CN107266475A - A kind of imidazolidine and thiazolopyridin hydrochloric acid salt compounds and preparation method thereof - Google Patents
A kind of imidazolidine and thiazolopyridin hydrochloric acid salt compounds and preparation method thereof Download PDFInfo
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- CN107266475A CN107266475A CN201710477086.0A CN201710477086A CN107266475A CN 107266475 A CN107266475 A CN 107266475A CN 201710477086 A CN201710477086 A CN 201710477086A CN 107266475 A CN107266475 A CN 107266475A
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- imidazolidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
- C07D513/14—Ortho-condensed systems
Abstract
The invention discloses a kind of imidazolidine and thiazolopyridin hydrochloric acid salt compounds and preparation method thereof, belong to technical field of medicine synthesis.Technical scheme main points are：A kind of imidazolidine with bioactivity and thiazolopyridin hydrochloric acid salt compounds, with following structure：
Description
Technical field
The invention belongs to technical field of medicine synthesis, and in particular to a kind of imidazolidine bithiophene with bioactivity is simultaneously
Pyridine hydrochloride class compound and preparation method thereof.
Background technology
Nitrogen-containing heterocycle compound is because it has good bioactivity and is given birth in the human health such as medicine and agricultural chemicals and agricultural
Played an important role in production.In recent years, effect of this kind of material in medicine and Agrochemicals is increasingly apparent, most of miscellaneous
The novel pesticide of ring class is to warm-blooded animal toxicity very little, and the toxicity to birds, fish is also very low, and this is the research and development of novel agrochemical medicine
There is provided extremely wide application prospect.Thienopyridinepyrimiderivatives class compound has sterilization, anti-filterability cause of disease well
The bioactivity such as body, anticonvulsion and weeding.Another classical medicine-prasugrel of thienopyridine, chemical entitled 2- [2- second
Acyloxy -6,7- dihydro-thiophene simultaneously [3,2-c] pyridine -5 (4H)-yl] -1- cyclopropyl -2- (2- fluorophenyls) ethyl ketone is by day
This Sankyo companies and the oral anti-diabetic agent thing of Eli Lilly companies of U.S. joint development, and it is beautiful with July 10 in 2009
Food and Drug Admistraton of state (FDA) approval listing.The medicine is mainly used in receiving the patient of angioplasty therapy, to reduce art
Thrombosis causes the risk of heart attack afterwards, and Antiplatelet therapy greatly reduces the Protein in Patients With Acute Coronary Syndrome heart
The incidence of flesh infarct.Prasugrel and interventional procedure use in conjunction treatment angiocardiopathy will also turn into a kind of medical science trend.
Imidazo thiophenes such as d, l- 2,3,4,6- tetrahydrochysenes -2- oxygen -1H- thienos [3,4-d] imidazoles -4- valeric acids are synthesis
The important intermediate of biotin.Therefore, there is weight very much to Thienopyridines and the research of imidazo thiophenes
Want meaning.
The content of the invention
Present invention solves the technical problem that there is provided it is a kind of operation is simple, raw material is cheap and easy to get, reaction efficiency compared with
The high and reproducible imidazolidine bithiophene with bioactivity and pyridine hydrochloride class compound and preparation method thereof.
The present invention is to solve above-mentioned technical problem to adopt the following technical scheme that, the imidazolidine bithiophene with bioactivity
And pyridine hydrochloride class compound, it is characterised in that with following structure：Wherein R is to formonitrile HCN benzene
Base, the tert-butyl group, phenyl, trifluoromethyl, rubigan or m-methoxyphenyl.
The preparation side of imidazolidine bithiophene of the present invention with bioactivity and pyridine hydrochloride class compound
Method, it is characterised in that concretely comprise the following steps：(1) under nitrogen protection, 4- carbonyl pyridines and di-tert-butyl dicarbonate are in triethanolamine
Under catalysis, 1-Boc-4- carbonyl pyridines are obtained using methanol as solvent；(2) 1-Boc-4- carbonyl pyridines and pyrrolidines are added to
In hexamethylene, using a hydration p-methyl benzenesulfonic acid or pyridine hydrobromide salt as catalyst, returned in Dean-Stark distillers
Room temperature, filtering reacting liquid are cooled to after stream reaction 5h, filtrate sequentially adds absolute methanol and simple substance after evaporating solvent hexamethylene
Sulphur, then in 0 DEG C of methanol solution added dissolved with cyanamide, is warmed to room temperature after adding, and methanol is steamed after reaction 5h, then through column chromatography
Separating-purifying is obtained(3) by compoundIt is added in solvent, adds acetyl bromide class compound, plus
Heat is to flowing back, and Boc- imidazolidines bithiophene and pyridine compounds and their is made in TLC monitoring raw material reactions completely, and wherein solvent is 1,
4- dioxane, toluene, N, N- dimethylformamides, n-butanol or dimethyl sulfoxide (DMSO), acetyl bromide class compound are to acetyl bromide
The bromo- 3,3- dimethyl -2- carbonyls-butane of base benzonitrile, 1-, acetyl bromide benzene, acetyl bromide fluoroform, to chlorobenzene acetyl
Bromide or meta-methoxy phenylacetyl bromide；(4) by the Boc- imidazolidines bithiophene of gained, simultaneously pyridine compounds and their is containing salt
Boc groups are sloughed in the methanol solution of acid and obtain imidazolidine bithiophene and pyridine hydrochloride class compound.
