CN114163401A - Preparation method and application of N-benzenesulfonyl formamidine compound - Google Patents
Preparation method and application of N-benzenesulfonyl formamidine compound Download PDFInfo
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Abstract
The invention relates to a preparation method and application of an N-benzenesulfonyl formamidine compound, belonging to the technical field of organic synthesis. The preparation method comprises the following steps: adding secondary amine, cyano-sulfonyl oxime ether, organic base and solvent into a reactor, stirring and reacting for a period of time at a certain temperature, and after the reaction is finished, washing, extracting, drying, separating, rotary evaporating and purifying to obtain the target product N-benzenesulfonyl formamidine compound. The preparation method of the N-benzenesulfonyl formamidine compound can be applied to the post-structural modification of drug molecules and drug intermediates, and the obtained compound has potential application in sterilization. The synthetic reaction route of the invention has the characteristics of simple and convenient operation, mild condition, high yield, relatively easy post-treatment, suitability for large-scale preparation and the like.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method and application of N-benzenesulfonyl formamidine compounds.
Background
N-benzenesulfonylformamidine is an important compound, and the skeleton of the N-benzenesulfonylformamidine widely exists in a plurality of compound molecules with broad spectrum of pharmacological activity and biological activity. Many bioactive compounds having the structure of N-benzenesulfonylformamidine have been developed into drugs having bactericidal and anti-inflammatory effects. For example, ethidium bromide (ebrodine) is the first H2 receptor antagonist with gastric mucosal protective, anti-helicobacter pylori (Hp) and anti-secretory effects, and has been marketed in spain 1997.
In the prior art, the synthesis of N-benzenesulfonylformamidine compounds by conversion of benzenesulfonyl azide or benzenesulfonamide has been developed (j.am.chem.soc.,2005,127,2038; org.lett.,2011,13, 6152; j.org.chem.,2020,85,2092), but these methods have some disadvantages, such as: 1) use of a dangerous and explosive sulfonyl azide; 2) under the action of a metal catalyst, metal residue is easily caused; 3) the reaction temperature is high, and the operation is inconvenient.
Therefore, the method for preparing the N-benzenesulfonylformamidine compound has the advantages of mild reaction conditions, high yield, safe and simple operation, relatively easy post-treatment, suitability for large-scale synthesis, and important research significance and application value. In addition, the developed synthetic strategy is further applied to the structural later modification of drug molecules or drug key intermediates, so that N-benzenesulfonyl formamidine compounds with novel structures are constructed, and new compounds with potential bactericidal activity are expected to be obtained from the N-benzenesulfonyl formamidine compounds, so that the N-benzenesulfonyl formamidine compounds have very wide research and development prospects.
Disclosure of Invention
The invention aims to provide a preparation method which has the advantages of mild condition, high yield, safe and simple operation, relatively easy post-treatment and suitability for large-scale synthesis of the N-benzenesulfonylformamidine compound.
The invention also aims to provide the preparation method which can be applied to the post-structural modification of drug molecules and drug intermediates, and the obtained compound has potential application in sterilization.
In a first aspect, the present invention provides a process for the preparation of an N-benzenesulfonylformamidine compound of the invention, which may be prepared according to the following reaction scheme:
adding secondary amine, cyano-sulfonyl oxime ether, organic base and solvent into a reactor, stirring and reacting for a period of time at a certain temperature, and after the reaction is finished, washing, extracting, drying, separating, rotary evaporating and purifying to obtain the target product N-benzenesulfonyl formamidine compound.
Wherein the organic base is triethylamine, 1, 4-diazabicyclo [2,2,2] octane, N-dimethylpyridine or 1, 8-diazabicycloundec-7-ene.
The solvent is dimethyl sulfoxide, N-dimethylformamide, toluene, dichloromethane, tetrahydrofuran or acetonitrile.
The temperature is 25-80 ℃.
The mass ratio of the secondary amine, the cyano sulfonyl oxime ether and the organic base is as follows: secondary amine: cyano sulfonyl oxime ether: 3.0 to 5.0% of an organic base: 1: 1.0 to 2.0.
