (4.38 g), i.e., the target product compound 3-2, with a yield of 71%.

[0108] Example 8: Synthesis of Compound 4

[0109]

[0110] Compound 3-2 (5.1 g, 0.01 mol) and MeOH (20 mL) were placed in a 100 mL four-necked flask. Magnetic stirring was turned on, sodium methoxide (1.08 g) was added at 20-25°C, and the mixture was reacted at 20-25°C for 12 hours. After the reaction, methanol was evaporated under reduced pressure at 20-25°C, 20 mL of water and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow oil. The yellow oil was dissolved in a 10% aqueous sulfuric acid solution (40 mL) and reacted at 50-60°C for 5 hours. The mixture was cooled to 20-25°C, 20 mL of dichloromethane was added, and the mixture was stirred and allowed to stand for separation. The aqueous layer was extracted twice with dichloromethane (20 mL*2). The dichloromethane phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow solid. 5 mL of ethanol was added for pulping and a white solid (2.1 g) was obtained by filtration, i.e., the target compound 4 with a yield of 64%.

[0111] Example 9: Synthesis of Compound 2-3

[0112]

[0113] Compound 1 (3.25 g, 0.01 mol), DCM (30 mL), triethylamine (1.1 g) and Boc anhydride (3.27 g) were placed in a 100 ml four-necked flask. The mixture was stirred with magnetic force and reacted at 20-25 °C for 3 hours. After the reaction, 20 mL of water was added, the organic phase was separated, and the mixture was washed once with 10 mL of saturated sodium bicarbonate solution. The organic phase was separated and concentrated to dryness under reduced pressure at 35-40 °C to obtain a crude product, which was then recrystallized with ethyl acetate (3 ml) and n-heptane (15 ml) to obtain a light yellow solid (2.97 g), i.e., the target product, compound 2-3, with a yield of 70%.

[0114] Example 10: Synthesis of Compound 3-3

[0115]

[0116] Compound 2-3 (4.25 g, 0.01 mol), ethyl chloroacetate (1.36 g), and THF (45 ml) were placed in a 100 ml four-necked flask. Magnetic stirring was turned on, and t-BuOK (1.85 g) was slowly added at 20-25°C. After the addition, the mixture was reacted at 20-25°C for 15 hours. After the reaction, 20 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate were added, and the mixture was stirred and separated. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a brown oil. The crude product was separated by column chromatography [mobile phase was n-heptane: ethyl acetate = 1:1 (volume ratio)] to obtain a light yellow oil (3.83 g), i.e., the target product compound 3-3, with a yield of 75%.

[0117] Example 11: Synthesis of Compound 4

[0118]

[0119] Compound 3-3 (5.1 g, 0.01 mol) and MeOH (20 mL) were placed in a 100 mL four-necked flask. Magnetic stirring was turned on, sodium methoxide (1.08 g) was added at 20-25°C, and the mixture was reacted at 20-25°C for 12 hours. After the reaction, methanol was evaporated under reduced pressure at 20-25°C, 20 mL of water and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow oil. The yellow oil was dissolved in a 10% aqueous sulfuric acid solution (40 mL) and reacted at 50-60°C for 5 hours. The mixture was cooled to 20-25°C, 20 mL of dichloromethane was added, and the mixture was stirred and allowed to stand for separation. The aqueous layer was extracted twice with dichloromethane (20 mL*2). The dichloromethane phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow solid. 5 mL of ethanol was added for pulping and a white solid (2.8 g) was obtained by filtration, i.e., the target compound 4 with a yield of 82%.

