CN103086965A - Niacin p-acetylamino phenyl ester compound and synthesis method thereof - Google Patents
Niacin p-acetylamino phenyl ester compound and synthesis method thereof Download PDFInfo
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- CN103086965A CN103086965A CN2012105666560A CN201210566656A CN103086965A CN 103086965 A CN103086965 A CN 103086965A CN 2012105666560 A CN2012105666560 A CN 2012105666560A CN 201210566656 A CN201210566656 A CN 201210566656A CN 103086965 A CN103086965 A CN 103086965A
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- nicotinic acid
- acetylaminobenzene
- ester cpds
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- phenyl ester
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Abstract
The invention belongs to the technical field of medical synthesis, and in particular relates to a niacin p-acetylamino phenyl ester compound and a synthesis method thereof. The synthesis method of the niacin p-acetylamino phenyl ester compound comprises: based on niacin and p-acetylamino phenyl ester as raw materials, under the existence of a condensation agent DCC and the action of an organic amine catalyst, carrying out condensation reaction at normal temperature or by heating in an organic solvent free from reactive hydrogen. The synthesis method of the niacin p-acetylamino phenyl ester compound has the advantages of simple method, mild reaction condition, easiness and simplicity in operation, high productivity, easiness in the separation of by-products and the separation of substrate, good product quality, high yield and low cost, and is suitable for large-scale industrial production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, relate in particular to nicotinic acid acetylaminobenzene ester cpds and synthetic method thereof.
Background technology
Nicotinic acid acetparaminosalol phenyl ester is that integrated use prodrug principle of design and structure are spelled and the basic design of principle is synthesized collaborative prodrug, after it enters human body, can be hydrolyzed gradually by the esterase in small intestine, discharge free nicotinic acid and acamol, they can not only show physiologically active separately, also have synergy.Nicotinic acid belongs to vitamin B group.When consumption surpasses dosage as the VITAMIN effect, the effect of obvious adjusting blood fat can be arranged, it is a kind of lipid regulating agent that sure curative effect is arranged, but the therapeutic dose required due to nicotinic acid is larger, and easily produce flush, itch, induced ulcer disease, increase the weight of the side effects such as diabetes and gout, limited its clinical application.The effect of the little blood vessel of nicotinic acid skin expansion be due to its increase endogenous prostaglandin(PG) synthetic due to, acamol is PGSI exactly, can alleviate the flush that nicotinic acid causes, the symptoms such as itch; Have simultaneously slow releasing function, slowly decompose in vivo, drug effect is steady in a long-term, has solved the vasodilation speed that exists when nicotinic acid uses separately and has easily caused too soon the side-effect problem of angiorrhexis.In sum, nicotinic acid acetparaminosalol phenyl ester can be used as a kind of novel blood lipid-lowering medicine.
Along with the arrival of social population's aging, the disease ratios such as hypertension that caused by hyperlipidemia in the elderly's cardiovascular disorder just are being increases trend year by year, and people's life security in serious threat.Therefore, seek evident in efficacy, safe and reliable blood lipid-lowering medicine, be one of long-term and popular research topic of the world of medicine always.
About nicotinic acid acetylaminobenzene ester synthesis method, what see at present bibliographical information is to adopt chemical two step synthesis, and synthetic route is as follows:
Take nicotinic acid, sulfur oxychloride, acamol as raw material, first nicotinic acid and sulfur oxychloride are reacted under DMF catalysis and make nicotinic acid villaumite hydrochlorate, and then under cryosel bath condition, organic amine is made catalyzer, make crude product with the acamol reaction in acetone solvent, obtain product after ethyl alcohol recrystallization, yield 26.7%.There are the problems such as esterification yield is low, cryosel is bathed the operational condition harshness, production cost is high in this route.Simultaneously, sulfur oxychloride is faint yellow or pink liquid, and pungent odor is arranged, and is poisonous, and its steam can stimulate eyes and mucous membrane, makes tunica mucosa bronchiorum impaired, and operating environment will be very abominable, will produce suitability for industrialized production to hinder.
