CN104447933A - Synthesis method for medical-grade deslanoside - Google Patents
Synthesis method for medical-grade deslanoside Download PDFInfo
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- CN104447933A CN104447933A CN201410802506.4A CN201410802506A CN104447933A CN 104447933 A CN104447933 A CN 104447933A CN 201410802506 A CN201410802506 A CN 201410802506A CN 104447933 A CN104447933 A CN 104447933A
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- Prior art keywords
- deslanoside
- pharmaceutical grade
- carbonate
- lanatoside
- synthetic method
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J19/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 by a lactone ring
- C07J19/005—Glycosides
Abstract
The invention discloses a synthesis method for medical-grade deslanoside. The synthesis method comprises the following steps: (1) dissolving lanatosides C into methanol; (2) dissolving carbonate into water; (3) dropwise adding a carbonate solution to a methanol solution of the lanatosides C, and reacting at room temperature for 20-24 hours; and (4) filtering, wetting and washing the obtained solid with methanol, naturally airing, and drying in vacuum, so as to obtain the medical-grade deslanoside. The method is simple to operate, short in production cycle, high in yield, high in purity, and beneficial to industrialized production; only 20mL of methanol is required for producing 1g of product; the yield reaches 98%; and the purity is 98.8%.
Description
Technical field
The invention belongs to medicinal chemistry art, be specifically related to a kind of synthetic method of pharmaceutical grade Deslanoside.
Background technology
The chemical name of Deslanoside is: 3-[(O-β-D-Glucopyranyl-(1 → 4)-O-2,6-dideoxy-β-D-core-own pyrans glycosyl-(1 → 4)-O-2,6-dideoxy-β-D-core-own pyrans glycosyl-(1 → 4)-O-2,6-dideoxy-β-D-core-own pyrans glycosyl) oxo]-12,14-dihydroxyl-heart steroid-20 (22)-alkene lactone, molecular formula is C
47h
74o
19, molecular weight is 943.09.Deslanoside belongs to injection, and commodity are called cedilanid, is anti-arrhythmic, is mainly used in heart failure.Because its effect is very fast, be applicable to the patient of acute cardiac insufficiency or chronic cardiac insufficiency acute exacerbation, also can be used for controlling companion's atrial fibrillation of rapid ventricular rate, the Ventricular Rate of atrial flutter patients, sometimes slow for termination of supraventricular tachycardia onset.Pharmaceutical grade Deslanoside is white crystalline powder; Odorless, bitter; Have draw moist.Slightly soluble in methyl alcohol, atomic molten in ethanol, almost insoluble in water or trichloromethane.Calculate, containing C by dry product
47h
74o
19should be 96.0%-102.0%.
The synthetic method of current Deslanoside is mainly obtained by reacting by lanatoside C deacetylate, has following open source literature to report:
1933, Arthur Stoll and Walter Kreis is at German periodical Helvetica Chimica Acta, report the preparation technology of Deslanoside in 1933,16:1390-1407, method is as follows: be dissolved in by 5.6g lanatoside C in 184mL methyl alcohol, 0.271g calcium hydroxide is soluble in water, filter respectively, mix under room temperature, hold over night, be adjusted to neutrality with 0.1N hydrochloric acid again, filter and obtain first part Deslanoside crude product 2.96g.Then mother liquor being revolved steaming to there is no methyl alcohol, filtering and obtaining second section Deslanoside crude product 1.66g.The thick product of 4.62g after merging is dissolved in 100mL hot methanol, filters and obtains molten clear liquid, reheat backflow 10 minutes, and cooling is separated out, and suction filtration obtains 2.95g Deslanoside highly finished product.
1975, Pekic B etc., at English Periodicals Planta Medica, reported the new preparation process of Deslanoside in 1975,27:178-181.Author reports, makes catalyzer, lanatoside C is carried out methanol decomposition reaction, can obtain Deslanoside with a small amount of sodium methylate.Method is as follows: 5g lanatoside C is added on 10
-2in the methanol solution 100mL of mol/L sodium methylate, place 4 hours room temperature 22 DEG C, can complete deacetylation, with in Glacial acetic acid and sodium methylate, boil off methyl alcohol, the Deslanoside crude product ethyl alcohol recrystallization obtained, obtains acetyl lanatoside highly finished product.The overall yield that this method obtains is 80-90%, and by product is less than 5%.Author reports, by detecting the dynamic process of lanatoside C deacetylation, proves that this new alcoholysis reaction system is better than CH on productive rate
3oH-Ca (OH)
2, and CH
3oH or CH
3cH
2oH and volatile organic weak base carry out the hydrolysis reaction system of lanatoside C.
