CN101235011A - N-amino-1,2-cyclopentanediformylimine and preparation method thereof - Google Patents
N-amino-1,2-cyclopentanediformylimine and preparation method thereof Download PDFInfo
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- CN101235011A CN101235011A CNA2008100601281A CN200810060128A CN101235011A CN 101235011 A CN101235011 A CN 101235011A CN A2008100601281 A CNA2008100601281 A CN A2008100601281A CN 200810060128 A CN200810060128 A CN 200810060128A CN 101235011 A CN101235011 A CN 101235011A
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Abstract
The invention discloses an N-amino-1, 2-cyclopentane dicarboximide whose formula is represented as right. The invention also discloses a corresponding preparation method which comprises using cyclopentane ortho-anhydride as raw material, carrying out hydrazine hydrate in solvent for refluxing reaction for 0.5-12h while the mol ratio of cyclopentane ortho-anhydride and hydrazine hydrate is 1:1-2.5, removing solvent after reaction, and drying to obtain N-amino-1, 2-cyclopentane dicarboximide. The N-amino-1, 2-cyclopentane dicarboximide can be used as the intermediate of gliclazide, thereby reducing the reaction route of gliclazide to reduce waste.
Description
Technical field
The present invention relates to a kind of organism N-amino-1,2-cyclopentanediformylandne and chemical synthesis process thereof.
Background technology
N-amino-1,2-cyclopentanediformylandne are the key intermediates of preparation gliclazide (Gliclazide).Gliclazide is a s-generation sulfonylurea oral antidiabetic drug, has hypoglycemic and improves the dual function of coagulation function, is widely used clinically.The synthetic of gliclazide is raw material with the adjacent dioctyl phthalate imines of pentamethylene usually, in tetrahydrofuran (THF) with LiAlH
4The reaction, the reduction obtain heterocyclic (Griot, R.SiegfriedAkt.-Ges., Zofingen, Switz.Helvetica Chimica Acta.1959,42:67-72); This material is dissolved in the acetic acid with the Sodium Nitrite reaction obtains N-nitroso-group-3-azabicyclooctane, obtain six hydrogen-2-cyclopentano pyrryl amine (JP05065270A) through zinc powder reduction again, last and tolylsulfonylurea condensation obtains product (JP06041073A).Reaction process is as follows:
The main drawback of this reaction process is a complex steps, just can obtain product, the reaction cost height through the reaction of 4 steps.
Summary of the invention
The technical problem to be solved in the present invention provides a kind of N-amino-1,2-cyclopentanediformylandne and preparation method thereof, this N-amino-1, the 2-cyclopentanediformylandne can be as synthetic hypoglycemic drug---the intermediate of gliclazide, thereby shorten the reaction scheme of gliclazide, effectively reduce waste.
In order to solve the problems of the technologies described above, the invention provides a kind of N-amino-1, the 2-cyclopentanediformylandne, its chemical structural formula is:
The present invention also provides N-amino-1, the preparation method of 2-cyclopentanediformylandne is a raw material with the adjacent dicarboxylic acid anhydride of pentamethylene, carries out back flow reaction with hydrazine hydrate in solvent, reaction times is 0.5～12 hour, mol ratio=1: 1～2.5 of adjacent dicarboxylic acid anhydride of pentamethylene and hydrazine hydrate; Reaction removes solvent after finishing, and drying obtains N-amino-1, the 2-cyclopentanediformylandne.
Improvement as preparation method of the present invention: earlier the adjacent dicarboxylic acid anhydride of pentamethylene is put into solvent, then hydrazine hydrate is added in the solvent with the form that drips, described dropping is that normal temperature or reflux conditions drip down.
Further improvement as preparation method of the present invention: solvent is the mixed solution of mixed solution, other organic solvent except that alcohols and ester class and alcohol organic solvent of water, alcohol organic solvent, ester class organic solvent, other organic solvent except that alcohols and ester class and water or the mixed solution of other organic solvent except that alcohols and ester class and ester class organic solvent.Alcohol organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, ethylene glycol, glycol ether, hexalin or benzylalcohol; Ester class organic solvent is ethyl acetate, methyl acetate or butylacetate.Other organic solvent except that alcohols and ester class is hydro carbons (for example being pentane, hexane, hexanaphthene, sherwood oil, benzene, toluene or dimethylbenzene), halohydrocarbon (chloroform, methylene dichloride or ethylene dichloride), acetone, butanone pimelinketone or tetrahydrofuran (THF).The mol ratio of the adjacent dicarboxylic acid anhydride of solvent and pentamethylene is 1～50: 1.
