CN107879973A - A kind of process for purification of mannityl nicotinate - Google Patents
A kind of process for purification of mannityl nicotinate Download PDFInfo
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- CN107879973A CN107879973A CN201711096797.XA CN201711096797A CN107879973A CN 107879973 A CN107879973 A CN 107879973A CN 201711096797 A CN201711096797 A CN 201711096797A CN 107879973 A CN107879973 A CN 107879973A
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- mannityl
- nicotinate
- purification
- water
- ternary solvent
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of process for purification of mannityl nicotinate, comprises the following steps：Mannityl nicotinate crude product is added in ternary solvent system, temperature rising reflux to whole dissolvings, add activated carbon decolorizing, filtering, filtrate normal pressure concentration and evaporation, obtain mannityl nicotinate fine work.Present invention process process is simple, easily operated, refines high income up to more than 92%, and obtained finished product crystal formation is obvious, the problem of in the absence of chloride and exceeded solution color.
Description
Technical field
The present invention relates to a kind of process for purification of mannityl nicotinate, belongs to medicinal chemistry arts.
Background technology
Mannityl nicotinate also known as mannitol hexanicotinate, chemical name are six pyridine-3-carboxylic acid hexitol esters, and English name is
Mannityl Nicotinate, molecular formula C42H32N6O12, its structural formula is as follows：
。
Mannityl nicotinate is a kind of cardiovascular drugs, has expansion blood vessel and reduces blood fat, is clinically used for treatment hat
Worry, cerebral thrombus, atherosclerosis, hypertension, hyperlipemia.Mannityl nicotinate and similar drugs --- Inositol Nicotinate and
Sorbierite nicotinate compares, played faster than both other more facile hydrolysis, drug effect in vivo, and can also alleviate nicotinic acid in itself
The side effect such as Blushing and upset,gastro-intestinal caused by strong expandable peripheral action.As the world and Chinese aging phenomenon are more next
More serious, mannityl nicotinate belongs to antineoplastic, the angiocarpy of the elderly's demand the most as blood lipid-lowering medicine is efficiently depressured
Medicine, the similar drug category of slimming drugs three, market prospects are boundless.
The production technology of mannityl nicotinate be by nicotinic acid in the basic solvents such as pyridine, triethylamine with POCl3 or chlorination
Sulfoxide is reacted, then is reacted with mannitol to obtain mannityl nicotinate crude product, and crude product obtains sweet dew six by decolorizing and refining
Cigarette ester fine work.The existing process for purification of mannityl nicotinate is predominantly following two：Crude product dissolves in N,N-dimethylformamide,
Decolourize, filtering, filtrate decompression is concentrated to give product；Crude product dissolves under acid condition in purified water or alcohols solvent, decolourized, mistake
Filter, filtrate adds in alkali and precipitation obtains product.
Above two mannityl nicotinate process for purification has limitation：Refined, existed with DMF
Product solubility in the solvent is little, causes solvent load big, while high boiling DMF easily causes
Dissolvent residual is exceeded in product, and the solvent liver function of operating personnel, renal function are poisoned it is larger；Chinese patent
CN102964298A uses mannityl nicotinate crude product is water-soluble with sodium carbonate in purified water plus after dissolving with hydrochloric acid, decolouring, filtering
Refined in liquid with the technical scheme separated out, the process for refining avoids using DMF, but is prepared in crude product
During can be wrapped up in the product with neutralizing the salts substances such as caused chloride in Crystallization Process, the final mass detection of product
Chloride, solution color detection edge occurs, even transfinites and refined phenomenon of doing over again again, at the same exist product particle compared with
Carefully, material is tacky causes in centrifugation difficulty, centrifugal process the salt that the loss of mother liquor strip is larger, wraps up in the product to be difficult to wash
Only it is only 88% or so that it is relatively low, which, to refine yield,；Chinese patent CN103819399B is used mannityl nicotinate crude product in alcohols solvent
In plus sulfuric acid or hydrochloric acid or acetate dissolution, decolouring, filtering after carried out with sodium salt or piece alkali or ammoniacal liquor with the technical scheme of precipitation
Refined, the process for refining is equally that the principle separated out using foregoing sour solution-off color plus alkali is refined, the difference is that molten in acid adding
Solution preocess with the addition of alcohols solvent and need multiple subtractive process（It is not added with including a decolorizing and refining and three times carbon system）
Mannityl nicotinate product can be obtained.The technical scheme supervenes salts substances so as to lead during equally running into neutralization analysis of material
Its parcel is caused to be difficult to clean in the product, product chloride and solution chromogenic indicator check final product quality fluctuation caused by edge；Analysis
Going out product particle, tacky compared with thin and material to cause in the difficult, centrifugal process of centrifugation mother liquor strip to be lost larger；It is repeatedly refined to cause
Refined yield low only 73% or so.
