CN105061247A - Improved synthesis method for dencichine - Google Patents
Improved synthesis method for dencichine Download PDFInfo
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- CN105061247A CN105061247A CN201510511479.XA CN201510511479A CN105061247A CN 105061247 A CN105061247 A CN 105061247A CN 201510511479 A CN201510511479 A CN 201510511479A CN 105061247 A CN105061247 A CN 105061247A
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Abstract
The invention discloses an improved synthesis method for dencichine, and belongs to the fields of medicine and chemical engineering. Dencichine is a white solid, and can be used for hemostasis by shortening blood coagulation time and thrombinogen time, thereby being important medicine; while, natural dencichine is low in extraction rate, and low in profit margin. The improved synthesis method is an efficient way to obtain dencichine according to a chemosynthesis method, and is low in cost, suitable for industrial production, and low in reaction cost, thereby providing an important reference for industrialization.
Description
Technical field
The present invention relates to a kind of improvement of synthetic method of dencichine, belong to medicine, chemical technology field.
Background technology
Dencichine is a kind of white solid, and dencichine plays anastalsis by shortening clotting time, prothrombin time etc., is a kind of important medical body.But natural dencichine extraction yield is low, and profit margin is little.This method is a kind of effective way being obtained dencichine by chemical synthesis process, and with low cost, can suitability for industrialized production.
Summary of the invention
This patent, by the exploration of dencichine building-up process and optimization, finally obtains the synthesis technique of synthesis dencichine.Dencichine is a kind of important medical body.
The synthetic method of dencichine of the present invention, be adopt altheine to be raw material, react with tert-Butyl dicarbonate under room temperature in basic solution, obtain Boc-L-l-asparagine, Boc-L-l-asparagine reacts with iodobenzene diacetate in acidic mixed solvent system, obtain degraded product Boc-L-2,3-diaminopropionic acid, Boc-L-2,3-diaminopropionic acid and oxalyl chloride are 1, in 4-dioxane, room temperature reaction 6 hours, obtains crude product dencichine after process, and recrystallization obtains sterling dencichine.
The synthetic method of above-mentioned dencichine, is characterized in that: described basic solution, refers to the acetone and water mixed solvent that are dissolved with salt of wormwood or sodium hydroxide, alkali used does not singly refer to salt of wormwood and sodium hydroxide, also comprises sodium carbonate, potassium hydroxide, sodium bicarbonate, the mineral alkalis such as saleratus.
The synthetic method of above-mentioned dencichine, is characterized in that: described acidic mixed solvent system, refers to the mixed solvent system of acetonitrile, ethyl, saturated citric acid solution and water, organic solvent used does not singly only have acetonitrile and ethyl acetate, also comprise acetone, DMF.
The synthetic method of above-mentioned dencichine, is characterized in that: described Boc-L-2,3-diaminopropionic acid and oxalyl chloride room temperature reaction 6 hours in Isosorbide-5-Nitrae-dioxane.Solvent wherein does not singly refer to Isosorbide-5-Nitrae-dioxane, also comprises tetrahydrofuran (THF), acetonitrile and acetone.Wherein react 6 hours, also comprise reaction 1 to 12 hour.
The synthetic method of above-mentioned dencichine, is characterized in that: the synthetic method of described dencichine obtains: get 6.01g sodium hydroxide, be dissolved in 100mL water, be cooled to 0 degree, add 20gL-l-asparagine, stir after 30 minutes, add 200mL acetone and 31.4gK
2cO
3, keep temperature not higher than 5 degree, drip 39.6g tert-Butyl dicarbonate, rise to room temperature reaction after 24 hours, after adding 300mL water dissolution, after 0.5mol/LHCl regulates pH to 6-7, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 5), retain aqueous phase, after aqueous phase regulates pH to 3-4 with 0.5mol/LHCl, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 10), anhydrous sodium sulfate drying, after being spin-dried for, obtain 33gBoc-L-l-asparagine, 33gBoc-L-l-asparagine is dissolved in 96mL ethyl acetate, 96mL acetonitrile, in the saturated citric acid of 1.0mL and 48mL water, after being cooled to 0 degree, add 33.3g iodobenzene diacetate in batches, rise to room temperature reaction 4 hours, solid is had to separate out, after reaction system is down to 0 degree, filter the solid of separating out in reaction, solid is spin-dried for, obtain 30gBoc-L-2, 3-diaminopropionic acid, 30gBoc-L-2, 3-diaminopropionic acid is dissolved in 200mL1, in 4-dioxane, after dissolving completely, after being cooled to 0 degree, slow dropping 20g oxalyl chloride, rise to room temperature reaction 5 hours, after the cancellation that adds water reaction, solid is had to separate out, filter, washing, dry, obtain crude product dencichine, after recrystallization, obtain 40g sterling dencichine.
