CN113527155A - Preparation method of gliclazide - Google Patents

Preparation method of gliclazide Download PDF

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CN113527155A
CN113527155A CN202110078337.4A CN202110078337A CN113527155A CN 113527155 A CN113527155 A CN 113527155A CN 202110078337 A CN202110078337 A CN 202110078337A CN 113527155 A CN113527155 A CN 113527155A
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compound
formula
reaction
substituted phenyl
gliclazide
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于帅
刘阿情
郭雷雷
王锦裕
郑辉
高照波
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Zhejiang Siwei Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/50—Compounds containing any of the groups, X being a hetero atom, Y being any atom
    • C07C311/52—Y being a hetero atom
    • C07C311/54—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea
    • C07C311/57—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/61—Y being a hetero atom either X or Y, but not both, being nitrogen atoms, e.g. N-sulfonylurea having sulfur atoms of the sulfonylurea groups bound to carbon atoms of six-membered aromatic rings having nitrogen atoms of the sulfonylurea groups further bound to another hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D301/00—Preparation of oxiranes
    • C07D301/02—Synthesis of the oxirane ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

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Abstract

The invention relates to the field of medicine synthesis, in particular to a preparation method of gliclazide and an intermediate thereof. The preparation method comprises the following steps of Mannich reaction, amino protection reaction, Perkin reaction, epoxidation reaction, hydrolysis reaction, decarboxylation reaction and reductive amination reaction:

Description

Preparation method of gliclazide
Technical Field
The invention relates to the technical field of drug synthesis, in particular to a novel method for synthesizing gliclazide.
Background
Gliclazide, english name: gliclazide; the molecular formula is as follows: c15H21N3O3S; CAS number: 21187-98-4; the chemical name is 1- (hexahydro-cyclopentyl [ c ]]Pyrrole-2 (IH) -yl) -3- (4-methylphenyl-) sulfonylurea (l- (hexahydro droycloxpen [ c ]]pyrrol-2(IH)-yl)-3-[(4-methylphengl)sulphonyl]urea)); the chemical structure is shown as formula I:
Figure BDA0002906347620000011
gliclazide is a second-generation sulfonylurea oral hypoglycemic agent, is mainly used for treating type II (non-insulin dependent) diabetes, can reduce blood sugar, can improve the blood coagulation function of a diabetic patient, and improves or delays the occurrence of vascular complications of the diabetic patient, and is widely used clinically.
The most key process for synthesizing gliclazide is the synthesis of octahydrocyclopenta [ c ] pyrrole. There have been many reports at home and abroad, and there are mainly the following synthetic routes:
at present, the methods reported in Japanese patents (publication Nos. JP05065270 and JP06041073) are widely used domestically for producing the gliclazide side chain. The method takes cyclopentane imide as a raw material and obtains a target product through the steps of reduction, nitrosation, zinc powder reduction and the like:
Figure BDA0002906347620000012
in the production method, the step of reducing the cyclopentane imide into the octahydro cyclopenta [ c ] pyrrole has the problems of high reduction difficulty, high price of used reducing agents such as lithium aluminum hydride and alkali metal hydride, easy explosion, high risk in transportation and use and the like, so a new method is needed for preparing the octahydro cyclopenta [ c ] pyrrole.
WO2009/55467 reports another synthetic method: the N-benzyl cyclopentimide is firstly subjected to LiAlH4After reduction, the target compound octahydrocyclopentane [ C ] is obtained in two steps by hydrogenation reduction of 10% palladium on carbon (Pd/C) with 55% total yield]And (3) pyrrole. The method comprises the following steps:
Figure BDA0002906347620000021
the yield of the final product is not higher than 55%; in addition, a large amount of aluminum hydride (LiAlH) is required4) And LiAlH4The reagent is a chemical reagent which is very sensitive to water, and when the reagent is used in a laboratory, because the use amount is small, the risk can be tolerated: however, in the industrial production, the danger is very large due to the large using amount, and the excessive reducing agent LiAlH is treated in the reduction reaction process and after treatment4The heat is released violently, and under the condition of local uneven heat, safety accidents such as explosion and the like are easy to happen
Chinese patent (CN201310627653.8) discloses a method for using NaBH4Is a reducing agent, ZnCl2Synthesizing octahydrocyclopentane [ C ] by reducing cyclopentimide in proper solvent as promoter]A method for producing pyrrole.
