CN108178759B - Synthesis method of α -adrenoceptor antagonist - Google Patents
Synthesis method of α -adrenoceptor antagonist Download PDFInfo
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- CN108178759B CN108178759B CN201810009566.9A CN201810009566A CN108178759B CN 108178759 B CN108178759 B CN 108178759B CN 201810009566 A CN201810009566 A CN 201810009566A CN 108178759 B CN108178759 B CN 108178759B
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- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
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Abstract
The invention discloses α -adrenoceptor antagonist 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) The synthesis conditions and method used in the invention have simple operation, cheap and easily-purchased raw materials and short production period, and can be used for preparing α -adrenergic receptor antagonist 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -a ketone hydrochloride.
Description
Technical Field
The invention belongs to the field of drug synthesis, and particularly relates to α -adrenoceptor antagonist 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -ketone hydrochloride and its synthesis process.
Background
Adrenergic receptors (adrenergical receptors) are a class of G-protein coupled receptors, which are targets of catecholamines, particularly norepinephrine (norepinephrine) and epinephrine (epinephrine). Adrenergic receptors, which are present in organs innervated by sympathetic postfibers, can be divided into two types, β and α.
α 1-adrenergic receptors are members of the G protein-coupled receptor superfamily after activation, heterotrimeric G protein Gq activates phospholipase C (PLC), leading to an increase in IP3 and calcium.
In contrast to α 2-adrenergic receptor, α -adrenergic receptor in the skeletal muscle arterial vasculature is more inhibitory, the attenuation of vessel contraction mediated by α adrenergic receptor occurs only in heavy exercise, only the active muscle α -adrenergic receptor will be blocked, the resting muscle will not block its α -adrenergic receptor, so the overall effect will be α 1-adrenergic mediated vessel contraction.
α 2-adrenergic receptors are usually located on the vasomotor functional terminals, where the release of norepinephrine (norepinephrine) is inhibited in negative feedback form, it is also located on vascular smooth muscle cells of certain blood vessels, such as those found in the cutaneous arterioles or veins, where they are located next to the more abundant α 1-adrenergic receptors α 2-adrenergic receptors bind to norepinephrine released by the fibers behind the sympathetic ganglia and epinephrine released by the adrenal medulla (epinephrine), with a slightly higher affinity to norepinephrine (norepinephrine). it has several general functions in common with α 1-adrenergic receptors, but also has its own specific effects. α 2-adrenergic receptor agonists (activators) are often used in veterinary anesthesia, where the effects of sedation, muscle relaxation and analgesia are affected by the action on the Central Nervous System (CNS).
In view of the α -important role of adrenergic receptors in human physiological processes, the development of adrenergic receptor antagonists has been of great interest for the treatment of diseases such as cardiovascular, hypertension and prostate.
Disclosure of Invention
The compound of the invention, 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) The keto hydrochloride has antagonistic action on α -adrenergic receptor, and has wide pharmaceutical application prospect.
The invention adopts the following route to synthesize α -adrenoceptor antagonist 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -a ketone hydrochloride;
5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The conditions for the synthesis of pyrimidine 3 are:
mixing 2- (piperazin-1-yl) pyrimidine hydrochloride 2 (1-2 equivalents), base B1 (2-3 equivalents) and solvent S1 (1-20 times), stirring at 0-20 deg.C for 30-60 min; adding 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Heating pyrimidine 1 to reflux, and stirring for 12-20 hours; cooling to 20-40 deg.C, adding water (1-20 times), and stirring for 1-2 hr; cooling to 0-10 ℃, stirring for 2-5 hours, filtering to obtain 5- (methylthio) -3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]And (3) a pyrimidine.
The alkali B1 is selected from sodium carbonate, potassium hydroxide, sodium bicarbonate or potassium bicarbonate; the preferred base B1 is sodium or potassium carbonate.
Solvent S1 is selected from dimethylformamide, dichloromethane, dimethylacetamide, acetonitrile or ethyl acetate; preferred solvents S1 are dimethylformamide, dimethylacetamide or acetonitrile.
