CN104774197B - A kind of preparation method of benzimidizole derivatives - Google Patents
A kind of preparation method of benzimidizole derivatives Download PDFInfo
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- CN104774197B CN104774197B CN201410011205.XA CN201410011205A CN104774197B CN 104774197 B CN104774197 B CN 104774197B CN 201410011205 A CN201410011205 A CN 201410011205A CN 104774197 B CN104774197 B CN 104774197B
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Abstract
The present invention relates to the preparation method technical field of compound, more particularly to a kind of preparation method of the medical compounds for hypertension therapeutic, the compound belongs to benzimidizole derivatives, and specially Azilsartan is shown in specification formula into the substitution product after ester, its structural formula（4）.Effect experiment result shows that the bioavilability and activity of the compound will be higher than Azilsartan.The present invention reacts five yuan of furazan ring intermediates of generation with natrium nitrosum, then be condensed the formula of preparing in the basic conditions with Azilsartan using cinnamyl alcohol as initiation material under conditions of acetic acid makees solvent（4）Compound, reaction condition is gently easy to operate, can obtain the product of high-purity, and HPLC purity is more than 97%.
Description
Technical field
The present invention relates to the preparation method technical field of compound, and in particular to a kind of hypertension therapeutic medical compounds
Preparation method, the compound belong to benzimidizole derivatives.
Background technology
The exploitation of angiotonin II receptor agonist hypotensor starts from the seventies in last century, first of such product
Marketed drug be 1994 come out the Losartan Potassium developed cooperatively by Dupont＆Merck companies, from the medicine Sweden list with
Coming, sartans are quickly grown, and up to the present have Valsartan in succession, candesartan Cilexetil, Irbesartan, eprosartan, he
8 single preparationss of ephedrine such as Suo Shatan, Telmisartan and olmesartan medoxomil and 4 compound preparations are approved by the FDA in the United States listing.
Azilsartan is the angiotensin II receptor antagonist medicine of a treatment vascular hypertension being in research and development
Thing, it is used for treating vascular hypertension, and the currently the only angiotensin II receptor antagonist (Sha Tan in late-stage clinical
Class) medicine.As the Azilsartan (azilsartan medoxomil, INN, code TAK-491) of pro-drug, 2010
April 28, the medicine that Japanese Takeda Pharmaceutical Company Limited (Takeda) is researched and developed complete phase iii clinical trial, obtained within 2011 beautiful
State FDA ratifies, and the medicine is a kind of angiotensin II receptor antagonist, be can be used alone or together with other blood-pressure drugs
Use, be considered the next-generation of candesartan Cilexetil.
Code name is that QR01009 compound (being hereinafter described as " formula (4) compound ") is that auspicious medicine is opened in applicant Wuhan
The improved Azilsartan esters compound of industry Co., Ltd, is documented in entitled " benzimidizole derivatives and its system first
In the Chinese patent application 201210367692.4 (applying date be 2012 on September 28) of Preparation Method and medical usage ", this application
Because later application requires its domestic priority and deemed withdrawal, later application for it is entitled " benzimidizole derivatives and its
The Chinese patent application 201310042669.2 (applying date is on 2 4th, 2013) of preparation method and medical usage ", its biology
Availability and activity will be higher than Azilsartan, and its chemical constitution is as follows：
The content of the invention
In order to fill up in the prior art for the preparation method blank of formula (4) compound, it is an object of the invention to provide one
Brief, the easy to operate method of kind route carrys out formula (4) compound.
Realize that the technical scheme of the object of the invention is as follows：
A kind of preparation method of formula (4) compound,
Comprise the following steps：
The first step, cinnamyl alcohol and natrium nitrosum react five yuan of furazan rings of generation under conditions of acetic acid makees solvent, and formula is made
(2) compound；
Second step, formula (2) compound and Azilsartan (formula (3) compound) DMAP (DMAP) be catalyzed,
Reacted under paratoluensulfonyl chloride and alkali existence condition, be condensed formula (4) compound.
Wherein, second step reaction alkali used is selected from potassium carbonate, cesium carbonate, triethylamine, pyridine, sodium acid carbonate, diisopropyl
Any one in base ethamine, preferably triethylamine.
Wherein, the reaction temperature of second step reaction is 25-100 DEG C, preferably 25-35 DEG C.
Wherein, the solvent of second step reaction is selected from dichloromethane, tetrahydrofuran, DMF, acetonitrile, chlorine
Any one in imitative, acetone, carbon tetrachloride, ethyl acetate, preferably dichloromethane.
