CN102850257B - The preparation method of 1,2-cyclopentanediformylandne - Google Patents
The preparation method of 1,2-cyclopentanediformylandne Download PDFInfo
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- CN102850257B CN102850257B CN201210343760.3A CN201210343760A CN102850257B CN 102850257 B CN102850257 B CN 102850257B CN 201210343760 A CN201210343760 A CN 201210343760A CN 102850257 B CN102850257 B CN 102850257B
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- Prior art keywords
- alcohols
- cyclopentanediformylandne
- sodium salt
- pimelinketone
- methane amide
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- 0 O=C1C(CCCC2)C2=N*2(CC*CC2)NC1 Chemical compound O=C1C(CCCC2)C2=N*2(CC*CC2)NC1 0.000 description 4
- UZHVXJZEHGSWQV-UHFFFAOYSA-N C(C1)CC2C1CNC2 Chemical compound C(C1)CC2C1CNC2 UZHVXJZEHGSWQV-UHFFFAOYSA-N 0.000 description 1
- PJHBYLVTGMWDQF-UHFFFAOYSA-N C=C(C(NSc(cc1)ccc1N)=O)N1CC(CCC2)C2C1 Chemical compound C=C(C(NSc(cc1)ccc1N)=O)N1CC(CCC2)C2C1 PJHBYLVTGMWDQF-UHFFFAOYSA-N 0.000 description 1
- AJLXEQGMJVJHLC-SPWRCNBUSA-N CC(C(CCC1)C1C(C1)O)([C@H]1N)O Chemical compound CC(C(CCC1)C1C(C1)O)([C@H]1N)O AJLXEQGMJVJHLC-SPWRCNBUSA-N 0.000 description 1
- DRCJYFKOAFMDFL-UHFFFAOYSA-N CNC(C(CCCC1S)C1=O)=O Chemical compound CNC(C(CCCC1S)C1=O)=O DRCJYFKOAFMDFL-UHFFFAOYSA-N 0.000 description 1
- TXFDMCPBDPAULJ-UHFFFAOYSA-N NC(C(CCCC1Br)C1=O)=O Chemical compound NC(C(CCCC1Br)C1=O)=O TXFDMCPBDPAULJ-UHFFFAOYSA-N 0.000 description 1
- FJYWNYLUZBMVKI-UHFFFAOYSA-N NN1CC(CCC2)C2C1 Chemical compound NN1CC(CCC2)C2C1 FJYWNYLUZBMVKI-UHFFFAOYSA-N 0.000 description 1
- QCWDCTDYSDJKTP-UHFFFAOYSA-N O=C(C1C2CCC1)NC2=O Chemical compound O=C(C1C2CCC1)NC2=O QCWDCTDYSDJKTP-UHFFFAOYSA-N 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N O=C1CCCCC1 Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- FSCBDDOKZIRLCN-UHFFFAOYSA-N O=NN1CC(CCC2)C2C1 Chemical compound O=NN1CC(CCC2)C2C1 FSCBDDOKZIRLCN-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a kind of preparation method of 1,2-cyclopentanediformylandne, its chemical structural formula is as shown in the right side.Preparation method, be with alpha-brominated pimelinketone methane amide for raw material, in alcohols and alcohols sodium salt, carry out low-temp reaction, the reaction times is 0.5 ~ 1.5 hour, mol ratio=1:1 ~ 2 of alpha-brominated pimelinketone methane amide and alcohols sodium salt; After reaction terminates, desolvation, continues to be warming up to 180 ~ 220 DEG C, carries out condensation, remove alcoholic solvent, use appropriate solvent recrystallization, obtain 1,2-cyclopentanediformylandne.1,2-cyclopentanediformylandne of the present invention as the intermediate of gliclazide, can prepare 1 with traditional technology Ammonia Process, 2-cyclopentanediformylandne is compared, and has yield high, consumes energy low, the advantages such as waste water is few, for suitability for industrialized production provides a feasible operational path.