3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -the conditions of synthesis of the ketone hydrochloride are:
reacting 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Mixing pyrimidine 3 and solvent S2 (1-20 times), and stirring at 0-20 deg.C for 10-60 min; adding alkali B2 (2-4 equivalent weight) into the system, heating to reflux, and stirring for 18-24 hours; cooling to 20-40 deg.C, adding sodium periodate (0.8-1.2 equivalent), and stirring for 8-12 hr; filtering, concentrating the filtrate, and diluting the obtained concentrate with solvent S3 (1-20 times); adding concentrated hydrochloric acid (1-2 equiv.), stirring at 0-20 deg.C for 4-6 hr, and filtering to obtain the final product.
The base B2 is selected from potassium carbonate, potassium hydroxide, sodium hydroxide, triethylamine or diisopropylethylamine; preferred bases B2 are potassium carbonate, sodium hydroxide or potassium hydroxide; the most preferred base B2 is sodium hydroxide.
Solvent S2 is selected from methanol, ethanol, isopropanol, acetonitrile or water; preferred solvents S2 are ethanol, acetonitrile or water.
Solvent S3 is selected from methanol, ethanol, dichloromethane, ethyl acetate or acetonitrile; preferred solvents S3 are methanol, ethanol or acetonitrile; the most preferred solvent S3 is acetonitrile.
The principle of the invention is as follows:
3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine 1 and 2- (piperazine-1-yl) pyrimidine hydrochloride 2 are subjected to substitution reaction under the action of sodium carbonate to obtain 5- (methylthio) -3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]And (3) a pyrimidine. 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Thiomethyl elimination of pyrimidine 3 followed by the formation of the hydrochloride salt, 3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -a ketone hydrochloride;
the synthesis conditions and the method used by the invention have simple operation, cheap and easily-purchased raw materials and short production period, and can prepare α -adrenergic receptor antagonist 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -keto hydrochloride, providing sufficient 3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -a ketone hydrochloride.
Detailed Description
The invention will be further illustrated with reference to specific examples:
example 1
A method for synthesizing α -adrenoceptor antagonist, the process is as follows;
5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The conditions for the synthesis of pyrimidine 3 are:
mixing 2- (piperazin-1-yl) pyrimidine hydrochloride 2, sodium carbonate and dimethylformamide and stirring at 0 ℃ for 30 minutes;
adding 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Heating pyrimidine 1 to reflux, and stirring for 12 hours;
cooling to 20 ℃, adding water, and stirring for 1 hour;
cooling to 10 ℃, stirring for 2 hours, and filtering to obtain 5- (methylthio) -3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine 3;
wherein the sodium carbonate and the 3- (bromomethyl) are selected from5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The molar ratio of the pyrimidine 1 is 2: 1;
2- (piperazin-1-yl) pyrimidine hydrochloride 2 and 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The molar ratio of the pyrimidine 1 is 1: 1;
dimethylformamide and 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The volume using ratio of the pyrimidine 1 is 1: 1;
water with 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The volume ratio of the pyrimidine 1 is 10: 1;
reacting 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Mixing pyrimidine 3 and methanol, and stirring at 10 ℃ for 20 minutes;
adding triethylamine into the system, heating to reflux, and stirring for 18 hours;
cooling to 20 ℃, adding sodium periodate, and stirring for 8 hours;
filtering, concentrating the filtrate, and diluting the obtained concentrate with dichloromethane;
adding concentrated hydrochloric acid, stirring at 0-20 deg.C for 4 hr, and filtering to obtain 3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -a ketone hydrochloride;
triethylamine and 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The molar ratio of the pyrimidine 3 is 2: 1;
sodium periodate and 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The molar using ratio of the pyrimidine 3 is 0.8: 1;
concentrated hydrochloric acid with 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The molar ratio of the pyrimidine 3 is 2: 1;
methanol with 5- (methylthio) -3- ((4- (pyrimidine-2-)Yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The volume using ratio of the pyrimidine 3 is 10: 1;
dichloromethane and 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]The volume using ratio of the pyrimidine 3 is 8: 1.