Above two methods are in later stage actual use, have and further improve and change, the document Advanced Synthesis and Catalysis that such as MuramatsuWataru and Yoshimatsu Hirofumi is delivering, 2013, use sodium methylate alcohol enzymatic hydrolysis system in 13:2518-2524, difference replaces sodium methylate in previous Glacial acetic acid He unnecessary with ammonium chloride.Equally, calcium hydroxide hydrolyzation system has this step saving hydrochloric acid tune pH in the use in later stage, but all in re-crystallization step, uses a large amount of methyl alcohol.For the improvement in these two kinds of methods, be only suitable for on a small quantity reaction in, for the iodine in industrial production, other report does not carry out the improvement of description effect, also does not report example to illustrate and can produce pharmaceutical grade Deslanoside in a large number by high productivity.Therefore, in the Deslanoside synthetic method of having reported for work, a kind of high-efficient simple ground large-scale production process is lacked, particularly from controlling consumption of organic solvent and being easy to production 2 consideration.
For bibliographical information two kinds of synthetic methods we verify, calcium hydroxide hydrolyzation system is applied more extensive in a large amount of productions of reality, but we find problems when attempting lanatoside C hydrolysis reaction by this method, such as calcium hydroxide difficulty is dissolved in water, obtain clear soln after generally will filtering could use, add operation, and its actual concentration is stablized not and affects reaction yield, in reaction process, product separates out time point instability, and reaction monitoring display by product is more.In amplification is produced, different batches product affects obviously by the configuring condition of calcium hydroxide, its crude yield about 75%, also needs methyl alcohol by ratio of weight and the number of copies for the amount of 1:150 is refined just can obtain pharmaceutical grade product, ultimate yield average out to 65%, content is all below 97%.Sodium methylate method is comparatively strong due to alkalescence own, causes reacting being difficult to control, and by product is more, its crude yield about 87%, and purity only has about 80%, so need ethanol by ratio of weight and the number of copies for the amount of 1:180 is come exquisitely just can obtain pharmaceutical grade product.Sum up us can obtain the repeated confirmatory experiment of above-mentioned two kinds of methods, produce qualified pharmaceutical grade Deslanoside, 1g product needed is about 300mL methyl alcohol or measures more ethanol.In sum, the currently known methods reported all exists that solvent load is large, productive rate is low, purity is low, have to pass through recrystallizing methanol step, operates the shortcomings such as more loaded down with trivial details.
Summary of the invention
The present invention is directed to above-mentioned weak point and the synthetic method of a kind of pharmaceutical grade Deslanoside provided, its have simple to operate, solvent load is few, productive rate is high, purity advantages of higher.
For achieving the above object, the technical solution adopted for the present invention to solve the technical problems is:
A synthetic method for pharmaceutical grade Deslanoside, comprises the following steps:
(1) lanatoside C is dissolved in methyl alcohol;
(2) by dissolves carbonate in water;
(3) carbonate aqueous solution is dropped in the methanol solution of lanatoside C, under room temperature, react 20-24 hour;
(4) filter, gained solid through methanol rinses, naturally dry, namely obtain pharmaceutical grade Deslanoside after vacuum-drying.
Further, in step (1), the quality of lanatoside C and the volume ratio of methyl alcohol are 5:94-95.
Further, in step (2), the weight ratio of carbonate and water is 1:12-38.
Further, in step (2), carbonate is salt of wormwood, sodium carbonate, cesium carbonate.
Further, carbonate aqueous solution drops in the methanol solution of lanatoside C in (3) by step, and time for adding is 30 minutes, and the mol ratio of lanatoside C and carbonate is 1:1.15-1.20, and temperature of reaction is 25 DEG C.
Further, in step (4), vacuum-drying temperature is 100-105 DEG C, and the time is 4-5 hour.
The synthetic method of a kind of pharmaceutical grade Deslanoside provided by the invention, mainly has following several beneficial effect:
(1) complex operation in prior art, the production cycle is long, and produce 1g product needed and consume 300mL methyl alcohol, and the present invention is simple to operate, the production time shortens, and solvent load is few, and producing 1g product only needs 20mL methyl alcohol, is conducive to factorial praluction.
(2) yield is high, purity is high, and yield reaches 98%, and purity is 98.8%.
Accompanying drawing explanation
Fig. 1 is the color atlas in embodiment 1.
Fig. 2 is the color atlas in embodiment 2.