Compared with prior art, it is the advantages of the inventive method with beneficial effect：
Using cinnamyl alcohol as initiation material, synthesized under conditions of acetic acid makees solvent with natrium nitrosum among five yuan of furazan rings
Body, then it is condensed formula (4) compound in the basic conditions with Azilsartan, reaction condition is gently easy to operate, can obtain height
The product of purity, HPLC measure product purity more than 97%.
Embodiment
Applicant will be described in further detail to the inventive method in conjunction with specific embodiments below.
Chemical reagent used is conventional reagent in following examples, wherein, formula (3) compound is Azilsartan, is purchased from
Shanghai Han Jing Chemical Co., Ltd.s, technical grade, purity>95%.
Formula (2), (3), the structural formula of (4) compound are shown in the record of Summary.
Embodiment 1：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound
10.0g cinnamyl alcohols and 10ml glacial acetic acid are added into 50ml there-necked flasks, 0 DEG C is cooled to after stirring and dissolving, will
15.50g (3eq) natrium nitrosum is dissolved in wiring solution-forming in 20g water, and the water-soluble of natrium nitrosum is added dropwise between 0 DEG C to 5 DEG C in temperature control
Liquid, it is added dropwise, after 0 DEG C of stirring 5min, is warming up to room temperature reaction 12h.Stop reaction, add 50ml water, ethyl acetate extraction
(40ml*2), merges organic phase, and saturated common salt is washed once, anhydrous sodium sulfate drying, is spin-dried for, obtains 20.0g crude products；Crude product is used
40ml acetonitriles dissolve, and add 10.0g acidic aluminas, and 60 DEG C are stirred at reflux reaction 3h, and solvent is spin-dried for, solid 100ml acetic acid
Ethyl ester is dissolved, and filters, and solid is washed (50ml*2) with ethyl acetate, and it is 8- that filtrate is washed till pH value with dilute sodium hydroxide (5%-10%)
9, liquid separation, aqueous phase is extracted with ethyl acetate once (50ml) again, merges organic phase, and saturated common salt is washed, anhydrous sodium sulfate drying,
It is spin-dried for, obtains 15.0g crude products.Silica gel post separation (petroleum ether：Ethyl acetate=7:1-3:1) sterling 5.0g, yield, are obtained
35.0%.1H-NMR (400MHz, CDCl3):δ7.85-7.82(m,2H),7.61-7.54(m,3H),4.77-4.76(d,2H,J
=4.89Hz), 2.82 (bs, 1H)；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml dichloromethane are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, (0.1eq is based on formula (3) compound) 4- dimethylamino pyrroles of catalytic amount
Pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3), merge organic layer, saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, is obtained
To light yellow solid 3.80g, crude product adds the mashing of 20ml methyl tertiary butyl ether(MTBE)s, filters, obtain white solid powder 3.08g, receives
Rate：94%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ 4.59 (2H, q), δ 5.16 (2H, s), δ 5.65 (2H, s), δ
6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：149-152 DEG C, HPLC purity：97.3%.
Embodiment 2：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml dichloromethane are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.45g (2eq) potassium carbonate stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains product 1.77g, yield：54%.1H-NMR (400MHz, CDCl3)：δ 1.48 (3H, t), δ 4.58 (2H, q), δ
5.18 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-152
DEG C, HPLC purity：96.6%.
Embodiment 3：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml dichloromethane are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 3.43g (2.0eq) cesium carbonate stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains product 1.25g, yield：38.1%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ 4.60 (2H, q),
δ 5.17 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：149-152
DEG C, HPLC purity：95.5%.
Embodiment 4：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml N, N- diformazans are added into 100ml there-necked flasks
Base formamide, sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- bis- of catalytic amount (0.1eq is based on formula (3) compound)
Methylamino pyridine, 1.7g (2.5eq) diisopropylethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.
Dichloromethane extraction (80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate is done
It is dry, it is spin-dried for, re crystallization from toluene, obtains product 1.8g, yield：54.9%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ
4.59 (2H, q), δ 5.16 (2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；
Fusing point：149-152 DEG C, HPLC purity：95.3%.
Embodiment 5：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml dichloromethane are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.2g (2.0eq) pyridine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 1.6g, yield：48.8%.1H-NMR (400MHz, CDCl3)：δ 1.46 (3H, t), δ 4.59 (2H, q), δ
5.17 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：149-153
DEG C, HPLC purity：95.5%.
