CN1743315A - 2-substituted-4,4,5,5-tetramethyl-1-hydroxyimidazoline, and its synthesis and use - Google Patents
2-substituted-4,4,5,5-tetramethyl-1-hydroxyimidazoline, and its synthesis and use Download PDFInfo
- Publication number
- CN1743315A CN1743315A CN 200410074209 CN200410074209A CN1743315A CN 1743315 A CN1743315 A CN 1743315A CN 200410074209 CN200410074209 CN 200410074209 CN 200410074209 A CN200410074209 A CN 200410074209A CN 1743315 A CN1743315 A CN 1743315A
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- Prior art keywords
- tetramethyl
- tetrahydroglyoxaline
- hydroxyl
- compound
- chcl
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- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000003252 repetitive effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000005201 scrubbing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229940083618 sodium nitroprusside Drugs 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 230000000283 vasomotion Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
This invention relates to a preparation method for a group of the compound whose general formula is I, in which R is among substituted phenyl, furyl and pyridyl. The process is: in the condition of bromine, 2-nitropropane is condensed into 2, 3-dimethyl-2, 3-dinitrobutane which is next reduced into 2, 3-dimethyl-2, 3-dihydroxyamidobutane by zinc powder; under the condition of ammonium chloride; 2, 3-dimethyl-2, 3-dihydroxyamidobutane and substituted benzaldehyde (or furaldehyde or pyridylaldehyde) are cyclized into 1, 3-dihydroxy-2-substituted-4, 4, 5, 5-tetramethyl imidazolidiny, which is later oxidized into 2-substituted-4, 4, 5, 5-tetramethyl-1, 3-dioxyimidazoline; in the condition of acid, 2-substituted-4, 4, 5, 5-tetramethyl-1, 3-dioxyimidazoline is reduced into 2-substituted-4, 4, 5, 5-tetramethyl-1-oxyimidazoline, which is ultimately deoxidized into 2-substituted-4, 4, 5, 5-tetramethyl-1-hydroxyimidazoline. The compound can be used to relax blood vessels.
Description
Technical field
The present invention relates to the novel 2-of a class and replace-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline, and synthetic and application.
Background technology
Blood vessel is overstretched can to cause a series of diseases, for example can cause vascular hypertension.Seeking vasodilator drug is one of emphasis of new drug research.Existing vasodilator drug mainly comprises ACE inhibitor, α
1Receptor-blocking agent, calcium antagonist, phthalazine derivatives, potassium channel openers and nitro vasodilator.ACE inhibitor is because can diastole artery and vein, so can reduce the whole body peripheral vascular resistance, bring high blood pressure down (old repairing. renin-angiotensin and inhibitor thereof. see: the Chen Xiu chief editor. cardiovascular pharmacology. first version Beijing: People's Health Publisher, 1989,237).The generation alleviating vascular contraction of ACE inhibitor by reducing Ang II, induce NO and PGI by the effect of preserving BK
2Generate, and then vasodilator, reduce sympathetic nerve to cardiovascular tension force by the release that suppresses the sympathetic nerve mediator.α
1Receptor-blocking agent high selectivity retardance vascular smooth muscle postsynaptic membrane α
1Acceptor is to α
1Acceptor has high affinity, can antagonism α
1The vasoconstriction of receptor stimulant methoxamedrine and neophryn and boosting (van Zwieten PA.Development and trends in the drug treatment of essential hypertension.JHypertension 1992,10 (Suppl.7), S1).Calcium antagonist suppresses the outer Ca of born of the same parents by the retardation to calcium channel
2+Stride stream in the film, reduce Free Ca in the vascular smooth muscle cell
2+, and make vascular smooth muscle relaxation.Calcium antagonist mainly produces antihypertensive function by expansion arteriole and reduction peripheral vascular resistance.The contractile response that high potassium depolarize causes is to depend on the outer Ca of born of the same parents
2+Stride stream in the film, calcium antagonist can suppress Ca outside the born of the same parents in the experiment of myocardium vessel unstriated muscle sample
2+Stride stream in the film (old repairing. renin-angiotensin and inhibitor thereof. see: the Chen Xiu chief editor. cardiovascular pharmacology. (second edition) Beijing: People's Health Publisher, 1996,325).Phthalazine derivatives mainly acts on the vasodilation that arteriole produces vast scope, selectivity reduces cerebral arteries, coronary artery and arteriorenal vascular resistance, and to less (the .Gerber JG of skeletal muscle and skin heart effect, Nies AS.Antihypertensive agents and the drug therapy of hypertension, In:Goodman and Gilman ' s.The Pharmacological basis of therapeutics.8th ed, Pergamon, New York:Macmillan 1990,784).Potassium channel openers meta-bolites in vivo can increase the vascular smooth muscle cell film to K
+Permeability, promote K in the born of the same parents
+Outflow, cause that vascular smooth muscle cell film hyperpolarization makes vascular smooth muscle relaxation and blood pressure drops (Murdoch D.Brogden RN.Sustainedrelease nifedipine formulations.Drugs 1991,41,737).The nitro vasodilator comprises that mononitrate ester healer and NO donor can discharge NO, cGMP is raise and lax vascular smooth muscle, also have an effect of platelet aggregation-against.The mononitrate ester healer part produces NO at vessel wall after liver metabolism.The acceptor of NO is the active centre iron ion on the soluble guanylate cyclase, their in conjunction with after the three-dimensional structure of guanylate cyclase is changed improve the activity of enzyme.The intracellular cGMP generation increases inhibition PKC phosphorylation can cause Ca
2+Ca in interior stream, the reduction cell
2+Discharge, increase Ca in the born of the same parents
2+Discharge, finally reduce Ca in the born of the same parents
2+Concentration.Contractile protein is to Ca
2+Susceptibility also weaken K on the muscle cell membrane
+The activity of passage also descends, thereby causes vasorelaxation.NO donor such as Sodium Nitroprusside, 1,2,5-oxadiazoles, CHF2206 all can discharge NO vasodilation (Ferioli R et al.a new class of furoxan derivative as NO donors:mechanism of action and biological activety.Br J Pharmacol 1995,114,816; Civellim, et al.CHF2206, a new potent vasodilating and antiaggregating drug aspotential nitric oxide donor.Eur J Pharmacol 1994,255,17; Blatter CA, Wier WG.Nitric oxide decreases[Ca
2+]: in vascular smooth muscle by inhibition of thecalcium current.Cell Calcium 1994,255,17).
2-substituted-phenyl-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline belongs to stable nitroxyl free radical, remarkable vasodilator, do not influence Hemodynamics character (the Ryusuke Tsunoda of the myocardial contraction and the recycle system, Ken Okumura.Vasodilator effect of carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-l-oxylin the coronary circulation:in vivo and invitro studies.European Journal of Pharmacology 1994,262,55-63).The contriver notices, 2-replaces-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline increases volume of blood flow and do not reduce arteriotony, enters blood and still have effect after 30 minutes.2-replaces-4,4,5, and these advantages of 5-tetramethyl--1-oxygen base tetrahydroglyoxaline make it obviously be different from clinical existing vasodilator medicine.Development 2-replaces-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline has obvious significance.
Summary of the invention
Technical problem to be solved by this invention provides a kind of novel 2-and replaces-4,4,5,5-tetramethyl--1-hydroxyl imidazolinium compounds.
Technical problem to be solved by this invention also is to provide novel 2-to replace-4,4,5, the preparation method and the application thereof of 5-tetramethyl--1-hydroxyl imidazolinium compounds.
Compound provided by the invention is the compound as general formula I,
General formula I
Wherein, R is R
1 nThe phenyl that replaces, or furyl, or pyridyl, the substituting group in the substituted-phenyl is R
1 n, n=0,1 or 2, when n=1, R
1 1Be 2-hydroxyl, 3-hydroxyl, 4-hydroxyl, 4-methyl, 4-methoxyl group, 2,4-dimethoxy, 3,4-dimethoxy, 3,4-(methylenedioxy), 4-dimethylamino, 2-fluorine, 4-chlorine, 4-bromine, 2-nitro, 3-nitro, 4-nitro; When n=2, R
1 2Be 3-hydroxyl-4-methoxyl group, 3-methoxyl group-4-hydroxyl, 2,4-dichloro, 3,4-dichloro.
The present invention also provides the preparation method of compound of Formula I, and this method comprises: at alkali and Br
2Existing down, the condensation of 2-nitropropane generates 2,3-dimethyl-2,3-dinitrobenzene butane; At NH
4Cl exists to descend 2, and 3-dimethyl-2,3-dinitrobenzene butane are 2 by zinc powder reduction, 3-dimethyl-2,3-dihydroxy amido butane; 2,3-dimethyl-2,3-dihydroxy amido butane and substituted benzaldehyde or furfural or pyridylaldehyde cyclization generate 1, and 3-dihydroxyl-2-replaces-4,4,5,5-tetramethyl-imidazolidine; 1,3-dihydroxyl-2-replaces-4,4,5, and 5-tetramethyl-imidazolidine is oxidized to 2-for oxidized dose and replaces-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline; Under acidic conditions, 2-replaces-4,4,5, and 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are reduced agent and are reduced to 2-replacement-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline; 2-replaces-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is reduced to 2-and replaces-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline, i.e. compound of general formula I.
Above-mentioned synthetic method can be used following procedural representation:
Wherein the definition of R as mentioned above.
The present invention also provides the vasorelaxation action of compound of Formula I.
Embodiment
In order to explain the present invention, provide a series of embodiment below.These examples are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
General rule: intermediate and degree of purity of production confirm that with TLC EI-MS measures with the Trace MS System mass spectrograph of U.S. Thermo Finnigan company.Infrared spectra (IR) adopts Avatar 360 Fourier transformation infrared spectrometers of U.S. Nicolet company to measure.Nuclear magnetic resonance spectrum (NMR) adopts NEC AL-300FTNMR System to measure.The micro-fusing point instrument of the X75 that fusing point adopts Beijing instrument electric light instrument plant of section to produce is measured, and thermometer is not proofreaied and correct.Silica gel for chromatography is produced by Haiyang Chemical Plant, Qingdao.
