CN1951978A - Carbowax modifier of nicotinic acid and its synthesis method - Google Patents
Carbowax modifier of nicotinic acid and its synthesis method Download PDFInfo
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- CN1951978A CN1951978A CNA2006101171116A CN200610117111A CN1951978A CN 1951978 A CN1951978 A CN 1951978A CN A2006101171116 A CNA2006101171116 A CN A2006101171116A CN 200610117111 A CN200610117111 A CN 200610117111A CN 1951978 A CN1951978 A CN 1951978A
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Abstract
The invention discloses a carbowax decoration and synthesizing method of niacin in the drug intermediate and synthetic technical domain, which comprises the following steps: 1. reacting carbowax and niacin-chloroformyl to obtain rought product of niacin decorated by carbowax; 2. purifying the rough product; obtaining brown powder as refined product. The invention saves cost, which improves drug carrying quantity.
Description
Technical field
A kind of carbowax modifier of nicotinic acid and synthetic method thereof relate to pharmaceutical intermediate and synthesis technical field thereof, belong to chemistry and pharmaceutical chemistry synthetic technology.
Background of invention
Nicotinic acid is significant clinically small-molecule drug, need long term administration when being used for the treatment of rheumatism, gout chronic diseases, and the transformation period of nicotinic acid is shorter, and for keeping certain Plasma Concentration, the palpus frequent drug administration will cause tangible peak valley effect like this.Nicotinic acid acidity is stronger in addition, and during oral administration, often gi tract being produced stimulates.
Nontoxic, the no teratogenecity of polyoxyethylene glycol (PEG), non-immunogenicity, inexpensive, the source is abundant, has extraordinary water-soluble and biocompatibility, when coupling drug divides the period of the day from 11 p.m. to 1 a.m, its premium properties can be given the medicine after the modification, change its biology in the aqueous solution and distribute behavior and solvability.PEG produces the space barrier around the medicine of its modification, reduce the enzymolysis of medicine, avoids very fast elimination in renal metabolism, the prolong drug transformation period, and medicine can be discerned by immune system cell, help bringing into play drug effect.This field of macromole modified medicaments is a hot research in recent years.Nicotinic acid can prolong the nicotinic acid transformation period, increase solvability after modifying with PEG, helps absorption of human body; Alleviate its hormesis.
Though nicotinic acid had been had report with the research that PEG modifies, but can only synthesize monohydroxy polyoxyethylene glycol/nicotinic acid modifier and (see that thesis topic is " it is big monomeric synthetic to contain medicine end group PEG ", Shen Liangjun, Li Qinghai is published in Anhui Normal University's journal, 2002, the 154th ~ 153 page of the 25th phase).The synthetic method of the polyethyleneglycol modified nicotinic acid of this monohydroxy is that the monohydroxy polyoxyethylene glycol mixes with nicotinic acid, adopt dicyclohexylcarbodiimide (DCC) dehydration, with under the condition of Dimethylamino pyridine (DMAP) as catalyzer, synthesized monohydroxy polyoxyethylene glycol/nicotinic acid modifier.But raw material DCC in this method and DMAP are relatively more expensive, and cost is higher; And the productive rate of the middle monohydroxy polyoxyethylene glycol/nicotinic acid modifier of this method is very low, is 40%～50%.
Summary of the invention
The objective of the invention is to disclose the carbowax modifier of the nicotinic acid of a kind of pair of hydroxyl, another object of the present invention provides a kind of method of carbowax modifier of nicotinic acid of synthetic above-mentioned pair of hydroxyl, this method technology is simple, with low cost, and productive rate can reach 80 ~ 85%.
In order to achieve the above object, the synthetic carbowax modifier that has made nicotinic acid of the present invention with following two hydroxyl structures, its structural formula is as follows:
N represents 45～450 integer.
Soluble in water under the carbowax modifier room temperature of nicotinic acid of the present invention.Be dissolved in methylene dichloride, trichloromethane, tetrahydrofuran (THF), acetone, ethanol, N, most organic solvents such as dinethylformamide are insoluble to ether, and sherwood oil is the brown solid powder.
The carbowax modifier that obtains nicotinic acid of the present invention adopted for two steps finished: earlier with polyoxyethylene glycol and nicotinic acid-chlorine formylation thing reaction, make the raw product of the carbowax modifier of nicotinic acid.Purify the then raw product of carbowax modifier of nicotinic acid makes the highly finished product of the carbowax modifier of nicotinic acid.
