CN103626649B - A kind of method preparing Pelretin acid - Google Patents
A kind of method preparing Pelretin acid Download PDFInfo
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- CN103626649B CN103626649B CN201310547437.2A CN201310547437A CN103626649B CN 103626649 B CN103626649 B CN 103626649B CN 201310547437 A CN201310547437 A CN 201310547437A CN 103626649 B CN103626649 B CN 103626649B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/29—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of hydroxy groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention provides a kind of method preparing Pelretin acid, the method with trans farnesol for starting raw material, through oxidizing reaction, Wittig-Horner reaction, hydrolysis reaction preparation, starting raw material is easy to get, and reaction conditions is gentle, easy and simple to handle, reaction process can reduce the generation of isomer, enables crude product purity reach more than 85%, is convenient to purifying, the product of more than 99% can be obtained after recrystallization, be applicable to preparation of industrialization satisfactory Pelretin acid starting material medicine.
Description
Technical field
The present invention relates to pharmaceutical synthesis field, be specifically related to the preparation method treating the acid of hepatocellular carcinoma recurrence medicine Pelretin.
Background technology
Pelretin acid Peretinoin (NIK333) is alltrans polyenic compounds, and be the vitamin A homologue of a kind of oral administration hepatocellular carcinoma recurrence, it is by transforming growth factor (TGF-α) cell death inducing.This medicine is developed by Japanese Kowa company Ltd, its chemistry (2E, 4E, 6E, 10E) by name-3,7,11,15-tetramethyl--2,4,6,10,14-16 carbon 5 alkene acid, and structural formula is:
There is multiple double bond in the chemical structure of this compound, in synthesis, easily produce multiple cis-trans-isomer, add purifying difficulty, reduce productive rate.The synthetic method of prior art mainly contains three kinds, in patent US4988732, have description.
Method one: with (3E, 5E, 9E)-6,10,14-trimethylammonium 15 carbon-3; 5,9,13-tetraene-2-ketone is starting raw material, under 60%NaH exists; take normal hexane as solvent, with phosphonoacetate, witting-horner under reflux conditions occurs and react, obtain (2E, 4E; 6E, 10E)-3,7,11; 15-tetramethyl-16 carbon-2,4,6,10; 14-pentenoic acid ethyl ester, gained compound makees solvent with Virahol, exists and hydrolysis reaction occurs, obtain Pelretin acid at KOH.
Method two: with 1-methyl-4-((2E, 6E)-3, 7, 11-trimethylammonium 12 carbon-2, 6, 10-trialkenyl alkylsulfonyl) benzene is starting raw material, take tetrahydrofuran (THF) as solvent,-50 DEG C drip n-Butyl Lithium under nitrogen protection, after dropwising, drip the tetrahydrofuran solution of (E)-ethyl-4-bromo-3-methyl but-2-ene acid methyl esters again, stir 30 minutes, obtain (2E, 6E, 10E)-ethyl-3, 7, 11, 15-tetramethyl--5-toluenesulphonic acids base 16 carbon-2, 6, 10, 14-triolefin acid esters, gained compound makees solvent with Virahol, exist at KOH and hydrolysis reaction occurs, obtain Pelretin acid.
Method three: with (2E, 6E)-3,7; 11-trimethylammonium-2,6,10-12 carbon triolefin-1-aldehyde is starting raw material; take normal heptane as solvent; there is witting-horner react with (E)-ethyl-3-((diethoxy phosphoryl) methyl)-2-olefin(e) acid ethyl ester under sodium ethylate effect under room temperature, obtain (2E, 4E; 6E; 10E)-3,7,11; 15-tetramethyl-16 carbon-2; 4,6,10; 14-pentenoic acid ethyl ester; gained compound makees solvent with Virahol, exists and hydrolysis reaction occurs, obtain Pelretin acid at KOH.
The starting raw material of aforesaid method is all expensive, not easily obtains in a large number from the market, and the temperature of reaction of method two requires that need nitrogen protection, conditional request is high, is therefore not suitable for suitability for industrialized production for-50 DEG C.And repeat by experiment to find, do solvent hydrolysis with Virahol and transesterify can occur in reaction process, configuration is caused to change further, reduce product purity, adopt sodium ethylate to do alkali in method three and carry out witting-horner reaction, multiple cis-isomeride can be produced and large percentage, cause product purity low, and be difficult to purifies and separates.Two isomer structure formulas that in isomer, content is larger are as follows:
Therefore be necessary to make further research the synthetic method of Pelretin acid, find the method for applicable suitability for industrialized production, and quality product meet the requirement of bulk drug.