Description
Technical field
The present invention relates to a kind of chemical synthesis process of organism 1,2-cyclopentanediformylandne, belong to the field of chemical synthesis.
Background technology
1,2-cyclopentanediformylandne is the important intermediate of preparation gliclazide (Gliclazide).Gliclazide is s-generation sulfonylurea oral antidiabetic drug, be used for the treatment of non insulin dependent diabetes (type ii diabetes), there is the hypoglycemic dual function with improving coagulation function, and have slight lipid metabolism improvement result, side effect is little, is widely used clinically.
The synthesis of gliclazide can react preparation by N-amino-3-azabicyclo [3.3.0] octane and tolysulfonyl amido ethyl formate etc., and 1,2-cyclopentanediformylandne is then the key intermediate of synthesis N-amino-3-azabicyclo [3.3.0] octane, and the yield of this intermediate is on the low side.Gliclazide usually using pimelinketone and urea as starting raw material, through condensation, hydrolysis, bromination, rearrangement, amination, reduction, nitrosification, restore, the series reaction such as condensation again, obtain the finished product.And 1,2-cyclopentanediformylandne is the key intermediate of synthesis gliclazide, if by conventional amine metallization processes yield lower (~ 68%), then directly have influence on overall yield, and then promoted the overall high expensive of gliclazide.
By existing technology utilization pimelinketone and urea as starting material, synthesis 1,2-cyclopentanediformylandne, condensation, hydrolysis, bromo, rearrangement and amination need be experienced and amount to five steps, wherein from bromo-derivative to aminate, namely 1,2-cyclopentanediformylandne, its yield only has 47%.
The yield of 1,2-pentamethylene dicarboxylic anhydride synthesis, 1,2-cyclopentanediformylandne is adopted to be only 51% and 67.23%(Geoffrey C.C, Barry J.S, etc.Synthetic communications, 1981,11,447-454; J.E.
Brenner, J.Org.Chem., 1961,26,22-27), and raw material made by 1,2-pentamethylene dicarboxylic anhydride pimelinketone, then need six-step process just can obtain, step is longer, does not have economic worth.
With 1,2-pentamethylene diformamide for raw material, through alkaline hydrolysis, need refine and obtain 1,2-pentamethylene dioctyl phthalate, then through dehydration, form acid anhydrides, then through underpressure distillation, more logical ammonia is re-refined, yield only has 57.66%.And the preparation of 1,2-pentamethylene diformamide is inherently from alpha-brominated pimelinketone methane amide as Material synthesis, if so from alpha-brominated pimelinketone methane amide as starting raw material, then total recovery is only 46.12%.This method also exists when becoming acid anhydrides from acid in addition, and raw materials used is diacetyl oxide, and acid anhydrides thing has charing phenomenon when high temperature purification, and yield is lower, and raw materials cost is high.Domestic patent (CN1876636A) in addition, report with 1,2-pentamethylene diformamide for raw material, through salify, cyclization, its yield is 82.15%, although yield increases, there is the particular requirement of high temperature energy consumption and equipment, mention in patent in addition 1,2-pentamethylene diformamide raw material, be generally synthesized by alpha-brominated pimelinketone methane amide, then total recovery also only has 65.72%.
Summary of the invention
In order to solve above-mentioned technical problem, the technical problem to be solved in the present invention is to provide that a kind of total recovery is high, raw materials cost is low and the preparation method of easy 1, the 2-cyclopentanediformylandne of purifying.
Its preparation method is for starting material adopts one pot process 1 with alpha-brominated pimelinketone methane amide, 2-cyclopentanediformylandne, this product can as the intermediate of synthesis hypoglycemic drug gliclazide, effectively improve yield, reduce cost and energy consumption, shorten the production cycle, decrease the discharge of the three wastes.
