CN104693027B - A kind of method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds - Google Patents
A kind of method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds Download PDFInfo
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Abstract
The present invention relates to medicine intermediate technical field, particularly to a kind of method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds, the method includes 2, epihydric acid 2 ester type compound with as the C of reaction dissolvent1～C3The open loop under gaseous hydrogen chloride or its aqueous solution effect of chain saturated monohydroxy alcohol, prepares 2-hydroxyl-3-alkoxyl propionic ester compounds。The method safety of the present invention, nontoxic, with low cost, operational approach, be suitable to industrialization。
Description
Technical field
The present invention relates to medicine intermediate technical field。In particular it relates to Endothelin Receptor inhibitor intermediate, particularly to a kind of method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds。
Background technology
Endothelin is a kind of peptide being made up of 21 seed amino acids, and it is synthesized by the endothelium of blood vessel and discharges。Endothelin is a kind of effective vasoconstrictor and antiotasis has very strong effect。Increasing or the Endothelin of abnormality is released in peripheral vessels, Renal vascular and cerebral blood vessel and causes lasting vasoconstriction, this contraction may result in disease。The patient of hypertension, memory myocardial infarction, cerebrovascular high pressure, Reynolds syndrome, atherosclerosis and respiratory tract spasm is had been found that the Endothelin blood plasma level increased。Therefore, the material that specific suppression Endothelin is combined on receptor should also be as the above-mentioned different Endothelin physiologic effect of antagonism and is therefore valuable medicine。
Now finding, 2-hydroxyl-3-alkoxypropan acid derivative is the good inhibitor of endothelin receptor, and 2-hydroxyl-3-alkoxyl propionic ester compounds is as its important intermediate, and the synthesis studying it has great importance。
At present, the existing related introduction to synthesis 2-hydroxyl-3-alkoxyl propionic ester compounds。Such as, JournalofMedicinalChemistry, 1996, vol.39, the preparation method of a kind of 2-hydroxyl-3-alkoxyl propionic ester disclosed in #11p.2123 2128, it adopts Lewis acid BF3.Et2O or Catalyzed by p-Toluenesulfonic Acid 2, epihydric acid 2 ester type compound and alcohol effect, reach the effect of open loop of epoxy compound, but BF3.Et2O is a kind of inflammable, poisonous and has the reagent of strong impulse and aggressive, easily decomposes the fluohydric acid gas smog producing severe toxicity in humid air, though the method is suitable to laboratory research, but is unsuitable for the enforcement that industrialization is amplified。Further, p-methyl benzenesulfonic acid reacts in alcohol, easily generates p-toluenesulfonic esters, has genotoxicity, as avoiding in the synthesis of medicine intermediate using。
JournaloftheChemicalSociety, PerkinTransactions1:OrganicandBio-OrganicChemistry (1972-1999), 1977, P.1773-1776 with sulfuric acid catalysis 2 disclosed in, epihydric acid 2 ester type compound reacts with alcohol, synthesizes 2-hydroxyl-3-alkoxyl propionic ester。It is demonstrated experimentally that above-mentioned reaction can occur sulphuric acid, but sulphuric acid is easily esterified with alcohol, generates the materials such as hypertoxic dimethyl sulfate, should also be as avoiding in the synthesis of medicine intermediate。
Summary of the invention
For above-mentioned technological deficiency, it is an object of the invention to provide a kind of safety non-toxic and be suitable to the method synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds of industrialized production。
The above-mentioned purpose of the present invention is realized by following method, the method includes, using Formula II compound and the formula III compound open loop under gaseous hydrogen chloride or its aqueous solution effect as reaction dissolvent, preparing compound of formula I (i.e. 2-hydroxyl-3-alkoxyl propionic ester compounds)；
Described compound of formula I is:
Described Formula II compound is:
Described formula III compound is:
R4-OH
(III)