Simultaneously pyridine hydrochloride class compound is preparing tool to imidazolidine bithiophene of the present invention with bioactivity
There is the application in antiplatelet aggregative activity medicine.
The present invention has synthesized a series of imidazolidine bithiophenes with bioactivity and pyridine hydrochloric acid by new method
Salt compounds, operation is simple for course of reaction, and raw material is cheap and easy to get, and reaction efficiency is higher and repeated preferable, and biology is living
Property effect is obvious.
Embodiment
The above to the present invention is described in further details by the following examples, but this should not be interpreted as to this
The scope for inventing above-mentioned theme is only limitted to following embodiment, and all technologies realized based on the above of the present invention belong to this hair
Bright scope.
Embodiment 1
50g 4- carbonyl pyridines (compound 1) (0.5mol) are dissolved in 200mL methanol, under nitrogen protective condition, delayed
Slowly add 220g triethanolamines and 120g di-tert-butyl dicarbonates, add after 70 DEG C of back flow reaction 12h, revolving removes methanol, plus
It is extracted with ethyl acetate after entering a certain amount of water, steams organic phase solvent and obtain 1-Boc-4- carbonyl pyridines 82g.
Embodiment 2
In Dean-Stark distillers, 1-Boc-4- carbonyl pyridines 50g (0.25mol) is added hexamethylene 300mL
In, add the hydration p-methyl benzenesulfonic acid 0.5g of pyrrolidines 20g (0.275mol) and one (2.63mmol), temperature rising reflux reaction 5h
After be cooled to room temperature, filtering reacting liquid steams the solvent hexamethylene in filtrate, after resulting distillation product add it is anhydrous
In methanol 500mL, elemental sulfur 8g (0.25mol) is added, reaction temperature is set as 0 DEG C, is slowly added dropwise dissolved with cyanamide 10.5g
The methanol solution of (0.25mol), is warmed to room temperature after dripping, and steams solvent after reaction 5h, then purify and (wash through column chromatography for separation
De- agent：Petroleum ether：Ethyl acetate=1:2) 38g of compound 3 is obtained.
1H NMR(400MHz,CD3OD):δ 4.26 (s, 2H), 3.56 (t, J=5. 7Hz, 2H), 2.44- 2.40 (m,
2H),1.36(s,9H).MS(ESI)m/z:256.3(M+H+)。
Embodiment 3
In Dean-Stark distillers, 1-Boc-4- carbonyl pyridines 50g (0.25mol) is added hexamethylene 300mL
In, add cold after pyrrolidines 20g (0.275mol) and pyridine hydrobromide salt 0.42g (2.63mmol), temperature rising reflux reaction 5h
But to room temperature, filtering reacting liquid steams the solvent hexamethylene in filtrate, and the product after resulting distillation is added absolute methanol
In 500mL, elemental sulfur 8g (0.25mol) is added, reaction temperature is set as 0 DEG C, is slowly added dropwise dissolved with cyanamide 10.5g
The methanol solution of (0.25mol), is warmed to room temperature after dripping, and solvent is steamed after reaction 5h, then purify (elution through column chromatography for separation
Agent：Petroleum ether：Ethyl acetate=1:2) 35g of compound 3 is obtained.
1H NMR(400MHz,CD3OD):δ 4.26 (s, 2H), 3.56 (t, J=5.7H z, 2H), 2.44- 2.40 (m,
2H),1.36(s,9H).MS(ESI)m/z:256.3(M+H+)。
Embodiment 4
In reaction bulb, the 50g of compound 3 (0.2mol) is added, to acetyl bromide benzene acetonitrile 48g (0.22mol) and 1,
4- dioxane 500mL, under nitrogen protection, are heated to backflow, TLC monitoring raw material reactions are complete, are down to room temperature, are slowly added to one
Quantitative sodium bicarbonate solution, regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reactions liquid 3 times, is merged organic
Phase, is spin-dried for organic phase and purifies (eluant, eluent through column chromatography for separation again：Petroleum ether：Ethyl acetate=5:1) 32g of compound 4 is obtained.