Midbody compound 2,3-dimethyl-2, the preparation of 3-dinitrobenzene butane
34.5g (0.39mol, 35ml) the 2-nitropropane is added in 65ml NaOH (6mol/l) aqueous solution.Bathe under the agitation condition at cryosel, drip 10ml (0.19mol) Br
2, drip in the 1h.Add 128ml ethanol then.Reaction mixture refluxes in 84 ℃ and stirs 3h, the sheet insolubles occurs.Take advantage of heat to pour in the 400ml frozen water reaction mixture.Leach precipitation, get 25g (73%) title compound, be the white plates crystallization, mp 110-112 ℃.
Midbody compound 2,3-dimethyl-2, the preparation of 3-dihydroxy amido butane
With 7.0g (40mmol) 2,3-dimethyl-2,3-dinitrobenzene butane and 4.0g NH
4Cl is suspended in 80ml ethanol (50%) solution.Ice bath stirs down.In 3h, add the 16.0g zinc powder.After zinc powder adds, remove ice bath, continue stirring at room reaction 3h, then with the reaction solution suction filtration.Filter cake is with 50% aqueous ethanolic solution repetitive scrubbing.It is 2 that filtrate that merges and washings are transferred pH with concentrated hydrochloric acid, is evaporated to muddy.Adding an amount of salt of wormwood in slurry, after mixing thoroughly, use apparatus,Soxhlet's, is to extract 6h with chloroform.Extracting solution is evaporated on a small quantity, separates out 2.60g (44%) title compound behind the adding sherwood oil, is white crystals, mp 157-159 ℃.
Embodiment 1
2-phenyl-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
212mg (2mmol) phenyl aldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 16h, TLC shows that raw material point disappears.Leach 401mg (85%) 1,3-dihydroxyl-2-phenyl-4,4,5,5-tetramethyl-imidazolidine is white solid, is directly used in next step reaction.Sample behind the TLC purifying, EI-MS:236.3[M]
+R
f0.64 (CHCl
3/ CH
3OH, 10: 1), mp:168-169; IR (KBr) 3340 (OH); 1600,1450;
1H-NMR (CDCl
3-d) δ (ppm)=1.14 (s, 12H ,-CH
3), 4.78 (s, 1H ,-CH), 7.31-7.51 (m, 5H, Ar-H), 7.71 (s, 2H, N-OH); Ultimate analysis: C
13H
20N
2O
2Calculated value is C 66.07, and H 8.53, and N 11.85; Measured value is C 66.25, H 8.71N 11.71.
95mg (0.4mmol) 1,3-dihydroxyl 2-phenyl-4,4,5,5-tetramethyl-glyoxalidine quinoline is dissolved in the 5ml methyl alcohol.In the solution that obtains, add 0.5g PbO
2, behind the stirring at room 0.5h, TLC shows that raw material point disappears.The elimination solid.Be evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 74mg (80%) 2-phenyl-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is black-and-blue crystal.R
f0.54 (CHCl
3/ CH
3OH, 20: 1); Mp 84-85 ℃; EI-MS 233[M]
+, 201[M-32]
+, 145[M-88]
+IR (KBr) 1610,1450 (phenyl ring).Ultimate analysis: C
13H
17N
2O
2Calculated value is C66.93 H 7.34, and N 12.01; Measured value is C 66.69H 7.55, and N 11.98.
250mg (1.07mmol) 2-phenyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 15ml methyl alcohol, adds 0.5ml water, 500mgNaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution by black-and-blue become orange red.Concentrating under reduced pressure is removed most of solvent, is transferred pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution.TLC detects and is single point.Filter, be evaporated under the filtrate room temperature dried, 232mg (99%) 2-phenyl-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red oil, R
f0.61 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 217[M]
+Ultimate analysis: C
13H
17N
2The O calculated value is C 71.86H 7.89, and N 12.89; Measured value is C 71.69 H 7.75, and N 12.99.
55mg (0.25mmol) 2-phenyl-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 38mg (69%) title compound, be light yellow solid, R
f0.15 (CHCl
3/ CH
3OH, 20: 1); Mp 173-175 ℃; EI-MS (m/z): 218[M]
+ 1H-NMR (CDCl
3-d) δ (ppm)=1.15 (s, 12H ,-CH
3), 7.29-7.62 (m, 5H, Ar-H); Ultimate analysis: C
13H
18N
2The O calculated value is C 71.53H 8.31, and N 12.83;
Embodiment 2
2-(2 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
244mg (2mmol) salicylic aldehyde (2-hydroxy benzaldehyde) and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 1.5ml methyl alcohol, behind the stirring at room 20h, TLC shows that raw material point disappears, leach 287mg (57%) 1,3-dihydroxyl-2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.73 (CHCl
3/ CH
3OH, 6: 1).Be directly used in next step reaction.Sample is through TLC purifying, EI-MS:252[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.08 (s, 12H ,-CH
3), 4.63 (s, 1H ,-CH), 6.70 (m, 2H, Ar-H), 7.14 (m, 2H, Ar-H), 8.12 (s, 1H ,-OH), 8.35 (s, 2H, N-OH); IR (KBr): 3325,1600,1500,765.Ultimate analysis: C
13H
20N
2O
3Calculated value is C 61.88, and H 7.99, and N 11.10; Measured value is C 61.65, and H 7.77, and N 11.41.
160mg (0.63mmol) 1,3-dihydroxyl-2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 40ml methyl alcohol, adds 0.5g PbO in this solution
2, behind the stirring at room 60min, TLC shows that raw material point disappears.The elimination solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 100mg (64%) 2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue solid; R
f0.75 (CHCl
3/ CH
3OH, 20: 1); Mp 83-85 ℃; EI-MS:249[M]
+, 217[M-32]
+IR (KBr): 3345,1610,1500,1450; 760.Ultimate analysis: C
13H
17N
2O
3Calculated value is C 62.64, and H 6.87, and N 11.24; Measured value is C 62.80, and H 6.65, and N 11.41.
50mg (0.21mmol) 2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 5ml methyl alcohol, add 0.5ml water, 100mg NaNO
2, drip 2N HCl and transfer pH5, stirring at room 60min, reaction solution becomes redness by purple, removes most of solvent under reduced pressure, transfers pH 6-7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, be evaporated under the filtrate room temperature dried, 47mg (96%) 2-(2 ,-hydroxy phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange red oily matter, R
f0.83 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 233[M]
+IR (KBr): 1610,1450,760.Ultimate analysis: C
13H
17N
2O
2Calculated value is C 66.93, and H 7.35, and N 12.01; Measured value is C 66.75, and H 7.11, and N 12.33.
59mg (0.25mmol) 2-(2 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 29mg (49%) title compound, be light yellow solid, R
f0.11 (CHCl
3/ CH
3OH, 20: 1); Mp 137-139 ℃; EI-MS (m/z): 234[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.11 (s, 12H ,-CH
3), 6.76 (m, 2H, Ar-H), 7.34 (m, 2H, Ar-H), 8.15 (s, 1H, Ar-OH); Ultimate analysis: C
13H
18N
2O
2Calculated value is C 66.64H 7.74, N11.96;
Embodiment 3
2-(3 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
245mg (2mmol) 3-hydroxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol stirring at room 24h, TLC shows that raw material point disappears, leach 304mg (60.3%) 1,3-dihydroxyl-2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is white powder, R
f0.56 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:252[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 4.51 (s, 1H ,-CH), 6.89 (m, 4H, Ar-H), 7.71 (s, 1H ,-OH), 7.95 (s, 2H, N-OH); IR (KBr): 3320,1600,1500,880,795,695.Ultimate analysis: C
13H
20N
2O
3Calculated value is C 61.88, and H 7.99, N, 11.10; Measured value is C 61.67, and H 7.74, N, 11.31.
252mg (1mmol) 1,3-dihydroxyl-2-(3 '-hydroxy phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 40ml methyl alcohol.In this solution, add 0.7g PbO
2, behind the stirring at room 10min, TLC shows that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 192mg (76%) 2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue rhomboidan.R
f0.33(CHCl
3/CH
3OH，20∶1)；mp 137-139℃；EI-MS：249[M]
+，218[M-31]
+；IR(KBr)：3340、1590、1500、1450、880、800、690。Ultimate analysis: C
13H
17N
2O
3Calculated value is: C 62.64, and H 6.87, and N 11.24; Measured value is C 62.80, and H 6.68, N11.01.
55mg (0.22mmol) 2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 5ml methyl alcohol, adds 0.5ml water, 100mg NaNO
2, drip 2NHCl and make the pH value be about 5, stirring at room 60min, reaction solution is become orange-yellow by blueness, the most of solvent of pressure reducing and steaming, and residue is transferred pH 6-7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer is behind the anhydrous sodium sulfate drying, TLC detects and to be to filter single point, filtrate decompression concentrate as for, get 29mg (56%) 2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow oil, R
f0.52 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 233[M]
+IR (KBr): 3340,1590,880,790.Ultimate analysis: C
13H
17N
2O
2Calculated value is: C 66.93, and H 7.35, and N 12.01; Measured value is C 66.70, and H 7.52, and N 12.24.
59mg (0.25mmol) 2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 32mg (55%) title compound, be light yellow solid, R
f0.10 (CHCl
3/ CH
3OH, 20: 1); Mp 173-174 ℃; EI-MS (m/z): 234[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 7.12 (m, 4H, Ar-H), 7.81 (s, 1H, Ar-OH); Ultimate analysis: C
13H
18N
2O
2Calculated value is C 66.64 H 7.74, and N 11.96.