Preparing Wittig-Horner reaction in the method for Pelretin acid in prior art adopts sodium ethylate to do alkali, but found through experiments, adopt sodium ethylate to do alkali and can produce more cis-isomeride A and isomer B, contriver to crude product the product carried out before and after recrystallization carry out analysis find, after recrystallization, the content of isomer A reduces more, but the content of isomer B reduces very little, and therefore isomer B is difficult to separation and purification, affects the purity of the finished product.Contriver attempts carrying out experiment sieving to other alkali, to reducing the content of the particularly isomer B of isomer in product.The experimental result that employing sodium ethylate does alkali and other single alkali is as follows:
| Alkali | Isomer A content | Isomer B content | Purity | Yield |
| Sodium ethylate | 19％ | 10.5％ | 62％ | 60％ |
| Sodium methylate | 19％ | 12.3％ | 61.3％ | 59％ |
| Potassium tert.-butoxide | 13.6％ | 9.8％ | 71％ | 70％ |
| Trimethyl carbinol lithium | 9.7％ | 8.8％ | 75％ | 73％ |
From the above results, adopt sodium ethylate and sodium methylate in single alkali, content of isomer that potassium tert.-butoxide produces is comparatively large, two kinds of content of isomer that trimethyl carbinol lithium produces are less, but the content of the isomer B of more difficult removing is still larger.Contriver attempts investigating and adopts mixed base and different solvents on the impact of content of isomer, the results are shown in following table:
As seen from the above table, when tetrahydrofuran (THF) (THF) makees solvent, the content of isomer adopting the mixed base of sodium ethylate or sodium methylate and trimethyl carbinol lithium to produce reduces many compared to single alkali, particularly the content of isomer B reduces obvious especially, when dimethyl formamide is solvent, the content of isomer A and isomer B all reduces.
Step 2) described mixed base preferred alcohol sodium or sodium methylate mix with trimethyl carbinol lithium, and most preferred ethanol sodium mixes with trimethyl carbinol lithium.When reaction solvent is tetrahydrofuran (THF), in described mixed base, the mol ratio of the first alkali and trimethyl carbinol lithium is 1:1 ~ 6, preferred 1:1 ~ 4, most preferably 1:4; When reaction solvent is dimethyl formamide, in described mixed base, the mol ratio of the first alkali and trimethyl carbinol lithium is 1 ~ 2:1.
Wittig-Horner adopts the rudimentary property organic solvent extractions such as sherwood oil, isopropyl ether or normal hexane after completion of the reaction, and successively with methanol/water solution, saturated sodium-chloride water solution washing, concentrated after dry.
Step 3) hydrolysis reaction prior art adopt Virahol be that solvent is hydrolyzed, but find that compound IV transesterification reaction can occur and causes product purity to decline, therefore contriver has carried out experiment sieving with further Optimization Technology to the solvent of hydrolysis reaction, find to adopt tetrahydrofuran (THF), 1, the mixed solvent of the organic solvents such as 4-dioxane, acetonitrile, ethanol and water carries out, as the solvent of hydrolysis reaction, transesterification reaction to occur, the mixed solvent of preferred alcohol and water.Above-mentioned steps 3) volume ratio of organic solvent and water is 1 ~ 5:1 in mixed solvent described in hydrolysis reaction, preferred 3:1.
Step 3) described in alkali be the one of sodium hydroxide, potassium hydroxide, lithium hydroxide, preferred potassium hydroxide; Step (3) hydrolysising reacting temperature is 25 ~ 75 DEG C, preferably 40 ~ 60 DEG C.
Step 3) after hydrolysis reaction, adjust pH is to acid, and extraction, dry, the Compound I crude product that concentrated removing organic solvent obtains, crude product can adopt the mixed solvent of first alcohol and water to carry out recrystallization one or many and obtain Compound I sterling.
