CN105348250A - Medicinal compound pepper acid hexamethylene diamine and preparation process thereof - Google Patents
Medicinal compound pepper acid hexamethylene diamine and preparation process thereof Download PDFInfo
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- CN105348250A CN105348250A CN201510715683.3A CN201510715683A CN105348250A CN 105348250 A CN105348250 A CN 105348250A CN 201510715683 A CN201510715683 A CN 201510715683A CN 105348250 A CN105348250 A CN 105348250A
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- hexamethylene diamine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The invention discloses a medicinal compound pepper acid hexamethylene diamine and a preparation process thereof. The pepper acid hexamethylene diamine has a chemical structural formula shown as below. The process comprises the following steps: (1) preparation of potassium piperate; (2) preparation of pepper acid; (3) preparation of ethyl piperate; and (4) preparation of pepper acid hexamethylene diamine. The invention has the following advantages: 1, piperic acid hexamethylene diamine is a semi-natural compound with significant hypolipidemic effect, and is a novel compound; the mice administration test proves that the pepper acid hexamethylene diamine has significant effect in reducing serum total cholesterol, triglyceride and the low density lipoprotein in animals with hyperlipemia; and no toxic reaction is found in the acute toxicity and cell experiments; 2, the pepper acid hexamethylene diamine as a substitute for statin drugs can create annual revenue of 2-5 billion U.S. dollars by just occupying 1/10 of the international market share, so as to achieve great economic benefits; and 3, the synthesis and production technology of pepper acid hexamethylene diamine have not been found home and abroad, and the invention is a pioneering innovation.
Description
Technical field
The present invention relates to a kind of compound and preparation technology thereof, particularly a kind of medicinal compound piperinic acid hexanediamine and preparation technology thereof.
Background technology
At present, cardiovascular and cerebrovascular disease have the advantages that sickness rate is high, disability rate is high, mortality ratio is high and recurrence rate is high.This kind of disease has become in the whole world " number one killer " of harm humans health.Annual 3000 ten thousand people in the whole world die from the relative disease that hyperlipidemia causes.China's hyperlipidemia related disorder patients number reaches 200,000,000.Epidemiology, experimental zoology and clinical study all show, atherosclerosis is the most important Hazard Factor of cardiovascular and cerebrovascular disease, Adjust-blood lipid can not only delay or alleviate the development of arteriosclerotic lesion, and the sickness rate of coronary heart disease and mortality ratio can be made obviously to reduce.Fat regulation medicine conventional in China market has kind more than 20, has certain curative effect.But be mostly import or imitation medicine, not rare obvious toxic side effect, can not meet the needs of clinical patients far away.Although lipid-lowering statins market is very large, play great role for curing hyperlipidaemia.But statins also has certain toxic side effect, as dysfunction of liver, thrombopenia, oligoleukocythemia etc.In addition, recently find that Simvastatin has carcinogenic clinical case, therefore, strong, that side reaction the is less lipid-regulation medicine of exploitation effect for reducing fat is development trend.Therefore, for improving China to the prevention of cardiovascular and cerebrovascular disease, treatment ability and Scientific research level, being engaged in the atherosclerotic kind new medicine of the control with independent intellectual property right, having become our the important of medical sci-tech worker and pursued a goal.Research and development can adjusting blood lipid, prevent and treat atherosclerotic new drug, meaning is very huge.
Summary of the invention
The object of the present invention is to provide one to have no side effect, reducing blood lipid significant medicinal compound piperinic acid hexanediamine and preparation technology thereof.
The technical solution used in the present invention is, this medicinal compound piperinic acid hexanediamine, and its chemical structural formula is as follows:
Chinese name: piperinic acid hexanediamine; English name: pepperacidhexamethylenediamine; Molecular weight: 316; Molecular formula: C
18h
24o
3n
2; Fusing point: 139.3 ~ 141.0 DEG C; Color: white; Shape: needle crystal.