Embodiment 4
2-(4 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
244mg (2mmol) p-Hydroxybenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and behind the stirring at room 8h, TLC shows that raw material point disappears.Filter 257mg (51%) 1,3-dihydroxyl-2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.67 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.EI-MS：252[M]
+；
1H-NMR(DMSO-d
6)δ(ppm)＝1.03(s，6H，-CH
3)，1.05(s，6H，-CH
3)，4.39(s，1H，-CH)，6.70(d，J＝6.9Hz，2H，Ar-H)，7.23(d，J＝6.9Hz，2H，Ar-H)，7.63(s，1H，Ar-OH)，7.85(s，2H，N-OH)；IR(KBr)：3310、1610、1500、1450、830。Ultimate analysis: C
13H
20N
2O
3Calculated value is: C 61.88, and H 7.99, and N 11.10; Measured value is C 61.66, and H 7.78, and N 11.23.
126mg (0.5mmol) 1,3-dihydroxyl-2-(4 '-hydroxy phenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 300mg PbO
2, behind the stirring at room 40min, TLC shows that raw material point disappears.The elimination solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 65mg (52%) 2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue look solid.R
f0.13(CHCl
3/CH
3OH，20∶1)；mp 134-135℃，EI-MS：249[M]
+，218[M-31]
+；IR(KBr)：3250、1500、1490、840。Ultimate analysis: C
13H
17N
2O
3Calculated value is: C 62.64, and H 6.87, and N 11.24; Measured value is C 62.81, and H 6.65, and N 11.40.
25mg (0.1mmol) 2-(4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 3ml methyl alcohol, adds 0.5ml water, adds 50mg NaNO
2, drip 2N HCl, become glassy yellow until the color of reaction solution, transfer pH=6～7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried, gets 15mg (65%) 2-(4 '-hydroxy phenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow solid, mp 98-100 ℃.R
f0.36 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 235[M+2]
+Ultimate analysis: C
13H
17N
2O
2Calculated value is: C 66.93, and H 7.35, N, 12.01; Measured value is C 66.70, and H 7.54, N, 12.25.
60mg (0.25mmol) 2-(3 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 36mg (59%) title compound, be light yellow solid, R
f0.10 (CHCl
3/ CH
3OH, 20: 1); Mp 197-198 ℃; EI-MS (m/z): 234[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 6.76 (d, J=6.9Hz, 2H, Ar-H), 7.45 (d, J=6.9Hz, 2H, Ar-H), 7.73 (s, 1H, Ar-OH); Ultimate analysis: C
13H
18N
2O
2Calculated value is C 66.64 H 7.74, and N 11.96.
Embodiment 5
2-(4 '-aminomethyl phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
240mg (2mmol, 0.236ml) 4-tolyl aldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and behind the stirring at room 12h, TLC shows that raw material point disappears.Filter 350mg (60%) 1,3-dihydroxyl-2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.61 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.EI-MS：250[M]
+；
1H-NMR(DMSO-d
6)δ(ppm)＝1.14(s，6H，-CH
3)，1.19(s，6H，-CH
3)，1.37(s，3H，-CH
3)，4.90(s，1H，-CH)，7.68(d，J＝9.0Hz，2H，Ar-H)，8.22(d，J＝5.7Hz，2H，Ar-H)，8.35(s，2H，N-OH)；IR(KBr)：3335、2985、1600、1500、815。Ultimate analysis: C
14H
22N
2O
2Calculated value is: C 67.17, and H 8.86, and N 11.19; Measured value is C 67.32, and H 8.62, and N 11.40.
250mg (1mmol) 1,3-dihydroxyl-2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol.In this solution, add 0.5g PbO
2, behind the stirring at room 30min, TLC shows that raw material point disappears.The elimination solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 197mg (80%) 2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue solid.R
f0.88(CHCl
3/CH
3OH，20∶1)；mp 86-88℃；EI-MS：247[M]
+，215[M-32]
+；IR(KBr)：2980、1610、1500、1450、810。Ultimate analysis: C
14H
19N
2O
2Calculated value is: C 67.99, and H 7.74, N, 11.33; Measured value is C 67.77, and H 7.91, N, 11.55.
250mg (1mmol) 2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 15ml methyl alcohol, adds 0.5ml water, adds 500mg NaNO
2, drip 2N HCl, after the color of reaction solution became glassy yellow, transfers pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution, TLC detected and is to filter single point, filtrate decompression is concentrated into dried.Filter 200mg (86%) 2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange/yellow solid, mp156-157 ℃.R
f0.93 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 231[M]
+Ultimate analysis: C
14H
19N
2The O calculated value is C 72.69, and H 8.28, N12.11; Measured value is C 72.80, and H 8.42, N12.32.
58mg (0.25mmol) 2-(4 '-aminomethyl phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 41mg (70%) title compound, be light yellow solid, R
f0.15 (CHCl
3/ CH
3OH, 20: 1); Mp 79-81 ℃; EI-MS (m/z): 232[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.15 (s, 12H ,-CH
3), 1.38 (s, 3H ,-CH
3), 7.50 (d, J=9.0Hz, 2H, Ar-H), 8.12 (d, J=5.7Hz, 2H, Ar-H); Ultimate analysis: C
14H
20N
2The O calculated value is C 72.38H 8.68, N12.06.
Embodiment 6
2-(4 '-p-methoxy-phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
273mg (2mmol) 4-methoxybenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and stirring at room 16h, TLC show that raw material point disappears.Filter 372mg (70%) 1,3-dihydroxyl-2-(4 '-p-methoxy-phenyl) 4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.52 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.EI-MS：266[M]
+；
1H-NMR(DMSO-d
6)δ(ppm)＝0.99(s，6H，-CH
3)，1.03(s，6H，-CH
3)，3.73(s，3H，-OCH
3)，4.56(s，1H，-CH)，6.88(d，J＝4.2Hz，2H，Ar-H)，7.38(d，J＝5.7Hz，2H，Ar-H)，7.77(s，2H，N-OH)；IR(KBr)：3340、2835、1600，1500、825。Ultimate analysis: C
14H
22N
2O
3Calculated value is C 63.14, and H 8.33, and N 10.52; Measured value is C 63.31, and H 8.55, and N 10.71.
266mg (1mmol) 1,3-dihydroxyl-2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol.In this solution, add 0.6g PbO
2, stirring at room 30min, TLC show that raw material point disappears.The elimination solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 258mg (97%) 2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue solid, R
f0.54 (CHCl
3/ CH
3OH, 20: 1); Mp 89-92 ℃; EI-MS:263[M]
+, 231[M-32]
+IR (KBr): 2830,1600,835.Ultimate analysis: C
14H
19N
2O
3Calculated value is C63.86, and H 7.27, and N 10.64; Measured value is C 63.64, and H 7.41, and N 10.42.
250mg (0.95mmol) 2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is dissolved in the 15ml methyl alcohol, adds 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution removes most of solvent under reduced pressure by the black-and-blue vermilion red that becomes, and transfers pH=6～7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer is behind the anhydrous sodium sulfate drying, TLC detects and is single point, filters, and it is dried that filtrate decompression is concentrated into, get 212mg (86%) 2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red solid; Mp 42-43 ℃, R
f0.63 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 247[M]
+IR (KBr): 2830,1610,840.Ultimate analysis: C
14H
19N
2O
2Calculated value is C 67.99, and H 7.74, N, 11.33; Measured value is C 67.77, and H 7.55, and N 11.55.
62mg (0.25mmol) 2-(4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg (moisture 45%) 5%Pd/C powder, and the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 51mg (83%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 81-83 ℃; EI-MS (m/z); 248[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.01 (s, 12H ,-CH
3), 3.73 (s, 3H ,-OCH
3), 6.80 (d, J=4.2Hz, 2H, Ar-H), 7.51 (d, J=5.7Hz, 2H, Ar-H); Ultimate analysis: C
14H
20N
2O
2Calculated value is C 67.71 H 8.12, N11.28.
Embodiment 7
2-(2 ', 4 '-dimethoxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
332mg (2mmol) 2,4-dimethoxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 5ml methyl alcohol, and stirring at room 20h, TLC show that raw material point disappears.Filter 349mg (59%) 1,3-dihydroxyl-2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.49 (CHCl
3/ CH
3OH, 10: 1).Be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:296[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 12H ,-CH
3), 3.72 (s, 6H ,-OCH
3), 4.99 (s, 1H ,-CH), 7.45 (m, 3H, Ar-H), 7.79 (s, 2H, N-OH); IR (KBr): 3295,2825,1600,1500,1450,810,865.Ultimate analysis: C
15H
24N
2O
4Calculated value is C 60.79, and H 8.16, and N 9.45; Measured value is C 60.54, and H 8.38, and N 9.66.
296mg (1mmol) 1,3-dihydroxyl-2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 15min, TLC show that raw material point disappears.The elimination solid, filtrate decompression is concentrated into dried.Residue column chromatography for separation (chloroform is an eluent) gets 249mg (85%) 2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline.Be purple solid, R
f0.37 (CHCl
3/ CH
3OH, 20: 1); Mp 75-77 ℃; EI-MS:293[M]
+, 261[M-32]
+IR (KBr): 2830,1610,1590,1450,805,870.Ultimate analysis: C
15H
21N
2O
4Calculated value is C 61.42, and H 7.22, and N 9.55; Measured value is C 61.61, and H 7.43, and N 9.72.
290mg (1mmol) 2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution is become orange-yellow by blueness, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point, filter, filtrate decompression is concentrated into dried.Get 178mg (64%) 2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow solid, mp 77-79 ℃; R
f0.41 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 277[M]
+IR (KBr): 2850,1610,1590,1500,805,830.Ultimate analysis: C
15H
21N
2O
3Calculated value is C 64.96, and H 7.63, and N 10.10; Measured value is C 64.72, and H 7.41, and N 10.22.
