CN102850283A - Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound - Google Patents

Triazolyl-containing amino-dithio formic ether compound as well as preparation method and application of compound Download PDF

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CN102850283A
CN102850283A CN2012103971126A CN201210397112A CN102850283A CN 102850283 A CN102850283 A CN 102850283A CN 2012103971126 A CN2012103971126 A CN 2012103971126A CN 201210397112 A CN201210397112 A CN 201210397112A CN 102850283 A CN102850283 A CN 102850283A
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CN102850283B (en
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刘宏民
段迎超
张恩
叶先炜
王蒙蒙
郑甲信
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Zhengzhou University
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Abstract

The invention discloses a triazolyl-containing amino-dithio formic ether compound as well as a preparation method and application of the compound which is taken as a new antineoplastic medicament lead compound, belonging to the field of pharmaceutical chemistry. According to the invention, 1, 2, 3-triazole active fragment is introduced into the structure of amino-dithio formic ether by click chemistry, thus the preparation method is simple, efficient and environment-friendly. The triazolyl-containing amino-dithio formic ether compound has the structure general formula shown in the specification, and has excellent antineoplastic activity for multiple tumour cells, can be used as a candidate or lead compound for the further development to be applied to the preparation of the antineoplastic medicaments.

Description

One class contains dithiocarbamates compound, preparation method and the application thereof of triazolyl
Technical field
The present invention relates to the pharmaceutical chemistry field, be specifically related to a class contain triazolyl the dithiocarbamates compound, they the preparation method and as the application of the new antitumor drug lead compound of a class.
Background technology
Click chemistry is proposed first by the Americanized scholar Sharpless of calendar year 2001 Nobel chemistry Prize winner, the triazo-compound and the alkynyl compounds reaction that mainly refer at present class Cu (I) catalysis generate 1, the reaction of 2,3-triazole 5-membered ring compounds.Because plurality of advantages such as its reaction conditions is gentle, productive rate is high, and product postprocessing is simple and in the establishment of the optimization of lead compound, compound library, being widely applied.1,2,3-triazoles has shown multiple interesting biological activity, and is for example antibiotic, anti-inflammatory, antianaphylaxis, tuberculosis, HIV (human immunodeficiency virus)-resistant activity etc.All has the 1,2,3-triazoles structure fragment in the medicines structure of many listings, for example beta-lactamase inhibitor Tazobactam Sodium (formula .1).Recently, its application in the antitumor drug lead compound is found receives increasing concern.A plurality of research groups utilize click chemistry with 1,2,3-triazoles with are connected pharmacophoric group and connect, syntheticly obtained some and had the compound of outstanding anti-tumor activity.For example Kamal group introduces 1,2,3-triazoles (formula .2) in podophyllotoxin, synthetic obtained the compound that a series of anti-tumor activities are better than etoposide ( H.M.Sampath Kumar. European Journal of Medicinal Chemistry. 2011, 46,1983-1991).Marvin J. Miller with 1,2,3-triazoles and fragrant acid amides in conjunction with (formula .3), found the novel compound with excellent anti-tumor activity of a class ( Marvin J. Miller. J. Med. Chem. 2010 , 53,3389-3395).
Figure 958486DEST_PATH_IMAGE001
In addition, dithiocarbamates compound because its biological activity widely, as has the effect such as antibiotic, anti-inflammatory, desinsection, antitumor, radioprotective and chelating heavy metal and causes the extensive concern in pharmaceutical chemistry field.Utilize click chemistry that the 1,2,3-triazoles active fragments is incorporated in the dithiocarbamates structure, synthesizing new contains the dithiocarbamates compound of triazolyl, has no at present the pertinent literature report.Novel the synthetic of dithiocarbamates compound that contains the triazolyl structure will be enriched click chemistry in the application in pharmaceutical chemistry field, widen the research field of dithiocarbamates compound.Simultaneously, to further research new type antineoplastic medicine, the medicine of developing one's own intellectual property is significant.
Summary of the invention
The object of the present invention is to provide the novel dithiocarbamates compound that contains triazolyl with anti-tumor activity of a class.
It is a kind of simple efficient that another object of the present invention is to provide, the synthetic method that contains the dithiocarbamates compound of triazolyl of environmental protection.
A further object of the present invention is to provide the application of described compound in the preparation antitumor drug.
The dithiocarbamates compound that a class of the present invention contains triazolyl has respectively following general formula:
Figure 769009DEST_PATH_IMAGE002
R 1Be the alkyl of C1-C7 or the substituted alkyl of C1-C7; R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or the polysubstituted fluorine of C1-C5, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group etc. of replacing of different positions; N=0-4.