The invention provides a kind of method preparing Pelretin acid, the method with trans farnesol for starting raw material, through oxidizing reaction, Wittig-Horner reaction, hydrolysis reaction preparation, starting raw material is easy to get, and reaction conditions is gentle, easy and simple to handle, reaction process can reduce the generation of isomer, enables crude product purity reach more than 85%, is convenient to purifying, the product of more than 99% can be obtained after recrystallization, be applicable to preparation of industrialization satisfactory Pelretin acid starting material medicine.
Below by the embodiment of embodiment, the present invention will be further described.
Summary of the invention
The invention provides a kind of method preparing Pelretin acid, the method raw material is easy to get, and reaction conditions is gentle, and easy and simple to handle, crude product purity reaches more than 85%, is convenient to purifying, is applicable to suitability for industrialized production.
A kind of method preparing Pelretin acid provided by the invention, is characterized in that, carry out according to following reaction formula:
Comprise following steps:
1) oxidizing reaction: with the trans farnesol of Compound II per for starting raw material, obtains (2E, 6E)-3 with 2-iodosobenzoic acid or Dai Si-Martin reagent for oxygenant carries out oxidizing reaction, 7,11-trimethylammonium-2,6,10-12 carbon triolefin-1-aldehyde and compound III;
2) Wittig-Horner reaction: (E)-ethyl-3-(diethoxy phosphoryl) methyl of dissolution with solvents will be used respectively)-2-olefin(e) acid ethyl ester and compound III join successively in the solvent that alkali exists and be obtained by reacting (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-16 carbon-2,4,6,10,14-pentenoic acid ethyl ester and compound IV, wherein said alkali is the mixed base of a kind of and trimethyl carbinol lithium in sodium ethylate, sodium methylate, sodium hydride, potassium tert.-butoxide, and described solvent is tetrahydrofuran (THF) or dimethyl formamide;
3) hydrolysis reaction: compound IV be hydrolyzed in a solvent in the presence of a base and be obtained by reacting Compound I and Pelretin acid, wherein solvent is the mixed solvent of a kind of organic solvent in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, ethanol and water.
Step 1) when oxygenant adopts 2-iodosobenzoic acid, solvent is dimethyl sulfoxide (DMSO) (DMSO) in oxidizing reaction, is methylene dichloride with solvent during Dai Si-Martin reagent.Described oxidizing reaction is carried out in room temperature.Adopt above-mentioned two kinds of oxygenants can make the not oxidized one-tenth carboxylic acid of trans farnesol, and do not change its configuration, do not produce isomer impurities.And adopting other mild oxidizer such as PCC (pyridinium chloro-chromate) and Manganse Dioxide, to make oxidation effectiveness bad, Manganse Dioxide can not be oxidized completely, can only be oxidized 20% at most.And isomer is comparatively large, PCC reaction is very fast, but the isomer of the configuration reversal produced is more, reaches more than 40%.
Step 1) temperature of reaction is room temperature, pours in frozen water after completion of the reaction, add the rudimentary property organic solvent extractions such as sherwood oil, isopropyl ether or normal hexane by reaction solution, organic phase is dry, obtains compound III after concentrated.
Step 2) temperature of reaction is-30 ~ 10 DEG C, when tetrahydrofuran (THF) makees solvent, temperature of reaction is preferably lower scope-30 ~-10 DEG C, when dimethyl sulfoxide (DMSO) makees solvent preferably between 0 ~ 10 DEG C, due to the generation of isomer also can be controlled more than 0 DEG C, can save energy.
Embodiment
Embodiment one oxidizing reaction (with 2-acyl group phenylformic acid for oxygenant)
2-acyl group phenylformic acid (324.8g) is joined in reaction flask, adds DMSO (1000ml) stirring and dissolving, drip Compound II per (200g), finish stirring at room temperature reaction 1h; Immediately reaction solution is poured into after completion of the reaction in previously prepd frozen water (2000g) (0-5 DEG C), add sherwood oil (1000ml), stirred for several minute, decompress filter, filter cake is washed with appropriate sherwood oil again, filtrate separates aqueous phase, concentrates and obtain colourless liquid compound III (196g) after organic phase anhydrous magnesium sulfate drying.
