CN105461727A - Refining method of nalfurafine - Google Patents
Refining method of nalfurafine Download PDFInfo
- Publication number
- CN105461727A CN105461727A CN201510868150.9A CN201510868150A CN105461727A CN 105461727 A CN105461727 A CN 105461727A CN 201510868150 A CN201510868150 A CN 201510868150A CN 105461727 A CN105461727 A CN 105461727A
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- Prior art keywords
- furan
- coffee
- draws
- purification
- receiving
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Tea And Coffee (AREA)
Abstract
The invention discloses a refining method of nalfurafine. The refining method comprises the following steps: (1) putting a nalfurafine crude product into methanol, carrying out heating and backflow till the nalfurafine crude product is dissolved completely, filtering, adding concentrated hydrochloric acid to adjust the pH to be 1, separating nalfurafine hydrochloride, washing with petroleum ether, and drying; (2) dissolving dried nalfurafine hydrochloride into trichloro methane, adding a saturated sodium carbonate solution till the pH is 7, stirring uniformly, allowing the stirred mixture to stand still for crystallization, and carrying out filtering and drying to obtain a nalfurafine refined product. The refining method is simple, and high in product yield and purity; no amplified effect is generated after enlarged production, so that the refining method is particularly suitable for industrial production.
Description
Technical field
The present invention relates to a kind of process for purification, be specifically related to a kind of furan of receiving and draw the process for purification of coffee.Belong to medical art.
Background technology
Hydrochloric acid is received furan and is drawn coffee to be morphinan quaternary ammonium salt, its chemistry (2E)-N-[(5R by name, 6R)-17-(Cvclopropvlmethvl)-4,5-epoxy-3,14-dihydroxyl morphinan-6-base]-3-(3-furyl)-N-methyl-propen amide hydrochloride, structural formula is as follows:
Experimentation on animals shows that this compound has antipruritic effect, also has analgesic effect simultaneously.Therefore this compound is developed as the analgesic drug product of uraemic patients's itch medicine and treatment moderate and severe pain simultaneously.The itch indication of disease of its treatment hemodialysis patients is ratified.
Root it is documented, its base, and furan of namely receiving draws the process for purification of coffee to mainly contain recrystallization and column chromatography for separation two kinds.Disclose the refining furan of receiving of recrystallization method in patent application CN1111900A and draw coffee, be by the concentrated organic layer of drying, heating for dissolving in ethyl acetate 630mL, dissolves post-heating and heats up in a steamer 150mL, leave standstill and make its recrystallization.Patent application WO2010006119A1 discloses the refining furan of receiving of column chromatography and draws coffee, is utilize methylene dichloride: methyl alcohol=20:1 carries out silicagel column column chromatography.
As everyone knows, although the method purification effect of column chromatography is good, yield is low, the cycle is long, cost is high, and is unfavorable for suitability for industrialized production.The method purification effect of existing single solvent recrystallization is undesirable.
Summary of the invention
The object of the invention is for overcoming above-mentioned the deficiencies in the prior art, providing a kind of furan of receiving to draw the process for purification of coffee.
For achieving the above object, the present invention adopts following technical proposals:
Furan of receiving draws a process for purification for coffee, comprises step as follows:
(1) furan of receiving draws coffee crude product to add in methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with petroleum ether, dry;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, and after stirring, leave standstill crystallization, filtration drying, furan of must receiving draws coffee highly finished product.
Preferably, furan of receiving described in draws the mass volume ratio of coffee crude product and methyl alcohol to be 1g:10 ~ 15mL.
Further preferably, furan of receiving described in draws the mass volume ratio of coffee crude product and methyl alcohol to be 1g:12mL.
Preferably, furan of receiving described in draws the mass volume ratio of coffee crude product and sherwood oil to be 1g:5 ~ 8mL.
Further preferably, furan of receiving described in draws the mass volume ratio of coffee crude product and sherwood oil to be 1g:6mL.
Preferably, petroleum ether is utilized 2 ~ 3 times.
Preferably, the drying in step (1) is 50 ~ 60 DEG C of drying under reduced pressure.
Preferably, the drying in step (2) is vacuum-drying.