Fig. 3 is the color atlas in embodiment 3.
Fig. 4 is the color atlas in embodiment 4.
Fig. 5 is the color atlas in embodiment 5.
Embodiment
Below in conjunction with drawings and Examples, the present invention is further detailed explanation:
Embodiment 1
1, synthetic method
(1) 5g lanatoside C is added in reaction flask, then add 95mL methyl alcohol, fully stir;
(2) 0.808g salt of wormwood is dissolved in 23mL water;
(3) in the methanol solution of lanatoside C, drip wet chemical, time for adding is 30 minutes, and reaction process fully stirs, temperature of reaction is 25 DEG C, and the reaction times is 24 constantly little, and the display of TLC thin-layer chromatography only has product point, pH=7, now reacts end;
(4) filter, filter cake dries after draining with a small amount of methanol rinses naturally, then proceeds to loft drier 100-105 DEG C vacuum-drying 4 hours, obtains 4.5g white solid.Do not need refining methanol process both to obtain meeting the Deslanoside salable product of Chinese Pharmacopoeia standard, yield is 94%.
2, detection method
HPLC operation steps is as follows: get the pharmaceutical grade Deslanoside be obtained by reacting, add a small amount of methyl alcohol ultrasonic dissolution, dilute with moving phase acetonitrile-methanol-water (volume ratio is 232:148:620), make containing 0.2mg pharmaceutical grade Deslanoside in every 1mL solution, as need testing solution.Precision measures 1mL need testing solution and is placed in 100mL volumetric flask, with moving phase acetonitrile-methanol-water (volume ratio is 232:148:620) constant volume, shake up, in contrast solution, carry out high performance liquid chromatography test, octadecylsilane chemically bonded silica is as weighting agent, water is as mobile phase A, and acetonitrile-methanol (volume ratio is 22 ︰ 14), as Mobile phase B, carries out gradient elution by table 1, flow velocity is 1.0mL/min, and determined wavelength is 220nm.Number of theoretical plate calculates by Deslanoside peak and is not less than 2000.Get contrast solution 20ul injection liquid chromatography, regulate detection sensitivity, make main peak divide the peak height of chromatographic peak to be about 25% of full range.Precision measures need testing solution and each 20ul of contrast solution again, respectively injection liquid chromatography, and record color atlas, HPLC analysed preparation purity reaches 98.5%, and color atlas is shown in Fig. 1, and analytical results is in table 2.
If any impurity peaks in the color atlas of need testing solution, single impurity peak area must not be greater than 5 times (5%) of contrast solution main peak area, each impurity peak area and 10 times (10%) of contrast solution main peak area must not be greater than.
Table 1 wash-out table
| Time (min) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 62 | 38 |
| 20 | 62 | 38 |
| 21 | 48 | 52 |
| 45 | 48 | 52 |
| 46 | 62 | 38 |
| 51 | 62 | 38 |
Embodiment 2
1, synthetic method
(1) 25g lanatoside C is added in reaction flask, then add 475mL methyl alcohol, fully stir;
(2) 4.2g salt of wormwood is dissolved in 128mL water;
(3) in the methanol solution of lanatoside C, drip wet chemical, time for adding is 30 minutes, and reaction process fully stirs, and temperature of reaction is 25 DEG C, and the reaction times is 20 constantly little, and the display of TLC thin-layer chromatography only has product point, pH=7, and reaction terminates;
(4) filter, filter cake dries after draining with a small amount of methanol rinses naturally, then proceeds to loft drier 100-105 DEG C vacuum-drying 4 hours, obtains 23.0g white solid.Do not need refining methanol process both to obtain meeting the Deslanoside salable product of Chinese Pharmacopoeia standard, yield is 96%.
2, detection method
HPLC operation steps is identical with embodiment 1, and HPLC analysed preparation purity reaches 98.7%, and color atlas is shown in Fig. 2, and analytical results is in table 3.
Embodiment 3
1, synthetic method
(1) 120g lanatoside C is added in reaction flask, then add 2.273L methyl alcohol, fully stir;
(2) 20.2g salt of wormwood is dissolved in 639mL water;
(3) in the methanol solution of lanatoside C, drip wet chemical, time for adding is 30 minutes, and reaction process fully stirs, and temperature of reaction is 25 DEG C, and the reaction times is 20 constantly little, and the display of TLC thin-layer chromatography only has product point, pH=7, and reaction terminates;
(4) filter, filter cake dries after draining with a small amount of methanol rinses naturally, then proceeds to loft drier 100-105 DEG C vacuum-drying 5 hours, obtains 112.7g white solid.Do not need refining methanol process both to obtain meeting the Deslanoside salable product of Chinese Pharmacopoeia standard, yield is 98%.
