CN101665509A - 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof - Google Patents
4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof Download PDFInfo
- Publication number
- CN101665509A CN101665509A CN200910152892A CN200910152892A CN101665509A CN 101665509 A CN101665509 A CN 101665509A CN 200910152892 A CN200910152892 A CN 200910152892A CN 200910152892 A CN200910152892 A CN 200910152892A CN 101665509 A CN101665509 A CN 101665509A
- Authority
- CN
- China
- Prior art keywords
- ethyl
- beta
- ketone
- reaction
- tertiary butyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses 4-1H-1,2,3-triazole-beta-lactam derivative and a preparation method thereof, comprising the following steps: 1) adding (1'R,3R,4R)-4-acetoxyl group-3-(1'-tertiary butyl dimethyl silica) ethyl-azetidine-2-ketone, NaN3 and solvent into a reaction flask, stirring for reaction, concentrating to remove solvent, adding ethyl acetate and water, mixing evening and stewing, educingthe organic phase, extracting the aqueous phase with ethyl acetate, merging the organic phase, washing with saturated saline solution, adding anhydrous Na2SO4, stewing and drying, concentrating, purifying the crude product through column chromatography to obtain the white solid of (1'R,3R,4R)-4-acetoxyl group-3-(1'-tertiary butyl dimethyl silica) ethyl-azetidine-2-ketone; and 2) adding (1'R,3R,4R)-4-acetoxyl group-3-(1'-tertiary butyl dimethyl silica) ethyl-azetidine-2-ketone, alkyne, catalyst and solvent into a reaction bottle, stirring for reaction, concentrating, purifying the crude productthrough column chromatography to obtain the 4-1H-1,2,3-triazole-beta-lactam derivant. The method in the invention has the advantages of good stereoselectivity and regioselectivity, high yield coefficient and convenient and simple operation.
Description
Technical field
The present invention relates to the preparation method of compound, relate in particular to a kind of 4-1H-1,2,3-triazole-beta-lactam derivatives and preparation method thereof.
Background technology
Since nineteen twenty-eight Alexander Fleming discovery penicillin, β-Nei Xiananleikangshengsu has been brought into play very important effect aspect bacterial-infection resisting.But cause bacterium that β-Nei Xiananleikangshengsu has been produced significant resistance owing to be extensive use of microbiotic
[1], the drug effect of beta-lactam antibiotics also presents downward trend gradually, this owing to the β-Nei Xiananmei of evolving out in some bacterial bodies can the catalysis beta-lactam hydrolysis, thereby make it lose drug effect.Therefore, the activity and the selectivity of traditional penicillin medicine molecule can not satisfy present demand, be badly in need of the new β-Nei acid amide class antibiosis of exploitation and usually resist the resistance of bacterium, or the exploitation beta-lactamase inhibitor is to suppress β-Nei Xiananmei to antibiotic hydrolytic action.On the other hand, studies show that monocycle beta-lactam has antibiotic activity in addition, for example, some monocycle beta-lactam molecule derivants (2-azetidinone) are the potential inhibitors of serine protease, they to cause human body chronic tissue and destroy and the human leukocyte elastase of some other disease (human leucocyte elastase HLE) also has immune deficiency individuality (AIDS) to show certain pharmaceutical activity
[2]Trans 2-azetidinones (Ezetimibe,
) also can be used as cholesterol absorption inhibitor (CAI) treatment cardiovascular disorder
[3]The monocycle beta-lactam derivative that the 4-indoles replaces acts on nervus centralis and antiinflammation is arranged
[4]1H-1,2, the 3-triazole class compounds has pharmaceutical activity widely, and it has significant effect at aspect such as antibiotic, antiviral
[5]Therefore, synthetic 4-1H-1,2,3-triazole-beta-lactam derivatives has important practical significance for the new Beta-lactam medicine of exploitation.
Reference:
[1]Fisher,J.F.;Meroueh,S.O.;Mobashery,S.Chem.Rev.2005,105,395.
