CN102627633A - New method for purifying elubiol - Google Patents
New method for purifying elubiol Download PDFInfo
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- CN102627633A CN102627633A CN2012100758937A CN201210075893A CN102627633A CN 102627633 A CN102627633 A CN 102627633A CN 2012100758937 A CN2012100758937 A CN 2012100758937A CN 201210075893 A CN201210075893 A CN 201210075893A CN 102627633 A CN102627633 A CN 102627633A
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- health azoles
- new health
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- elubiol
- water
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- 0 CCN=C(C1)CC1NCCOCC(CO)OCC(*C=CC=C([C@]1(C)*2C11)Cl)=C*21Cl Chemical compound CCN=C(C1)CC1NCCOCC(CO)OCC(*C=CC=C([C@]1(C)*2C11)Cl)=C*21Cl 0.000 description 2
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Abstract
The invention discloses a new method for purifying elubiol. 2-methyl-2-pentanone which is used in present elubiol recrystallization has a high price, is not economic, and is detrimental to the human health because ketone chemicals are residual in products. The method of the invention comprises the following steps: 1, dissolving crude elubiol with a mixed solution of water and a low chain alkyl alcohol at 50-85DEG C; and 2, decoloring by adding active carbon to the elubiol-dissolved mixed solution, filtering to remove carbon, crystallizing by cooling to a certain temperature, filtering again, and drying. According to obtained fine elubiol, the content is above 99.0%, the HPLC purity is above 99.5%, and the melting point is between 127.6DEG C and 130DEG C. The method of the invention has the advantages of conciseness, low cost, good stability of the purified elubiol, and total molar yield of the reaction of 89-91%.
Description
Technical field
The invention belongs to technical field of chemistry and chemical engineering, relate in particular to a kind of new health azoles New Method of Purification.
Background technology
New health azoles is the verivate of KETOKONAZOL (II), and chemistry is by name: cis-4-[4-[[2-(2,4 dichloro benzene base)-2-(1H-imidazoles-1-ylmethyl)-1,3-dioxolane-4-yl] methoxyl group] phenyl]-1-piperazine carboxylic acid ethyl ester (I), and structural formula is following:
New health azoles is the same with traditional imidazoles antimicrobial product KETOKONAZOL, is a kind of imidazoles New-type wide-spectrum antifungal products, can suppress the biosynthesizing of fungi ergosterol, and changes the composition of other lipoid substance of cytolemma.Candidiasis, Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis and coccidioides immitis etc. all there is antagonistic action; But compare with KETOKONAZOL; The latter can not be used for personal care articles, and new health azoles is water-soluble better than KETOKONAZOL, is fit to the personal care articles field use; Listed European personal care articles use range in, market outlook are boundless.
Synthesizing of new health azoles; In U.S. Pat 4335125, with suitable-[2-(2,4 dichloro benzene base)-2-(1H-imidazoles-1-ylmethyl)-1; 3-dioxolane-4-yl] methyl alcohol p-toluenesulfonic esters (III; The active ester pattern) be raw material, get with 4-(4-hydroxy phenyl)-1-piperazine carboxylic acid ethyl ester (IV) condensation, specific as follows:
In US4335125, new health azoles is with 2-methyl-2 pentanone recrystallization, and the new health azoles fusing point that obtains is 112.2 ℃
In world patent WO93/18743, new health azoles is synthetic to be to be starting raw material with the KETOKONAZOL, and after hydrolysis, acidylate, refining and commentaries on classics crystal formation obtains the new health azoles of I type, and is specific as follows:
Its purification is with 2-methyl-2 pentanone crystallization, and reaction is 84.9% with crystallization yield, and the back makes the transition to the I type with acetone, and the yield of transition is 82.1%, obtains the total recovery 69.7% of I type, 127.6 ℃ of the new health azoles fusing points of I type.
In WO93/18743, also mentioned the I type and the II type proterties of new health azoles, the DSC maximum peak of dystectic I type is at 127.6 ℃, and the DSC maximum peak of low-melting II type is at 110.9 ℃, the I type is more stable than II type, preferentially is used for the makeup that human body is used.
In above-mentioned two patents, recrystallization is all used 2-methyl-2 pentanone, and not only price is high, uneconomical, and the ketone chemical residues is disadvantageous to HUMAN HEALTH in product.
In Chinese patent prospectus CN101665490A; Mention and use re-crystallizing in ethyl acetate; Recrystallization yield 69.8%
84.5%; Use ETHYLE ACETATE organism recrystallization, but yield is not high, and does not mention the fusing point of product.
