Technical field
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The present invention relates to a kind of synthetic method of urapidil pharmaceutical intermediate 1,3-dimethyl-6-(3-hydroxypropyl) amino uracil.
Background technology
Urapidil medicine has the effect blocking postsynaptic receptor and the effect blocking periphery alpha-2 receptor, but based on the former.In addition, it still has the effect of activation maincenter five hydroxytryptamine 1A acceptor, and the sympathetic feedback and playing that can reduce medulla oblongata cardio-vascular regulating center reduces blood pressure.The diastole effect of this product to vein is greater than the effect to artery, does not affect intracranial blood pressure when step-down.This product still can reduce load and mean pulmonary arterial pressure before and after heart, improves cardiac output and cardiac output, reduces renal vascular resistance, has no significant effect heart rate.After oral this product slow releasing capsule, bioavailability is 72%.With plasma protein binding ratio about 80%.Main at intrahepatic metabolism, part meta-bolites still may have antihypertensive activity.T1/2 about 5 hours.Be usually used in all types of hypertension (oral) to share with diuretic antihypertensive medicine, β blocking agent; Also the controlled hypotension (intravenous injection) for raising hypertension before, during and after hypertensive crisis and operation.This product has periphery and the dual hypotensive effect of maincenter.Periphery mainly blocks postsynaptic α 1 acceptor, distends the blood vessels and significantly reduces Peripheral resistance.Also there is more weak presynaptic α 2 retardation simultaneously, block the vasoconstriction effect (being different from the peripheral action of Prazosin) of catecholamine; Central action, mainly through exciting serotonin-1A (5-HT1a) acceptor, reduces the sympathetic feedback regulation of Medulla oblongata cardiovascular center and step-down (being different from the central action of clonidine).Hypotensive while, this product generally can not cause reflex tachycardia.In open clinical Journal of Sex Research, systolic pressure and diastolic pressure 3.1% and 2.1% can be reduced respectively during individual event anesthesia, 12% and 6.7% are reduced to respectively to hypertensive patient.This medicine is to essential hypertension Be very effective.And antihypertensive effect is not had to normotensive.During spinal anesthesia, systolic pressure about 32%, diastolic pressure 27% can be reduced significantly.In the patient of cardiac insufficiency, apply urapidil can reduce oxygen consumption of myocardium, reduce lung wedge pressure and Peripheral resistance, improve left ventricular function, increase cardiac output.Urapidil does not affect sugar and metabolism of fat, does not also damage renal function.Animal experiment study shows, significant central pressure reduction effect can be caused to cat vertebral artery injection urapidil, its central pressure reduction effect does not mediate by maincenter alpha 2-adrenoceptor, and alpha-2 receptor retarding agent can not block the central pressure reduction effect of urapidil.Urapidil has the sedative effect of moderate to rat, and this effect is not also by the impact of alpha-2 receptor retarding agent.Studies have found that, when after the intracisternal injection 1mg urapidil giving hypertension dog after anesthesia, the blood pressure of hypertension dog starts to decline, but heart rate still remains on the front level of contrast.When injected dose reaches 2 ~ 4mg, heart rate starts to decline, but blood pressure returns to the front level of contrast, has no reflex tachycardia.1,3-dimethyl-6-(3-hydroxypropyl) amino uracil is as urapidil pharmaceutical intermediate, and its synthetic method is good and bad for raising pharmaceutical synthesis quality product, reduces by-products content and has Important Economic meaning.
Summary of the invention
The object of the present invention is to provide a kind of synthetic method of urapidil pharmaceutical intermediate 1,3-dimethyl-6-(3-hydroxypropyl) amino uracil, comprise the steps:
I () is being provided with agitator, thermometer, in the reaction vessel of reflux exchanger, add 1, 3-dimethyl-6-hydroxyuracil (2) 0.61mol, 3-amino-1-propyl alcohol 0.72-0.75mol, sodium sulfite solution 0.16mol, control stirring velocity 130-160rpm, raise solution temperature to 150--160 DEG C, reaction 90-120min, reduce solution temperature to 60--65 DEG C, add hexanaphthene 230ml, backflow 30-50min, filter, filtrate reduces temperature to 5--9 DEG C, leave standstill 30-35h, crystallize out, filter, gained crystal uses brine successively, acetonitrile wash, dewatering agent dewaters, recrystallization in Virahol, obtain white crystal 1, 3-dimethyl-6-(3-hydroxypropyl) amino uracil (1), wherein, sodium sulfite solution massfraction described in step (i) is 30-35%, hexanaphthene massfraction described in step (i) is 60-65%, salts solution described in step (i) is any one in saltpetre, sodium sulfate, acetonitrile massfraction described in step (i) is 70-75%, dewatering agent described in step (i) is any one in Anhydrous potassium carbonate, activated alumina, and the Virahol massfraction described in step (i) is 90-95%.
