CN103030609A - Method for preparing repaglinide - Google Patents
Method for preparing repaglinide Download PDFInfo
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- CN103030609A CN103030609A CN2012101319250A CN201210131925A CN103030609A CN 103030609 A CN103030609 A CN 103030609A CN 2012101319250 A CN2012101319250 A CN 2012101319250A CN 201210131925 A CN201210131925 A CN 201210131925A CN 103030609 A CN103030609 A CN 103030609A
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
The invention relates to a method for preparing repaglinide, which is low in cost and is suitable for industrial production. The method comprises the following steps: 1, in the presence of alkali, sodium carbonate or potassium carbonate, reacting (S)-amine which shown as a formula (II) with dimethyl malonate to obtain a compound shown as a formula (III); 2, in the presence of alkali, sodium carbonate or potassium carbonate, reacting the compound show as the formula (III) with a compound shown as a formula (IV), wherein R represents a protecting group which is selected from methyl, ethyl, tertiary butyl and benzyl; 3, in the presence of alkali, sodium carbonate or potassium carbonate, hydrolyzing the compound shown as the formula (IV), wherein the alkaline hydrolysis temperature is between 50 DEG C and 60 DEG C; and in the presence of acid, carrying out decarboxylation to obtain repaglinide shown as a formula (I).
Description
Technical field
The present invention relates to the method for preparing repaglinide of the low and suitable suitability for industrialized production of a kind of cost.
Background technology
The chemistry of repaglinide is called S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amino carbonyl methyl] phenylformic acid, it is a kind of novel orally-taken blood sugar reducing medicine, can promote insulin secretion, have the characteristics fast, that action time is short that absorb, can in the type ii diabetes patient, simulate the physiological insulin secretion, effectively control postprandial hyperglycemia, higher protein binding rate is arranged, can not accumulate in tissue, security is good.Repaglinide both can be used as a line antidiabetic medicine and had used separately, also can increase curative effect with other antidiabetic drug combined utilization, for the treatment of type ii diabetes provides a kind of new means.
Various kinds of document has been reported the synthetic of repaglinide, and its route mainly is to obtain compound (VII) with formula (II) compound and formula (VI) compound condensation, obtains product (I) through hydrolysis again, and its technical process is as follows:
In various bibliographical informations (such as US5312924, US2005/0107614 or CN1571769), the researchist is studied for the condensation process of formula (II) with formula (VI), to improve yield, reduces cost.But undeniablely be, in the important intermediate (VI) of its use synthetic, such as institute's report among the document CN1800139, need use super base n-Butyl Lithium in the reaction, and under-80 ℃, carry out; In document CN1500772 report, need in the reaction to use super base sodium hydrogen, and have a reaction to need under 150 ℃ of high temperature, to carry out; In document US 2004249188 reports, reaction needs to use the highly toxic product sodium cyanide; At document Organic Process Research Development, 6 (2), 184-186 in 2002 reports, needs to use the dangerous and expensive reagent such as n-Butyl Lithium, DMPU in the reaction; In document WO 2001035900 reports, need to use the dangerous and expensive reagent such as lithium diisopropylamine, DMPU in the reaction, above-mentioned various methodologies, difficulty and the danger of the suitability for industrialized production of intermediate (VI) have inevitably been increased, increase cost, thereby increased repaglinide production cost and danger.
Therefore developing an operational path that can solve an above-mentioned difficult problem has great importance and is worth.CN200710103833.0 provides the operational path of a new preparation repaglinide, namely at first with formula (II) compound and dimethyl malonate generation nucleophilic reaction, then with the intermediate 4-iodo-salicylic acid ester that is easy to get (can be obtained by 4-ASA two steps reaction) condensation, finally by hydrolysis, decarboxylation makes finished product, it has efficiently, low toxicity, low dangerous, and simple operation and other advantages is an operational path with fine industrial prospect.
