CN101475476A - Gefarnate compound and method for synthesizing the same - Google Patents
Gefarnate compound and method for synthesizing the same Download PDFInfo
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- CN101475476A CN101475476A CNA2009100008977A CN200910000897A CN101475476A CN 101475476 A CN101475476 A CN 101475476A CN A2009100008977 A CNA2009100008977 A CN A2009100008977A CN 200910000897 A CN200910000897 A CN 200910000897A CN 101475476 A CN101475476 A CN 101475476A
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Abstract
The invention relates to a gefarnate compound and a synthesis method thereof. The method comprises the following steps that: nerolidol, trimethyl orthoacetate and butyric acid are mixed, heated and subjected to reaction and then reduced-pressure distillation so as to obtain a product (1); sodium hydroxide and N,N-dimethylformamide are added to the product (1); after a certain period of reaction, acetone is added to the product (1); solids are separated out, filtered and dissolved in water; the pH value of the solids is regulated through sulfuric acid; the solids are extracted through ethyl acetate; an organic phase is washed through distilled water, dried through solid desiccant and subjected to reduced-pressure distillation to remove organic solvent so as to give a product (2); the product (2) is added with geraniol and xylene for reflux reaction; water formed in the reaction is removed; the xylene is removed through reduced-pressure distillation; the remainder is added with aether for dissolution and washed; the organic phase is dried through the solid desiccant; the organic solvent is removed through distillation; fractions at a temperature between 166 and 170 DEG C are collected through reduced-pressure distillation; and a light yellow liquid, namely gefarnate is obtained.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of synthetic method of gefarnate.
Background technology
Gefarnate is an isoprenoid, has the metabolism of acceleration, regulates stomach function and gastric acid secretion, strengthens effects such as mucous membrane protection.Mechanism of action may be to directly act on gastric epithelial cell, strengthens the ability of its antiulcer agent factor.Be used for the treatment of gastric and duodenal ulcer, acute and chronic gastritis, colitis, stomach spasm etc.
The present domestic gefarnate raw material listing of still not having, gefarnate is separating obtained by Caulis et Folium Brassicae capitatae at first, the back is synthesized into by Adami etc., given birth to by Japan that rolling is flourish supports the list marketing of medicine Co., Ltd., this medicine is with treatment, prophylactic effect, since emerging, treatment gastroenteropathy patient is countless, obtains high evaluation at international medical community, the more consistent high praise of patient.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of gefarnate.
The technical solution adopted in the present invention is:
The invention provides a kind of synthetic method of gefarnate, it is characterized in that comprising the steps:
(1) nerolidol and trimethyl orthoacetate carry out reacting by heating in the presence of acid catalyst, remove acid catalyst, unnecessary raw material and the methyl alcohol that reacts generation after the reaction, get product (1);
(2) in product (1), add sodium hydroxide and N, dinethylformamide reacts, the reaction back adds organic solvent A, separate out solid, regulate the pH value after solid is water-soluble to acid, again with the organic solvent B extraction, after organic phase distilled water wash, solid drier drying, remove organic solvent, get product (2);
(3) in product (2), add Geraniol and dimethylbenzene, back flow reaction, the water of dereaction generation and unnecessary dimethylbenzene are removed in the reaction back, residuum adds organic solvent C dissolving, after the washing, and organic phase solid drier drying, remove organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, get little yellow liquid, are gefarnate.
Above-mentioned described synthetic method is characterized in that, the acid catalyst in the step (1) is an organic acid, preferably contains the alkyl acid of 1-5 carbon atoms, is more preferably butyric acid.
As preferably, in the step of aforesaid method (1), react the trimethyl orthoacetate that the back underpressure distillation is removed lower boiling methyl alcohol, butyric acid and do not had to have reacted.
The above-mentioned described synthetic method of the present invention, it is characterized in that, described organic solvent A, organic solvent B, organic solvent C can be identical, also can be different, independently be selected from acetone, ethanol, methyl alcohol, Virahol, trichloromethane, ethyl acetate, phenylacetate, methyl benzoate, methyl acetate, butylacetate, ether, acetonitrile respectively; Wherein, preferred organic solvent A is an acetone, and organic solvent B is an ethyl acetate, and organic solvent C is an ether.
