CN103172656B - Synthetic process of 3-dimethyl tertiary butyl siloxyl glutaric anhydride - Google Patents
Synthetic process of 3-dimethyl tertiary butyl siloxyl glutaric anhydride Download PDFInfo
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- CN103172656B CN103172656B CN201310112698.1A CN201310112698A CN103172656B CN 103172656 B CN103172656 B CN 103172656B CN 201310112698 A CN201310112698 A CN 201310112698A CN 103172656 B CN103172656 B CN 103172656B
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Abstract
The invention discloses a synthetic process of 3-dimethyl tertiary butyl siloxyl glutaric anhydride. The process comprises the following steps of: performing reaction of citric acid and chlorosulfonic acid in a mole ratio of 1:3-4, cooling, adding to water, and filtering to obtain 1,3-acetone dicarboxylic acid; performing backflow reaction of 1,3-acetone dicarboxylic acid and acetic anhydride in a mole ratio of 1:5-10, cooling and filtering to obtain a product 1,3-acetone dicarboxylic acid anhydride; dissolving 1,3-acetone dicarboxylic acid anhydride in ethyl acetate, and performing reaction under the effect of a catalyst to obtain 3-hydroxyl glutaric anhydride; based on chloroform as a solvent, performing reaction of 3-hydroxyl glutaric anhydride, tertiary butyl dimethyl chlorosilane and imidazole, cooling, adding to water, layering, taking the chloroform layer, drying with anhydrous sodium sulfate, filtering and concentrating the filtrate to obtain 3-dimethyl tertiary butyl siloxyl glutaric anhydride. The process provided by the invention is mild in reaction condition, few in reaction step, environment-friendly and low in cost, and can be used for industrialized production.
Description
Technical field
The present invention relates to the synthesis technique of compound, particularly relate to a kind of synthesis technique of 3-dimethyl tertiary butyl siloxy Pyroglutaric acid.
Background technology
3-dimethyl tertiary butyl siloxy Pyroglutaric acid is the key intermediate of synthesis reducing blood-fat class medicine Rosuvastatin of new generation and pitavastatin.With 3-hydroxyl ethyl glutarate for raw material obtains 3-hydroxyl pentanedioic acid sodium salt through hydroxyl protection, hydrolysis, cyclization obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid (Theisen P D, Heathcock, C H.
journal of Organic Chemistry, 1988,53 (10): 2374; Karanewsky D S. US, 4,804,770 (1989); Ponnuswamy, A. E. WO, 2008/130678 (2008); Kumar, K.V. 2008/130638 (2008); Peter W, Michel G.
canadian Journal of Chemistry, 2006,84 (10): 1226; Heathcock, C H,
journal of Medicinal Chemistry, 1987,30 (10): 1858; .(the Jiang Chengjun such as Jiang Chengjun; Gao Bo; contain malachite. Scientific and Technological Institutes Of Zhejiang's journal; 2008; 20 (2): 107-109) take citric acid as starting raw material; through oleum oxidative decarboxylation, with ethanol synthesis esterification, hydrogenating reduction, hydroxyl protection, Ester hydrolysis, again closed loop, obtain 3-dimethyl tertiary butyl siloxy Pyroglutaric acid with total recovery 30.3%.(the Tang Xinjun such as Tang Xinjun, Xu Jianbing, Zang Yangling. fine-chemical intermediate, 2008,38(3): 33-35) take citric acid as starting raw material, obtain β-ketoglutaric acid through vitriol oil oxidative decarboxylation, with ethanol synthesis lactate synthesis propanedioic acid diethyl dicarboxylate, then obtain synthesis 3-hydroxyl ethyl glutarate with potassium borohydride reduction.Zhao Xuliang etc. (Zhao Xuliang, Shandong Technology Univ's master thesis, 2009) are that starting raw material has synthesized 3-dimethyl tertiary butyl siloxy Pyroglutaric acid through oleum oxidation, esterification, reduction, hydroxyl protection, saponification, dehydration condensation with citric acid.
Summary of the invention
The object of the invention is to overcome the deficiencies in the prior art, a kind of synthesis technique of 3-dimethyl tertiary butyl siloxy Pyroglutaric acid is provided.