Figure BDA0002906347620000022
The method has severer reaction condition, and the NaBH used4/ZnCl2The reduction system is easy to generate a large amount of zinc-containing industrial wastewater in actual industrial production, and does not meet the requirements of environmental protection and green chemistry.
Chinese patent (CN201710165539) discloses a preparation method of a gliclazide intermediate octahydrocyclopenta [ c ] pyrrole.
Figure BDA0002906347620000023
When the octahydrocyclopenta [ c ] pyrrole is prepared by the method, a toluene solution of red aluminum is used as a reducing agent, the reaction condition is mild and easy to control, and the reaction yield is improved, but the red aluminum used as the reducing agent is high in price, and products after reaction are difficult to treat and large in dosage, so that the method is not beneficial to industrial production.
The patent reports a brand-new synthesis method of gliclazide, which has the advantages of mild reaction conditions, environmental protection, less three wastes and no need of using high-risk reducing agents. In addition, the conventional synthetic route of gliclazide is that an octahydrocyclopenta [ c ] pyrrole intermediate is synthesized, nitrosation reaction is carried out to introduce nitroso, and then reduction is carried out to hydrazine. The process inevitably introduces genotoxic impurities of nitrogen nitroso, thereby making the quality control work of gliclazide API difficult. By contrast, the route can directly synthesize the gliclazide through simple five-step reaction, and avoids the introduction of genotoxic impurities of the nitroso group, so that the genotoxic risk of the gliclazide API is greatly reduced.
Disclosure of Invention
The invention provides a brand-new synthesis method of gliclazide, which has the advantages of mild reaction conditions, environmental protection, less generation of three wastes, no need of using a high-risk reducing agent and suitability for industrial production and preparation.
In order to realize the purpose of the invention, the invention provides the following technical scheme:
firstly, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 1, and the structural formula is as follows:
Figure BDA0002906347620000031
in a second aspect, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 2, and the structural formula is as follows:
Figure BDA0002906347620000032
wherein R is1Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl of (a), aryl, aralkyl, aroyl, phenyl, substituted phenyl; the silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
In a third aspect, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 2-1 and has the following structural formula:
Figure BDA0002906347620000033
in a fourth aspect, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 3, and the structural formula is as follows:
Figure BDA0002906347620000034
wherein R is1，R2Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl of (a), aryl, aralkyl, aroyl, phenyl, substituted phenyl; the silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the takingThe substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
In a fifth aspect, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 3-1, and has the following structural formula:
Figure BDA0002906347620000041
in a sixth aspect, the invention provides a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 4, and the structural formula is as follows:
Figure BDA0002906347620000042
in a seventh aspect, the present invention provides a method for preparing a gliclazide intermediate compound with a structure of formula 1, which is characterized in that the intermediate compound N-tosylhydraziecarboxamide, cyclopentanone and formaldehyde are subjected to Mannich reaction under the conditions of acid and a reaction solvent to prepare:
Figure BDA0002906347620000043
the acid is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, 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.
In an eighth aspect, the invention provides a preparation method of a gliclazide intermediate body formula 2, which is characterized in that the gliclazide intermediate body formula 2 is prepared by performing amino protection reaction on a compound of a formula 1 and an amino protection reagent under the conditions of a catalyst, alkali and a solvent:
Figure BDA0002906347620000051
the solvent is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene and chlorobenzene;
the alkali is triethylamine, DIPEA, DBU, pyridine, DBN and DABCO.
In a ninth aspect, the invention provides a preparation method of a gliclazide intermediate formula 2-1, which is characterized in that the gliclazide intermediate formula is prepared by performing amino protection reaction on a compound of formula 1 and acetic anhydride under the conditions of a catalyst, alkali and a solvent:
Figure BDA0002906347620000052
the solvent is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene and chlorobenzene;
the alkali is triethylamine, DIPEA, DBU, pyridine, DBN and DABCO.
In a tenth aspect, the present invention provides a method for preparing a gliclazide intermediate, formula 3, which is characterized in that the gliclazide intermediate is prepared from a compound of formula 2 and alkyl chloroacetate through a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent:
Figure BDA0002906347620000053
the solvent is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tertiary butanol, toluene and chlorobenzene;
the alkali is potassium tert-butoxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide and sodium ethoxide.