example 2
The synthesis conditions of 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 are:
mixing 2- (piperazin-1-yl) pyrimidine hydrochloride 2 (120 g), sodium carbonate (127 g) and dimethylformamide (120 mL), stirring at 0-20 ℃ for 30-60 minutes; adding 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine 1 (155 g), heated to reflux and stirred for 12-20 hours; cooling to 20-40 ℃, adding water (360 mL), and stirring for 1-2 hours; cooling to 0-10 ℃, stirring for 2-5 hours, and filtering to obtain a white solid, namely 5- (methylthio) -3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine 3 (173 g, 88%).
HPLC purity 98% (retention time: 8.12 min.) mp 171 and 173 ℃.1H NMR (400 MHz,DMSO-d6) δ = 7.57 (m, 1H), 7.35 (d, 1H), 7.28 (m, 1H), 6.88 (m, 2H), 4.55 (m,1H), 4.07 (m, 1H), 3.93 (dd, 2H), 2.97 (m, 4H), 2.76 (m, 3H), 2.61 (s, 3H),2.55 (m, 3H) ppm;13C NMR (100 MHz, DMSO-d6): δ = 162.3, 157.4, 153.2, 152.6,147.1, 146.5, 144.4, 126.8, 118.6, 62.8, 59.4, 58.7, 55.6, 53.2, 51.5, 47.8ppm; m/z (MS-ESI): 395.52 [M + 1]+.
3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) -the conditions of synthesis of the ketone hydrochloride are:
reacting 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine 3 (139 g) was mixed with ethanol (278 mL) in 0-2Stirring for 10-60 min at 0 deg.C; adding sodium hydroxide (46.5 g) into the system, heating to reflux, and stirring for 18-24 hours; cooling to 20-40 deg.C, adding sodium periodate (76 g), and stirring for 8-12 hr; filtering, concentrating the filtrate, and diluting the obtained concentrate with acetonitrile (300 mL); adding concentrated hydrochloric acid (55 mL), stirring at 0-20 deg.C for 4-6 hr, and filtering to obtain 3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c]Pyrido [2,3-e]Pyrimidine-5 (3)H) Ketone hydrochloride (125.4 g, 85%).
HPLC purity 97% (retention time: 9.28 min.); mp 252-;1H NMR (400 MHz,DMSO-d6) δ = 7.79 (d, 1H), 7.49 (m, 1H), 7.08 (m, 2H), 6.94 (m, 2H), 6.87 (m,2H), 4.48 (m, 1H), 4.04 (m, 1H), 3.90 (dd, 1H), 3.77 (s, 3H), 3.37 (m, 4H),2.95 (m, 4H), 2.83 (m, 1H), 2.67 (m, 2H) ppm;13C NMR (100 MHz, DMSO-d6): δ =171.1, 164.2, 152.5, 141.1, 134.8, 129.1, 123.2, 115.1, 111.2, 76.6, 60.5,54.4, 54.1, 50.8, 49.7 ppm; m/z (MS-ESI): 364.42 [M - HCl + 1]+.
example 2 biological Activity assay
Male SD rats, weight (300 + -25) g, carotid bleeding and death, anal and caudal muscle samples were taken. Is then put into a reactor (95% O)2+5 %CO2) In Krebs liquid of mixed gas, the specimen is fixed in an isolated organ perfusion system, the bath temperature is 37 ℃, the pH of nutrient solution is 7.4, the resting load is 1 g, and the balance is 1 h. After the base line is stable, cocaine hydrochloride of 30 mu mol/L, hydrocortisone of 30 mu mol/L and propranolol of 1 mu mol/L are added into the perfusion fluid. Preparing a new forskolin cumulative dose-response curve (CRC) after 20 min, repeatedly determining the new forskolin CRC in the presence of three different concentrations of prazosin and the compound of the invention, and obtaining pA by a Schild mapping method2Value (antagonism parameter, which refers to the negative logarithm of the concentration of competitive antagonist at a dose ratio of 2).