Preferred in the general formula I: R 1Alkyl for C1-C4; R 2Single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or the polysubstituted fluorine of C1-C3, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group etc. of replacing for different positions; N=0-2.
Be preferably as follows compound in the general formula I: I-1:R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=1;
I-2:R 1=(CH 3) 3C-, R 2=p-Cl, the derivative of n=1;
I-3: R 1=(CH 3) 3C-, R 2=o-OH, the derivative of n=1;
I-4:R 1=(CH 3) 3C-, R 2=p-Br, the derivative of n=1;
I-5:R 1=(CH 3) 3C-, R 2=p-CH 3, the derivative of n=1;
I-6:R 1=(CH 3) 3C-, R 2=p-OCH 3, the derivative of n=1;
I-7:R 1=(CH 3) 3C-, R 2=o-CF 3, the derivative of n=1;
I-8:R 1=(CH 3) 3C-, R 2=m, p-diCl, the derivative of n=1;
I-9:R 1=(CH 3) 3C-, R 2=m, p, m-triOCH 3, the derivative of n=1;
I-10: R 1=(CH 3) 3C-, R 2=o, o-diF, the derivative of n=1;
I-11: R 1=(CH 3) 3C-, R 2=m, p-diBr, the derivative of n=1;
I-12:R 1=PhCH 2-, R 2=o-F, the derivative of n=1;
I-13:R 1=PhCH 2-, R 2=p-Cl, the derivative of n=1;
I-14:R 1=PhCH 2-, R 2=p-CH 3, the derivative of n=1;
I-15:R 1=PhCH 2-, R 2=p-OCH 3, the derivative of n=1;
I-16:R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=0;
I-17: R 1=(CH 3) 3C-, R 2=p-CF 3, the derivative of n=0.
Preferred among the general formula I I: R 2Single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or the polysubstituted fluorine of C1-C3, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group etc. of replacing for different positions; N=0-2.
Be preferably as follows compound among the general formula I I:
II-1: R 2=o-F, the derivative of n=1;
II-2:R 2=p-Cl, the derivative of n=1;
II-3:R 2=p-CH 3, the derivative of n=1;
II-4: R 2=p-Br, the derivative of n=1;
II-5:R 2=p-OCH 3, the derivative of n=1;
II-6:R 2=m, p-diCl, the derivative of n=1;
II-7:R 2=m, p, m-triOCH 3, the derivative of n=1;
II-8:R 2=o, o-diF, the derivative of n=1;
II-9:R 2=m, p-diBr, the derivative of n=1;
II-10:R 2=o-CF 3, the derivative of n=0.
The dithiocarbamates compound that a class of the present invention contains triazolyl mainly makes by following method:
1. the preparation method of general formula (I)
In the organic solvent, under the alkaline condition, compound and various chloro-formic ester generation acylation reaction with general formula (II) get general formula (I) compound.Used organic solvent be acetone, N, N-dimethyl formamide, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane one of them or any two or three mixture wherein; Used alkali is the mineral alkalis such as the organic basess such as pyridine, triethylamine, DMAP (DMAP), diisopropyl ethyl amine or yellow soda ash, salt of wormwood, sodium bicarbonate, sodium hydroxide, potassium hydroxide.Reaction is usually at 0-90 0Carry out between the C.Products therefrom obtains straight product through purifications such as column chromatography or recrystallizations.The recrystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, the chloroform or two kinds mixture wherein.
Figure 114540DEST_PATH_IMAGE003
In the formula, R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or the polysubstituted fluorine of C1-C5, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group etc. of replacing of different positions; N=0-4.
2. the preparation method of general formula (II):
R in the general formula (I) 1=(CH 3) 3C-, R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or the polysubstituted fluorine of C1-C5, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group etc. of replacing of different positions; Compound shown in during n=0-4 is sloughed tertbutyloxycarbonyl under organic solvent, acidic conditions, get general formula (II) compound.Used acid is trifluoroacetic acid, hydrogenchloride, hydrogen bromide etc.; Used organic solvent is methylene dichloride, Isosorbide-5-Nitrae-dioxane, ethyl acetate, tetrahydrofuran (THF) etc.; Temperature of reaction is at-10-60 0Between the C, usually carry out in room temperature.Products therefrom obtains straight product through purifications such as column chromatography or recrystallizations.
