The object of the present invention is to provide a kind of than the better novel NO-NSAID of existing medicine, they discharge NO and DC in vivo, the performance anti-inflammatory action, also reduce or eliminate simultaneously the gi tract toxic side effect of DC, can be used as anti-inflammation analgesia medicine, be used for the treatment of diseases such as rheumatic, rheumatoid arthritis, osteoarthritis.
But the present invention also aims to provide the preparation method of the suitability for industrialized production of a kind of novel NO-NSAID.
Technical scheme of the present invention is as follows:
Wherein: R
1Represent O, NH; R
2Representative-(CH
2)
2-, n=3-5; CH
2C ≡ CCH
2CH
2CH (CH
3) CH
2CH
2
CH
2CH
2OCH
2CH
2:-PhCH
2-(m,p)。
General formula I I compound:
Wherein: R
3Representative-PhCH
2-(o, m, p);-Ph-(m, p).
Wherein: R
3Representative-PhCH
2-(o, m, p);-Ph-(m, p).
General formula I V compound:
Compound of Formula I preparation method, it is characterized in that: after the reaction of diclofenac sodium (DC-Na) and halohydrin again with the furazan oxynitride condensation that replaces, perhaps DC and hydroxyl or amino furazan oxynitride (Ip) condensation in the presence of dicyclohexyl carbimide (DCC)
Wherein: R
1Represent OH, NH
2R
2Representative-(CH
2)
n-, n=3-5; CH
2C ≡ CCH
2CH
2CH (CH
3) CH
2CH
2CH
2CH
2OCH
2CH
2-PhCH
2-(m, p).
Concrete reactions steps is:
Wherein: X represents Br, Cl; N=3-5; Perhaps:
General formula I I compounds process for production thereof is characterized in that: the furazan oxynitride (IIp) of DC and hydroxyl
Condensation in the presence of DCC,
Wherein: R
3Representative-PhCH
2-(o, m, p);-Ph-(m, p).Concrete reactions steps is:
Compound of formula III preparation method is characterized in that: furazan oxynitride (IIIp) condensation in the presence of DCC of DC and hydroxyl,
Wherein, R
2Representative-PhCH
2-(o, m, p);-Ph-(m, p).Concrete reactions steps is;
General formula I V compounds process for production thereof is characterized in that: DC and nitre oxygen sylvan (IVp) condensation in the presence of DCC.
Concrete reactions steps is:
General formula I, II, III, IV compound are used to prepare anti-inflammatory, anodyne.
The pharmacological evaluation of general formula I, II, III, IV compound is as follows.1 anti-inflammatory activity, 1.1 p-Xylol cause the influence of mice ear
Experimental technique is seen: Xu Shuyun, Bian Rulian, Chen Xiu chief editor, " pharmacological experimental methodology " second edition, Beijing people's health press, version in 1991.
DC-Na is available from Yicheng, Hubei 5-linked pharmaceutical factory, and specification is medicinal, down together.
Nitrofenac is synthetic by patent (EP, the patent No. 738706) method, and its structure is proved conclusively through wave spectrum.Nitrofenac is known nitrate esters NO-DC (WO94/04484), and bibliographical information is arranged, and its anti-inflammatory activity and DC are suitable, and gastrointestinal side effect is less than DC, thus with it as the reference medicine, down with.
All medicines all use 0.5% Xylo-Mucine (CMC-Na) to be made into 1.57 * 10
-3The suspension of mol/L is with volumetric molar concentrations such as DC-Na.Oily matter then adds the dimethyl sulfoxide (DMSO) of soup cumulative volume 5% earlier, adds the 0.5%CMC-Na of cumulative volume 95% again, fully mixing.The DC-Na dosage is set at 20mg/kg, and this dosage is converted by human dosage.
The mouse fasting is 12 hours before the experiment, but can't help water.To the mouse stomach administration, the administration volume is 0.4ml/10g.Administration evenly is coated with dimethylbenzene 20 μ l with the wide both sides of mouse right ear with microsyringe after 1 hour and causes inflammation, and left auricle compares.After causing scorching 30 minutes mouse is taken off cervical vertebra and put to death, take off two ears, respectively get an auricle in same position with punch tool (diameter is 7mm) and weigh along the auricle baseline.Causing the inflammation sheet weight of picking up the ears deducts
Control sides auricle weight is the swelling degree.Each group data is carried out t check, the significance of comparative group differences.