In an eleventh aspect, the invention provides a preparation method of a gliclazide intermediate formula 3-1, which is characterized in that the gliclazide intermediate formula is prepared from a compound of formula 2-1 and ethyl chloroacetate through a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent:
Figure BDA0002906347620000061
the solvent is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tertiary butanol, toluene and chlorobenzene;
the alkali is potassium tert-butoxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide and sodium ethoxide.
In a twelfth aspect, the invention provides a preparation method of a gliclazide intermediate formula 4, which is characterized in that the gliclazide intermediate is prepared by hydrolysis reaction of a compound of formula 3 in alkali and a solvent, and decarboxylation reaction in acid and the solvent:
Figure BDA0002906347620000062
the solvent is an alcohol with less than or equal to five carbons;
the alkali is sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium methoxide, potassium ethoxide and sodium ethoxide;
the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.
In a thirteenth aspect, the invention provides a preparation method of a gliclazide intermediate formula 4, which is characterized in that the gliclazide intermediate is prepared by hydrolysis reaction of a compound of formula 3-1 in alkali and a solvent, and decarboxylation reaction in acid and the solvent:
Figure BDA0002906347620000063
the solvent is an alcohol with less than or equal to five carbons;
the alkali is sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium methoxide, potassium ethoxide and sodium ethoxide;
the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.
In a fourteenth aspect, the present invention provides a preparation method of gliclazide, which is characterized in that the gliclazide is prepared from a compound of formula 4 through a reductive amination reaction under the conditions of a metal reducing agent, an acidic activating agent and a solvent:
Figure BDA0002906347620000071
the activating agent is hydrochloric acid, acetic acid, formic acid or trifluoroacetic acid;
the metal reducing agent is trimethoxy sodium borohydride, potassium borohydride, sodium borohydride or cyano sodium borohydride;
the solvent is an alcohol with less than or equal to five carbons.
In a fifteenth aspect, the present invention provides a method for preparing gliclazide, which is characterized in that a compound of formula 1 is prepared by a Mannich reaction of a compound N-tosylhydratecarboxamide, cyclopentanone and formaldehyde under the conditions of acid and a reaction solvent, a compound of formula 2 is prepared by an amino protection reaction of a compound of formula 1 and an amino protection reagent under the conditions of a catalyst, alkali and a solvent, a compound of formula 3 is prepared by a Perkin reaction and an epoxidation reaction of a compound of formula 2 and alkyl chloroacetate under the conditions of alkali and a solvent, a compound of formula 3 is subjected to a hydrolysis reaction under an alkaline condition, a decarboxylation reaction is performed under an acidic condition to prepare a compound of formula 4, and a compound of formula 4 is prepared by a reductive amination reaction under the conditions of a metal reducing agent, an acidic activator and a solvent:
Figure BDA0002906347620000072
wherein R is1，R2Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl of (a), aryl, aralkyl, aroyl, phenyl, substituted phenyl; the silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
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.
The solvent in the amino protection reaction step is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene and chlorobenzene; the alkali is triethylamine, DIPEA, DBU, pyridine, DBN and DABCO.
The solvent in the Perkin reaction step is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butyl alcohol, toluene and chlorobenzene; the alkali is potassium tert-butoxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide and sodium ethoxide.
The solvent in the hydrolysis and decarboxylation reaction step is alcohol with less than or equal to five carbons; the alkali is sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium methoxide, potassium ethoxide and sodium ethoxide; the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.
The activating agent in the reductive amination step is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid: the metal reducing agent is trimethoxy sodium borohydride, potassium borohydride, sodium borohydride or cyano sodium borohydride; the solvent is an alcohol with less than or equal to five carbons.
In a sixteenth aspect, the invention provides a preparation method of gliclazide, which is characterized in that a compound of formula 1 is prepared by a Mannich reaction of a compound N-tosylhydratecarboxamide, cyclopentanone and formaldehyde under the conditions of acid and a reaction solvent, a compound of formula 2-1 is prepared by an amino protection reaction of a compound of formula 1 and acetic anhydride under the conditions of a catalyst, alkali and a solvent, a compound of formula 2-1 and ethyl chloroacetate are prepared by a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent to obtain a compound of formula 3-1, a hydrolysis reaction of a compound of formula 3-1 is performed under an alkaline condition, a decarboxylation reaction is performed under an acidic condition to prepare a compound of formula 4, and the compound of formula 4 is prepared by a reductive amination reaction under the conditions of a metal reducing agent, an acidic activating agent and a solvent:
Figure BDA0002906347620000081
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.