The second aspect of the invention relates to a preparation method of the N-benzenesulfonylformamidine compound, which can be applied to the later structural modification of drug molecules and drug intermediates, and the obtained compound is applied to sterilization.
The drug molecules of the invention comprise amoxapine and norfloxacin. The drug intermediates comprise 3- (1-piperazinyl) -1, 2-benzisothiazole (key intermediates of drugs such as ziprasidone, perospiroprerione, lurasidone and the like), 1- (4-chlorobenzhydryl) piperazine (key intermediates of drugs such as clocycline hydrochloride, oxazine, cetirizine and the like) and 6-fluoro-3- (piperidine-4-yl) benzo [ D ] isoxazole (key intermediates of drugs such as risperidone, paliperidone, iloperidone and the like). Of course, the drug molecules and drug intermediates described in the present invention are not limited to the above-exemplified ranges.
The invention has the beneficial effects that: the preparation method of the N-benzenesulfonyl formamidine compound has the characteristics of simple and convenient operation, mild condition, high yield, relatively easy post-treatment, suitability for large-scale preparation, effective avoidance of the use of metal catalysts and hazardous reagents and the like; the preparation method of the N-benzenesulfonyl formamidine compound can be applied to the post-structural modification of drug molecules and drug intermediates, and the obtained compound has potential application in sterilization.
Drawings
FIG. 1 is a NMR spectrum of Compound 1a prepared in the example of the present invention;
FIG. 2 is a NMR carbon spectrum of Compound 1a prepared in the examples of the present invention;
FIG. 3 is a NMR spectrum of Compound 1b prepared in example of the present invention;
FIG. 4 is a NMR carbon spectrum of Compound 1b prepared in example of the present invention;
FIG. 5 is a NMR spectrum of Compound 1c prepared in example of the present invention;
FIG. 6 is a NMR carbon spectrum of Compound 1c prepared in example of the present invention;
FIG. 7 is a NMR spectrum of Compound 1d prepared in example of the present invention;
FIG. 8 is a NMR carbon spectrum of Compound 1d prepared in example of the present invention;
FIG. 9 is a NMR spectrum of Compound 1e prepared in example of the present invention;
FIG. 10 is a NMR carbon spectrum of Compound 1e prepared in example of the present invention;
FIG. 11 is a NMR spectrum of Compound 1f prepared in example of the present invention;
FIG. 12 is a NMR carbon spectrum of Compound 1f prepared in example of the present invention;
FIG. 13 is a NMR spectrum of 1g of compound prepared in example of the present invention;
FIG. 14 is a NMR carbon spectrum of 1g of compound prepared in example of the present invention;
FIG. 15 is a NMR spectrum of compound prepared in example of the invention for 1 h;
FIG. 16 is a NMR carbon spectrum of compound prepared in example of the invention for 1 h;
FIG. 17 is a NMR spectrum of Compound 1i prepared in example of the present invention;
FIG. 18 is a NMR carbon spectrum of Compound 1i prepared in example of the present invention;
FIG. 19 is a NMR spectrum of Compound 2a prepared in example of the present invention;
FIG. 20 is a NMR carbon spectrum of Compound 2a prepared in example of the invention;
FIG. 21 is a NMR spectrum of Compound 2b prepared in example of the invention;
FIG. 22 is a NMR carbon spectrum of Compound 2b prepared in example of the invention;
FIG. 23 is a NMR spectrum of Compound 2c prepared in example of the present invention;
FIG. 24 is a NMR carbon spectrum of Compound 2c prepared in example of the invention;
FIG. 25 is a NMR spectrum of Compound 2d prepared in example of the present invention;
FIG. 26 is a NMR carbon spectrum of Compound 2d prepared in example of the invention;
FIG. 27 is a NMR spectrum of Compound 2e prepared in example of the present invention;
FIG. 28 is a NMR carbon spectrum of Compound 2e prepared in example of the present invention.