Figure 343527DEST_PATH_IMAGE004
3. R in the general formula (I) 1=(CH 3) 3Preparation method during C-:
In the organic solvent, compound ( IV) and logical formula V in compound at CuI/ organic bases, CuSO 4/ sodium ascorbate or Cu/CuSO 41,3-cycloaddition reaction occurs under the condition, and used organic bases is triethylamine, diisopropyl ethyl amine; Used organic solvent is acetonitrile, butanol/water, tetrahydrofuran (THF)/water, DMF/water, ethanol/water etc.; Temperature of reaction is at 0-90 0Between the C, usually carry out in room temperature.Products therefrom obtains straight product through purifications such as column chromatography or recrystallizations.The recrystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, the chloroform or two kinds mixture wherein.
Figure 141718DEST_PATH_IMAGE005
Figure 340619DEST_PATH_IMAGE006
R in the logical formula V 2Same with the Compound Phase of n and general formula (I).
4. the preparation method of general formula (IV):
In the solvent, under alkaline condition and dithiocarbonic anhydride, propargyl bromide or propargyl chloride generation nucleophilic reaction, used alkali is a kind of in yellow soda ash, salt of wormwood, sodium phosphate, 11 water sodium phosphates, potassiumphosphate, saleratus, sodium bicarbonate, the triethylamine etc. with the available tertbutyloxycarbonyl list of commerce protection piperazine; Used solvent is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water one of them or any two or three mixture wherein; Products therefrom obtains straight product through purifications such as column chromatography or recrystallizations.The recrystallization solvent for use is a kind of in ethanol, methyl alcohol, acetonitrile, acetone, ethyl acetate, tetrahydrofuran (THF), methylene dichloride, the chloroform or two kinds mixture wherein.
Compared with prior art, the present invention utilizes classical click chemistry that the 1,2,3-triazoles activity unit is combined with dithiocarbamates first, and is simple efficient, the synthetic dithiocarbamates compound that contains triazole structure of environmental protection.The anti tumor activity in vitro evaluation result shows, the dithiocarbamates compound that contains triazole structure provided by the present invention is to MCF-7, MGC-803, and EC109 and PC-3 human tumor cell have obvious restraining effect, R in its formula of (I) 2=o-F; R 1=(CH 3) 3C-; The compound anti tumor activity in vitro of n=1 obviously is better than 5-fluor-uracil, can be used as candidate or the lead compound of further exploitation, is applied to prepare antitumor drug.
Embodiment:
For the present invention is better illustrated, as follows especially exemplified by embodiment:
The preparation of logical formula V is with reference to making with Publication about Document:
(a) Ina Wilkening.; Giuseppe del Signore.; C. P. R. Hackenberger. Chem. Commun. 2011, 47, 349-351. (b) Mingyu Hu.; Junqi Li.; ShaoQ Yao. Org. Lett, 2008, 10, 5529-5531.
Embodiment 1Intermediate ( IV) preparation
With CS 2(10mmol) dropwise join tertbutyloxycarbonyl list protection piperazine (10mmol) and Na 3PO 4In the acetone soln (6mmol), stirring at room adds propargyl bromide (11mmol) stirring reaction after 30 minutes, and TLC follows the tracks of detection.After reaction finishes, suction filtration, filtrate decompression is concentrated, enriched material with methylene dichloride (3 * 50mL) and the saturated aqueous common salt extraction, merge organic phase, anhydrous sodium sulfate drying, concentrating under reduced pressure, enriched material recrystallization or column chromatography for separation get compound IVYield 92%, white solid. 1H NMR (400 MHz, Actone-d 6, δ, ppm): 4.28 (br, 2H), 4.14 (d, 2H, J=2.68Hz), 4.00 (br, 2H), 3.58 (br, 4H), 2.78 (t, 1H, J=2.68Hz), 1.46 (s, 9H); HRMS (ESI) calcd for C 13H 21N 2O 2S 2 [M+H] +:301.1044, found: 301.1046.
Embodiment 2Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=1 ( I-1) preparation
With compound IV(5mmol) use THF-H with 2-luorobenzyl nitrine (5mmol) 2The lower cupric sulfate pentahydrate (0.25mmol) that adds is stirred in O (30-30mL) dissolving, sodium ascorbate (0.5mmol), stirring at room reaction 3-4 hour, tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(40mL), reaction system merges organic phase with EtOAc(3 * 50mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-1Yield 79.0%, white solid, fusing point: 109-110 oC.IR( KBr, cm -1) ν :3454, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695; 1H NMR (400 MHz, CDCl 3, δ , ppm): 7.66 (s, 1H), 7.09-7.38 (m, 4H), 5.55 (s, 2H), 4.69 (s, 2H), 3.52 (t, 4H, J=5.20Hz), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.42, 161.72, 159.26, 154.41, 144.00, 130.89, 130.81, 130.51, 130.48, 124.82, 124.78, 122.96, 121.98, 121.84, 115.92, 115.71, 80.63, 47.66, 47.61, 53.4, 31.84, 28.34; HRMS(ESI) calcd for C 20H 27FN 5O 2S 2 [M+H] +: 452.1590, found: 452.1598.