Whole reaction process can represent with following reaction formula:
The invention has the advantages that: the middle-chain decreasing reaction, reduce temperature of reaction and reaction times, improve reaction yield.
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Embodiment
Below in conjunction with concrete embodiment, the invention will be further described:
A kind of synthetic method of urapidil pharmaceutical intermediate 1,3-dimethyl-6-(3-hydroxypropyl) amino uracil
Example 1:
Agitator is being installed, thermometer, in the reaction vessel of reflux exchanger, add 1, 3-dimethyl-6-hydroxyuracil (2) 0.61mol, 3-amino-1-propyl alcohol 0.72mol, massfraction is 30% sodium sulfite solution 0.16mol, control stirring velocity 130rpm, raise solution temperature to 150 DEG C, reaction 90min, reduce solution temperature to 60 DEG C, adding massfraction is 60% hexanaphthene 230ml, backflow 30min, filter, filtrate reduces temperature to 5 DEG C, leave standstill 30h, crystallize out, filter, gained crystal washs with potassium nitrate solution successively, massfraction is 70% acetonitrile wash, Anhydrous potassium carbonate dewaters, be recrystallization in 90% Virahol at massfraction, obtain white crystal 1, 3-dimethyl-6-(3-hydroxypropyl) amino uracil 105.24g, yield 81%.
Example 2:
Agitator is being installed, thermometer, in the reaction vessel of reflux exchanger, add 1, 3-dimethyl-6-hydroxyuracil (2) 0.61mol, 3-amino-1-propyl alcohol 0.73mol, massfraction is 32% sodium sulfite solution 0.16mol, control stirring velocity 150rpm, raise solution temperature to 155 DEG C, reaction 110min, reduce solution temperature to 62 DEG C, adding massfraction is 62% hexanaphthene 230ml, backflow 40min, filter, filtrate reduces temperature to 7 DEG C, leave standstill 32h, crystallize out, filter, gained crystal washs with metabisulfite solution successively, massfraction is 72% acetonitrile wash, activated alumina dewaters, be recrystallization in 92% Virahol at massfraction, obtain white crystal 1, 3-dimethyl-6-(3-hydroxypropyl) amino uracil 109.14g, yield 84%.
Example 3:
Agitator is being installed, thermometer, in the reaction vessel of reflux exchanger, add 1, 3-dimethyl-6-hydroxyuracil (2) 0.61mol, 3-amino-1-propyl alcohol 0.75mol, massfraction is 35% sodium sulfite solution 0.16mol, control stirring velocity 160rpm, raise solution temperature to 160 DEG C, reaction 120min, reduce solution temperature to 65 DEG C, adding massfraction is 65% hexanaphthene 230ml, backflow 50min, filter, filtrate reduces temperature to 9 DEG C, leave standstill 35h, crystallize out, filter, gained crystal washs with potassium nitrate solution successively, massfraction is 75% acetonitrile wash, Anhydrous potassium carbonate dewaters, be recrystallization in 95% Virahol at massfraction, obtain white crystal 1, 3-dimethyl-6-(3-hydroxypropyl) amino uracil 118.24g, yield 91%.
Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A2B adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A2B AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A 2B AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (Ki = 9 nM) for the A2B AdoR, but it is only 2-fold selective versus the A1 AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A2B AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF3 at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A2B AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and 36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A2B AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A2B AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A2B AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (Ki = 1 nM) A2B AdoR antagonist with high selectivity (990-, 690-, and -) for the human A1, A2A, and A3 AdoRs.
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