CN102702138A - Repaglinide compound and novel production method thereof - Google Patents
Repaglinide compound and novel production method thereof Download PDFInfo
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Abstract
The invention relates to a repaglinide compound and a novel production method thereof. The method comprises the following steps: step 1) dissolving the raw material repaglinide in an organic solvent which is not immiscible with water, and filtering to remove insoluble impurities, so as to obtain primary filtrate; step 2) adding adsorptive inorganic substances into the primary filtrate, fiercely stirring, standing, and filtering to remove the adsorptive inorganic substances, so as to obtain a secondary filtrate; step 3) adding the aqueous solution of alkali metal or alkali earth metal alkyls oxide into the secondary filtrate for treatment, heating optionally during the treatment process, then reducing the temperature, standing, layering, and separating out a water phase, so as to obtain an organic phase containing repaglinide; and step 4) adding an alcohols solvent into the organic phase, regulating the pH value to be 3.0-5.5 with acid, recrystallizing by controlling the temperature, centrifuging and washing precipitated crystal, and drying so as to obtain the refined repaglinide compound. According to the invention, the situation that the repaglinide raw material has lower purity both in home and abroad is basically changed, the problems of rough repaglinide and repaglinide active pharmaceutical ingredients are solved; the method is simple and easy to control and be used for industrialized production; and the product quality of the preparation is improved and the toxic and side effects are reduced.
Description
Technical field
The present invention relates to a kind of repaglinide compound with and new preparation method, belong to medical technical field.
Background technology
Repaglinide (Repaglinide) is white or off-white color crystalline powder, and odorless, chemical name are (S+)-2-oxyethyl group-4-[2-[3-methyl isophthalic acid-[2-(piperidino) phenyl] butyl]-amino]-2-carbonyl ethyl phenylformic acid, molecular formula C
27H
36N
2O
4, molecular weight: 452.59, structural formula is:
Repaglinide is a kind of new oral ofhypoglycemic medicine of methyl benzene methanamine phenylformic acid family, is the non-sulfonylurea oral hypoglycemic, is used to treat type II diabetes; To be repaglinide combine with specific receptors on the beta Cell of islet film its mechanism of action, promotes to close with acceptor link coupled ATP sensitive potassium channel, suppresses potassium ion from the β cell drain; The cytolemma depolarize; Calcium channel is open, and flow of calcium ions promotes insulin secretion.Its effect is faster than sulfonylurea, so hypoglycemic activity is very fast after the meal.The glucose of taking when having meal for first is regulated medicine.Biggest advantage is to imitate the physiological secretion of Regular Insulin, effectively controls postprandial hyperglycemia thus.
US5; 312; 924 have reported the synthetic of this repaglinide compound at first, and substituted toluylic acid and benzyl amine derivatives be at carbonyl dimidazoles, N; Condensation under N '-NSC 57182 or triphenyl phosphorus, triethylamine, tetracol phenixin exist obtains the shielded midbody of carboxyl, obtains repaglinide through hydrolysis.In the technology that this patent is mentioned, utilize N, N '-NSC 57182 synthesizes, and product needed just can be removed sub product N through recrystallization repeatedly, and N '-NSC 30023 has improved production cost; Utilize the synthetic product yield that obtains of carbonyl dimidazoles catalysis low, have only 50～55%, and the carbonyl dimidazoles price is more expensive; Utilize triphenyl phosphorus, triethylamine, tetracol phenixin to synthesize, though yield increases, product purity is low.
WO2003/027072A discloses a kind of method for preparing repaglinide, is in the presence of trimethyl-acetyl chloride and alkali, makes (the S)-amine of its Chinese style II and the protection carboxylic acid reaction of formula IV, removes protection base back and obtains repaglinide.Yet the effect of removing the carboxylic acid protecting group through acidic hydrolysis or alkaline hydrolysis or hydrogenolytic cleavage is unsatisfactory, and unreacted midbody and other degradation productions cause the purity of repaglinide not high.
Also disclose other synthesis modes in the prior art, for example disclose reaction and processing mode separately among CN100537552C, the CN101481363B etc.Though finally make title product, the method for further pure repaglinide crude product all be not provided.At present, domestic each preparation manufacturer mainly relies on import repaglinide bulk drug to carry out packing, the producer of domestic capable these article of production, and its yield and product purity are also lower.Therefore, the purity that how to improve repaglinide is present problem demanding prompt solution, has important social benefit and economic benefit.