The solvent in the amino protection reaction step is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene and chlorobenzene; the alkali is triethylamine, DIPEA, DBU, pyridine, DBN and DABCO.
The solvent in the Perkin reaction step is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, tert-butyl alcohol, toluene and chlorobenzene; the alkali is potassium tert-butoxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide and sodium ethoxide.
The solvent in the hydrolysis and decarboxylation reaction step is alcohol with less than or equal to five carbons; the alkali is sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium methoxide, potassium ethoxide and sodium ethoxide; the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.
The activating agent in the reductive amination step is hydrochloric acid, acetic acid, formic acid and trifluoroacetic acid; the metal reducing agent is trimethoxy sodium borohydride, potassium borohydride, sodium borohydride or cyano sodium borohydride; the solvent is an alcohol with less than or equal to five carbons.
The gliclazide prepared by the method has mild reaction conditions, is green and environment-friendly, generates less three wastes, does not need to use high-risk reducing agents, and is suitable for industrial production and preparation.
Detailed Description
The invention is further defined in the following examples. It should be understood that these examples, while indicating the preferred embodiment of the invention, are given by way of illustration only, and are not limiting upon the claims of the invention.
Example 1: synthesis of Compound 1
Figure BDA0002906347620000091
A250 mL four-necked flask was charged with N-tosylhydraziecarboxamide (5g, 0.0218mol), cyclopentanone (1.83g, 0.0218mol), paraformaldehyde (0.5g) and ethanol (50 mL). Starting magnetic stirring, and stirring and dissolving at 0-5 ℃. Concentrated hydrochloric acid (5mL) was added at 0-5 ℃. Heating to reflux reaction for 6 hr to complete the conversion of the material. Concentrating the reaction solution at 35-40 ℃ under reduced pressure until the reaction solution is dry, adding ethyl acetate (30g) and water (30g), separating out an organic phase, adding ethyl acetate (30g) into a water phase, combining the organic phases, washing the organic phase once by using 15g of saturated sodium bicarbonate aqueous solution, separating out the organic phase, concentrating the organic phase at 35-40 ℃ under reduced pressure until the organic phase is dry to obtain a yellow sticky substance, adding 7g of isopropanol, heating to 75-80 ℃ for clearing, stopping heating, naturally cooling and crystallizing to obtain a white solid (5.3g), namely the target compound 1, with the yield of 75%.
Example 2: synthesis of Compound 2-1
Figure BDA0002906347620000092
A100 mL four-necked flask was charged with Compound 1(3.25g, 0.01mol), DCM (30mL), triethylamine (1.1g), DMAP (0.12g) and acetic anhydride (1.12 g). Starting magnetic stirring, and reacting for 3 hours at 20-25 ℃. After the reaction is finished, 20mL of water is added, an organic phase is separated, the organic phase is washed once by 10mL of saturated sodium bicarbonate solution, the organic phase is separated, the organic phase is concentrated to be dry at 35-40 ℃ under reduced pressure, a crude product is obtained, and the crude product is recrystallized by ethyl acetate (3mL) and n-heptane (15mL) to obtain a light yellow solid (2.64g), namely the target product compound 2-1, with the yield of 72%.
Example 3: synthesis of Compound 3-1
Figure BDA0002906347620000101
A100 ml four-necked flask was charged with Compound 2-1(4.2g, 0.011mol), ethyl chloroacetate (1.34g), and THF (40 ml). Starting magnetic stirring, slowly adding t-BuOK (1.85g) at 20-25 ℃, and reacting for 15 hours at 20-25 ℃ after the addition is finished. After the reaction is finished, 20mL of saturated ammonium chloride aqueous solution and 20mL of ethyl acetate are added, the mixture is stirred and separated, the water phase is extracted twice by ethyl acetate (20mL x2), organic phases are combined, the mixture is concentrated to be dry at 35-40 ℃ under reduced pressure, a brown oily substance is obtained, and the crude product is separated by column chromatography (mobile phase is n-heptane: ethyl acetate which is 2: 1 (volume ratio)) to obtain a light yellow oily substance (2.6g), namely the target product compound 3-1, with the yield of 52%.