In order to solve the problems of the technologies described above, the invention provides a kind of preparation method of 1,2-cyclopentanediformylandne, its chemical structural formula is:
Using alpha-brominated pimelinketone methane amide as raw material, carry out low-temp reaction in alcohols and alcohols sodium salt, the reaction times is 0.5 ~ 1.5 hour, alpha-brominated pimelinketone methane amide and alcohols sodium salt are with suitable mol ratio, after reaction terminates, desolvation, continues to be warming up to 180 ~ 220 DEG C, carry out condensation, remove alcoholic solvent, gained debris getting adds ethyl acetate or other appropriate solvents, through activated carbon decolorizing, crystallization obtains 1,2-cyclopentanediformylandne.
Improvement as preparation method of the present invention: employ alcohols and alcohols sodium salt thereof and adopt the mode dripped.
Further improvement as preparation method of the present invention: alcoholic solvent is the alcohol organic solvent such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol, glycol ether, hexalin, benzylalcohol; Alcohols sodium salt is the sodium salt of the corresponding alcohols such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol, glycol ether, hexalin, benzylalcohol.
Further improvement as preparation method of the present invention: the alcohols mass ratio of alcohols sodium salt is the alcoholic solution of 10 ~ 60%.
Further improvement as solvent used by purification process of the present invention: esters solvent is the based organic solvent such as methyl-formiate, ethyl formate, methyl acetate, ethyl acetate, tetraethyl silicate, and aromatic solvents is benzene,toluene,xylene, oil of mirbane, benzyl cyanide etc.; Be the alcohol organic solvent such as methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol, glycol ether, hexalin, benzylalcohol as alcoholic solvent.
Reaction equation of the present invention can be expressed as:
The product adopting method of the present invention to prepare, through gas phase-spectrometer analysis, determines the molecular ion peak (M of M=139
+, 100), and 111 (M
+,-CO, 26.87), 96 (M
+,-CONH, 83.29), 68 (M
+,-CONHCO, 59.61) and fragment ion.Through infrared analysis, at 1704cm
-1there is the charateristic avsorption band of amidocarbonylation carbon-oxygen bond (-C=O), at 3292 cm
-1, 3172cm
-1there is the charateristic avsorption band of hydrogen bound to nitrogen (-N-H).Fusing point, at 230-240 DEG C, conforms to the fusing point of actual product, is finally defined as 1,2-cyclopentanediformylandne.
By 1,2-cyclopentanediformylandne of the present invention for the production of gliclazide, reaction process is as follows:
In sum, adopt 1,2-cyclopentanediformylandne of the present invention, original two-step reaction can be merged into one kettle way, effectively can improve yield, and be conducive to environmental protection reduction production cost, be suitable for large-scale batch production.
Embodiment
Below in conjunction with specific embodiment, the invention will be further described:
Embodiment 1: a kind of preparation method of 1,2-cyclopentanediformylandne, carry out following steps successively:
Being equipped with churned mechanically 250mL there-necked flask, add 70ml methyl alcohol, the alpha-brominated pimelinketone methane amide of 30g, is cooled to 0-5 DEG C, slowly drips the 50ml methanol solution containing 14.8 grams of methyl alcohol sodium salts, after dropwising, and insulated and stirred 30 minutes.
After reaction terminates, should be common distillation by device, steam except alcoholic solvent, at starting to be warming up to 180 ~ 220 DEG C afterwards, carry out the solvent that underpressure distillation removing generates, after cooling, add ethyl acetate 150ml, add gac 5g, reflux 1 hour, filtered while hot, the crystallization of filtrate normal temperature obtains product 1,2-cyclopentanediformylandne, vacuum-drying 1 hour at 40 DEG C, obtains product 14.58 g, and yield is 76.55%.
Embodiment 2: a kind of preparation method of 1,2-cyclopentanediformylandne, carry out following steps successively:
Being equipped with churned mechanically 250mL there-necked flask, add 100ml methyl alcohol, the alpha-brominated pimelinketone methane amide of 30g, is cooled to 0-5 DEG C, slowly drips the 20ml methanol solution containing 7.4 grams of methyl alcohol sodium salts, after dropwising, and insulated and stirred 30 minutes.