[0120] Example 12: Synthesis of Compound 3-4

[0121]

[0122] Compound 2-1 (4.2 g, 0.011 mol), methyl chloroacetate (1.29 g), and THF (40 ml) were placed in a 100 ml four-necked flask. Magnetic stirring was turned on, and t-BuOK (1.85 g) was slowly added at 20-25°C. After the addition, the mixture was reacted at 20-25°C for 15 hours. After the reaction, 20 mL of saturated aqueous ammonium chloride solution and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2). The organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a brown oil. The crude product was separated by column chromatography [mobile phase was n-heptane: ethyl acetate = 2: 1 (volume ratio)] to obtain a light yellow oil (2.5 g), i.e., the target product compound 3-4, with a yield of 51%.

[0123] Example 13: Synthesis of Compound 4

[0124]

[0125] Compound 3-4 (4.4 g, 0.01 mol) and MeOH (20 mL) were placed in a 100 mL four-necked flask. Magnetic stirring was turned on, sodium methoxide (1.08 g) was added at 20-25°C, and the mixture was reacted at 20-25°C for 12 hours. After the reaction, methanol was evaporated under reduced pressure at 20-25°C, 20 mL of water and 20 mL of ethyl acetate were added, and the layers were separated by stirring. The aqueous phase was extracted twice with ethyl acetate (20 mL x 2), and the organic phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow oil. The yellow oil was dissolved in a 10% aqueous sulfuric acid solution (40 mL) and reacted at 50-60°C for 5 hours. The mixture was cooled to 20-25°C, 20 mL of dichloromethane was added, and the mixture was stirred and allowed to stand for separation. The aqueous layer was extracted twice with dichloromethane (20 mL*2). The dichloromethane phases were combined and concentrated to dryness under reduced pressure at 35-40°C to obtain a yellow solid. 5 mL of ethanol was added for pulping and a white solid (2.3 g) was obtained by filtration, i.e., the target compound 4 with a yield of 68%.

Claims

1. A compound of the intermediate formula 1 for preparing gliclazide, the structural formula is as follows:

2. A compound of the intermediate formula 2 for preparing gliclazide, the structural formula is as follows: in, R 1 C 2-11 Acyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl.

3. A compound of the intermediate formula 2-1 for preparing gliclazide, the structural formula is as follows:

4. A compound of the intermediate formula 3 for preparing gliclazide, the structural formula is as follows: in, For R 1 C 2-11 acyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; R 2 It is methyl or ethyl.

5. A compound of the intermediate formula 3-1 for preparing gliclazide, the structural formula is as follows:

6. A compound of the intermediate formula 4 for preparing gliclazide, the structural formula is as follows:

7. A method for preparing a compound of formula 1 as an intermediate for preparing gliclazide, characterized in that: The compound N-[(4-methylphenyl)sulfonyl]-hydrazide carboxamide, cyclopentanone and formaldehyde are reacted in an acid and a reaction solvent to obtain the following:

8. A method for preparing a gliclazide intermediate of formula 2, characterized in that: The compound of formula 1 and an amino protecting agent are reacted under the conditions of a catalyst, a base and a solvent to obtain: Among them, R 1 C 2-11 Acyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl.

9. A method for preparing a gliclazide intermediate of formula 2-1, characterized in that: The compound of formula 1 and acetic anhydride are prepared by amino protection reaction under the conditions of catalyst, base and solvent:

10. A method for preparing a gliclazide intermediate of formula 3, characterized in that: The compound of formula 2 and alkyl chloroacetate are prepared by Perkin reaction and epoxidation reaction under the conditions of base and solvent: Among them, R 1 C 2-11 acyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; R 2 It is methyl or ethyl.

11. A method for preparing a gliclazide intermediate of formula 3-1, characterized in that: The compound of formula 2-1 and ethyl chloroacetate are prepared by Perkin reaction and epoxidation reaction in the presence of a base and a solvent:

12. A method for preparing a gliclazide intermediate of formula 4, characterized in that: The compound of formula 3 is subjected to a hydrolysis reaction in a base and a solvent, and then subjected to a decarboxylation reaction in an acid and a solvent to obtain: Among them, R 1 C 2-11 acyl, trimethylsilyl, triethylsilyl, tri-n-butylsilyl, tert-butyldimethylsilyl; R 2 It is methyl or ethyl.