Example 4: synthesis of Compound 4
Figure BDA0002906347620000102
A100 mL four-necked flask was charged with Compound 3-1(4.4g, 0.01mol) and MeOH (20 mL). Starting magnetic stirring, adding sodium methoxide at 20-25 ℃, and reacting for 12 hours at 20-25 ℃. And (3) after the reaction is finished, evaporating methanol under reduced pressure at 20-25 ℃, adding 20mL of water and 20mL of ethyl acetate, stirring for layering, extracting the water phase twice with ethyl acetate (20mL of x2), combining organic phases, and concentrating under reduced pressure at 35-40 ℃ until the organic phases are dried to obtain a yellow oily substance. The yellow oily substance is dissolved in 10% sulfuric acid aqueous solution (40mL) and reacted for 5 hours at 50-60 ℃. Cooling to 20-25 ℃, adding 20mL of dichloromethane, stirring, standing for layering, extracting the water layer twice (20mL x2) with dichloromethane, combining dichloromethane phases, concentrating at 35-40 ℃ under reduced pressure to dryness to obtain a yellow solid, adding 5mL of ethanol, pulping, and filtering to obtain a white solid (2.4g), namely the target compound 4, with the yield of 71%.
Example 5: synthesis of Compound 5
Figure BDA0002906347620000103
A100 mL single neck flask was charged with Compound 4(2.3g, 0.0067mol), MeOH (15mL), and hydrochloric acid (2 mL). Starting magnetic stirring, slowly adding sodium triacetoxyborohydride (1.72 g) at 20-25 ℃, and continuing to react for 2 hours at 20-25 ℃ after the addition is finished. After the reaction is finished, concentrating under reduced pressure at 35-40 ℃ until the reaction is dried to obtain a yellow solid, adding 5mL of dichloromethane, pulping for 1 hour, and filtering to obtain an off-white solid (1.34g), namely the target product compound 5, with the yield of 62%.
Example 6: synthesis of Compound 2-2
Figure BDA0002906347620000111
A100 mL four-necked flask was charged with Compound 1(3.25g, 0.01mol), DCM (30mL), triethylamine (1.1g) and benzoyl chloride (2.10 g). Starting magnetic stirring, and reacting for 3 hours at 20-25 ℃. After the reaction is finished, 20mL of water is added, an organic phase is separated, the organic phase is washed once by 10mL of saturated sodium bicarbonate solution, the organic phase is separated, the organic phase is concentrated to be dry at 35-40 ℃ under reduced pressure, a crude product is obtained, and the crude product is recrystallized by ethyl acetate (3mL) and n-heptane (15mL) to obtain a light yellow solid (3.40g), namely the target product compound 2-2, with the yield of 80%.
Example 7: synthesis of Compound 3-2
Figure BDA0002906347620000112
A100 ml four-necked flask was charged with Compound 2-2(5.0g, 0.012mol), ethyl chloroacetate (1.47g), and THF (45 ml). Starting magnetic stirring, slowly adding t-BuOK (1.96g) at 20-25 ℃, and reacting for 15 hours at 20-25 ℃ after the addition is finished. After the reaction is finished, 20mL of saturated ammonium chloride aqueous solution and 20mL of ethyl acetate are added, the mixture is stirred and separated, the water phase is extracted twice by ethyl acetate (20mL x2), organic phases are combined, the mixture is concentrated to be dry at 35-40 ℃ under reduced pressure, a brown oily substance is obtained, and the crude product is separated by column chromatography (mobile phase is n-heptane: ethyl acetate which is 1: 1 (volume ratio)) to obtain a light yellow oily substance (4.38g), namely the target product compound 3-2, with the yield of 71%.
Example 8: synthesis of Compound 4
Figure BDA0002906347620000113
A100 mL four-necked flask was charged with Compound 3-2(5.1g, 0.01mol) and MeOH (20 mL). Starting magnetic stirring, adding sodium methoxide (1.08g) at 20-25 ℃, and reacting for 12 hours at 20-25 ℃. And (3) after the reaction is finished, evaporating methanol under reduced pressure at 20-25 ℃, adding 20mL of water and 20mL of ethyl acetate, stirring for layering, extracting the water phase twice with ethyl acetate (20mL of x2), combining organic phases, and concentrating under reduced pressure at 35-40 ℃ until the organic phases are dried to obtain a yellow oily substance. The yellow oily substance is dissolved in 10% sulfuric acid aqueous solution (40mL) and reacted for 5 hours at 50-60 ℃. Cooling to 20-25 ℃, adding 20mL of dichloromethane, stirring, standing for layering, extracting the water layer twice (20mL x2) with dichloromethane, combining dichloromethane phases, concentrating at 35-40 ℃ under reduced pressure to dryness to obtain a yellow solid, adding 5mL of ethanol, pulping, and filtering to obtain a white solid (2.1g), namely the target compound 4, with the yield of 64%.