[2](a)Bonneau,P.R.;Hasani,F.;Plouffe,C.;Malenfant,E.;LaPlante,S.R.;Guse,I.;Ogilvie,W.W.;Plante,R.;Davidson,W.C.;Hopkins,J.L.;Morelock,M.M.;Cordingley,M.G.;Déziel,R.J.Am.Chem.Soc.1999,121,2965;(b)Borthwick,A.D.;Weingarten,G.;Haley,T.M.;Tomaszewski,M.;Wang,W.;Hu,Z.;Bédard,J.;Jin,H.;Yuen,L.Mansour,T.S.Bioorg.Med.Chem.Lett.1998,8,365;(c)Yoakim,C.;Ogilvie,W.W.;Cameron,D.R.;Chabot,C.;Guse,I.;Haché,B.;Naud,J.;O’Meara,J.A.;Plante,R.;Déziel,R.J.Med.Chem.1998,41,2882.
[3](a)Rosenblum,S.B.;Huynh,T.;Afonso,A.;Davis,H.R.;Yumibe,N.;Clader,J.W.;Burnett,D.A.J.Med.Chem.1998,41,973;(b)Clader,J.W.;Burnett,D.A.;Caplen,M.A.;Domalski,M.S.;Dugar,S.;Vaccaro,W.;Sher,R.;Browne,M.E.;Zhao,H.;Burrier,R.E.;Salisbury,B.H.;Davis,R.J.Med.Chem.1996,39,3684.
[4]Agarwal,R.;Agarwal,C.;Singh,C.;et?al.Indian?J.Chem.Sect.B.1989,28,893.
[5]Genin,M.J.;Allwine,D.A.;Anderson,D.J.;etc.J.Med.Chem.2000,43,953.
Summary of the invention
This provides a class 4-1H-1, and 2,3-triazole-beta-lactam derivatives and preparation method thereof.
4-1H-1,2,3-triazole-beta-lactam derivatives, its structural formula is:
Wherein: R
1=t-Butyldimethylsilyl (TBDMS);
R
2=C
6H
5,p-EtC
6H
5,p-OMeC
6H
5,t-Butyl,Cyclopropyl,Hydroxyethyl,n-Hexyl,
4-1H-1,2, the preparation method of 3-triazole-beta-lactam derivatives comprises the steps:
1) in reaction flask, add 10mmol (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone, 10~50mmol NaN
3With 30~80mL solvent, stir, temperature of reaction is 25~100 ℃, stopped reaction when raw material no longer reduces, concentrate to remove and desolvate, add 30~60mL ethyl acetate and 30~60mL water, leave standstill after mixing, tell organic phase, the water ethyl acetate extraction, merge organic phase, use the saturated common salt water washing, add anhydrous Na
2SO
4Standing and drying concentrates, and crude product is through column chromatography purification, obtain (1 ' R, 3R, 4R)-4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone white solid;
2) in reaction flask, add 1mmol (1 ' R, 3R, 4R)-4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone), 1~5mmol phenylacetylene, 0.01~0.2mmol catalyzer and 5~10mL solvent, stir, temperature of reaction is 25~100 ℃, stopped reaction when raw material no longer reduces, concentrate, crude product obtains 4-1H-1 through column chromatography purification, 2,3-triazole-beta-lactam derivatives.
Described solvent is acetonitrile, ethanol, dimethyl formamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or water.Described catalyzer is CuCl, CuBr or CuI, and catalyst levels is 1~20mol%.
4-1H-1 of the present invention, 2,3-triazole-beta-lactam derivatives has kept the steric configuration of substrate, and 1,2,3-triazoles ring wherein is single 1,4-position configuration.Method of the present invention has characteristics three-dimensional and that regioselectivity is good, yield is high, easy and simple to handle.
Embodiment
Following examples will help to understand the present invention, but be not limited to content of the present invention:
Embodiment 1 (1 ' R, 3R, 4R)-preparation of 4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (2)
In 150mL single port bottle, add (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (1) (20mmol, 5.74g), NaN
3(20mmol 1.95g) and the 60mL acetonitrile, stirs, and is heated to 70 ℃ of reactions, follows the tracks of reaction process (the smoked colour developing of iodine) with TLC, no longer reduces to raw material, stops heating, and reaction solution is cooled to room temperature.Concentrate and remove solvent acetonitrile, add 50mL ethyl acetate and 30mL water and mix, leave standstill in separating funnel, tell organic layer, water layer merges organic phase with ethyl acetate extraction (20mL * 3), with saturated common salt water washing (20mL * 2), adds an amount of anhydrous Na
2SO
4Standing and drying.(sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 5.13g, yield 95% with column chromatography to concentrate the crude product that obtains.Mp:70.9-71.2℃;IR(KBr):3174,2105,1770cm
-1;
1H?NMR(CDCl
3):δ6.50(1H,br?s,NH),4.96(1H,s,4-H),4.17(1H,m),3.12(1H,dd,J=2.0Hz,3-H),1.20(3H,d,J=6.4Hz),0.81(9H,s),0.02,0.01(total?6H,each?s);
13C?NMR(CDCl
3):δ166.76,66.65,65.36,64.23,25.91,22.58,18.12,-4.10,-4.89;MS(ESI):m/z292.9[M+Na
+].