Embodiment 3Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=p-Cl, the derivative of n=1 ( I-2) preparation
With compound IV(3mmol) use THF-H with 4-chlorobenzyl nitrine (3mmol) 2O(20-20mL) the lower cupric sulfate pentahydrate (0.15mmol) that adds is stirred in dissolving, and sodium ascorbate (0.3mmol) finishes stirring at room reaction 2-3 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-2Yield 85.5%, white solid, fusing point: 177-178 oC.IR ( KBr, cm -1) ν :3446, 3130, 2979, 2914, 1678, 1491, 1422, 1224, 1161, 1024, 994, 932, 777, 543, 499; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.59 (s, 1H), 7.35 (d, 2H, J=8.44Hz), 7.20 (d, 2H, J=8.44Hz), 5.45 (s, 2H), 4.68 (s, 2H), 4.29 (br, 2H), 3.90 (br, 2H), 3.54 (t, 4H, J=5.24Hz), 1.47(s, 9H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.4, 154.4, 144.4, 134.8, 134.1, 129.4, 129.3, 122.8, 80.7, 53.4, 31.7, 28.4; HRMS(ESI) calcd for C 20H 27ClN 5O 2S 2 [M+H] +: 468.1295, found: 468.1291.
Embodiment 4Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=o-OH, the derivative of n=1 ( I-3) preparation
With compound IV(5mmol) use THF-H with 2-hydroxybenzyl nitrine (5mmol) 2O(30-30mL) the lower cupric sulfate pentahydrate (0.25mmol) that adds is stirred in dissolving, and sodium ascorbate (0.5mmol) finishes stirring at room reaction 1-2 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 50mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-3Yield 78.7%, white solid, fusing point: 105-106 oC.IR ( KBr, cm -1) ν : 3447, 2975, 1691, 1460, 1423, 1219, 1167, 1039, 935, 788, 746; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.59 (s, 1H), 7.34-7.87 (m, 3H), 5.55 (s, 2H), 4.72 (s, 2H), 4.26 (br, 2H), 3.92 (br, 2H), 3.56 (t, 4H, J=5.24Hz), 1.47 (s, 9H); 13C NMR (100 MHz, acetone-d 6,δ, ppm): 195.7, 154.8, 141.9, 133.7, 133.1, 133.1, 130.2, 129.71, 127.7, 123.6, 78.4, 50.8, 31.8, 27.6; HRMS(ESI) calcd for C 20H 28N 5O 3S 2 [M+H] +: 450.1634, found: 450.1638.
Embodiment 5Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=p-Br, the derivative of n=1 ( I-4) preparation
With compound IV(5mmol) dissolve with tertiary butanol and water (40-40mL) with 4-bromobenzyl nitrine (5mmol), stir lower adding cupric sulfate pentahydrate (0.25mmol), sodium ascorbate (0.5mmol) finishes stirring at room reaction 2-3 hour, and tracking monitor reacts.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-4Yield 81.7%, white solid, fusing point: 145-146 oC.IR ( KBr, cm -1) ν :3455, 3123, 2989, 2914, 1688, 1491, 1422, 1224, 1161, 1024, 994, 960, 777, 565; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.76 (s, 1H), 7.54(d, 2H, J=8.08Hz), 7.38 (d, 2H, J=8.08Hz), 5.60 (s, 2H), 4.69(s, 2H), 4.28 (br, 2H), 3.92 (br, 2H), 3.55 (t, 4H, J=5.24Hz), 1.48(s, 9H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.4, 155.4, 143.8, 132.9, 131.1, 129.4, 129.8, 121.8, 80.9, 53.5, 32.7, 28.4; HRMS(ESI) calcd for C 20H 27BrN 5O 2S 2 [M+H] +:512.0790, found: 512.0793
Embodiment 6Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=p-CH 3, the derivative of n=1 ( I-5) preparation
With compound IV(5mmol) dissolve with acetonitrile (40mL) with 4-methyl-benzyl nitrine (5mmol), stir lower adding cuprous iodide (0.5mmol), triethylamine (10mmol) finishes stirring at room reaction 4-6 hour, and tracking monitor reacts.After reaction finishes, with the reaction system vacuum concentration, enriched material EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-5Yield 79.9%, white solid, fusing point: 182-183 oC.IR ( KBr, cm -1) ν:3454, 2975, 1682, 1457, 1422, 1224, 1078, 994, 933, 867, 772, 524; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.55 (s, 1H), 7.16(s, 4H), 5.43 (s, 2H), 4.67 (s, 2H), 4.29 (br, 2H), 3.91 (br, 2H), 3.51 (t, 4H, J=5.16Hz), 2.35 (s, 3H), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.5, 154.4, 138.7, 131.6, 129.8, 128.1, 80.6, 54.01, 31.9, 28.4, 21.2; HRMS(ESI) calcd for C 21H 30N 5O 2S 2 [M+H] +: 448.1841, found: 448.1840.
