CN102399141A - Preparation method of novel gefarnate key intermediate - Google Patents
Preparation method of novel gefarnate key intermediate Download PDFInfo
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Abstract
The invention discloses a novel method for preparing a key intermediate (4E, 8E) -5, 9, 13-trimethyl-4, 8, 12-tetradecatrienoic acid of gefarnate, belonging to the field of medicines. The method comprises the steps of reacting nerolidol with hydrogen chloride to obtain an intermediate (III), and condensing with diethyl malonate to obtain an Intermediate (IV); then hydrolyzing and acidifying to obtain an intermediate (V), and finally removing a carboxylic acid to obtain the gefarnate key intermediate. The preparation method of the invention effectively avoids methanol with high toxicity and flammable and explosive ether used in the prior patent technology in the production process, thereby increasing the safety; mild reaction conditions, simple operation and more suitability for industrial production. The key intermediate of the gefarnate can be directly prepared into the gefarnate with geraniol by a method well known by the technical personnel in the field without purification, and the purity can reach more than 99.5 percent.
Description
Technical field
The present invention relates to formula (I) compound (4E, 8E)-5,9,13-trimethylammonium-4,8, the preparation method of 12-14 trienic acids, this compound is the key intermediate of preparation gastric mucosal protection medicine gefarnate, belongs to the pharmaceutical field.
Background technology
Gefarnate (Gefarnate) is chemical to be called (4E, 8E)-5,9,13-trimethylammonium-4,8,12-14 trienic acids-(2E)-3, and 7-dimethyl--2,6-octadiene ester, its chemical structural formula is shown below.
Gefarnate
Gefarnate is an isoprenoid, is extracted and get by the volume cabbage heart at first, afterwards is synthesized into by Adami etc.Be used to treat gastric and duodenal ulcer, acute and chronic gastritis, colitis, stomach spasm etc.Have the metabolism of acceleration, regulate stomach function and gastric acid secretion, strengthen effects such as mucous membrane protection.Mechanism of action possibly be to directly act on gastric epithelial cell, strengthens the ability of its antiulcer agent factor.
Formula (I) compound (4E; 8E)-5,9,13-trimethylammonium-4; 8; 12-14 trienic acids are key intermediates of preparation gastric mucosal protection medicine gefarnate, and fewer about the synthetic report of formula (I) compound at present, domestic rarely seen Chinese patent (CN101475476A, CN101805260A) has been reported following synthetic route.
Patent CN101475476A:
Patent CN101805260A:
In the synthetic route of patent CN101475476A and patent CN101805260A, all adopting peruviol is starting raw material, through reacting 10～25 hours for 155 ℃ at high temperature with trimethyl orthoacetate or triethly orthoacetate; Hydrolysis and obtain formula (I) compound (4E under the alkaline condition then through acidifying; 8E)-5,9,13-trimethylammonium-4; 8,12-14 trienic acids.In the reaction process pyroreaction time longer, it is bigger to consume energy, and low about 55% (with the peruviol) of total molar yield.
Used trimethyl orthoacetate synthetic compound 2 among the patent CN101475476A; All contain methyl alcohol in the first step reaction of this method and the by product of second step reaction; Methyl alcohol has bigger toxicity and volatile; Human body can cause damage and affect one's power of vision after sucking methanol steam respiratory mucosa, therefore adopts the method for preparing gefarnate high to the pollution level of environment.
Patent CN101805260A improves on this basis, uses triethly orthoacetate and uses ethanol as solvent, and this method has been avoided use methyl alcohol, but has used ether in this route, and the purifying of midbody and product has all used column chromatography, is not suitable for suitability for industrialized production.
Based on the pharmacy value of gefarnate and good market outlook, yield is higher, energy consumption is lower, processing safety is higher to explore one, and suitable suitability for industrialized production gefarnate key intermediate formula (I) compound (4E; 8E)-5,9,13-trimethylammonium-4; 8, the route of 12-14 trienic acids is extremely important.
Summary of the invention
The inventor is through the further investigation to the synthetic route of gefarnate key intermediate formula (I) compound, and through test of many times, yield is higher, energy consumption is lower, processing safety is higher to provide one, is more suitable for the process method in suitability for industrialized production.
The invention provides a gefarnate key intermediate formula (I) compound 4E, 8E)-5,9,13-trimethylammonium-4,8, the new preparation process of 12-14 trienic acids.
