CN102746280A - Pyrimidone compound and preparation method thereof - Google Patents
Pyrimidone compound and preparation method thereof Download PDFInfo
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- CN102746280A CN102746280A CN2012102058582A CN201210205858A CN102746280A CN 102746280 A CN102746280 A CN 102746280A CN 2012102058582 A CN2012102058582 A CN 2012102058582A CN 201210205858 A CN201210205858 A CN 201210205858A CN 102746280 A CN102746280 A CN 102746280A
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- 0 CC=C(C(c1nnn[n]1*)=CC=C)c1ccc(CN2C(c3ccncc3)=NC(CC(C3)C(N(C)C)=O)=C3C2=O)cc1 Chemical compound CC=C(C(c1nnn[n]1*)=CC=C)c1ccc(CN2C(c3ccncc3)=NC(CC(C3)C(N(C)C)=O)=C3C2=O)cc1 0.000 description 6
- ICFDLVSOTOGEEA-UHFFFAOYSA-N COC(C(CC1C(OC)=O)CC1=O)=O Chemical compound COC(C(CC1C(OC)=O)CC1=O)=O ICFDLVSOTOGEEA-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to the field of pharmaceutical chemistry synthesis, and specially relates to a pyrimidone compound and a preparation method thereof. Experiments on antagonistic action of in-vivo angiotensin II of awake rats with normal blood pressures show that the pyrimidone compound has a significant antagonistic action of in-vivo angiotensin II and can be applied to prepare drugs for treating cardiovascular diseases.
Description
Technical field
The present invention relates to the synthetic field of pharmaceutical chemistry, be specifically related to a kind of pyrimidinone compound and preparation method thereof.
Background technology
Cardiovascular disorder is claimed blood circulation diseases again, is a series of diseases that relate to blood circulation, mainly refers to the disease of heart and blood vessel and so on.
In recent years, learn that renin-angiotonin system plays central role in regulating human blood-pressure through various data to experiment in vitro that animal is cooked.Angiotensin II is made up of 8 amino acid, is to be produced by angiotensin converting enzyme (ACS) the cracking angiotonin I that is distributed on lung's arteries.Specific receptors in angiotensin II and blood vessel, unstriated muscle, kidney and the suprarenal gland interacts, and lures that blood pressure and electrolyte concentration increase into.Therefore, develop the antagonist of angiotensin II, suppress the effect of angiotensin II, thereby reach the cardiovascular disorder that treatment causes owing to angiotensin II and its receptors bind through its acceptor of selective exclusion.
Once the someone proposed to be similar to the peptide antagonists of angiotensin II, but their clinical application receives some restrictions, and was short such as the transformation period, can not oral administration and localised blood pressure increase etc.In recent years, there is relevant report to point out to use non-peptide class angiotensin II antagonists (U.S. Pat 4207324, US 4340598, US 4576958, US 4582847 and US 4880804; European patent EP 028834, EP245637, EP253310, EP291969, EP323841 and EP324377) treat this type of cardiovascular disorder.European patent EP 028834 has disclosed by the substituted imidazolium compounds of xenyl (for example Losartan) with EP253310, and EP245637 has disclosed Imidazopyridine (for example L158,809) as effective angiotensin II antagonists.
In EP407342, EP419048 and EP445811 patent, disclosed and 6 yuan of similar pyrimidinone compounds of heterocycle structure of The compounds of this invention, it comprises and 5 yuan of very large nitrogen of imidazolium compounds difference.But the activity of this pyrimidinone compound is lower than the activity of imidazolium compounds described in EP028834 and the EP253310.
In patent WO96/08476, disclosed and the similar pyrimidinones of The compounds of this invention, experiment in vitro (expand in the research 10 at extracorporeal blood vessel by rabbit aorta
-8To 10
-9Produce the restraining effect of 60-70% during mmol/L), its activity is higher than 50 times of known imidazolium compounds in the above-mentioned patented claim or equates with it.
Summary of the invention
The object of the present invention is to provide one type of new pyrimidine ketone compounds.
The contriver is through synthetic to pyrimidinones and to the research repeatedly and the screening of the antagonistic action of angiotensin II; Found one type of new pyrimidinones with pharmaceutical use; This pyrimidinones is different from any existing antagonist that is used for angiotensin II, aspect activity and action time, all is superior to pyrimidinone compound or the imidazolium compounds described in the above-mentioned patent.
The present invention is specifically related to the compound shown in the following general formula I structure:
Wherein: R is C
1-C
4Alkane, aromatic hydrocarbon, aromatic heterocycle hydrocarbon or
R
1, R
2Independently be selected from C
1-C
4Alkane or aromatic base alkane;
N=1,2 or 3.
Wherein, R specifically refers to ethyl, n-propyl, normal-butyl, phenyl, pyridine, pyrimidine, pyrazine, furyl, thienyl or thiazolyl.
The part of compounds with formula I structure that the present invention relates to is:
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-phenyl-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-(4-pyridyl)-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-phenyl-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4,5,6,7,8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(dimethylamino)-N, N-dimethyl--4-oxygen-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--2-(N-methyl-N-phenyl amino)-4-oxygen-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(N-ethyl-N-phenyl amino)-N, N-dimethyl--4-oxygen-4,5,6,7,8,9-tetrahydrochysene-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides.
Another object of the present invention is, the preparation method of one type of novel pyrimidinones is provided.
The preparation route of formula I compound:
Wherein: R is C
1-C
4Alkane, aromatic hydrocarbon, aromatic heterocycle hydrocarbon or
R
1, R
2Independently be selected from C
1-C
4Alkane or aromatic base alkane;
N=1,2 or 3.
Specifically preparation process of compound according to the invention is: the starting material cyano compound at first with the hydrogen chloride gas precursor reactant; And then and ammonia gas react, can make the midbody II, ring closure reaction takes place and obtains the midbody III in midbody II and 3-carbonyl ester cpds under the Pottasium Hydroxide effect; The substituted biphenyl benzyl of midbody III and tetrazolium bromine reacts under the sodium hydride condition and obtains the midbody IV; After the hydrolysis of midbody IV, the hydrochloride reaction with n n dimetylaniline under condensing agent DMTMM condition obtains midbody V, and midbody V is under the condition of trifluoromethanesulfanhydride anhydride and pyridine; Obtain the midbody VI with the ammonium sulfide reaction, promptly obtain formula I compound behind the midbody VI deprotection.