Wherein, above-mentioned described synthetic method is characterized in that, is with inorganic acid for adjusting pH value 1-6 in the step (2), and preferred described mineral acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.As preferably, in the described step (2), adopting mass percent is that 10% sulphur acid for adjusting pH value is 3.
Above-mentioned described solid drier is not particularly limited, and for example can be anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina.
The above-mentioned described synthetic method of the present invention is characterized in that, washing described in the step (3) is to be that 10% sodium carbonate solution washs with distilled water and/or mass percent.
As the present invention's one preferred specific embodiments, the synthetic method of described gefarnate comprises the steps:
1) nerolidol, trimethyl orthoacetate and butyric acid are mixed, be heated to 130 ℃, reacted 25 hours, the trimethyl orthoacetate that removes methyl alcohol and butyric acid and do not have to have reacted is steamed in underpressure distillation, gets resultant product (1);
2) in product (1), add solid sodium hydroxide and N, dinethylformamide, 60 ℃ were reacted 2 hours, cool to room temperature adds acetone, stirs and separates out solid, filter, the gained solid is water-soluble, is 3 with the sulphur acid for adjusting pH value, extract with the ethyl acetate gradation, merge the organic phase distilled water wash, use the solid drier drying again, remove by filter siccative, the underpressure distillation organic solvent gets product (2);
3) in product (2), add Geraniol and dimethylbenzene, back flow reaction 8 hours, remove the water that reaction generates by adopting azeotropic to steam, underpressure distillation dimethylbenzene, residuum adds ether dissolution, use twice of sodium carbonate solution and distilled water wash respectively, organic phase solid drier drying is steamed and is removed organic solvent, and 166～170 ℃ of cuts are collected in underpressure distillation, get little yellow liquid, be gefarnate.
Wherein, described solid drier is anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina, is preferably anhydrous magnesium sulfate.
The present invention obtains gefarnate for synthetic, for gefarnate provides a kind of new preparation method, and has also filled up the blank of domestic gefarnate synthetic technology.
Description of drawings
Fig. 1 is a process flow sheet of the present invention
Embodiment
Below by embodiment the present invention is described in further details.
Embodiment 1
1) nerolidol 100g, trimethyl orthoacetate 106.7g and butyric acid 5.13g are mixed, be heated to 130 ℃, reacted 25 hours, the trimethyl orthoacetate that removes lower boiling methyl alcohol and butyric acid and do not have to have reacted is steamed in underpressure distillation, gets resultant product (1);
2) in product (1), add solid sodium hydroxide 22.3g and N, dinethylformamide 100ml, 60 ℃ were reacted 2 hours, cool to room temperature adds acetone 300ml, stirs and separates out solid, filter, the gained solid is water-soluble, is 3 with 10% sulphur acid for adjusting pH value, with ethyl acetate 200ml extraction, merge organic phase respectively, use the 150ml distilled water wash, use anhydrous magnesium sulfate drying again, remove by filter siccative, the underpressure distillation organic solvent gets product (2) 70.8g;
3) in product (2), add Geraniol 123.9g and dimethylbenzene 112ml, back flow reaction 8 hours is removed the water that reaction generates, underpressure distillation dimethylbenzene by adopting azeotropic to steam, residuum adds the 300ml ether dissolution, use the 10% sodium carbonate solution washed twice of 150ml respectively, use distilled water wash twice again, the organic phase anhydrous magnesium sulfate drying, steam and remove organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, get little yellow liquid 96g, yield 89.4%.