Embodiment 2 (1 ' R, 3R, 4R)-preparation of 4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (2)
In 50mL single port bottle, add (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (1) (10mmol, 2.87g) and NaN
3(50mmol 3.25g), adds the 80mL dimethyl formamide, mixture solution stirs, and is heated to 100 ℃, insulation reaction, follow the tracks of reaction process (iodine smoked colour developing) with TLC, no longer reduce to raw material, stop heating, reaction solution is cooled to room temperature, and adding 30mL water mixes and changes separating funnel over to, adds the 100mL ethyl acetate extraction, tell organic layer, water layer merges organic phase with ethyl acetate extraction (30mL * 2), with saturated common salt water washing (20mL * 2), add an amount of anhydrous Na
2SO
4Standing and drying.(sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 2.16g, yield 80% through column chromatography to concentrate the crude product that obtains.
Embodiment 3 (1 ' R, 3R, 4R)-preparation of 4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (2)
Operation is with embodiment 2, with 30mL water as solvent, temperature of reaction is 80 ℃, and reaction finishes, and adds the 50mL ethyl acetate and mixes, in separating funnel, leave standstill, tell organic layer, water layer 20mL ethyl acetate extraction merges organic phase, with saturated common salt water washing (20mL * 2), add an amount of anhydrous Na
2SO
4Standing and drying.(sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 4.86g, yield 90% through column chromatography to concentrate the crude product that obtains.
Embodiment 4 (1 ' R, 3R, 4R)-preparation of 4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (2)
In 50mL single port bottle, add (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (1) (10mmol, 2.87g) and NaN
3(50mmol 3.25g), adds the 80mL dimethyl sulfoxide (DMSO), 25 ℃ of stirring reactions are followed the tracks of reaction process (iodine smoked colour developing) with TLC, no longer reduce to raw material, stop heating, reaction solution is cooled to room temperature, and adding 30mL water mixes and changes separating funnel over to, add the 100mL ethyl acetate extraction, tell organic layer, water layer merges organic phase with ethyl acetate extraction (30mL * 2), with saturated common salt water washing (20mL * 2), add an amount of anhydrous Na
2SO
4Standing and drying.(sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 1.35g, yield 50% through column chromatography to concentrate the crude product that obtains.
Embodiment 5 (1 ' R, 3R, 4R)-preparation of 4-(4-phenyl-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3a)
In 25mL single port bottle, add trinitride (2) (0.27g, 1mmol) CuI (0.0096g, 0.05mmol), phenylacetylene (0.20g, 2mmol) and the 4mL acetonitrile, 25 ℃ of stirrings, TLC follows the tracks of reaction process, disappears stopped reaction to the raw material trinitride.Concentration of reaction solution, directly column chromatography (sherwood oil: ethyl acetate=5: 1), obtain white solid 0.35g, yield 94.2%.Mp:114.6-115.4℃;IR(KBr):3315,1794,1768,1646,1555,1464cm
-1;
1H?NMR(CDCl
3):δ8.04(1H,s),7.82(2Hm),7.44-7.35(3H,m),6.89(1H,br?s,NH),6.34(1H,s,4-H),4.35(1H,m),3.56(1H,m),1.28(3H,d,J=6.4Hz),0.90(9H,s),0.12,0.11(total?6H,each?s);
13C?NMR(CDCl
3):δ166.6,148.9,130.2,129.2,128.8,125.9,117.2,68.8,64.3,63.4,25.9,22.4,18.2,-4.0,-4.9;Ms-ESI:395.2[M+Na
+],373.1[M+H
+].