Wherein, R1For C1～C5Alkyl, R2And R3It is each independently aryl, R4For C1～C3Straight or branched alkyl。
Preferably, R1For methyl, ethyl, isopropyl, n-pro-pyl, isobutyl group, normal-butyl, the tert-butyl group, n-pentyl or isopentyl。
Preferably, R2And R3It is each independently phenyl。
Preferably, R4For methyl, ethyl, isopropyl or n-pro-pyl。
In the method for the invention, described open loop is to carry out at the temperature of 20～50 DEG C, it is preferable that described open loop carries out 1～2 hour。
In the method for the invention, the Formula II compound relative to 1mol, the molal quantity of described hydrogen chloride is 0.2～0.6mol, it is preferred to 0.3～0.5mol。
In the method for the invention, the Formula II compound relative to 1mol, the consumption of formula III compound is 1～3L, it is preferred to 1.5～2.5L。
For obtaining the said method of the present invention, the present inventor has paid the effort of hardships, has carried out substantial amounts of research, it has been found that phosphoric acid and nitric acid can also with 2, epihydric acid 2 ester type compound reaction preparation 2-hydroxyl-3-alkoxyl propionic ester compounds。Result of the test shows, although above 2 kinds of acid all energy catalysis 2,2-hydroxyl-3-alkoxyl propionic ester is prepared in epihydric acid 2 ester type compound and alcohol effect, but:
Phosphoric acid can etching glass, and the instrument of laboratory and workshop mostly is glass material, therefore reacts that equipment requirements is higher, and industrialization is difficult to realize；
Nitric acid has oxidisability, and the reactant not being suitable in structure containing reproducibility functional group, therefore the scope of application of nitric acid is limited, does not have promotional value。
The present inventor attempts using gaseous hydrogen chloride or its aqueous solution to carry out catalysis 2, epihydric acid 2 ester type compound open loop, it was unexpectedly found that gaseous hydrogen chloride or its aqueous solution not only have outstanding catalytic action, it is obtained in that highly purified product, and the method is also nontoxic, safe, with low cost and is suitable to industrialized production。
The present inventor is by finding after great many of experiments, the inventive method is particularly well-suited to the synthesis on 3 carbon with the 2-hydroxyl-3-alkoxyl propionic ester compounds of monosubstituted or polysubstituted group, it is preferable that have 1 to 2 aryl on 3 carbon, it is highly preferred that 3 carbon have 1 to 2 phenyl；Described alkoxyl can be methoxyl group, ethyoxyl, positive propoxy, isopropoxy or phenoxy group etc.。Such as, 2-hydroxyl-3-alkoxyl propionic ester the compounds being suitable for can be 2-hydroxy-3-methoxy-3, 3-diphenyl-propionic acid methyl ester, 2-hydroxyl-3-ethyoxyl-3, 3-diphenyl-propionic acid methyl ester, 2-hydroxyl-3-isopropoxy-3, 3-diphenyl-propionic acid methyl ester, 2-hydroxyl-3-propoxyl group-3, 3-diphenyl-propionic acid methyl ester, 2-hydroxyl-3-phenoxy group-3, 3-diphenyl-propionic acid methyl ester, 2-hydroxy-3-methoxy-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-ethyoxyl-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-isopropoxy-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-propoxyl group-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-phenoxy group-3, 3-diphenylprop acetoacetic ester etc.。
Compared with prior art, the preparation method of the present invention has but is not limited to advantages below:
1. the reagent used by the present invention is hydrogen chloride or its aqueous solution, compares BF3.Et2O toxicity is little, nonflammable, uses comparatively safe；Comparing p-methyl benzenesulfonic acid, hydrochloric acid is not related to genotoxicity, is particularly suited for the synthesis of medicine intermediate 2-hydroxyl-3-alkoxyl propionic ester compounds；Comparing sulphuric acid, the inventive method will not produce the materials such as the bigger dimethyl sulfate of toxicity or dithyl sulfate, safer。
2. the applied range of the inventive method agents useful for same hydrochloric acid, buying is convenient, with low cost, and its catalysis 2, and epihydric acid 2 ester type compound and alcohol are swift in response, and by-product is few, it is adaptable to laboratory and large-scale industrial production。
