CN100591667C - N-amino-1,2-cyclopentane dicarboximide and its preparation method - Google Patents

Abstract

The invention discloses an N-amino-1,2-cyclopentane dicarboximide, whose chemical structural formula is: (see the formula on the right). The invention also discloses its preparation method: take cyclopentane phthalic anhydride as raw material, carry out reflux reaction with hydrazine hydrate in a solvent, the reaction time is 0.5 to 12 hours, the moles of cyclopentane phthalic anhydride and hydrazine hydrate Ratio=1:1～2.5; after the reaction, the solvent is removed and dried to obtain N-amino-1,2-cyclopentanedicarboximide. The N-amino-1,2-cyclopentane dicarboximide of the invention can be used as an intermediate of gliclazide, thereby shortening the reaction route of gliclazide and effectively reducing waste.

Description

N-amino-1,2-cyclopentane dicarboximide and its preparation method

technical field

The invention relates to an organic substance N-amino-1,2-cyclopentane dicarboximide and its chemical synthesis method.

Background technique

N-amino-1,2-cyclopentanedicarboximide is a key intermediate for the preparation of Gliclazide. Gliclazide is a second-generation sulfonylurea oral hypoglycemic drug, which has dual effects of lowering blood sugar and improving blood coagulation function, and is widely used clinically. The synthesis of gliclazide usually takes cyclopentane phthalic acid imide as raw material, reacts with LiAlH in tetrahydrofuran, and _reduces to obtain the azacyclic ring (Griot, R.SiegfriedAkt.-Ges., Zofingen, Switz.Helvetica Chimica Acta .1959, 42:67-72); this substance was dissolved in acetic acid and reacted with sodium nitrite to obtain N-nitroso-3-azabicyclooctane, which was then reduced by zinc powder to obtain hexahydro-2-cyclo Penpyrrolylamine (JP05065270A), and finally condensed with p-toluenesulfonylurea to obtain the product (JP06041073A). The reaction process is as follows:

The main disadvantage of this reaction process is that the steps are cumbersome, and the product can only be obtained through 4 steps of reaction, and the reaction cost is high.

Contents of the invention

The technical problem to be solved in the present invention is to provide a kind of N-amino-1,2-cyclopentane dicarboximide and preparation method thereof, this N-amino-1,2-cyclopentane dicarboximide can As an intermediate in the synthesis of the hypoglycemic drug gliclazide, it can shorten the reaction route of gliclazide and effectively reduce waste.

In order to solve the above technical problems, the invention provides a kind of N-amino-1,2-cyclopentane dicarboximide, its chemical structural formula is:

The present invention also provides a preparation method of N-amino-1,2-cyclopentanedicarboximide, which uses cyclopentane phthalic anhydride as raw material and reflux reaction with hydrazine hydrate in a solvent, and the reaction time is 0.5 ~12 hours, the molar ratio of cyclopentane phthalic anhydride to hydrazine hydrate=1:1~2.5; after the reaction, the solvent is removed and dried to obtain N-amino-1,2-cyclopentane dicarboximide .

As an improvement of the preparation method of the present invention: first put cyclopentane phthalic anhydride into the solvent, and then add hydrazine hydrate into the solvent in the form of dropwise addition, and the dropwise addition is at normal temperature or under reflux conditions.

As a further improvement of the preparation method of the present invention: the solvent is a mixture of water, alcohol organic solvents, ester organic solvents, other organic solvents except alcohols and esters and water, other organic solvents except alcohols and esters. A mixture of organic solvents and alcohol organic solvents, or a mixture of organic solvents other than alcohols and esters and ester organic solvents. Alcohol organic solvents are methanol, ethanol, propanol, isopropanol, butanol, isobutanol, ethylene glycol, diethylene glycol, cyclohexanol or benzyl alcohol; ester organic solvents are ethyl acetate, methyl acetate or butyl acetate. Other organic solvents besides alcohols and esters are hydrocarbons (such as pentane, hexane, cyclohexane, petroleum ether, benzene, toluene or xylene), halogenated hydrocarbons (chloroform, dichloromethane or dichloromethane) ethane), acetone, methyl ethyl ketone cyclohexanone or tetrahydrofuran. The molar ratio of solvent to cyclopentane phthalic anhydride is 1-50:1.