13. A method for preparing a gliclazide intermediate of formula 4, characterized in that: The compound of formula 3-1 is subjected to a hydrolysis reaction in a base and a solvent, and then subjected to a decarboxylation reaction in an acid and a solvent to obtain:

14. A method for preparing gliclazide, characterized in that: The compound of formula 4 is prepared by reductive amination reaction in the presence of a metal reducing agent, an acidic activator and a solvent:

15. A method for preparing gliclazide, characterized in that: The compound of formula 1 is prepared by subjecting the compound N-[(4-methylphenyl)sulfonyl]-hydrazide carboxamide and cyclopentanone and formaldehyde to a Mannich reaction under the conditions of an acid and a reaction solvent; the compound of formula 1 and an amino protecting agent are subjected to an amino protecting reaction under the conditions of a catalyst, a base and a solvent to prepare a compound of formula 2; the compound of formula 2 and an alkyl chloroacetate are subjected to a Perkin reaction and an epoxidation reaction under the conditions of a base and a solvent to prepare a compound of formula 3; the compound of formula 3 is subjected to a hydrolysis reaction under alkaline conditions and then to a decarboxylation reaction under acidic conditions to prepare a compound of formula 4; and the compound of formula 4 is subjected to a reductive amination reaction under the conditions of a metal reducing agent, an acidic activating agent and a solvent to prepare: Among them, R 1 C 2-11 Acyl, dimethylsilyl, diethylsilyl, di-n-butylsilyl, tert-butyldimethylsilyl; R 2 It is methyl or ethyl.

16. A method for preparing gliclazide, characterized in that: The compound of formula 1 is prepared by subjecting the compound N-[(4-methylphenyl)sulfonyl]-hydrazide carboxamide and cyclopentanone and formaldehyde to a Mannich reaction under the conditions of an acid and a reaction solvent. The compound of formula 1 and acetic anhydride are subjected to an amino protection reaction under the conditions of a catalyst, a base and a solvent to prepare a compound of formula 2-1. The compound of formula 2-1 and methyl chloroacetate are subjected to a Perkin reaction and an epoxidation reaction under the conditions of a base and a solvent to prepare a compound of formula 3-1. The compound of formula 3-1 is subjected to a hydrolysis reaction under alkaline conditions and then to a decarboxylation reaction under acidic conditions to prepare a compound of formula 4. The compound of formula 4 is then subjected to a reductive amination reaction under the conditions of a metal reducing agent, an acidic activator and a solvent to prepare:

17. The preparation method according to claim 7, 15 or 16, wherein the acid in the Mannich reaction step is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, aluminum chloride; and the reaction solvent is ethanol, methanol, isopropanol, n-propanol, butanol, tert-butanol, tetrahydrofuran, DMF, dichloromethane, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, toluene, chlorobenzene.

18. The preparation method according to claim 8, 9, 15 or 16, wherein the solvent in the amino protection reaction step is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, chlorobenzene; and the base is triethylamine, DIPEA, DBU, pyridine, DBN, DABCO.

19. The preparation method according to claim 10, 11, 15 or 16, wherein the solvent in the Perkin reaction step is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butanol, toluene and chlorobenzene; and the base is potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide.

20. The preparation method according to claim 12, 13, 15 or 16, wherein the solvent in the hydrolysis and decarboxylation reaction steps is an alcohol with less than or equal to five carbon atoms; the base is sodium methoxide, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium methoxide, potassium ethoxide, sodium ethoxide; and the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.

21. The preparation method according to claim 14, 15 or 16, wherein the activator in the reductive amination reaction step is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid; the metal reducing agent is sodium trimethoxyborohydride, potassium borohydride, sodium borohydride, sodium cyanoborohydride; and the solvent is an alcohol with less than or equal to five carbon atoms.

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