1H NMR(400MHz,CDCl3):δ 7.89 (d, J=8.8Hz, 2H), 7.6 6- 7.64 (m, 3H), 4.54 (s,
2H), 3.86 (t, J=5.6Hz, 2H), 2. 79 (m, 2H), 1.49 (s, 9H) .MS (ESI) m/z:380.9(M+H+).
Embodiment 5
In reaction bulb, the 50g of compound 3 (0.2mol) is added, to acetyl bromide benzene acetonitrile 48g (0.22mol) and first
Benzene 500mL, under nitrogen protection, is heated to backflow, TLC monitoring raw material reactions are complete, are down to room temperature, are slowly added to a certain amount of carbon
Sour hydrogen sodium solution, regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reactions liquid 3 times, merges organic phase, be spin-dried for
Organic phase purifies (eluant, eluent through column chromatography for separation again：Petroleum ether：Ethyl acetate=5:1) 27g of compound 4 is obtained.
1H NMR(400MHz,CDCl3):δ 7.89 (d, J=8.8Hz, 2H), 7.6 6- 7.64 (m, 3H), 4.54 (s,
2H), 3.86 (t, J=5.6Hz, 2H), 2. 79 (m, 2H), 1.49 (s, 9H) .MS (ESI) m/z:380.9(M+H+).
Embodiment 6
In reaction bulb, the 50g of compound 3 (0.2mol) is added, to acetyl bromide benzene acetonitrile 48g (0.22mol) and two
Methyl sulfoxide 500mL, under nitrogen protection, is heated to backflow, TLC monitoring raw material reactions are complete, are down to room temperature, are slowly added to certain
The sodium bicarbonate solution of amount, regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reactions liquid 3 times, merges organic phase,
It is spin-dried for organic phase and purifies (eluant, eluent through column chromatography for separation again：Petroleum ether:Ethyl acetate=5:1) 24g of compound 4 is obtained.
1H NMR(400MHz,CDCl3):δ 7.89 (d, J=8.8Hz, 2H), 7.6 6- 7.64 (m, 3H), 4.54 (s,
2H), 3.86 (t, J=5.6Hz, 2H), 2. 79 (m, 2H), 1.49 (s, 9H) .MS (ESI) m/z:380.9(M+H+).
Embodiment 7
In reaction bulb, the 32g of compound 4 (0.085mol) is added in methanol 500mL, under the conditions of 0 DEG C, slow drop
Plus the methanol solution containing 4M hydrochloric acid, the reaction of reaction 2h, TLC monitoring raw material is warmed to room temperature after dripping completely, a part is steamed
Methanol, cooling crystallization, suction filtration reaction solution obtains crystal, and the 27g of compound 5 is obtained after filter cake drying.
1H NMR(400MHz,CD3OD):δ 8.52 (s, 1H), 8.00 (d, J=8.4Hz, 2H), 7.86 (d, J=
8.4Hz, 2H), 4.52 (s, 2H), 3.78 (t, J=6.0Hz, 2H), 3.29- 3.26 (m, 2H) .MS (ESI) m/z:281.2(M
+H+)。
Embodiment 8
In reaction bulb, the 50g of compound 3 (0.2mol), bromo- 3, the 3- dimethyl -2- carbonyls-butane 40g of 1- are added
(0.22mol) and Isosorbide-5-Nitrae-dioxane 500mL, under nitrogen protection, are heated to backflow, TLC monitoring raw material reactions are complete, are down to room
Temperature, is slowly added to a certain amount of sodium bicarbonate solution, and regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reaction liquid
3 times, merge organic phase, be spin-dried for organic phase and purify (eluant, eluent through column chromatography for separation again：Petroleum ether：Ethyl acetate=10:1) obtain
The 34g of compound 6.
1H NMR(400MHz,CDCl3)δ:7.02 (s, 1H), 4.49 (s, 2H), 3.81 (t, J=5.2Hz, 2H), 2.71
(t, J=5.2Hz, 2H), 1.48 (s, 9H), 1.33 (s, 9H) .MS (ESI) m/z:335.8(M+H+).
Embodiment 9
In reaction bulb, the 34g of compound 6 (0.1mol) is added in dichloromethane 200mL, under the conditions of 0 DEG C, slowly
The methanol solution containing 4M hydrochloric acid is added dropwise, the reaction of reaction 2h, TLC monitoring raw material is warmed to room temperature after dripping completely, one is steamed
Divide methanol, cooling crystallization, suction filtration reaction solution obtains crystal, the 25g of compound 7 is obtained after filter cake drying.