Summary of the invention
The objective of the invention is deficiency, a kind of new health azoles New Method of Purification is provided to prior art.
The technical solution adopted for the present invention to solve the technical problems step is following:
Step (1). the mixing solutions of water and low paraffinic hydrocarbons alcohol; Temperature be 50
85 ℃ of new health azoles bullions of dissolving down, in the mixing solutions ratio of water and low paraffinic hydrocarbons alcohol be 3/7
1/19;
Low paraffinic hydrocarbons alcohol in the described step (1) comprises methyl alcohol, ethanol, propyl alcohol, Virahol; The mixing solutions of described water and low paraffinic hydrocarbons alcohol and new health azoles bullion weight ratio be 10/1
2/1;
Step (2). in the mixing solutions that has dissolved new health azoles bullion; Add activated carbon decolorizing; After filtering de-carbon, be cooled to-5
15 ℃ of crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is more than 99.0%; HPLC purity is more than 99.5%, fusing point 127.6
between 130 ℃;
As preferably; The temperature of the new health azoles of the dissolving bullion described in the step (1) be 75
80 ℃; Low paraffinic hydrocarbons alcohol is ethanol; In the mixing solutions water and alcoholic acid ratio be 1/1
3/17, water and alcoholic acid mixing solutions and new health azoles bullion weight ratio be preferred 4/1
3/1;
As preferably, the Tc described in the step (2) be 0
5 ℃.
Preferred as further; Low paraffinic hydrocarbons alcohol described in the step (1) is ethanol, in the mixing solutions water and alcoholic acid ratio be 3/7
1/4.
Beneficial effect of the present invention is following:
With the present invention's new health azoles of purifying; The product purity that method is succinct, with low cost, the back of purifying obtains is more than 99.5%; Content is more than 99.0%; Fusing point 127.6-130 ℃, the good stability of products that obtains, and react total molar yield 89
91%.
Embodiment
Below in conjunction with embodiment the present invention is described further.
Embodiment 1
Step (1). water and alcoholic acid mixing solutions are 50 ℃ of new health azoles bullions of dissolving down in temperature, and water and alcoholic acid ratio are 3:7 in the mixing solutions,
Described water and alcoholic acid mixing solutions and new health azoles bullion weight ratio be 10:1;
Step (2). in the mixing solutions that has dissolved new health azoles bullion, add activated carbon decolorizing, behind the filtration de-carbon, be cooled to-5 ℃ of post crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is 99.3%; HPLC purity is 99.7%, fusing point 127.6
129 ℃.
Embodiment 2
Step (1). water and alcoholic acid mixing solutions are 75 ℃ of new health azoles bullions of dissolving down in temperature, and water and alcoholic acid ratio are 3:10 in the mixing solutions;
Described water and alcoholic acid mixing solutions and new health azoles bullion weight ratio be 7:2;
Step (2). in the mixing solutions that has dissolved new health azoles bullion, add activated carbon decolorizing, behind the filtration de-carbon, be cooled to 3 ℃ of post crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is 99.8%; HPLC purity is 99.9%, fusing point 128.5
130 ℃.
Embodiment 3
Step (1). water and alcoholic acid mixing solutions are 85 ℃ of new health azoles bullions of dissolving down in temperature, and water and alcoholic acid ratio are 1:19 in the mixing solutions;
Described water and alcoholic acid mixing solutions and new health azoles bullion weight ratio be 2:1;
Step (2). in the mixing solutions that has dissolved new health azoles bullion, add activated carbon decolorizing, behind the filtration de-carbon, be cooled to 5 ℃ of post crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is 99.1%; HPLC purity is 99.6%, fusing point 128
129 ℃.
Embodiment 4
Step (1). the mixing solutions of water and methyl alcohol is 85 ℃ of new health azoles bullions of dissolving down in temperature, and the ratio of water and methyl alcohol is 1:4 in the mixing solutions;
The mixing solutions of described water and methyl alcohol and new health azoles bullion weight ratio be 2:1;
Step (2). in the mixing solutions that has dissolved new health azoles bullion, add activated carbon decolorizing, behind the filtration de-carbon, be cooled to 15 ℃ of post crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is 99.1%; HPLC purity is 99.6%, fusing point 128
129 ℃.