Preparation route provided by the invention is as follows:
The invention provides a gefarnate key intermediate formula (I) compound 4E, 8E)-5,9,13-trimethylammonium-4,8, the preparation method of 12-14 trienic acids comprises following synthesis step:
Step is 1. with peruviol (II) and hcl reaction, and washing, drying, concentrating under reduced pressure remove front-end volatiles, obtain midbody (III).
2. step reacts midbody (III) and ethyl malonate, reacting by heating in salt of wormwood/acetone, and potassiumiodide is done catalyst reaction, and decompression goes to obtain midbody (IV) behind the front-end volatiles.
3. step adds midbody (IV) in the ethanolic soln of alkali, after the heating saponification reaction, boil off ethanol, extraction, and the water intaking phase, acidifying, organic phase is got in extraction again, and the lower boiling front-end volatiles are fallen in underpressure distillation behind the washing and drying, obtain midbody (V).
4. step to the direct heating under vacuum decarboxylic reaction of midbody (V), obtains orange-yellow oily liquid, i.e. gefarnate key intermediate formula (I) compound 4E, 8E)-5,9,13-trimethylammonium-4,8,12-14 trienic acids.
The 1. middle hydrogenchloride of step is hydrogen chloride gas and various solution thereof.Solution comprises the ethanolic soln of hydrogenchloride, the methanol solution of hydrogenchloride etc.
The molar ratio of 1. middle peruviol of step and hydrogenchloride is 1: 1～10, preferred 1: 1.5～5.5, more preferably 1: 2～3.Temperature of reaction is-5～40 ℃.Preferred 15～25 ℃.
The 2. described catalysts of step is Soiodin, potassiumiodide, and reaction system is for being salt of wormwood/acetone, salt of wormwood/acetonitrile or its combination.
The 2. described temperature of reaction of step is 50～80 ℃, preferred 60～70 ℃; Reaction times is 2～8 hours, preferred 3～5 hours.
The 2. described midbody of step (III) is 1: 1～10 with the mol ratio of salt of wormwood, and preferred molar ratio is 1: 2～4.
The step 3. ethanolic soln of middle alkali is the ethanolic soln of Pottasium Hydroxide or the ethanolic soln of sodium hydroxide.Wherein the mol ratio of sodium hydroxide or Pottasium Hydroxide and midbody (IV) is preferably 2～6: 1.
The 3. middle saponified temperature of reaction of step is 60～100 ℃, preferred 80～90 ℃; Reaction times is 2～5 hours, preferred 3.5～4.5 hours.
The 3. middle souring agent of step is preferably hydrochloric acid or dilute sulphuric acid or its diluent, and employed extraction solvent is preferably ETHYLE ACETATE or isopropyl ether, more preferably ETHYLE ACETATE.
The step 4. temperature of reaction of middle decarboxylation is 130～170 ℃, preferred 140～150 ℃, and 2～4 hours decarboxylation time, preferred 3 hours; More than the decarboxylation vacuum tightness 100mmHg.
Compared with prior art, the present invention has obtained effect preferably, is embodied in:
Although route step of the present invention long (4 step), every step line yield is all higher, and total molar yield is near 70% (with peruviol), far above prior art 55%.
Route of the present invention has been avoided the long pyroreaction (155 ℃ of reactions of high temperature 10～25 hours) of existing patented technology basically, effectively reduces energy consumption.
The solvent that route of the present invention mainly uses is ethanol, acetoneand ethyl acetate, has effectively avoided bigger two kind solvent methyl alcohol and the inflammable and explosive ether of toxicity that existing patented technology is used, and has increased security.
Route reaction mild condition of the present invention, no low-temp reaction and tangible pyroreaction, easy and simple to handle, be more suitable in suitability for industrialized production.The formula that makes (I) compound 4E, 8E)-5,9; 13-trimethylammonium-4,8,12-14 trienic acids; Need not purifying, can be directly and the method known by one of skill in the art of Geraniol make gefarnate, purity (gefarnate two isomer total amounts) can reach more than 99.5%.
Gefarnate purity test method: performance liquid chromatography-evaporative light scattering detection (HPLC-ELSD) method, chromatographic column are Agilent C18 chromatographic column (150mm * 4.6mm, 5 μ m); Moving phase is methyl alcohol-acetonitrile (55: 45), flow velocity 1.0mL/min, and column temperature: 30 ℃, (with the air is carrier gas to the evaporation photodetector, flow velocity 2L/m in
-1, 70 ℃ of drift tube temperatures); Trial-product concentration 45 μ g/ml; Sample size 20 μ L detect.