Summary of the invention
In order to overcome the low defective of repaglinide purity that above-mentioned prior art provides, the invention provides a kind of method of refining repaglinide compound.
The repaglinide that process for purification provided by the invention was directed against is the repaglinide bulk drug of the prepared repaglinide bullion of present known compound method or commercially available or import, below is referred to as the raw material repaglinide that the present invention adopts.
The inventor through comprising the process for purification of following treatment step, can increase substantially the purity of raw material repaglinide through discovering:
Step 1), with the raw material repaglinide be dissolved in the immiscible organic solvent of water in, remove by filter insoluble impurities, obtain first-time filtrate;
Step 2), in first-time filtrate, add the adsorptivity inorganic substance, vigorous stirring leaves standstill after-filtration and removes the adsorptivity inorganic substance, obtains secondary filtrating;
Step 3), the aqueous solution that in secondary filtrating, adds basic metal or alkaline-earth metal alkyl oxide is handled, the optional heating in treating processes, cooling then, standing demix separates water then, obtains to contain the organic phase of repaglinide;
Step 4) adds alcoholic solvent in organic phase, in 3.0～5.5 scopes, and controlled temperature carries out recrystallization with acid for adjusting pH value, and with the crystal centrifuge washing of separating out, drying obtains the purified repaglinide.
The following specifically describes the present invention.
Step 1), with the raw material repaglinide be dissolved in the immiscible organic solvent of water in, remove by filter insoluble impurities, obtain first-time filtrate.
Said organic solvent is preferably chloroform, ETHYLE ACETATE, hexanaphthene, benzene, toluene, perhaps by two or three mixed solvent that forms wherein.
Through discovering; There are two types of impurity property materials of lipotropy and wetting ability in repaglinide crude product or the repaglinide bulk drug; The solvent of introducing in the for example preparation process, various raw material and intermediate product and bacterial endotoxin generally are lipophilic, can be dissolved in the organic solvent.Owing to drawing various trace minerals that siccative that the catalyzer that uses in the moist moisture of bringing into, the preparation process and/or its carrier, post-processing stages introduce and raw material and reagent itself contains admittedly and heavy metal etc., then be insoluble in the organic solvent.These impurity property materials affect the purity of raw material repaglinide.Repaglinide through will be to be purified is dissolved in the organic solvent, utilizes separation modes such as simple filtering can effectively remove the impurity property material that these are insoluble to organic solvent.
Step 2), in first-time filtrate, add the adsorptivity inorganic substance, vigorous stirring leaves standstill after-filtration and removes the adsorptivity inorganic substance, obtains secondary filtrating.
Have been found that; The lipotropy impurity that exists in repaglinide crude product or the repaglinide bulk drug, the solvent of introducing in the for example preparation process, various raw material and intermediate product and bacterial endotoxin generally can contact and partly or wholly remove with sorbent material through making raw material repaglinide solution.
Said adsorptivity inorganic substance can be gac, aluminum oxide or molecular sieve.
According to one embodiment of the present invention, in first-time filtrate, add the gac that accounts for overall solution volume 0.1-1% (g/ml), 15-30min is stirred in 30-40 ℃ of insulation, removes by filter gac then.
According to another embodiment of the present invention, in first-time filtrate, add the aluminum oxide that accounts for overall solution volume 0.05-1% (g/ml), 10-40min is stirred in insulation at a certain temperature, removes by filter aluminum oxide then.The temperature of said insulation can be in room temperature between the reflux temperature of solvent.Experimental study shows that temperature is low more, and the adsorption effect of aluminum oxide is poor more, and therefore suitably high temperature helps its adsorption effect of aluminum oxide performance, and the effect of removing impurity is also good more, but the too high meeting of temperature causes product yield slightly to reduce.Therefore suitable TR is 25-45 ℃, preferred 30-40 ℃, and more preferably 33-37 ℃.
According to another embodiment of the present invention; In first-time filtrate, add the molecular sieve (being also referred to as synthetic zeolite) that accounts for overall solution volume 0.1-1% (g/ml), preferably adopt the molecular sieve that mean pore size is
preferred
.Molecular sieve is as the widely used material of sorbent material in the industry.The molecular sieve that is fit to use is preferably A type molecular sieve and X type molecular sieve.
