CN104693027A - Method for synthesizing 2-hydroxy-3-alkoxy propionate compounds - Google Patents
Method for synthesizing 2-hydroxy-3-alkoxy propionate compounds Download PDFInfo
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- CN104693027A CN104693027A CN201310662568.5A CN201310662568A CN104693027A CN 104693027 A CN104693027 A CN 104693027A CN 201310662568 A CN201310662568 A CN 201310662568A CN 104693027 A CN104693027 A CN 104693027A
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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
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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Abstract
The invention relates to the technical field of medical intermediates and particularly relates to a method for synthesizing 2-hydroxy-3-alkoxy propionate compounds. The method comprises the step of carrying out ring opening on 2,3-epoxy acrylate compounds and C1-C3 chain saturated monohydric alcohol serving as a reaction solvent in the presence of gaseous hydrogen chloride or a water solution of gaseous hydrogen chloride, so as to prepare the synthesizing 2-hydroxy-3-alkoxy propionate compounds. The method is safe, free of toxic, low in cost and suitable for industrial production.
Description
Technical field
The present invention relates to medicine intermediate technical field.Particularly, the present invention relates to Endothelin Receptor inhibitor intermediate, particularly a kind of method of synthesizing 2-hydroxyl-3-alkoxyl propionic ester compounds.
Background technology
Endothelin is a kind of peptide be 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 has very strong effect to antiotasis.Increase or the endothelin of abnormality is released in surrounding blood vessel, Renal vascular and cerebral blood vessel and causes lasting vasoconstriction, this contraction can cause disease.Concerning the endothelin blood plasma level having found the patient of hypertension, memory myocardial infarction, cerebrovascular high pressure, Reynolds syndrome, atherosclerosis and respiratory tract spasm to increase.Therefore, therefore specific suppression endothelin is combined in the material on acceptor should the above-mentioned different endothelin physiologic effect of antagonism be also also valuable medicine.
Now find, 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, Journal of Medicinal Chemistry, discloses a kind of preparation method of 2-hydroxyl-3-alkoxyl propionic ester in 1996, vol.39, #11p.2123 – 2128, and it adopts Lewis acid BF
3.Et
2o or Catalyzed by p-Toluenesulfonic Acid 2, epihydric acid 2 ester compound and alcohol effect, reach the effect of open loop of epoxy compound, but BF
3.Et
2o is a kind of inflammable, poisonous and have the reagent of strong impulse and aggressive, easily decomposes the hydrogen fluoride smog producing severe toxicity, though the method is suitable for laboratory study, be unsuitable for the enforcement that industrialization is amplified in damp atmosphere.Further, tosic acid reacts in alcohol, easily generates p-toluenesulfonic esters, has genotoxicity, uses as avoiding in the synthesis of medicine intermediate.
Journal of the Chemical Society, Perkin Transactions1:Organic andBio-Organic Chemistry (1972-1999), 1977, P.1773-1776 disclose with sulfuric acid catalysis 2 in, epihydric acid 2 ester compound and alcohol react, synthesis 2-hydroxyl-3-alkoxyl propionic ester.Experiment proves, above-mentioned reaction can occur sulfuric acid, but sulfuric acid is easy and alcohol carries out esterification, generates the materials such as the methyl-sulfate of severe toxicity, also should avoid in the synthesis of medicine intermediate.
Summary of the invention
For above-mentioned technological deficiency, the object of this invention is to provide a kind of safety non-toxic and be suitable for the method for the synthesis 2-hydroxyl-3-alkoxyl propionic ester compounds of suitability for industrialized production.
Above-mentioned purpose of the present invention is realized by following method, the method comprises formula II compound and the formula III compound open loop under gaseous hydrogen chloride or its aqueous solution effect as reaction solvent, obtained formula I (i.e. 2-hydroxyl-3-alkoxyl propionic ester compounds);
Described formula I is:
Described formula II compound is:
Described formula III compound is:
R
4-OH
(III)
Wherein, R
1for C
1~ C
5alkyl, R
2and R
3be aryl independently of one another, R
4for C
1~ C
3straight or branched alkyl.