Detailed Description
The present invention will be further described with reference to the following examples, which will help to further understand the present invention. These examples are provided for illustrative purposes only and are not intended to limit the scope or the principles of the invention.
Preparation examples:
example 1: preparation of N- (morpholinomethylene) benzenesulfonamide
To a 25mL Schlenk flask was added cyanosulfonimide (150mg,0.5mmol), morpholine (175mg,2.0mmol), 1, 4-diazabicyclo [2,2]Octane (85mg,0.75mmol) and 2.5mL of dimethyl sulfoxide were added, and the mixture was stirred in a 60 ℃ oil bath for 24 hours. TLC check reaction was complete, water (10mL) was added to dilute the mixture and extracted with ethyl acetate (3X 10mL) and the organics combinedThe layer was washed with saturated brine (15mL), anhydrous MgSO4Drying and then concentration in vacuo, the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate as eluent) to give the desired product 1a 100mg as a white solid in 78% yield.1H NMR(400MHz,CDCl3)δ3.50(t,J＝4.8Hz,2H),3.69(s,4H),3.76(t,J＝4.8Hz,2H),7.45–7.49(m,2H),7.51–7.55(m,1H),7.88–7.91(m,2H),8.20(s,1H)；13C NMR(100MHz,CDCl3)δ157.8,142.1,132.1,128.9,126.6,66.9,66.0,50.4,44.3；IR(KBr)ν2920,2850,1615,1445,1344,1147,1088,858cm-1；HRMS(ESI):calcd for C11H15N2O3S[M+H]+255.0798,found 255.0523。
Example 2: preparation of N- (thiomorpholinylmethylene) benzenesulfonamide
Analogously to example 1, thiomorpholine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the desired product 1b 99mg is obtained as a white solid in 73% yield.1H NMR(400MHz,CDCl3)δ2.63(t,J＝5.6Hz,2H),2.70(t,J＝5.2Hz,2H),3.72(t,J＝5.2Hz,2H),3.91(t,J＝5.2Hz,2H),7.44–7.48(m,2H),7.49–7.53(m,1H),7.85–7.88(m,2H),8.18(s,1H)；13C NMR(100MHz,CDCl3)δ158.2,142.1,132.1,128.9,126.6,53.4,46.4,28.3,26.9；IR(KBr)ν2920,2851,1607,1446,1352,1283,1146,1089,891cm-1；HRMS(ESI):calcd for C11H15N2O2S2[M+H]+271.0569,found 271.0264。
Example 3: preparation of N- ((4-methylpiperidin-1-yl) methylene) benzenesulfonamide
And embodiments thereof1 analogous procedure, 4-methylpiperidine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, 95mg of the expected product 1c are obtained in the form of a white solid with a yield of 71%.1H NMR(400MHz,CDCl3)δ0.94(d,J＝6.4Hz,3H),1.07–1.23(m,2H),1.60–1.70(m,2H),1.73–1.79(m,1H),2.78(dt,J＝13.2Hz,3.2Hz,1H),3.25(dt,J＝12.8Hz,3.2Hz,1H),3.54–3.58(m,1H),4.36–4.41(m,1H),7.41–7.50(m,3H),7.85–7.92(m,2H),8.11(s,1H)；13C NMR(100MHz,CDCl3)δ157.4,142.6,131.8,128.7,126.4,51.3,44.0,34.4,32.9,30.7,21.5；IR(KBr)ν2926,2870,1614,1446,1336,1147,1088,921,872cm-1；HRMS(ESI):calcd for C13H19N2O2S[M+H]+267.1162,found 267.1106。
Example 4: preparation of N- ((4-phenylpiperidin-1-yl) methylene) benzenesulfonamide