Summary of the invention
In order to solve above-mentioned technical problem, the purpose of this invention is to provide a kind of method for preparing nicotinic acid acetparaminosalol phenyl ester, the method is simple, reaction conditions is gentle, and is easy to operation, simultaneously, good product quality, yield is high, cost is low, is suitable for large-scale industrial production.
In order to realize above-mentioned purpose, the present invention has adopted following technical scheme:
The synthetic method of nicotinic acid acetylaminobenzene ester cpds, the method is take nicotinic acid, paracetamol as raw material, under condensing agent DCC exists, under the organic amine catalyst action in the organic solvent that does not contain reactive hydrogen under normal temperature or heating condensation reaction make, its chemical equation is as follows:
。
As preferably, the molar ratio of above-mentioned nicotinic acid and paracetamol, DCC is 1～1.4:1:1.
As preferably, above-mentioned organic solvent is one or more mixing in DMF, acetone, methylene dichloride, triethylamine, pyridine and DMSO.
As preferably, the consumption of above-mentioned organic solvent be the paracetamol quality 2-10 doubly.
As preferably, above-mentioned organic amine catalyzer is one or more mixing in 4-N.N-dimethylamino pyridine, triethylamine, DMA, toluoyl amine.
As preferably, above-mentioned catalyzer is 4-N.N-dimethylamino pyridine or DMA.
As preferably, above-mentioned the method also comprises treating process, the method for described refining employing ethyl alcohol recrystallization.
The present invention is owing to having adopted above-mentioned technical scheme, adopt single stage method to simplify synthetic route, method is simple, and reaction conditions is gentle, and is easy to operation, reactant and condensing agent reaction with same mole, productive rate is high, even there is a small amount of water also not affect the generation of acylate in system, by-product of dicyclohexylurea is both water insoluble, also be insoluble to organic solvent, be easy to separate; Simultaneously product nicotinic acid acetparaminosalol phenyl ester is water insoluble, and substrate separates than being easier to, and good product quality, yield is high, cost is low, is suitable for the method for large-scale industrial production.
Description of drawings
Fig. 1 is the nucleus magnetic hydrogen spectrum figure of the nicotinic acid acetparaminosalol phenyl ester for preparing of the present invention.
The infrared spectrum (KBr) of the nicotinic acid acetparaminosalol phenyl ester of Fig. 2 the present invention preparation.
Embodiment
Below with specific embodiment, technical scheme of the present invention is described, but protection scope of the present invention is not limited to this.
Molar ratio is nicotinic acid: paracetamol: DCC=1.1:1:1.
Under anhydrous condition, 2.25g nicotinic acid, 3.42gDCC, 1gDMAP, 2.5g paracetamol are added in there-necked flask, add appropriate anhydrous propanone dissolving under normal temperature condition, stirring reaction 3 h, filter, filtrate is poured in appropriate frozen water, separates out the crystal of white, filters, dry, get nicotinic acid acetparaminosalol phenyl ester (II) 3.48g, yield 82.08%, 145～146 ℃ of fusing points.
The nucleus magnetic hydrogen spectrum figure of nicotinic acid acetparaminosalol phenyl ester is listed in the table below 1 according to spectrogram with the chemical shiftsum correlation parameter referring to Fig. 1:
Table 1 nicotinic acid acetparaminosalol phenyl ester
1HNMR (CDCl
3) parameter
| Absorption peak | δ（ppm） | Little peak number | Number of hydrogen atoms |
| 1* | 1.40 | m | 6 |
| 2 | 2.18 | s | 3 |
| 3 | 7.18 | d | 2 |
| 4 | 7.49 | t | 1 |
| 5 | 7.59 | t | 2 |
| 6 | 7.77 | s | 1 |
| 7 | 8.46 | d | 1 |
| 8 | 8.86 | d | 1 |
| 9 | 9.38 | s | 1 |
*: this group hydrogen is the recrystallization solvent peak.