Preferably, R
1for methyl, ethyl, sec.-propyl, n-propyl, isobutyl-, normal-butyl, the tertiary butyl, n-pentyl or isopentyl.
Preferably, R
2and R
3be phenyl independently of one another.
Preferably, R
4for methyl, ethyl, sec.-propyl or n-propyl.
In the method for the invention, described open loop carries out at the temperature of 20 ~ 50 DEG C, and preferably, described open loop carries out 1 ~ 2 hour.
In the method for the invention, relative to the formula II compound of 1mol, the mole number of described hydrogenchloride is 0.2 ~ 0.6mol, is preferably 0.3 ~ 0.5mol.
In the method for the invention, relative to the formula II compound of 1mol, the consumption of formula III compound is 1 ~ 3L, is preferably 1.5 ~ 2.5L.
For obtaining aforesaid method of the present invention, the present inventor has paid hard effort, has carried out large quantifier elimination, finds that phosphoric acid and nitric acid also can with 2, epihydric acid 2 ester compound reaction preparation 2-hydroxyl-3-alkoxyl propionic ester compounds.Test-results shows, although above 2 kinds of acid all energy catalysis 2,2-hydroxyl-3-alkoxyl propionic ester is prepared in epihydric acid 2 ester compound and alcohol effect:
Phosphoric acid can etching glass, and the instrument of laboratory and production plant mostly is glass material, therefore reacts higher to equipment requirements, and industrialization is difficult to realize;
Nitric acid has oxidisability, and be not suitable for the reactant containing reductibility functional group in structure, 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, the open loop of epihydric acid 2 ester compound, find that gaseous hydrogen chloride or its aqueous solution not only have outstanding katalysis unexpectedly, can obtain highly purified product, and the method is also nontoxic, safe, with low cost and be suitable for suitability for industrialized production.
The present inventor is by finding after great many of experiments, the inventive method is specially adapted to the synthesis of the 2-hydroxyl-3-alkoxyl propionic ester compounds 3 carbon with monosubstituted or polysubstituted group, preferably, 3 carbon has 1 to 2 aryl, more preferably, 3 carbon has 1 to 2 phenyl; Described alkoxyl group can be methoxyl group, oxyethyl group, positive propoxy, isopropoxy or phenoxy group etc.Such as, 2-hydroxyl-3-alkoxyl propionic ester the compounds be applicable to can be 2-hydroxy-3-methoxy-3, 3-diphenyl-propionic acid methyl esters, 2-hydroxyl-3-oxyethyl group-3, 3-diphenyl-propionic acid methyl esters, 2-hydroxyl-3-isopropoxy-3, 3-diphenyl-propionic acid methyl esters, 2-hydroxyl-3-propoxy--3, 3-diphenyl-propionic acid methyl esters, 2-hydroxyl-3-phenoxy group-3, 3-diphenyl-propionic acid methyl esters, 2-hydroxy-3-methoxy-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-oxyethyl group-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-isopropoxy-3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-propoxy--3, 3-diphenylprop acetoacetic ester, 2-hydroxyl-3-phenoxy group-3, 3-diphenylprop acetoacetic ester etc.
Compared with prior art, preparation method of the present invention has but is not limited to following advantage:
1. the reagent that the present invention is used is hydrogenchloride or its aqueous solution, compares BF
3.Et
2o toxicity is little, nonflammable, uses comparatively safe; Compare toluenesulphonic acids, hydrochloric acid does not relate to genotoxicity, is more suitable for the synthesis for medicine intermediate 2-hydroxyl-3-alkoxyl propionic ester compounds; Compare sulfuric acid, the inventive method can not produce the materials such as the larger methyl-sulfate of toxicity or ethyl 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, epihydric acid 2 ester compound and alcohol are swift in response, and by product is few, are applicable to laboratory and large-scale industrial production.