4) ultimate analysis C:72.9%; H:15.7%; O:11.4% (theoretical value C:72.8%; H:15.8%; O:11.4%)
Embodiment 2
1) nerolidol 100g, trimethyl orthoacetate 134.7g and acetate 6.44g are mixed, be heated to 130 ℃, reacted 25 hours, the trimethyl orthoacetate that removes lower boiling methyl alcohol and acetate and do not have to have reacted is steamed in underpressure distillation, gets resultant product (1);
2) in product (1), add solid sodium hydroxide 25.78g and N, dinethylformamide 150ml, 60 ℃ were reacted 2 hours, cool to room temperature adds ethanol 200ml, stirs and separates out solid, filter, the gained solid is water-soluble, is 3.5 with 1mol/L salt acid for adjusting pH value, with methyl acetate 200ml extraction, merge organic phase respectively, use the 200ml distilled water wash, use anhydrous sodium sulfate drying again, remove by filter siccative, the underpressure distillation organic solvent gets product (2) 71.5g;
3) in product (2), add Geraniol 124.2g and dimethylbenzene 125ml, back flow reaction 8 hours is removed the water that reaction generates, underpressure distillation dimethylbenzene by adopting azeotropic to steam, residuum adds the 400ml ether dissolution, use the 10% sodium carbonate solution washed twice of 200ml respectively, use distilled water wash twice again, the organic phase anhydrous sodium sulfate drying, steam and remove organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, get little yellow liquid 94.7g, yield 88.2%.
4) ultimate analysis C:72.9%; H:15.5%; O:11.6% (theoretical value C:72.8%; H:15.8%; O:11.4%)
Embodiment 3
1) nerolidol 100g, trimethyl orthoacetate 100g and formic acid 5.14g are mixed, be heated to 130 ℃, reacted 25 hours, the trimethyl orthoacetate that removes lower boiling methyl alcohol and formic acid and do not have to have reacted is steamed in underpressure distillation, gets resultant product (1);
2) in product (1), add solid sodium hydroxide 20.14g and N, dinethylformamide 80ml, 60 ℃ were reacted 2 hours, cool to room temperature adds Virahol 100ml, stirs and separates out solid, filter, the gained solid is water-soluble, is 3.8 with 10% phosphorus acid for adjusting pH value, with methyl benzoate 100ml extraction, merge organic phase respectively, use the 150ml distilled water wash, use the anhydrous calciumsulphate drying again, remove by filter siccative, the underpressure distillation organic solvent gets product (2) 69.1g;
3) in product (2), add Geraniol 122.2g and dimethylbenzene 110ml, back flow reaction 8 hours is removed the water that reaction generates, underpressure distillation dimethylbenzene by adopting azeotropic to steam, residuum adds the dissolving of 200ml acetonitrile, use the 10% sodium carbonate solution washed twice of 100ml respectively, use distilled water wash twice again, organic phase anhydrous calciumsulphate drying, steam and remove organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, get little yellow liquid 93.2g, yield 86.8%.
4) ultimate analysis C:72.6%; H:15.9%; O:11.5% (theoretical value C:72.8%; H:15.8%; O:11.4%)
Embodiment 4
(1) differentiates
Get embodiment 1, embodiment 2, embodiment 3 samples, adding diethyl ether respectively makes dissolving and dilution make the solution that contains 0.1g among every 1ml approximately in right amount, as need testing solution.Measure according to vapor-phase chromatography (two appendix VE of Chinese Pharmacopoeia version in 2005).With methyl silicone rubber (SE-30) is stationary phase, and coating concentration is 5%, and column temperature is 230 ℃, measures need testing solution 1 μ l, inject gas chromatograph, record color atlas.The result: the relative retention time of cis gefarnate and trans gefarnate is 0.9:1.0, and the result is consistent with the gefarnate reference substance.
(2) the related substance inspection is according to high performance liquid chromatography.
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are weighting agent, are moving phase with acetonitrile-water (95:5), and the detection wavelength is 210nm, and number of theoretical plate calculates by the gefarnate peak and is not less than 2000.
Detection method is got embodiment 1, embodiment 2, embodiment 3 samples, add respectively dissolve with ethanol and the dilution make the solution that contains 1.0mg among every 1ml approximately, as need testing solution; Get the gefarnate reference substance, add dissolve with ethanol and the dilution make the solution that contains 1.0mg among every 1ml approximately, precision is measured 1ml, puts in the 100ml measuring bottle, adds alcohol dilution to scale, shakes up, in contrast solution.Precision is measured need testing solution and each 10 μ l of contrast solution, inject liquid chromatograph respectively, the record color atlas is to 3 times of principal constituent peak retention time, and reference substance is consistent with trial-product main peak retention time as a result, and the related substance inspection meets the pharmaceutical grade requirement in the trial-product.