The preparation technology of above-mentioned medicinal compound piperinic acid hexanediamine, comprise the following steps: the preparation of (1) GB-K: first 95% ethanol is poured in double-layer glass reaction kettle, add that KOH solid stirs and make it dissolve, and heat, again piperine solid is put into reactor, continue reflux 8 hours, after reaction terminates, reaction system is cooled 15 hours in room temperature, extract supernatant liquor out, use 95% ethanol purge again, make PH=7 ~ 8, extract supernatant liquor out, namely obtain piperinic acid sylvite, (2) preparation of piperinic acid: add deionized water and piperinic acid sylvite is dissolved, become brown color transparent liquid, the volume ratio dripping hydrochloric acid and water is above HCl: H
2the hydrochloric acid solution of O=1: 1, regulator solution PH=1 ~ 2, now separate out piperinic acid yellow solid, place precipitation, extract supernatant liquor out, again by washed with de-ionized water to PH=6 ~ 7, decompress filter, less than 100 DEG C dry 24 hours, (3) preparation of piperic acid ethyl ester: first dehydrated alcohol is poured in reactor, drip the vitriol oil under stirring state, opening makes it dispel the heat, then adds piperinic acid, installs prolong and thermometer, and reflux 8 hours, adds saturated Na while hot
2cO
3solution neutralization reactant, adds deionized water dissolving suspended substance, cooling, with distilled water cleaning, and decompress filter, 50 DEG C of oven dry, (4) preparation of piperinic acid hexanediamine: first dehydrated alcohol is poured in reactor, add under stirring state after catalyst metal sodium dissolves completely and add hexanediamine and piperic acid ethyl ester again, install prolong and thermometer, in nitrogen protection situation, raise temperature of reaction gradually to 65-70 DEG C, backflow is continued 48 hours with TLC tracking monitor, reaction terminates to occur white precipitate in rear solution, after reaction solution fully cools, suction filtration removing solid part, the filtrate obtained joins in distilled water, now there is a large amount of white precipitates in solution, stir suction filtration after 3 hours and retain solid part, crude product is obtained after drying, pure drying is washed with the mixed solvent of ethyl acetate and normal hexane 1: 1 volume ratio, then recrystallization purifying, obtain white solid, i.e. piperinic acid hexanediamine.
Owing to taking technique scheme, therefore the present invention has the following advantages: one is hypolipidemic activity material piperinic acid hexanediamine, being extracting and developing, the significant half-natural compound of reducing blood lipid that filters out from conventional anaesthetic material, is a kind of compound of new synthesis.The present invention is by Kunming strain small white mouse disorders of lipid metabolism medicine-feeding test, repeatedly confirm that piperinic acid hexanediamine all has remarkable reducing effect to hyperlipidemia animal serum total cholesterol, triglyceride and low-density lipoprotein, do not find any toxic reaction in anxious poison and cell experiment, can patent medicine be developed as.Two is a kind of blood lipid-lowering medicines with independent intellectual property right of China's shortcoming.Medicinal compound piperinic acid hexanediamine of the present invention, if in the future can substitute statins, enters international drug market, as long as occupy world market 1/10 share, every year can extra earning 20-50 hundred million dollars, and economic benefit is huge.Three is the synthesis technique and the production technology that also do not find piperinic acid hexanediamine both at home and abroad, and this is a ground-breaking innovation.The scale up test technique of synthesizing piperinic acid hexanediamine is determined, for production lipopenicillinase chemistry patent medicine is laid a good foundation by the orthogonal experiment of various condition and stability experiment.
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail.
Embodiment 1, this medicinal compound piperinic acid hexanediamine, its chemical structural formula is as follows:
Chinese name: piperinic acid hexanediamine; English name: pepperacidhexamethylenediamine; Molecular weight: 316; Molecular formula: C
18h
24o
3n
2; Fusing point: 139.3 ~ 141.0 DEG C; Color: white; Shape: needle crystal.