Beneficial effect of the present invention:
The present invention has abandoned conventional recrystallization method, first in methyl alcohol, adds concentrated hydrochloric acid acidifying, separates out hydrochloric acid and receives furan and draw coffee, eliminate the impurity that polarity is larger in this process; Hydrochloric acid is received furan and is drawn coffee with petroleum ether, eliminates the impurity that polarity is less; Then furan of being received by hydrochloric acid draws coffee to be reduced to base in trichloromethane, separates out to receive furan and draw coffee from trichloromethane, eliminates further and receives furan and draw the impurity that coffee Polarity comparision is close.The inventive method is simple, and the yield of product and purity high.Amplify after producing, without scale effect, be specially adapted to suitability for industrialized production.
Embodiment
Below in conjunction with embodiment, the present invention will be further elaborated, should be noted that following explanation is only to explain the present invention, not limiting its content.
The furan of receiving that the present invention relates to draws coffee crude product to be prepare according to the method for patent application CN1111900A reference example 5, and by the organic layer of acquisition with after saturated common salt water washing, namely the residue concentrating rear acquisition by dried over sodium sulfate is.
Embodiment 1:
A kind of furan of receiving of the present invention draws the process for purification of coffee, comprises step as follows:
(1) furan of being received by 1g draws coffee crude product to add in 10mL methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with 5mL petroleum ether 2 times, and 50 DEG C of drying under reduced pressure;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, after stirring, leave standstill crystallization, filter, vacuum-drying, furan of must receiving draws coffee highly finished product 0.95g, purity: 99.89%, and all lists are assorted is all less than 0.1%.
Embodiment 2:
A kind of furan of receiving of the present invention draws the process for purification of coffee, comprises step as follows:
(1) furan of being received by 10g draws coffee crude product to add in 150mL methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with 80mL petroleum ether 3 times, and 60 DEG C of drying under reduced pressure;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, after stirring, leave standstill crystallization, filter, vacuum-drying, furan of must receiving draws coffee highly finished product 9.6g, purity: 99.90%, and all lists are assorted is all less than 0.1%.
Embodiment 3:
A kind of furan of receiving of the present invention draws the process for purification of coffee, comprises step as follows:
(1) furan of being received by 100g draws coffee crude product to add in 1200mL methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with 600mL petroleum ether 2 times, and 55 DEG C of drying under reduced pressure;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, after stirring, leave standstill crystallization, filter, vacuum-drying, furan of must receiving draws coffee highly finished product 98g, purity: 99.86%, and all lists are assorted is all less than 0.1%.
Embodiment 4:
A kind of furan of receiving of the present invention draws the process for purification of coffee, comprises step as follows:
(1) furan of being received by 10kg draws coffee crude product to add in 100L methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with 60L petroleum ether 3 times, and 60 DEG C of drying under reduced pressure;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, after stirring, leave standstill crystallization, filter, vacuum-drying, furan of must receiving draws coffee highly finished product 9.88kg, purity: 99.89%, and all lists are assorted is all less than 0.1%.
Embodiment 5:
A kind of furan of receiving of the present invention draws the process for purification of coffee, comprises step as follows:
(1) furan of being received by 100kg draws coffee crude product to add in 1200L methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with 8L petroleum ether 2 times, and 50 DEG C of drying under reduced pressure;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, after stirring, leave standstill crystallization, filter, vacuum-drying, furan of must receiving draws coffee highly finished product 98.7kg, purity: 99.92%, and all lists are assorted is all less than 0.1%.
Embodiment 1 ~ 5 can be found out, process for purification yield of the present invention is more than 95%, and purity is not less than 99.8%, and does not have scale effect after amplifying production, is suitable for suitability for industrialized production.
Although above-mentioned, the specific embodiment of the present invention is described; but not limiting the scope of the invention; on the basis of technical scheme of the present invention, those skilled in the art do not need to pay various amendment or distortion that creative work can make still within protection scope of the present invention.