Embodiment 7Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=p-OCH 3, the derivative of n=1 ( I-6) preparation
With compound IV(3mmol) dissolve with acetonitrile (30mL) with 4-methoxy-benzyl nitrine (3mmol), stir lower adding cuprous iodide (0.3mmol), triethylamine (6mmol) finishes stirring at room reaction 2-3 hour, and tracking monitor reacts.After reaction finishes, with the reaction system vacuum concentration, enriched material EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing, anhydrous sodium sulfate drying filters, filtrate decompression is concentrated, and the enriched material re-crystallizing in ethyl acetate gets product I-6Yield 85.8%, white solid, fusing point: 129-130 oC.IR ( KBr, cm -1) ν :3502, 3125, 2975,1686, 1542, 1453, 1281, 1173, 1016, 982, 932, 775, 698 ; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.54 (s, 2H), 7.21 (d, 2H, J=8.0), 6.88 (d, 2H, J=8.0), 5.41 (s, 2H), 4.67 (s, 2H), 4.29 (br, 2H), 3.90 (br, 2H),3.80 (s, 3H), 3.51 (t, 4H, J=5.2Hz), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl 3, δ, ppm): 196.4, 164.0, 161.6, 154.4, 130.5, 130.5, 130.0, 129.9, 116.2, 116.0, 80.7, 53.4, 31.8, 28.3; HRMS (ESI) calcd for C 21H 30N 5O 3S 2 [M+H] +: 464.1790, found:464.1794.
Embodiment 8Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=o-CF 3, the derivative of n=1 ( I-7) preparation
With compound IV(5mmol) dissolve with acetonitrile (40mL) with 2-trifluoromethyl benzyl nitrine (5mmol), stir lower adding cuprous iodide (0.5mmol), diisopropyl ethyl amine (7.5mmol) finishes stirring at room reaction 2-3 hour, and tracking monitor reacts.After reaction finishes, with the reaction system vacuum concentration, enriched material EtOAc(50mL) dissolving, use dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, the saturated common salt water washing is used the saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-7Yield 81.5%, white solid, fusing point: 138-139 oC.IR( KBr, cm -1) ν:3454, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695; 1H NMR (400 MHz, CDCl 3, δ , ppm): 8.15 (s, 1H), 7.04-7.39 (m, 4H), 5.54 (s, 2H), 4.83 (s, 2H), 4.30 (br, 2H), 3.91(br, 2H) 3.52 (t, 4H, J=5.24Hz), 1.47(s, 9H); HRMS (ESI) calcd for C 21H 27F 3N 5O 2S 2 [M+H] +: 502.1558, found:502.1559.
Embodiment 9R shown in the general formula (I) 1=(CH 3) 3C-, R 2=m, p-diCl, the derivative of n=1 ( I-8) preparation
With compound IV(4mmol) with 3,4-dichloro benzyl nitrine (4mmol) stirs lower adding cupric sulfate pentahydrate (0.8mmol) with tertiary butanol and water (30-30mL) dissolving, and copper powder (4mmol) finishes stirring at room reaction 3-5 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-8Yield 90.2%, white solid, fusing point: 153-154 oC.IR ( KBr, cm -1) ν:3129, 2984, 1693, 1470, 1347, 1159, 1131, 990, 963, 798, 740, 698, 542 ; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.64 (s, 1H), 7.43 (d, 1H, J= 8.28), 7.35 (d, 1H, J= 1.96), 7.08 (dd, 1H, J 1=2.00, J 2=8.24), 5.44 (s, 2H), 4.70 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.52 (t, 4H, J=5.08Hz), 1.47 (s, 9H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.3, 154.4, 144.6, 134.8, 133.3, 133.1, 131.1, 129.9, 127.2, 122.9, 80.7, 52.8, 31.7, 28.3; HRMS (ESI) calcd for C 20H 26Cl 2N 5O 2S 2 [M+H] +: 502.0905, found: 502.0900.