After reaction terminates, should be common distillation by device, steam except alcoholic solvent, at starting to be warming up to 180 ~ 220 DEG C afterwards, carry out the solvent that underpressure distillation removing generates, after cooling, add ethyl acetate 150ml, add gac 5g, reflux 1 hour, filtered while hot, the crystallization of filtrate normal temperature obtains product 1,2-cyclopentanediformylandne, at 40 DEG C, vacuum-drying 1 hour, obtains product 13.79g, and yield is 72.41%.
Embodiment 3 ~ 11: change the solvent in above-described embodiment 1 or 2, alcohols sodium salt concentration, reaction times, corresponding embodiment 3 ~ 11 can be obtained.Particular content is in table 1, and the product yield of each embodiment gained is in table 1.
The concrete data of table 1, embodiment 3-11
What enumerate in addition is only several specific embodiments of the present invention.Obviously, the invention is not restricted to above embodiment, can also other, all scenario that such as those of ordinary skill in the art can directly derive from content disclosed by the invention or associate, all should think protection scope of the present invention.
Claims (1)
1.1, the preparation method of 2-cyclopentanediformylandne, it is characterized in that: using α-bromo pimelinketone methane amide as raw material, low-temp reaction is carried out in alcohols and alcohols sodium salt, reaction times is 0.5 ~ 1.5 hour, α-bromo pimelinketone methane amide and alcohols sodium salt, with suitable mol ratio, react after terminating, desolvation, continue to be warming up to 180 ~ 220 DEG C, carry out condensation, remove alcoholic solvent, gained debris getting adds ethyl acetate or other appropriate solvents, through activated carbon decolorizing, crystallization obtains 1,2-cyclopentanediformylandne
The concrete operation step of described low-temp reaction is: first by α-bromo pimelinketone methane amide joins in alcoholic solvent, then at low temperatures the alcoholic solution of alcohols sodium salt is dripped, described alcoholic solvent is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol, glycol ether, hexalin, benzylalcohol, described alcohols sodium salt is methyl alcohol, ethanol, propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, ethylene glycol, glycol ether, hexalin, benzylalcohol, the mol ratio of α-bromo pimelinketone methane amide and alcohols sodium salt is 1:1 ~ 2, the alcohols mass ratio of described alcohols sodium salt is the alcoholic solution of 10 ~ 60%, other appropriate solvents that gained debris getting adds are toluene, alcohols.
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| CN109206358B (en) * | 2018-09-14 | 2021-10-29 | 济南爱思医药科技有限公司 | Synthesis method of 1, 2-cyclopentadiimide |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0132392B1 (en) * | 1983-07-22 | 1992-01-02 | Ici Australia Limited | Asymmetric synthesis of alpha-substituted-alpha-cyanomethyl alcohols |
| CN1314340A (en) * | 2000-03-21 | 2001-09-26 | 山东省医药工业研究所 | Method for preparing cyclopentane imide |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0132392B1 (en) * | 1983-07-22 | 1992-01-02 | Ici Australia Limited | Asymmetric synthesis of alpha-substituted-alpha-cyanomethyl alcohols |
| CN1314340A (en) * | 2000-03-21 | 2001-09-26 | 山东省医药工业研究所 | Method for preparing cyclopentane imide |
Non-Patent Citations (2)
| Title |
|---|
| I. N. Tarabara,等.Synthesis, Structure, and Transformations of New Endic Anhydride Derivatives.《Russian Journal of Organic Chemistry》.2002,第38卷(第9期),第1354-1363页. * |
| 格列齐特关键中间体顺式-1,2-环戊烷二甲酰亚胺的合成;张柯华;《上海医药工业研究院博士学位论文》;20011231;第15-16页 * |
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Effective date of registration: 20170213 Address after: 274500 Heze Chemical Industrial Park, Dongming, Shandong, China Patentee after: Shandong Hongzhi Biotechnology Co., Ltd. Address before: 274500 the Yellow River Road, Dongming, Shandong, Heze Patentee before: Shandong Fangming Pharmaceutical Group Co., Ltd. |
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