Now describe concrete steps of the present invention in detail:
The preparation of the raw product of the carbowax modifier of the first step nicotinic acid
With the polyoxyethylene glycol is raw material, adds the highly finished product of nicotinic acid-chlorine formylation thing, adds solvent, adds triethylamine.Solvent is benzene, toluene.Earlier by polyoxyethylene glycol: the highly finished product of nicotinic acid-chlorine formylation thing: solvent: triethylamine=1: (0.06～0.2): (0.1～0.2): (2.5～4.5) weight ratio is measured; then under nitrogen atmosphere and magnetic agitation; refluxed 24 hours down in 60～80 ℃ of oil baths, make the raw product of the carbowax modifier of nicotinic acid.The structural formula of the carbowax modifier of nicotinic acid is
In the formula, n represents 45～450 integer;
The purification of the carbowax modifier raw product of the second step nicotinic acid
The raw product of the carbowax modifier of the nicotinic acid that the first step is made filters, and filtrate decompression boils off most of solvent, concentrated solution, with the anhydrous diethyl ether precipitation, with the benzene dissolving, placement is spent the night then; Repeat above-mentioned filtration, underpressure distillation, anhydrous diethyl ether post precipitation with ether washing three times, vacuum-drying makes the brown solid powder to constant weight, is the carbowax modifier highly finished product product of nicotinic acid.
The carbowax modifier water soluble of nicotinic acid of the present invention, ethanol, benzene, tetrahydrofuran (THF), toluene, chloroform, dichloromethane solvent are insoluble to ether, sherwood oil.
Raw material nicotinic acid in the aforesaid method-chlorine formylation thing needs synthetic voluntarily.Synthetic method is seen document (paper topic day synthesizing for the hypolipidemic nicomol.Lu Tao, Shi Xinzhong, Chen Jijun, Liu Youqiang.Chinese Journal of Pharmaceuticals Chinese Journal of Pharmaceutical 1997.28 (4): 154).Synthesis step is as follows:
A. nicotinic acid and thionyl chloride react, and make the raw product of nicotinic acid-chlorine formylation thing
Earlier by nicotinic acid: thionyl chloride=1～1.2: 1.7～2 weight ratios are measured, under magnetic agitation, slowly drip thionyl chloride then, dropwise, 70～90 ℃ of oil baths, reaction 1～6h, reaction has bubble to produce, no solid and when no longer including the bubble generation in the question response mixture, stopped reaction makes the raw product of nicotinic acid-chlorine formylation thing;
B. the purify raw product of nicotinic acid-chlorine formylation thing obtains highly finished product
The excessive thionyl chloride of elder generation's pressure reducing and steaming adds exsiccant benzene again, boils, and removes benzene under reduced pressure after cleaning with benzene again, behind the evaporate to dryness, gets white solid, is nicotinic acid-chlorine formylation thing highly finished product.
The solvent of the first step of the synthetic method of the carbowax modifier of described nicotinic acid is benzene or toluene.
Compare with background technology, beneficial effect of the present invention is:
1. raw material polyoxyethylene glycol among the present invention and thionyl chloride source is abundant, and cost is low.And the raw material monohydroxy polyoxyethylene glycol of background technology, DCC and DMAP cost height.
2. the raw material polyoxyethylene glycol among the present invention contains two hydroxyls, so each macromole is than the monohydroxy polyoxyethylene glycol drug loading height in the background technology.
3. because the present invention by activating nicotinic acid earlier, receives it on polyoxyethylene glycol, therefore compare with the synthetic route of background technology, synthetic route is simple, and the reaction times is short, the production efficiency height.
4. because the synthesis material that the present invention adopts is easy distillatory thionyl chloride, and used DMAP is difficult for distillation and removes in the background technology, and therefore to have the purification of products method simple for method of the present invention, is easy to the advantage of purifying.
5. product productive rate of the present invention is 80～85%, and the product productive rate of background technology is 40～50%, and productive rate improves 2 times and not only reduces cost, and the drug effect raising, takes also safer.
6. contain degradable ester bond in the carbowax modifier of nicotinic acid of the present invention, can reach slow release effect; Have amphipathicly, improved the water-soluble of nicotinic acid, be beneficial to absorption of human body, alleviate nicotinic acid tart hormesis.
Description of drawings
Fig. 1 is Fourier transform infrared spectroscopy (IR) figure of the carbowax modifier of nicotinic acid among the embodiment 1.
Fig. 2 be the carbowax modifier of nicotinic acid among the embodiment 1 nucleus magnetic resonance (
1H-NMR) figure.