Table 1. compound p-Xylol causes influence (n=10, the x ± s) of mice ear
Compound swelling degree (mg) compound swelling degree (mg)
CMC-Na 11.31±3.23
# I
4 9.97±2.39
DC-Na 7.30±2.10
* I
5 7.32±2.30
*
Nitrofenac 8.67±3.56 II
1 10.64±1.65
#
I
1 8.74±1.20 II
2 7.25±1.86
**
I
2 9.91±2.87 II
3 9.55±0.74
*
I
3 9.00±3.61 IV
1 6.31±1.45
*
Compare with CMC-Na,
*P<0.05,
*P<0.01
Compare with DC-Na,
#P<0.05
By table 1 as seen, compound N itrofenac, I
1, I
2, I
3, I
4, I
5, II
2, II
3And IV
1Anti-inflammatory activity and DC-Na are suitable, there was no significant difference (P<0.05).1.2 on Carrageenan causes the influence of rat paw edema
Experimental technique is seen: Cirino G, Peers SH, Flower RJ, et al.Human recombinantlipocortin 1 has acute local anti-inflammatory properties in the rat pawedema test.Proc Natl Acad Sci USA, 1989,86:3428.
Select active compound I
1, I
2, I
3, I
4, I
5, II
2, IV
1Conduct is tried thing with Nitrofenac, and all is made into 3.14 * 10 with 0.5%CMC-Na
-3The suspension of mol/L is with volumetric molar concentrations such as DC-Na.Oily matter then adds the dimethyl sulfoxide (DMSO) of soup cumulative volume 5% earlier, adds 0.5% CMC-Na of cumulative volume 95% again, abundant mixing, and the DC-Na dosage is set at 10mg/kg, and this dosage is converted by human dosage.
Every group of 10 rats, preceding fasting 18-22 hour of experiment, but can't help water.To the rat oral gavage administration, the administration volume is 1ml/100g.After the administration 30 minutes, inject 1% carrageenin (sterile saline preparation) 0.1ml down to the right back sufficient plantar aponeurosis of rat, mensuration causes before the inflammation and causes scorching back 1,2,3,4,5 hours right back sufficient sole of the foot volumes of rat, with its sufficient sole of the foot volume difference that causes scorching front and back is the swelling degree, carries out the t check, the significance of comparative group differences.
The injection carrageenin causes that the right back sufficient sole of the foot volume of rat obviously increases in after the inflammation 5 hours.Give DC-Na in advance, can significantly reduce sufficient sole of the foot volumetrical increasing amount.Compare IV with the CMC-Na group
1Paw swelling (2 hours some P<0.001 have obviously been alleviated at 2 hours, 3 hours and 4 hours points; 3,4 hours some P<0.05), especially at 2 little time points, IV
1Anti-inflammatory action be better than DC-Na (P<0.01).Compare with CMC-Na group, there were significant differences (P<0.05) at 3 little time points (P<0.01) and 4,5 little time points for Nitrofenac; I
4There were significant differences (P<0.05) at 3,4 little time points; I
5There were significant differences (P<0.01) at 4 little time points.Nitrofenac and I
4, I
5Anti-inflammatory activity and DC-Na suitable.II
2Anti-inflammatory action at 5 little time points obviously is better than DC-Na (P<0.05).2. to the influence of rat gastrointestinal tract
Experimental technique is with reference to Xu Shuyun, Bian Rulian, " pharmacological experimental methodology " second edition of Chen Xiu chief editor, Beijing people's health press, 1991.
Select Compound I
4, I
6, II
2, IV
1Conduct is tried thing with Nitrofenac.Dosage and medicine preparation are with 1.2.Every group of 8 rats (DC-Na organizes 11), gastric infusion is 7 days continuously, measures before the administration and the variation of administration body weight in latter stage, and observation and comparative drug are to the influence of rat gastrointestinal tract after the last administration.
