CN103508934A

CN103508934A - Preparation method of gliclazide

Info

Publication number: CN103508934A
Application number: CN201210218532.3A
Authority: CN
Inventors: 蔡华军
Original assignee: Weihai Weitai Medical Technology Development Co Ltd
Current assignee: Weihai Weitai Medical Technology Development Co Ltd
Priority date: 2012-06-27
Filing date: 2012-06-27
Publication date: 2014-01-15

Abstract

The invention discloses a synthetic process for preparing gliclazide with low-cost raw materials and high yield. The synthetic process comprises the following reaction steps: 1, preparing N-amino-1,2-cyclopentane phthalic amide by a reaction of 1,2-cyclopentane phthalic anhydride and hydrazine hydrate; 2, reducing the N-amino-1,2-cyclopentane phthalic amide; and 3, preparing the gliclazide by a reaction of methylphenylsulfonylurea and the product reduced in the step 2. By adopting the synthetic process, the N-amino-1,2-cyclopentane phthalic amide is reduced by using an NaBH4/concentrated H2SO4 system from cheap 1,2-cyclopentane phthalic anhydride; an expensive reagent LiA1H4 is avoided. Therefore, the production cost is greatly reduced.

Description

A kind of preparation method of gliclazide

Technical field:

The present invention relates to that a kind of to be used for the treatment of the alone dietary control of sequela of growing up invalid, and without the preparation method of the gliclazide (Gliclazide) of light, the medium-sized diabetes of Ketosis-prone, belong to field of medicaments.

Background technology:

Gliclazide is researched and developed by French SERVIER company, is s-generation sulfourea oral hypoglycemic, and normal people and diabetic subject are all had to hypoglycemic activity.The alone dietary control of sequela that is mainly used in growing up is invalid, and without light, the medium-sized diabetes of Ketosis-prone.Early than 1972, in France, go on the market, within 1985, introduce after China, obtained numerous doctors and expert's consistent favorable comment.Its chemical structural formula is as follows:

The synthetic method that gliclazide is more traditional is as follows:

Reaction is from the industry raw material 1 that is easy to get, and the adjacent dicarboximide of 2-pentamethylene starts, through LiAlH ₄reduction, obtains 3-azabicyclo [3.3.0] octane; Under acidic conditions, react with Sodium Nitrite again, generate nitroso compound; Through zinc powder reduction, obtain six hydrogen-2-cyclopentano pyrryl amine (amino-heterocycles); Last and tolylsulfonylurea condensation obtains product gliclazide.

This route part of greatest concern is LiAlH ₄use.On the one hand, LiAlH ₄price is higher, and reaction cost can be in any more; On the other hand, LiAlH ₄it is a kind of high-risk chemical; because it has higher reactive behavior; can with the material vigorous reaction with active hydrogen; discharge large calorimetric; while therefore using this material; very strict to the content requirement of water in system, and reaction requires anaerobic, all brings very big inconvenience to the setting of operation and reactive system.

So the present invention is devoted to provide a kind of method that route is brief, low-cost, high yield is prepared gliclazide.

Summary of the invention:

Main purpose of the present invention is to adopt the adjacent dicarboxylic acid anhydride of 1,2-pentamethylene to react with hydrazine hydrate, and a step obtains N-amino-1, the adjacent dicarboximide of 2-pentamethylene.

Another object of the present invention is to adopt NaBH ₄/ dense H ₂sO ₄reduction system N-amino 1, the adjacent diformamide of 2-pentamethylene, avoids using expensive LiAlH ₄, both saved cost, reduced again operation difficulty, be more suitable for suitability for industrialized production.

Method of the present invention specifically comprises the following steps:

(1) under reflux state, in pentamethylene neighbour dicarboxylic acid anhydride/ethanol system, slowly drip the hydrazine hydrate of 1.05eq., GC follows the tracks of reaction extremely completely.Remove second alcohol and water, obtain thick liquid, crystallisation by cooling.Solid is pulverized to frozen water making beating half an hour, suction filtration, gained solid drying at room temperature 12 hours in vacuum drying oven.

(2) vitriol oil slowly adds in tetrahydrofuran (THF), puts to room temperature standby.(1) in, product is dissolved in tetrahydrofuran (THF), adds sodium borohydride, under ice-water bath is cooling, slowly drips the above-mentioned vitriol oil/tetrahydrofuran solution preparing.Finish, reflux, GC follows the tracks of reaction to complete.Naturally cooling, slowly drips methyl alcohol cancellation reaction, and normal pressure steams and desolventizes, and obtains soup compound, adds 1M aqueous sodium hydroxide solution, By Hydrolysis At Room Temperature 1h.Extraction, GC shows product content > 90%, reacts salify with HC1/ methanol solution.