Further improvement as preparation method of the present invention: hydrazine hydrate is that massfraction is 25%～85% hydrazine hydrate aqueous solution.
Reaction equation of the present invention can be expressed as:
The product that adopts method preparation of the present invention has been determined the molecular ion peak of M=154 through gas phase-spectrometer analysis, and the succimide negative ion fragment of M=98.Through infrared analysis, at 1707cm
-1(charateristic avsorption band C=O) is at 3297cm the amidocarbonylation carbon-oxygen bond to have occurred
-1, 3174cm
-1(charateristic avsorption band N-H), and be bimodal proves primary amine the amino nitrogen hydrogen bond to have occurred.Finally be defined as N-amino-1, the 2-cyclopentanediformylandne.
With N-amino-1 of the present invention, the 2-cyclopentanediformylandne is used for the production gliclazide, and reaction process is as follows:
In sum, adopt N-amino-1 of the present invention, 2-cyclopentanediformylandne production gliclazide has shortened reactions steps, and helps environmental protection and reduce production costs; Be suitable for large-scale batch process.
Embodiment
Below in conjunction with specific embodiment the present invention is further described:
Embodiment 1: a kind of N-amino-1, the preparation method of 2-cyclopentanediformylandne, carry out following steps successively:
In reflux condensing tube, churned mechanically 250mL there-necked flask are housed, add the adjacent dicarboxylic acid anhydride of 14g pentamethylene, 50mL methyl alcohol, be heated to backflow after, slowly drip the hydrazine hydrate aqueous solution of 7mL 85%, dropwise the back and continued back flow reaction 6 hours.
After reaction finishes, stop heating, reaction solution to Rotary Evaporators place underpressure distillation is gone out solvent and water, obtain thick liquid, obtain product N-amino-1 after the cooling, the 2-cyclopentanediformylandne, in 30 ℃ of dryings 12 hours, obtain product 13.5g under the vacuum, yield is 87.7%.
Embodiment 2: a kind of N-amino-1, the preparation method of 2-cyclopentanediformylandne, carry out following steps successively:
In reflux condensing tube, churned mechanically 250mL there-necked flask are housed, add the adjacent dicarboxylic acid anhydride of 14g pentamethylene, 50mL methyl alcohol, normal temperature drip the hydrazine hydrate of 7mL 85% down, dropwise post-heating to refluxing 7 hours reaction times.
After reaction finishes, stop heating, reaction solution to Rotary Evaporators place underpressure distillation is gone out solvent and water, obtain thick liquid, obtain product N-amino-1 after the cooling, the 2-cyclopentanediformylandne, in 30 ℃ of dryings 12 hours, obtain product 13.2g under the vacuum, yield is 85.7%.
Embodiment 3～11: change solvent, hydrazine hydrate concentration and hydrazine hydrate consumption, reaction times in the foregoing description 1 or 2, can obtain respective embodiments 3～11.Particular content sees Table 1, and the product yield of each embodiment gained sees Table 1.