All rat fasting are after 12 hours, pluck eyeball and get hematometry hematological indices (red blood cell count(RBC), content of hemoglobin), put to death rat with the cervical vertebra dislocation method, open the abdominal cavity immediately, collect ight soil from rectum and carry out occult blood test by the test kit method, and the taking-up gi tract, vertically cut open and carry out visual inspection, the hemorrhage situation of comprehensive evaluation animal gastrointestinal tract.2.1 influence to rat body weight
Table 2 compound is to the influence of rat body weight
Compound initial stage body weight (g) body weight in latter stage (g)
CMC-Na 203.88±16.62 227.57±24.60
DC-Na 201.67±19.99 191.00±17.49
*
Nitrofenac 208.63±14.72 211.14±10.30
I
4 196.57±9.76 210.12±15.20
I
5 200.88±17.98 217.00±25.33
II
2 197.12±19.00 210.00±23.92
IV
1 201.50±14.74 213.12±15.66
Compare with CMC-Na,
*P<0.05
By table 2 as seen, DC-Na group rat obviously reduces (P<0.05) in administration body weight in latter stage, does not all have significant difference (P>0.05) and compare before the body weight of other all compound group rats and the administration.2.2 the Anatomical Observation of rat gastrointestinal tract
Table 3. compound is to the influence of rat gastrointestinal tract
Animals survived animal gastrointestinal tract during the compound administration
The mortality ratio opinion rating
CMC-Na 0/8 0
DC-Na 5/11 3
Nitrofenac 1/8 2
I
4 0/8 1
I
5 0/8 1
II
2 0/8 0
IV
1 0/8 0
0 grade: no ulcer
1 grade: the mucomembranous surface erosion
2 grades: deep ulcer or chamber face diffuse necrosis
3 grades: perforated ulcer
By table 3 as seen, the DC-Na group has 5 rats deaths, and Nitrofenac organizes 1 rats death, and other groups there is no the phenomena of mortality.By the gi tract score value as can be known, I
4, I
5, II
2, IV
1The gastrointestinal side effect of group rat is all less than DC-Na group and Nitrofenac group.2.3 occult blood test
Experiment adopts the Pyramidon filter paper method of improvement to carry out.
Occult blood test kit Fecal OB-II available from Baso Diagnostic Inc.
Table 4 occult blood test result
CMC-Na Nitrofenac I
4I
5II
2IV
1Average mark 8 14.00 11.25 11.38 11.75 9.88Gradit 1.0 2.1667 1.7083 1.7292 1.7917 1.4792Ridit 0.5 1.0833 0.8542 0.8646 0.8958 0.7396 test of significance 1.0 2.78
*1.55 1.61 1.79 0.90 compare with CMC-Na,
*P<0.01
By table 4 as seen, except that Nitrofenac group, difference (P>0.05) that all test-compound groups compare with the CMC-Na group that there are no significant.2.4 hematological indices
Table 5. compound is learned the influence of index to rat blood
Compound of red cell counting (* 10
12/ L) content of hemoglobin (g/L)
CMC-Na 7.77±0.706
# 131.33±9.83
##
Nitrofenac 6.93±0.538
* 113.71±6.52
**
I
4 7.44±0.840 129.38±9.13
**
I
5 7.85±1.047 130.62±11.8
##
II
2 9.00±0.837
### 144.20±6.18
###
IV
1 8.46±0.864
### 142.86±8.40
###
Compare with CMC-Na,
*P<0.05,
*P<0.01,
Compare with Nitrofenac,
#P<0.05,
##P<0.01,
###P<0.001
By table 5 as seen, test-compound I
4, I
5, II
2And IV
1Content of hemoglobin and the II of group rat
2And IV
1The red blood cell count(RBC) of group rat is pointed out I than the Nitrofenac height
4, I
5, II
2And IV
1The situation of losing blood of group rat is lighter.Releasing research in the 3 NO bodies
Experiment is undertaken by kit method-nitrate reductase method.
The NO test kit is available from the poly-Lik-Sang thing engineering in medicine institute in Nanjing.
Select Compound I
4, I
5, II
2, IV
1Conduct is tried thing with Nitrofenac.Its dosage, mode and soup preparation are measured the content of NO in the rat blood serum with 1,2.
