CN101139337A - Novel method for preparing substituted thenoic acid ester and uses thereof - Google Patents
Novel method for preparing substituted thenoic acid ester and uses thereof Download PDFInfo
- Publication number
- CN101139337A CN101139337A CNA200610112395XA CN200610112395A CN101139337A CN 101139337 A CN101139337 A CN 101139337A CN A200610112395X A CNA200610112395X A CN A200610112395XA CN 200610112395 A CN200610112395 A CN 200610112395A CN 101139337 A CN101139337 A CN 101139337A
- Authority
- CN
- China
- Prior art keywords
- sub
- formula
- reaction
- compound
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a preparation method of the substituted thiophene formate as shown in formula (I), wherein the R<SUB>1</SUB>, R<SUB>2</SUB>, R<SUB>3</SUB> and R<SUB>4</SUB> can be the same and can be different; and the R<SUB>1</SUB>, R<SUB>2</SUB>, R<SUB>3</SUB> and R<SUB>4</SUB> respectively represent the alkyl of the straight chain or branched-chain of C<SUB>1</SUB>-C<SUB>10</SUB>, or the aryl of C<SUB>6</SUB>-C<SUB>12</SUB>, wherein the aryl can be replaced with 1 to 4 substituted bases. The present invention provides a novel method of preparing the substituted thiophene formate as shown in formula (I); the method is more economical and less harmful to the environment. The compound of the formula (I) produced in the present invention can be used for the synthesis of strontium ranelate.
Description
Invention field
The present invention relates to the new preparation method of the substituted thiophene manthanoate shown in the formula (I),
Formula (I) compound that obtains according to the inventive method can be used for synthetic thunder Buddhist nun acid or thunder Buddhist nun hydrochlorate and hydrate thereof.
Background of invention
European patent EP 0415850 discloses salt, preparation method and the therepic use thereof of thunder Buddhist nun acid, and especially its strontium salt (Strontium Ranelate) has very high pharmacology value, particularly Tu Chu osteoporosis performance.
At present, if osteoporosis class drug main bisphosphonates comprises alendronate sodium, sharp thiophene Alendronate etc., these bis-phosphonic acids compounds are cheap for manufacturing cost.And the medicinal specification of Strontium Ranelate be 2 grams/time, the cost that therefore reduces Strontium Ranelate has very important significance with regard to tool.
Chinese patent CN1500783A discloses the synthetic method and the application thereof of ester thiohenic acid of the intermediate-replacement of Strontium Ranelate, the principal character of this patent is for being starting raw material with 3-keto-glutaric acid dimethyl ester, compound shown in the synthesis type (II), formula (II) compound again with the reaction of the ester of bromoacetic acid, obtain four esters shown in the formula (III).
Yet, aforesaid method yield low (65%), long reaction time (5 days) is not suitable for large-scale commercial production.
Chinese patent CN1500784A discloses the new synthetic method and the application thereof of the ester thiohenic acid that replaces, the principal character of this patent is during with the reaction of formula (IV) compound and bromacetate, shortens the reaction times, improves reaction efficiency by the phase-transfer catalyst that utilizes quaternary ammonium type.
Though this patent has improved reaction efficiency by using phase-transfer catalyst, but the bromacetate of its use and the cost of phase-transfer catalyst are still higher, and bromacetate is well known in the art to the intense stimulus of biology, this just causes the risk of environmental disruption is increased the increase of manufacturing cost.
Therefore be necessary to seek more economically a kind of and less preparation method,, make its medical expense drop to general patient acceptable degree to reduce the cost of Strontium Ranelate to environmental hazard.
Goal of the invention
The purpose of this invention is to provide more economically a kind of and,, make its medical expense drop to general patient acceptable degree to reduce the cost of Strontium Ranelate to the novel method of the less preparation substituted thiophene manthanoate of environmental hazard.
Summary of the invention
The invention provides the novel method of the substituted thiophene manthanoate shown in more economically a kind of and less preparation formula (I) to environmental hazard:
Wherein, R
1, R
2, R
3And R
4Can be the same or different, and represent C separately
1-C
10The alkyl of straight or branched, or C
6-C
12Aryl, wherein aryl can at random be replaced by 1-4 substituting group.
As previously mentioned, all use bromacetate to be one of reaction mass in the method for the key intermediate of present known preparation Strontium Ranelate-substituted thiophene manthanoate, and bromacetate has strong impulse to biology and price is higher, and causing it to be easy to endanger the environment and the mankind and manufacturing cost increases.
For addressing the above problem, the inventor has carried out deep research.Found that and chloracetate that pungency less comparatively cheap with cost can be easy in suitable reaction conditions and solvent and the substituted thiophene manthanoate shown in the preparation formula (I) with high yield.With the substituted thiophene manthanoate shown in the formula (I) is raw material, can prepare highly purified Strontium Ranelate through conventional simple hydrolysis reaction and salt-forming reaction.The reaction scheme of the substituted thiophene manthanoate shown in the formula (I) is as follows:
R
1, R
2, R
3And R
4Can be the same or different, and represent C separately
1-C
10The alkyl of straight or branched, or C
6-C
12Aryl, wherein aryl can at random be replaced by 1-4 substituting group.Wherein, preferred C
1-C
10The alkyl of straight or branched, more preferably methyl and ethyl.