Example 9: synthesis of Compounds 2-3
Figure BDA0002906347620000121
A100 mL four-necked flask was charged with Compound 1(3.25g, 0.01mol), DCM (30mL), triethylamine (1.1g) and Boc anhydride (3.27 g). Starting magnetic stirring, and reacting for 3 hours at 20-25 ℃. After the reaction is finished, 20mL of water is added, an organic phase is separated, the organic phase is washed once by 10mL of saturated sodium bicarbonate solution, the organic phase is separated, the organic phase is concentrated to be dry at 35-40 ℃ under reduced pressure, a crude product is obtained, and the crude product is recrystallized by ethyl acetate (3mL) and n-heptane (15mL) to obtain a light yellow solid (2.97g), namely the target product compound 2-3, with the yield of 70%.
Example 10: synthesis of Compound 3-3
Figure BDA0002906347620000122
A100 ml four-necked flask was charged with compound 2-3(4.25g, 0.01mol), ethyl chloroacetate (1.36g), and THF (45 ml). Starting magnetic stirring, slowly adding t-BuOK (1.85g) at 20-25 ℃, and reacting for 15 hours at 20-25 ℃ after the addition is finished. After the reaction is finished, 20mL of saturated ammonium chloride aqueous solution and 20mL of ethyl acetate are added, the mixture is stirred and separated, the water phase is extracted twice by ethyl acetate (20mL x2), organic phases are combined, the mixture is concentrated to be dry at 35-40 ℃ under reduced pressure, a brown oily substance is obtained, and the crude product is separated by column chromatography (mobile phase is n-heptane: ethyl acetate which is 1: 1 (volume ratio)) to obtain a light yellow oily substance (3.83g), namely the target product compound 3-3, with the yield of 75%.
Example 11: synthesis of Compound 4
Figure BDA0002906347620000123
A100 mL four-necked flask was charged with Compound 3-3(5.1g, 0.01mol) and MeOH (20 mL). Starting magnetic stirring, adding sodium methoxide (1.08g) at 20-25 ℃, and reacting for 12 hours at 20-25 ℃. And (3) after the reaction is finished, evaporating methanol under reduced pressure at 20-25 ℃, adding 20mL of water and 20mL of ethyl acetate, stirring for layering, extracting the water phase twice with ethyl acetate (20mL of x2), combining organic phases, and concentrating under reduced pressure at 35-40 ℃ until the organic phases are dried to obtain a yellow oily substance. The yellow oily substance is dissolved in 10% sulfuric acid aqueous solution (40mL) and reacted for 5 hours at 50-60 ℃. Cooling to 20-25 ℃, adding 20mL of dichloromethane, stirring, standing for layering, extracting the water layer twice (20mL x2) with dichloromethane, combining dichloromethane phases, concentrating at 35-40 ℃ under reduced pressure to dryness to obtain a yellow solid, adding 5mL of ethanol, pulping, and filtering to obtain a white solid (2.8g), namely the target compound 4, with the yield of 82%.
Example 12: synthesis of Compounds 3-4
Figure BDA0002906347620000131
A100 ml four-necked flask was charged with Compound 2-1(4.2g, 0.011mol), methyl chloroacetate (1.29 g), and THF (40 ml). Starting magnetic stirring, slowly adding t-BuOK (1.85g) at 20-25 ℃, and reacting for 15 hours at 20-25 ℃ after the addition is finished. After the reaction is finished, 20mL of saturated ammonium chloride aqueous solution and 20mL of ethyl acetate are added, the mixture is stirred and separated, the water phase is extracted twice by ethyl acetate (20mL x2), organic phases are combined, the mixture is concentrated to be dry at 35-40 ℃ under reduced pressure, a brown oily substance is obtained, and the crude product is separated by column chromatography (mobile phase is n-heptane: ethyl acetate which is 2: 1 (volume ratio)) to obtain a light yellow oily substance (2.5g), namely the target product compound 3-4, with the yield of 51%.