In analogy to example 1, 4-phenylpiperidine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 1d 118mg is obtained as a white solid with a yield of 72%.1H NMR(400MHz,CDCl3)δ1.64–1.80(m,2H),1.91–1.94(m,1H),1.99–2.02(m,1H),2.75–2.83(m,1H),2.90(dt,J＝13.2Hz,3.2Hz,1H),3.43(dt,J＝13.2Hz,2.8Hz,1H),3.70–3.75(m,1H),4.59–4.64(m,1H),7.16–7.18(m,2H),7.21–7.25(m,1H),7.30–7.34(m,2H),7.45–7.54(m,3H),7.90–7.93(m,2H),8.20(s,1H)；13C NMR(100MHz,CDCl3)δ157.6,144.1,142.5,131.9,128.8,126.9,126.7,126.6,51.6,44.4,42.3,33.7,32.2；IR(KBr)ν2922,2850,1614,1446,1334,1283,1146,1088,877,753cm-1；HRMS(ESI):calcd for C18H21N2O2S[M+H]+329.1318,found 329.0892。
Example 5: preparation of N- ((4-phenylpiperazin-1-yl) methylene) benzenesulfonamide
In analogy to example 1, N-phenylpiperazine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 1e 134mg is obtained as a white solid with a yield of 81%.1H NMR(400MHz,CDCl3)δ3.18(t,J＝5.2Hz,2H),3.25(t,J＝5.2Hz,2H),3.63(t,J＝5.2Hz,2H),3.82(t,J＝5.2Hz,2H),6.90–6.95(m,3H),7.26–7.31(m,2H),7.45–7.56(m,3H),7.89–7.94(m,2H),8.24(s,1H)；13C NMR(100MHz,CDCl3)δ157.7，150.5,142.2,132.1,129.4,128.9,126.6,121.4,117.3,50.4,50.3,49.1,43.8；IR(KBr)ν2921,2850,1614,1496,1446,1343,1287,1230,1147,1089,1016,883cm-1；HRMS(ESI):calcd for C17H20N3O2S[M+H]+330.1271,found 330.1410。
Example 6: preparation of N- ((4- (4-methoxyphenyl) piperazin-1-yl) methylene) benzenesulfonamide
In analogy to example 1, N-p-methoxyphenylpiperazine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 1f 162mg is obtained as a white solid with a yield of 90%.1H NMR(400MHz,CDCl3)δ3.05(t,J＝4.8Hz,2H),3.12(t,J＝4.8Hz，2H)，3.62(t，J＝5.2Hz，2H),3.76(s，3H),3.81(t，J＝5.2Hz,2H)，6.86(dd,J＝18.4Hz,9.2Hz,4H),7.45–7.54(m,3H)，7.89–7.92(m，2H),8.22(s，1H)；13C NMR(100MHz,CDCl3)δ157.6,155.0,144.8,142.3,132.0,128.8,126.6，119.6，114.7,55.6,51.7,50.6，50.5,44.0；IR(KBr)ν2920,2834,1610,1512,1446,1346,1298,1247,1148,1089,1019,885cm-1；HRMS(ESI):calcd for C18H22N3O3S[M+H]+360.1376,found 360.1419。
Example 7: preparation of N- (aziridin-1-ylmethylene) benzenesulfonamides
Analogously to example 1, cycloheximide: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, 1g of the expected product, 104mg, is obtained in the form of a white solid with a yield of 78%.1H NMR(400MHz,CDCl3)δ1.51–1.57(m,4H),1.69–1.76(m,4H),3.47(t,J＝6.0Hz,2H),3.52(t,J＝6.0Hz,2H),7.40–7.49(m,3H),7.84–7.91(m,2H),8.17(s,1H)；13C NMR(100MHz,CDCl3)δ159.0,142.7,131.7,128.7,126.3,52.9,47.4,29.7,27.8,26.8,25.9；IR(KBr)ν2923,2852,1604,1445,1340,1297,1145,1088,905,839,750cm-1；HRMS(ESI):calcd for C13H19N2O2S[M+H]+267.1162,found 267.0795。
Example 8: preparation of N, N-diisopropyl-N' - (benzenesulfonyl) carboxamide