Description of drawings
Formula (I) the compound 4E of Fig. 1 for making with route of the present invention, 8E)-5,9,13-trimethylammonium-4,8, the gefarnate that 12-14 trienic acids and Geraniol reaction make, the high-efficient liquid phase chromatogram of purity test (HPLC figure).Formula (I) the compound 4E of Fig. 2 for making with route of the present invention, 8E)-5,9,13-trimethylammonium-4,8, the gefarnate that 12-14 trienic acids and Geraniol reaction make, the analytical results table of purity test, purity (gefarnate two isomer total amounts) 99.5%.
Embodiment
Following examples are to specify the present invention, and unrestricted the present invention.
Embodiment 1.
In three mouthfuls of glass reaction bottles of 500mL, add trans peruviol 104g (0.47mol), feed hydrogen chloride gas under the room temperature, TLC follows the tracks of the peruviol (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that whether reacts completely; The iodine colour developing), reaction is finished, and washs 1 time with saturated nacl aqueous solution 100mL, again with saturated sodium bicarbonate solution 100mL washing 1 time, with saturated nacl aqueous solution 100mL washing 1 time, adds anhydrous sodium sulfate drying then, filters, and gets midbody (III) 110.3g.
110g joins in the there-necked flask of 1000ml with midbody (III); Add salt of wormwood 202g, Soiodin 1.6g, ethyl malonate 76g, acetone 200ml; Temperature rising reflux reaction (60～70 ℃ of interior temperature), TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing) about 4 hours, reaction was finished, and normal pressure reclaims acetone; In reaction flask, add the 200ml purified water and be stirred to the salt of wormwood dissolving, divide water-yielding stratum, collected organic layer; Merge organic layer, use anhydrous sodium sulfate drying, suction filtration; 100 ℃ of front-end volatiles are removed in the organic layer decompression, and residuum is midbody (IV) 146.3g.
[0042] in three mouthfuls of glass reaction bottles of 1000mL, adds midbody (IV) 145.8g (0.4mol), adding Pottasium Hydroxide 67.2g (1.2mol), 95% ethanol 600ml; Intensification (80～90 ℃ of interior temperature) refluxed 4 hours, and TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing), reaction is finished, and concentrating under reduced pressure does not ooze to there being ethanol; Add purified water 500ml dissolving, the sulfuric acid with 10% is transferred pH to 1～3, adds ETHYLE ACETATE 300ml * 3 extractions; The combined ethyl acetate layer with saturated sodium-chloride 200ml washing, adds anhydrous sodium sulfate drying; Filter, filtrate decompression is concentrated into till the no ETHYLE ACETATE, gets midbody (V) 110.2g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (V) 106g (0.34mol), 140～150 ℃ of decompression heating of temperature are 3 hours in controlling, and get midbody (I) compound 4E after the cooling, 8E)-5,9, and 13-trimethylammonium-4,8,12-14 trienic acid 85.4g.
Embodiment 2.
In three mouthfuls of glass reaction bottles of 500mL, add trans peruviol 104g (0.47mol), stir under the room temperature and add ethanol solution of hydrogen chloride down, TLC follows the tracks of the peruviol (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that whether reacts completely; The iodine colour developing), reaction is finished, and washs 1 time with saturated nacl aqueous solution 100mL, again with saturated sodium bicarbonate solution 100mL washing 1 time, with saturated nacl aqueous solution 100mL washing 1 time, adds anhydrous sodium sulfate drying then, filters, and gets midbody (III) 101.7g.
100g joins in the there-necked flask of 1000ml with midbody (III); Add salt of wormwood 250g, Soiodin 1.6g, ethyl malonate 73g, acetone 200ml; Temperature rising reflux reaction (60～70 ℃ of interior temperature), TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing) about 5 hours, reaction was finished, and normal pressure reclaims acetone; In reaction flask, add the 200ml purified water and be stirred to the salt of wormwood dissolving, divide water-yielding stratum, collected organic layer; Merge organic layer, use anhydrous sodium sulfate drying, suction filtration; 100 ℃ of front-end volatiles are removed in the organic layer decompression, and residuum is midbody (IV) 142.0g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (IV) 140.0g, add Pottasium Hydroxide 64.5g, 95% ethanol 600ml, heat up (80～90 ℃ of interior temperature) refluxed 4 hours, and TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing), reaction is finished, and concentrating under reduced pressure does not ooze to there being ethanol; Add purified water 500ml dissolving, the sulfuric acid with 10% is transferred pH to 1～3, adds ETHYLE ACETATE 300ml * 3 extractions; The combined ethyl acetate layer with saturated sodium-chloride 200ml washing, adds anhydrous sodium sulfate drying; Filter, filtrate decompression is concentrated into till the no ETHYLE ACETATE, gets midbody (V) 107.6g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (V) 106g, 140～150 ℃ of decompression heating of temperature are 2 hours in controlling, and get midbody (I) compound 4E after the cooling, 8E)-5,9, and 13-trimethylammonium-4,8,12-14 trienic acid 83.1g.