69mg (0.25mmol) 2-(2 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 43mg (63%) title compound, be light yellow solid, R
f0.12 (CHCl
3/ CH
3OH, 20: 1); Mp 97-99 ℃; EI-MS (m/z): 278[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 12H ,-CH
3), 3.73 (s, 6H ,-OCH
3), 7.32 (m, 3H, Ar-H); Ultimate analysis: C
15H
22N
2O
3Calculated value is C 64.73 H 7.97, and N 10.06.
Embodiment 8
2-(3 ', 4 '-dimethoxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
677mg (4mmol) 3,4-dimethoxy benzaldehyde and 292mg (4mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, and stirring at room 20h, TLC show that raw material point disappears, filter 390mg (33%) 1,3-dihydroxyl-2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.52 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample obtains object behind the TLC purifying, EI-MS:296[M]
+ 1H-NMR (DMSO-d
6): δ (ppm)=1.05 (s, 12H ,-CH
3), 3.74 (s, 6H ,-OCH
3), 4.53 (s, 1H ,-CH), 6.85 (m, 3H, Ar-H), 7.85 (s, 2H, N-OH); IR (KBr): 3310,2825,1610,1500,815,865.Ultimate analysis: C
15H
24N
2O
4Calculated value is C 60.79, and H 8.16, N, 9.45; Measured value is C 60.55, and H 8.01, N, 9.67.
296mg (1mmol) 1,3-dihydroxyl-2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 100ml methyl alcohol.In this solution, add 1.0g PbO
2, stirring at room 20min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 246mg (83%) 2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue square crystal.R
f0.34(CHCl
3/CH
3OH，20∶1)；mp 95-97℃；EI-MS：293[M]
+；IR(KBr)：2830、1600、1450、820、870。Ultimate analysis: C
15H
21N
2O
4Calculated value is: C 61.42, and H 7.22, and N 9.55; Measured value is C 61.63, and H 7.01, and N 9.34.
290mg (1mmol) 2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution is become orange-yellow by blueness, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7, chloroform extraction with saturated sodium bicarbonate aqueous solution, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression concentrates, and gets 138mg (50%) 2-(3 ', 4 '-dimethoxy phenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow solid, mp 74-75 ℃; R
f0.43 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 277[M]
+Ultimate analysis: C
15H
21N
2O
3Calculated value is C 64.96, and H 7.63, and N 10.10; Measured value is C 64.72, and H 7.41, and N 10.31.
69mg (0.25mmol) 2-(3 ', 4 '-dimethoxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 27mg (40%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 89-90 ℃; EI-MS (m/z): 278[M]
+ 1H-NMR (DMSO-d
6): δ (ppm)=1.05 (s, 12H ,-CH
3), 3.75 (s, 6H ,-OCH
3), 6.93 (m, 3H, Ar-H); Ultimate analysis: C
15H
22N
2O
3Calculated value is C 64.73, and H 7.97, and N 10.06.
Embodiment 9
2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
300mg (2mmol) piperonylaldehyde and 296mg (2mmol) 2 ,-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, stirring at room 24h, TLC shows raw material point disappearance, filter 240mg (43%) 1,3-dihydroxyl-2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl-imidazolidine, be colourless powder, R
f0.47 (CHCl
3/ CH
3OH, 40: 1).Be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:280[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.11 (s, 12H ,-CH
3), 4.66 (s, 1H ,-CH), 5.99 (s, 2H ,-CH
2), 6.90 (m, 3H, Ar-H), 7.83 (s, 2H, N-OH); IR (KBr): 3315,1600,1235,1105,910.Ultimate analysis: C
14H
20N
2O
4Calculated value is C 59.99, and H 7.19, and N 9.99; Measured value is C 59.78, and H 7.01, and N 9.75.
200mg (0.71mmol) 1,3-dihydroxyl-2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol, adds 0.8g PbO in this solution
2, stirring at room 15min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 162mg (64%) 2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue solid.R
f0.75(CHCl
3/CH
3OH，20∶1)；mp 97-99℃；EI-MS：277[M]
+，246[M-32]
+；IR(KBr)：1600、1240、1100、910。Ultimate analysis: C
14H
17N
2O
4Calculated value is C 60.64, and H 6.18, and N 10.10; Measured value is C 60.82, and H 6.36, and N 10.32.
300mg (1.1mmol) 2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, dripping 2N HCl, to transfer pH be 5, stirring at room 60min, reaction solution is become orange red by blueness, concentrating under reduced pressure is removed most of solvent, and transferring pH with saturated sodium bicarbonate aqueous solution is 6-7, chloroform extraction, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, be evaporated to dried under the filtrate room temperature.Get 230mg (81%) 2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange red solid, mp 46-47 ℃; R
f0.82 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 261[M]
+IR (KBr): 1450,935,1260,3420.Ultimate analysis: C
14H
17N
2O
3Calculated value is C 64.35, and H 6.56, N, 10.72; Measured value is C 64.14, and H 6.33, N, 10.91.
65mg (0.25mmol) 2-(3 ', 4 '-methylene dioxy phenyl group)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 47mg (72%) title compound, be light yellow solid, R
f0.12 (CHCl
3/ CH
3OH, 20: 1); Mp 109-110 ℃; EI-MS (m/z): 262[M]
+ 1H-MR (DMSO-d
6) δ (ppm)=1.15 (s, 12H ,-CH
3), 5.99 (s, 2H ,-CH
2), 7.02 (m, 3H, Ar-H); Ultimate analysis: C
14H
18N
2O
3Calculated value is C 64.73 H 7.97, and N 10.06;
Embodiment 10
2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
304mg (2mmol) 3-hydroxyl, 4-methoxybenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, stirring at room 20h, TLC show raw material point disappearance, filter 276mg (49%) 1,3-dihydroxyl-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl-imidazolidine, be colourless powder, R
f0.52 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:282[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.04 (s, 6H ,-CH
3) 3.72 (s, 3H ,-OCH
3), 4.53 (s, 1H ,-CH), 6.82 (s, 2H, Ar-H), 6.94 (s, 1H, Ar-H), 7.65 (s, 1H ,-OH), 8.04 (s, 2H, N-OH); IR (KBr): 3340,2825,1600,1500,1450,825.Ultimate analysis: C
14H
22N
2O
4Calculated value is C 59.56, H7.85, and N 9.92; Measured value is C 59.24, and H 7.62, and N 9.71.
141mg (0.5mmol) 1,3-dihydroxyl-2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 20min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 95mg (68%) 2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue colored crystal.R
f0.34(CHCl
3/CH
3OH，20∶1)；mp 117-119℃；EI-MS：279[M]
+，247[M-32]
+；IR(KBr)：3320、2830、1590、1500、1460、820。Ultimate analysis: C
14H
19N
2O
4Calculated value is C 60.20, and H 6.86, and N 10.03; Measured value is C 60.41, and H 7.01, and N 10.10.
250mg (0.9mmol) 2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH5, stirring at room 60min, reaction solution is become orange-yellow by blueness, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7, chloroform extraction with saturated sodium bicarbonate aqueous solution, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried, gets 106mg (45%) 2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow solid, mp 70-71 ℃; R
f0.45 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 263[M]
+Ultimate analysis: C
14H
19N
2O
3Calculated value is C 63.86, and H 7.27, and N 10.64; Measured value is C 63.65, and H 7.05, N 10.8l.
65mg (0.25mmol) 2-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 26mg (40%) title compound, be light yellow solid, R
f0.19 (CHCl
3/ CH
3OH, 20: 1); Mp 156-157 ℃; EI-MS (m/z): 264[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.05 (s, 12H ,-CH
3), 3.73 (s, 3H ,-OCH
3), 6.63 (s, 2H, Ar-H), 6.98 (s, 1H, Ar-H), 7.07 (s, 1H, Ar-H), 7.59 (s, 1H, Ar-OH); Ultimate analysis: C
14H
20N
2O
3Calculated value is C 63.62, and H 7.63, and N 10.60.
Embodiment 11
2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
304mg (2mmol) 3-methoxyl group, 4-hydroxy benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, stirring at room 20h, TLC show raw material point disappearance, filter 186mg (33%) 1,3-dihydroxyl-2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine, be colourless powder, R
f0.47 (CHCl
3/ CH
3OH, 6: 1).Be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:282[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.00 (s, 6H ,-CH
3), 1.03 (s, 6H ,-CH
3), 3.74 (s, 3H ,-OCH
3), 4.4l (s, 1H ,-CH), 6.70 (d, J=7.8Hz, 1H, Ar-H), 6.85 (d, J=8.1Hz, 1H, Ar-H), 7.02 (s, 1H, Ar-H), 7.68 (s, 1H ,-OH), 8.05 (s, 2H, N-OH); IR (KBr): 3310,2840,1600,1500,1450,815,870.Ultimate analysis: C
14H
22N
2O
4Calculated value is C 59.56, and H 7.85, and N 9.92; Measured value is C59.33, and H 7.62, and N 9.70.
141mg (0.5mmol) 1,3-dihydroxyl-2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 15min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 100mg (71%) 2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue solid, R
f0.38 (CHCl
3/ CH
3OH, 20: 1); Mp 83-85 ℃; EI-MS:279[M]
+, 247[M-32]
+IR (KBr): 3340,2830,1590,1490,1450,820,875.Ultimate analysis: C
14H
19N
2O
4Calculated value is C 60.20, and H 6.86, and N 10.03; Measured value is C 60.41, and H 7.02, and N 9.88.