For these reasons, it is necessary to exploitation is a kind of improve mannityl nicotinate purifying yield and improve product chloride and
The process for purification of solution color.
The content of the invention
The defects of purpose of the present invention is aiming at prior art, there is provided a kind of process for purification of mannityl nicotinate, specifically
Comprise the following steps：
Mannityl nicotinate crude product is added in ternary solvent system, temperature rising reflux to whole dissolvings, add activated carbon decolorizing, mistake
Filter, filtrate normal pressure concentration and evaporation, obtains mannityl nicotinate fine work.Wherein ternary solvent system is chloralkane/water/alcohol system, three
First dicyandiamide solution is made up of following components：70~85 volume % chloralkane, 5~10 volume % water and 10~25 volume %'s
Alcohol, in this case, the ratio selected in the scope must add up to 100 volume %.
Chloralkane is selected from dichloromethane or chloroform in ternary solvent system, and alcohol is selected from methanol, ethanol or isopropanol；
In one embodiment of the invention, it is molten in the ternary using dichloromethane, water and ethanol as ternary solvent system
Preferred usage rate is 75 in agent system：10：The dichloromethane of 15 parts by volume：Water：Ethanol.It will be appreciated, however, that using any
Suitable parts by volume ratio will realize identical effect.
Mannityl nicotinate crude product is added in methylene chloride/water/ethanol ternary solvent system, temperature rising reflux is molten to whole
Solution, activated carbon decolorizing, filtering are added, filtrate concentration and evaporation obtains mannityl nicotinate fine work, and ternary solvent system is comprising ratio
75：10：The dichloromethane of 15 parts by volume：Water：Ethanol.
In one embodiment of the invention, using dichloromethane, water and methanol as ternary solvent system, this three
Preferred usage rate is 80 in first dicyandiamide solution：5：The dichloromethane of 15 parts by volume：Water：Methanol.It will be appreciated, however, that use
Any suitable parts by volume ratio will realize identical effect.
Mannityl nicotinate crude product is added in methylene chloride/water/methanol ternary solvent system, temperature rising reflux is molten to whole
Solution, activated carbon decolorizing, filtering are added, filtrate concentration and evaporation obtains mannityl nicotinate fine work, and ternary solvent system is comprising ratio
80：5：The dichloromethane of 15 parts by volume：Water：Methanol.
In one embodiment of the invention, using chloroform, water and isopropanol as ternary solvent system, at this
Preferred usage rate is 80 in ternary solvent system：8：The chloroform of 12 parts by volume：Water：Isopropanol.It will be appreciated, however, that
Identical effect will be realized using any suitable parts by volume ratio.
Mannityl nicotinate crude product is added in chloroform/water/isopropanol ternary solvent system, temperature rising reflux is molten to whole
Solution, activated carbon decolorizing, filtering are added, filtrate concentration and evaporation obtains mannityl nicotinate fine work, and ternary solvent system is comprising ratio
80：8：The chloroform of 12 parts by volume：Water：Isopropanol.