Reaction solvent is an inert solvent, comprises haloalkanes such as trichloromethane, methylene dichloride, ethylene dichloride, ethylene dibromide, freon class; Alkane such as normal hexane, hexanaphthene, pentamethylene, sherwood oil; Aromatic hydrocarbon such as benzene,toluene,xylene; Aliphatic nitriles such as acetonitrile, propionitrile, butyronitrile; Aliphatic ketone such as acetone, butanone; And dipolar aprotic solvent such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane.Wherein, dipolar aprotic solvents such as aliphatics nitrile, aliphatics ketone and dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO), tetrahydrofuran (THF), dioxane, more preferably aliphatics nitrile, aliphatics ketone.
Temperature of reaction is generally 30 ℃～120 ℃, and preferred 40 ℃～100 ℃, more preferably 50 ℃～90 ℃.
Following embodiment only is to describe in detail the present invention, and unrestricted the present invention.
Embodiment 1:5-amino-3-(2-oxyethyl group-2-oxoethyl)-4-cyano group-2-thiophene ethyl formate
Respectively 700 milliliters of ethanol, 500 gram 3-keto-glutaric acid diethyl esters and 200 gram propane dinitrile are added in the reaction flask, vigorous stirring adds 250 gram morpholines, stirring reaction 1 hour.Add 100 gram sulphur powder, be heated to backflow.Keep back flow reaction 3 hours, and be cooled to room temperature, in impouring 1500 ml waters, separate out a large amount of solids.Filter, the washing of 200 ml waters, 50 ℃ of forced air dryings get light yellow solid 520 grams, yield: 75% to constant weight.
Embodiment 2:Two (2-oxyethyl group-2-oxoethyl) amino-3-(2-oxyethyl group-2-oxoethyl) of 5-[-4-cyano group-2-thiophene ethyl formate
To restrain in the acetone that add to 3000 milliliters according to 5-amino-3-(2-oxyethyl group-2-the oxoethyl)-4-cyano group-2-thiophene ethyl formate 500 of embodiment 1 preparation, add 20 gram trimethyl benzyl ammonia chlorides, 600 gram ethyl chloroacetates, 500 gram Anhydrous potassium carbonates, stir, be heated to backflow.Kept back flow reaction 12 hours, and be cooled to room temperature, filter, concentrated filtrate is to doing.Add 1000 ml methanol, reflux 1 hour, ice-water bath stirred 5 hours down, filtered, and 50 ℃ of forced air dryings get white solid 640 grams, yield: 80% to constant weight.
Embodiment 3:Strontium Ranelate
To restrain in the water that adds to 3000 milliliters according to two (2-oxyethyl group-2-oxoethyl) amino-3-(2-oxyethyl group-2-oxoethyl) of the 5-[of embodiment 2 preparations-4-cyano group-2-thiophene ethyl formate 300, add 350 gram strontium hydroxides, stir, be heated to backflow.Keep back flow reaction 6 hours, and filtered 300 milliliters of hot water drip washing.80 ℃ of vacuum-dryings get white solid 315 grams, yield: 93% to constant weight.
Claims (4)
1. the new preparation method of the substituted thiophene manthanoate shown in the preparation formula (I),
In the formula, R
1, R
2, R
3And R
4Can be the same or different, and represent C separately
1-C
10The alkyl of straight or branched, or C
6-C
12Aryl, wherein aryl can at random be replaced by 1-4 substituting group.
Being characterized as of this method: in solvent, with the compound (meaning of each symbol is same as above in the formula) shown in the formula (II)
With chloroacetic ester reaction, thus compound shown in the preparation formula (I).
2. the method for claim 1 wherein adds phase-transfer catalyst in described reaction system.
3. method as claimed in claim 2, wherein said phase-transfer catalyst are quaternary ammonium salt.