Embodiment 3.
In three mouthfuls of glass reaction bottles of 500mL, add trans peruviol 104g (0.47mol), stir under the room temperature and add hydrogen chloride methanol solution down, TLC follows the tracks of the peruviol (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that whether reacts completely; The iodine colour developing), reaction is finished, and washs 1 time with saturated nacl aqueous solution 100mL, again with saturated sodium bicarbonate solution 100mL washing 1 time, with saturated nacl aqueous solution 100mL washing 1 time, adds anhydrous sodium sulfate drying then, filters, and gets midbody (III) 104.2g.
100g joins in the there-necked flask of 1000ml with midbody (III); Add salt of wormwood 200g, Soiodin 1.6g, ethyl malonate 73g, acetone 200ml; Temperature rising reflux reaction (60～70 ℃ of interior temperature), TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing) about 5 hours, reaction was finished, and normal pressure reclaims acetone; In reaction flask, add the 200ml purified water and be stirred to the salt of wormwood dissolving, divide water-yielding stratum, collected organic layer; Merge organic layer, use anhydrous sodium sulfate drying, suction filtration; 100 ℃ of front-end volatiles are removed in the organic layer decompression, and residuum is midbody (IV) 141.4g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (IV) 140.0g, add Pottasium Hydroxide 64.5g, 95% ethanol 600ml, heat up (75～85 ℃ of interior temperature) refluxed 5 hours, and TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing), reaction is finished, and concentrating under reduced pressure does not ooze to there being ethanol; Add purified water 500ml dissolving, the sulfuric acid with 10% is transferred pH to 1～3, adds ETHYLE ACETATE 300ml * 3 extractions; The combined ethyl acetate layer with saturated sodium-chloride 200ml washing, adds anhydrous sodium sulfate drying; Filter, filtrate decompression is concentrated into till the no ETHYLE ACETATE, gets midbody (V) 103.1g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (V) 100g, 150～160 ℃ of decompression heating of temperature are 2 hours in controlling, and get midbody (I) compound 4E after the cooling, 8E)-5,9, and 13-trimethylammonium-4,8,12-14 trienic acid 78.8g.
Embodiment 4.
In three mouthfuls of glass reaction bottles of 500mL, add trans peruviol 104g (0.47mol) ,-5～5 ℃ are stirred down and add hydrogen chloride gas down, and TLC follows the tracks of the peruviol (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that whether reacts completely; The iodine colour developing), reaction is finished, and washs 1 time with saturated nacl aqueous solution 100mL, again with saturated sodium bicarbonate solution 100mL washing 1 time, with saturated nacl aqueous solution 100mL washing 1 time, adds anhydrous sodium sulfate drying then, filters, and gets midbody (III) 94.2g.
90g joins in the there-necked flask of 1000ml with midbody (III); Add salt of wormwood 180g, Soiodin 1.4g, ethyl malonate 70g, acetonitrile 200ml; Temperature rising reflux reaction (70～80 ℃ of interior temperature), TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing) about 5 hours, reaction was finished, and normal pressure reclaims acetonitrile; In reaction flask, add the 200ml purified water and be stirred to the salt of wormwood dissolving, divide water-yielding stratum, collected organic layer; Merge organic layer, use anhydrous sodium sulfate drying, suction filtration; 100 ℃ of front-end volatiles are removed in the organic layer decompression, and residuum is midbody (IV) 123.4g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (IV) 120.0g, add Pottasium Hydroxide 55.5g, 95% ethanol 500ml, heat up (70～80 ℃ of interior temperature) refluxed 6 hours, and TLC follows the tracks of the (developping agent: ETHYLE ACETATE: sherwood oil=1: 9 that reacts completely; The iodine colour developing), reaction is finished, and concentrating under reduced pressure does not ooze to there being ethanol; Add purified water 500ml dissolving, the sulfuric acid with 10% is transferred pH to 1～3, adds ETHYLE ACETATE 300ml * 3 extractions; The combined ethyl acetate layer with saturated sodium-chloride 200ml washing, adds anhydrous sodium sulfate drying; Filter, filtrate decompression is concentrated into till the no ETHYLE ACETATE, gets midbody (V) 94.7g.