Summary of the invention
The purpose of this invention is to provide a kind of method for preparing repaglinide, described method comprises:
1) in the presence of alkali, make (the S)-amine shown in the formula (II) and dimethyl malonate react to get compound shown in the formula (III),
2) in the presence of alkali, make the reaction of compound shown in compound shown in the formula (III) and the formula (IV),
In the formula, R represents protecting group, is selected from methyl, ethyl, the tertiary butyl or benzyl;
3) compound is hydrolyzed in the presence of alkali shown in the formula (V), and the alkaline hydrolysis temperature is 50～60 ℃; Then decarboxylation makes repaglinide in the presence of acid.
The objective of the invention is further to be reached by following technical scheme, the above-mentioned method for preparing repaglinide, be characterized in step 1), 2), 3) in used alkali be selected from organic bases or mineral alkali, wherein organic bases is selected from sodium methylate, sodium ethylate or potassium tert.-butoxide; Mineral alkali is selected from yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide.
The objective of the invention is further to be reached by following technical scheme, the above-mentioned method for preparing repaglinide, its characteristics are step 3) in used acid be selected from hydrochloric acid, sulfuric acid, nitric acid or trifluoroacetic acid.
On the basis of CN200710103833.0, the present invention is surprised to find that with the alkaline hydrolysis Temperature Setting be 50～60 ℃ of output that can greatly improve repaglinide.
Embodiment
In order to illustrate in greater detail the present invention, provide following preparation example.But scope of the present invention is not to be defined in this.
Embodiment one
1): (S)-preparation of 3-(4-methyl-2-(2-(piperidin-1-yl) phenyl) penta-2-base amino)-3-oxygen methyl propionate
(S)-3-methyl-2 (2-piperidyl phenyl)-1-butylamine (12 gram, 0.049 mole) is dissolved in 120 ml methanol, stir the lower Anhydrous potassium carbonate (25 gram) that adds, dimethyl malonate (20 gram, 0.15 mole), back flow reaction 6 hours, filtered while hot is removed solid, and mother liquor is concentrated to be done, and adds ethyl acetate/normal hexane (1: 5) stirring and crystallizing, filter, get white solid: 12.5 grams.
MP：82-84℃。
2): 2-oxyethyl group-4-(preparation of 3-methoxyl group-1-((S)-4-methyl-2-(2-(piperidin-1-yl) phenyl-2-is amino)-1,3-two Ethylene Oxides-2-yl) ethyl benzoate
With intermediate of upper step (10 grams, 0.029 mole, embodiment one preparation) is dissolved in 100 milliliters of dehydrated alcohols, add sodium ethylate (10 grams, 0.147 mole), cryosel is bathed cooling lower (5 ℃-0 ℃), drip compound 4-iodo-2-ethoxy benzonitrile acetoacetic ester (8.8 grams, 0.03 mole) be dissolved in 50 milliliters ethanol solution, added in one hour, room temperature reaction 2 hours, concentrated doing adds 100 milliliters in water, ethyl acetate (50 milliliters * 3) is extracted, the saturated brine washing, drying is filtered, the concentrated solid of doing to get, use ethyl acetate: normal hexane=recrystallization got intermediate (7) in 1: 8: 12.3 grams.
3): S (+)-2-oxyethyl group-4-[N-{1-(2-piperidyl phenyl)-3-methyl isophthalic acid-butyl } amino carbonyl methyl] benzoic preparation
With intermediate of upper step (12 the gram, 0.0235 mole, embodiment two preparations) be dissolved in 120 ml methanol, add 40 milliliters in water, sodium hydroxide 6 grams (0.15 mole), be warming up to 50 ℃, stirring and refluxing reaction 3 hours concentrates and removes most of solvent, add 13.5 milliliters of concentrated hydrochloric acids, slowly be heated to 80 and spend above until there is bubble to emerge, be warming up to again 100 ℃, insulation reaction 30 minutes, add 120 milliliters of entry, stir, transfer PH=4, cooling, filter, wash to such an extent that target compound is repaglinide: 11.6 grams.