250mg (0.9mmol) 2-(3 '-methoxy 4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mgNaNO
2, drip 2NHCl and transfer pH 5, stirring at room 60min, reaction solution is become orange-yellow by blueness, remove most of solvent under reduced pressure, transfers pH 6-7 with saturated sodium bicarbonate aqueous solution, chloroform extraction, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried.Get 95mg (40%) 2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow oil, R
f0.50 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 263[M]
+Ultimate analysis: C
14H
19N
2O
3Calculated value is C 63.86, and H 7.27, and N 10.64; Measured value is C 63.65, and H 7.04, and N 10.42.
65mg (0.25mmol) 2-(3 '-methoxy-4 '-hydroxy phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 21mg (32%) title compound, be light yellow solid, R
f0.11 (CHCl
3/ CH
3OH, 20: 1); Mp 113-115 ℃; EI-MS (m/z): 264[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.02 (s, 12H ,-CH
3), 3.74 (s, 3H ,-OCH
3), 6.65 (d, J=7.8Hz, 1H, Ar-H), 6.96 (d, J=8.1Hz, 1H, Ar-H), 7.01 (s, 1H, Ar-H), 7.62 (s, 1H, Ar-OH); Ultimate analysis: C
14H
20N
2O
3Calculated value is C 63.62, and H 7.63, and N 10.60.
Embodiment 12
2-(4 '-dimethylamino phenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
298mg (2mmol) 4-N, N-dimethylbenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol, stirring at room 20h, TLC show raw material point disappearance, filter 173mg (31%) 1,3-dihydroxyl-2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl-imidazolidine, be colourless powder, R
f0.53 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample is through TLC purifying, EI-MS:279[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 2.85 (s, 6H ,-CH
3), 4.01 (s, 1H ,-CH), 6.68 (d, J=8.7Hz, 2H, Ar-H), 7.25 (d, 2H, J=8.7Hz, Ar-H), 7.60 (s, 2H, N-OH); IR (KBr): 3345,2840,1595,1450,840.Ultimate analysis: C
15H
25N
3O
2Calculated value is C 64.49, and H 9.02, and N 15.04; Measured value is C 64.70, and H 9.23, and N 15.25.
140mg (0.5mmol) 1,3-dihydroxyl-2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 40min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 92mg (66%) 2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue colored crystal, R
f0.51 (CHCl
3/ CH
3OH, 20: 1); Mp 151-154 ℃; EI-MS:276[M]
+, 244[M-32]
+IR (KBr): 2850,1595,1500,845.Ultimate analysis: C
15H
22N
3O
2Calculated value is C 65.19, and H 8.02, and N 15.21; Measured value is C 65.41, and H 8.25, and N 15.00.
250mg (0.96mmol) 2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mgNaNO
2, drip 2NHCl and transfer pH 5, stirring at room 60min, reaction solution is become orange-yellow by blueness, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7, chloroform extraction with saturated sodium bicarbonate aqueous solution, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression concentrates, and gets 117mg (47%) 2-(4 '-dimethylamino phenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is yellow solid, mp 85-86 ℃; R
f0.67 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 260[M]
+Ultimate analysis: C
15H
22N
3The O calculated value is C 69.20, and H 8.52, and N 16.14; Measured value is C 69.41, and H 8.74, and N 16.01.
65mg (0.25mmol) 2-(4 '-dimethylamino phenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 29mg (45%) title compound, be light yellow solid, R
f0.11 (CHCl
3/ CH
3OH, 20: 1); Mp 65-67 ℃; EI-MS (m/z): 261[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 2.85 (s, 6H ,-CH
3), 6.62 (d, J=8.7Hz, 2H, Ar-H), 7.44 (d, 2H, J=8.7Hz, Ar-H); Ultimate analysis: C
15H
23N
3The O calculated value is C 68.93 H 8.87, and N 16.08;
Embodiment 13
2-(2 '-fluorophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
248mg (2mmol) 2-fluorobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and stirring at room 24h, TLC show that raw material point disappears, filter 366mg (72%) 1,3-dihydroxyl-2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization.R
f0.69 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:254[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.07 (s, 12H ,-CH
3), 4.95 (s, 1H ,-CH), 7.18 (m, 2H, Ar-H), 7.68 (dd, J=8.7Hz, 2H, Ar-H), 8.14 (s, 2H, N-OH); IR (KBr): 3310,1600,1500,1130,1235,775.Ultimate analysis: C
13H
19N
2O
2The F calculated value is C 61.40, and H 7.53, and N 11.02; Measured value is C 61.21, and H 7.32, and N 11.24.
254mg (1mmol) 1,3-dihydroxyl-2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 30min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 218mg (87%) 2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue colored crystal.R
f0.52(CHCl
3/CH
3OH，20∶1)；mp 112-114℃；EI-MS：251[M]
+，219[M-32]
+；IR(KBr)：1610、1450、1135、1230、770。Ultimate analysis: C
13H
16N
2O
2The F calculated value is C 62.14, and H 6.42, and N 11.15; Measured value is C 62.36, and H 6.65, and N 11.47.
250mg (1.06mmol) 2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution by black-and-blue become orange red, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7, chloroform extraction with saturated sodium bicarbonate aqueous solution, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried.Get red thick liquid 219mg (a 88%) 2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red thick liquid, R
f0.69 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 235[M]
+Ultimate analysis: C
13H
16N
2The OF calculated value is C 66.36, and H 6.85, and N 11.91; Measured value is C 66.58, and H 6.66, and N 11.70.
59mg (0.25mmol) 2-(2 '-fluorophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 44mg (76%) title compound, be light yellow solid, R
f0.12 (CHCl
3/ CH
3OH, 20: 1); Mp 111-112 ℃; EI-MS (m/z): 236[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.11 (s, 12H ,-CH
3), 7.06-7.60 (m, 4H, Ar-H); Ultimate analysis: C
13H
17N
2The OF calculated value is C 66.08, H7.25, and N 11.86;
Embodiment 14
2-(4 '-chloro-phenyl-)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
281mg (2mmol) 4-chloro-benzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol, and stirring at room 12h, TLC show that raw material point disappears.Filter 330mg (61%) 1,3-dihydroxyl-2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.73 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.EI-MS：270[M]
+；
1H-NMR(CDCl
3-d)δ(ppm)＝1.03(s，6H，-CH
3)，1.07(s，6H，-CH
3)，4.50(s，1H，-CH)，7.38(d，J＝8.7Hz，2H，Ar-H)，7.48(d，J＝8.4Hz，2H，Ar-H)，7.80(s，2H，N-OH)；IR(KBr)：3325、1600、1500、1085、825。Ultimate analysis: C
13H
19N
2O
2The Cl calculated value is C57.67, and H 7.07, and N 10.35; Measured value is C 57.44, and H 7.25, and N 10.13.
250mg (0.92mmol) 1,3-dihydroxyl-2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 0.5g PbO
2Stirring at room 10min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 240mg (97%) 2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is the tiny needle-like crystal of blueness.R
f0.67(CHCl
3/CH
3OH，20∶1)；mp 103-105℃；EI-MS：267[M]
+，179[M-88]
+；IR(KBr)：1590、1500、1090(Cl)、820。Ultimate analysis: C
13H
16N
2O
2The Cl calculated value is C 58.32, and H 6.02, and N 10.46; Measured value is C 58.55, and H 6.25, and N 10.23.
250mg (0.99mmol) 2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution by black-and-blue become orange red, concentrating under reduced pressure is removed most of solvent, transfers pH 6-7, chloroform extraction with saturated sodium bicarbonate aqueous solution, the combined chloroform layer, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried, gets 208mg (83%) 2-(4 '-chloro-phenyl-)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red thick liquid, R
f0.73 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 251[M]
+IR (KBr): 1600,1090,835.Ultimate analysis: C
13H
16N
2The OCl calculated value is C 62.03, and H 6.41, and N 11.13; Measured value is C 62.25, and H 6.64, and N 11.35.
63mg (0.25mmol) 2-(4 '-chloro-phenyl-)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 46mg (73%) title compound, be light yellow solid, R
f0.14 (CHCl
3/ CH
3OH, 20: 1); Mp 94-95 ℃; EI-MS (m/z): 252[M]
+ 1H-NMR (CDCl
3-d) δ (ppm)=1.05 (s, 6H ,-CH
3), 1.07 (s, 6H ,-CH
3), 7.30 (d, J=8.7Hz, 2H, Ar-H), 7.56 (d, J=8.4Hz, 2H, Ar-H); Ultimate analysis: C
13H
17N
2The OCl calculated value is C 61.78, and H 6.78, and N 11.08;
Embodiment 15
2-(4 '-bromophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
370mg (2mmol) p-bromobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 2ml methyl alcohol.Reaction solution stirring at room 16h, TLC show that raw material point disappears.Filter 320mg (51%) 1,3-dihydroxyl-2-(4 '-bromophenyl)-4,4,5,5-tetramethyl-imidazolidine is colorless solid, is directly used in next step reaction.Sample behind the TLC purifying, EI-MS:314[M]
+R
f0.69 (CHCl
3/ CH
3OH, 10: 1); IR (KBr): 3310,1590,1450,1075,830.
1H-NMR(CDCl
3-d)δ(ppm)＝1.14(s，12H，-CH
3)，4.77(s，1H，-CH)，7.37(d，J＝8.4Hz，2H，Ar-H)，7.47(d，J＝7.8Hz，2H，Ar-H)，7.73(s，2H，N-OH)。Ultimate analysis: C
13H
19N
2O
2The Br calculated value is C 49.54, and H 6.08, and N 8.89; Measured value is C 49.67, and H 6.31, and N 8.66.