(3) upper step product and 1.1eq. tolylsulfonylurea are added in toluene, reflux, TLC follows the tracks of reaction to complete.Decompression rotary evaporation, except most toluene, adds water, normal temperature crystallization, and suction filtration, solid washes with water, re-crystallizing in ethyl acetate, 80 ℃ of vacuum-dryings obtain product, and HPLC shows that purity is 99.7%.

Embodiment:

Embodiment 1:N-amino-1, the adjacent dicarboximide of 2-pentamethylene

In being housed, the 1L tetra-strength bottles of mechanical stirring, prolong, dropping funnel add the adjacent dicarboxylic acid anhydride (50g, 357mmol) of 1,2-pentamethylene, 250mL ethanol, reflux.Slowly drip 80% hydrazine hydrate (24.4mL, 375mmol), dropwise rear continuation backflow, gas phase is followed the tracks of reaction to completely, reacts and approximately needs 8h.Stop heating, naturally be down to room temperature, decompression time rotary evaporation desolventizes, and obtains thick liquid, washes out solid after cooling.Comminuted solids, under ice-water bath is cooling, 50mL cold water is pulled an oar half an hour, suction filtration, solid in 30 ℃ of freeze-day with constant temperature 12h, obtains product 46g in vacuum drying oven, yield 83.6%, fusing point is 11.3～114.6 ℃, gas phase purity 98.2%.

2: six hydrogen-2-cyclopentano pyrryl amine hydrochlorates of embodiment

The vitriol oil of 75.0mL is carefully diluted in the tetrahydrofuran (THF) of 200mL, blackening, puts to room temperature.

In the there-necked flask of 3L, add N-amino-1, the tetrahydrofuran (THF) of the adjacent dicarboximide (212.7g, 1.38mol) of 2-pentamethylene and 1.5L, is stirred to solid under room temperature and dissolves completely, adds sodium borohydride (130g, 3.45mol) in batches.System is placed under ice-water bath cooling.The tetrahydrofuran (THF) diluent that drips the vitriol oil when system temperature is down to 5～10 ℃, dropwises, reflux, and gas phase is followed the tracks of reaction to completely, approximately needs 14～16h.

After reaction finishes, be naturally down to room temperature, drip methyl alcohol cancellation reaction, stir 30min.Normal pressure steams most solvent (about 1L) and obtains white soup compound, adds 1.5L aqueous sodium hydroxide solution (5M), exothermic heat of reaction, stirring at room 1h.

System is proceeded to stratification in separating funnel.Fen Qu upper strata, colourless or weak yellow liquid, vapor detection purity > 90%.Product crude product (tetrahydrofuran solution) is directly used in next step and prepares hydrochloride.

The THF solution of upper crude reaction is cooled to 0-10 ℃, drips hydrochloric acid/methanol solution, regulate pH=1-2.Be evaporated to solvent-freely, obtain thick liquid, the making beating of 100mL ethyl acetate room temperature, suction filtration, obtains white solid 201g, yield 89%.

Embodiment 3: the preparation of gliclazide

In being housed, the 250mL tri-strength bottles of mechanical stirring, prolong add six hydrogen-2-cyclopentano pyrryl amine hydrochlorate (20g, 123mmol), tolylsulfonylurea (29g, 135mmol), 100mL toluene, reflux, it is complete that thin-layer chromatography is followed the tracks of reaction ester, approximately needs 2～3h.After reaction finishes, remove toluene under reduced pressure, add 100mL water, stirring at room crystallization 12h.Suction filtration, a small amount of cold water washing solid, re-crystallizing in ethyl acetate, in 80 ℃ of freeze-day with constant temperature 12h, obtains product 34.1g in vacuum drying oven, yield 85.8%.

Claims

1. a method of preparing gliclazide, is characterized in that the method experiences following process:

The adjacent dicarboxylic acid anhydride of the first step pentamethylene reacts the adjacent diformamide of preparation N-Aminocyclopentane with hydrazine hydrate;

Second step NaBH ₄/ dense H ₂sO ₄the adjacent diformamide of reduction system N-Aminocyclopentane; And

The 3rd step tolylsulfonylurea reacts preparation gliclazide with upper step reduzate.

2. preparation method according to claim 1, in the first step, hydrazine hydrate concentration used is 30%-85%, preferably 80%.

3. preparation method according to claim 1, in second step, n (NaBH ₄): n (dense H ₂sO ₄)=1～10: 1, preferably 2～4: 1.

4. preparation method according to claim 1, in step the three steps, reaction solvent is toluene.