Embodiment two
The operation substantially with embodiment one, only with 3) in the alkaline hydrolysis temperature replace with 55 ℃ by 50 ℃, output be 11.5 the gram.
Embodiment three
The operation substantially with embodiment one, only with 3) in the alkaline hydrolysis temperature replace with 60 ℃ by 50 ℃, output be 11.6 the gram.
Claims (5)
1. the method for repaglinide shown in the preparation formula (I):
Described method comprises:
1) in the presence of alkali, yellow soda ash or salt of wormwood, make (the S)-amine shown in the formula (II) and dimethyl malonate react to get compound shown in the formula (III),
2) in the presence of alkali, yellow soda ash or salt of wormwood, make the reaction of compound shown in compound shown in the formula (III) and the formula (IV),
Wherein, the R representative is selected from the protecting group of methyl, ethyl, the tertiary butyl or benzyl;
3) compound is hydrolyzed in the presence of alkali, yellow soda ash or salt of wormwood shown in the formula (V), and the alkaline hydrolysis temperature is 50～60 ℃; Then decarboxylation makes the repaglinide of formula (I) in the presence of acid.
2. method according to claim 1 is characterized in that described alkali is selected from organic bases or mineral alkali.
3. described method according to claim 2 is characterized in that described organic bases is selected from sodium methylate, sodium ethylate or potassium tert.-butoxide.
4. described method according to claim 2 is characterized in that described mineral alkali is selected from sodium hydroxide or potassium hydroxide.
5. method according to claim 1 is characterized in that 3) in used acid be selected from hydrochloric acid, sulfuric acid, nitric acid or trifluoroacetic acid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101319250A CN103030609A (en) | 2012-04-28 | 2012-04-28 | Method for preparing repaglinide |
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| Application Number | Priority Date | Filing Date | Title |
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| CN2012101319250A CN103030609A (en) | 2012-04-28 | 2012-04-28 | Method for preparing repaglinide |
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| CN103030609A true CN103030609A (en) | 2013-04-10 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129419A (en) * | 2017-12-22 | 2018-06-08 | 陈益德 | A kind of Synthetic method of repaglinide |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5312924A (en) * | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US20040249188A1 (en) * | 2003-05-29 | 2004-12-09 | Dr. Reddy's Laboratories Limited | Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide) |
| CN100537552C (en) * | 2007-05-16 | 2009-09-09 | 江苏豪森药业股份有限公司 | Method for preparing Repaglinide |
-
2012
- 2012-04-28 CN CN2012101319250A patent/CN103030609A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5312924A (en) * | 1983-12-30 | 1994-05-17 | Dr. Karl Thomae Gmbh | Phenylacetic acid benzylamides |
| US20040249188A1 (en) * | 2003-05-29 | 2004-12-09 | Dr. Reddy's Laboratories Limited | Process for the preparation of 3-ethoxy-4-(alkoxy carbonyl)-phenyl acetic acid. (an intermediate of repaglinide) |
| CN100537552C (en) * | 2007-05-16 | 2009-09-09 | 江苏豪森药业股份有限公司 | Method for preparing Repaglinide |
Non-Patent Citations (2)
| Title |
|---|
| PATEL MANVI，等: "Preparation, Characterization and in Vitro Evaluation of Repaglinide Binary Solid Dispersions with Hydrophilic Polymers", 《INTERNATIONAL JOURNAL OF DRUG DEVELOPMENT & RESEARCH》 * |
| 彭勇，等: "瑞格列奈及其中问体合成的研究进展", 《河北师范大学学报／自然科学版》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108129419A (en) * | 2017-12-22 | 2018-06-08 | 陈益德 | A kind of Synthetic method of repaglinide |
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Application publication date: 20130410 |