1H NMR(400MHz,CD3OD)δ:8.12 (s, 1H), 4.67 (s, 2H), 3.88 (t, J=6.0Hz, 2H), 3.41
(t, J=6.0Hz, 2H), 1.58 (s, 9H) .MS (ESI) m/z:236.1(M+H+).
Embodiment 10
In reaction bulb, the 50g of compound 3 (0.2mol), acetyl bromide benzene 43g (0.22mol) and n-butanol are added
500mL, under nitrogen protection, is heated to backflow, TLC monitoring raw material reactions are complete, are down to room temperature, are slowly added to a certain amount of carbonic acid
Hydrogen sodium solution, regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reactions liquid 3 times, merges organic phase, be spin-dried for organic
After phase (eluant, eluent is purified through column chromatography for separation：Petroleum ether：Ethyl acetate=10:1) 35g of compound 8 is obtained.
1H NMR(400MHz,CD3OD)δ:7.94 (s, 1H), 7.79 (d, J=7. 6Hz, 2H), 7.40 (t, J=
7.2Hz, 2H), 7.32- 7.28 (t, J=7.2Hz, 1H), 4.58 (s, 2H), 3.87 (t, J=6.0 Hz, 2H), 2.85-
2.82(m,2H),1.54(s,9H).MS(ESI)m/z:356.2(M+H+)。
Embodiment 11
In reaction bulb, the 35g of compound 8 (0.1mol) is added in methanol 200mL, under the conditions of 0 DEG C, is slowly added dropwise
Methanol solution containing 4M hydrochloric acid, is warmed to room temperature the reaction of reaction 2h, TLC monitoring raw material completely, steams a part of first after dripping
Alcohol, cooling crystallization, suction filtration reaction solution obtains crystal, and the 24g of compound 9 is obtained after filter cake drying.
1H NMR(400MHz,D2O)δ:8.19(s,1H),7.72- 7.66(m,2H),7.60-7.48(m,3H),4.56
(s, 2H), 3.81- 3.72 (t, J=5.6Hz, 2H), 3.29- 3.22 (t, J=6.0Hz, 2H) .MS (ESI) m/z:256.3(M
+H+)。
Embodiment 12
In reaction bulb, the 30g of compound 3 (0.12mol), acetyl bromide fluoroform 25g (0.13mol) and 1 are added,
4- dioxane 600mL, under nitrogen protection, are heated to backflow, TLC monitoring raw material reactions are complete, are down to room temperature, are slowly added to one
Quantitative sodium bicarbonate solution, regulation reaction solution pH is 7-8, then with ethyl acetate 800mL extractive reactions liquid 3 times, is merged organic
Phase, is spin-dried for after organic phase purifying (eluant, eluent through column chromatography for separation：Petroleum ether：Ethyl acetate=10:1) compound 10 is obtained
18g。
1H NMR(400MHz,CDCl3)δ:7.63 (s, 1H), 4.56 (s, 2H), 3.86 (t, J=5.6Hz, 2H),
2.79- 2.78(m,2H),1.48(s,9H)；MS(ESI)m/z:347.8(M+H+).
Embodiment 13
In reaction bulb, the 18g of compound 10 (0.05mol) is added in methanol 200mL, under the conditions of 0 DEG C, slow drop
Plus the methanol solution containing 4M hydrochloric acid, the reaction of reaction 2h, TLC monitoring raw material is warmed to room temperature after dripping completely, a part is steamed
Methanol, cooling crystallization, suction filtration reaction solution obtains crystal, and the 10g of compound 11 is obtained after filter cake drying.
1H NMR(400MHz,CD3OD)δ:8.16 (s, 1H), 3.95 (s, 2H), 3.25 (t, J=6.0Hz, 2H),
2.82- 2.79(m,2H).MS(ESI)m/z:248.2(M+H+)。
Embodiment 14
Platelet aggregation inhibitory activity is tested
From healthy male rabbit, random packet.If normal and ticlopidine control group, gastric infusion, dosage 30mg/
kg-1.Normal group gives the CMC-Na that equivalent mass concentration is 0.5%.2h after administration, is injected intraperitoneally 40mg/kg-1 penta
Barbital sodium (1mL/kg-1) is anaesthetized, collection rabbit hearts position blood, with the sodium citrate anti-freezing that mass concentration is 3.8%,
Platelet rich plasma (PRP) and platelet poor plasma (PPP) are prepared respectively, by adenosine diphosphate (ADP) (final concentration：1.5μmol/L-1)
Add with induced platelet aggregation, relative light transmission is detected at 37 DEG C 5 minutes, maximum effect during observation be used to calculate
The maximum platelet aggregation rate and inhibiting rate of induction.Inhibiting rate (%)=(aggregation of aggregation maximum-test group of control group is most
Big value)/control group aggregation maximum * 100%.