Embodiment 5
Step (1). in reaction kettle, drop into 10% hydrochloric acid of 100KG KETOKONAZOL and 110KG, reacted 20 hours down, be cooled to room temperature at 85 ℃; The toluene that adds 400L then slowly adds 50% sodium hydroxide solution of 96.5KG again, separates out crystalline solid, and is centrifugal, with 40KG water washing filter also, dry, oven dry, the 92.1KG hydrolyzate, HPLC purity is more than 99.5%, yield 100%.
Step (2). the 92.1KG hydrolyzate that step (1) is obtained drops in the reaction kettle; Drop into 520KG methylene dichloride and 36KG salt of wormwood again, drip the 25KG Vinyl chloroformate under the room temperature, stirring reaction is 3 hours then; Add water 300KG; Organic phase is got in layering, and underpressure distillation is reclaimed methylene dichloride to doing De Xinkang azoles bullion.
Step (3). the new health azoles bullion that will obtain, add in the 400KG water-ethanol mixing solutions (weight ratio 25:75), be heated to 75 ℃ and dissolve clear; After adding the carbon filtration, cooling, crystallization; Filter, drain, oven dry; Get the new health azoles of 95.6KG, HPLC purity 99.6%, chemistry titration content 99.4%; 128.5 ℃ of fusing points 127.6
, total recovery 90.5%.
Claims (4)
1. new health azoles New Method of Purification is characterized in that, comprises the steps:
Step (1). the mixing solutions of water and low paraffinic hydrocarbons alcohol; Temperature be 50
85 ℃ of new health azoles bullions of dissolving down, in the mixing solutions ratio of water and low paraffinic hydrocarbons alcohol be 3/7
1/19;
Low paraffinic hydrocarbons alcohol in the described step (1) comprises methyl alcohol, ethanol, propyl alcohol, Virahol; The mixing solutions of described water and low paraffinic hydrocarbons alcohol and new health azoles bullion weight ratio be 1/10
2/1;
Step (2). in the mixing solutions that has dissolved new health azoles bullion; Add activated carbon decolorizing; After filtering de-carbon, be cooled to-5
15 ℃ of crystallizations; And then filter and drying; The new health azoles elaboration content that obtains is more than 99.0%; HPLC purity is more than 99.5%, fusing point 127.6
between 130 ℃.
2. new health azoles New Method of Purification according to claim 1; The temperature that it is characterized in that the new health azoles of the dissolving bullion described in the step (1) be 75
80 ℃; Low paraffinic hydrocarbons alcohol is ethanol; In the mixing solutions water and alcoholic acid ratio be 1/1
3/17;, water and alcoholic acid mixing solutions and new health azoles bullion weight ratio be preferred 4/1
3/1.
3. new health azoles New Method of Purification according to claim 1; It is characterized in that the low paraffinic hydrocarbons alcohol described in the step (1) is ethanol, in the mixing solutions water and alcoholic acid ratio be 3/7
1/4.
4. new health azoles New Method of Purification according to claim 1, it is characterized in that the Tc described in the step (2) be 0
5 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100758937A CN102627633A (en) | 2012-03-21 | 2012-03-21 | New method for purifying elubiol |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012100758937A CN102627633A (en) | 2012-03-21 | 2012-03-21 | New method for purifying elubiol |
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| CN2012100758937A Pending CN102627633A (en) | 2012-03-21 | 2012-03-21 | New method for purifying elubiol |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4144346A (en) * | 1977-01-31 | 1979-03-13 | Janssen Pharmaceutica N.V. | Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles |
| WO1993018743A1 (en) * | 1992-03-20 | 1993-09-30 | Janssen Pharmaceutica N.V. | Agent for regulating the greasiness of the skin |
| CN101665490A (en) * | 2008-09-01 | 2010-03-10 | 浙江东亚药业有限公司 | Method for preparing ketoconazole derivatives |
| CN102070620A (en) * | 2011-01-25 | 2011-05-25 | 南京白敬宇制药有限责任公司 | Preparation method of antibacterial ester |
-
2012
- 2012-03-21 CN CN2012100758937A patent/CN102627633A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4144346A (en) * | 1977-01-31 | 1979-03-13 | Janssen Pharmaceutica N.V. | Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles |
| WO1993018743A1 (en) * | 1992-03-20 | 1993-09-30 | Janssen Pharmaceutica N.V. | Agent for regulating the greasiness of the skin |
| CN101665490A (en) * | 2008-09-01 | 2010-03-10 | 浙江东亚药业有限公司 | Method for preparing ketoconazole derivatives |
| CN102070620A (en) * | 2011-01-25 | 2011-05-25 | 南京白敬宇制药有限责任公司 | Preparation method of antibacterial ester |
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Application publication date: 20120808 |