Mannityl nicotinate crude product soluble,very slightly in the chloralkane including dichloromethane, chloroform etc., not soluble in water,
Methanol, ethanol, isopropanol etc., but in the in the mixed solvent of chloralkane and alcohol, and must in the case where adding water energy
Enough realize preferably is dissolved.If in experimenting, we find out that add water ratio it is too low, even if continue increase chloralkane and
The ratio of the dosage of alcohol, adjustment chloralkane and alcohol can not cause mannityl nicotinate dissolving crude product；But exceedingly increase water
Ratio, can equally suppress dissolving of the ternary solvent to mannityl nicotinate crude product.Therefore chloralkane in ternary solvent body, water and
The ratio of alcohol is critically important.
Compared with prior art, the present invention has advantages below：
1. present invention process process is simple, easily operated, solve that existing process for refining long-term existence yield is relatively low, chlorine of product
The problems such as compound and poor solution color, yield is refined up to more than 92%, chloride index checking is ＜ 10ppm, far below 100ppm
Limit standard, solution color check all it is qualified；
2. present invention process avoids using high boiling DMF, salt thing is not produced in addition in subtractive process
Matter, in the absence of product particle is separated out compared with thin and tacky material phenomenon, fine work is also just not present and centrifuges in difficult and centrifugal process
The problem of loss of mother liquor strip is larger；
3. the mannityl nicotinate fine work that present invention process obtains is substantially better than prior art in terms of product crystal formation and color and luster, existing
There is process for refining to obtain product, do not have for a long time or be barely perceivable crystal formation, the product crystal formation that present invention process obtains is bright
It is aobvious, it is white crystalline powder, the portion better than regulation white powder issues legal requirements.
Embodiment
The present invention is made of example below for example, these examples are intended to help the technological means for understanding the present invention.But
It should be understood that these embodiments are exemplary, the invention is not limited in this.
Embodiment one
By in the ternary solvent system of 100kg mannityl nicotinates crude product input 900L dichloromethane, 120L water and 180L ethanol, rise
The all dissolvings in 30 minutes of warm return stirring, add 5kg activated carbons, continue return stirring and decolourize 1 hour, filtering, and filtrate normal pressure is dense
Contracting, is evaporated to interior 80 DEG C of temperature, is cooled to less than 20 DEG C, and centrifugation, purifying is washed, dry 93kg mannityl nicotinate fine work, dry to contain
Amount 99.82%, chloride ＜ 10ppm, solution color are qualified.
Embodiment two
By in the ternary solvent system of 100kg mannityl nicotinates crude product input 1200L dichloromethane, 75L water and 225L methanol, rise
The all dissolvings in 1 hour of warm return stirring, add 5kg activated carbons, continue return stirring and decolourize 1.5 hours, filtering, and filtrate normal pressure is dense
Contracting, is evaporated to interior 65 DEG C of temperature, is cooled to less than 20 DEG C, centrifugation, purifying washing, dry 92.7kg mannityl nicotinate fine work, dry
Content 100.01%, chloride ＜ 10ppm, solution color are qualified.
Embodiment three
By the ternary solvent system of 100kg mannityl nicotinates crude product input 1000L chloroforms, 100L water and 150L isopropanols
In, temperature rising reflux stirs all dissolvings in 1 hour, adds 5kg activated carbons, continues return stirring and decolourizes 1 hour, filtering, and filtrate is normal
Concentration is pressed, is evaporated to interior 85 DEG C of temperature, is cooled to less than 20 DEG C, centrifugation, purifying is washed, dry that 92.5kg mannityl nicotinates are smart
Product, dry content 99.26%, chloride ＜ 10ppm, solution color are qualified.
Claims (8)
1. a kind of process for purification of mannityl nicotinate, it is characterised in that described process for purification comprises the following steps：
Mannityl nicotinate crude product is added in ternary solvent system, temperature rising reflux to whole dissolvings, add activated carbon decolorizing, mistake
Filter, filtrate normal pressure concentration and evaporation obtain mannityl nicotinate fine work, and wherein ternary solvent system is chloralkane/water/alcohol system, and three
First dicyandiamide solution is made up of following components：70~85 volume % chloralkane, 5~10 volume % water and 10~25 volume %'s
Alcohol, in this case, the ratio selected in the scope must add up to 100 volume %.