4. the method for the hydrate of synthetic thunder Buddhist nun acid, its strontium salt and described salt the method is characterized in that by formula (II) compound be raw material:
Make the reaction of formula (II) compound and chloroacetic ester, obtain corresponding four esters and be converted into thunder Buddhist nun acid or the hydrate of its strontium salt and strontium salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610112395XA CN101139337A (en) | 2006-09-04 | 2006-09-04 | Novel method for preparing substituted thenoic acid ester and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200610112395XA CN101139337A (en) | 2006-09-04 | 2006-09-04 | Novel method for preparing substituted thenoic acid ester and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101139337A true CN101139337A (en) | 2008-03-12 |
Family
ID=39191465
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA200610112395XA Pending CN101139337A (en) | 2006-09-04 | 2006-09-04 | Novel method for preparing substituted thenoic acid ester and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101139337A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665483A (en) * | 2008-09-01 | 2010-03-10 | 河北医科大学 | Environmentally-friendly synthesis method for strontium ranelate intermediate compound II |
| CN101812048A (en) * | 2010-04-06 | 2010-08-25 | 浙江东亚药业有限公司 | Synthesis method of strontium ranelate and hydrate thereof |
| CN102180864A (en) * | 2011-03-28 | 2011-09-14 | 中国药科大学 | Preparation method of strontium ranelate |
| WO2013113319A1 (en) | 2012-01-31 | 2013-08-08 | Pharmathen S.A. | Process for the preparation of strontium ranelate, intermediate or hydrates thereof |
| CN104230883A (en) * | 2014-09-02 | 2014-12-24 | 中国科学院青岛生物能源与过程研究所 | Preparation method of 3-amido-2-isopropyl thiophenecarboxylate |
-
2006
- 2006-09-04 CN CNA200610112395XA patent/CN101139337A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101665483A (en) * | 2008-09-01 | 2010-03-10 | 河北医科大学 | Environmentally-friendly synthesis method for strontium ranelate intermediate compound II |
| CN101665483B (en) * | 2008-09-01 | 2013-01-23 | 河北医科大学 | Synthesis method for strontium ranelate intermediate compound II |
| CN101812048A (en) * | 2010-04-06 | 2010-08-25 | 浙江东亚药业有限公司 | Synthesis method of strontium ranelate and hydrate thereof |
| CN101812048B (en) * | 2010-04-06 | 2012-11-14 | 浙江东亚药业有限公司 | Synthesis method of strontium ranelate and hydrate thereof |
| CN102180864A (en) * | 2011-03-28 | 2011-09-14 | 中国药科大学 | Preparation method of strontium ranelate |
| WO2013113319A1 (en) | 2012-01-31 | 2013-08-08 | Pharmathen S.A. | Process for the preparation of strontium ranelate, intermediate or hydrates thereof |
| CN104230883A (en) * | 2014-09-02 | 2014-12-24 | 中国科学院青岛生物能源与过程研究所 | Preparation method of 3-amido-2-isopropyl thiophenecarboxylate |
| CN104230883B (en) * | 2014-09-02 | 2017-08-22 | 中国科学院青岛生物能源与过程研究所 | A kind of preparation method of the thiophenic acid isopropyl ester of 3 amino 2 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103524440B (en) | The preparation method of gout therapertics Lesinurad and Lesinurad intermediate | |
| CN101139337A (en) | Novel method for preparing substituted thenoic acid ester and uses thereof | |
| CN104530040A (en) | Novel method for synthesizing 1,2,3-thiadiazole-5-formamidine compound | |
| ES2722854B2 (en) | PROCEDURE TO PREPARE N - ((1R, 2S, 5S) -2 - ((2 - ((5-CHLOROPIRIDIN-2-IL) AMINO) -2-OXOACETIL) AMINO) -5- (DIMETHYL CARBAMOIL) CYCLHEXIL) CARBAMATE OF THIRD -BUTYL | |
| KR101539761B1 (en) | Method for preparing compounds through a novel Michael-addition reaction using water or various acids as additives | |
| CN109705146B (en) | 2-aminobenzo [4, 5] thieno [3, 2-d ] thiazole, derivative and synthetic method thereof | |
| CN109503547B (en) | Process for preparing benzodithiolane derivatives | |
| CN101845048A (en) | Synthetic method of 2-nitro-2,3-dihydrofuran derivative | |
| CN103450092B (en) | Synthesis method of metronidazole-sulfanilamide derivatives | |
| CN102050782A (en) | Preparation method of spirofluorene acridine intermediate | |
| CA2380853C (en) | Process for the preparation of acylated 1,3-dicarbonyl compounds | |
| CN103755701B (en) | A kind of preparation method with optically active pyrrole quinoline amine salt and corresponding pyrrole quinoline amine thereof | |
| CN101219967A (en) | Process for producing 2-nitryl substituted benzene ethane nitrile compounds | |
| JPS61165339A (en) | Production of amide compound | |
| CN103265497B (en) | Intermediate compound 4-chloro-6-amino-7-hydroxyquinazoline required for synthesis of tinib antineoplastic drug and preparation method thereof | |
| CN102850252A (en) | Preparation method for 3,5,5'-trisubstituted hydantoin | |
| PL190946B1 (en) | Intermediate product for use in obtaining 2-imidazolyn-5-ones | |
| CN110294781A (en) | One kind Schiff of thiadiazolyl group containing ferrocenyl and preparation method thereof | |
| BR112012032171B1 (en) | METHOD FOR THE PRODUCTION OF N-REPLACED 2-AMINO-4- (HYDROXYMETHYPHOSPHINYL) -2-BUTENOIC ACID | |
| CN109574866A (en) | A kind of preparation method of 2,6- dimethyl benzene amine long-chain compound | |
| CN103387494B (en) | The method preparing 2-hydroxyl-4,5-dimethoxybenzoic acid | |
| CN101508672B (en) | Method of preparing 1,4-dihydrogen pyridine derivatives | |
| CN101357902B (en) | Method for preparing N- formyl-2H-4chloroquinoline derivate | |
| JP2007269661A (en) | Phosphoric amide compound and method for producing the same | |
| CN105218457A (en) | A kind of preparation method of 3,5,5 '-three replacement-2-thiohydantoin |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080312 |