(3) proterties inspection
The sample that result: embodiment 1-3 makes is little yellow and the liquid of faint terpinum flavor is arranged, and 165～168 ℃ of boiling points are dissolved in alcohol, ether, dimethyl formamide, acetone, fatty oil, water insoluble, first phthalein amine, ethylene glycol, vinylcarbinol and glycerine.
Above-mentioned experimental result shows: embodiment 1-3 sample is differentiated and is checked that all the listing gefarnate raw material with product in contrast is consistent, the conformance with standard requirement, and embodiment 1-3 prepared products are gefarnate.
According to the above embodiments the present invention has been made detailed description.It should be noted that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (10)
1, a kind of synthetic method of gefarnate is characterized in that comprising the steps:
(1) nerolidol and trimethyl orthoacetate carry out reacting by heating in the presence of acid catalyst, remove acid catalyst, unnecessary raw material and the methyl alcohol that reacts generation after the reaction, get product (1);
(2) in product (1), add sodium hydroxide and N, dinethylformamide reacts, the reaction back adds organic solvent A, separate out solid, regulate the pH value after solid is water-soluble to acid, again with the organic solvent B extraction, after organic phase distilled water wash, solid drier drying, remove organic solvent, get product (2);
(3) in product (2), add Geraniol and dimethylbenzene, back flow reaction, the water of dereaction generation and unnecessary dimethylbenzene are removed in the reaction back, residuum adds organic solvent C dissolving, after the washing, organic phase solid drier drying is removed organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, obtain gefarnate.
2, synthetic method as claimed in claim 1 is characterized in that, the acid catalyst in the step (1) is an organic acid, preferably contains the alkyl acid of 1-5 carbon atoms, is more preferably butyric acid.
3, as the described synthetic method of claim 1-2, it is characterized in that the trimethyl orthoacetate that reaction back underpressure distillation is removed lower boiling methyl alcohol, butyric acid and do not had to have reacted in the step (1).
4, as the described synthetic method of claim 1-3, it is characterized in that, described organic solvent A, organic solvent B, organic solvent C can be identical, also can be different, independently be selected from acetone, ethanol, methyl alcohol, Virahol, trichloromethane, ethyl acetate, phenylacetate, methyl benzoate, methyl acetate, butylacetate, ether, acetonitrile respectively; Wherein, preferred organic solvent A is an acetone, and organic solvent B is an ethyl acetate, and organic solvent C is an ether.
5, as the described synthetic method of claim 1-4, it is characterized in that, is with inorganic acid for adjusting pH value 1-6 in the step (2), and preferred described mineral acid is hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid.
6, synthetic method as claimed in claim 5 is characterized in that, is that 10% sulphur acid for adjusting pH value is 3 with mass percent in the step (2).
As the described synthetic method of claim 1-6, it is characterized in that 7, described solid drier is anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina.
As the described synthetic method of claim 1-7, it is characterized in that 8, washing described in the step (3) is to be that 10% sodium carbonate solution washs with distilled water and/or mass percent.
9, the synthetic method of gefarnate as claimed in claim 1 is characterized in that comprising the steps:
(1) nerolidol, trimethyl orthoacetate and butyric acid are mixed, be heated to 130 ℃, reacted 25 hours, the trimethyl orthoacetate that removes methyl alcohol and butyric acid and do not have to have reacted is steamed in underpressure distillation, gets resultant product (1);
(2) in product (1), add solid sodium hydroxide and N, dinethylformamide, 60 ℃ were reacted 2 hours, cool to room temperature adds acetone, stirs and separates out solid, filter, the gained solid is water-soluble, and the sulphur acid for adjusting pH value with 10% is 3, extract with the ethyl acetate gradation, merge the organic phase distilled water wash, use the solid drier drying again, remove by filter siccative, the underpressure distillation organic solvent gets product (2);
(3) in product (2), add Geraniol and dimethylbenzene, back flow reaction 8 hours, remove the water that reaction generates by adopting azeotropic to steam, underpressure distillation dimethylbenzene, residuum adds ether dissolution, uses twice of sodium carbonate solution and distilled water wash respectively, organic phase solid drier drying, steam and remove organic solvent, 166～170 ℃ of cuts are collected in underpressure distillation, get gefarnate.
