CN1048244C - Method for preparation of 4-hydroxy coumarin - Google Patents
Method for preparation of 4-hydroxy coumarin Download PDFInfo
- Publication number
- CN1048244C CN1048244C CN94104204A CN94104204A CN1048244C CN 1048244 C CN1048244 C CN 1048244C CN 94104204 A CN94104204 A CN 94104204A CN 94104204 A CN94104204 A CN 94104204A CN 1048244 C CN1048244 C CN 1048244C
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- China
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- reaction
- sodium methylate
- condensation reaction
- hydroxy coumarin
- condensing agent
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Abstract
The present invention relates to a preparation method of 4-hydroxyl coumarine, which comprises: cetylsalicylic acid methyl ester is used as a raw material, liquid paraffin is used as a carrier and sodium methoxide is used as a condensing agent for carrying out an intramolecular claisen condensation reaction to prepare 4-hydroxy-coumarin; the 4-hydroxy-coumarin is acidified for obtaining products. Compared with sodium metal used by a background technology, the present invention has the advantages of more safety and no affect of product yield and quality.
Description
That the present invention relates to is the preparation method of medicine, pesticide intermediate 4 hydroxy coumarin.
4 hydroxy coumarin (4-Hydroxycoumarin) is treatment cardiovascular disease medicine--the important intermediate of Syncumar, temparin, also be synthetic anti-coagulant rodenticide warfarin (Warfarin), the key intermediate of Coumatetralyl (Racumin), big grand (Talon), bromadiolone (Bromadilone).Its preparation method is a lot of, and (Zhang Zhi is auspicious, " agricultural chemicals ", 1～2 page of 1987 6 phase; Yang Zangxiong etc., " Taiwan science " 38 (1) 1～7 pages (1984), CA, 101,21093oh), the beginning of this century, Pouly and Loekemann propose to make 4 hydroxy coumarin with Methylrodin and sodium Metal 99.5 effect, but a lot (Ber.4828～43 (1915) of product impurity, CA, 7,1052), afterwards, Mark A, Stahmann etc. have carried out more perfect research, and Methylrodin is a condensing agent with the sodium Metal 99.5 in the presence of carrier liq paraffin, carry out intramolecularly claisen condensation reaction and get this product, 202～206 ℃ of mp, yield 22%, 212～214 ℃ of mp (JACS65 2285～2287 (1943)) behind the recrystallization.The full chapter of wood, Yang Yijing have carried out the optimization of processing condition on this basis, 180～200 ℃ of temperature of reaction, reaction times 120min are advisable, yield can reach 30～31% (" Acta Pharmaceutica Sinica " Vol 13 No.6 451～454 (1966)) according to reports, and Romania has realized suitability for industrialized production (CA509399) in 1954 with this method.Directly use sodium Metal 99.5 to make condensing agent, special is danger close in suitability for industrialized production, but pin has just fire hazard or blast accidentally.
The purpose of this invention is to provide a kind of condensing agent of safe and effective claisen condensation reaction, can make this reaction safety, successfully carry out.
The present invention proposes to replace sodium Metal 99.5 to make the condensing agent of condensation reaction with sodium methylate.Industrial methanol sodium is the methanol solution of sodium methylate, and its content is 27～31%, is by the reaction of anhydrous methanol and sodium hydroxide and get, has stable preferably.Preparation method of the present invention is: the methanol solution of whiteruss, sodium methylate is dropped in the reactor, stirring heating, still internal reaction fluid temperature raises gradually along with methyl alcohol is steamed then, sodium methylate is suspended in the whiteruss in the time of 160～260 ℃, along with splashing into the fused Methylrodin, the methyl alcohol that reaction produces is promptly steamed, and dropwises the back and continues reaction 1～5h.Its reaction formula:
Be cooled to and add entry below 100 ℃ with the fragrant plain sodium salt of dissolving 4-hydroxyl, and separate with the whiteruss layering back water layer through acidifying etc. handle faint yellow 4 hydroxy coumarin elaboration, 210～213 ℃ of mp, whiteruss can continue to do reaction carriers after treatment to be used, and does not influence the quality and quantity of this reactor product.The proportioning raw materials of reaction that the present invention participates in is: Methylrodin: sodium methylate: whiteruss=1mol: 0.5～1.0mol: 200～400ml, temperature of reaction is 160～260 ℃.
The present invention compares outstanding advantage with background technology comparatively gentle with character, and use the sodium methylate of going up safety as condensing agent, makes condensation reaction smooth.This has opened up the road of a safety for the fragrant element of suitability for industrialized production 4-hydroxyl.