Under the situation of " A type " molecular sieve, tetrahedron is assembled, and it is octahedra to make that they constitute top rake.These octahedra self arrangements with simple cubic crystal structure form its hole and have the network of the diameter of
approximately.Via opening or hole, these holes are accessible, and said opening or hole can be stopped up by cationic moiety ground.When these positively charged ions derive from sodium; These holes have the opening diameter of
, so produce " 4A " molecular sieve.The crystalline structure of such molecular sieve can be represented by chemical formula:
Na
12[(AlO
2)
12(SiO
2)
12] .XH
2O, wherein, the X representative belongs to water molecules (crystal water) number of said structure, and X can be up to 27, and this accounts for 28.5 weight % of anhydrous zeolite.
The unit cell of X zeolite is a tetrahedron; The identical polyhedron of those types that exists among this tessarace quilt and the zeolite A occupies, and said polyhedron is connected with four other polyhedrons through the octahedra minor structure that is formed by the dicyclo that contains eight Sauerstoffatoms separately.The central point on each bar limit is always occupied by Sauerstoffatom, and silicon and aluminium atom occupy polyhedral each summit.The empirical formula of this structure is: Na
88Al
88Si
1040
384220H
2O.
Filtrating and the molecular sieve that contains repaglinide at 100～2200kPa, preferably under atmospheric pressure contacts under 20 ℃～60 ℃, preferred 30 ℃～40 ℃ temperature, through vigorous stirring, makes after the fully absorption, through removing by filter molecular sieve.
Step 3), the aqueous solution that in secondary filtrating, adds basic metal or alkaline-earth metal alkyl oxide is handled, the optional heating in treating processes, cooling then, standing demix separates water then, obtains to contain the organic phase of repaglinide.
Can use any basic metal or alkaline-earth metal alkyl oxide (being alcoholate) in principle, preferred as alkali alkoxide, the more preferably alkoxide of sodium or potassium, for example sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
Basic metal or alkaline-earth metal alkyl oxide can preferably carry out in 40-70 ℃ of scope in 30-80 ℃ of scope the processing of repaglinide, more preferably in 50-60 ℃ of scope, carry out.
The time of this processing was generally several minutes to several hours, was preferably 30 minutes to 6 hours, more preferably 1 hour to 4 hours, most preferably was 2 to 3 hours.
After above-mentioned processing, to lower the temperature, standing demix separates water then, obtains to contain the organic phase of repaglinide.
Do not receive the constraint of any principle; Step 3) of the present invention adopts basic metal or alkaline-earth metal alkyl oxide to handle the effect that why can reach purification; Be based on following reason: the method final step that much obtains repaglinide is the protection base that removes carboxyl; Such as ester group is the common protection base of carboxyl, causes existing in the repaglinide bullion a small amount of ester class impurity.In the presence of the such alkaline matter of basic metal or alkaline-earth metal alkyl oxide, residual Ester can hydrolysis generate repaglinide, has so not only effectively reduced impurity, and has advantageously increased the productive rate of target product.In addition, some impurity property materials also can be dissolved in the aqueous phase at basic metal or alkaline-earth metal alkyl oxide place, through separating after the layering, have realized separating of this part impurity property material and repaglinide.
Step 4) adds alcoholic solvent in organic phase, in 3.0～5.5 scopes, and controlled temperature carries out recrystallization with acid for adjusting pH value, and with the crystal centrifuge washing of separating out, drying obtains the purified repaglinide.
Said alcohols is preferably methyl alcohol, ethanol, propyl alcohol and butanols, more preferably methyl alcohol and ethanol, and basic metal or the pairing alcohol of alkaline-earth metal alkyl oxide anionicsite are identical in most preferably employed alcohol and the step 3).For example, if use sodium methylate or potassium methylate in the step 3), then this step uses methyl alcohol as solvent, if use sodium ethylate or potassium ethylate in the step 3), then this step is used ethanol.
During acid for adjusting pH value, used acid can be common mineral acid and organic acid, for example hydrochloric acid, sulfuric acid, formic acid, acetate, phenylformic acid, Phenylsulfonic acid, toluene sulfonic acide, and acid concentration can be in the 0.1M-1M scope, preferred 0.2M-0.6M.In said solution environmental, suitable pH value is in 3.0～5.5 scopes, and preferred pH value is 3.5～5.0.