The preparation technology of above-mentioned medicinal compound piperinic acid hexanediamine, comprise the following steps: the preparation of (1) GB-K: first 95% ethanol is poured in double-layer glass reaction kettle, add that KOH solid stirs and make it dissolve, and heat, again piperine solid is put into reactor, continue reflux 8 hours, after reaction terminates, reaction system is cooled 15 hours in room temperature, extract supernatant liquor out, use 95% ethanol purge again, make PH=7 ~ 8, extract supernatant liquor out, namely obtain piperinic acid sylvite, (2) preparation of piperinic acid: add deionized water and piperinic acid sylvite is dissolved, become brown color transparent liquid, the volume ratio dripping hydrochloric acid and water is above HCl: H
2the hydrochloric acid solution of O=1: 1, regulator solution PH=1 ~ 2, now separate out piperinic acid yellow solid, place precipitation, extract supernatant liquor out, again by washed with de-ionized water to PH=6 ~ 7, decompress filter, less than 100 DEG C dry 24 hours, (3) preparation of piperic acid ethyl ester: first dehydrated alcohol is poured in reactor, drip the vitriol oil under stirring state, opening makes it dispel the heat, then adds piperinic acid, installs prolong and thermometer, and reflux 8 hours, adds saturated Na while hot
2cO
3solution neutralization reactant, adds deionized water dissolving suspended substance, cooling, with distilled water cleaning, and decompress filter, 50 DEG C of oven dry, (4) preparation of piperinic acid hexanediamine: first dehydrated alcohol is poured in reactor, add under stirring state after catalyst metal sodium dissolves completely and add hexanediamine and piperic acid ethyl ester again, install prolong and thermometer, in nitrogen protection situation, raise temperature of reaction gradually to 65-70 DEG C, backflow is continued 48 hours with TLC tracking monitor, reaction terminates to occur white precipitate in rear solution, after reaction solution fully cools, suction filtration removing solid part, the filtrate obtained joins in distilled water, now there is a large amount of white precipitates in solution, stir suction filtration after 3 hours and retain solid part, crude product is obtained after drying, pure drying is washed with the mixed solvent of ethyl acetate and normal hexane 1: 1 volume ratio, then recrystallization purifying, obtain white solid, i.e. piperinic acid hexanediamine.
Claims (2)
1. a medicinal compound piperinic acid hexanediamine, is characterized in that its chemical structural formula is as follows:
Chinese name: piperinic acid hexanediamine; English name: pepperacidhexamethylenediamine; Molecular weight: 316; Molecular formula: C
18h
24o
3n
2; Fusing point: 139.3 ~ 141.0 DEG C; Color: white; Shape: needle crystal.
2. the preparation technology of a medicinal compound piperinic acid hexanediamine as claimed in claim 1, it is characterized in that comprising the following steps: the preparation of (1) GB-K: first 95% ethanol is poured in double-layer glass reaction kettle, adding that KOH solid stirs makes it dissolve, and heat, again piperine solid is put into reactor, continue reflux 8 hours, after reaction terminates, reaction system is cooled 15 hours in room temperature, extract supernatant liquor out, use 95% ethanol purge again, make PH=7 ~ 8, extract supernatant liquor out, namely obtain piperinic acid sylvite, (2) preparation of piperinic acid: add deionized water and piperinic acid sylvite is dissolved, become brown color transparent liquid, the volume ratio dripping hydrochloric acid and water is above HCl: H
2the hydrochloric acid solution of O=1: 1, regulator solution PH=1 ~ 2, now separate out piperinic acid yellow solid, place precipitation, extract supernatant liquor out, again by washed with de-ionized water to PH=6 ~ 7, decompress filter, less than 100 DEG C dry 24 hours, (3) preparation of piperic acid ethyl ester: first dehydrated alcohol is poured in reactor, drip the vitriol oil under stirring state, opening makes it dispel the heat, then adds piperinic acid, installs prolong and thermometer, and reflux 8 hours, adds saturated Na while hot
2cO
3solution neutralization reactant, adds deionized water dissolving suspended substance, cooling, with distilled water cleaning, and decompress filter, 50 DEG C of oven dry, (4) preparation of piperinic acid hexanediamine: first dehydrated alcohol is poured in reactor, add under stirring state after catalyst metal sodium dissolves completely and add hexanediamine and piperic acid ethyl ester again, install prolong and thermometer, in nitrogen protection situation, raise temperature of reaction gradually to 65-70 DEG C, backflow is continued 48 hours with TLC tracking monitor, reaction terminates to occur white precipitate in rear solution, after reaction solution fully cools, suction filtration removing solid part, the filtrate obtained joins in distilled water, now there is a large amount of white precipitates in solution, stir suction filtration after 3 hours and retain solid part, crude product is obtained after drying, pure drying is washed with the mixed solvent of ethyl acetate and normal hexane 1: 1 volume ratio, then recrystallization purifying, obtain white solid, i.e. piperinic acid hexanediamine.