Example 13: synthesis of Compound 4
Figure BDA0002906347620000132
A100 mL four-necked flask was charged with compound 3-4(4.4g, 0.01mol) and MeOH (20 mL). Starting magnetic stirring, adding sodium methoxide (1.08g) at 20-25 ℃, and reacting for 12 hours at 20-25 ℃. And (3) after the reaction is finished, evaporating methanol under reduced pressure at 20-25 ℃, adding 20mL of water and 20mL of ethyl acetate, stirring for layering, extracting the water phase twice with ethyl acetate (20mL of x2), combining organic phases, and concentrating under reduced pressure at 35-40 ℃ until the organic phases are dried to obtain a yellow oily substance. The yellow oily substance is dissolved in 10% sulfuric acid aqueous solution (40mL) and reacted for 5 hours at 50-60 ℃. Cooling to 20-25 ℃, adding 20mL of dichloromethane, stirring, standing for layering, extracting the water layer twice (20mL x2) with dichloromethane, combining dichloromethane phases, concentrating at 35-40 ℃ under reduced pressure to dryness to obtain a yellow solid, adding 5mL of ethanol, pulping, and filtering to obtain a white solid (2.3g), namely the target compound 4, with the yield of 68%.

Claims (21)

1. A compound for preparing an intermediate of gliclazide, which has a structure shown in formula 1, and has a structural formula as follows:
Figure FDA0002906347610000011
2. a compound for preparing an intermediate of gliclazide, which has a structure as shown in formula 2, and has the following structural formula:
Figure FDA0002906347610000012
wherein R is1Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl of (a), aryl, aralkyl, aroyl, phenyl, substituted phenyl; the silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
3. A compound of an intermediate formula 2-1 structure for preparing gliclazide, the structural formula is as follows:
Figure FDA0002906347610000013
4. a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 3, and has the following structural formula:
Figure FDA0002906347610000014
wherein is R1，R2Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl. The silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
5. A compound of an intermediate formula 3-1 structure for preparing gliclazide, the structural formula is as follows:
Figure FDA0002906347610000021
6. a compound for preparing an intermediate of gliclazide, which has a structure shown in formula 4, and has the following structural formula:
Figure FDA0002906347610000022
7. a preparation method of a gliclazide intermediate compound with a structure shown in formula 1 is characterized in that the gliclazide intermediate compound is prepared by Mannich reaction of a compound N-tosylhydratecarboxamide, cyclopentanone and formaldehyde under the conditions of acid and a reaction solvent:
Figure FDA0002906347610000023
8. the preparation method of the gliclazide intermediate body type 2 is characterized in that the gliclazide intermediate body type 2 is prepared by performing amino protection reaction on a compound of a formula 1 and an amino protection reagent under the conditions of a catalyst, alkali and a solvent:
Figure FDA0002906347610000024
9. a preparation method of a gliclazide intermediate formula 2-1 is characterized in that the gliclazide intermediate formula is prepared by amino protection reaction of a compound of a formula 1 and acetic anhydride under the conditions of a catalyst, alkali and a solvent:
Figure FDA0002906347610000031
10. the preparation method of the gliclazide intermediate body 3 is characterized in that the gliclazide intermediate body is prepared from a compound shown in a formula 2 and alkyl chloroacetate through a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent:
Figure FDA0002906347610000032
11. a preparation method of a gliclazide intermediate formula 3-1 is characterized in that the gliclazide intermediate formula is prepared by Perkin reaction and epoxidation reaction of a compound of a formula 2-1 and ethyl chloroacetate under the conditions of alkali and a solvent:
Figure FDA0002906347610000033
12. the preparation method of the gliclazide intermediate body 4 is characterized in that the gliclazide intermediate body is prepared by carrying out hydrolysis reaction on a compound of a formula 3 in alkali and a solvent and then carrying out decarboxylation reaction in acid and the solvent:
Figure FDA0002906347610000034
13. the preparation method of the gliclazide intermediate body 4 is characterized in that the gliclazide intermediate body is prepared by carrying out hydrolysis reaction on a compound of a formula 3-1 in alkali and a solvent and then carrying out decarboxylation reaction in acid and the solvent:
Figure FDA0002906347610000041