Surprisingly, after this step process, obtain the repaglinide crystal of based on very high purity.Its reason possibly be this step 1)-3) removed the impurity property material that recrystallization is had disadvantageous effect, and be more suitable in this mixed solvent that forms from organic solvent and alcohol recrystallization through the repaglinide that basic metal or alkaline-earth metal alkyl oxide were handled and separate out.
When carrying out recrystallization, earlier at elevated temperatures, as 40-90 ℃, preferred 50-80 ℃; More preferably under 60-70 ℃, the repaglinide solution that step 3) is obtained concentrates, and adds the alcoholic solvent that accounts for liquor capacity 50-80% then; Under stirring state slowly the cooling, when temperature reaches room temperature, with acid for adjusting pH value in 3.0～5.5 scopes; Continue to stir and cooling, between 15 ℃ to 5 ℃, in this process, have crystal slowly to separate out.The optional repaglinide crystal seed that drops in temperature-fall period.After placing 5-24 hour, crystallization is complete, filters or spinning, and washing adopts air to dry or the drying mode drying.
The repaglinide highly finished product of above-mentioned embodiment gained, according to high effective liquid chromatography for measuring, its purity generally greater than 99.7%, is white crystal greater than 99.6%.
In view of the powder flowbility of repaglinide, intrinsic dissolution rate, Pickering property and preparation operability huge to the influence of its active performance and the preparation prepared, and the repaglinide that purity is largely increased dissolution rate, the property prepared and stable aspect also corresponding obvious improvement.Therefore, be fit to be mixed with the medicine that is used to treat type II diabetes fully according to the inventive method purified repaglinide.
The present invention has fundamentally changed the lower present situation of domestic and international repaglinide material purity, has solved the difficult problem that rough repaglinide and repaglinide bulk drug face.That the inventive method also has is easy, be easy to control and the characteristics of suitability for industrialized production.
Embodiment
Below come further to explain or explanation content of the present invention through embodiment.But the embodiment that is provided should not be understood that protection domain of the present invention is constituted restriction.
HPLC measures the purity of repaglinide:
Method: chromatographic column is Kromasil C18, and moving phase is 0.05mol/L ammonium acetate buffer (pH4.0)-methyl alcohol (20:80), and flow velocity is 1.0ml/min, and the detection wavelength is 243nm, and sample size is 20 μ l.
Embodiment 1
(Venture Pharmaceutical (Hainan) Co., Ltd., lot number: 20091101), the content that HPLC records repaglinide is 95% to get long repaglinide bulk drug of 10g date manufactured.This repaglinide bullion is dissolved in the 80ml chloroform, after fully stirring, makes the repaglinide dissolving, remove by filter insoluble impurities, collect first-time filtrate.
The gac that in this first-time filtrate, adds 0.6g, 20min is stirred in 35 ℃ of insulations, filters the deactivation charcoal, collects secondary filtrating.
The sodium ethylate aqueous solution 20ml that in above-mentioned secondary filtrating, adds 1M handles, and treatment temp is 60 ℃, and the treatment time is 3 hours, is cooled to room temperature then, and standing demix separates water then, obtains to contain the organic phase of repaglinide.
The organic phase that is obtained is warming up to 60-70 ℃ concentrates, add the absolute ethyl alcohol that accounts for liquor capacity 60% then, slowly cooling under stirring state; When temperature reaches room temperature; In 4.0～4.5 scopes, continue to stir and drop into the repaglinide crystal seed, slowly cooling with the second acid for adjusting pH value; Until 10 ℃, there is crystal slowly to separate out.After placing 10 hours, crystallization is complete, filtering separation, and with pure water washing 3 times, air dries.
Get white repaglinide 9.2g, fusing point: 126.2 ℃-127.8 ℃, it is 99.7% that performance liquid chromatography records repaglinide purity.
Embodiment 2
Get the out of date repaglinide bulk drug of 10g, the content that HPLC records repaglinide is 92%.This repaglinide bullion is dissolved in the 100ml toluene, after fully stirring, makes the repaglinide dissolving, remove by filter insoluble impurities, collect first-time filtrate.
The aluminum oxide that in this first-time filtrate, adds 0.5g, 30min is stirred in 40 ℃ of insulations, filters deoxygenated aluminium, collects secondary filtrating.