Above-mentioned with L-asparagine, tert-Butyl dicarbonate, iodobenzene diacetate and oxalyl chloride etc. are that the chemical reaction of Material synthesis dencichine and reaction formula are as follows:
(1) reaction equation of L-asparagine and tert-Butyl dicarbonate is:
(2) reacted, the DeR equation of Boc-L-l-asparagine is:
(3) reacted, the reaction equation of Boc-L-2,3-diaminopropionic acid and oxalyl chloride is:
(4) after having reacted, add water cancellation, after recrystallization, obtains 40g dencichine sterling.
Embodiment
Embodiment:
The synthetic method of described dencichine obtains: get 6.01g sodium hydroxide, be dissolved in 100mL water, be cooled to 0 degree, add 20gL-l-asparagine, stir after 30 minutes, add 200mL acetone and 31.4gK
2cO
3, keep temperature not higher than 5 degree, drip 39.6g tert-Butyl dicarbonate, rise to room temperature reaction after 24 hours, after adding 300mL water dissolution, after 0.5mol/LHCl regulates pH to 6-7, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 5), retain aqueous phase, after aqueous phase regulates pH to 3-4 with 0.5mol/LHCl, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 10), anhydrous sodium sulfate drying, after being spin-dried for, obtain 33gBoc-L-l-asparagine, 33gBoc-L-l-asparagine is dissolved in 96mL ethyl acetate, 96mL acetonitrile, in the saturated citric acid of 1.0mL and 48mL water, after being cooled to 0 degree, add 33.3g iodobenzene diacetate in batches, rise to room temperature reaction 4 hours, solid is had to separate out, after reaction system is down to 0 degree, filter the solid of separating out in reaction, solid is spin-dried for, obtain 30gBoc-L-2, 3-diaminopropionic acid, 30gBoc-L-2, 3-diaminopropionic acid is dissolved in 200mL1, in 4-dioxane, after dissolving completely, after being cooled to 0 degree, slow dropping 20g oxalyl chloride, rise to room temperature reaction 5 hours, after the cancellation that adds water reaction, solid is had to separate out, filter, washing, dry, obtain crude product dencichine, after recrystallization, obtain 40g sterling dencichine.
Claims (5)
1. the synthetic method of a dencichine is improved, be adopt altheine to be raw material, react with tert-Butyl dicarbonate under room temperature in basic solution, obtain Boc-L-l-asparagine, Boc-L-l-asparagine reacts with iodobenzene diacetate in acidic mixed solvent system, obtain degraded product Boc-L-2,3-diaminopropionic acid, Boc-L-2,3-diaminopropionic acid and oxalyl chloride are 1, in 4-dioxane, room temperature reaction 6 hours, obtains crude product dencichine after process, and recrystallization obtains sterling dencichine.
2. the synthetic method of dencichine as claimed in claim, it is characterized in that: described basic solution, refer to the acetone and water mixed solvent that are dissolved with salt of wormwood or sodium hydroxide, alkali used does not singly refer to salt of wormwood and sodium hydroxide, also comprise sodium carbonate, potassium hydroxide, sodium bicarbonate, the mineral alkalis such as saleratus.
3. the synthetic method of dencichine as claimed in claim, it is characterized in that: described acidic mixed solvent system, refer to the mixed solvent system of acetonitrile, ethyl, saturated citric acid solution and water, organic solvent used does not singly only have acetonitrile and ethyl acetate, also comprise acetone, DMF.
4. the synthetic method of dencichine as claimed in claim, is characterized in that: described Boc-L-2,3-diaminopropionic acid and oxalyl chloride room temperature reaction 6 hours in Isosorbide-5-Nitrae-dioxane.Solvent wherein does not singly refer to Isosorbide-5-Nitrae-dioxane, also comprises tetrahydrofuran (THF), acetonitrile and acetone.Wherein react 6 hours, also comprise reaction 1 to 12 hour.