2, detection method
HPLC operation steps is identical with embodiment 1, and HPLC analysed preparation purity reaches 98.8%, and color atlas is shown in Fig. 3, and analytical results is in table 4.
Embodiment 4
1, synthetic method
(1) 5g lanatoside C is added in reaction flask, then add 95mL methyl alcohol, fully stir;
(2) 0.62g sodium carbonate is dissolved in 23mL water;
(3) in the methanol solution of lanatoside C, drip aqueous sodium carbonate, time for adding is 30 minutes, and reaction process fully stirs, and temperature of reaction is 25 DEG C, and the reaction times is 24 constantly little, and the display of TLC thin-layer chromatography only has product point, pH=7, and reaction terminates;
(4) filter, filter cake dries after draining with a small amount of methanol rinses naturally, then proceeds to loft drier 100-105 DEG C vacuum-drying 4 hours, obtains 4.3g white solid.Do not need refining methanol process both to obtain meeting the Deslanoside salable product of Chinese Pharmacopoeia standard, yield is 90%.
2, detection method
HPLC operation steps is identical with embodiment 1, and HPLC analysed preparation purity reaches 98.0%, and color atlas is shown in Fig. 4, and analytical results is in table 5.
Embodiment 5
1, synthetic method
(1) 5g lanatoside C is added in reaction flask, then add 95mL methyl alcohol, fully stir;
(2) 1.906g cesium carbonate is dissolved in 23mL water;
(3) in the methanol solution of lanatoside C, drip cesium carbonate aqueous solution, time for adding is 30 minutes, and reaction process fully stirs, and temperature of reaction is 25 DEG C, and the reaction times is 24 constantly little, and the display of TLC thin-layer chromatography only has product point, pH=7, and reaction terminates;
(4) filter, filter cake dries after draining with a small amount of methanol rinses naturally, then proceeds to loft drier 100-105 DEG C vacuum-drying 4 hours, obtains 4.2g white solid.Do not need refining methanol process both to obtain meeting the Deslanoside salable product of Chinese Pharmacopoeia standard, yield is 88%.
2, detection method
HPLC operation steps is identical with embodiment 1, and HPLC analysed preparation purity reaches 98.0%, and color atlas is shown in Fig. 5, and analytical results is in table 6.
Conclusion:
In embodiment 1-5, the analytical results of HPLC is respectively in Table 2-6.
HPLC analytical results in table 2 embodiment 1
HPLC analytical results in table 3 embodiment 2
HPLC analytical results in table 4 embodiment 3
HPLC analytical results in table 5 embodiment 4
HPLC analytical results in table 6 embodiment 5
HPLC analytical data illustrates, this analytical procedure is appropriate, and appearance time is suitable for, qualified by area normalization method gained sample purity.
The whole technical process of embodiment 1-5 the results are shown in Table 7:
The Comparative result of table 7 embodiment 1-5
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | |
| Carbonate | Salt of wormwood | Salt of wormwood | Salt of wormwood | Sodium carbonate | Cesium carbonate |
| Methyl alcohol (mL) | 21.11 | 20.65 | 20.17 | 22.09 | 22.62 |
| Yield (%) | 94 | 96 | 98 | 90 | 88 |
| Purity (%) | 98.5 | 98.7 | 98.8 | 98 | 98 |
Note: the consumption of methyl alcohol consumes methyl alcohol volume for producing 1g product needed.
The reaction product that embodiment 1-5 obtains is white crystalline powder, and odorless, is slightly soluble in methyl alcohol, water insoluble, conforms to Deslanoside character, reaches pharmaceutical grade Deslanoside standard.But as known from Table 7: in embodiment 3, production pharmaceutical grade Deslanoside quantity of methyl alcohol used is minimum, yield is the highest, reach 98%, purity is also the highest, reaches 98.8%, therefore according to the technical process production pharmaceutical grade Deslanoside of embodiment 3, cost is minimum, yield is the highest, and purity is the highest, and effect is best.
Claims (8)
1. a synthetic method for pharmaceutical grade Deslanoside, is characterized in that, comprises the following steps:
(1) lanatoside C is dissolved in methyl alcohol;
(2) by dissolves carbonate in water;
(3) carbonate aqueous solution is dropped in the methanol solution of lanatoside C, under room temperature, react 20-24 hour;
(4) filter, gained solid through methanol rinses, naturally dry, namely obtain pharmaceutical grade Deslanoside after vacuum-drying.
2. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, in step (1), the quality of lanatoside C and the volume ratio of methyl alcohol are 5:94-95.
3. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, in step (2), the weight ratio of carbonate and water is 1:12-38.
4. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, in step (2), carbonate is salt of wormwood, sodium carbonate, cesium carbonate.
5. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, carbonate aqueous solution drops in the methanol solution of lanatoside C in (3) by step, and time for adding is 30 minutes.
6. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, the mol ratio of lanatoside C and carbonate is 1:1.15-1.20.
7. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, in step (3), temperature of reaction is 25 DEG C.
8. the synthetic method of a kind of pharmaceutical grade Deslanoside according to claim 1, is characterized in that, in step (4), vacuum-drying temperature is 100-105 DEG C, and the time is 4-5 hour.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107082794A (en) * | 2017-05-27 | 2017-08-22 | 成都倍特药业有限公司 | A kind of Deslanoside novel crystal forms and preparation method thereof |
| CN107118248A (en) * | 2017-05-27 | 2017-09-01 | 成都倍特药业有限公司 | A kind of process for purification of high-purity Deslanoside |
| CN110498828A (en) * | 2019-08-30 | 2019-11-26 | 上海旭东海普药业有限公司 | A kind of preparation method of Deslanoside and impurity |
| CN110530993A (en) * | 2019-08-30 | 2019-12-03 | 上海旭东海普药业有限公司 | A kind of detection method of the improved Deslanoside in relation to substance |
| CN114591388A (en) * | 2022-03-28 | 2022-06-07 | 江苏中渊化学品有限公司 | Extraction method of high-purity deacetyl hairy flower glycoside suitable for industrialization |
-
2014
- 2014-12-22 CN CN201410802506.4A patent/CN104447933B/en active Active
Non-Patent Citations (3)
| Title |
|---|
| B. PEKIÉ ET AL: "A New Method Of Preparation of Deacetyl-lanatosides", 《PLANTA MEDICA》, vol. 27, 31 December 1975 (1975-12-31), pages 178 - 181 * |
| WATARU MURAMATSU ET AL: "Regio- and Stereochemical Controlled Koenigs–Knorr-Type Monoglycosylation of Secondary Hydroxy Groups in Carbohydrates Utilizing the High Site Recognition Ability of Organotin Catalysts", 《ADV. SYNTH. CATAL.》, vol. 355, 5 September 2013 (2013-09-05), pages 2518 - 2524 * |
| 张德成: "脱乙酰毛花洋地黄甙的新制备法", 《国际药学研究杂志》, no. 1, 28 February 1977 (1977-02-28), pages 44 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107082794A (en) * | 2017-05-27 | 2017-08-22 | 成都倍特药业有限公司 | A kind of Deslanoside novel crystal forms and preparation method thereof |
| CN107118248A (en) * | 2017-05-27 | 2017-09-01 | 成都倍特药业有限公司 | A kind of process for purification of high-purity Deslanoside |
| CN107082794B (en) * | 2017-05-27 | 2019-11-29 | 成都倍特药业有限公司 | A kind of Deslanoside crystal form and preparation method thereof |
| CN110498828A (en) * | 2019-08-30 | 2019-11-26 | 上海旭东海普药业有限公司 | A kind of preparation method of Deslanoside and impurity |
| CN110530993A (en) * | 2019-08-30 | 2019-12-03 | 上海旭东海普药业有限公司 | A kind of detection method of the improved Deslanoside in relation to substance |
| CN110530993B (en) * | 2019-08-30 | 2022-03-15 | 上海旭东海普药业有限公司 | Improved detection method of deacetylated hairy glycoside related substance |
| CN110498828B (en) * | 2019-08-30 | 2022-10-04 | 上海旭东海普药业有限公司 | Preparation method of deacetyl hairy flower glycoside and impurities |
| CN114591388A (en) * | 2022-03-28 | 2022-06-07 | 江苏中渊化学品有限公司 | Extraction method of high-purity deacetyl hairy flower glycoside suitable for industrialization |
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Address after: No. 15 high tech Zone Gaopeng road in Chengdu city of Sichuan Province in 610041 Patentee after: Chengdu Beite Pharmaceutical Co., Ltd Address before: No. 15 high tech Zone Gaopeng road in Chengdu city of Sichuan Province in 610041 Patentee before: CHENGDU BRILLIANT PHARMACEUTICAL Co.,Ltd. |