The sodium methylate aqueous solution 30ml that in above-mentioned secondary filtrating, adds 0.5M handles, and treatment temp is 65 ℃, and the treatment time is 2 hours, is cooled to room temperature then, and standing demix separates water then, obtains to contain the organic phase of repaglinide.
The organic phase that is obtained is warming up to 70-75 ℃ concentrates, add the anhydrous methanol that accounts for liquor capacity 70% then, slowly cooling under stirring state; When temperature reaches room temperature; In 3.5～4.0 scopes, continue to stir and drop into the repaglinide crystal seed, slowly cooling with the first acid for adjusting pH value; Until 12 ℃, there is crystal slowly to separate out.After placing 15 hours, crystallization is complete, and spinning is with pure water washing 3 times, oven dry.
Get white repaglinide 8.8g, fusing point: 126.1 ℃-127.8 ℃, it is 99.6% that performance liquid chromatography records repaglinide purity.
Embodiment 3
(Venture Pharmaceutical (Hainan) Co., Ltd., lot number: 20111101), the content that HPLC records repaglinide is 96.5% to get 10g repaglinide bulk drug.This repaglinide bullion is dissolved in the 90ml ETHYLE ACETATE, after fully stirring, makes the repaglinide dissolving, remove by filter insoluble impurities, collect first-time filtrate.
The A type molecular sieve that in this first-time filtrate, adds 0.5g, 25min is stirred in 40 ℃ of insulations, filters and takes off molecular sieve, collects secondary filtrating.
The potassium ethylate aqueous solution 25ml that in above-mentioned secondary filtrating, adds 0.8M handles, and treatment temp is 50 ℃, and the treatment time is 4 hours, is cooled to room temperature then, and standing demix separates water then, obtains to contain the organic phase of repaglinide.
The organic phase that is obtained is warming up to 65-75 ℃ concentrates, add the absolute ethyl alcohol that accounts for liquor capacity 55% then, slowly cooling under stirring state; When temperature reaches room temperature; In 3.2～4.0 scopes, continue to stir and drop into the repaglinide crystal seed, slowly cooling with 1M salt acid for adjusting pH value; Until 10 ℃, there is crystal slowly to separate out.After placing 15 hours, crystallization is complete, filtering separation, and with pure water washing 3 times, air dries.
Get white repaglinide 9.3g, fusing point: 126.3 ℃-128.0 ℃, it is 99.8% that performance liquid chromatography records repaglinide purity.
Embodiment 4
Get 10g by US5, the repaglinide crude product that 312,924 disclosed methods make, the content that HPLC records repaglinide is 89%.This repaglinide bullion is dissolved in 100ml benzene and the toluene 1:1 mixed solvent, after fully stirring, makes the repaglinide dissolving, remove by filter insoluble impurities, collect first-time filtrate.
The aluminum oxide that in this first-time filtrate, adds 0.4g, 25min is stirred in 42 ℃ of insulations, filters deoxygenated aluminium, collects secondary filtrating.
The potassium methylate aqueous solution 40ml that in above-mentioned secondary filtrating, adds 0.8M handles, and treatment temp is 60 ℃, and the treatment time is 3 hours, is cooled to room temperature then, and standing demix separates water then, obtains to contain the organic phase of repaglinide.
The organic phase that is obtained is warming up to 70-75 ℃ concentrates, add the anhydrous methanol that accounts for liquor capacity 60% then, slowly cooling under stirring state; When temperature reaches room temperature; In 4.8～5.2 scopes, continue to stir and drop into the repaglinide crystal seed, slowly cooling with 2M first acid for adjusting pH value; Until 10 ℃, there is crystal slowly to separate out.After placing 18 hours, crystallization is complete, and spinning is with pure water washing 3 times, oven dry.
Get white repaglinide 8.5g, fusing point: 126.2 ℃-127.9 ℃, it is 99.7% that performance liquid chromatography records repaglinide purity.
According to the above embodiments the present invention has been made detailed description.What need explanation is that above embodiment is just to illustrating the present invention.Under the prerequisite that does not depart from spirit of the present invention and essence, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be in protection scope of the present invention.