Embodiment 6：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml dichloromethane are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.45g (2.0eq) sodium acid carbonate stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) is taken to merge organic layer, saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, first
Benzene recrystallizes, and obtains solid 0.9g, yield：27.4%.1H-NMR (400MHz, CDCl3)：δ 1.46 (3H, t), δ 4.58 (2H,
Q), δ 5.15 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-
152 DEG C, HPLC purity：95.7%.
Embodiment 7：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml tetrahydrofurans are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 1.8g, yield：54.9%.1H-NMR (400MHz, CDCl3)：δ 1.46 (3H, t), δ 4.58 (2H, q), δ
5.17 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：147-152
DEG C, HPLC purity：95.6%.
Embodiment 8：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml N, N- diformazans are added into 100ml there-necked flasks
Base formamide, sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- bis- of catalytic amount (0.1eq is based on formula (3) compound)
Methylamino pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloro
Methane extraction (80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, saturated common salt washing, anhydrous sodium sulfate drying,
It is spin-dried for, re crystallization from toluene, obtains solid 1.9g, yield：57.9%.1H-NMR (400MHz, CDCl3)：δ 1.48 (3H, t), δ
4.59 (2H, q), δ 5.17 (2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；
Fusing point：148-151 DEG C, HPLC purity：95.6%.
Embodiment 9：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
Addition 1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml acetonitriles into 100ml there-necked flasks, then according to
Secondary addition 1.2g (1.2eq) paratoluensulfonyl chloride, the DMAP of catalytic amount (0.1eq is based on formula (3) compound),
1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 1.6g, yield：48.8%.1H-NMR (400MHz, CDCl3)：δ 1.48 (3H, t), δ 4.60 (2H, q), δ
5.17 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-153
DEG C, HPLC purity：95.8%.
Embodiment 10：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
Addition 1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml chloroforms into 100ml there-necked flasks, then according to
Secondary addition 1.2g (1.2eq) paratoluensulfonyl chloride, the DMAP of catalytic amount (0.1eq is based on formula (3) compound),
1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 2.5g, yield：76.2%.1H-NMR (400MHz, CDCl3)：δ 1.46 (3H, t), δ 4.58 (2H, q), δ
5.15 (2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-152
DEG C, HPLC purity：95.7%.
Embodiment 11：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
Addition 1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml acetone into 100ml there-necked flasks, then according to
Secondary addition 1.2g (1.2eq) paratoluensulfonyl chloride, the DMAP of catalytic amount (0.1eq is based on formula (3) compound),
1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts (80*
3) organic layer is merged, saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene is tied again
Crystalline substance, obtain solid 2.0g, yield：61%.1H-NMR (400MHz, CDCl3)：δ 1.46 (3H, t), δ 4.57 (2H, q), δ 5.14
(2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-153 DEG C,
HPLC purity：95.8%.
Embodiment 12：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml carbon tetrachloride are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 2.3g, yield：70.1%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ 4.59 (2H, q), δ
5.16 (2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：147-152
DEG C, HPLC purity：95.2%.
Embodiment 13：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml ethyl acetate are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 5h is reacted at room temperature, then add 50ml water quenchings and go out reaction.Dichloromethane extracts
(80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate drying, is spin-dried for, toluene
Recrystallization, obtains solid 1.8g, yield：54.9%.1H-NMR (400MHz, CDCl3)：δ 1.48 (3H, t), δ 4.60 (2H, q), δ
5.17 (2H, s), δ 5.66 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：147-153
DEG C, HPLC purity：95.7%.
Room temperature in above example 1-13 is set as 25 DEG C -30 DEG C.
Embodiment 14：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50ml tetrahydrofurans are added into 100ml there-necked flasks,
Sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- dimethylamino pyrroles of catalytic amount (0.1eq is based on formula (3) compound)
Pyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 50 DEG C of reaction 2h are warming up to, then add 50ml water quenchings and go out reaction.Dichloromethane
Alkane extraction (80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, saturated common salt washing, anhydrous sodium sulfate drying, rotation
It is dry, obtain solid 2.6g, yield：78.8%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ 4.58 (2H, q), δ 5.15
(2H, s), δ 5.65 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：148-152 DEG C,
HPLC purity：95.6%.