NO content in table 6. rat blood serum " and (μ mol/L) measurement result (n=6, x ± s)
Compound 1 hour 3 hours
CMC-Na 18.63±8.07
### 15.93±5.80
###
Nitrofenac 54.08±6.05
*** 49.77±9.91
***
I
4 25.94±6.52
### 28.72±9.75
*##
I
5 29.62±11.74
** 28.89±7.08
**##
II
2 27.24±8.21
### 27.78±2.75
**###
IV
1 28.87±8.75
### 51.77±23.25
**
Compare with CMC-Na,
*P<0.01,
* *P<0.001
Compare with Nitrofenac,
#P<0.05,
##P<0.01,
###P<0.001
By table 6 as seen, compare with CMC-Na, Nitrofenac obviously increases (P<0.001), Compound I 1 hour and 3 hours NO burst sizes
4, I
5, II
2Obviously increase 3 hours some NO burst sizes.IV
1At the NO of 3 little time points burst size and Nitrofenac suitable (P>0.05).
Below be the embodiment of The compounds of this invention, these embodiment also do not mean that limitation of the present invention.
Embodiment 1a) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2-hydroxy methacrylate (Ip
1) (0.63g, 2mmol), (0.34g, 4mmol), (0.68ml, 0.8g 10mmol) are dissolved in 10ml N with a small amount of potassiumiodide to ethylene chlorhydrin to sodium bicarbonate, in the dinethylformamide (DMF), are heated to 80 ℃, and reaction solution is a reddish-brown with DC-Na.After the cooling, in reaction solution impouring 60ml water, with ethyl acetate (3 * 20ml) extractions.Merge organic layer, with 5: 2 ethyl acetate: sherwood oil (60-90 ℃) recrystallization, must orange powder shape solid 0.65g, yield 91%, mp60-62 ℃.IR(KBr,cm
-1):3276,1720
1H?NMR(CDCl
3),δ(ppm):3.85-3.88(m,4H),4.28-4.31(t,2H),6.55-6.58(d,1H),6.94-7.02(m,2H),7.11-7.17(m,1H),7.23-7.25(dd,1H),7.26-7.36(d,2H)。ESI-MS:340.1 (M+H)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(3-benzenesulfonyl-1,2,2-ethoxyethyl acetate (I of 5-oxadiazole-2-oxide compound-4-)
1) with 3,4-two benzenesulfonyls-1,2,5-oxadiazole-2-oxide compound (0.37g, 1mmol) and Ip
1(0.34g 1.2mmol) is dissolved in the 10ml tetrahydrofuran (THF) (THF), and (0.08ml 1.2mmol), gradually has muddy the generation to splash into 25% aqueous sodium hydroxide solution.Reaction solution is poured in the 100ml water, added 6N hydrochloric acid and transfer pH=7.(3 * 20ml) extractions add the saturated common salt washing, anhydrous magnesium sulfate drying after organic layer merges with ethyl acetate.After the filtration filtrate decompression is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got white powder solid 0.51g, yield 76%, mp124-125 ℃ in 1: 6.IR(KBr,cm
-1):3333,1724
1H?NMR(CDCl
3),δ(pmm):3.87(s,2H),4.40-4.90(m,4H),6.40-8.10(m,13H)ESI-MS:564.3(M+H)
+
Embodiment 2a) preparation 4-(3-benzenesulfonyl-1,2, the oxygen butanols (Ip of 5-oxadiazole-2-oxide compound-4-)
2) with 1, and the 4-butyleneglycol (0.9ml, 10mmol) with 3,4-two benzenesulfonyls-1,2, (0.73g 2mmol) is dissolved among the 15ml THF 5-oxadiazole-2-oxide compound, and (0.36ml 3mmol), gradually has muddy the generation to splash into 25% aqueous sodium hydroxide solution.React after 1 hour solid filtering.Concentrated filtrate adds 50ml water in resistates, (3 * 20ml) extracting twice add the saturated common salt washing once after organic layer merges, use anhydrous magnesium sulfate drying with ethyl acetate.After the filtration filtrate decompression is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got white powder solid 0.48g, yield 76%, mp70-72 ℃ in 1: 4.IR(KBr,cm