Embodiment titanium dioxide reaction (to wear this Martin reagent for oxygenant)
Dai Si-Martin reagent (209g) is added reaction flask, adds methylene dichloride (1500ml), mechanical stirring, Compound II per (100g) is added dropwise in reaction solution, and stirring at room temperature reaction 30min, sampling, reacts completely.Filter, filtrate uses saturated sodium bicarbonate aqueous solution (500ml) successively, and saturated aqueous common salt (300ml) is washed, anhydrous sodium sulfate drying, concentrates and obtains colourless liquid compound III (93g).Embodiment three Wittig-Horner reacts (sodium ethylate and tert-butyl lithium mixed base, THF)
Sodium ethylate (6.36g) and trimethyl carbinol lithium (18.18g) is added in reaction flask, add anhydrous THF (1000ml) to stir, pass into nitrogen protection, be cooled to-20 DEG C, compound (E)-ethyl-3-((diethoxy phosphoryl) methyl)-2-olefin(e) acid ethyl ester (78.00g) is added drop-wise in reaction flask after dissolving with appropriate THF, drip complete temperature control stirring reaction 1h, getting after the appropriate THF of compound III (50.00g) dissolves is added drop-wise in reaction flask again, temperature control is below-15 DEG C, drip complete temperature control stirring reaction 4-6h, add sherwood oil (1000ml) after completion of the reaction, use 10% aqueous ammonium chloride solution (500ml) successively, the methanol aqueous solution (500ml) of 75%, saturated sodium-chloride is washed (500ml), anhydrous sodium sulfate drying, concentrate and obtain tan solid compound IV (66.20g), purity 88.05%, productive rate 88.30%, content of isomer: isomer A10.01%, isomer B1.94%.
Embodiment 4 Wittig-Horner reacts (sodium ethylate and tert-butyl lithium mixed base, DMF)
Sodium ethylate (11.6g) and trimethyl carbinol lithium (13.6g) is added in reaction flask, add dry DMF (250ml) to stir, pass into nitrogen protection, be cooled to 0 DEG C-10 DEG C, compound (E)-ethyl-3-((diethoxy phosphoryl) methyl)-2-olefin(e) acid ethyl ester (78g) is added drop-wise in reaction flask after dissolving with appropriate DMF, temperature control is below 10 DEG C, drip complete temperature control stirring reaction 1h, getting after the appropriate DMF of compound III (50g) dissolves is added drop-wise in reaction flask again, temperature control is below 10 DEG C, drip complete temperature control stirring reaction 1-2h, add sherwood oil (1000ml) after completion of the reaction, use 10% aqueous ammonium chloride solution (500ml) successively, the methanol aqueous solution (500ml) of 75%, saturated sodium-chloride is washed (500ml), anhydrous sodium sulfate drying, concentrate and obtain tan solid compound IV (64.2g), purity 86.6%, productive rate 85.6%, content of isomer: isomer A6.3%, isomer B5.1%.
Embodiment 5 hydrolysis reaction (alcohol-water makees solvent)
Potassium hydroxide (59g), ethanol (450ml), water (150ml), compound IV (116g) is added in reaction flask, be heated with stirring to 60 DEG C of reaction 1-2h, then heating is stopped, add 500ml water, the hydrochloric acid of 6N regulates PH to 2-3, isopropyl ether (400ml × 3) extracts, anhydrous magnesium sulfate drying, concentrate and obtain yellow solid compound I (97.6g), purity 89.18%, sterling 65.37g is obtained again, purity 99.9% through methyl alcohol and water mixed solvent recrystallization.
Embodiment 6 hydrolysis reaction (Isosorbide-5-Nitrae-dioxane-water makees solvent)
Potassium hydroxide (30.55g) is added in reaction flask, 1, 4-dioxane (150ml), water (75ml), compound IV (60.00g), be heated with stirring to 60 DEG C of reaction 12h, detect through Ultra Performance Liquid Chromatography, compound IV reacts completely, stop heating, add 150ml water, the hydrochloric acid of 6N regulates PH to 2-3, isopropyl ether (200ml × 3) extracts, anhydrous magnesium sulfate drying, concentrate and obtain yellow solid compound I (50.42g), purity 89.95%, sterling 32.27g is obtained again through methyl alcohol and water mixed solvent recrystallization, purity 99.9%.