Embodiment 6 (1 ' R, 3R, 4R)-preparation of 4-(4-phenyl-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3a)
In 25mL single port bottle, add trinitride (2) (0.27g, 1mmol), CuI (0.0096g, 0.05mmol), phenylacetylene (0.20g, 5mmol) with the 10mL acetonitrile, be warming up to 70 ℃ of stirring reactions, TLC follows the tracks of reaction process, disappear stopped reaction to the raw material trinitride.Concentration of reaction solution, directly column chromatography (sherwood oil: ethyl acetate=5: 1), obtain white solid 0.34g, yield 94%.
Embodiment 7 (1 ' R, 3R, 4R)-preparation of 4-(4-cyclopropyl-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3b)
In 25mL single port bottle, add trinitride (2) (0.27g, 1mmol), CuI (0.0096g, 0.05mmol), 1-cyclopropyl alkynes (0.13g, 2mmol) with the 5mL acetonitrile, be warming up to 70 ℃ under stirring, TLC follows the tracks of reaction process, no longer reduce to the raw material trinitride, stop.Concentration of reaction solution, (sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 0.29g, yield 87% to crude product through column chromatography.Mp:133.0-133.7℃;IR(KBr):3448,1783,1652,1558,1341cm
-1;
1H?NMR(CDCl
3)δ7.50(s,1H),6.71(1H,br?s,-NH),6.25(s,1H),4.34-4.32(dd,1H,J=6.4,2.8Hz),3.49(m,1H,3-H),1.96(m,1H),1.25(d,3H,J=6.4Hz),0.99-0.95(m,2H),0.88(s,9H),0.84-0.87(m,2H),0.11,0.10(total?6H,each?s);
13C?NMR(CDCl
3):δ166.5,151.6,117.2,68.5,64.3,63.1,26.0,22.4,18.2,8.1,7.0,-4.0,-4.9;Ms-ESI:359.2[M+Na
+],337.2[M+H
+].
Embodiment 8 (1 ' R, 3R, 4R)-preparation of 4-(4-butyl-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3c)
In 25mL single port bottle, add trinitride (2) (0.27g, 1mmol), CuI (0.0096g, 0.05mmol), 1-hexin (0.082g, 1mmol) and under the stirring of 5mL acetonitrile be warming up to 70 ℃, TLC follows the tracks of reaction process, no longer reduces to the raw material trinitride, stops.Concentration of reaction solution, (sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 0.31g to crude product, yield 88% through column chromatography.Mp:70.6-71.1℃;IR(KBr):3209,1778,1750,1358cm
-1;
1H?NMR(CDCl
3):δ7.54(s,1H),6.87(1H,br?s,-NH),6.26(d,J=1.2Hz,1H),4.34(dd,1H,J=6.35,2.9Hz),3.51(m,1H,3-H),2.73(t,2H,J=7.7Hz),1.64-1.67(m,2H),1.36-1.41(m,2H),1.26(d,3H,J=6.4Hz),0.95(t,3H,J=7.4Hz),0.89(s,9H),0.11,0.09(total?6H,each?s);
13C?NMR(CDCl
3):δ166.7,149.7,118.2,68.4,64.3,63.1,31.6,25.9,25.6,22.5,22.4,18.2,14.0,-4.0,-4.9;Ms-ESI:375.2[M+Na
+],353.0[M+H
+].
Embodiment 9 (1 ' R, 3R, 4R)-preparation of 4-(4-(1 '-hydroxyl sec.-propyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3d)
With 3-hydroxyl-3 methyl isophthalic acids-butine is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=2: 1) obtain white solid 0.30g, yield 85%.Mp:137.3-137.9℃;IR(KBr):3217,1776,1752cm
-1;
1H?NMR(CDCl
3):δ7.72(s,1H),6.80(1H,br?s,-NH),6.26(1H,d,J=0.95Hz,4-H),4.33-4.35(1H,m),3.52(1H,dd,J=2.7,1.9Hz,3-H),2.69(1H,br?s,-OH),1.64(6H,s),1.27(3H,d,J=6.3Hz),0.90(9H?s,),0.11,0.10(total6H,each?s);
13C?NMR(CDCl
3):δ166.5,156.8,117.1,68.8,68.5,64.3,63.3,30.6,25.9,22.5,18.2,-4.0,-4.9;Ms-ESI:377.2[M+Na
+].