-1):3353
1H?NMR(CDCl
3),δ(ppm):1.74-1.79(m,2H),1.98-2.03(m,2H),2.%(s,1H),3.76-3.78(t,2H),4.47-4.79(t,2H),7.61-7.64(t,2H),7.76-7.79(t,1H),8.05-8.07(d,2H)。ESI-MS:315.2 (M+H)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(3-benzenesulfonyl-1,2, oxygen butyl ester (I of 5-oxadiazole-2-oxide compound-4-)
2) with Ip
2Be dissolved in the 15ml anhydrous methylene chloride, and adding DC (0.53g, 1.8mmol), the dicyclohexyl carbimide (DCC, 0.37g, 1.8mmol), 4-N, several of N-Dimethylamino pyridines (DMAP).Stirring at room 2 hours, the adularescent precipitation generates.Filter, filtrate is concentrated, the residue silica gel column chromatography, ethyl acetate-sherwood oil (60-90 ℃) mixed solution wash-out got yellow oil 0.73g, yield 82% in 1: 9.IR(film,cm
-1):3320,1722
1H?NMR(CDCl
3),δ(ppm):1.82-1.88(m,2H),1.90-1.95(m,2H),3.83(s,2H),4.23-4.25(t,2H),4.41-4.43(t,2H),6.54-6.58(d,1H),6.87(s,1H),6.93-7.00(m,2H),7.12-7.14(t,1H),7.22(d,1H),7.33-7.34(m,2H),7.57-7.60(t,2H),7.71-7.74(t,1H),8.03-8.05(d,2H)。ESI-MS:614.0(M+Na)
+
Embodiment 3a) preparation (3-benzenesulfonyl-1,2, the oxygen-3-butanols (Ip of 5-oxadiazole-2-oxide compound-4-)
4) with reference to Ip
2The preparation method make by 1,3 butylene glycol.Get white cotton-shaped solid, yield 77%, mp 101-103 ℃ with 1: 1 ethyl acetate-sherwood oil (60-90 ℃) recrystallization.IR (KBr, cm
-1): 3437
1H NMR (CDCl
3), δ (ppm): 1.30-1.32 (d, 3h), 1.67 (s, 1H), 1.92-2.08 (m, 2H), and 4.07-4.13 (m, 1H), 4.51-4.69 (m, 2H), 7.59-7.65 (t, 2H), and 7.73-7.79 (t, 1H), 8.04-8.07 (dd, 2H) .ESI-MS:315.1 (M+H)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-(3-benzenesulfonyl-1,2, oxygen-3-butyl ester (I of 5-oxadiazole-2-oxide compound-4-)
4) with reference to I
2The preparation method by Ip
4Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got colorless oil, yield 82% in 1: 8.IR(film,cm
-1):3327,1722
1H?NMR(CDCl
3),δ(ppm):1.35-1.37(d,3H),2.12-2.18(m,2H),3.80(s,2H),4.36-4.44(m,2H),5.15-5.21(m,1H),6.53-7.34(m,8H),7.55-7.85(m,5H)。ESI-MS:614.0(M+Na)
+
Embodiment 4a) preparation 2-[2-(3-benzenesulfonyl-1,2, the oxygen ethyl oxygen of 5-oxadiazole-2-oxide compound-4-)] ethanol (Ip
5) with reference to Ip
2The preparation method make by glycol ether.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got faint yellow oily thing, yield 80% in 1: 3.IR(film,cm
-1):3419
1HNMR(CDCl
3),δ(ppm):2.19(s,1H),3.50-3.80(m,4H),3.80-4.00(m,2H),4.50-4.70(m,2H),7.61-8.13(m,5H)。ESI-MS:353.0 (M+Na)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2-[2-(3-benzenesulfonyl-1,2, the oxygen ethyl of 5-oxadiazole-2-oxide compound-4-)] 2-ethoxyethyl acetate (I
5) with reference to I
2The preparation method by Ip
5Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 83%, mp93-96 ℃ in 1: 3.IR(KBr,cm
-1):3367,1740
1H?NMR(CDCl
3),δ(ppm):3.80-3.82(t,2H),3.85-3.86(m,4H),4.34-4.36(t,2H),4.50-4.52(t,2H),6.53-7.34(m,8H),7.58-8.07(m,5H)。ESI-MS:630.0(M+Na)
+
Embodiment 5a) preparation 3-(3-benzenesulfonyl-1,2, the oxygen propylamine (Ip of 5-oxadiazole-2-oxide compound-4-)
5) with reference to Ip
2The preparation method make by n-propyl alcohol amine.Methyl alcohol-chloroform column chromatography got faint yellow oily thing, yield 43% in 1: 20.IR (film, cm
-1): 3410