Experiment through clear-headed normal pressure rat being carried out the antagonistic action of angiotensin II in the body finds that pyrimidinones of the present invention has significant angiotensin II antagonistic action, can be used as the purposes in the preparation treatment cardiovascular disease medicine.
Embodiment
Below in conjunction with embodiment the present invention is made further detailed description, but is not limitation of the present invention, all any this areas of doing according to the disclosure of invention be equal to replacement, all belong to protection scope of the present invention.
Room temperature is meant 10 to 25 ℃ envrionment temperature among the embodiment.
The preparation of embodiment 1 midbody valeryl amidine
Under 0 ° of C, the positive valeronitrile of 150g is dissolved in the 400ml THF, to wherein ceaselessly feeding HCl gas to supersaturation, stirring at room 8 hours.Then, vacuum concentration is removed ethanol and excessive HCl gas.In residue, add the 500ml ether, stir, the solid that filters generation is also with the washing of 300ml ether, vacuum-drying.This solid is dissolved in the 400ml ethanol, under 0 ° of C, feeds ammonia, after 1 hour, the insolubles in the filtering reacting liquid, concentrated filtrate have solid to produce during to about 150ml, filter.Filtrating continues to be condensed into oily matter, places in the refrigerator (refrigerator temperature is-4 ° of C) to spend the night this oily matter, can obtain 75g valeryl amidine, and yield is 41.5%.
Embodiment 2 midbodys methyl-2-butyl-4-hydroxyl-5,6,7, the preparation of 8-tetrahydro quinazoline-6-methyl carbonate
Under 25 ° of C, with the valeryl amidine and the 96g 4-carbonyl-1 of 10g embodiment 1 preparation, 3-cyclohexyl dioctyl phthalate methyl esters is dissolved in the 50ml methyl alcohol, adds 8.4g Pottasium Hydroxide therein.This reaction solution stirring at room is after 12 hours, and agitation condition adds 60ml water down, and it is also dry to filter the solid that produces.Dried solid is dissolved in the ethanol of 30ml again, slowly adds the 6g sulphinyl chlorine, and 60 ° of C stirred 8 hours down then.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and transfer PH to 8, filter the solid and the vacuum-drying that produce, obtain 16g methyl-2-butyl-4-hydroxyl-5,6,7,8-tetrahydro quinazoline-6-methyl carbonate, yield are 62%, MS, m/z: [M+H]
+265.1.
Embodiment 3 midbody methyl 2-butyl-4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1,1 '-biphenyl]-the 4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-methyl-formiate
Under 25 ° of C, with 10g by the compound dissolution of embodiment 2 preparation at 50mlN, in the dinethylformamide; Add 2g sodium hydride (60% oily disperse object); Stir after 30 minutes, add 31.2g 4-[2 '-trityl-5-tetrazyl] phenyl-benzyl bromine, be warming up to 50 ° of C then and stirred 2 hours.After being cooled to room temperature, reaction solution is slowly poured in the 400ml water of stirring, filtered the solid and the vacuum-drying that produce, obtain 18.6g methyl 2-butyl-4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; 1'-biphenyl]-the 4-yl) methyl)-3,4,5; 6,7,8-six hydrogen quinazoline-6-methyl-formiate; Yield is 66%, MS, m/z: [M+H]
+741.3.
Embodiment 4 midbody 2-butyl-N, N-dimethyl--4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1,1 '-biphenyl]-the 4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carboxamide
Under 25 ° of C, the compound dissolution that 10g embodiment 3 is prepared slowly adds the aqueous solution of 7.3ml10% sodium hydroxide then in the mixed solvent of 15ml methyl alcohol and THF (volume ratio is 1:3), stirred afterwards 1 hour.The aqueous hydrochloric acid that in this reaction solution, adds 4mol/L is to PH5-6, revolves to steam methyl alcohol and THF, and the residue water extracts with chloroform, and chloroform is used anhydrous magnesium sulfate drying mutually, and suction filtration revolves and steams chloroform.The residue that will revolve after the steaming is dissolved in the THF of 20ml, add 5.7g 4-(4,6-dimethoxy-1; 3; 5-triazine-2-yl)-and the hydrochloride (DMTMM) of 4-methylmorpholine, stirring at room is after 2 hours, slowly adds the 2.2g Dimethylammonium chloride and stirring at room 12 hours.Filter undissolved solid, filtrating is revolved dried.Residue is dissolved in the 50ml chloroform, washes three times, uses anhydrous magnesium sulfate drying, vacuum concentration.Residue obtains 9g 2-butyl-N with ETHYLE ACETATE and sherwood oil (volume ratio is 1:4) recrystallization, N-dimethyl--4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; 1'-biphenyl]-the 4-yl) methyl)-3,4,5; 6; 7,8-six hydrogen quinazoline-6-carboxamide, two step yields are 88%.MS，m/z：[M+H]
+754.4。
Embodiment 5 midbody 2-butyl-N, N-dimethyl--4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbon thioamides
Under-20 ° of C conditions, compound and 0.63g pyridine that 2g embodiment 4 is prepared are dissolved in the 20ml methylene dichloride, to wherein dropwise adding 0.9g trifluoromethanesulfanhydride anhydride (1.2eq), are warming up to 25 ° of C naturally, stir 2 hours.Under 0 ° of C, this reaction solution is dropwise joined in 20% ammonium sulfide solution of 3ml, reaction is 2 hours under-5 ° of C.Then, this reaction solution is used filtered through silica gel, and filtrating is revolved to steam to remove and desolvated.Residue is used re-crystallizing in ethyl acetate, and vacuum-drying obtains 1.65g2-butyl-N, N-dimethyl--4-oxygen-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-3; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 81%.MS，m/z：[M+H]
+770.4。
Embodiment 6 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbon thioamides
In 10ml methyl alcohol, to wherein adding the 6ml10% aqueous hydrochloric acid, reflux 1 hour is cooled to room temperature, vacuum concentration with the compound dissolution of 1.5g embodiment 5 preparation.Residue is dissolved in the chloroform, with saturated sodium hydrogencarbonate washing, anhydrous magnesium sulfate drying, suction filtration concentrates.Residue after concentrating obtains 0.9g 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3 with methyl alcohol and ETHYLE ACETATE (1:50) recrystallization; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 90%.