In a similar manner to example 1, diisopropylamine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the target product is obtained in 1h 110mg as a white solid with a yield of 82%.1H NMR(400MHz,CDCl3)δ1.21(d,J＝6.8Hz,6H),1.30(d,J＝6.8Hz,6H),3.63–3.73(m,1H),4.46–4.57(m,1H),7.42–7.50(m,3H),7.84–7.87(m,2H),8.24(s,1H)；13C NMR(100MHz,CDCl3)δ156.5,142.8,131.7,128.7,126.3,48.6,48.0,23.6,19.6；IR(KBr)ν2978,2922,2850,1602,1453,1338,1282,1144,1087,891,839cm-1；HRMS(ESI):calcd for C13H21N2O2S[M+H]+269.1318,found 269.1325。
Example 9: preparation of N-methyl-N-phenyl-N' - (benzenesulfonyl) formamide
In analogy to example 1, N-methylaniline: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the desired product, 1i 94mg, was obtained as an oily liquid in a yield of 68%.1H NMR(400MHz，CDCl3)δ3.44(s,3H),7.19(d，J＝7.6Hz,2H),7.32(t,J＝7.6Hz,1H),7.39–7.44(m,2H),7.47–7.56(m,3H),7.92–7.95(m,2H),8.57(s,1H)；13C NMR(100MHz,CDCl3)δ158.6,143.2,141.8,132.2,129.9,128.9,127.5,126.7,122.1,36.2；IR(KBr)ν2927,2852,1604,1575,1447，1338,1299,1148,1086,892,778cm-1；HRMS(ESI):calcd for C13H21N2O2S[M+H]+275.0849,found 275.0484。
The application example is as follows:
example 10: the preparation method of the invention is applied to the structural modification of antidepressant amoxapine
Analogously to example 1, amoxapine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 2a 183mg is obtained as a white solid in 76% yield.1H NMR(400MHz,CDCl3)δ3.52–3.77(m,8H),7.00–7.05(m,1H),7.08–7.14(m,3H)，7.19(d,J＝8.4Hz,1H),7.29(d，J＝2.8Hz,1H),7.41(dd,J＝8.4Hz,2.4Hz,1H),7.45–7.54(m,3H),7.88–7.91(m,2H),8.27(s,1H)；13C NMR(100MHz,CDCl3)δ159.4,158.3,157.9,151.7,142.1,139.5,133.2,132.1,130.7,128.8,128.7,127.2,126.6,126.0,125.4,124.5,123.0,120.3,49.9,47.6,46.7,43.5cm-1；IR(KBr)ν2921,2851,1607,1559,1470,1346,1300,1284,1237,1147,1090,1009,883cm-1；HRMS(ESI):calcd for C24H22ClN4O3S[M+H]+481.1096,found 481.1226。
Example 11: the preparation method of the invention is applied to the structural modification of antibacterial norfloxacin
In analogy to example 1, norfloxacin: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 2b 127mg is obtained as a white solid with a yield of 52%.1H NMR(400MHz，(CD3)2SO)δ1.38(t，J＝7.2Hz，3H)，2.59–2.62(m,2H),2.73–2.76(m,2H),3.32–3.36(m,4H),4.53(q,J＝14.0Hz,6.8Hz,2H)，5.50(s,1H)，7.15(d，J＝7.2Hz，1H)，7.42–7.51(m，5H),7.86(d，J＝13.2Hz,1H)，8.89(s，1H),15.31(s，1H)；13C NMR(100MHz，(CD3)2SO)δ176.2，166.2,154.2,151.7，148.5，145.4，145.3,137.2,133.0,129.1，129.0，127.9，119.6，119.5，115.9，111.3，111.1，107.1，106.3,106.2,60.7,49.4,49.3,49.2,48.9,14.4cm-1；IR(KBr)ν3402,2922,2851,1687,1628,1476,1275,1260,1025,999,750cm-1；HRMS(ESI):calcd for C23H24FN4O5S[M+H]+487.1446,found 487.1013。
Example 12: the preparation method of the invention is the structural modification application of the key intermediate 3- (1-piperazinyl) -1, 2-benzisothiazole of the antipsychotic drug