Embodiment 10 (1 ' R, 3R, 4R)-preparation of 4-(4-methylol-1 hydrogen-1,2,3-triazoles-1-yl) 3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3e)
With 3-hydroxyl-1-propine is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=2: 1) obtain white solid 0.28g, yield 86%.Mp:124.0-125.8℃;IR(KBr):3392,1777,1445,1142cm
-1;
1H?NMR(CDCl
3):δ7.82(1H,s),7.39(1H,br?s,-NH),6.22(1H,s,4-H,4-H),4.73(2H,s),4.31-4.33(m,1H),3.70(1H,br,-OH),3.48(1H,s,3-H),1.25(3H,d,J=6.3Hz),0.89(9H,s),0.10,0.09(total?6H,each?s);
13C?NMR(CDCl
3):δ166.9,148.7,120.1,68.4,64.3,63.4,56.2,25.9,22.5,18.2,-4.1,-4.9;MS(ESI):349.2[M+Na
+],327.2[M+H
+].
Embodiment 11 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
With 4-ethylbenzene acetylene is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.31g, yield 88%.Mp?51.8-53.4℃;IR(KBr):3448,2960,1786,1259,846cm
-1;
1H NMR(CDCl
3):δ7.99(1H,s),7.73-7.75(2H,m),7.26-7.27(2H,m),6.81(1H,br?s,-NH),6.34(1H,d,J=1.13Hz,4-H),4.35(1H,m),3.56(1H,m,3-H),2.69(q,2H),1.25-1.29(6H,m),0.92(9H,s),0.13,0.12(total?6H,each?s);
13C?NMR(CDCl
3):δ166.6,149.1,145.1,128.7,127.6,126.0,116.8,68.8,64.4,63.4,28.9,25.9,22.5,18.2,15.7,-4.0,-4.9;MS(ESI):m/z?423.2[M+Na
+],401.2[M+H
+].
Embodiment 12 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
In 25mL single port bottle, add trinitride (2) (0.27g, 1mmol) CuI (0.0096g, 0.05mmol), 4-ethylbenzene acetylene (0.13g, 1mmol) with the 4mL acetonitrile, 70 ℃ of following stirring reactions, TLC follows the tracks of reaction process, disappear stopped reaction to the raw material trinitride.Concentration of reaction solution, directly column chromatography (sherwood oil: ethyl acetate=5: 1), obtain white solid 0.31g, yield 88%.
Embodiment 13 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, with tetrahydrofuran (THF) as reaction solvent, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.21g, yield 60%.
Embodiment 14 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, with ethanol as reaction solvent, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.25g, yield 72%.
Embodiment 15 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, and as catalyzer, consumption is 5mol% with CuCl, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.30g, yield 85%.
Embodiment 16 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, and as catalyzer, consumption is 5mol% with CuBr, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.30g, yield 85%.
Embodiment 17 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, and as catalyzer, consumption is 1mol% with CuI, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.28g, yield 80%.
Embodiment 18 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-ethylphenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3f)
Operation is with embodiment 7, and as catalyzer, consumption is 20mol% with CuI, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.31g, yield 88%.
Embodiment 19 (1 ' R, 3R, 4R)-preparation of 4-(4-(4 '-p-methoxy-phenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3g)
With 4-anisole acetylene is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=4: 1) obtain white solid 0.375g, yield 90%.Mp?147.6-148.9℃;IR(KBr):3384,2958,1778,1254,830cm
-1;
1H?NMR(CDCl
3):δ7.94(1H,s),7.71-7.73(2H,m),6.93-6.97(1H,br?s,-NH),6.31(1H,d,J=0.9Hz,4-H),4.35(1H,m),3.83(3H,s),3.54(1H,m,3-H),1.26(3H,t,J=6.4Hz),0.90(9H,s),0.12,0.11(total?6H,each?s);
13CNMR(CDCl
3):δ166.6,160.1,148.8,127.3,122.9,116.4,114.6,68.7,64.3,63.3,55.5,25.9,22.4,18.2,-4.0,-4.9;MS(ESI):m/z?425.2[M+Na
+],403.2[M+H
+].