The concrete data of table 1, embodiment 3～11
| Embodiment | Raw material consumption g | Solvent and consumption mL | The concentration % of hydrazine hydrate aqueous solution and consumption ml | Hydrazine hydrate drips mode | Reaction times h | Yield % |
| 3 | 14 | Ethanol (100mL) | 80％，10ml | Reflux and drip | 7 | 82.6 |
| 4 | 20 | Water (60mL) | 85％，8ml | Normal temperature drips | 3 | 78.6 |
| 5 | 14 | Ethyl acetate (30mL), ethanol (50mL) | 65％，15ml | Reflux and drip | 6 | 76.4 |
| 6 | 20 | Methyl alcohol (120mL) | 25％，40ml | Normal temperature drips | 0.5 | 76.6 |
| 7 | 20 | Toluene (120mL) | 85％，22ml | Reflux and drip | 5 | 72.8 |
| 8 | 20 | Methyl alcohol (80mL), ethylene dichloride (20mL) | 85％，15ml | Normal temperature drips | 2 | 78.3 |
| 9 | 40 | Ethanol (250mL) | 45％，40ml | Normal temperature drips | 12 | 64.2 |
| 10 | 14 | Sherwood oil (60mL), methyl alcohol (60mL) | 85％，8ml | Reflux and drip | 6 | 82.4 |
| 11 | 14 | Glycol ether (80mL) | 85％，7ml | Reflux and drip | 4 | 79.2 |
Synthesizing of embodiment 12, six hydrogen-2-cyclopentano pyrryl amine:
In reflux condensing tube, churned mechanically 250mL there-necked flask are housed, add the 80mL tetrahydrofuran (THF), be preheated to and add the 25g aluminum chloride about 50 ℃, add the 12g POTASSIUM BOROHYDRIDE after stirring 10min, add 15.4gN-amino-1 behind the restir 15min, the 2-cyclopentanediformylandne is heated to backflow, reacts 7 hours.Reaction finishes postcooling, and with the extraction of 50 * 3mL toluene, extraction liquid adds hydrochloric acid, is acidified to pH ≈ 3, and underpressure distillation goes out toluene and less water, obtains the product hydrochloride, and uses ethyl alcohol recrystallization, obtains the hydrochloride 12.8g of product, and yield is 78.7%.
Synthesizing of embodiment 13, gliclazide:
In reflux condensing tube, churned mechanically 250mL there-necked flask are housed, add the hydrochloride of 16.3g six hydrogen-2-cyclopentano pyrryl amine, the 22g tolylsulfonylurea, 100mL DMF is heated to backflow, reacts about 2 hours.Reaction finishes to drip water 100mL, is cooled to about 10 ℃ and separates out material, filters, and an amount of washing obtains the product gliclazide.In 80 ℃ of dryings 12 hours, obtain product 28.2g under the vacuum, fusing point is 163.1～165.3 ℃, and yield is 87.2%.
At last, it is also to be noted that what more than enumerate only is several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, many distortion can also be arranged.All distortion that those of ordinary skill in the art can directly derive or associate from content disclosed by the invention all should be thought protection scope of the present invention.
Claims (9)
1, a kind of N-amino-1, the 2-cyclopentanediformylandne is characterized in that its chemical structural formula is:
2, as claim 1 described N-amino-1, the preparation method of 2-cyclopentanediformylandne, it is characterized in that: with the adjacent dicarboxylic acid anhydride of pentamethylene is raw material, in solvent, carry out back flow reaction with hydrazine hydrate, reaction times is 0.5～12 hour, mol ratio=1: 1～2.5 of adjacent dicarboxylic acid anhydride of pentamethylene and hydrazine hydrate; Reaction removes solvent after finishing, and drying obtains N-amino-1, the 2-cyclopentanediformylandne.
3, according to claim 2 described N-amino-1, the preparation method of 2-cyclopentanediformylandne, it is characterized in that: earlier the adjacent dicarboxylic acid anhydride of pentamethylene is put into solvent, then hydrazine hydrate is added in the solvent with the form that drips, described dropping is that normal temperature or reflux conditions drip down.
4, according to claim 2 or 3 described N-amino-1, the preparation method of 2-cyclopentanediformylandne is characterized in that: described solvent is the mixed solution of mixed solution, other organic solvent except that alcohols and ester class and alcohol organic solvent of water, alcohol organic solvent, ester class organic solvent, other organic solvent except that alcohols and ester class and water or the mixed solution of other organic solvent except that alcohols and ester class and ester class organic solvent.
5, according to claim 4 described N-amino-1, the preparation method of 2-cyclopentanediformylandne is characterized in that: described alcohol organic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, isopropylcarbinol, ethylene glycol, glycol ether, hexalin or benzylalcohol; Described ester class organic solvent is ethyl acetate, methyl acetate or butylacetate.
6, according to claim 5 described N-amino-1, the preparation method of 2-cyclopentanediformylandne is characterized in that: described other organic solvent except that alcohols and ester class is hydro carbons, halohydrocarbon, acetone, butanone pimelinketone or tetrahydrofuran (THF).
7, according to claim 6 described N-amino-1, the preparation method of 2-cyclopentanediformylandne, it is characterized in that: described hydro carbons is pentane, hexane, hexanaphthene, sherwood oil, benzene, toluene or dimethylbenzene, and described halohydrocarbon is chloroform, methylene dichloride or ethylene dichloride.