The technological thought of above example only to illustrate the invention, it is impossible to which protection scope of the present invention is limited with this, it is every
According to technological thought proposed by the present invention, any change done on the basis of technical scheme each falls within the scope of the present invention
Within.
Claims (2)
1. the preparation method of a kind of imidazolidine bithiophene and pyridine hydrochloride class compound, it is characterised in that the compound has
There is following structure：Wherein R is to formonitrile HCN phenyl, the tert-butyl group, phenyl, trifluoromethyl, rubigan
Or m-methoxyphenyl；
Described preparation method, is concretely comprised the following steps：
(1) under nitrogen protection, 4- carbonyl pyridines are used as solvent with di-tert-butyl dicarbonate under triethanolamine catalysis using methanol
Obtain 1-Boc-4- carbonyl pyridines；
(2) 1-Boc-4- carbonyl pyridines and pyrrolidines are added in hexamethylene, with a hydration p-methyl benzenesulfonic acid or pyridine hydrogen
Bromate is cooled to room temperature as catalyst in Dean-Stark distillers after back flow reaction 5h, filtering reacting liquid, filtrate is steamed
Send and absolute methanol and elemental sulfur are sequentially added after solvent hexamethylene, then in 0 DEG C of methanol solution added dissolved with cyanamide, add
After be warmed to room temperature, steam methanol after reaction 5h, then obtain through column chromatography for separation purificationWherein use eluant, eluent：Stone
Oily ether：Ethyl acetate=1:2；
(3) by compoundIt is added in solvent, adds acetyl bromide class compound, is heated to backflow, TLC monitoring
Raw material reaction is made Boc- imidazolidines bithiophene and pyridine compounds and their completely, wherein solvent be Isosorbide-5-Nitrae-dioxane, toluene,
DMF, n-butanol or dimethyl sulfoxide (DMSO), acetyl bromide class compound be to acetyl bromide benzonitrile, 1- bromo- 3,
3- dimethyl -2- carbonyls-butane, acetyl bromide benzene, acetyl bromide fluoroform, to chloro acetyl bromine or meta-methoxy benzene second
Acid bromide RCOBr；
(4) by the Boc- imidazolidines bithiophene of gained, simultaneously pyridine compounds and their sloughs Boc in the methanol solution containing hydrochloric acid
Group obtains imidazolidine bithiophene and pyridine hydrochloride class compound.
2. the imidazolidine bithiophene and pyridine hydrochloride class compound described in claim 1 are being prepared with platelet aggregation-against
Application in drugs with function.
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| US4244952A (en) * | 1978-09-28 | 1981-01-13 | Yoshitomi Pharmaceutical Industries, Ltd. | Imidazo[2',1':2,3]-thiazolo[5,4-c]pyridines and composition thereof for treating immune diseases |
| US20070093501A1 (en) * | 2003-12-17 | 2007-04-26 | Takeda Pharmaceutical Company Limited | Urea derivative, process for producing the same, and use |
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2015
- 2015-06-17 CN CN201510336201.3A patent/CN104926839B/en active Active
- 2015-06-17 CN CN201710477086.0A patent/CN107266475A/en active Pending
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| US4244952A (en) * | 1978-09-28 | 1981-01-13 | Yoshitomi Pharmaceutical Industries, Ltd. | Imidazo[2',1':2,3]-thiazolo[5,4-c]pyridines and composition thereof for treating immune diseases |
| US20070093501A1 (en) * | 2003-12-17 | 2007-04-26 | Takeda Pharmaceutical Company Limited | Urea derivative, process for producing the same, and use |
| FR2910895A1 (en) * | 2006-12-29 | 2008-07-04 | Biopharmed Sarl | New imino-tetrahydrobenzothiazole compounds, are Met-receptor inhibitors useful for preventing the migration of metastases or tumor cells |
| US20080207650A1 (en) * | 2007-01-11 | 2008-08-28 | Roger Victor Bonnert | Chemical Compounds 636 |
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| ALESSANDRO FURLAN ET AL.: ""Identification of new aminoacid amides containing the imidazo[2,1-b]benzothiazol-2-ylphenyl moiety as inhibitors of tumorigenesis by oncogenic Met signaling"", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
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Application publication date: 20171020 |