MS，m/z：[M+H]
+528.2
1H-NMR(CDCl
3)：δ7.88(d，2H)，7.49-7.41(m，2H)，7.36-7.25(m，4H)，4.97(s，2H)，3.07(s，6H)，2.49-2.42(m，1H)，2.39-2.29(m，2H)2.25-2.11(m，2H)，1.79-1.70(m，1H)，1.64(t，2H)，1.46-1.27(m，4H)，0.88(t，3H)。
Embodiment 7 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-methyl-4-oxygen-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
With reference to the preparation method of embodiment 2, with positive penta amidine of 5g and 45g 4-oxocyclopentyl-1, the reaction of 3-two methyl carbonates obtains compound 2-butyl-4-hydroxyl-6,7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate (9.4g, yield are 75%);
With reference to the preparation method of embodiment 3, with 5g 2-butyl-4-hydroxyl-6,7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate and 16.6g 5-(4'-(brooethyl)-[1; The 1'-xenyl]-the 2-yl)-reaction of 1-trityl-1 hydrogen-tetrazolium obtains compound 2-butyl-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate (13.7g, yield are 95.2%);
With reference to the preparation method of embodiment 4, with 5g 2-butyl-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6, under the effect of condensing agent DMTMM, obtain compound 2-butyl-N after 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate hydrolysis with the reaction of the hydrochloride of n n dimetylaniline; N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide (4.66g, yield are 91.5%);
With reference to the preparation method of embodiment 5, with 4g 2-butyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] obtains compound 2-butyl-N after pyrimidine-the 6-carbonic acid amide cures, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides (3.8g, yield are 93.4%);
With reference to the preparation method of embodiment 6, with 3g 2-butyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides obtains compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4 after hydrochloric acid holder protection; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides (1.9g, yield are 95.2%).
MS，m/z：[M+H]
+514.2
1H-NMR(CDCl
3)：δ7.83(d，2H)，7.43-7.38(m，2H)，7.35-7.23(m，4H)，4.95(s，2H)，3.03(s，6H)，2.75-2.68(m，3H)，2.52-2.41(m，2H)，1.55(t，2H)，1.44-1.25(m，4H)，0.86(t，3H)。
The preparation of embodiment 8 midbody benzenyl amidines
Under 0 ° of C, the 50g cyanobenzene is dissolved in the 200ml THF, to wherein ceaselessly feeding HCl gas, transfer 25 ° of C to and stirred 6 hours to supersaturation.Then, vacuum concentration is removed ethanol and excessive HCl gas.In residue, add the 150ml ether, stir, the solid that filters generation is also with the washing of 100ml ether, vacuum-drying.This solid is dissolved in the 200ml ethanol, under 0 ° of C, feeds ammonia, after 1 hour, the insolubles in the filtering reacting liquid, concentrated filtrate have solid to produce during to about 50ml, filter.Filtrating continues to be condensed into oily matter, places in the refrigerator (refrigerator temperature is-4 ° of C) to spend the night this oily matter, can obtain the 44.4g benzenyl amidine, and yield is 76.2%.
Embodiment 9 midbody 2-phenyl-4-hydroxyls-6, the preparation of 7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
Under 25 ° of C, with the benzenyl amidine and the 37.5g 4-oxo-cyclopentyl-1 of 5g embodiment 8 preparations, 3-two methyl carbonates are dissolved in the 50ml methyl alcohol, add 3.5g Pottasium Hydroxide therein.This reaction solution stirring at room is after 12 hours, and agitation condition adds 60ml water down, and it is also dry to filter the solid that produces.Dried solid is dissolved in the ethanol of 30ml again, slowly adds the 2.5g sulphinyl chlorine, and 60 ° of C stirred 8 hours down then.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and transfer PH to 8, filter the solid and the vacuum-drying that produce, obtain 7.7g methyl-2-butyl-4-hydroxyl-5,6,7,8-tetrahydro quinazoline-6-methyl carbonate, yield are 71.2%, MS, m/z: [M+H]
+271.1.
Embodiment 10 midbody 2-phenyl-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
Under 25 ° of C, with 5g by the compound dissolution of embodiment 9 preparation at 50ml N, in the N-NMF; Add 0.9g sodium hydride (60% oily disperse object); Stir after 30 minutes, add 15.5g 4-[2 '-trityl-5-tetrazyl] phenyl-benzyl bromine, be warming up to 50 ° of C then and stirred 2 hours.After being cooled to room temperature, reaction solution is slowly poured in the 200ml water of stirring, filtered the solid and the vacuum-drying that produce; Obtain 9.9g2-phenyl-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 72%; MS, m/z: [M+H]
+747.3.
Embodiment 11 midbody 2-phenyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide
Under 25 ° of C, the compound dissolution that 5g embodiment 10 is prepared slowly adds the aqueous solution of 1.9ml10% sodium hydroxide then in the mixed solvent of 30ml methyl alcohol and THF (volume ratio is 1:3), stirred afterwards 1 hour.The aqueous hydrochloric acid that in this reaction solution, adds 4mol/L revolves to steam and removes methyl alcohol and THF to pH=5-6, and the residue water extracts with chloroform, and chloroform is used anhydrous magnesium sulfate drying mutually, and suction filtration revolves and steams chloroform.The residue that will revolve after the steaming is dissolved in the THF of 20ml, add 2.8g 4-(4,6-dimethoxy-1; 3; 5-triazine-2-yl)-and the hydrochloride (DMTMM) of 4-methylmorpholine, stirring at room is after 2 hours, slowly adds the 1.1g Dimethylammonium chloride and stirring at room 12 hours.Filter undissolved solid, filtrating is revolved dried.Residue is dissolved in the 50ml chloroform, washes three times, uses anhydrous magnesium sulfate drying, vacuum concentration.Residue is with ETHYLE ACETATE and sherwood oil (volume ratio is 1:4) recrystallization; Obtain 4.6g 2-phenyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide, two step yields are 91%.MS，m/z：[M+H]
+760.3。
Embodiment 12 midbody 2-phenyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
Under-20 ° of C conditions, with the midbody 2-phenyl-N of 2g embodiment 11 preparations, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide and 0.62g pyridine are dissolved in the 20ml methylene dichloride; To wherein dropwise adding 0.89g trifluoromethanesulfanhydride anhydride (1.2eq), be warming up to 25 ° of C naturally, stirred 2 hours.Under 0 ° of C, this reaction solution is dropwise joined in 20% ammonium sulfide solution of 3ml, reaction is 2 hours under-5 ° of C.Then, this reaction solution is used filtered through silica gel, and filtrating is revolved to steam to remove and desolvated.Residue is used re-crystallizing in ethyl acetate; Vacuum-drying obtains 1.81g 2-phenyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides, yield 88.7%.MS，m/z：[M+H]
+776.3。
Embodiment 13 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-methyl-4-oxygen-2-phenyl-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
In 10ml methyl alcohol, to wherein adding 6ml 10% aqueous hydrochloric acid, reflux 1 hour is cooled to room temperature, vacuum concentration with the compound dissolution of 1.5g embodiment 5 preparation.Residue is dissolved in the chloroform, with saturated sodium hydrogencarbonate washing, anhydrous magnesium sulfate drying, suction filtration concentrates.Residue after concentrating obtains 0.92g3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3 with methyl alcohol and ETHYLE ACETATE (1:50) recrystallization; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 89%.