In analogy to example 1, 3- (1-piperazinyl) -1, 2-benzisothiazole: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, obtaining meshThe title product, 2c 153mg, was obtained as a white solid in 79% yield.1H NMR(400MHz,CDCl3)δ3.53–3.56(m，2H),3.61–3.64(m,2H),3.71–3.73(m,2H),3.88–3.90(m,2H),7.39(t,J＝8.0Hz,1H),7.46–7.55(m,4H)，7.82–7.86(m,2H),7.89–7.91(m,2H),8.28(s,1H)；13C NMR(100MHz,CDCl3)δ162.7,157.9,153.0,142.1,132.1,128.9,128.0,127.6,126.6,124.4,123.4,120.8,50.2,50.1,49.3,43.6cm-1；IR(KBr)ν2921,2850,1610,1561,1493,1446,1345,1285,1117,1089,1012,882cm-1；HRMS(ESI):calcd for C18H19N4O2S2[M+H]+387.0944,found 387.1051。
Example 13: the preparation method of the invention is applied to structural modification of 1- (4-chlorobenzhydryl) piperazine which is a key intermediate of antiallergic drugs
In analogy to example 1, 1- (4-chlorobenzhydryl) piperazine: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 2d 163mg is obtained as a white solid with a yield of 72%.1H NMR(400MHz,CDCl3)δ2.39(t,J＝5.2Hz,2H),2.44–2.47(m,2H),3.47(t,J＝5.2Hz,2H),3.60–3.70(m,2H),4.26(s,1H),7.19–7.35(m,9H),7.43–7.53(m,3H),7.85–7.88(m,2H),8.13(s,1H)；13C NMR(100MHz,CDCl3)δ157.4,142.3,141.1,140.3,133.2,132.0,129.2,129.1,129.0,128.8,127.8,127.7,126.6,75.0,51.8,50.8,50.7，44.0cm-1；IR(KBr)ν2921,2818,1614,1487,1446,1347,1284,1148,1089,999,891cm-1；HRMS(ESI):calcd for C24H25ClN3O2S[M+H]+454.1351,found 454.0895。
Example 14: the preparation method of the invention is the structural modification application of the key intermediate 6-fluoro-3- (piperidine-4-yl) benzo [ D ] isoxazole of antipsychotic drugs
Analogously to example 1, 6-fluoro-3- (piperidin-4-yl) benzo [ D]Isoxazoles: cyano sulfonyl oxime ether: 1, 4-diazabicyclo [2, 2]]The ratio of the amount of the feed materials of the octane is as follows: 4.0: 1: 1.5, the expected product 2e 137mg is obtained as a white solid with a yield of 71%.1H NMR(400MHz,CDCl3)δ1.92–2.02(m,1H),2.05–2.26(m,3H),3.19–3.26(m,1H),3.37–3.45(m,1H),3.48–3.55(m,1H),3.83(dt,J＝13.6Hz,3.6Hz,1H),4.44(dt,J＝13.6Hz,3.6Hz,1H),7.09(dt,J＝8.8Hz,2.4Hz,1H),7.27(dd,J＝8.4Hz,2.0Hz,1H),7.45–7.54(m,3H),7.59–7.62(m,1H),7.88–7.91(m,2H),8.23(s,1H)；13C NMR(100MHz,CDCl3)δ164.4(d,JC-F＝250.1Hz),164.0(d,JC-F＝13.6Hz),159.5,157.7,142.2,132.1,128.9,126.6,122.1(d,JC-F＝11.0Hz),116.9,113.0(d,JC-F＝25.4Hz),97.8(d,JC-F＝26.5Hz),50.3,43.2,33.5,30.4,29.3cm-1；IR(KBr)ν2929,2853,1611,1495,1447,1354,1273,1147,1088,997,882cm-1；HRMS(ESI):calcd for C19H19FN3O3S[M+H]+388.1126,found 388.0735。
Example 15: the bactericidal activity test of the compounds 2a to 2e obtained from the drug molecules and the drug intermediates modified by the preparation method of the invention on plant pathogenic fungi
The synthesized compound was tested for bactericidal activity against Rhizoctonia cerealis (Rhizoctonia cerealis) and Colletotrichum orbicularis (Colletotrichum orbiculare) by hyphal growth inhibition at a concentration of 100 mg/L.