Example
In the 10L metal reaction still of the filled column that the band still head is housed, agitator, dropping funnel, methanol solution 1260ml (the 1210g that successively adds 2400ml (2004g) whiteruss and industrial goods sodium methylate, about 6mol), stirring heating, along with steaming of methyl alcohol, reacting liquid temperature constantly raises, methyl alcohol almost steams to the greatest extent during to 200 ℃, stop heating, drip fused Methylrodin 1600g (8.25mol), constantly steam the methyl alcohol that reaction produces therebetween.Dropwise through 0.5h approximately, continue reaction 2h again, needing heating this moment is 200 ± 20 ℃ to keep the reaction solution temperature.Be cooled to below 100 ℃, add cold water 7L, stirring heating 0.5h, 60 ℃ of liquid temperature, divide water-yielding stratum, add 3.5L water again in still, stir 15min, layering, the water layer of telling merges with the last water layer of telling, and is total to 11.7L (11.7kg), and this is the 4 hydroxy coumarin sodium-salt aqueous solution.Add concentrated hydrochloric acid (about 40ml), regulate PH and reach 5～6, add gac 240g, be heated with stirring to 90 ℃, be chilled to room temperature again, elimination slag 670g, filtrate is acidified to PH with the concentrated hydrochloric acid of about 600ml and reaches 1～2, centrifuging, cold water washing gets the wet crude product 1077g of 4 hydroxy coumarin.Add water 30L and above-mentioned crude product in the 50L still, heated and stirred is to boiling, and filtered while hot is removed impurity, to separate out faint yellow crystallization when filtrate is cooled to room temperature, filter, washing, filter cake dry 4 hydroxy coumarin 273g (1.69mol), mp210～213 ℃, yield 20.5%.
Claims (4)
1, a kind of preparation method of 4 hydroxy coumarin, be to be raw material with the Methylrodin, with the whiteruss is carrier, under the condensing agent effect, carry out intramolecularly claisen condensation reaction and generate the 4 hydroxy coumarin sodium salt, carry out acidifying then and make 4 hydroxy coumarin, it is characterized by condensing agent is sodium methylate; The condensation reaction condition is: 160～260 ℃ of temperature of reaction; Reaction times 1～5h; The condensation reaction proportioning raw materials is:
Methylrodin: sodium methylate: whiteruss=1mol: 0.5～1.0mol: 200～400ml.
2, method as claimed in claim 1, it is characterized by used condensing agent sodium methylate is the methanol solution of sodium methylate, content is 27～31%.
3, method as claimed in claim 1 is characterized by the condensation reaction condition and is: 180～240 ℃ of temperature of reaction; Reaction times 1.5～2.0h.
4, method as claimed in claim 1, the processing sequence that it is characterized by condensation reaction is: the methanol solution of whiteruss and sodium methylate is added in the reactor, stirring heating, steam methyl alcohol, treat to drip when the still temperature reaches temperature of reaction the fused Methylrodin, the methyl alcohol that reaction produces is steamed simultaneously, adds the material back and continues reaction 2h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94104204A CN1048244C (en) | 1994-04-13 | 1994-04-13 | Method for preparation of 4-hydroxy coumarin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN94104204A CN1048244C (en) | 1994-04-13 | 1994-04-13 | Method for preparation of 4-hydroxy coumarin |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1101045A CN1101045A (en) | 1995-04-05 |
| CN1048244C true CN1048244C (en) | 2000-01-12 |
Family
ID=5031484
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94104204A Expired - Fee Related CN1048244C (en) | 1994-04-13 | 1994-04-13 | Method for preparation of 4-hydroxy coumarin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1048244C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101633867B (en) * | 2009-08-05 | 2011-12-28 | 成都大帝汉克生物科技有限公司 | Artificially prepared coumarin |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH026481A (en) * | 1988-06-24 | 1990-01-10 | Nippon Synthetic Chem Ind Co Ltd:The | Production of 4-hydroxycoumarin |
| JPH0236178A (en) * | 1988-07-22 | 1990-02-06 | Nippon Synthetic Chem Ind Co Ltd:The | Production of 4-hyroxycoumarin |
-
1994
- 1994-04-13 CN CN94104204A patent/CN1048244C/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH026481A (en) * | 1988-06-24 | 1990-01-10 | Nippon Synthetic Chem Ind Co Ltd:The | Production of 4-hydroxycoumarin |
| JPH0236178A (en) * | 1988-07-22 | 1990-02-06 | Nippon Synthetic Chem Ind Co Ltd:The | Production of 4-hyroxycoumarin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1101045A (en) | 1995-04-05 |
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