Above-mentioned two figure illustrate that the synthetic product is the highly finished product of the carbowax modifier of nicotinic acid.
Embodiment
The preparation of the raw product of the carbowax modifier of the first step nicotinic acid
With the polyoxyethylene glycol is raw material, adds the highly finished product of nicotinic acid-chlorine formylation thing, adds solvent, adds triethylamine.Solvent is a benzene.The add-on of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is respectively 10.6g (2.4mmol), 1.43g, 30ml and 3.5ml.The weight ratio of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is 1: (0.06～0.2): (0.1～0.2): (2.5～4.5).Under nitrogen atmosphere and the magnetic agitation, 80 ℃ of oil baths refluxed 24 hours down, made the raw product of the carbowax modifier of nicotinic acid.The structural formula of the carbowax modifier of nicotinic acid is
In the formula, n represents 90;
The purification of the carbowax modifier raw product of the second step nicotinic acid
The product that the first step is made filters, filtrate decompression is boiled off most of solvent, get concentrated solution, precipitate with anhydrous diethyl ether, dissolve with benzene then, placement is spent the night, and repeats above-mentioned filtration, underpressure distillation, anhydrous diethyl ether precipitation, with ether washing three times, vacuum-drying is to constant weight, make the carbowax modifier highly finished product of nicotinic acid, product is brown solid powder 10.5g, productive rate 85%.
Above-mentioned solvent benzol can change toluene into.
The highly finished product of described nicotinic acid-chlorine formylation thing are pressed A, B two steps preparation,
A. nicotinic acid-chlorine formylation thing is synthetic
Get nicotinic acid 1.24g (10mmol), in the 50ml round-bottomed flask, add purified thionyl chloride 3ml (40mmol), under magnetic agitation, slowly drip, dropwise 70 ℃ of oil baths, reaction 1h, reaction has bubble to produce, no solid and when no longer including the bubble generation in the question response mixture, stopped reaction.
B. product is refining
The thionyl chloride that pressure reducing and steaming is excessive adds dry benzene, boils several minutes, removes benzene under reduced pressure, behind the evaporate to dryness, gets white solid, promptly gets nicotinic acid-chlorine formylation thing.
The preparation of the raw product of the carbowax modifier of the first step nicotinic acid
With the polyoxyethylene glycol is raw material, adds the highly finished product of nicotinic acid-chlorine formylation thing, adds solvent, adds triethylamine.Solvent is a benzene.The add-on of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is respectively 5.3g (2.4mmol), 1.78g, 30ml and 3.5ml.The weight ratio of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is 1: 0.33: 5.7: 0.66.Under nitrogen atmosphere and the magnetic agitation, 60 ℃ of oil baths refluxed 24 hours down, made the raw product of the carbowax modifier of nicotinic acid.The structural formula of the carbowax modifier of nicotinic acid is
In the formula, n represents 45;
The purification of the carbowax modifier raw product of the second step nicotinic acid
The product that the first step is made filters, filtrate decompression is boiled off most of solvent, get concentrated solution, precipitate with anhydrous diethyl ether, dissolve with benzene then, placement is spent the night, and repeats above-mentioned filtration, underpressure distillation, anhydrous diethyl ether precipitation, with ether washing three times, vacuum-drying is to constant weight, make the carbowax modifier highly finished product of nicotinic acid, product is brown solid powder 6.0g, productive rate 85%.
The highly finished product of described nicotinic acid-chlorine formylation thing are pressed embodiment 1 preparation.
Embodiment 3
The preparation of the raw product of the carbowax modifier of the first step nicotinic acid
With the polyoxyethylene glycol is raw material, adds the highly finished product of nicotinic acid-chlorine formylation thing, adds solvent, adds triethylamine.Solvent is a benzene.The add-on of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is respectively 14.8g (2.4mmol), 1.78g, 30ml and 3.5ml.The weight ratio of highly finished product, solvent and the triethylamine of polyoxyethylene glycol, nicotinic acid-chlorine formylation thing is 1: 0.12: 2.0: 0.24.Under nitrogen atmosphere and the magnetic agitation, 90 ℃ of oil baths refluxed 24 hours down, made the raw product of the carbowax modifier of nicotinic acid.The structural formula of the carbowax modifier of nicotinic acid is
In the formula, n represents 136;
The purification of the carbowax modifier raw product of the second step nicotinic acid
The product that the first step is made filters, filtrate decompression is boiled off most of solvent, get concentrated solution, precipitate with anhydrous diethyl ether, dissolve with benzene then, placement is spent the night, and repeats above-mentioned filtration, underpressure distillation, anhydrous diethyl ether precipitation, with ether washing three times, vacuum-drying is to constant weight, make the carbowax modifier highly finished product of nicotinic acid, product is brown solid powder 13.3g, productive rate 80%.