1H NMR (CDCl
3), δ (ppm): 2.03-2.12 (m, 2H), 2.86 (s, 2H), 2.98-3.03 (t, 2H), 4.51-4.55 (t, 2H), 7.58-8.06 (m, 5H) .ESI-MS:300.0 (M+H)
+B) preparation N-[3-(3-benzenesulfonyl-1,2, the oxygen propyl group of 5-oxadiazole-2-oxide compound-4-)]-2-(2,6-dichlorobenzene amido) phenylacetamide (I
8) with reference to I
2The preparation method by Ip
2Make.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got the white powder solid in 3: 7, yield 83%, mp 165-168 ℃ (dec), yield 71%.IR(KBr,cm
-1):3417,3296,1648
1H?NMR(CDCl
3),δ(ppm):2.10-2.27(m,2H),3.45(s,1H),3.56-3.59(t,2H),3.78(s,2H),4.52-4.54(t,2H),6.50-7.34(m,8H),7.63-8.09(m,5H)。ESI-MS:599.0(M+Na)
+
Embodiment 6a) preparation 3-(4-phenyl-1,2, the anisole methyl alcohol (IIp of 5-oxadiazole-2-oxide compound-3-)
1) with 3-methylol-4-phenyl-1,2, (0.25g 1.3mmol) is dissolved in the 10ml methylene dichloride 5-oxadiazole-2-oxide compound, add anhydrous pyridine (0.24ml, 3.4mmol) after, splash into thionyl chloride (0.25ml, 3.4mmol), reaction solution is yellow clear solution, stirred overnight at room temperature.Reaction solution is washed one time with the 40ml frozen water, and it is neutral being washed till water layer with saturated sodium bicarbonate aqueous solution, again with saturated common salt washing, dry organic layer.Filtering and concentrating gets orange-yellow oily thing.This product is dissolved among the 15ml DMF, and (0.2g, 1.6mmol), (Ig, 7.2mmol) with a small amount of potassiumiodide, reaction is 3 hours under the room temperature for Anhydrous potassium carbonate for salicylic alcohol between adding.In reaction solution impouring water, and the usefulness ether (3 * 20ml) extractions, ether layer 20ml aqueous sodium hydroxide washes washes with water to neutrality again, after the saturated common salt washing, dry organic layer.Filter, filtrate is concentrated back column chromatography [3: 7 ethyl acetate-sherwood oils (60-90 ℃)] get orange red oily matter, get yellow solid 0.24g, yield 62%, mp66-68 ℃ after the vacuum-drying.IR(KBr,cm
-1):3460
1H?NMR(CDCl
3),δ(ppm):1.07(s,1H),4.70(s,2H),5.11(s,2H),6.90-7.33(m4H),7.50-7.87(m,5H)。ESI-MS:321.2 (M+Na)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-3-(4-phenyl-1,2, anisole methyl esters (II of 5-oxadiazole-2-oxide compound-3-)
1) with reference to I
2The preparation method by IIp
1Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 75%, mp116-118 ℃ in 1: 2.IR(KBr,cm
-1):3417,3296,1648
1H?NMR(CDCl
3),δ(ppm):3.88(s,2H),4.97(s,2H),5.17(s,2H),6.47-7.32(m,12H),7.49-7.82(m,5H)。ESI-MS:576.3(M+Na)
+
Embodiment 7a) preparation 4-(4-phenyl-1,2, the anisole methyl alcohol (IIp of 5-oxadiazole-2-oxide compound-3-)
2) with reference to IIp
1The preparation method make by salicylic alcohol.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got white solid, yield 69%, mp64-66 ℃ in 1: 4.IR(KBr,cm
-1):3353
1H?NMR(CDCl
3),δ(ppm):2.08(s,1H),4.65(s,2H),5.11(s,2H),6.98-7.34(q,4H),7.51-7.86(m,5H)。ESI-MS:321.2 (M+Na)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-4-(4-phenyl-1,2, anisole methyl esters (II of 5-oxadiazole-2-oxide compound-3-)
2) with reference to I
2The preparation method by IIp
2Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 71%, mp91-94 ℃ in 1: 2.IR (KBr, cm
-1): 3448,1715
1H NMR (CDCl