Claims (9)
1. repaglinide compound comprises following treatment step:
Step 1), with the raw material repaglinide be dissolved in the immiscible organic solvent of water in, remove by filter insoluble impurities, obtain first-time filtrate;
Step 2), in first-time filtrate, add the adsorptivity inorganic substance, vigorous stirring leaves standstill after-filtration and removes the adsorptivity inorganic substance, obtains secondary filtrating;
Step 3), the aqueous solution that in secondary filtrating, adds basic metal or alkaline-earth metal alkyl oxide is handled, the optional heating in treating processes, cooling then, standing demix separates water then, obtains to contain the organic phase of repaglinide;
Step 4) adds alcoholic solvent in organic phase, in 3.0～5.5 scopes, and controlled temperature carries out recrystallization with acid for adjusting pH value, and with the crystal centrifuge washing of separating out, drying obtains the purified repaglinide.
2. according to the method for making of the repaglinide compound of claim 1, it is characterized in that,
In the step 1), said organic solvent is chloroform, ETHYLE ACETATE, hexanaphthene, benzene, toluene, perhaps by two or three mixed solvent that forms wherein.
3. according to the method for making of the repaglinide compound of claim 1 or 2, it is characterized in that step 2) in, said adsorptivity inorganic substance can be gac, aluminum oxide or molecular sieve.
4. according to the method for making of the repaglinide compound of one of claim 1 to 3; It is characterized in that; Step 2) in, in first-time filtrate, adds gac or the aluminum oxide of 0.05-1% (g/ml) or the molecular sieve of 0.1-1% (g/ml) that accounts for overall solution volume 0.1-1% (g/ml).
5. according to the method for making of the repaglinide compound of one of claim 1 to 4; It is characterized in that, in the step 3), said basic metal or alkaline-earth metal alkyl oxide preferred as alkali alkoxide; The more preferably alkoxide of sodium or potassium, for example sodium methylate, sodium ethylate, potassium methylate or potassium ethylate.
6. according to the method for making of the repaglinide compound of one of claim 1 to 5, it is characterized in that in the step 4), said alcohols is methyl alcohol, ethanol, propyl alcohol and butanols, more preferably methyl alcohol and ethanol.
7. according to the method for making of the repaglinide compound of claim 6, it is characterized in that,
In the step 4) in employed alcohol and the step 3) basic metal or the pairing alcohol of alkaline-earth metal alkyl oxide anionicsite identical.
8. according to the method for making of the repaglinide compound of one of claim 1 to 7; It is characterized in that in the step 4), said acid is hydrochloric acid, sulfuric acid, formic acid, acetate, phenylformic acid, Phenylsulfonic acid or toluene sulfonic acide; Acid concentration is 0.1M-1M; Preferred 0.2M-0.6M, regulating p H value is 3.0～5.5, preferred 3.5～5.0.
9. the repaglinide compound that makes according to the method for one of claim 1 to 8, according to high effective liquid chromatography for measuring, its purity generally greater than 99.7%, is white crystal greater than 99.6%.
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| CN109293612A (en) * | 2018-10-18 | 2019-02-01 | 武汉中科光谷绿色生物技术有限公司 | A method of N-acetyl-neuraminate hydrate is prepared by adjusting solution hydrogen ion concentration |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010046360A1 (en) * | 2008-10-20 | 2010-04-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of substantially optically pure repaglinide and precursors thereof |
| CN101772491A (en) * | 2007-06-06 | 2010-07-07 | 阿克塔维什集团Ptc公司 | Repaglinide substantially free of dimer impurity |
| CN101220007B (en) * | 2008-01-16 | 2010-09-15 | 浙江耐司康药业有限公司 | Method for producing repaglinide |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101772491A (en) * | 2007-06-06 | 2010-07-07 | 阿克塔维什集团Ptc公司 | Repaglinide substantially free of dimer impurity |
| CN101220007B (en) * | 2008-01-16 | 2010-09-15 | 浙江耐司康药业有限公司 | Method for producing repaglinide |
| WO2010046360A1 (en) * | 2008-10-20 | 2010-04-29 | Krka, Tovarna Zdravil, D.D., Novo Mesto | Process for the preparation of substantially optically pure repaglinide and precursors thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109293612A (en) * | 2018-10-18 | 2019-02-01 | 武汉中科光谷绿色生物技术有限公司 | A method of N-acetyl-neuraminate hydrate is prepared by adjusting solution hydrogen ion concentration |
| CN109293612B (en) * | 2018-10-18 | 2022-07-26 | 武汉中科光谷绿色生物技术有限公司 | Method for preparing N-acetylneuraminic acid hydrate by adjusting concentration of hydrogen ions in solution |
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