The compound of the invention is carried out pA2And (4) measuring the value. pA is2Higher values indicate a greater ability to antagonize α -adrenoceptor the pA of the compounds of the invention determined2Values are listed in the following table:
Claims (6)
1. a method for synthesizing α -adrenoceptor antagonist, which is characterized in that the process has the following route;
the synthesis conditions of 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 are:
mixing 2- (piperazin-1-yl) pyrimidine hydrochloride 2, base B1 and solvent S1, stirring at 0-20 ℃ for 30-60 minutes;
adding 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 1 into the system, heating to reflux, and stirring for 12-20 hours;
cooling to 20-40 deg.C, adding water, and stirring for 1-2 hr;
cooling to 0-10 ℃, stirring for 2-5 hours, and filtering to obtain 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3;
wherein the alkali B1 is selected from sodium carbonate, potassium hydroxide, sodium bicarbonate or potassium bicarbonate, and the molar ratio of the alkali B1 to the 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 1 is 2-3: 1;
the molar ratio of 2- (piperazine-1-yl) pyrimidine hydrochloride 2 to 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 1 is 1-2: 1;
the solvent S1 is selected from dimethylformamide, dichloromethane, dimethylacetamide, acetonitrile or ethyl acetate, and the volume ratio of 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 1 is 1-20: 1;
the volume ratio of water to 3- (bromomethyl) -5- (methylthio) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 1 is 1-20: 1;
the α -adrenoceptor antagonist is 3- ((4- (pyrimidine-2-yl) piperazine-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine-5 (3H) -ketone hydrochloride, and the synthetic method comprises the following steps:
mixing 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 and solvent S2, stirring at 0-20 ℃ for 10-60 minutes;
adding alkali B2 into the system, heating to reflux, and stirring for 18-24 hours;
cooling to 20-40 deg.C, adding sodium periodate, and stirring for 8-12 hr;
filtering, concentrating the filtrate, and diluting the obtained concentrate with a solvent S3;
adding concentrated hydrochloric acid, stirring at 0-20 deg.C for 4-6 hr, and filtering to obtain 3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 6-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidin-5 (3H) -one hydrochloride;
wherein the base B2 is selected from potassium carbonate, potassium hydroxide, sodium hydroxide, triethylamine or diisopropylethylamine, and the molar ratio of 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 is 2-4: 1;
the molar ratio of sodium periodate to 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 is 0.8-1.2: 1;
the molar ratio of concentrated hydrochloric acid to 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 is 1-2: 1;
the solvent S2 is selected from methanol, ethanol, isopropanol, acetonitrile or water, and the volume ratio of the solvent S2 to 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 is 1-20: 1;
the solvent S3 is selected from methanol, ethanol, dichloromethane, ethyl acetate or acetonitrile, and the volume ratio of the solvent S3 to 5- (methylthio) -3- ((4- (pyrimidin-2-yl) piperazin-1-yl) methyl) -2, 3-dihydroimidazo [1,2-c ] pyrido [2,3-e ] pyrimidine 3 is 1-20: 1.
2. the process of claim 1, wherein the solvent S1 is dimethylformamide, dimethylacetamide or acetonitrile.
3. The process of claim 1 wherein the base B1 is sodium carbonate or potassium carbonate.
4. The process of claim 1, wherein the solvent S2 is ethanol, acetonitrile or water.
5. The process of claim 1, wherein the solvent S3 is methanol, ethanol or acetonitrile.
6. The process of claim 1 wherein the base B2 is selected from the group consisting of potassium carbonate, sodium hydroxide and potassium hydroxide.
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| Studies on quinazolinones. 3: Novel and efficient route to the synthesis of conformationally restricted analogues of ketanserin and SGB-1534 as antihypertensive agents;Ji-Wang Chern等;《Bioorganic & Medicinal Chemistry Letters》;19911231;第1卷(第11期);第571-574页 * |
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