10, synthetic method as claimed in claim 9 is characterized in that, described solid drier is anhydrous magnesium sulfate, Calcium Chloride Powder Anhydrous, anhydrous sodium sulphate, anhydrous calciumsulphate or activated alumina, is preferably anhydrous magnesium sulfate.
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805260A (en) * | 2010-04-06 | 2010-08-18 | 蔡伦 | Preparation method of gefarnate |
| CN101973879A (en) * | 2010-09-27 | 2011-02-16 | 广安凯特医药化工有限公司 | Gefarnate preparation method |
| CN102146039A (en) * | 2011-01-19 | 2011-08-10 | 北京莱瑞森医药科技有限公司 | Process for synthesizing gefarnate compound |
| CN102399141A (en) * | 2011-09-09 | 2012-04-04 | 南京瑞尔医药有限公司 | New preparation method for gefarnate key intermediate |
| CN103012140A (en) * | 2013-01-08 | 2013-04-03 | 湖南方盛制药股份有限公司 | Preparation method of gefarnate |
| CN103614426A (en) * | 2013-11-20 | 2014-03-05 | 湖北理工学院 | Method for preparing gefarnate |
| CN104370731A (en) * | 2013-08-15 | 2015-02-25 | 南京瑞尔医药有限公司 | Gefarnate key intermediate refining or reaction solution direct post-processing method |
| CN104496812A (en) * | 2014-11-26 | 2015-04-08 | 千辉药业（安徽）有限责任公司 | Preparation method of gefarnate |
-
2009
- 2009-01-21 CN CN200910000897A patent/CN100594209C/en not_active Expired - Fee Related
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101805260A (en) * | 2010-04-06 | 2010-08-18 | 蔡伦 | Preparation method of gefarnate |
| CN101805260B (en) * | 2010-04-06 | 2013-07-24 | 蔡伦 | Preparation method of gefarnate |
| CN101973879A (en) * | 2010-09-27 | 2011-02-16 | 广安凯特医药化工有限公司 | Gefarnate preparation method |
| CN101973879B (en) * | 2010-09-27 | 2013-03-13 | 广安凯特医药化工有限公司 | Gefarnate preparation method |
| CN102146039B (en) * | 2011-01-19 | 2013-06-05 | 北京莱瑞森医药科技有限公司 | Process for synthesizing gefarnate compound |
| CN102146039A (en) * | 2011-01-19 | 2011-08-10 | 北京莱瑞森医药科技有限公司 | Process for synthesizing gefarnate compound |
| CN102399141A (en) * | 2011-09-09 | 2012-04-04 | 南京瑞尔医药有限公司 | New preparation method for gefarnate key intermediate |
| CN103012140A (en) * | 2013-01-08 | 2013-04-03 | 湖南方盛制药股份有限公司 | Preparation method of gefarnate |
| CN103012140B (en) * | 2013-01-08 | 2016-02-17 | 湖南方盛制药股份有限公司 | The preparation method of gefarnate |
| CN104370731A (en) * | 2013-08-15 | 2015-02-25 | 南京瑞尔医药有限公司 | Gefarnate key intermediate refining or reaction solution direct post-processing method |
| CN103614426A (en) * | 2013-11-20 | 2014-03-05 | 湖北理工学院 | Method for preparing gefarnate |
| CN103614426B (en) * | 2013-11-20 | 2016-06-15 | 湖北理工学院 | A kind of method preparing gefarnate |
| CN104496812A (en) * | 2014-11-26 | 2015-04-08 | 千辉药业（安徽）有限责任公司 | Preparation method of gefarnate |
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