3. the aftertreatment of the inventive method is the stirring and crystallizing that adds water, and can obtain highly purified product, easy and simple to handle, is convenient to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, the embodiment provided only in order to illustrate the present invention, instead of in order to limit the scope of the invention.
In the following embodiments, 3,3-phenylbenzene-2 of employing, epihydric acid 2 methyl esters, 3,3-phenylbenzene-2, epihydric acid 2 ethyl ester, 3,3-phenylbenzene-2, epihydric acid 2 isopropyl ester and 3,3-phenylbenzene-2, epihydric acid 2 propyl ester 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-phenylbenzene-2, epihydric acid 2 methyl esters is dissolved in 2.4 liters of anhydrous isopropyl alcohols, stir at 20 DEG C, slowly add 48 grams of hydrochloric acid, add, keep system temperature at 20 DEG C, stir and add 4.8 premium on currency after 1 hour, continue to stir half an hour, suction filtration, isolate solid phase prod, vacuum drying at 50 DEG C, obtains 2-hydroxyl-3-isopropoxy-3,3-diphenyl-propionic acid methyl esters.
Productive rate: 95.5%
HPLC purity: 99.7%
embodiment 2
By 10 kilogram of 3,3-phenylbenzene-2, epihydric acid 2 ethyl ester is dissolved in 120 liters of anhydrous methanols, stir at 25 DEG C, slowly add 2 kilograms of hydrochloric acid, finish, keep system temperature at 30 DEG C, stir and add 150 premium on currency after 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.
Productive rate: 96.2%
HPLC purity: 99.3%
embodiment 3
By 450 gram of 3,3-phenylbenzene-2, epihydric acid 2 propyl ester is dissolved in 2.7 liters of dehydrated alcohols, stir at 30 DEG C, slowly add 80 grams of hydrochloric acid, finish, maintain the temperature at 40 DEG C, stir and add 3 premium on currency after 1.5 hours, stir 0.5 hour, suction filtration, filter cake is vacuum drying at 50 DEG C, obtain 2-hydroxyl-3-oxyethyl group-3,3-diphenylprop propyl propionate.
Productive rate: 95.7
HPLC purity: 99.1%
embodiment 4
By 8 kilogram of 3,3-phenylbenzene-2, epihydric acid 2 methyl esters is dissolved in 64 liters of anhydrous propyl alcohol, stir at 20 DEG C, slowly add 1.4 kilograms of hydrochloric acid, finish, maintain the temperature at 50 DEG C, stir and add 60 premium on currency after 2 hours, stir 1 hour, blowing, rejection filter, filter cake is vacuum drying at 50 DEG C, obtains 2-hydroxyl-3-propoxy--3,3-diphenyl-propionic acid methyl esters.
Productive rate: 94.8%
HPLC purity: 99.6%
embodiment 5
By 10 gram 3,3-phenylbenzene-2, epihydric acid 2 isopropyl ester is dissolved in 100 milliliters of anhydrous methanols, stirs, slowly add 4 grams of hydrochloric acid at 20 DEG C, add, keep system temperature at 40 DEG C, (extract reaction solution, HPLC detects major product 97% to stir 1 hour, impurity containing 2%), after add 100 ml waters, continue stir half an hour, suction filtration, isolate solid phase prod, vacuum drying at 50 DEG C, obtains 2-hydroxy-3-methoxy-3,3-diphenylprop isopropyl propionate, get product and again carry out HPLC detection, major product more than 99%.
Productive rate: 93.1%
HPLC purity: 99.7%
embodiment 6
By 10 gram 3,3-phenylbenzene-2, epihydric acid 2 isopropyl ester is dissolved in 100 milliliters of anhydrous methanols, stir at 20 DEG C, slowly pass into 1.48 grams of gaseous hydrogen chlorides, led to, keep system temperature at 40 DEG C, stir 1 hour (extract reaction solution, HPLC detects major product 99%), after add 100 ml waters, continue to stir half an hour, suction filtration, isolates solid phase prod, vacuum drying at 50 DEG C, obtain 2-hydroxy-3-methoxy-3,3-diphenylprop isopropyl propionate, gets product and again carries out HPLC detection, major product more than 99%.