In three mouthfuls of glass reaction bottles of 1000mL, add midbody (V) 90g, 150～160 ℃ of decompression heating of temperature are 2 hours in controlling, and get midbody (I) compound 4E after the cooling, 8E)-5,9, and 13-trimethylammonium-4,8,12-14 trienic acid 68.3g.
Claims (11)
1. the synthesis preparation method method of a gefarnate, its preparation process is following:
A, with peruviol (II) and hcl reaction, washing, dry, concentrating under reduced pressure remove front-end volatiles, obtain midbody (III).
B, with the reaction of midbody (III) and ethyl malonate, reacting by heating in salt of wormwood/acetone, potassiumiodide is done catalyst reaction, decompression goes to obtain midbody (IV) behind the front-end volatiles;
C, in the ethanolic soln of alkali, add midbody (IV), after the heating saponification reaction, boil off ethanol, extraction, the water intaking phase, acidifying, organic phase is got in extraction again, and the lower boiling front-end volatiles are fallen in underpressure distillation behind the washing and drying, obtain midbody (V).
D, to the direct heating under vacuum decarboxylic reaction of midbody (V), obtain orange-yellow oily liquid, i.e. gefarnate key intermediate formula (I) compound 4E, 8E)-5,9,13-trimethylammonium-4,8,12-14 trienic acids.
2. according to claim 1a step, it is characterized in that hydrogenchloride is hydrogen chloride gas and various solution thereof.Solution comprises the ethanolic soln of hydrogenchloride, the methanol solution of hydrogenchloride etc.
3. according to claim 1a step, the molar ratio that it is characterized in that peruviol and hydrogenchloride is 1: 1～10, preferred 1: 1.5～5.5, more preferably 1: 2～3.
4. according to claim 1a step, it is characterized in that its temperature of reaction temperature is-10～50 ℃, 15～25 ℃ of preferred room temperatures.
5. according to claim 1b step, it is characterized in that employed catalyzer is preferably Soiodin or potassiumiodide, is more preferably potassiumiodide.
6. according to claim 1b step, it is characterized in that employed solvent is preferably acetone or acetonitrile, more preferably acetone.
7. according to claim 1b step, it is characterized in that employed alkali is preferably salt of wormwood, mol ratio is 1～10, preferred 2～4.
8. according to claim 1c step, it is characterized in that the ethanolic soln of the alkali that uses is preferably the ethanolic soln of sodium hydroxide or the ethanolic soln of Pottasium Hydroxide.Wherein the mol ratio of sodium hydroxide or Pottasium Hydroxide and midbody (IV) is preferably 2～6: 1.
9. according to claim 1c step, the saponified temperature of reaction is 60～100 ℃, preferred 80～90 ℃; Reaction times is 2～5 hours, preferred 3.5～4.5 hours.
10. according to claim 1c step, it is characterized in that the acid of using is preferably hydrochloric acid or dilute sulphuric acid or its diluent, employed extraction solvent is preferably ETHYLE ACETATE or isopropyl ether, more preferably ETHYLE ACETATE.
11. according to right 1d step, the temperature of reaction of decarboxylation is 130～170 ℃, preferred 140～150 ℃, and 2～4 hours decarboxylation time, preferred 3 hours; More than the decarboxylation vacuum tightness 100mmHg.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107200687A (en) * | 2016-03-16 | 2017-09-26 | 信越化学工业株式会社 | Method for producing 4 methyloctanoic acid ethyl esters |
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| CN101475476A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Gefarnate compound and method for synthesizing the same |
| 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 |
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2011
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| CN101475476A (en) * | 2009-01-21 | 2009-07-08 | 海南美大制药有限公司 | Gefarnate compound and method for synthesizing the same |
| 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 |
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| A.T.HUZMAMOB等: "《Improved procedure for producing geranyl esters of (4E/Z,8E)-(4E/Z,8Z)-farnanesylacetic acid》", 《KHIMIKO FARMATSEVTICHESKII ZHURNAL》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN107200687A (en) * | 2016-03-16 | 2017-09-26 | 信越化学工业株式会社 | Method for producing 4 methyloctanoic acid ethyl esters |
| CN107200687B (en) * | 2016-03-16 | 2020-12-11 | 信越化学工业株式会社 | Process for producing ethyl 4-methyloctanoate |
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Application publication date: 20120404 |