Embodiment 20 with water as reaction solvent preparation (1 ' R, 3R, 4R)-4-(4-(4 '-p-methoxy-phenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3g)
Operation is with embodiment 19, and as reaction solvent, reaction finishes with 10mL water, adds the 20mL ethyl acetate and mixes, in separating funnel, leave standstill, tell organic layer, water layer 20mL ethyl acetate extraction, merge organic phase,, add an amount of anhydrous Na with saturated common salt water washing (20mL * 2)
2SO
4Standing and drying.The concentrated crude product that obtains is through column chromatography (sherwood oil: ethyl acetate=5: 1) purifying, crude product column chromatography (sherwood oil: ethyl acetate=5: 1) obtain white solid 0.375g, yield 90%.
Embodiment 21 with water as reaction solvent preparation (1 ' R, 3R, 4R)-4-(4-(4 '-p-methoxy-phenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3g)
Operation is with embodiment 7,, stirs as reaction solvent with dimethyl sulfoxide (DMSO), is heated to 100 ℃ of reactions, and TLC follows the tracks of reaction process, disappears stopped reaction to the raw material trinitride.Adding 10mL water mixes and changes separating funnel over to, adds the 20mL ethyl acetate extraction, tells organic layer, and water layer merges organic phase with ethyl acetate extraction (20mL * 2), with saturated common salt water washing (30mL * 2), adds an amount of anhydrous Na
2SO
4Standing and drying.(sherwood oil: ethyl acetate=5: 1) purifying obtains white solid 0.35g, yield 85% through column chromatography to concentrate the crude product that obtains.
Embodiment 22 (1 ' R, 3R, 4R)-4-(4 '-tertiary butyl)-1 hydrogen-1,2,3-triazoles-1-yl)-preparation of 3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3h)
With 3,3 dimethyl ethyl acetylene is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=4: 1) obtain white solid 0.375g, yield 90%.Mp.133.8-134.5℃,IR(KBr):2961,2936,1780,1047,846cm
-1;
1H?NMR(CDCl
3):δ7.55(1H,s),7.02(1H,br?s,-NH),6.24(1H,s,4-H),4.35(1H,m),3.52(1H,m,3-H),1.34(9H,s),1.28(3H,d,J=6.4Hz),0.89(9H,s),0.09,0.10(total?6H,each?s);
13C?NMR(CDCl
3):δ166.7,158.8,116.4,68.3,64.4,63.2,31.1,30.5,25.9,22.5,18.2,-4.0,-4.9;MS(ESI):m/z375.2[M+Na
+],353.2[M+H
+].
Embodiment 23 (1 ' R, 3R, 4R)-4-(4-methoxycarbonyl)-1 hydrogen-1,2,3-triazoles-1-yl)-preparation of 3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3i)
With the propargylic acid methyl esters is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=4: 1) obtain white solid 0.31g, yield 88%.Mp:139.4-140.6℃;IR(KBr):2951,1788,1745,1374,1214,1042cm
-1.
1H?NMR(CDCl
3):δ8.41(1H,s),7.08(1H,br?s,NH),6.35(1H,s,4-H),4.35(1H,m),3.95(3H,s)3.56(1H,m),1.28(3H,d,J=6.4Hz),0.88(9H,s),0.11,0.10(total 6H,each s);
13C NMR(CDCl
3):δ166.1,161.0,140.8,125.7,68.9,64.3,63.7,52.6,25.9,22.4,18.1,-4.0,-4.9;MS(ESI):m/z?376.9[M+Na
+]。
Embodiment 24 (1 ' R, 3R, 4R)-4-(4-ethoxycarbonyl)-1 hydrogen-1,2,3-triazoles-1-yl)-preparation of 3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3j)
With the propargylic acid ethyl ester is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=4: 1) obtain white solid 0.324g, yield 88%.Mp:142.1-143.9℃;IR(KBr):2936,1790,1739,1209,1040cm