3. the post processing of the inventive method is the stirring and crystallizing that adds water, and can obtain highly purified product, easy and simple to handle, it is simple to industrialized production。
Detailed description of the invention
Below in conjunction with detailed description of the invention, the present invention being described in further detail, the embodiment provided is only for illustrating the present invention, rather than in order to limit the scope of the present invention。
In the following embodiments, 3,3-diphenyl-2 of employing, epihydric acid 2 methyl ester, 3,3-diphenyl-2, epihydric acid 2 ethyl ester, 3,3-diphenyl-2, epihydric acid 2 isopropyl ester and 3,3-diphenyl-2, epihydric acid 2 propyl ester is all purchased from the open-minded Chemical Co., Ltd. in Jiangsu, technical grade；Hydrochloric acid mass concentration is 37%, technical grade。
Embodiment 1
By 600 gram of 3,3-diphenyl-2, epihydric acid 2 methyl ester is dissolved in 2.4 liters of anhydrous isopropyl alcohols, stir at 20 DEG C, be slowly added to 48 grams of hydrochloric acid, add, keep system temperature at 20 DEG C, add 4.8 liters of water after stirring 1 hour, continue to stir half an hour, sucking filtration, isolate solid product, vacuum drying at 50 DEG C, obtains 2-hydroxyl-3-isopropoxy-3,3-diphenyl-propionic acid methyl ester。
Productivity: 95.5%
HPLC purity: 99.7%
Embodiment 2
By 10 kilogram of 3,3-diphenyl-2, epihydric acid 2 ethyl ester is dissolved in 120 liters of absolute methanols, stir at 25 DEG C, be slowly added to 2 kilograms of hydrochloric acid, finish, keep system temperature at 30 DEG C, add 150 liters of water after stirring 1 hour, stir 2 hours, blowing, rejection filter, filter cake is vacuum drying at 50 DEG C, obtains 2-hydroxy-3-methoxy-3,3-diphenylprop acetoacetic ester。
Productivity: 96.2%
HPLC purity: 99.3%
Embodiment 3
By 450 gram of 3,3-diphenyl-2, epihydric acid 2 propyl ester is dissolved in 2.7 liters of dehydrated alcohol, stir at 30 DEG C, it is slowly added to 80 grams of hydrochloric acid, finishes, maintain the temperature at 40 DEG C, 3 liters of water are added after stirring 1.5 hours, stirring 0.5 hour, sucking filtration, filter cake is vacuum drying at 50 DEG C, obtain 2-hydroxyl-3-ethyoxyl-3,3-diphenylprop propyl propionate。
Productivity: 95.7
HPLC purity: 99.1%
Embodiment 4
By 8 kilogram of 3,3-diphenyl-2, epihydric acid 2 methyl ester is dissolved in 64 liters of anhydrous propanol, stir at 20 DEG C, be slowly added to 1.4 kilograms of hydrochloric acid, finish, maintain the temperature at 50 DEG C, add 60 liters of water after stirring 2 hours, stir 1 hour, blowing, rejection filter, filter cake is vacuum drying at 50 DEG C, obtains 2-hydroxyl-3-propoxyl group-3,3-diphenyl-propionic acid methyl ester。
Productivity: 94.8%
HPLC purity: 99.6%
Embodiment 5
By 10 gram 3,3-diphenyl-2, epihydric acid 2 isopropyl ester is dissolved in 100 milliliters of absolute methanols, stirs, be slowly added to 4 grams of hydrochloric acid at 20 DEG C, add, keeping system temperature at 40 DEG C, (extracting reaction solution, HPLC detects major product 97% to stir 1 hour, impurity containing 2%), 100 milliliters of water of rear addition, continue to stir half an hour, sucking filtration, isolate solid product, vacuum drying at 50 DEG C, obtains 2-hydroxy-3-methoxy-3,3-diphenylprop isopropyl propionate, take product and again carry out HPLC detection, major product more than 99%。
Productivity: 93.1%
HPLC purity: 99.7%
Embodiment 6
By 10 gram 3,3-diphenyl-2, epihydric acid 2 isopropyl ester is dissolved in 100 milliliters of absolute methanols, stir at 20 DEG C, be slowly introducing 1.48 grams of gaseous hydrogen chlorides, led to, keep system temperature at 40 DEG C, stir 1 hour (extracting reaction solution, HPLC detects major product 99%), 100 milliliters of water of rear addition, continue to stir half an hour, sucking filtration, isolates solid product, vacuum drying at 50 DEG C, obtain 2-hydroxy-3-methoxy-3,3-diphenylprop isopropyl propionate, takes product and again carries out HPLC detection, major product more than 99%。
Productivity: 94.3%
HPLC purity: 99.8%