MS，m/z：[M+H]
+534.2
1H-NMR(CDCl
3)：δ7.857-.82(m，4H)，7.53-7.40(m，5H)，7.33-7.30(m，4H)，4.95(s，2H)，3.06(s，6H)，2.76-2.73(m，3H)，2.52-2.50(m，2H)。
The preparation of embodiment 14 midbody 4-picolyl ethers
Under 0 ° of C, 50g 4-cyanopyridine is dissolved in the 200ml THF, to wherein ceaselessly feeding HCl gas, transfer 25 ° of C to and stirred 6 hours to supersaturation.Then, vacuum concentration is removed ethanol and excessive HCl gas.In residue, add the 150ml ether, stir, the solid that filters generation is also with the washing of 100ml ether, vacuum-drying.This solid is dissolved in the 200ml ethanol, under 0 ° of C, feeds ammonia, after 1 hour, the insolubles in the filtering reacting liquid, concentrated filtrate have solid to produce during to about 50ml, filter.Filtrating continues to be condensed into oily matter, places in the refrigerator (refrigerator temperature is-4 ° of C) to spend the night this oily matter, can obtain 25.8g 4-picolyl ether, and yield is 44.3%.Embodiment 15 midbody 2-(4-pyridyl)-4-hydroxyl-6, the preparation of 7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
Under 25 ° of C, with the 4-picolyl ether and the 37.4g 4-oxo-cyclopentyl-1 of 5g embodiment 14 preparations, 3-two methyl carbonates are dissolved in the 50ml methyl alcohol, add 3.5g Pottasium Hydroxide therein.This reaction solution stirring at room is after 12 hours, and agitation condition adds 60ml water down, and it is also dry to filter the solid that produces.Dried solid is dissolved in the ethanol of 30ml again, slowly adds the 2.5g sulphinyl chlorine, and 60 ° of C stirred 9 hours down then.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and transfer PH to 8, filter the solid and the vacuum-drying that produce; Obtain 7.9g 2-(4-pyridyl)-4-hydroxyl-6,7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 73.5%; MS, m/z: [M+H]
+272.1.
Embodiment 16 midbody 2-(4-pyridyl)-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
Under 25 ° of C, with 5g by the compound dissolution of embodiment 16 preparation at 50mlN, in the dinethylformamide; Add 1g sodium hydride (60% oily disperse object); Stir after 30 minutes, add 15.3g 4-[2 '-trityl-5-tetrazyl] phenyl-benzyl bromine, be warming up to 50 ° of C then and stirred 1 hour.After being cooled to room temperature, reaction solution is slowly poured in the 200ml water of stirring, filtered the solid and the vacuum-drying that produce; Obtain 10.2g2-(4-pyridyl)-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 75.1%; MS, m/z: [M+H]
+748.3.
Embodiment 17 midbody 2-(4-pyridyl)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide
Under 25 ° of C, the compound dissolution that 5g embodiment 17 is prepared slowly adds the aqueous solution of 2ml 10% sodium hydroxide then in the mixed solvent of 30ml methyl alcohol and THF (volume ratio is 1:3), stirred afterwards 1 hour.The aqueous hydrochloric acid that in this reaction solution, adds 4mol/L is to PH=5-6, revolves to steam methyl alcohol and THF, and the residue water extracts with chloroform, and chloroform is used anhydrous magnesium sulfate drying mutually, and suction filtration revolves and steams chloroform.The residue that will revolve after the steaming is dissolved in the THF of 20ml, add 2.8g 4-(4,6-dimethoxy-1; 3; 5-triazine-2-yl)-and the hydrochloride (DMTMM) of 4-methylmorpholine, stirring at room is after 2 hours, slowly adds the 1.2g Dimethylammonium chloride and stirring at room 12 hours.Filter undissolved solid, filtrating is revolved dried.Residue is dissolved in the 50ml chloroform, washes three times, uses anhydrous magnesium sulfate drying, vacuum concentration.Residue is with ETHYLE ACETATE and sherwood oil (volume ratio is 1:4) recrystallization; Obtain 4.55g 2-(4-pyridyl)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide, two step yields are 90%.MS，m/z：[M+H]
+761.3。Embodiment 18 midbody 2-(4-pyridyl)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
Under-20 ° of C conditions, compound and 0.6g pyridine that 2g embodiment 17 is prepared are dissolved in the 20ml methylene dichloride, to wherein dropwise adding 0.9g trifluoromethanesulfanhydride anhydride (1.2eq), are warming up to 25 ° of C naturally, stir 2 hours.Under 0 ° of C, this reaction solution is dropwise joined in 20% ammonium sulfide solution of 3ml, reaction is 2.5 hours under-5 ° of C.Then, this reaction solution is used filtered through silica gel, and filtrating is revolved to steam to remove and desolvated.Residue is used re-crystallizing in ethyl acetate; Vacuum-drying obtains 1.7g2-(4-pyridyl)-N, N-methyl-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides, yield 83.3%.MS，m/z：[M+H]
+777.3。Embodiment 19 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-methyl-4-oxygen-2-(pyridin-4-yl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
In 10ml methyl alcohol, to wherein adding the 6ml10% aqueous hydrochloric acid, reflux 3 hours is cooled to room temperature, vacuum concentration with the compound dissolution of 1.5g embodiment 18 preparation.Residue is dissolved in the chloroform, with saturated sodium hydrogencarbonate washing, anhydrous magnesium sulfate drying, suction filtration concentrates.Residue after concentrating obtains 0.85g 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3 with methyl alcohol and ETHYLE ACETATE (1:50) recrystallization; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 82%.