A certain amount of the target compound was accurately weighed and dissolved in 5mL of methanol to obtain a mother liquor having a concentration of 10 mg/mL. Then, 1mL of the mother liquor was aspirated and added to 150mL of PSA medium to prepare a medium having a drug concentration of 100. mu.g/mL, and this medium was used for preliminary screening. Perforating thallus with sampler, inoculating the thallus cake onto the culture medium plate, culturing at 25 deg.C for 3-5 days, and measuring the diameter when the thallus on the non-drug control culture medium plate grows to two thirds of the plate. Each strain was tested in triplicate and the growth inhibition rate of the drug treatment was calculated.
A(％)＝[(B-C)/(B)]×100
A is the inhibition, B is the blank diameter, C is the treatment diameter
The test results are shown in table 1:
TABLE 1 preliminary fungicidal Activity data for Compounds 2a to 2e
The bactericidal activity test result shows that the N-benzenesulfonyl formamidine compounds 2a to 2e have certain bactericidal activity on two test fungi of rhizoctonia cerealis and cucumber colletotrichum, especially the compound 2b has relatively high bactericidal activity, which indicates that the compounds have potential application in the aspect of sterilization.
Although the present invention has been described with reference to the specific embodiments, it should be understood that the scope of the present invention is not limited thereto, and those skilled in the art will appreciate that various modifications and variations can be made without inventive changes in the present invention.
Claims (6)
1. A preparation method of an N-benzenesulfonyl formamidine compound is characterized by comprising the following steps:
adding secondary amine, cyano-sulfonyl oxime ether, organic base and solvent into a reactor, reacting for 12-24 hours at 25-80 ℃, washing, extracting, drying, separating, rotary evaporating and purifying to obtain the N-benzenesulfonyl formamidine compound.
2. The method of preparing an N-benzenesulfonylformamidine compound of claim 1, characterized in that: the organic base is triethylamine, 1, 4-diazabicyclo [2,2,2] octane, N-dimethylpyridine or 1, 8-diazabicycloundec-7-ene; the solvent is dimethyl sulfoxide, N-dimethylformamide, toluene, dichloromethane, tetrahydrofuran or acetonitrile.
3. The method for preparing an N-benzenesulfonylformamidine compound as claimed in claim 1, wherein the ratio of the amounts of the secondary amine, cyano-sulfonyl oxime ether and organic base is 3.0-5.0: 1: 1.0 to 2.0.
4. The use of an N-benzenesulfonylformamidine compound as defined in claim 1 in the post-structural modification of pharmaceutical molecules and pharmaceutical intermediates, the resulting compound being useful in sterilization.
5. The use of a process for the preparation of an N-benzenesulfonylcarboxamidine compound according to claim 4 wherein the drug molecules are amoxapine and norfloxacin.
6. The use of a process for the preparation of an N-benzenesulfonylcarboxamidine compound according to claim 4, wherein the pharmaceutical intermediate is 3- (1-piperazinyl) -1, 2-benzisothiazole, 1- (4-chlorobenzhydryl) piperazine or 6-fluoro-3- (piperidin-4-yl) benzo [ D ] isoxazole, and the 3- (1-piperazinyl) -1, 2-benzisothiazole is an intermediate of ziprasidone, pipilone, lurasidone; 1- (4-chloro benzhydryl) piperazine is an intermediate of chlorocyclazine hydrochloride, hydroxyzine and cetirizine, and 6-fluoro-3- (piperidine-4-yl) benzo [ D ] isoxazole is an intermediate of risperidone, paliperidone and iloperidone.
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