Embodiment 10R shown in the general formula (I) 1=(CH 3) 3C-, R 2=m, p, m-triOCH 3, the derivative of n=1 ( I-9) preparation
With compound IV(5mmol) with 3,4,5-trimethoxy benzyl azide (5mmol) stirs lower adding cupric sulfate pentahydrate (1mmol) with tertiary butanol and water (40-40mL) dissolving, and copper powder (5mmol) finishes stirring at room reaction 3-5 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-9Yield 83.4%, white solid, fusing point: 134-135 oC.IR( KBr, cm -1) ν:3453, 2979, 1693, 1494, 1478, 1279, 1167, 1012, 986, 932, 791, 757, 695 ; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.63 (s, 1H), 6.48 (s, 2H), 5.41 (s, 2H), 4.70 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.85 (s, 3H), 3.84 (s, 6H), 3.55 (t, 4H, J=5.24Hz), 1.48 (s, 9H);HRMS (ESI) calcd for C 23H 34N 5O 2S 2 [M+H] +: 524.2001, found: 524.2005.
Embodiment 11Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=o, o-diF, the derivative of n=1 ( I-10) preparation
With compound IV(5mmol) with 2,6-difluorobenzyl nitrine (5mmol) is used THF-H 2O(30-30mL) the lower cupric sulfate pentahydrate (1mmol) that adds is stirred in dissolving, and copper powder (5mmol) finishes stirring at room reaction 2-3 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-10Yield 78.4%, white solid, fusing point: 141-142 oC.IR( KBr, cm -1) ν :3354, 2987, 1689, 1494, 1465, 1279, 1167, 1012, 992, 791, 757, 695; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.80 (s, 1H), 6.78-7.69 (m, 3H), 5.54 (s, 2H), 4.75 (s, 2H), 4.30 (br, 2H), 3.90 (br, 2H), 3.56 (t, 4H, J=5.28Hz), 1.48 (s, 9H);HRMS (ESI) calcd for C 20H 26F 2N 5O 2S 2 [M+H] +:470.1496, found:470.1498.
Embodiment 12Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=m, p-diBr, the derivative of n=1 ( I-11) preparation
With compound IV(5mmol) with 3,4-dibromo-benzyl nitrine (5mmol) is used THF-H 2O(40-40mL) the lower cupric sulfate pentahydrate (1mmol) that adds is stirred in dissolving, and copper powder (5mmol) finishes stirring at room reaction 3-5 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-11Yield 86.5%, white solid, fusing point: 117-118 oC.IR( KBr, cm -1) ν:3467, 2989, 1698, 1494, 1478, 1285, 1167, 1012, 996, 932, 791, 757, 695; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.60 (s, 1H), 6.68-7.53 (m, 3H), 5.50 (s, 2H), 4.75 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.55(t, 4H, J=5.20Hz),1.48(s, 9H);HRMS(ESI) calcd for C 20H 26Br 2N 5O 2S 2 [M+H] +:589.9895, found:589.9893.
Embodiment 13Shown in the general formula (I), R 1=PhCH 2-, R 2=o-F, the derivative of n=1 ( I-12) preparation
With compound II-1(3mmol) with methylene dichloride (20mL) dissolving, add salt of wormwood (3mmol), Carbobenzoxy Chloride (3.3mmol), stirring at room is reacted to compound II-ICompletely dissolve.After reaction finishes, with the reaction system suction filtration, filtrate water, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-12Yield 74.6%, white solid, fusing point: 138-139 oC.IR( KBr, cm -1) ν :3446, 3061, 1686, 1492, 1465, 1422, 1360, 1211, 1095, 791, 761, 693, 584; 1H NMR (400 MHz, CDCl 3, δ, ppm): 7.66 (s, 1H), 7.08-7.37 (m, 9H), 5.54 (s, 2H), 5.15 (s, 2H), 4.69 (s, 2H), 4.30 (br, 2H), 3.95 (br, 2H), 3.61 (t, 4H, J=5.20Hz); 13C NMR (100 MHz, CDCl 3, δ, ppm): 196.61, 161.73, 159.27, 155.04, 143.97, 136.21, 130.94, 130.85, 130.54, 130.51, 128.30, 128.09, 124.84, 124.80, 123.04, 121.93, 121.79, 115.94, 115.73, 67.64, 47.72, 47.68, 43.02, 31.85; HRMS(ESI) calcd for C 23H 25ClN 5O 2S 2 [M+H] +: 486.1434, found: 486.1432.