The synthesis technique of 3-dimethyl tertiary butyl siloxy Pyroglutaric acid comprises the steps:
1) mol ratio is that the citric acid of 1:3 ~ 4 and chlorsulfonic acid react 1 ~ 4 hour at 60 ~ 80 DEG C, is cooled to 10 ~ 20 DEG C, is added to the water, filter, obtain 1,3-β-ketoglutaric acid;
2) mol ratio is 1,3-β-ketoglutaric acid of 1:5 ~ 10 and diacetyl oxide back flow reaction 10 ~ 12 hours, is cooled to 10 ~ 20 DEG C, filters, obtain 1,3-β-ketoglutaric acid acid anhydride;
3) be dissolved in ethyl acetate by 1,3-β-ketoglutaric acid acid anhydride, at 1-5MPa hydrogen pressure, 100-150 DEG C, react 5-10 hour, filtering catalyst under catalyst action, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid;
4) take chloroform as solvent, mol ratio is that the 3-hydroxyl Pyroglutaric acid of 1:1 ~ 1.2:1 ~ 1.2, TERT-BUTYL DIMETHYL CHLORO SILANE, imidazoles were 10 ~ 30 DEG C of reactions 1 ~ 4 hour, be cooled to 10 ~ 20 DEG C, be added to the water, layering, gets chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid.
Described catalyzer is Raney Ni, Pd/C, Ru/C or Pt/C.
Reaction conditions of the present invention is gentle, and reactions steps is few, environmental friendliness, and cost is low, may be used for industrialized production.
Embodiment
Reaction equation of the present invention is as follows:
embodiment 1
In 250ml there-necked flask, add 19.2 grams of citric acids, under violent stirring, drip 34.9 grams of chlorsulfonic acids, 60 DEG C of reactions 1 hour, be cooled to 10 DEG C, join in 500ml water, filter, dry, obtain 1,3-β-ketoglutaric acid 11.7 grams; In 250ml there-necked flask, add 7.3 gram of 1,3-β-ketoglutaric acid, then add 20.4 grams of diacetyl oxide back flow reaction 10 hours, be cooled to 10 DEG C, filter, obtain 1,3-β-ketoglutaric acid acid anhydride 5.76 grams; By 5.76 gram 1,3-β-ketoglutaric acid acid anhydride is dissolved in 80ml ethyl acetate, then join in 100ml high-pressure hydrogenation reactor, 1MPa hydrogen pressure, 100 DEG C, react 5 hours under 0.1 gram of Raney Ni catalyst action, filter Raney Ni catalyzer, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid 5.70 grams; 100ml chloroform is added, 13.0 grams of 3-hydroxyl Pyroglutaric acids, 15.1 grams of TERT-BUTYL DIMETHYL CHLORO SILANE, 6.8 grams of imidazoles, 10 DEG C of reactions 1 hour in 250ml there-necked flask, be cooled to 10 DEG C, be added to the water, layering, gets chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid 20.5 grams, fusing point 80-81 DEG C
1h-NMR(CDCl
3) δ: 0.08 (s, 6H, CH
3), 1.00 (s, 9H, CH
3), 2.26 (d, 4H, CH
2), 5.00 (m, H, CH).
embodiment 2
In 250ml there-necked flask, add 19.2 grams of citric acids, under violent stirring, drip 46.6 grams of chlorsulfonic acids, 80 DEG C of reactions 4 hours, be cooled to 20 DEG C, join in 500ml water, filter, dry, obtain 1,3-β-ketoglutaric acid 11.9 grams; In 250ml there-necked flask, add 14.6 gram of 1,3-β-ketoglutaric acid, then add 51.0 grams of diacetyl oxide back flow reaction 12 hours, be cooled to 20 DEG C, filter, obtain 1,3-β-ketoglutaric acid acid anhydride crude product 11.0 grams; By 5.76 gram 1,3-β-ketoglutaric acid acid anhydride is dissolved in 80ml ethyl acetate, then join in 100ml high-pressure hydrogenation reactor, 5MPa hydrogen pressure, 150 DEG C, react 10 hours under 0.1 gram of Pd/C catalyst action, filter Pd/C catalyzer, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid 5.72 grams; 100ml chloroform is added in 250ml there-necked flask, 13.0 grams of 3-hydroxyl Pyroglutaric acids, 18.1 grams of TERT-BUTYL DIMETHYL CHLORO SILANE, 8.2 grams of imidazoles, 30 DEG C of reactions 4 hours, be cooled to 20 DEG C, be added to the water, layering, get chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid 22.1 grams.
embodiment 3
In 250ml there-necked flask, add 18.2 grams of citric acids, under violent stirring, drip 40.6 grams of chlorsulfonic acids, 80 DEG C of reactions 3 hours, be cooled to 20 DEG C, join in 500ml water, filter, dry, obtain 1,3-β-ketoglutaric acid 11.0 grams; In 250ml there-necked flask, add 13.5 gram of 1,3-β-ketoglutaric acid, then add 50.0 grams of diacetyl oxide back flow reaction 12 hours, be cooled to 20 DEG C, filter, obtain 1,3-β-ketoglutaric acid acid anhydride crude product 10.0 grams; By 5.70 gram 1,3-β-ketoglutaric acid acid anhydride is dissolved in 80ml ethyl acetate, then join in 100ml high-pressure hydrogenation reactor, 5MPa hydrogen pressure, 150 DEG C, react 10 hours under 0.1 gram of Ru/C catalyst action, filter Ru/C catalyzer, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid 5.70 grams; 100ml chloroform is added in 250ml there-necked flask, 13.1 grams of 3-hydroxyl Pyroglutaric acids, 18.0 grams of TERT-BUTYL DIMETHYL CHLORO SILANE, 8.0 grams of imidazoles, 30 DEG C of reactions 4 hours, be cooled to 20 DEG C, be added to the water, layering, get chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid 21.3 grams.