8, according to claim 7 described N-amino-1, the preparation method of 2-cyclopentanediformylandne is characterized in that: the mol ratio of the adjacent dicarboxylic acid anhydride of described solvent and pentamethylene is 1～50: 1.
9, according to claim 8 described N-amino-1, the preparation method of 2-cyclopentanediformylandne is characterized in that: described hydrazine hydrate is that massfraction is 25%～85% hydrazine hydrate aqueous solution.
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011054312A1 (en) * | 2009-11-09 | 2011-05-12 | 浙江九洲药业股份有限公司 | Method for preparing gliclazide and its intermediate |
| CN102382034A (en) * | 2010-09-06 | 2012-03-21 | 山东方明药业股份有限公司 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN102584677A (en) * | 2012-02-07 | 2012-07-18 | 安徽金鼎医药有限公司 | Method for preparing gliclazide |
| CN102924362A (en) * | 2012-10-26 | 2013-02-13 | 浙江工业大学 | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride |
| CN103183632A (en) * | 2011-12-29 | 2013-07-03 | 山东方明药业集团股份有限公司 | Purification method of 3-azabicyclo-octane hydrochloride |
| CN103601666A (en) * | 2013-11-28 | 2014-02-26 | 遵义医学院 | Preparation method of octahydrocyclopentane[C]pyrrole |
| CN106588746A (en) * | 2016-11-25 | 2017-04-26 | 盘锦格林凯默科技有限公司 | Preparation method of gliclazide side chain and preparation method of gliclazide |
| CN108084080A (en) * | 2018-01-22 | 2018-05-29 | 安徽金鼎医药股份有限公司 | A kind of preparation method of gliclazide intermediate hexahydro cyclopentano [c] pyrrole radicals -2- amine hydrochlorates |
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
-
2008
- 2008-03-11 CN CN200810060128A patent/CN100591667C/en not_active Expired - Fee Related
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011054312A1 (en) * | 2009-11-09 | 2011-05-12 | 浙江九洲药业股份有限公司 | Method for preparing gliclazide and its intermediate |
| CN102050778B (en) * | 2009-11-09 | 2012-09-05 | 浙江九洲药业股份有限公司 | Method for synthesizing gliclazide and intermediate thereof |
| CN102382034B (en) * | 2010-09-06 | 2013-03-27 | 山东方明药业集团股份有限公司 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN102382034A (en) * | 2010-09-06 | 2012-03-21 | 山东方明药业股份有限公司 | Synthetic method of N-amino-3-azabicyclo[3,3,0]octane hydrochloride |
| CN103183632A (en) * | 2011-12-29 | 2013-07-03 | 山东方明药业集团股份有限公司 | Purification method of 3-azabicyclo-octane hydrochloride |
| CN102584677A (en) * | 2012-02-07 | 2012-07-18 | 安徽金鼎医药有限公司 | Method for preparing gliclazide |
| CN102584677B (en) * | 2012-02-07 | 2014-01-08 | 安徽金鼎医药有限公司 | Method for preparing gliclazide |
| CN102924362A (en) * | 2012-10-26 | 2013-02-13 | 浙江工业大学 | Preparation method of hexahydro-2-cyclopentyl-pyrryl amine hydrochloride |
| CN103601666A (en) * | 2013-11-28 | 2014-02-26 | 遵义医学院 | Preparation method of octahydrocyclopentane[C]pyrrole |
| CN103601666B (en) * | 2013-11-28 | 2015-09-02 | 遵义医学院 | The preparation method of octahydro pentamethylene [C] pyrroles |
| CN106588746A (en) * | 2016-11-25 | 2017-04-26 | 盘锦格林凯默科技有限公司 | Preparation method of gliclazide side chain and preparation method of gliclazide |
| CN106588746B (en) * | 2016-11-25 | 2019-08-13 | 盘锦格林凯默科技有限公司 | The preparation method of gliclazide side chain and the preparation method of gliclazide |
| CN108084080A (en) * | 2018-01-22 | 2018-05-29 | 安徽金鼎医药股份有限公司 | A kind of preparation method of gliclazide intermediate hexahydro cyclopentano [c] pyrrole radicals -2- amine hydrochlorates |
| CN110372568A (en) * | 2019-08-22 | 2019-10-25 | 山东海佑福瑞达制药有限公司 | A kind of crystallization and preparation method thereof of gliclazide intermediate |
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