5. the synthetic method of dencichine as claimed in claim, is characterized in that: the synthetic method of described dencichine obtains: get 6.01g sodium hydroxide, be dissolved in 100mL water, be cooled to 0 degree, add 20gL-l-asparagine, stir after 30 minutes, add 200mL acetone and 31.4gK
2cO
3, keep temperature not higher than 5 degree, drip 39.6g tert-Butyl dicarbonate, rise to room temperature reaction after 24 hours, after adding 300mL water dissolution, after 0.5mol/LHCl regulates pH to 6-7, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 5), retain aqueous phase, after aqueous phase regulates pH to 3-4 with 0.5mol/LHCl, extraction (methylene dichloride: methyl alcohol, 4:1, 200mL × 10), anhydrous sodium sulfate drying, after being spin-dried for, obtain 33gBoc-L-l-asparagine, 33gBoc-L-l-asparagine is dissolved in 96mL ethyl acetate, 96mL acetonitrile, in the saturated citric acid of 1.0mL and 48mL water, after being cooled to 0 degree, add 33.3g iodobenzene diacetate in batches, rise to room temperature reaction 4 hours, solid is had to separate out, after reaction system is down to 0 degree, filter the solid of separating out in reaction, solid is spin-dried for, obtain 30gBoc-L-2, 3-diaminopropionic acid, 30gBoc-L-2, 3-diaminopropionic acid is dissolved in 200mL1, in 4-dioxane, after dissolving completely, after being cooled to 0 degree, slow dropping 20g oxalyl chloride, rise to room temperature reaction 5 hours, after the cancellation that adds water reaction, solid is had to separate out, filter, washing, dry, obtain crude product dencichine, after recrystallization, obtain 40g sterling dencichine.
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| CN201510511479.XA CN105061247A (en) | 2015-08-19 | 2015-08-19 | Improved synthesis method for dencichine |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439883A (en) * | 2015-12-11 | 2016-03-30 | 中国医学科学院药用植物研究所 | Preparation method and application of D-dencichine |
| CN109180532A (en) * | 2018-08-29 | 2019-01-11 | 南京天际联盟医药科技有限公司 | The high efficiency preparation method of D- dencichine |
| CN112125819A (en) * | 2020-08-19 | 2020-12-25 | 兰州百源基因技术有限公司 | Preparation method of sanchinin |
| CN113754551A (en) * | 2021-09-13 | 2021-12-07 | 云南西草资源开发有限公司 | Preparation method of hemostatic raw material sanchinin |
Citations (2)
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| CN1292377A (en) * | 2000-08-10 | 2001-04-25 | 昆明南国生物资源开发研究所 | Synthesis preparation method of high-effective hemostatic notoginseng extract |
| CN1292376A (en) * | 2000-08-10 | 2001-04-25 | 昆明南国生物资源开发研究所 | Synthesis method for preparing high-effective hemostatic notogiseng extract |
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2015
- 2015-08-19 CN CN201510511479.XA patent/CN105061247A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1292377A (en) * | 2000-08-10 | 2001-04-25 | 昆明南国生物资源开发研究所 | Synthesis preparation method of high-effective hemostatic notoginseng extract |
| CN1292376A (en) * | 2000-08-10 | 2001-04-25 | 昆明南国生物资源开发研究所 | Synthesis method for preparing high-effective hemostatic notogiseng extract |
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| LIN-HUA ZHANG ET AL.: "The Enantiospecific Synthesis of an Isoxazoline. A RGD Mimic Platelet GPIIb/IIIa Antagonist", 《J. ORG. CHEM.》 * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105439883A (en) * | 2015-12-11 | 2016-03-30 | 中国医学科学院药用植物研究所 | Preparation method and application of D-dencichine |
| CN109180532A (en) * | 2018-08-29 | 2019-01-11 | 南京天际联盟医药科技有限公司 | The high efficiency preparation method of D- dencichine |
| CN109180532B (en) * | 2018-08-29 | 2021-04-16 | 南京天际联盟医药科技有限公司 | High-efficiency preparation method of D-dencichine |
| CN112125819A (en) * | 2020-08-19 | 2020-12-25 | 兰州百源基因技术有限公司 | Preparation method of sanchinin |
| CN112125819B (en) * | 2020-08-19 | 2023-07-25 | 兰州百源基因技术有限公司 | Preparation method of dencichine |
| CN113754551A (en) * | 2021-09-13 | 2021-12-07 | 云南西草资源开发有限公司 | Preparation method of hemostatic raw material sanchinin |
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Address after: 710000 Shaanxi city of Xi'an province high tech Zone Jinye Road No. 69 C District No. 1 gazelle Valley F building 501 room Applicant after: Xi'an Yue biological Polytron Technologies Inc Address before: 710000 Shaanxi city of Xi'an province high tech Zone Jinye Road No. 69 C District No. 1 gazelle Valley F building 501 room Applicant before: Xi'an Day Natural Tech Co., Ltd. |
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