High-efficiency preparation method of D-dencichine
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A high-efficiency technology of notoginseng, applied in the field of high-efficiency preparation of D-notoginseng, can solve the problems of unfavorable scale-up production, excessive waste gas, poor solubility, etc.
Active Publication Date: 2019-01-11
南京天际联盟医药科技有限公司
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Embodiment 1
[0023] Embodiment 1: the synthesis of Boc-D-serine
[0024] Add 14L of water and 1.37kg of sodium hydroxide to a 50L reaction kettle. Under stirring, add 3kg of D-serine in batches. Add the reaction liquid, react at room temperature for 18 hours, cool down to 0°C, add concentrated hydrochloric acid dropwise, adjust the pH to 2-3.5, add 1.5kg of ethyl acetate for extraction three times, dry and spin to obtain 5kg of colorless oil.
Embodiment 2
[0025] Embodiment 2: the synthesis of Boc-D-serine
[0026] Add 14L of water and 5kg of potassium carbonate to a 50L reaction kettle, and add 3kg of D-serine in batches under stirring. The reaction solution was reacted at room temperature for 18 hours, cooled to 0 degrees, and saturated sodium bisulfate solution was added dropwise to adjust the pH to 2-3.5, and 1.5 kg of ethyl acetate was added to extract three times, dried and then spin-dried to obtain 4 kg of yellow oil.
Embodiment 3
[0027] Embodiment 3: the synthesis of Boc-D-serine mesylate
[0028] In a 10L three-neck flask, add 1kg Boc-D-serine and 5L dichloromethane and stir to dissolve, add 0.6kg triethylamine, cool down to 0 degrees, add 1.12kg methanesulfonyl chloride dropwise, after the dropwise addition, react at room temperature for 8 hours, After the reaction was completed, add 500ml of water to wash, 500ml of saturated sodium bisulfate solution, and 500ml of saturated sodium chloride solution. The organic layer was collected, dried, and spin-dried to obtain 1.13kg of yellow oil.
[0029] Embodiment 3: the synthesis of Boc-D-serine mesylate
[0030] In a 10L three-neck flask, add 1kg Boc-D-serine and 5L tetrahydrofuran and stir to dissolve, add 0.6kg sodium bicarbonate, and add 1.12kg methanesulfonyl chloride dropwise. After the addition is completed, react at room temperature for 8 hours. After the reaction is completed, spin Dry, add 1.5L dichloromethane to the residue, cool to 0-5°C, add 50...
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Abstract
The invention relates to a high-efficiency synthesis method of a hemostasis compound D-dencichine, comprising the following steps: firstly enabling D-serine to react with di-tert-butyl dicarbonate ester to generate Boc-D-serine, then generating Gabriel reaction with hydroxy of methylsulfonyl chloride activated Boc-D--serine to obtain N-alpha-Boc-D-alpha, beta-diaminopro, finally condensing with oxalate mono-methyl ester sylvite then performing hydrolytic acidification to obtain a dencichine crude product, and purifying to obtain a dencichine competitive product, with the product content reaching more than 99.8%. Compared with existing D-dencichine synthesis methods, the reaction condition is more mild, the operation is simple and convenient, the material cost is relatively low, and the hemostasis compound D-dencichine is environment-friendly, is suitable for industrial production, and solves the problem of resource for later development of clinical trial of D-dencichine.
Description
technical field [0001] The invention is a high-efficiency preparation method of the hemostatic compound D-notoginsin (ie β-N-diacetyl-D-α, β-diaminopropionic acid). Background technique [0002] Panax notoginseng, also known as Tianqi, belongs to the dry root of Panax notoginseng belonging to the genus Panax notoginseng of Araliaceae. It is used for hemoptysis, hematemesis, epistaxis, blood in the stool, metrorrhagia, traumatic bleeding, tingling pain in the chest and abdomen, and swelling and pain from tumbling. "Compendium of Materia Medica" records: Hemostasis, dispersing blood and relieving pain, for golden blade arrow wounds, falling stick sores, and bleeding, chew and apply it, or mix it at the end, the blood will stop immediately, mainly vomiting blood, epistaxis, and bleeding Bloody dysentery, metrorrhagia, persistent menstrual flow, postpartum hemorrhage, pain in blood circulation, red eyes and carbuncle, tiger bites and snake bites. "Compendium of Materia Medica S...
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