Productive rate: 94.3%
HPLC purity: 99.8%
Known by the detected result of embodiment 5 and 6, gaseous hydrogen chloride and its aqueous solution (hydrochloric acid) all can be used for preparation 2-hydroxyl-3-alkoxyl propionic ester compound, but the impurity of about 2% can be detected in the reaction solution of the latter, and in the former reaction solution, almost can't detect this impurity; After adding water crystallization, the product leached detects again, and all can't detect above-mentioned impurity in the product of 2 reactions, purity is all more than 99%, and productive rate difference is very little.Consider that use operation inconvenience and the corrodibility of hydrogenchloride gaseous state are strong, preferably using hydrochloric acid as reaction reagent.Should be understood that, the present invention does not limit the mass concentration of hydrochloric acid, but 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; but should be appreciated that foregoing description and be not used to limit the present invention, without departing from the spirit and scope of the present invention; any amendment of doing, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (7)
1. a method for synthetic compound of formula i, the method comprises formula II compound and the formula III compound open loop under gaseous hydrogen chloride or its aqueous solution effect as reaction solvent, obtained formula I;
Described formula I is:
Described formula II compound is:
Described formula III compound is:
R
4-OH
(III)
Wherein, R
1for C
1~ C
5alkyl, R
2and R
3be aryl independently of one another, R
4for C
1~ C
3straight or branched alkyl.
2. method according to claim 1, is characterized in that, R
1for methyl, ethyl, sec.-propyl, n-propyl, isobutyl-, normal-butyl, the tertiary butyl, n-pentyl or isopentyl.
3. method according to claim 1 and 2, is characterized in that, R
2and R
3be phenyl independently of one another.
4. according to the method in any one of claims 1 to 3, it is characterized in that, R
4for methyl, ethyl, sec.-propyl or n-propyl.
5. method according to any one of claim 1 to 4, described open loop carries out at the temperature of 20 ~ 50 DEG C, and preferably, described open loop carries out 1 ~ 2 hour.
6. method according to any one of claim 1 to 5, is characterized in that, relative to the formula II compound of 1mol, the mole number of described hydrogenchloride is 0.2 ~ 0.6mol, is preferably 0.3 ~ 0.5mol.
7. method according to any one of claim 1 to 6, is characterized in that, relative to the formula II compound of 1mol, the consumption of formula III compound is 1 ~ 3L, is preferably 1.5 ~ 2.5L.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2013
- 2013-12-06 CN CN201310662568.5A patent/CN104693027B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 (4)
| Title |
|---|
| F. MPANDASONI BANDA: "Anodic Oxidation. Part 16.l A Comparison of Chemical and Electrochemical", 《J.C.S. PERKIN I》 * |
| HARTMUT RIECHERS等: "Discovery and Optimization of a Novel Class of Orally Active Nonpeptidic", 《J. MED. CHEM.》 * |
| 张治国等: "环氧乙烷和环氧丙烷开环聚合", 《化学进展》 * |
| 杨惠等: "MCM-41负载S_2O_82-/TiO_2催化合成β-烷氧基醇", 《中国会议》 * |
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Address after: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee after: Tianjin Institute of Pharmaceutical Research Co.,Ltd. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research |
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Effective date of registration: 20220406 Address after: 300451 No. 29, Huixin Road, Binhai Science Park, Binhai New Area, Tianjin Patentee after: TIANJIN INSTITUTE OF PHARMACEUTICAL RESEARCH PHARMACEUTICAL RESPONSIBLE CO.,LTD. Address before: 300193 Tianjin City, Nankai District Anshan West Road No. 308 Patentee before: Tianjin Institute of Pharmaceutical Research Co.,Ltd. |