MS，m/z：[M+H]
+535.2
1H-NMR(CDCl
3)：δ8.75（d，2H），8.00(d，2H)，7.83-7.80(m，4H)，7.55-7.51(m，5H)，7.40-7.35(m，4H)，4.99(s，2H)，3.07(s，6H)，2.76-2.72(m，3H)，2.53-2.51(m，2H)。Embodiment 20 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-methyl-4-oxygen-2-phenyl-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbon thioamides
With reference to the preparation method of embodiment 9, with 5g benzenyl amidine and 40g 4-oxo cyclohexyl-1, the reaction of 3-two methyl carbonates obtains compound 4-hydroxy base-2-phenyl-5,6,7,8-tetrahydro quinazoline-6-methyl carbonate (9.1g, yield are 76.6%);
With reference to the preparation method of embodiment 10, with 5g 4-hydroxyl-2-phenyl-5,6,7; 8-tetrahydro quinazoline-6-methyl carbonate and 14.7g 5-(4'-(brooethyl)-[1, the 1'-xenyl]-2-yl)-1-trityl-1 hydrogen-tetrazolium reaction obtains compound 4-oxo-2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3; 4,5,6; 7,8-six hydrogen quinazoline-6-methyl carbonate (12.6g, yield are 93.8%);
With reference to the preparation method of embodiment 11, with 5g 4-oxo-2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3,4; 5,6,7; Under the effect of condensing agent DMTMM, obtain compound N, N-dimethyl--4-oxo 2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3 after 8-six hydrogen quinazoline-6-methyl carbonate hydrolysis with the reaction of the hydrochloride of n n dimetylaniline; 4,5,6; 7,8-six hydrogen quinazoline-6-carbonic acid amide (4.7g, yield are 93%);
With reference to the preparation method of embodiment 12, with 4g N, N-dimethyl--4-oxo 2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3; 4,5,6,7; 8-six hydrogen obtain compound N after quinazoline-the 6-carbonic acid amide cures, N-dimethyl--4-oxo 2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides (3.88g, yield are 95%);
With reference to the preparation method of embodiment 13, by 3g N, N-dimethyl--4-oxo 2-phenyl-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3,4; 5,6,7,8-six hydrogen quinazoline-6-carbon thioamides behind the hydrochloric acid deprotection, obtain 3-((2 '-(1 hydrogen-tetrazolium-5-yl)-[1; 1'-biphenyl]-the 4-yl) methyl)-N, N-dimethyl--4-oxygen-2-phenyl-3,4,5; 6,7,8-six hydrogen quinazoline-6-carbon thioamides (1.8g, yield are 86%).
MS，m/z：[M+H]
+548.7
1H-NMR(CDCl
3)：δ7.85-7.82(m，4H)，7.51-7.46(m，5H)，7.35-7.30(m，4H)，4.97(s，2H)，3.02(s，6H)，2.38-2.31(m，2H)，2.22-2.13(m，2H)，2.09-2.03(m，1H)，1.81-1.75(m，1H)，1.66-1.64(m，1H)。
Embodiment 21 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4,5,6,7,8, the preparation of 9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides
With reference to the preparation method of embodiment 2, with positive penta amidine of 5g and 51g 4-oxo suberyl-1, the reaction of 3-two methyl carbonates obtains compound 2-butyl-4-hydroxyl-6,7,8,9-tetrahydrochysene-5 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate (12.2g, yield are 88%);
With reference to the preparation method of embodiment 3, with 5g 2-butyl-4-hydroxyl-6,7,8; 9-tetrahydrochysene-5 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate and 15.0g 5-(4'-(brooethyl)-[1, the 1'-xenyl]-2-yl)-1-trityl-1 hydrogen-tetrazolium reaction obtains compound 2-butyl-4-oxo-3-((2'-(1-trityl 1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate (12.5g, yield are 92.2%);
With reference to the preparation method of embodiment 4, with 5g 2-butyl-4-oxo-3-((2'-(1-trityl 1 hydrogen-tetrazolium-5-yl)-[1,1 '-xenyl]-4-yl) methyl)-4,5; 6,7,8; Under the effect of condensing agent DMTMM, obtain compound 2-butyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4 after 9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate hydrolysis with the reaction of the hydrochloride of n n dimetylaniline; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbonic acid amide (4.58g, yield are 90%);
With reference to the preparation method of embodiment 5, with 4g 2-butyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7,8; 9-six hydrogen-3 hydrogen-suberyl [d] obtains compound 2-butyl-N after pyrimidine-the 6-carbonic acid amide cures, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1,1 '-xenyl]-the 4-yl) methyl)-4; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides (3.5g, yield are 86%);
With reference to the preparation method of embodiment 6, by 3g 2-butyl-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7,8; 9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides obtains 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4 after hydrochloric acid holder protection; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides (1.8g, yield are 89%).
MS，m/z：[M+H]
+542.3
1H-NMR(CDCl
3)：δ7.87(d，2H)，7.48-7.46(m，2H)，7.33-7.30(m，4H)，4.95(s，2H)，3.03(s，6H)，2.06-2.00(m，1H)，1.99-1.86(m，4H)，1.44-1.21(m，4H)。
Embodiment 22 midbody N, the preparation of N-dimethylguanidine
Under 25 ° of C, the 50g N-Cyanodimethylamine is dissolved in the exsiccant 200ml toluene, to wherein feeding ammonia; After 1 hour, the vacuum concentration reaction solution obtains crude product; Behind methyl alcohol and ETHYLE ACETATE (volume ratio is 1:1) recrystallization, obtain N, N-dimethylguanidine (50.9g, yield are 82%).