14. the preparation method of gliclazide is characterized in that the gliclazide is prepared by carrying out reductive amination reaction on a compound shown in a formula 4 under the conditions of a metal reducing agent, an acidic activating agent and a solvent:
Figure FDA0002906347610000042
15. a preparation method of gliclazide is characterized in that a compound of a formula 1 is prepared by a Mannich reaction of a compound N-tosylhydrateacarbxamide, cyclopentanone and formaldehyde under the conditions of acid and a reaction solvent, a compound of a formula 2 is prepared by an amino protection reaction of the compound of the formula 1 and an amino protection reagent under the conditions of a catalyst, alkali and a solvent, a compound of a formula 2 and alkyl chloroacetate are subjected to a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent to prepare a compound of a formula 3, the compound of the formula 3 is subjected to a hydrolysis reaction under an alkaline condition, a decarboxylation reaction is performed under an acidic condition to prepare a compound of a formula 4, and the compound of the formula 4 is prepared by a reduction reaction under the conditions of a metal reducing agent, an acidic activating agent and a solvent:
Figure FDA0002906347610000043
wherein is R1，R2Is C1-C8Silyl group of C2-11Acyl group of (2), C4-9Cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl. The silane group is tetramethylsilane group, trimethylsilyl group, triethylsilyl group, tri-n-butylsilyl group, and tert-butyldimethylsilyl group; the aryl is phenyl, furyl, thienyl or indolyl; the substituted phenyl is alkyl substituted phenyl, alkoxy alkyl substituted phenyl, nitro alkyl substituted phenyl or halogen substituted phenyl; the alkyl substituted phenyl is benzyl, benzhydryl or trityl; the alkoxy alkyl substituted phenyl is p-methoxybenzyl; the nitroalkyl substituted phenyl is p-nitrobenzyl; the halogen-substituted phenyl is p-chlorophenyl.
16. A preparation method of gliclazide is characterized in that a compound of a formula 1 is prepared by a Mannich reaction of a compound N-tosylhydrateacarbxamide, cyclopentanone and formaldehyde under the conditions of acid and a reaction solvent, a compound of a formula 2-1 is prepared by an amino protection reaction of the compound of the formula 1 and acetic anhydride under the conditions of a catalyst, alkali and a solvent, a compound of a formula 2-1 and ethyl chloroacetate are prepared by a Perkin reaction and an epoxidation reaction under the conditions of alkali and a solvent, a compound of a formula 3-1 is subjected to a hydrolysis reaction under an alkaline condition, a decarboxylation reaction is performed under an acidic condition to prepare a compound of a formula 4, and the compound of the formula 4 is prepared by a reductive amination reaction under the conditions of a metal reducing agent, an acidic activating agent and a solvent:
Figure FDA0002906347610000051
17. the production method according to claim 7, 15 or 16, wherein the Mannich reaction step acid is hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, acetic acid, phosphoric acid, nitric acid, boron trifluoride, zinc chloride, 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.
18. The production method according to claim 8, 9, 15 or 16, wherein the amino-protecting reaction step solvent is dichloromethane, tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether toluene, chlorobenzene; the alkali is triethylamine, DIPEA, DBU, pyridine, DBN and DABCO.
19. The production method according to claim 10, 11, 15 or 16, wherein the Perkin reaction step solvent is tetrahydrofuran, DMF, acetonitrile, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, t-butanol, toluene and chlorobenzene; the alkali is potassium tert-butoxide, sodium hydroxide, potassium methoxide, sodium methoxide, potassium ethoxide and sodium ethoxide.
20. The production method according to claim 12, 13, 15 or 16, wherein the hydrolysis and decarboxylation reaction step solvent is an alcohol of five carbons or less; the alkali is sodium methoxide, potassium tert-butoxide, sodium hydroxide, potassium methoxide, potassium ethoxide and sodium ethoxide; the acid is sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid and trifluoromethanesulfonic acid.
21. The method of claim 14, 15 or 16, wherein the reductive amination step activating agent is hydrochloric acid, acetic acid, formic acid, trifluoroacetic acid; the metal reducing agent is trimethoxy sodium borohydride, potassium borohydride, sodium borohydride or cyano sodium borohydride; the solvent is an alcohol with less than or equal to five carbons.
CN202110078337.4A 2020-04-15 2021-01-20 Preparation method of gliclazide Pending CN113527155A (en)

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