Testing result by embodiment 5 and 6, gaseous hydrogen chloride and its aqueous solution (hydrochloric acid) are used equally to preparation 2-hydroxyl-3-alkoxyl propionic ester compound, but the reactant liquor of the latter can detect the impurity of about 2%, and the former reactant liquor is nearly no detectable this impurity；After adding water crystallization, the product leached detects again, all can't detect above-mentioned impurity in the product of 2 reactions, and purity is all more than 99%, and productivity difference is only small。Consider that use operation inconvenience and the corrosivity of hydrogen chloride gaseous state are strong, it is preferable that using hydrochloric acid as reaction reagent。It should be appreciated that the present invention is not limiting as the mass concentration of hydrochloric acid, but in order to avoid containing the unacceptable too high by-product produced by water open loop in industry in product, it is the hydrochloric acid of 30～37% that hydrochloric acid is preferably concentrated hydrochloric acid such as mass concentration。
Although present invention has been detailed description; it is to be understood that, foregoing description is not limited to the present invention, without departing from the spirit and scope of the present invention; any amendment of being made, equivalent replacement, improvement etc., should be included within protection scope of the present invention。
Claims (10)
1. a method for synthetic compound of formula i, the method includes, using Formula II compound and the formula III compound open loop under gaseous hydrogen chloride or its aqueous solution effect as reaction dissolvent, preparing compound of formula I；
Described compound of formula I is:
Described Formula II compound is:
Described formula III compound is:
R4-OH
(III)
Wherein, R1For C1～C5Alkyl, R2And R3It is each independently aryl, R4For C1～C3Straight or branched alkyl。
2. method according to claim 1, it is characterised in that R1For methyl, ethyl, isopropyl, n-pro-pyl, isobutyl group, normal-butyl, the tert-butyl group, n-pentyl or isopentyl。
3. method according to claim 1, it is characterised in that R2And R3It is each independently phenyl。
4. method according to claim 1, it is characterised in that R4For methyl, ethyl, isopropyl or n-pro-pyl。
5. method according to any one of claim 1 to 4, it is characterised in that described open loop is to carry out at the temperature of 20～50 DEG C。
6. method according to claim 5, it is characterised in that described open loop carries out 1～2 hour。
7. method according to any one of claim 1 to 4, it is characterised in that the Formula II compound relative to 1mol, the molal quantity of described hydrogen chloride is 0.2～0.6mol。
8. method according to claim 7, it is characterised in that the Formula II compound relative to 1mol, the molal quantity of described gaseous hydrogen chloride is 0.3～0.5mol。
9. method according to any one of claim 1 to 4, it is characterised in that the Formula II compound relative to 1mol, the consumption of formula III compound is 1～3L。
10. method according to claim 9, it is characterised in that the Formula II compound relative to 1mol, the consumption of formula III compound is 1.5～2.5L。
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Citations (3)
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|---|---|---|---|---|
| CN101684099A (en) * | 2008-09-22 | 2010-03-31 | 天津药物研究院 | Propionic acid derivative of substituted aromatic ring and aromatic heterocycle and preparation method and application thereof |
| CN101768108A (en) * | 2008-12-30 | 2010-07-07 | 天津药物研究院 | Pyridine ring-substituted alpha-hydroxycarboxylic acid derivatives, preparation method thereof and use thereof |
| CN103333058A (en) * | 2013-05-10 | 2013-10-02 | 江苏科技大学 | Beta-alkoxy alcohol compound synthesis method |
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Patent Citations (3)
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|---|---|---|---|---|
| CN101684099A (en) * | 2008-09-22 | 2010-03-31 | 天津药物研究院 | Propionic acid derivative of substituted aromatic ring and aromatic heterocycle and preparation method and application thereof |
| CN101768108A (en) * | 2008-12-30 | 2010-07-07 | 天津药物研究院 | Pyridine ring-substituted alpha-hydroxycarboxylic acid derivatives, preparation method thereof and use thereof |
| CN103333058A (en) * | 2013-05-10 | 2013-10-02 | 江苏科技大学 | Beta-alkoxy alcohol compound synthesis method |
Non-Patent Citations (2)
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| MCM-41负载S_2O_82-/TiO_2催化合成β-烷氧基醇;杨惠等;《中国会议》;20130721;第274页 * |
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