Embodiment 23 midbody 2-dimethylamino-4-hydroxyls-6, the preparation of 7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
At room temperature, with the N of 10g embodiment 22 preparations, N-dimethylguanidine and 103g 4-oxocyclopentyl-1,3-two methyl carbonates are dissolved in the 200ml methyl alcohol, add 9.6g Pottasium Hydroxide therein.This reaction solution stirring at room is after 12 hours, and agitation condition adds 600ml water down, and it is also dry to filter the solid that produces.Dried solid is dissolved in the ethanol of 100ml again, slowly adds the 7g sulphinyl chlorine, and 60 ° of C stirred 8 hours down then.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and transfer PH to 8, filter the solid and the vacuum-drying that produce, obtain 21g 2-dimethylamino-4-hydroxyl-6,7-dihydro-5 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 77.2%, MS, m/z: [M+H]
+238.1.
Embodiment 24 midbody 2-dimethylamino-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate
At room temperature; With 10g by the compound dissolution of embodiment 23 preparation at 100ml N; In the dinethylformamide, add 2.0g sodium hydride (60% oily disperse object), stir after 30 minutes; Add 35.2g 4-[2 '-trityl-5-tetrazyl] phenyl-benzyl bromine, be warming up to 50 ° of C then and stirred 2 hours.After being cooled to room temperature, reaction solution is slowly poured in the 500ml water of stirring, filtered the solid and the vacuum-drying that produce; Obtain 20.45g 2-dimethylamino-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 68%; MS, m/z: [M+H]
+714.3.
Embodiment 25 midbody 2-dimethylamino-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide
At room temperature, the compound dissolution that 10g embodiment 24 is prepared slowly adds the aqueous solution of 7.5ml 10% sodium hydroxide then in the mixed solvent of 30ml methyl alcohol and THF (volume ratio is 1:3), stirred afterwards 1 hour.The aqueous hydrochloric acid that in this reaction solution, adds 4mol/L is to PH=5-6, revolves to steam methyl alcohol and THF, and the residue water extracts with chloroform, and chloroform is used anhydrous magnesium sulfate drying mutually, and suction filtration revolves and steams chloroform.The residue that will revolve after the steaming is dissolved in the THF of 30ml, add 5.8g 4-(4,6-dimethoxy-1; 3; 5-triazine-2-yl)-and the hydrochloride (DMTMM) of 4-methylmorpholine, stirring at room is after 4 hours, slowly adds the 2.3g Dimethylammonium chloride and stirring at room 12 hours.Filter undissolved solid, filtrating is revolved dried.Residue is dissolved in the 50ml chloroform, washes three times, uses anhydrous magnesium sulfate drying, vacuum concentration.Residue obtains 6.80g 2-dimethylamino-N through column chromatography purification, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbonic acid amide, two step yields are 66.8%.MS，m/z：[M+H]
+727.3。
Embodiment 26 midbody 2-dimethylamino-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
Under-20 ° of C conditions, compound and 1.60g pyridine that 5g embodiment 25 is prepared are dissolved in the 50ml methylene dichloride, to wherein dropwise adding the 2.25g trifluoromethanesulfanhydride anhydride, are warming up to room temperature naturally, stir 2 hours.Under 0 ° of C, this reaction solution is dropwise joined in 20% ammonium sulfide solution of 7.5ml, reaction is 5 hours under-5 ° of C.Then, this reaction solution is used filtered through silica gel, and filtrating is revolved to steam to remove and desolvated.Residue can obtain 3.10g 2-dimethylamino-N through column chromatography purification, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides, yield 62%.MS，m/z：[M+H]
+743.3。
Embodiment 27 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(dimethylamino)-N, N-methyl-4-oxygen-4,5,6, the preparation of 7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides
In 10ml methyl alcohol, to wherein adding 6.5ml 10% aqueous hydrochloric acid, reflux 1 hour is cooled to room temperature, vacuum concentration with the compound dissolution of 1.5g embodiment 26 preparation.Residue is dissolved in the chloroform, with saturated sodium hydrogencarbonate washing, anhydrous magnesium sulfate drying, suction filtration concentrates.Residue after concentrating obtains 0.88g 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3 with methyl alcohol and ETHYLE ACETATE (1:20) recrystallization; 4,5,6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 87.2%.
MS，m/z：[M+H]
+501.2
1H-NMR(CDCl
3)：δ7.91(d，2H)，7.51-7.47(m，2H)，7.36-7.33(m，4H)，4.93(s，2H)，3.05(s，6H)，2.85（s，6H），2.80-2.75(m，3H)，2.55-2.51(m，2H)。
The preparation of embodiment 28 midbody methyl isophthalic acid-guanidines
At room temperature, with 50gN-methyl N-phenyl cyanic acid amine solvent in exsiccant 200ml toluene, to wherein feeding ammonia; After 1 hour, the vacuum concentration reaction solution obtains crude product; Behind methyl alcohol and ETHYLE ACETATE (volume ratio is 1:1) recrystallization, obtain methyl isophthalic acid-guanidines 45g, yield is 80%.
Embodiment 29 midbody 4-hydroxyl-2-(N-methyl N-phenyl amino)-5,6,7, the preparation of 8-tetrahydro quinazoline-6-methyl carbonate
At room temperature, with the methyl isophthalic acid-guanidines and the 64.5g 4-oxo-cyclohexyl-1 of 10g embodiment 28 preparations, 3-two methyl carbonates are dissolved in the 200ml methyl alcohol, add 5.6g Pottasium Hydroxide therein.This reaction solution stirring at room is after 12 hours, and agitation condition adds 600ml water down, and it is also dry to filter the solid that produces.Dried solid is dissolved in the ethanol of 100ml again, slowly adds the 4.2g sulphinyl chlorine, and 60 ° of C stirred 6 hours down then.Be cooled to room temperature, add saturated sodium bicarbonate aqueous solution and transfer PH to 8, filter the solid and the vacuum-drying that produce, obtain 17g 4-hydroxyl-2-(N-methyl-N-phenyl amino)-5; 6,7,8-tetrahydro quinazoline-6-methyl carbonate; Yield is 81.1%, MS, m/z: [M+H]
+314.1.
Embodiment 30 midbody 4-oxo-2-(N-methyl-N-phenyl amino)-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-methyl carbonate
At room temperature, with 10g by the compound dissolution of embodiment 29 preparation at 100ml N, in the N-NMF; Add 1.5g sodium hydride (60% oily disperse object); Stir after 30 minutes, add 26.7g 4-[2 '-trityl-5-tetrazyl] phenyl-benzyl bromine, be warming up to 50 ° of C then and stirred 2 hours.After being cooled to room temperature, reaction solution is slowly poured in the 500ml water of stirring, filtered the solid and the vacuum-drying that produce; Obtain 17.9g 2-dimethylamino-4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5; 6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-methyl carbonate, yield is 71%; MS, m/z: [M+H]
+790.3.