3), δ (ppm): 3.86 (s, 2H), 5.12 (s, 2H), 5.14 (s, 2H), 6.55-7.35 (m, 12H), 7.54-7.88 (m, 5H) .FAB-MS:575.8 (M+1)
+Embodiment 8a) preparation 2-(4-phenyl-1,2, the anisole methyl alcohol (IIp of 5-oxadiazole-2-oxide compound-3-)
3) with reference to IIp
1The preparation method make by neighbour-salicylic alcohol.Ethyl acetate-sherwood oil (60-90 ℃) column chromatography got white solid, yield 71%, mp82-86 ℃ in 1: 4.IR(KBr,cm
-1):3509
1H?NMR(CDCl
3),δ(ppm):2.28(s,1H),4.56(s,2H),5.19(s,2H),6.96-7.35(m,4H),7.53-7.81(m,5H)。ESI-MS:321.2 (M+Na)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-2-(4-phenyl-1,2, anisole methyl esters (II of 5-oxadiazole-2-oxide compound-3-)
3) with reference to I
2The preparation method by IIp
3Make.Methylene dichloride-sherwood oil (60-90 ℃) column chromatography got the white powder solid, yield 65%, mp98-100 ℃ in 1: 2.IR(KBr,cm
-1):3357,1741
1H?NMR(CDCl
3),δ(ppm):3.78(s,2H),5.09(s,2H),5.10(s,2H),6.50-7.34(m,12H),7.48-7.82(m,5H)。ESI-MS:598.1(M+Na)
+
Embodiment 9a) preparation 3-(3-phenyl-1,2, the anisole methyl alcohol (IIIp of 5-oxadiazole-2-oxide compound-4-)
1) with 3-methylol-4-phenyl-1,2, (1.0g 5.2mmol) is dissolved in the 30ml toluene 5-oxadiazole-2-oxide compound, refluxes 3 days.The pressure reducing and steaming solvent, resistates column chromatography [1: 15 ethyl acetate-sherwood oil (60-90 ℃)] yellow oil, after freezing faint yellow solid (3-phenyl-4 methylol-1,2,5-oxadiazole-2-oxide compound), refer again to IIp
1The preparation method, ethyl acetate-sherwood oil (60-90 ℃) column chromatography got yellow oil, yield 60% in 1: 4.IR(film,cm
-1):3380
1H?NMR(CDCl
3),δ(ppm):1.59(s,1H),4.70(s,2H),5.23(s,2H),6.92-7.35(m,4H),7.48-7.93(m,5H)。ESI-MS:321.1 (M+Na)
+B) preparation 2-(2,6-dichlorobenzene amido) toluylic acid-3-(3-phenyl-1,2, anisole methyl esters (III of 5-oxadiazole-2-oxide compound-4-)
1) with reference to I
2The preparation method by IIIp
1Make.1:2 methylene dichloride-sherwood oil (60-90 ℃) column chromatography gets the white powder solid, yield 74%, mp132-135 ℃.IR(KBr,cm
-1):3366,1739
1H?NMR(CDCl
3),δ(ppm):3.87(s,2H),5.07(s,2H),5.18(s,2H),6.47-7.32(m,12H),7.46-7.89(m,5H).ESI-MS:598.2(M+Na)
+
Embodiment 10 preparation 2-(2,6-dichlorobenzene amido) toluylic acid-(3-nitre oxygen methyl) phenyl ester (IV
1) will between the hydroxyl bromobenzyl (0.5g 2.67mmol) is dissolved in the 10ml acetonitrile, and (0.54g, acetonitrile solution 3.20mmol) have faint yellow muddy the generation to add the 5ml Silver Nitrate.Stirring reaction 48 hours, the elimination precipitation concentrates filtrate, adds the dissolving of 10ml methylene dichloride, the elimination insolubles, filtrate concentrates, and gets faint yellow oily thing 0.43g.It is dissolved in the 15ml anhydrous methylene chloride, add DC (0.9g, 3.04mmol), DCC (0.63g, 3.0mmol), DMAP number.Stirred overnight at room temperature, the adularescent precipitation generates.Filter, filtrate is concentrated, ethyl acetate-sherwood oil (60-90 ℃) column chromatography got yellow granular crystal 0.89g, yield 81%, mp85-88 ℃ in 1: 15.IR(KBr,cm
-1):3372,3340,1737
1H?NMR(CDCl
3),δ(ppm):4.09(s,2H),5.40(s,2H),6.63-6.64(d,1H),6.77(s,1H),6.98-7.02(t,H),7.03-7.%(t,1H),7.13-7.22(m,3H),7.27-7.28(d,1H),7.35-7.38(m,3H),7.40-7.43(t,1H)ESI-MS:470.0(M+Na)
+