The highly finished product of described nicotinic acid-chlorine formylation thing are pressed embodiment 1 preparation.
When the synthetic product is used for the treatment of rheumatism, gout chronic diseases, can reduce administration number of times, reduce pungency stomach.
Claims (4)
1. the carbowax modifier of a nicotinic acid is characterized in that, this modifier has following structure,
N represents 45～450 integer.
2. the synthetic method of the carbowax modifier of the described nicotinic acid of claim 1 is characterized in that:
The preparation of the raw product of the carbowax modifier of the first step nicotinic acid
Earlier according to polyoxyethylene glycol: the highly finished product of nicotinic acid-chlorine formylation thing: solvent: triethylamine=1: 0.06～0.2: 0.1～0.2: 2.5～4.5 weight ratios are measured, add in the container successively then, under nitrogen atmosphere and magnetic agitation, refluxed 24 hours down in 60～80 ℃ of oil baths, make the raw product of the carbowax modifier of nicotinic acid;
The purification of the carbowax modifier raw product of the second step nicotinic acid
The raw product of the carbowax modifier of the nicotinic acid that the first step is made filters, and filtrate decompression boils off most of solvent, concentrated solution, with the anhydrous diethyl ether precipitation, with the benzene dissolving, placement is spent the night then; Repeat above-mentioned filtration, underpressure distillation, anhydrous diethyl ether post precipitation with ether washing three times, vacuum-drying makes the carbowax modifier highly finished product of nicotinic acid to constant weight, and product is the brown solid powder.
3. the synthetic method of the carbowax modifier of a kind of nicotinic acid according to claim 2 is characterized in that: the highly finished product of described nicotinic acid-chlorine formylation thing adopt following method synthetic:
A. earlier by nicotinic acid: thionyl chloride=1～1.2: 1.7～2 weight ratios are measured, under magnetic agitation, slowly drip thionyl chloride then, dropwise, 70～90 ℃ of oil baths, reaction 1～6h, reaction has bubble to produce, no solid and when no longer including the bubble generation in the question response mixture, stopped reaction makes the raw product of nicotinic acid-chlorine formylation thing;
B. the purify raw product of nicotinic acid-chlorine formylation thing: the thionyl chloride that first pressure reducing and steaming is excessive, add exsiccant benzene again, boil, remove benzene under reduced pressure after cleaning with benzene again, behind the evaporate to dryness, white solid, be nicotinic acid-chlorine formylation thing highly finished product.
4. the synthetic method of the carbowax modifier of a kind of nicotinic acid according to claim 2, it is characterized in that: described solvent is benzene or toluene.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101297974B (en) * | 2007-04-30 | 2010-09-29 | 周亚伟 | Pegylated glycosides of aerial parts of epimedium, and preparation and use thereof |
| CN101974150A (en) * | 2010-10-20 | 2011-02-16 | 华东师范大学 | Ibuprofen end group-containing polyethylene glycol medicine macromonomer and synthesis method thereof |
| CN105017519A (en) * | 2015-07-20 | 2015-11-04 | 湖南华腾制药有限公司 | Preparation method of polyethylene glycol-modified micromolecule drug |
| CN105017515A (en) * | 2015-07-20 | 2015-11-04 | 湖南华腾制药有限公司 | Preparation method of polyethylene glycol-modified material |
-
2006
- 2006-10-13 CN CNA2006101171116A patent/CN1951978A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101297974B (en) * | 2007-04-30 | 2010-09-29 | 周亚伟 | Pegylated glycosides of aerial parts of epimedium, and preparation and use thereof |
| CN101974150A (en) * | 2010-10-20 | 2011-02-16 | 华东师范大学 | Ibuprofen end group-containing polyethylene glycol medicine macromonomer and synthesis method thereof |
| CN105017519A (en) * | 2015-07-20 | 2015-11-04 | 湖南华腾制药有限公司 | Preparation method of polyethylene glycol-modified micromolecule drug |
| CN105017515A (en) * | 2015-07-20 | 2015-11-04 | 湖南华腾制药有限公司 | Preparation method of polyethylene glycol-modified material |
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