250mg (0.8mmol) 1,3-dihydroxyl-2-(4 '-bromophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 30ml methyl alcohol.In this solution, add 0.5g PbO
2Stir 10min, the filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 230mg (93%) 2-(4 '-bromophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is the tiny needle-like crystal of blueness.R
f0.85(CHCl
3/CH
3OH，20∶1)；mp 89-91℃，EI-MS：311[M]
+，279[M-32]
+；IR(KBr)：1600、1450、1070、825。Ultimate analysis: C
13H
16N
2O
2The Br calculated value is C 50.02, and H 5.17, N, 8.97; Measured value is C 50.23, and H 5.38, N, 8.75.
250mg (0.8mmol) 2-(4 '-bromophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution becomes orange redly by black-and-blue, concentrating under reduced pressure is removed most of solvent, transfer pH 6-7, chloroform extraction, combined chloroform layer with saturated sodium bicarbonate aqueous solution, behind the anhydrous sodium sulfate drying, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried, gets 232mg (98%) 2-(4 '-bromophenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red solid, mp 45-47 ℃; R
f0.95 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 296[M]
+IR (KBr): 1590,1480,1070,840.Ultimate analysis: C
13H
16N
2The OBr calculated value is C 52.72, and H 5.44, and N 9.46; Measured value is C 52.92, and H 5.67, and N 9.67.
73mg (0.25mmol) 2-(4 '-bromophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 59mg (81%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 73-75 ℃; EI-MS (m/z): 297[M]
+ 1H-NMR (CDCl
3-d) δ (ppm)=1.15 (s, 12H ,-CH
3), 7.46 (d, J=8.4Hz, 2H, Ar-H), 7.51 (d, J=7.8Hz, 2H, Ar-H).Ultimate analysis: C
13H
17N
2The OBr calculated value is C 52.54, and H 5.77, and N 9.43.
Embodiment 16
2-(2 ', 4 '-dichlorophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
350mg (2mmol) 2,4-chlorobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 3ml methyl alcohol, and stirring at room 20h, TLC show that raw material point disappears, filter 427mg (70%) 1,3-dihydroxyl-2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.69 (CHCl
3/ CH
3OH, 10: 1).Be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:305[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.11 (s, 12H ,-CH
3), 5.01 (s, 1H ,-CH), 7.52 (m, 3H, Ar-H), 7.79 (s, 2H, N-OH); IR (KBr): 3315,1590,1450,995,820,865.Ultimate analysis: C
13H
18N
2O
2Cl
2Calculated value is C 51.16, and H 5.94, and N 9.18; Measured value is C 51.37, and H 5.72, and N 9.37.
305mg (1mmol) 1,3-dihydroxyl-2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 80ml methyl alcohol, adds 1.0g PbO in this solution
2, stirring at room 40min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 265mg (88%) 2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is purple solid, R
f0.54 (CHCl
3/ CH
3OH, 20: 1); Mp 123-125 ℃; EI-MS:302[M]
+, 270[M-32]
+IR (KBr): 1590,1450,1000,825,870.Ultimate analysis: C
13H
15N
2O
2Cl
2Calculated value is C 51.67, and H 5.00, and N 9.27; Measured value is C 51.88, and H 5.21, and N 9.46.
300mg (1mmol) 2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl and transfer pH 5, stirring at room 60min, reaction solution to become orange-yellow by blueness, concentrating under reduced pressure removes most of solvent, transfer pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying with saturated sodium bicarbonate aqueous solution after, TLC detects and is single point.Filter, filtrate decompression is concentrated into dried.Get 255mg (90%) 2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is the orange crystal, mp 96-97 ℃ R
f0.66 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 286[M]
+IR (KBr): 1600,1460,1000,825,870.Ultimate analysis: C
13H
15N
2OCl
2Calculated value is C 54.56, and H 5.28, and N 9.79; Measured value is C 54.35, and H 5.19, and N 9.58.
71mg (0.25mmol) 2-(2 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 57mg (79%) title compound, be light yellow solid, R
f0.15 (CHCl
3/ CH
3OH, 20: 1); Mp 86-89 ℃; EI-MS (m/z): 287[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.12 (s, 12H ,-CH
3), 7.18-7.50 (m, 3H, Ar-H); Ultimate analysis: C
13H
16N
2OCl
2Calculated value is C 54.37, and H 5.62, and N 9.75.
Embodiment 17
2-(3 ', 4 '-dichlorophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
1.75g (10mmol) 3,4-chlorobenzaldehyde and 1.48g (10mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 10ml methyl alcohol, and stirring at room 20h, TLC show that raw material point disappears, filter 2.13g (70%) 1,3-dihydroxyl-2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.69 (CHCl
3/ CH
3OH, 10: 1).Be directly used in next step reaction.Sample behind the TLC purifying, EI-MS (m/z): 305[M]
+ 1H-NMR(DMSO-d
6)δ(ppm)＝1.06(s，12H，-CH
3)，4.99(s，1H，-CH)，7.66(m，3H，Ar-H)，7.92(s，2H，N-OH)。Ultimate analysis: C
13H
18N
2O
2Cl
2Calculated value is C51.16, and H 5.94, and N 9.18; Measured value is C 51.37, and H 5.75, and N 9.27.
610mg (2mmol) 1,3-dihydroxyl-2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 80ml methyl alcohol, adds 3g PbO
2, stirring at room 40min, TLC show that raw material point disappears.The filtering solid, be evaporated under the filtrate room temperature dried, residue column chromatography for separation (chloroform is an eluent), 530mg (88%) 2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is purple solid, R
f0.54 (CHCl
3/ CH
3OH, 20: 1); Mp:123-125 ℃; EI-MS (m/z): 302[M]
+Ultimate analysis: C
13H
15N
2O
2Cl
2Calculated value is C 51.67, and H 5.00, and N 9.27; Measured value is C51.45, and H 5.22, and N 9.46.
250mg (0.83mmol) 2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mgNaNO
2, drip 2NHCl and transfer pH 5, stirring at room 60min, reaction solution by blueness become orange-yellow, concentrating under reduced pressure is removed most of solvent, is transferred pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution is single point.Filter, be evaporated under the filtrate room temperature dried, 178mg (75%) 2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is the orange crystal, mp 66-67 ℃; R
f0.71 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 286[M]
+Ultimate analysis: C
13H
15N
2OCl
2Calculated value is C 54.56, and H 5.28, and N 9.79; Measured value is C 54.37, and H 5.09, and N 9.58.
71mg (0.25mmol) 2-(3 ', 4 '-dichlorophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 49mg (69%) title compound, be light yellow solid, R
f0.19 (CHCl
3/ CH
3OH, 20: 1); Mp 83-85 ℃; EI-MS (m/z): 287[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.09 (s, 12H ,-CH
3), 7.24-7.57 (m, 3H, Ar-H).Ultimate analysis: C
13H
16N
2OCl
2Calculated value is C 54.37, and H 5.62, and N 9.75.
Embodiment 18
2-(2 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
302mg (2mmol) 2-nitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 5ml methyl alcohol stirring at room 18h, TLC shows that raw material point disappears, filter 410mg (73%) 1,3-dihydroxyl-2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.54 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:281[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.00 (s, 6H ,-CH
3), 1.04 (s, 6H ,-CH
3), 5.37 (s, 1H ,-CH), 7.52 (d, J=6.6Hz, 1H, Ar-H), 7.72 (m, 2H, Ar-H), 8.05 (d, J=7.2Hz, 1H, Ar-H), 8.23 (s, 2H, N-OH); IR (KBr): 3325,1535,1365,1600,1450,750.Ultimate analysis: C
13H
19N
3O
4Calculated value is C 55.51, and H 6.81, and N 14.94; Measured value is C 55.73, and H 6.99, and N 14.72.
281mg (1mmol) 1,3-dihydroxyl-2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol, adds 0.5g PbO in this solution
2, stirring at room 40min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 208mg (75%) 2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is blue colored crystal, R
f0.49 (CHCl
3/ CH
3OH, 20: 1); Mp 145-147 ℃; EI-MS:278[M]
+, 246[M-32]
+IR (KBr): 1530,1360,1450,740.Ultimate analysis: C
13H
16N
3O
4Calculated value is C 56.11, and H 5.79, and N 15.10; Measured value is C 56.33, and H 5.57, and N 15.31.
130mg (0.47mmol) 2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 10ml methyl alcohol, add 0.5ml water, 250mg NaNO
2, drip 2N HCl transfer pH 5, stirring at room 60min, reaction solution by mazarine become orange-yellow, concentrating under reduced pressure is removed most of solvent, is transferred pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution is single point.Filter, filtrate decompression is concentrated into dried, gets 89mg (72%) 2-(2 '-nitrophenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange crystal, mp74-75 ℃; R
f0.52 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 262[M]
+Ultimate analysis: C
13H
16N
3O
3Calculated value is C 59.53, and H 6.15, and N 16.02; Measured value is C 59.74, and H 6.36, and N 16.21.
65mg (0.25mmol) 2-(2 '-nitrophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds the 5mg5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 46mg (71%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 113-115 ℃; EI-MS (m/z): 263[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=0.99 (s, 6H ,-CH
3), 1.04 (s, 6H ,-CH
3), 7.55 (d, J=6.6Hz, 1H, Ar-H), 7.68 (m, 1H, Ar-H), 7.88 (m, 1H, Ar-H), 8.22 (d, J=7.2Hz, 1H, Ar-H); Ultimate analysis: C
13H
17N
3O
3Calculated value is C 59.30, and H 6.51, and N 15.96.
Embodiment 19
2-(3 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
302mg (2mmol) 3-nitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 4ml methyl alcohol stirring at room 20h, TLC shows that raw material point disappears, filter 421mg (75%) 1,3-dihydroxyl-2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.51 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:281[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=0.52 (s, 12H ,-CH
3), 4.19 (s, 1H ,-CH), 7.04 (dd, J=8.7Hz, J=8.1Hz, 1H, Ar-H), 7.34 (d, J=6.0Hz, 1H, Ar-H), 7.57 (d, J=7.5Hz, 1H, Ar-H), 7.77 (s, 1H, Ar-H), 8.03 (s, 2H, N-OH); IR (KBr): 3315,1530,1360,1600,1500,875,790,685.Ultimate analysis: C
13H
19N
3O
4Calculated value is C 55.51, and H 6.81, and N 14.94; Measured value is C 55.74, and H 6.60, and N 14.72.