A kind of 2. process for purification of mannityl nicotinate according to claim 1, it is characterised in that：Kelene in ternary solvent system
Hydrocarbon is selected from dichloromethane or chloroform, and alcohol is selected from methanol, ethanol or isopropanol.
3. according to a kind of process for purification of mannityl nicotinate of claim 1 or 2, it is characterised in that：Described ternary solvent body
It is for methylene chloride/water/ethanol system.
4. according to a kind of process for purification of mannityl nicotinate of claim 1 or 2, it is characterised in that：Described ternary solvent body
It is for methylene chloride/water/methanol system.
5. according to a kind of process for purification of mannityl nicotinate of claim 1 or 2, it is characterised in that：Described ternary solvent body
It is for chloroform/water/Isopropanol Solvent.
A kind of 6. process for purification of mannityl nicotinate according to claim 3, it is characterised in that：Ternary solvent system includes ratio
For 75：10：The dichloromethane of 15 parts by volume：Water：Ethanol.
A kind of 7. process for purification of mannityl nicotinate according to claim 4, it is characterised in that：Ternary solvent system includes ratio
For 80：5：The dichloromethane of 15 parts by volume：Water：Methanol.
A kind of 8. process for purification of mannityl nicotinate according to claim 5, it is characterised in that：Ternary solvent system includes ratio
For 80：8：The chloroform of 12 parts by volume：Water：Isopropanol.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711096797.XA CN107879973A (en) | 2017-11-09 | 2017-11-09 | A kind of process for purification of mannityl nicotinate |
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| CN201711096797.XA CN107879973A (en) | 2017-11-09 | 2017-11-09 | A kind of process for purification of mannityl nicotinate |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438335A (en) * | 2018-12-22 | 2019-03-08 | 华中药业股份有限公司 | A kind of refining methd of Inositol Nicotinate |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6014M (en) * | 1966-09-22 | 1968-05-06 | ||
| CN1445216A (en) * | 2003-03-03 | 2003-10-01 | 中国科学院广州化学研究所 | Nicotinic acid ester of resveratrol and its synthetic method |
| CN102627601A (en) * | 2012-03-23 | 2012-08-08 | 天津中瑞药业有限公司 | Production technology of inositol nicotinate |
| CN102964298A (en) * | 2012-11-30 | 2013-03-13 | 华中药业股份有限公司 | Improved preparation method of mannityl nicotinate |
| CN103819399A (en) * | 2013-12-27 | 2014-05-28 | 青岛首和金海制药有限公司 | Method for producing high-purity mannityl nicotinate |
| CN105153025A (en) * | 2015-09-23 | 2015-12-16 | 潍坊盛瑜药业有限公司 | Inositol nicotinate polymorph A and preparing method thereof |
-
2017
- 2017-11-09 CN CN201711096797.XA patent/CN107879973A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR6014M (en) * | 1966-09-22 | 1968-05-06 | ||
| CN1445216A (en) * | 2003-03-03 | 2003-10-01 | 中国科学院广州化学研究所 | Nicotinic acid ester of resveratrol and its synthetic method |
| CN102627601A (en) * | 2012-03-23 | 2012-08-08 | 天津中瑞药业有限公司 | Production technology of inositol nicotinate |
| CN102964298A (en) * | 2012-11-30 | 2013-03-13 | 华中药业股份有限公司 | Improved preparation method of mannityl nicotinate |
| CN103819399A (en) * | 2013-12-27 | 2014-05-28 | 青岛首和金海制药有限公司 | Method for producing high-purity mannityl nicotinate |
| CN105153025A (en) * | 2015-09-23 | 2015-12-16 | 潍坊盛瑜药业有限公司 | Inositol nicotinate polymorph A and preparing method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109438335A (en) * | 2018-12-22 | 2019-03-08 | 华中药业股份有限公司 | A kind of refining methd of Inositol Nicotinate |
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