Embodiment 31 midbody N, N-dimethyl--4-oxo 2-(N-methyl-N-phenyl amino)-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbonic acid amide
At room temperature, the compound dissolution that 10g embodiment 30 is prepared slowly adds the aqueous solution of 7ml 10% sodium hydroxide then in the mixed solvent of 30ml methyl alcohol and THF (volume ratio is 1:3), stirred afterwards 1 hour.The aqueous hydrochloric acid that in this reaction solution, adds 4mol/L is to PH=5-6, revolves to steam methyl alcohol and THF, and the residue water extracts with chloroform, and chloroform is used anhydrous magnesium sulfate drying mutually, and suction filtration revolves and steams chloroform.The residue that will revolve after the steaming is dissolved in the THF of 30ml, add 5.3g 4-(4,6-dimethoxy-1; 3; 5-triazine-2-yl)-and the hydrochloride (DMTMM) of 4-methylmorpholine, stirring at room is after 4 hours, slowly adds the 2.1g Dimethylammonium chloride and stirring at room 12 hours.Filter undissolved solid, filtrating is revolved dried.Residue is dissolved in the 50ml chloroform, washes three times, uses anhydrous magnesium sulfate drying, vacuum concentration.Residue obtains 6.33g N through column chromatography purification, N-dimethyl--4-oxo 2-(N-methyl-N-phenyl amino)-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-3,4,5; 6; 7,8-six hydrogen quinazoline-6-carbonic acid amide, two step yields are 62.1%.MS，m/z：[M+H]
+803.4。
Embodiment 32 midbody N, N-methyl-4-oxo-2-(N-methyl-N-phenyl amino)-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbon thioamides
Under-20 ° of C conditions, compound and 1.5g pyridine that 5g embodiment 31 is prepared are dissolved in the 50ml methylene dichloride, to wherein dropwise adding the 2.1g trifluoromethanesulfanhydride anhydride, are warming up to room temperature naturally, stir 2 hours.Under 0 ° of C, this reaction solution is dropwise joined in 20% ammonium sulfide solution of 7ml, reaction is 5 hours under-5 ° of C.Then, this reaction solution is used filtered through silica gel, and filtrating is revolved to steam to remove and desolvated.Residue can obtain 3.08g N through column chromatography purification, N-dimethyl--4-oxo-2-(N-methyl-N-phenyl amino)-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-3,4,5; 6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 60.6%.MS，m/z：[M+H]
+819.4。
Embodiment 33 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--2-(N-methyl-N-phenyl amino)-4-oxygen-3,4,5,6,7, the preparation of 8-six hydrogen quinazoline-6-carbon thioamides
In 10ml methyl alcohol, to wherein adding 6.5ml 10% aqueous hydrochloric acid, reflux 1 hour is cooled to room temperature, vacuum concentration with the compound dissolution of 1.5g embodiment 32 preparation.Residue is dissolved in the chloroform, with saturated sodium hydrogencarbonate washing, anhydrous magnesium sulfate drying, suction filtration concentrates.Residue after concentrating obtains 0.95g 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N with methyl alcohol and ETHYLE ACETATE (1:20) recrystallization; N-methyl-2-(N-methyl-N-phenyl amino)-4-oxygen-3,4,5; 6; 7,8-six hydrogen quinazoline-6-carbon thioamides, yield 90%.
MS，m/z：[M+H]
+577.2
1H-NMR(CDCl
3)：δ7.85(d，2H)，7.49-7.46(m，2H)，7.45-7.23(m，6H)，6.70（m，3H），4.99(s，2H)，3.62(s，3H)，3.06(s，6H)，2.40-2.32(m，4H)，2.10-2.07(m，1H)，1.90-1.72(m，1H)，1.66-1.53(m，1H)。
Embodiment 34 compound 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(N-ethyl-N-phenyl amino)-N, N-dimethyl--4-oxygen-4,5,6,7,8, the preparation of 9-tetrahydrochysene-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides
With reference to the preparation method of embodiment 28,10g N-ethyl-N-benzyl cyanic acid amine and ammonia gas react obtain N-ethyl-N-benzyl guanidine (9.2g, yield are 83.2%);
Preparing method with reference to embodiment 29; 5g N-ethyl-N-benzyl guanidine and 29g 4-oxo suberyl-1; The reaction of 3-two methyl carbonates obtains compound 2-(N-ethyl-N-benzylamino)-4-hydroxyl-6,7,8; 9-tetrahydrochysene-5 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate (7.68g, yield are 77.2%);
With reference to the preparation method of embodiment 30,5g 2-(N-ethyl-N-benzylamino)-4-hydroxyl-6,7; 8,9-tetrahydrochysene-5 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate and 11.8g 5-(4'-(brooethyl)-[1, the 1'-xenyl]-2-yl)-1-trityl-1 hydrogen-tetrazolium reaction obtains compound 2-(N-ethyl-N-benzylamino)-4-oxo-3-((2'-(1-trityl 1 hydrogen-tetrazolium-5-yl)-[1; The 1'-xenyl]-the 4-yl) methyl)-4,5,6; 7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate (10.5g, yield are 90.2%);
With reference to the preparation method of embodiment 31,5g 2-(N-ethyl-N-benzylamino)-4-oxo-3-((2'-(1-trityl 1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4,5; 6,7,8; Under the effect of condensing agent DMTMM, obtain compound 2-(N-ethyl-N-benzylamino)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4 after 9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-methyl carbonate hydrolysis with the reaction of the hydrochloride of n n dimetylaniline; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbonic acid amide (4.5g, yield are 89.6%);
With reference to the preparation method of embodiment 32,4g 2-(N-ethyl-N-benzylamino)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7,8; 9-six hydrogen-3 hydrogen-suberyl [d] obtains compound 2-(N-ethyl-N-benzylamino)-N after pyrimidine-the 6-carbonic acid amide cures, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7; 8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides (2.85g, yield are 70%);
With reference to the preparation method of embodiment 33, by 2g 2-(N-ethyl-N-benzylamino)-N, N-dimethyl--4-oxo-3-((2'-(1-trityl-1 hydrogen-tetrazolium-5-yl)-[1, the 1'-xenyl]-4-yl) methyl)-4; 5,6,7,8; 9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides obtains 1.3g 3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(N-ethyl-N-phenyl amino)-N, N-methyl-4-oxygen-4 behind the hydrochloric acid deprotection; 5,6,7; 8,9-tetrahydrochysene-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides, yield is 88%.