281mg (1mmol) 1,3-dihydroxyl-2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol.In this solution, add 0.7g PbO
2, stirring at room 20min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 216mg (78%) 2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is the dark blue-green solid.R
f0.69(CHCl
3/CH
3OH，20∶1)；mp 162℃；EI-MS：278[M]
+，247[M-31]
+；IR(KBr)：1530、1350、1600、1450、880、790、680。Ultimate analysis: C
13H
16N
3O
4Calculated value is C 56.11, and H 5.79, and N 15.10; Measured value is C 56.32, and H 5.97, and N 15.31.
250mg (0.9mmol) 2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 20ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl transfer pH 5, stirring at room 60min, reaction solution by mazarine become orange-yellow, concentrating under reduced pressure is removed most of solvent, is transferred pH6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution is single point.Filter, filtrate decompression is concentrated into dried, gets 172mg (73%) 2-(3 '-nitrophenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange crystal, mp71-72 ℃; R
f0.78 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 262[M]
+IR (KBr): 1530,1350,1600,1450,800,680.Ultimate analysis: C
13H
16N
3O
3Calculated value is C 59.53, and H 6.15, and N 16.02; Measured value is C 59.34, and H 6.36, and N 16.23.
65mg (0.25mmol) 2-(3 '-nitrophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 43mg (66%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 97-99 ℃; EI-MS (m/z): 263[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=0.67 (s, 12H ,-CH
3), 7.14-7.45 (m, 3H, Ar-H); Ultimate analysis: C
13H
17N
3O
3Calculated value is C 59.30, and H 6.51, and N 15.96.
Embodiment 20
2-(4 '-nitrophenyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
302mg (2mmol) paranitrobenzaldehyde and 296mg (2mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 6ml methyl alcohol, and stirring at room 12h, TLC show that raw material point disappears.Filter 355mg (63%) 1,3-dihydroxyl-2-(4 '-nitrophenyl)-4,4,5,5-tetramethyl-imidazolidine is colourless crystallization, R
f0.59 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS:281[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.00 (s, 6H ,-CH
3), 1.05 (s, 6H ,-CH
3), 4.71 (s, 1H ,-CH), 7.70 (d, J=9.0Hz, 2H, Ar-H), 8.21 (d, J=7.2Hz, 2H, Ar-H), 8.40 (s, 2H, N-OH).IR(KBr)：3325、1365(NO
2)、1590、1500、1450、835。Ultimate analysis: C
13H
19N
3O
4Calculated value is C 55.51, and H 6.81, and N 14.94; Measured value is C 55.72, and H 6.60, and N 14.73.
281mg (1mmol) 1,3-dihydroxyl-2-(4 '-nitrophenyl)-4,4,5,5--tetramethyl-imidazolidine is dissolved in the 50ml methyl alcohol.In this solution, add 0.7gPbO
2, stirring at room 40min, TLC show that raw material point disappears.The filtering solid is evaporated to dried under the filtrate room temperature.Residue column chromatography for separation (chloroform is an eluent) gets 203mg (73%) 2-(4 '-nitrophenyl)-4,4,5,5-tetramethyl--1, and 3-dioxy base tetrahydroglyoxaline is the yellow-green colour crystal.R
f0.65(CHCl
3/CH
3OH，20∶1)；mp 175-176℃；EI-MS：278[M]
+，246[M-32]
+；IR(KBr)：1360、1600、1500、1450、830。Ultimate analysis: C
13H
16N
3O
4Calculated value is C 56.11, and H 5.79, and N 15.10; Measured value is C 56.34, and H 5.58, and N 15.32.
300mg (1.08mmol) 2-(4 '-nitrophenyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 15ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, dripping 2N HCl, to transfer pH 5, stirring at room 60min, reaction solution to be become redness, removed under reduced pressure most of solvent, transfer pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution by blue-greenish colour be single point.Filter,, filtrate decompression is concentrated into dried, gets 200mg (71%) 2-(4 '-nitrophenyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is red crystals, mp 119-120 ℃; R
f0.74 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 262[M]
+IR (KBr): 1350,1520,1600,1450,1450,860.Ultimate analysis: C
13H
16N
3O
3Calculated value is C 59.53, and H 6.15, and N 16.02; Measured value is C 59.32, and H 6.36, and N 16.24.
65mg (0.25mmol) 2-(4 '-nitrophenyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 41mg (63%) title compound, be light yellow solid, R
f0.13 (CHCl
3/ CH
3OH, 20: 1); Mp 131-132 ℃; EI-MS (m/z): 263[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 12H ,-CH
3), 7.88 (d, J=9.0Hz, 2H, Ar-H), 8.22 (d, J=7.2Hz, 2H, Ar-H).Ultimate analysis: C
13H
17N
3O
3Calculated value is C 59.30, and H 6.51, and N 15.96.
Embodiment 21
2-furyl-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
1.3g (13.6mmol, 1.12ml) furfural and 2g (13.6mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 15ml methyl alcohol, stirring at room 20h, TLC show raw material point disappearance, filter 1.86g (61%) 1,3-dihydroxyl-2-furyl-4,4,5,5-tetramethyl-imidazolidine, be colourless powder, R
f0.34 (CHCl
3/ CH
3OH, 10: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS (m/z): 226[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.04 (s, 12H ,-CH
3), 4.59 (s, 1H ,-CH), 6.37 (s, 2H ,=C-H), 7.58 (s, 1H ,=C-H), 7.92 (s, 2H, N-OH).Ultimate analysis: C
11H
18N
2O
3Calculated value is C 58.39, H, and 8.02, N 12.38; Measured value is C 58.60, H, and 8.24, N 12.16.
1.0g (4.4mmol) 1,3-dihydroxyl-2-furyl-4,4,5,5-tetramethyl-imidazolidine are dissolved in the 100ml methyl alcohol, adding 2.7g PbO
2, stirring at room 60min, TLC show be evaporated under raw material point disappearance, filtering solid, the filtrate room temperature dried, column chromatography for separation (chloroform is an eluent), must 658mg (67%) 2-furyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is blue colored crystal, R
f0.59 (CHCl
3/ CH
3OH, 20; 1); EI-MS (m/z): 223[M]
+, 191[M-32]
+Ultimate analysis: C
11H
15N
2O
3Calculated value is C59.18, and H 6.77, and N 12.55; Measured value is C 59.01, and H 6.58, and N 12.76.
200mg (0.9mmol) 2-furyl-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 10ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl transfer pH 5, stirring at room 60min, reaction solution by blueness become redness, concentrating under reduced pressure is removed most of solvent, is transferred pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution is single point.Filter, filtrate decompression is concentrated into dried, gets 144mg (77%) 2-furyl-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange red oily matter, R
f0.69 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 207[M]
+Ultimate analysis: C
11H
16N
2O
2Calculated value is C 63.75, and H 7.30, and N 13.52; Measured value is C 63.54, and H 7.48, and N 13.31.
51mg (0.25mmol) 2-furyl-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 37mg (72%) title compound, be light yellow solid, R
f0.12 (CHCl
3/ CH
3OH, 20: 1); Mp 95-96 ℃; EI-MS (m/z): 208[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.05 (s, 12H ,-CH
3), 6.30 (s, 2H ,=C-H), 7.40 (s, 1H ,=C-H).Ultimate analysis: C
11H
16N
2O
2Calculated value is C 63.44, and H 7.74, N13.45.
Embodiment 22
2-(3 '-pyridyl)-4,4,5, the preparation of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline
1.07g (10mmol) 3-pyridylaldehyde and 1.48g (10mmol) 2,3-dimethyl-2,3-dihydroxy amido butane is dissolved in the 10ml methyl alcohol stirring at room 20h, TLC shows that raw material point disappears, filter 1.63g. (69%) 1,3-dihydroxyl-2-(3 '-pyridyl)-4,4,5,5-tetramethyl-imidazolidine is colourless powder, R
f0.51 (CHCl
3/ CH
3OH, 6: 1), be directly used in next step reaction.Sample behind the TLC purifying, EI-MS (m/z): 238[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.04 (s, 6H ,-CH
3), 1.07 (s, 6H ,-CH
3), 4.55 (s, 1H ,-CH), 7.35 (s, 1H, Ar-H), 7.81 (s, 1H, Ar-H), 8.32 (s, 2H, N-OH), 8.46 (s, 1H, Ar-H) 8.62 (s, 1H, Ar-H).Ultimate analysis: C
12H
19N
3O
2Calculated value is C 60.74, H8.07, and N 17.71; Measured value is C 60.52, and H 8.28, and N 17.50.
479mg (2mmol) 1,3-dihydroxyl-2-(3 '-pyridyl)-4,4,5,5-tetramethyl-imidazolidine is dissolved in the 60ml methyl alcohol, adds 3g PbO
2, stirring at room 20min, TLC show that raw material point disappears.The filtering solid, be evaporated under the filtrate room temperature dried, column chromatography for separation (chloroform is an eluent), 300mg (65%) 2-(3 '-pyridyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is bluish voilet powder, R
f0.41 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 234[M]
+, 218[M-16]
+Ultimate analysis: C
12H
16N
3O
2Calculated value is C 61.52, and H 6.88, and N 17.94; Measured value is C 61.75, and H 6.67, and N 17.73.