Embodiment 15：A kind of preparation method of formula (4) compound, its step are as follows：
The first step：The preparation of formula (2) compound is the same as embodiment 1；
Second step：The preparation of formula (4) compound
1g formulas (2) compound, 2.4g (1eq) formula (3) compound and 50mlN, N- dimethyl are added into 100ml there-necked flasks
Formamide, sequentially add 1.2g (1.2eq) paratoluensulfonyl chloride, the 4- diformazans of catalytic amount (0.1eq is based on formula (3) compound)
Aminopyridine, 1.33g (2.5eq) triethylamine stirring and dissolving, 100 DEG C of reaction 2h are warming up to, then add 50ml water quenchings and go out reaction.
Dichloromethane extraction (80ml*3) merges organic layer, and saturated sodium bicarbonate aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate is done
It is dry, it is spin-dried for, obtains solid 2.2g, yield：66.7%.1H-NMR (400MHz, CDCl3)：δ 1.47 (3H, t), δ 4.61 (2H, q),
δ 5.18 (2H, s), δ 5.67 (2H, s), δ 6.9~7.9 (16H, m).ESI-MS (m/z, %) [M+H]+631；Fusing point：147-158
DEG C, HPLC purity：95.3%.
Formula (4) compound prepared by embodiment 1 carries out pharmacological effect research
Oral formula 1. (4) compound single-dose is to the antihypertensive effect of renal hypertensive rat
Wistar rats (are provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, body weight, 180-
200g, is randomly divided into 5 groups, negative control group (0.5%CMC-Na), positive controls (using Azilsartan as positive drug, by
Open the synthesis of auspicious medicine company optical valley biology city pharmaceutical chemistry portion of research and development centre in Wuhan) and tested formula (4) compound it is low, in, it is high by three
Individual dosage group (0.5,1.0,2.0mg/kg), all medicines are prepared in 0.5%CMC-Na, every group of 6-8 animal.Ligation one
The side arteria renalis, Two-kidney One-clip type renal hypertensive rat (RHR) model being formed, Post operation determines weekly a blood pressure, and continuous four
In week, blood pressure stabilization rise 4kPa rat is the successful rat of modeling.Before measuring blood pressure, rat is given with 39 DEG C of circulator bath tail sleeve
Rat-tail heats, after expanding tail veins, with tail sleeve method (BP2010A non-invasive blood pressure instruments, the limited public affairs of Beijing Ji'an get Er science and technology
Department, the street No.1 of ShangDi, Haidian District, BeiJing City ten) measure rat administration before, after gastric infusion 1,3,5,7,10 and 10h blood pressure and
Heart rate, each time point survey and averaged three times.Blood before maximum hypotensive value/administration after maximum hypotensive activity (%)=administration
Pressure value × 100%.
The antihypertensive effect of the oral formula of table 1. (4) compound and positive drug to renal hypertensive rat
Conclusion：In arteria renalis Hypertension Rats animal model is ligatured, formula (4) compound prepared by the present invention is shown
Hypotensive activity intensity is substantially better than positive drug Azilsartan, and the hypotensive activity duration approaches with Azilsartan fat.
24 hours after administration, the antihypertensive effect of positive drug Azilsartan fat is 20%, and formula (4) compound is 25%, antihypertensive effect and Ah
Qi Shatan esters are close.Formula (4) compound prepared by the present invention also has certain reduction to act on ligation arteria renalis rat heart rate,
Show in addition to significant hypotensive activity, the compound still has a certain degree of drop heart rate function.
Oral formula 2. (4) compound multiple dosing is to spontaneous hypertensive rat (SHR) antihypertensive effect
Male SHR (Beijing Vital River Experimental Animals Technology Co., Ltd., Beijing), 40 week old, 250-300 grams of body weight,
5 groups are randomly divided into, negative control group (0.5%CMC-Na), positive controls (Azilsartan, auspicious medicine company optical valley are opened by Wuhan
Biological pharmaceutical chemistry portion of city research and development centre synthesis provides, and prepares in 0.5%CMC-Na), tested formula (4) compound is low, in, it is high
Three dosage groups (all compounds are prepared in 0.5%CMC-Na), every group of 4-5 animal, are administered once a day, continuously give
Medicine 14 days, every time administration determine blood pressure and heart rate after 1 hour.Before measuring blood pressure, rat is with 39 DEG C of circulator bath tail sleeve to rat-tail
Heating, after expanding tail veins, with tail sleeve method (BP2010A non-invasive blood pressure instruments, Beijing Ji'an get Er Science and Technology Ltd.s, north
The street No.1 of Jing Shi Haidian District Shangdi ten) before measure rat administration, blood pressure and heart rate after gastric infusion, each time point surveys three times
Average.Pressure value × 100% before maximum hypotensive value/administration after maximum hypotensive activity (%)=administration.