Embodiment 14Shown in the general formula (I), R 1=PhCH 2-, R 2=p-Cl, the derivative of n=1 ( I-13) preparation
With compound II-2(3mmol) with acetone (20mL) dissolving, add salt of wormwood (3mmol), Carbobenzoxy Chloride (3.3mmol), stirring at room is reacted to compound II-2Completely dissolve.After reaction finishes, with the reaction system suction filtration, the filtrate vacuum concentration, the enriched material acetic acid ethyl dissolution, water, the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-13Yield 90.2%, white solid, fusing point: 114-115 oC.IR ( KBr, cm -1) ν :3446, 3056, 1697, 1511, 1474, 1425, 1360, 1130, 1094, 976, 785, 727, 692, 523; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.58 (s, 1H), 7.03-7.32(m, 9H), 5.45 (s, 2H), 5.15 (s, 2H), 4.67 (s, 2H), 4.29 (br, 2H), 3.94 (br, 2H), 3.59 (t, 4H, J=5.0Hz); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.53, 164.04, 161.57, 155.02, 143.97, 136.21, 130.54, 130.51, 129.98, 129.90, 128.60, 128.30, 128.08, 122.84, 116.19, 115.97, 67.62, 53.37, 43.01, 31.85; HRMS (ESI) calcd for C 23H 24FN 5NaO 2S 2 [M+Na] +: 508.1253, found: 508.1250.
Embodiment 15Shown in the general formula (I), R 1=PhCH 2-, R 2=p-CH 3, the derivative of n=1 ( I-14) preparation
With compound II-3(3mmol) with acetone (20mL) dissolving, add triethylamine (3.3mmol), Carbobenzoxy Chloride (3.3mmol), stirring at room is reacted to compound II-3Completely dissolve.After reaction finishes, with the reaction system suction filtration, filtrate vacuum concentration, enriched material acetic acid ethyl dissolution, use respectively dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-14Yield 81.8%, white solid, fusing point: 99-100 oC.IR ( KBr, cm -1) ν:3141, 2983, 1686, 1598, 1417, 1325, 1224, 1165, 1037, 993, 936, 858, 806, 771, 698, 540 ; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.55 (s, 1H), 7.14-7.37(m, 9H), 5.44 (s, 2H), 5.16 (s, 2H), 4.67 (s, 2H), 4.29(br, 2H), 3.96 (br, 2H), 3.59 (t, 4H, J=5.12Hz), 2.35(s, 3H); 13C NMR (100 MHz, CDCl 3,δ, ppm): 196.7, 155.0, 138.7, 136.2, 131.6, 129.8, 128.3, 128.1, 122.7, 114.5, 67.6, 54.0, 43.0, 32.0, 21.2; HRMS (ESI) calcd for C 24H 28N 5O 2S 2 [M+H] +: 482.1684, found: 482.1683.
Embodiment 16Shown in the general formula (I), R 1=PhCH 2-, R 2=p-OCH 3, the derivative of n=1 ( I-15) preparation
With compound II-5(4mmol) with acetonitrile (30mL) dissolving, add pyridine (4.4mmol), Carbobenzoxy Chloride (4.4mmol), stirring at room is reacted to compound II-5Completely dissolve.With the reactant vacuum concentration, the enriched material acetic acid ethyl dissolution was used respectively dilute hydrochloric acid after reaction finished, saturated sodium bicarbonate aqueous solution, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material re-crystallizing in ethyl acetate gets product I-15Productive rate 75.5%, white solid, fusing point: 113-114 oC.IR (KBr, cm -1) ν:3351, 3143, 2952, 1678, 1511, 1474, 1425, 1360, 1130, 1094, 976, 785, 727, 692, 523; 1H NMR (400 MHz, CDCl 3,δ, ppm):7.53 (s, 1H), 7.31-7.39 (m, 5H), 7.22 (d, 2H, J=8.64 ), 6.89 (d, 2H, J=8.68), 5.40 (s, 2H), 5.15 (s, 2H), 4.66 (s, 2H), 4.28(br, 2H), 3.89 (br, 2H), 3.80 (s, 3H), 3.61 (t, 4H, J=5.28Hz); 13C NMR (100 MHz, CDCl 3, δ, ppm):196.6, 159.9, 155.0, 143.8, 136.2, 129.6, 128.6, 128.3, 128.0, 126.6, 122.5, 114.5, 67.6, 55.4, 53.7, 43.0, 32.0; HRMS (ESI) calcd for C 24H 28N 5O 3S 2 [M+H] +: 498.1634, found: 498.1639.