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| CN201510715683.3A CN105348250A (en) | 2015-10-20 | 2015-10-20 | Medicinal compound pepper acid hexamethylene diamine and preparation process thereof |
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| CN201510715683.3A CN105348250A (en) | 2015-10-20 | 2015-10-20 | Medicinal compound pepper acid hexamethylene diamine and preparation process thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432173A (en) * | 2016-09-26 | 2017-02-22 | 内蒙古大学 | New chemical synthesis galactophore breast cancer medicine piperinic acid potassium |
| CN109394761A (en) * | 2018-12-18 | 2019-03-01 | 青岛大学 | A kind of novel effect for reducing blood fat of piperine |
| WO2019168058A1 (en) * | 2018-02-28 | 2019-09-06 | 持田製薬株式会社 | Novel photocrosslinkable alginic acid derivative |
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| CN1795851A (en) * | 2004-12-03 | 2006-07-05 | 内蒙古大学 | Application of compound of esters of piperic acid in preparing hypolipidemic or health products |
| CN102283830A (en) * | 2011-08-12 | 2011-12-21 | 博日吉汗格日勒图 | Hypolipemic application of potassium piperonyl pentadienoate |
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| CN103936710A (en) * | 2013-01-18 | 2014-07-23 | 内蒙古大学 | N-substituted piperonylic pentadiene amide derivative, its preparation method and its application |
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2015
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106432173A (en) * | 2016-09-26 | 2017-02-22 | 内蒙古大学 | New chemical synthesis galactophore breast cancer medicine piperinic acid potassium |
| CN106432173B (en) * | 2016-09-26 | 2018-09-25 | 内蒙古大学 | A kind of breast cancer targeted drug potassium pepper of new chemical synthesis |
| WO2019168058A1 (en) * | 2018-02-28 | 2019-09-06 | 持田製薬株式会社 | Novel photocrosslinkable alginic acid derivative |
| CN111918881A (en) * | 2018-02-28 | 2020-11-10 | 持田制药株式会社 | Novel photocrosslinkable alginic acid derivative |
| JPWO2019168058A1 (en) * | 2018-02-28 | 2021-02-12 | 持田製薬株式会社 | New photocrosslinkable alginic acid derivative |
| CN111918881B (en) * | 2018-02-28 | 2022-08-12 | 持田制药株式会社 | Novel photocrosslinkable alginic acid derivative |
| US11472891B2 (en) | 2018-02-28 | 2022-10-18 | Mochida Pharmaceutical Co., Ltd. | Photocrosslinkable alginic acid derivative |
| JP7346380B2 (en) | 2018-02-28 | 2023-09-19 | 持田製薬株式会社 | Novel photocrosslinkable alginic acid derivative |
| CN109394761A (en) * | 2018-12-18 | 2019-03-01 | 青岛大学 | A kind of novel effect for reducing blood fat of piperine |
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Application publication date: 20160224 |