As a further improvement of the preparation method of the present invention: the hydrazine hydrate is an aqueous solution of hydrazine hydrate with a mass fraction of 25% to 85%.

Reaction equation of the present invention can be expressed as:

The product prepared by the method of the present invention is analyzed by a gas phase-mass spectrometer, and the molecular ion peak of M=154 and the succinimide anion fragment of M=98 are confirmed. Through infrared analysis, the characteristic absorption peak of amide carbonyl carbon-oxygen bond (-C=O) appeared at 1707cm ^-1 , and the characteristic absorption peak of amino nitrogen hydrogen bond (-NH) appeared at 3297cm ^-1 and 3174cm ^-1 , and For the doublet, proved to be primary amine. It was finally determined to be N-amino-1,2-cyclopentane dicarboximide.

N-amino-1,2-cyclopentane dicarboximide of the present invention is used for producing gliclazide, and the reaction process is as follows:

In summary, adopting N-amino-1,2-cyclopentanedicarboximide of the present invention to produce gliclazide shortens the reaction steps, is beneficial to environmental protection and reduces production costs; it is suitable for large-scale batches Production.

Detailed ways

The present invention will be further described below in conjunction with specific embodiment:

Embodiment 1: A kind of preparation method of N-amino-1,2-cyclopentane dicarboximide, carries out following steps successively:

In a 250mL three-necked flask equipped with a reflux condenser and mechanical stirring, add 14g of cyclopentane phthalic anhydride and 50mL of methanol, after heating to reflux, slowly add 7mL of 85% hydrazine hydrate aqueous solution dropwise, and continue to reflux after the dropwise addition React for 6 hours.

After the reaction is over, stop heating, put the reaction solution to a rotary evaporator to distill off the solvent and water under reduced pressure to obtain a viscous liquid, and after cooling to obtain the product N-amino-1,2-cyclopentanedicarboximide, vacuum Dry at 30° C. for 12 hours to obtain 13.5 g of the product with a yield of 87.7%.

Embodiment 2: A kind of preparation method of N-amino-1,2-cyclopentane dicarboximide, carries out following steps successively:

In a 250mL three-necked flask equipped with a reflux condenser and mechanical stirring, add 14g of cyclopentane phthalic anhydride, 50mL of methanol, and add 7mL of 85% hydrazine hydrate dropwise at room temperature. After the dropwise addition, it is heated to reflux, and the reaction time is 7 Hour.

After the reaction is over, stop heating, put the reaction solution to a rotary evaporator to distill off the solvent and water under reduced pressure to obtain a viscous liquid, and after cooling to obtain the product N-amino-1,2-cyclopentanedicarboximide, vacuum Dry at 30° C. for 12 hours to obtain 13.2 g of the product with a yield of 85.7%.

Embodiments 3-11: By changing the solvent, the concentration of hydrazine hydrate, the dosage of hydrazine hydrate, and the reaction time in the above-mentioned embodiment 1 or 2, corresponding embodiments 3-11 can be obtained. The specific content is shown in Table 1, and the product yield of each embodiment gained is shown in Table 1.

The concrete data of table 1, embodiment 3～11

Example Amount of raw materials g Solvent and dosage mL Concentration % and dosage ml of hydrazine hydrate aqueous solution Hydrazine hydrate drop method Response time h Yield % 3 14 Ethanol (100mL) 80%, 10ml reflux drop 7 82.6 4 20 Water (60mL) 85%, 8ml Dropping at room temperature 3 78.6

5 14 Ethyl acetate (30mL), ethanol (50mL) 65%, 15ml reflux drop 6 76.4 6 20 Methanol (120mL) 25%, 40ml Dropping at room temperature 0.5 76.6 7 20 Toluene (120mL) 85%, 22ml reflux drop 5 72.8 8 20 Methanol (80mL), dichloroethane (20mL) 85%, 15ml Dropping at room temperature 2 78.3 9 40 Ethanol (250mL) 45%, 40ml Dropping at room temperature 12 64.2 10 14 Petroleum ether (60mL), methanol (60mL) 85%, 8ml reflux drop 6 82.4 11 14 Diethylene glycol (80mL) 85%, 7ml reflux drop 4 79.2

Embodiment 12, the synthesis of hexahydro-2-cyclopentapyrrolylamine:

In a 250mL three-necked flask equipped with a reflux condenser and mechanical stirring, add 80mL of tetrahydrofuran, preheat to about 50°C, add 25g of aluminum trichloride, stir for 10 minutes, add 12g of potassium borohydride, and then add 15.4g of N-amino -1,2-cyclopentane dicarboximide, heated to reflux, reacted for 7 hours. Cool down after the reaction, extract with 50×3mL toluene, add hydrochloric acid to the extract, acidify to pH ≈ 3, distill off toluene and a small amount of water under reduced pressure to obtain the product hydrochloride, and recrystallize with ethanol to obtain the product hydrochloride 12.8 g, the yield is 78.7%.

Embodiment 13, the synthesis of Gliclazide:

In a 250mL three-necked flask equipped with a reflux condenser and mechanical stirring, add the hydrochloride salt of 16.3g of hexahydro-2-cyclopentopyrrolylamine, 22g of p-toluenesulfonylurea, and 100mL of DMF, and heat to reflux, and the reaction is about 2 hours. At the end of the reaction, 100 mL of water was added dropwise, cooled to about 10°C to precipitate the material, filtered, and washed with appropriate amount of water to obtain the product gliclazide. It was dried at 80°C for 12 hours under vacuum to obtain 28.2g of the product with a melting point of 163.1-165.3°C and a yield of 87.2%.

Finally, it should be noted that the above examples are only some specific embodiments of the present invention. Obviously, the present invention is not limited to the above embodiments, and many variations are possible. All deformations that can be directly derived or associated by those skilled in the art from the content disclosed in the present invention should be considered as the protection scope of the present invention.

Claims (9)

1, a kind of N-amino-1,2-cyclopentane dicarboximide is characterized in that its chemical structural formula is:

2. The preparation method of N-amino-1,2-cyclopentane dicarboximide as claimed in claim 1 is characterized in that: taking cyclopentane phthalic anhydride as raw material, mixing hydrazine hydrate in a solvent Carry out reflux reaction, the reaction time is 0.5～12 hours, the molar ratio of cyclopentane phthalic anhydride and hydrazine hydrate=1:1～2.5; After the reaction is finished, the solvent is removed and dried to obtain N-amino-1,2- Cyclopentanedicarboximide. 3. The preparation method of N-amino-1,2-cyclopentane dicarboximide according to claim 2 is characterized in that: first put cyclopentane phthalic anhydride into the solvent, and then hydrate Hydrazine is added dropwise into the solvent, and the dropwise addition is at normal temperature or under reflux conditions. 4. The preparation method of N-amino-1,2-cyclopentane dicarboximide according to claim 2 or 3, characterized in that: the solvent is water, alcohol organic solvent, ester organic solvent , Mixed solution of organic solvents other than alcohols and esters and water, mixed solution of organic solvents other than alcohols and esters and organic solvents of alcohols, or organic solvents other than alcohols and esters Mixture with ester organic solvents. 5. The preparation method of N-amino-1,2-cyclopentanedicarboximide according to claim 4, characterized in that: the alcohol organic solvent is methanol, ethanol, propanol, isopropanol , butanol, isobutanol, ethylene glycol, diethylene glycol, cyclohexanol or benzyl alcohol; the ester organic solvent is ethyl acetate, methyl acetate or butyl acetate. 6. The preparation method of N-amino-1,2-cyclopentanedicarboximide according to claim 5, characterized in that: the other organic solvents except alcohols and esters are hydrocarbons, Halogenated hydrocarbons, acetone, butanone, cyclohexanone or tetrahydrofuran. 7. The preparation method of N-amino-1,2-cyclopentane dicarboximide according to claim 6, characterized in that: said hydrocarbons are pentane, hexane, cyclohexane, petroleum ether , Benzene, toluene or xylene, and the halogenated hydrocarbon is chloroform, dichloromethane or dichloroethane. 8. The preparation method of N-amino-1,2-cyclopentane dicarboximide according to claim 7, characterized in that: the molar ratio of the solvent to cyclopentane phthalic anhydride is 1- 50:1. 9. The method for preparing N-amino-1,2-cyclopentanedicarboximide according to claim 8, characterized in that: the hydrazine hydrate is an aqueous solution of hydrazine hydrate with a mass fraction of 25% to 85% .