-1;
1H?NMR(CDCl
3):δ8.39(1H,s),7.14(1H,br?s,NH),6.34(1H,s,4-H),4.41(2H,q),4.35(1H,m),3.54(1H,m),1.40(3H,m)1.27(3H,d,J=6.4Hz),0.87(9H,s),0.10,0.08(total?6H,each?s);
13C?NMR(CDCl
3):δ166.2,160.6,141.0,125.6,68.9,64.3,63.6,61.8,25.9,22.4,18.1,14.5,-4.0,-4.9;MS(ESI):m/z?390.9[M+Na
+]。
Embodiment 25 (1 ' R, 3R, 4R)-preparation of 4-(4-(tetrahydropyrans-2 '-oxygen methyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone (3k)
With 2-alkynes propoxy--tetrahydropyrans is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=4: 1) obtain yellow oil 0.357g, yield 87%; IR (CH
2Cl
2): 3262,2951,1788,1462,1132,832cm
-1 1H
1H NMR (CDCl
3): δ 7.84 (1H, s), 7.31 (1H, br s ,-NH), 6.26 (1H, s, 4-H), 4.86 (1H, m), 4.73-4.74 (1H, m), 4.61 (1H, m), 4.32-4.34 (1H, m), 3.89 (1H, m), 3.53 (1H, m), 1.60-1.73 (2H, m) 1.52-1.60 (4H, m) 1.25 (3H, t, J=6.4Hz), 0.89 (9H, s), 0.11,0.10 (total 6H, each s);
13CNMR (CDCl
3): δ 166.7,146.2,120.4,98.6,68.3,64.2,63.2,62.5,60.6,30.5,25.8,25.4,22.4,19.5,18.1, and-4.1 ,-4.9; MS (ESI): m/z 432.9[M+Na
+], 410.9[M+H
+].
Embodiment 26 (1 ' R, 3R, 4R)-preparation of 4-(4-(3 '-isobutyl amide phenyl)-1 hydrogen-1,2,3-triazoles-1-yl)-3-(1 '-tertiary butyl dimethyl Si) ethyl nitrogen heterocyclic din-2-ketone (3l)
With 3-Isopropamide base phenylacetylene is raw material, and operation is with embodiment 7, crude product column chromatography (sherwood oil: ethyl acetate=3: 1) obtain white solid 0.388g, yield 85%.Mp:95.1-97.2℃;IR(KBr):3317,2958,2930,1775,1376,1252cm
-1;
1H?NMR(CDCl
3):δ8.02(1H,s),8.01(1H,s),7.94(1H,s),7.79(1H,br?s,-NH),7.57-7.59(1H,m),7.47-7.49(1H,m),7.27-7.32(1H,m),6,27(1H,s,4-H),4.33-4.35(1H,m),3.57(1H,m,3-H),2.58(1H,m),1.26(3H,t,J=6.3Hz),1.24(6H,m,J=6.8Hz),0.85(9H,s),0.10,0.09(total?6H,each?s);
13CNMR(CDCl
3):δ176.3,166.8,148.3,139.1,130.7,129.8,121.5,120.1,117.9,117.2,68.4,64.3,63.4,36.7,25.9,22.4,19.8,18.1,-4.0,-4.9;MS(ESI):m/z479.9[M+Na
+],457.8[M+H
+].
Claims (4)
2. 4-1H-1,2, the preparation method of 3-triazole-beta-lactam derivatives is characterized in that comprising the steps:
1) in reaction flask, add 10mmol (1 ' R, 3R, 4R)-4-acetoxy-3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone, 10~50mmolNaN
3With 30~80mL solvent, stir, temperature of reaction is 25~100 ℃, stopped reaction when raw material no longer reduces, concentrate to remove and desolvate, add 30~60mL ethyl acetate and 30~60mL distilled water, leave standstill after mixing, tell organic phase, the water ethyl acetate extraction, merge organic phase, use the saturated common salt water washing, add anhydrous Na
2SO
4Standing and drying concentrates, and crude product is through column chromatography purification, obtain (1 ' R, 3R, 4R)-4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone white solid;
2) in reaction flask, add 1mmol (1 ' R, 3R, 4R)-4-azido--3-(1 '-tertiary butyl dimethyl Si) ethyl-nitrogen heterocyclic din-2-ketone), 1~5mmol alkynes, 0.01~0.2mmol catalyzer and 5~10mL solvent, stir, temperature of reaction is 25~100 ℃, stopped reaction when raw material no longer reduces, concentrate, crude product obtains 4-1H-1 through column chromatography purification, 2,3-triazole-beta-lactam derivatives.