embodiment 4
In 250ml there-necked flask, add 19.5 grams of citric acids, under violent stirring, drip 40.6 grams of chlorsulfonic acids, 80 DEG C of reactions 4 hours, be cooled to 15 DEG C, join in 500ml water, filter, dry, obtain 1,3-β-ketoglutaric acid 10.5 grams; In 250ml there-necked flask, add 15.6 gram of 1,3-β-ketoglutaric acid, then add 45.0 grams of diacetyl oxide back flow reaction 12 hours, be cooled to 20 DEG C, filter, obtain 1,3-β-ketoglutaric acid acid anhydride crude product 10.1 grams; By 5.0 gram 1,3-β-ketoglutaric acid acid anhydride is dissolved in 80ml ethyl acetate, then join in 100ml high-pressure hydrogenation reactor, 3MPa hydrogen pressure, 120 DEG C, react 8 hours under 0.1 gram of Pt/C catalyst action, filter Pt/C catalyzer, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid 5. 1 grams; 100ml chloroform is added in 250ml there-necked flask, 12.8 grams of 3-hydroxyl Pyroglutaric acids, 18.0 grams of TERT-BUTYL DIMETHYL CHLORO SILANE, 8.1 grams of imidazoles, 20 DEG C of reactions 3 hours, be cooled to 15 DEG C, be added to the water, layering, gets chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid 20.0 grams.
Claims (1)
1. a synthesis technique for 3-dimethyl tertiary butyl siloxy Pyroglutaric acid, is characterized in that comprising the steps:
1) mol ratio is that the citric acid of 1:3 ~ 4 and chlorsulfonic acid react 1 ~ 4 hour at 60 ~ 80 DEG C, is cooled to 10 ~ 20 DEG C, is added to the water, filter, obtain 1,3-β-ketoglutaric acid;
2) mol ratio is 1,3-β-ketoglutaric acid of 1:5 ~ 10 and diacetyl oxide back flow reaction 10 ~ 12 hours, is cooled to 10 ~ 20 DEG C, filters, obtain 1,3-β-ketoglutaric acid acid anhydride;
3) be dissolved in ethyl acetate by 1,3-β-ketoglutaric acid acid anhydride, at 1-5MPa hydrogen pressure, 100-150 DEG C, react 5-10 hour, filtering catalyst under catalyst action, concentrated ethyl acetate, obtains 3-hydroxyl Pyroglutaric acid;
4) take chloroform as solvent, mol ratio is that the 3-hydroxyl Pyroglutaric acid of 1:1 ~ 1.2:1 ~ 1.2, TERT-BUTYL DIMETHYL CHLORO SILANE, imidazoles were 10 ~ 30 DEG C of reactions 1 ~ 4 hour, be cooled to 10 ~ 20 DEG C, be added to the water, layering, gets chloroform layer, with anhydrous sodium sulfate drying, filter, concentrated filtrate, obtains 3-dimethyl tertiary butyl siloxy Pyroglutaric acid;
Described catalyzer is Raney Ni, Pd/C, Ru/C or Pt/C.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1622937A (en) * | 2002-01-31 | 2005-06-01 | 诺瓦提斯公司 | Process for the manufacture of HMG-coa reductase inhibitors |
| US20090076292A1 (en) * | 2007-04-18 | 2009-03-19 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin intermediates and process for the preparation of rosuvastatin |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1622937A (en) * | 2002-01-31 | 2005-06-01 | 诺瓦提斯公司 | Process for the manufacture of HMG-coa reductase inhibitors |
| US20090076292A1 (en) * | 2007-04-18 | 2009-03-19 | Teva Pharmaceutical Industries Ltd. | Rosuvastatin intermediates and process for the preparation of rosuvastatin |
Non-Patent Citations (3)
| Title |
|---|
| (R,S)-2-氨基丙醇的制备;蒋锦等;《中国医药工业杂志》;CNKI;20060110;第37卷(第1期);第8页化合物1的制备 * |
| Chain Elongation and Cyclization in Type III PKS DpgA;Hai-Chen Wu等;《ChemBioChem》;Wiley;20120411;第13卷(第6期);第862-871 * |
| 蒋成君等.3-(二甲基叔丁基硅氧基)戊二酸酐的合成.《浙江科技学院学报》.CNKI,2008,第20卷(第2期),第108页. * |
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