200mg (0.85mmol) 2-(3 '-pyridyl)-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are dissolved in the 10ml methyl alcohol, add 0.5ml water, 500mg NaNO
2, drip 2N HCl transfer pH 5, stirring at room 60min, reaction solution by blueness become redness,, concentrating under reduced pressure is removed most of solvent, transferred pH 6-7, chloroform extraction, combined chloroform layer, anhydrous sodium sulfate drying, TLC to detect with saturated sodium bicarbonate aqueous solution is single point.Filter, filtrate decompression is concentrated into dried, gets 134mg (72%) 2-(3 '-pyridyl)-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is orange red oily matter, R
f0.63 (CHCl
3/ CH
3OH, 20: 1); EI-MS (m/z): 218[M]
+Ultimate analysis: C
12H
17N
3The O calculated value is C 66.03, and H 7.39, and N 19.26; Measured value is C 66.25, and H 7.17, and N 19.50.
54mg (0.25mmol) 2-(3 '-pyridyl)-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is dissolved in the 10ml methyl alcohol, adds 5mg 5%Pd/C powder, the moisture 2.25mg of this powder, the confined reaction system after vacuumizing, feeds H in reaction system
2, after 30 minutes, TLC detects and is single point.Normal pressure filters, be evaporated under the filtrate room temperature dried, 43mg (79%) title compound, be light yellow solid, R
f0.11 (CHCl
3/ CH
3OH, 20: 1); Mp 87-89 ℃; EI-MS (m/z): 208[M]
+ 1H-NMR (DMSO-d
6) δ (ppm)=1.03 (s, 6H ,-CH
3), 1.12 (s, 6H ,-CH
3), 7.89-8.36 (m, 3H, Ar-H).Ultimate analysis: C
12H
17N
3The O calculated value is C 65.73, and H 7.81, and N 19.16.
Embodiment 23
The diastolic blood vessel activity of The compounds of this invention
Fasting is 12 hours before the body weight 250-300g male Wistar rat, art, freely drinks water, and dislocation of cervical vertebra causes death, and opens chest and wins thoracic aorta rapidly, peels off the reticular tissue that adheres to, and blood vessel is cut into the long arterial ring of 3-5mm, places in the 15ml perfusion bath.Bath fills 15ml Krebs-Henseleit (KH) liquid, and 37 ℃ of constant temperature pass to volume ratio 95%O
2-5%CO
2Gas.Fixedly the hook of arterial ring connects tonotransducer, traces the vasomotion curve on dual-trace recorder, and chart speed is 1mm/min.The adjustment resting tension is 1.0g, and (final concentration is 10 to give NE (norepinephrine) behind the balance 30min
-7Mol/L) artery is shunk to play the pre-effect that swashs.Flush away NE, (final concentration is 10 to give NE behind the balance 30min
-7Mol/L), wait to shrink tension force continually and steadily after the platform level, add dehydrated alcohol 15 μ l (blank) or add The compounds of this invention and be dissolved in the solution of 15 μ l dehydrated alcohols (final concentration is 1 * 10
-4).(final concentration is 10 to the vasorelaxation ability of The compounds of this invention with reducing NE
-7Mol/L) maximum collapse tensile per-cent is represented (n=6 has deducted the solvent factor, result such as table 1).
The vasodilator activity of table 1 The compounds of this invention
| Compound | X±SD(％) 1×10 -4mol/L | Compound | X±SD(％) 1×10 -4mol/L |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 embodiment 9 embodiment 10 embodiment 11 | 22.93±4.15 22.85±1.20 46.28±2.63 13.60±1.83 16.73±3.06 19.69±1.05 23.27±3.47 17.92±2.37 21.95±1.13 35.11±1.92 20.63±3.25 | Embodiment 12 embodiment 13 embodiment 14 embodiment 15 embodiment 16 embodiment 17 embodiment 18 embodiment 19 embodiment 20 embodiment 21 embodiment 22 | 6.63±2.72 22.70±3.83 23.78±2.19 18.40±3.46 15.93±1.13 22.78±2.73 60.20±3.72 81.80±3.21 72.70±3.36 36.62±4.32 25.28±4.01 |
Claims (10)
1, as the compound of general formula I wherein, R is a substituted-phenyl, or furyl, or pyridyl,
2, the method for synthetic compound of Formula I, this method comprises: the condensation of 2-nitropropane generates 2,3-dimethyl-2,3-dinitrobenzene butane in the presence of alkali and Br2; At NH
4Cl exists to descend 2, and 3-dimethyl-2,3-dinitrobenzene butane are 2 by zinc powder reduction, 3-dimethyl-2,3-dihydroxy amido butane; 2,3-dimethyl-2,3-dihydroxy amido butane and substituted benzaldehyde or furfural or pyridylaldehyde cyclization generate 1, and 3-dihydroxyl-2-replaces-4,4,5,5-tetramethyl-imidazolidine; 1,3-dihydroxyl-2-replaces-4,4,5, and 5-tetramethyl-imidazolidine is oxidized to 2-for oxidized dose and replaces-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline; Under acidic conditions, 2-replaces-4,4,5, and 5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are reduced agent and are reduced to 2-replacement-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline; 2-replaces-4,4,5, and 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is reduced to 2-and replaces-4,4,5,5-tetramethyl--1-hydroxyl tetrahydroglyoxaline, i.e. compound of general formula I.
3, the synthetic method of compound of Formula I as claimed in claim 2, the definition of general formula I is characterized in that as mentioned above, described the condensation of 2-nitropropane generated 2,3-dimethyl-2, and the alkali that 3-dinitrobenzene butane is used is NaOH.
4, the synthetic method of compound of Formula I as claimed in claim 2 is characterized in that, and is described with 1, and 3-dihydroxyl-2-replaces-4,4,5, and 5-tetramethyl-imidazolidine is oxidized to 2-and replaces-4,4,5,5-tetramethyl--1, and the oxygenant of 3-dioxy base tetrahydroglyoxaline is PbO
2
5, the synthetic method of compound of Formula I as claimed in claim 2, it is characterized in that, described with 2-replacement-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline is reduced to 2-and replaces-4,4,5, the acidic conditions of 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is that pH is 5, and the acid that is used for regulating pH can be all kinds of organic acids and mineral acid.
6, the synthetic method of compound of Formula I as claimed in claim 5 is characterized in that, described acid is hydrochloric acid.
7, the synthetic method of compound of Formula I as claimed in claim 2 is characterized in that, described with 2-replacement-4,4,5,5-tetramethyl--1,3-dioxy base tetrahydroglyoxaline are reduced to 2-and replace-4,4,5, and the reductive agent of 5-tetramethyl--1-oxygen base tetrahydroglyoxaline is NaNO
2
8, the synthetic method of compound of Formula I as claimed in claim 2 is characterized in that, and is described with 2-replacement-4,4,5,5-tetramethyl--1-oxygen base tetrahydroglyoxaline is reduced to 2-and replaces-4,4,5, the condition of 5-tetramethyl--1-hydroxyl tetrahydroglyoxaline is a catalytic hydrogenation, and catalyst system therefor can be various hydrogenation catalysts.
9, the synthetic method of compound of Formula I as claimed in claim 8 is characterized in that, described catalyzer is 5%Pd/C.
10, compound of Formula I, the definition of general formula I are used for the application of vasodilative medicine as mentioned above in preparation.
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|---|---|---|---|
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070531A (en) * | 2011-01-04 | 2011-05-25 | 中国人民解放军第四军医大学 | Microwave radiation injury protection medicines |
| CN102887859A (en) * | 2011-07-21 | 2013-01-23 | 首都医科大学 | Compound having analgesic and anti-inflammatory activity, preparation method thereof and application thereof |
| CN104844516A (en) * | 2015-03-31 | 2015-08-19 | 西安工业大学 | Dual-functional radiation damage protection drug containing phenols and synthesis and application thereof |
| US10806798B2 (en) | 2012-09-05 | 2020-10-20 | Shanghai Lumosa Therapeutics Co., Ltd. | Compound with effects of thrombolysis, free radical scavenging and thrombus-targeting |
| CN111995544A (en) * | 2020-06-30 | 2020-11-27 | 合肥工业大学 | Synthesis method and application of 4, 5-diphenyl imidazoline |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP3484584B2 (en) * | 1995-04-03 | 2004-01-06 | 株式会社同仁化学研究所 | Nitric oxide scavenger, detector and quantifier |
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2004
- 2004-09-03 CN CNB2004100742099A patent/CN1326839C/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102070531A (en) * | 2011-01-04 | 2011-05-25 | 中国人民解放军第四军医大学 | Microwave radiation injury protection medicines |
| CN102887859A (en) * | 2011-07-21 | 2013-01-23 | 首都医科大学 | Compound having analgesic and anti-inflammatory activity, preparation method thereof and application thereof |
| CN102887859B (en) * | 2011-07-21 | 2014-10-29 | 首都医科大学 | Compound having analgesic and anti-inflammatory activity, preparation method thereof and application thereof |
| US10806798B2 (en) | 2012-09-05 | 2020-10-20 | Shanghai Lumosa Therapeutics Co., Ltd. | Compound with effects of thrombolysis, free radical scavenging and thrombus-targeting |
| CN104844516A (en) * | 2015-03-31 | 2015-08-19 | 西安工业大学 | Dual-functional radiation damage protection drug containing phenols and synthesis and application thereof |
| CN104844516B (en) * | 2015-03-31 | 2017-12-19 | 西安工业大学 | Containing the difunctional radiation injury protection medicine of phenols and its synthesis and application |
| CN111995544A (en) * | 2020-06-30 | 2020-11-27 | 合肥工业大学 | Synthesis method and application of 4, 5-diphenyl imidazoline |
| CN111995544B (en) * | 2020-06-30 | 2023-06-16 | 合肥工业大学 | Synthesis method and application of 4, 5-diphenyl imidazoline |
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| CN1326839C (en) | 2007-07-18 |
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