3. a kind of 4-1H-1 according to claim 2,2, the preparation method of 3-triazole-beta-lactam derivatives, its feature is acetonitrile, ethanol, dimethyl formamide, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or water at described solvent.
4. a kind of synthetic 4-1H-1 according to claim 2,2, the method for 3-triazole-beta-lactam derivatives is characterized in that described catalyzer is CuCl, CuBr or CuI, catalyst levels is 1~20mol%.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200910152892A CN101665509A (en) | 2009-09-18 | 2009-09-18 | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN200910152892A CN101665509A (en) | 2009-09-18 | 2009-09-18 | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
CN101665509A true CN101665509A (en) | 2010-03-10 |
Family
ID=41802311
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200910152892A Pending CN101665509A (en) | 2009-09-18 | 2009-09-18 | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN101665509A (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102579468A (en) * | 2012-01-12 | 2012-07-18 | 浙江大学 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
CN102670594A (en) * | 2012-05-02 | 2012-09-19 | 浙江大学 | Appliance of 4bit-1H-1,2,3- triazole-Beta-lactam derivatives for resisting liver cancer |
-
2009
- 2009-09-18 CN CN200910152892A patent/CN101665509A/en active Pending
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102579468A (en) * | 2012-01-12 | 2012-07-18 | 浙江大学 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
CN102579468B (en) * | 2012-01-12 | 2013-09-04 | 浙江大学 | Application of 4-1H-1,2,3-triazole-beta-lactam derivative |
CN102670594A (en) * | 2012-05-02 | 2012-09-19 | 浙江大学 | Appliance of 4bit-1H-1,2,3- triazole-Beta-lactam derivatives for resisting liver cancer |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN101511796B (en) | Imidazole derivative | |
CN104349777B (en) | For treating the compound of Duchenne-Arandisease | |
CN101374834B (en) | Compounds and methods for modulating FXR | |
CN103204815B (en) | 4-(4-cyano-2-thioaryl)dihydropyrimidinones and use thereof | |
JP7038063B2 (en) | Pyrazolo [1,5-a] pyrimidinylcarboxamide compounds and their use in the treatment of medical disorders | |
JP7034935B2 (en) | Pyrrolo [1,2-a] pyrimidinylcarboxamide compounds and their use in the treatment of medical disorders | |
CN102791693A (en) | Hepatitis c virus inhibitors | |
KR20080104052A (en) | Novel dual action receptors antagonists (dara) at the at1 and eta receptors | |
CN101119969A (en) | Use of aryl- and heteroaryl-substituted tetrahydroisoquinolines to block reuptake of norepinephrine, dopamine, and serotonin | |
CN106986869A (en) | Compounds and methods for for antiviral therapy | |
WO2013043964A1 (en) | Acyclic cyanoethylpyrazoles as janus kinase inhibitors | |
CN105307655A (en) | Pyridazinone compounds and methods for the treatment of cystic fibrosis | |
JP2019510790A5 (en) | ||
CN102459239A (en) | Hepatitis c virus inhibitors | |
CN104892537B (en) | The synthetic method of Ezetimibe intermediate and Ezetimibe | |
CN1291988A (en) | Novel aromatic amides, preparation method and application as medicines | |
TWI773718B (en) | Poly-adp ribose polymerase (parp) inhibitors | |
KR20140033432A (en) | Polymorphs of (s)-pyrrolidine-1,2-dicarboxylic acid 2-amide 1-(??4-methyl-5-[2-(2,2,2-trifluoro-1,1-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl??-amide) | |
CN107108599A (en) | It is used as the trifluoromethyl alcohol of Ror γ t conditioning agents | |
CN105189508A (en) | Cycloalkyl nitrile pyrazolo pyridones as JANUS kinase inhibitors | |
CN102869667A (en) | Tricyclic pyridine derivatives, medicaments containing such compounds, their use and process for their preparation | |
CN101665509A (en) | 4 pos-1H-1,2,3-triazole-beta-lactam derivative and preparation method thereof | |
CN105308045B (en) | New 3,4-dihydro-2H-isoquinoline-1-one and 2,3-dihydro-isoindol-1-one compounds | |
CN105399737B (en) | Oxazolidinone compounds and application thereof | |
CN114106005A (en) | Nitrile derivative as dipeptidyl peptidase 1 inhibitor and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20100310 |