As known from Table 1: the position of each absorption peak is as follows:
HNMR: δ 2.1856(s, 3H ,-CH3), and 7.1818(d, 2 H, ArH), 7.5930 (d, 2 H, ArH), 7.4939 (t, 1H, PyC
5-H), 7.7681 (s, H ,-NHCOCH
3), 8.4605 (d, 1H, PyC
4-H), 8.8644 (d, 1H, PyC
6-H), 9.3846 (s, 1H, PyC
2-H), infer thus, conform to the target product structure.
The infrared spectrum (KBr) of nicotinic acid acetparaminosalol phenyl ester is referring to Fig. 2,3303 cm
-1The place is unsaturated carbon C-H stretching vibration absorption peak, 1667,1555,1505,1471 cm
-1One group of peak skeletal vibration absorption peak that is phenyl ring; 1728 cm
-1The place is the stretching vibration absorption peak of ester carbonyl group, 1285,1076cm
-1One group of peak stretching vibration absorption peak that is the ester carbon-oxygen bond; 3443,1667,1610,1422cm
-1The place is respectively N-H, the C=O of ethanamide, the stretching vibration absorption peak of N-H, C-N.
Claims (8)
1. nicotinic acid acetylaminobenzene ester cpds, it is characterized in that: this compound is take nicotinic acid, paracetamol as raw material, under condensing agent DCC exists, under the organic amine catalyst action in the organic solvent that does not contain reactive hydrogen normal temperature or the heating under condensation reaction make, its chemical equation is as follows:
2. the synthetic method of nicotinic acid acetylaminobenzene ester cpds, it is characterized in that: the method is take nicotinic acid, paracetamol as raw material, under condensing agent DCC exists, under the organic amine catalyst action in the organic solvent that does not contain reactive hydrogen normal temperature or the heating under condensation reaction make, its chemical equation is as follows:
3. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the molar ratio of nicotinic acid and paracetamol, DCC is 1～1.4:1:1.
4. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: organic solvent is one or more mixing in DMF, acetone, methylene dichloride, triethylamine, pyridine and DMSO.
5. the synthetic method of according to claim 2 or 4 described nicotinic acid acetylaminobenzene ester cpds is characterized in that: the consumption of organic solvent be the paracetamol quality 2-10 doubly.
6. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the organic amine catalyzer is one or more mixing in 4-N.N-dimethylamino pyridine, triethylamine, DMA, toluoyl amine.
7. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: catalyzer is 4-N.N-dimethylamino pyridine or DMA.
8. the synthetic method of nicotinic acid acetylaminobenzene ester cpds according to claim 2, it is characterized in that: the method also comprises treating process, the method for described refining employing ethyl alcohol recrystallization.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759800A (en) * | 2017-09-27 | 2018-03-06 | 金华职业技术学院 | A kind of nicotinic acid acetparaminosalol phenyl ester copper coordination polymer and preparation method thereof |
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| AT243263B (en) * | 1963-05-13 | 1965-11-10 | Lannacher Heilmittel | Process for the preparation of new esters of p-acetaminophenol |
| CN102227417A (en) * | 2008-09-29 | 2011-10-26 | 西特里斯药业公司 | Chromenone analogs as sirtuin modulators |
| WO2012137225A1 (en) * | 2011-04-08 | 2012-10-11 | Sphaera Pharma Pvt. Ltd | Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| AT243263B (en) * | 1963-05-13 | 1965-11-10 | Lannacher Heilmittel | Process for the preparation of new esters of p-acetaminophenol |
| CN102227417A (en) * | 2008-09-29 | 2011-10-26 | 西特里斯药业公司 | Chromenone analogs as sirtuin modulators |
| WO2012137225A1 (en) * | 2011-04-08 | 2012-10-11 | Sphaera Pharma Pvt. Ltd | Substituted methylformyl reagents and method of using same to modify physicochemical and/or pharmacokinetic properties of compounds |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107759800A (en) * | 2017-09-27 | 2018-03-06 | 金华职业技术学院 | A kind of nicotinic acid acetparaminosalol phenyl ester copper coordination polymer and preparation method thereof |
| CN107759800B (en) * | 2017-09-27 | 2020-09-29 | 金华职业技术学院 | Nicotinic acid p-acetaminophenyl ester copper coordination polymer and preparation method thereof |
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Application publication date: 20130508 |