Claims (8)
1. furan of receiving draws a process for purification for coffee, it is characterized in that, comprises step as follows:
(1) furan of receiving draws coffee crude product to add in methyl alcohol, and reflux is all dissolved to it, filters, adds concentrated hydrochloric acid to pH=1, separates out hydrochloric acid and receives furan and draw coffee, with petroleum ether, dry;
(2) furan of being received by dried hydrochloric acid draws coffee to be dissolved in trichloromethane, adds saturated sodium carbonate solution to pH=7, and after stirring, leave standstill crystallization, filtration drying, furan of must receiving draws coffee highly finished product.
2. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, it is characterized in that, described in receive furan and draw the mass volume ratio of coffee crude product and methyl alcohol to be 1g:10 ~ 15mL.
3. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, it is characterized in that, described in receive furan and draw the mass volume ratio of coffee crude product and methyl alcohol to be 1g:12mL.
4. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, it is characterized in that, described in receive furan and draw the mass volume ratio of coffee crude product and sherwood oil to be 1g:5 ~ 8mL.
5. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, it is characterized in that, described in receive furan and draw the mass volume ratio of coffee crude product and sherwood oil to be 1g:6mL.
6. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, it is characterized in that, utilizes petroleum ether 2 ~ 3 times.
7. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, and it is characterized in that, the drying in step (1) is 50 ~ 60 DEG C of drying under reduced pressure.
8. a kind of furan of receiving according to claim 1 draws the process for purification of coffee, and it is characterized in that, the drying in step (2) is vacuum-drying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510868150.9A CN105461727A (en) | 2015-12-01 | 2015-12-01 | Refining method of nalfurafine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510868150.9A CN105461727A (en) | 2015-12-01 | 2015-12-01 | Refining method of nalfurafine |
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| Publication Number | Publication Date |
|---|---|
| CN105461727A true CN105461727A (en) | 2016-04-06 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510868150.9A Pending CN105461727A (en) | 2015-12-01 | 2015-12-01 | Refining method of nalfurafine |
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| CN (1) | CN105461727A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181109A (en) * | 2021-04-02 | 2022-10-14 | 南京正大天晴制药有限公司 | Crystal of morphinan derivative and method for producing same |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1111900A (en) * | 1993-06-30 | 1995-11-15 | 东丽株式会社 | Antitussive |
| CN101686976A (en) * | 2007-04-26 | 2010-03-31 | 东丽株式会社 | Stable solid preparation comprising 4,5-epoxymorphinan derivative |
| CN101848714A (en) * | 2007-10-05 | 2010-09-29 | 东丽株式会社 | Remedy for relieving skin troubles comprising morphinan derivative or pharmacologically acceptable acid addition salt thereof as the active ingredient |
| WO2011009020A2 (en) * | 2009-07-16 | 2011-01-20 | Mallinckrodt Inc. | Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers |
| CN102325775A (en) * | 2009-02-23 | 2012-01-18 | 马林克罗特公司 | (+)-6-hydroxyl-morphinan or (+)-6-amino-morphinan derivative |
-
2015
- 2015-12-01 CN CN201510868150.9A patent/CN105461727A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1111900A (en) * | 1993-06-30 | 1995-11-15 | 东丽株式会社 | Antitussive |
| CN101686976A (en) * | 2007-04-26 | 2010-03-31 | 东丽株式会社 | Stable solid preparation comprising 4,5-epoxymorphinan derivative |
| CN101848714A (en) * | 2007-10-05 | 2010-09-29 | 东丽株式会社 | Remedy for relieving skin troubles comprising morphinan derivative or pharmacologically acceptable acid addition salt thereof as the active ingredient |
| CN102325775A (en) * | 2009-02-23 | 2012-01-18 | 马林克罗特公司 | (+)-6-hydroxyl-morphinan or (+)-6-amino-morphinan derivative |
| WO2011009020A2 (en) * | 2009-07-16 | 2011-01-20 | Mallinckrodt Inc. | Compounds and compositions for use in phototherapy and in treatment of ocular neovascular disease and cancers |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181109A (en) * | 2021-04-02 | 2022-10-14 | 南京正大天晴制药有限公司 | Crystal of morphinan derivative and method for producing same |
| CN115181109B (en) * | 2021-04-02 | 2024-06-04 | 南京正大天晴制药有限公司 | Crystal of morphinan derivative and process for producing the same |
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Application publication date: 20160406 |