Claims (14)
1. prepare a method for Pelretin acid, it is characterized in that, carry out according to following reaction formula:
Comprise following operation steps:
1) oxidizing reaction: with the trans farnesol of Compound II per for starting raw material, obtains (2E, 6E)-3 with 2-iodosobenzoic acid or Dai Si-Martin reagent for oxygenant carries out oxidizing reaction, 7,11-trimethylammonium-2,6,10-12 carbon triolefin-1-aldehyde and compound III;
2) Wittig-Horner reaction: (E)-ethyl-3-(diethoxy phosphoryl) methyl of dissolution with solvents will be used respectively)-2-olefin(e) acid ethyl ester and compound III join successively in the solvent that alkali exists and be obtained by reacting (2E, 4E, 6E, 10E)-3,7,11,15-tetramethyl-16 carbon-2,4,6,10,14-pentenoic acid ethyl ester and compound IV, wherein said alkali is the mixed base of a kind of and trimethyl carbinol lithium in sodium ethylate, sodium methylate, sodium hydride, potassium tert.-butoxide, and described solvent is tetrahydrofuran (THF) or dimethyl formamide;
3) hydrolysis reaction: compound IV be hydrolyzed in a solvent in the presence of a base and be obtained by reacting Compound I and Pelretin acid, wherein solvent is the mixed solvent of a kind of organic solvent in tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, acetonitrile, ethanol and water.
2. method according to claim 1, is characterized in that, step 1) when oxygenant adopts 2-iodosobenzoic acid, solvent is dimethyl sulfoxide (DMSO) in oxidizing reaction, is methylene dichloride with solvent during Dai Si-Martin reagent.
3. method according to claim 1, is characterized in that, step 1) temperature of reaction is room temperature.
4. method according to claim 1, is characterized in that, step 2) temperature of reaction is-30 ~ 10 DEG C.
5. method according to claim 4, is characterized in that, step 2) tetrahydrofuran (THF) when making solvent temperature of reaction be-30 ~-10 DEG C, when dimethyl formamide makees solvent, temperature of reaction is 0 ~ 10 DEG C.
6. method according to claim 1, is characterized in that, step 2) described alkali is the mixed base of sodium ethylate or sodium methylate and trimethyl carbinol lithium.
7. method according to claim 1, it is characterized in that, step 2) in when reaction solvent is tetrahydrofuran (THF), in described mixed base, the mol ratio of the first alkali and trimethyl carbinol lithium is 1: 1 ~ 6, when reaction solvent is dimethyl formamide, in described mixed base, the mol ratio of the first alkali and trimethyl carbinol lithium is 1 ~ 2: 1.
8. method according to claim 1, is characterized in that, step 2) adopt sherwood oil, isopropyl ether or n-hexane extraction after completion of the reaction, and successively with methanol/water solution, saturated sodium-chloride water solution washing, concentrated after dry.
9. method according to claim 1, is characterized in that, step 3) solvent described in hydrolysis reaction is the mixed solvent of second alcohol and water.
10. the method according to claim 1 or 10, is characterized in that, step 3) volume ratio of organic solvent and water is 1 ~ 5: 1 in mixed solvent described in hydrolysis reaction.
11. methods according to claim 1 or 10, is characterized in that, step 3) volume ratio of organic solvent and water is 3: 1 in mixed solvent described in hydrolysis reaction.
12. methods according to claim 1, is characterized in that, alkali described in step (3) is the one of sodium hydroxide, potassium hydroxide, lithium hydroxide.
13. methods according to claim 1, is characterized in that, step (3) hydrolysising reacting temperature is 25 ~ 75 DEG C.
14. methods according to claim 1, it is characterized in that, after step (3) hydrolysis reaction, adjust pH to acid, extraction, drying, the Compound I crude product that concentrated removing organic solvent obtains, crude product can adopt the mixed solvent of first alcohol and water to carry out recrystallization one or many and obtain Compound I sterling.
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| CN104387221B (en) * | 2014-11-24 | 2016-06-08 | 深圳万乐药业有限公司 | A kind of synthetic method of pelretin acid decarboxylation body impurity |
| CN104402690B (en) * | 2014-12-10 | 2016-08-24 | 国药一心制药有限公司 | The preparation method of method Buddhist nun's aldehyde and accompany the preparation method of auspicious tretinoin |
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