MS，m/z：[M+H]
+619.3
1H-NMR(CDCl
3)：δ7.81(d，2H)，7.47-7.45(m，2H)，7.39-7.25(m，9H)，4.95(s，2H)，4.27（s，2H），3.35(q，2H)，3.04(s，6H)，2.12-1.98(m，5H)，1.41-1.30(m，2H)，1.27-1.21(m，2H)，1.16(t，3H)。
Test Example is to the antagonistic action of angiotensin II in the clear-headed normal pressure rat body
100 of normal male SD rats are divided into 10 groups at random, and 10 every group (300-350g), be respectively embodiment 6,7,13,19,20,21,27,33,34 compound group and valsartan control groups 9 ages in week.Each organizes rats by intraperitoneal injection Sodital (50mg/kg) anesthesia, inserts sleeve pipe at left femoral artery and RFV, the dorsal part of conduit (50U/ml) to the neck that subcutaneous feeding heparin is filled.Spend the night, mouse is recovered from anesthesia, can arbitrarily drink water, but can not pickuping food.
Second day, with femoral catheter be connected pressure transducer (COBE 041-500-508, USA) on, (GRASS Model 7 USA) links to each other, with the monitoring arteriotony for this transverter and polygraph.After suitable starting time, in femoral vein, injecting angiotensin II (0.1 μ g/kg) 3 times between control period.
Constant volume orally give (p.o.) experimental compound and contrast medicine valsartan with 2ml/kg.
Repeat to give angiotensin II then at a fixed time.
Peak value restraining effect percentage ratio by experimental compound and several dosage of contrast medicine calculates ID
50Value, promptly experimental compound produces the needed dosage of 50% restraining effect with the contrast medicine to angiotensin II inductive blood pressure response.
Table 1 The compounds of this invention ID
50Determination data is following:
| Group | ID 50（mg/kg,p.o.） |
| Embodiment 6 compounds | 2.48 |
| Embodiment 7 compounds | 1.10 |
| Embodiment 13 compounds | 2.24 |
| Embodiment 19 compounds | 3.10 |
| Embodiment 20 compounds | 1.64 |
| Embodiment 21 compounds | 2.12 |
| Embodiment 27 compounds | 1.79 |
| Embodiment 33 compounds | 0.93 |
| Embodiment 34 compounds | 1.19 |
| The valsartan control group | 3.68 |
Show that according to The above results The compounds of this invention demonstrates the antagonistic action of angiotensin II preferably; For the ordinary skill of this area, be apparent that and do not departing from spirit of the present invention or scope; Can carry out multiple modification and variation to The compounds of this invention, compsn and method; Therefore, the present invention comprises modification of the present invention and variation, as long as in claim and its scope that is equal to.
Claims (4)
1. pyrimidinones has the structure as shown in the formula I:
Wherein: R is C
1-C
4Alkane, aromatic hydrocarbon, aromatic heterocycle hydrocarbon or
R
1, R
2Independently be selected from C
1-C
4Alkane or aromatic base alkane;
N=1,2 or 3.
2. according to the said compound of claim 1, it is characterized in that R specifically refers to ethyl, n-propyl, normal-butyl, phenyl, pyridine, pyrimidine, pyrazine, furyl, thienyl or thiazolyl.
3. according to the said compound of claim 1, it is characterized in that compound is specially:
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-phenyl-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-(4-pyridyl)-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--4-oxygen-2-phenyl-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-butyl-N, N-dimethyl--4-oxygen-4,5,6,7,8,9-six hydrogen-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(dimethylamino)-N, N-dimethyl--4-oxygen-4,5,6,7-tetrahydrochysene-3 hydrogen-cyclopentyl [d] pyrimidine-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-N, N-dimethyl--2-(N-methyl-N-phenyl amino)-4-oxygen-3,4,5,6,7,8-six hydrogen quinazoline-6-carbon thioamides;
3-((2'-(1 hydrogen-tetrazolium-5-yl)-[1,1'-biphenyl]-4-yl) methyl)-2-(N-ethyl-N-phenyl amino)-N, N-dimethyl--4-oxygen-4,5,6,7,8,9-tetrahydrochysene-3 hydrogen-suberyl [d] pyrimidine-6-carbon thioamides.
4. according to the said pyrimidinones of claim 1, it is characterized in that, as the purposes in the preparation treatment cardiovascular disease medicine.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2020370A1 (en) * | 1989-07-06 | 1991-01-07 | Peter Herold | Pyrimidine derivatives |
| WO1996008476A1 (en) * | 1994-09-17 | 1996-03-21 | Boryung Pharmaceutical Co., Ltd. | Pyrimidinone derivatives |
| CN1266468A (en) * | 1997-07-11 | 2000-09-13 | 杰胡达·T·沃沙维阿克 | Handle |
| WO2006094604A1 (en) * | 2005-03-11 | 2006-09-14 | Merck Patent Gmbh | Tetrahydro- and dihydroquinazolinones |
-
2012
- 2012-06-21 CN CN2012102058582A patent/CN102746280A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2020370A1 (en) * | 1989-07-06 | 1991-01-07 | Peter Herold | Pyrimidine derivatives |
| WO1996008476A1 (en) * | 1994-09-17 | 1996-03-21 | Boryung Pharmaceutical Co., Ltd. | Pyrimidinone derivatives |
| CN1266468A (en) * | 1997-07-11 | 2000-09-13 | 杰胡达·T·沃沙维阿克 | Handle |
| WO2006094604A1 (en) * | 2005-03-11 | 2006-09-14 | Merck Patent Gmbh | Tetrahydro- and dihydroquinazolinones |
Non-Patent Citations (1)
| Title |
|---|
| MARCUS W. NO1TZEL ET AL.: "Domino Reactions of Amidines with Methyl 2-Chloro-2-cyclopropylideneacetate as an Efficient Access to Cyclobutene-Annelated Pyrimidinones", 《ORGANIC LETTERS》, vol. 4, no. 5, 7 February 2002 (2002-02-07), pages 839 - 841 * |
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