Antihypertensive effect of the oral formula of table 2. (4) compound to spontaneous hypertensive rat (SHR)
Conclusion：In spontaneous hypertensive rat (SHR) animal model, formula (4) compound for preparing of the present invention show compared with
Strong hypotensive activity, hence it is evident that better than Azilsartan.After long term administration, the hypotensive activity of formula (4) compound is stable, animal
State is superior to Azilsartan administration group.In whole administration process, formula (4) compound prepared by the present invention is to SHR rats
Heart rate shows a certain degree of reduction effect, shows the work that the compound removes significant antihypertensive effect, still has preferably drop heart rate
With.
Influence of oral formula 3. (4) the compound single-dose to normal rat blood pressure
Wistar rats (are provided, Wuhan, Hubei) by Disease Prevention Control Center, Hubei Prov, male, body weight, 200-
250g, is randomly divided into 5 groups, negative control group (0.5%CMC-Na), positive controls (using Azilsartan as positive drug, by
Open the synthesis of auspicious medicine company optical valley biology city pharmaceutical chemistry portion of research and development centre in Wuhan) and tested formula (4) compound it is low, in, it is high three
Dosage group (0.5,1.0,2.0mg/kg, p.o., all medicines are prepared in 0.5%CMC-Na), every group of 8-10 animal.Survey
Before blood pressure, rat gives rat-tail to heat with 39 DEG C of circulator bath tail sleeve, after expanding tail veins, with tail sleeve method (BP2010A without
Create blood pressure instrument, Beijing Ji'an get Er Science and Technology Ltd.s, the street No.1 of ShangDi, Haidian District, BeiJing City ten) before measure rat administration, fill
0.5,1,2,4,8h blood pressure and heart rate, each time point survey and averaged three times after stomach administration.
As a result with conclusion：(0.5,1.0 and 2.0mg/kg, p.o., are prepared 0.5% three dosage of formula (4) compound
In CMC-Na) to normal rat blood pressure and heart rate without remarkable effect, show the compound to normal arterial pressure and heart rate without notable
Influence.
Specific embodiment described in this specification is only to spirit explanation for example of the invention.Skill belonging to the present invention
The technical staff in art field can make various modifications or supplement to described specific embodiment or use similar side
Formula substitutes, but without departing from the spiritual of the present invention or surmounts scope defined in appended claims.
Claims (7)
1. a kind of preparation method of formula (4) compound,
Comprise the following steps：
The first step, cinnamyl alcohol and natrium nitrosum react five yuan of furazan rings of generation under conditions of acetic acid makees solvent, and formula (2) is made and changes
Compound,
Second step, formula (2) compound and Azilsartan are in DMAP catalysis, paratoluensulfonyl chloride and alkali existence condition
Lower reaction, formula (4) compound is condensed,
2. preparation method according to claim 1, it is characterised in that：Second step reaction alkali used is selected from potassium carbonate, carbon
Any one in sour caesium, triethylamine, pyridine, sodium acid carbonate, diisopropylethylamine.
3. preparation method according to claim 2, it is characterised in that：Second step reaction alkali used is triethylamine.
4. preparation method according to claim 1, it is characterised in that：The reaction temperature of second step reaction is 25-100 DEG C.
5. preparation method according to claim 4, it is characterised in that：The reaction temperature of second step reaction is 25-35 DEG C.
6. preparation method according to claim 1, it is characterised in that：The solvent of second step reaction is selected from dichloromethane, four
Any one in hydrogen furans, N,N-dimethylformamide, acetonitrile, chloroform, acetone, carbon tetrachloride, ethyl acetate.
7. preparation method according to claim 6, it is characterised in that：The solvent of second step reaction is dichloromethane.
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| CN102351853A (en) * | 2011-08-29 | 2012-02-15 | 石药集团欧意药业有限公司 | Azilsartan medoxomil compound, preparation method and medicinal composition thereof |
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| CN102351853A (en) * | 2011-08-29 | 2012-02-15 | 石药集团欧意药业有限公司 | Azilsartan medoxomil compound, preparation method and medicinal composition thereof |
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