Embodiment 17Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=0 ( I-16) preparation
With compound IV(5mmol) use THF-H with 2-fluorophenyl nitrine (5mmol) 2O(30-30mL) the lower cupric sulfate pentahydrate (0.25mmol) that adds is stirred in dissolving, and sodium ascorbate (0.5mmol) finishes stirring at room reaction 2-3 hour, the tracking monitor reaction.Reaction adds H after finishing in reaction system 2O(30mL), reaction system merges organic phase with EtOAc(3 * 40mL) extraction, uses the saturated common salt water washing, and anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-16Productive rate 77.5%, white solid, fusing point: 178-179 oC.IR ( KBr, cm -1) ν:3447, 3086, 2983, 1694, 1456, 1419, 1224, 1165, 1012, 992, 939, 838, 746, 553; 1H NMR (400 MHz, CDCl 3,δ, ppm): 8.09 (s, 1H), 7.18-7.69 (m, 4H), 4.79 (s, 2H), 4.32 (br, 2H), 3.93 (br, 2H), 3.56 (t, 4H, J=5.20Hz), 1.47 (s, 9H); HRMS (ESI) calcd for C 19H 25FN 5O 2S 2 [M+H] +: 438.1434, found: 438.1437.
Embodiment 18Shown in the general formula (I), R 1=(CH 3) 3C-, R 2=m-CF 3, the derivative of n=0 ( I-17) preparation
With compound ( IV) (5mmol) dissolve with acetonitrile (20mL) with 3-trifluoromethyl nitrine (5mmol), stirring lower adding cuprous iodide (0.25mmol), triethylamine (0.5mmol) finishes stirring at room reaction 2-3 hour, and tracking monitor reacts.After reaction finishes, with the reaction system vacuum concentration, enriched material EtOAc(50mL) dissolving, use respectively dilute hydrochloric acid, saturated sodium bicarbonate aqueous solution, saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression is concentrated, the enriched material acetone recrystallization is used the saturated common salt water washing, anhydrous sodium sulfate drying, filter, filtrate decompression is concentrated, and the enriched material acetone recrystallization gets product I-17. productive rate 87.6%, white solid, fusing point: 109-110 oC.IR ( KBr, cm -1) ν:3142, 2983, 1686, 1598, 1483, 1417, 1325, 1224, 1165, 1071, 1037, 993, 936, 806, 771, 698, 540; 1H NMR (400 MHz, CDCl 3,δ, ppm): 8.21 (s, 1H), 7.64-8.01 (m, 4H), 4.82 (s, 2H), 4.34 (br, 2H), 3.95 (br, 2H), 3.57 (t, 4H, J=5.24Hz), 1.48 (s, 9H); HRMS (ESI) calcd for C 20H 25F 3N 5O2S 2 [M+H] +: 488.1402, found: 488.1398.
Embodiment 17Shown in the general formula (II), R 2=o-F, the derivative of n=1 ( II-1) preparation
With compound I-1(2mmol) with methylene dichloride (20mL) dissolving, add CF under the ice bath 3COOH (40mmol) finishes and changes the stirring at room reaction into, the tracking monitor reaction.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-1Yield 96.7%, faint yellow solid, fusing point: 93-94 oC.IR ( KBr, cm -1) ν :3138, 2910, 1693, 1474, 1425, 1219, 1132, 1031, 996, 933, 785, 763, 731, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.67 (s, 1H), 7.09-7.34 (m, 4H), 5.55 (s, 2H), 4.69 (s, 2H), 4.30 (br, 2H), 3.93 (br, 2H), 2.94 (t, 4H, J=4.76); HRMS (ESI) calcd for C 15H 19FN 5S 2 [M+H] +:352.1066, found: 352.1064.
Embodiment 18Shown in the general formula (II), R 2=p-Cl, the derivative of n=1 ( II-2) preparation
With compound I-2(2mmol) with methylene dichloride (20mL) dissolving, add CF under the ice bath 3COOH (40mmol) finishes and changes the stirring at room reaction into, the tracking monitor reaction.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-2Yield 97.9%, pale yellow colored solid bulk melting point: 138-139 oC.IR ( KBr, cm-1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.60 (s, 1H), 7.35 (d, 2H, J=8.12 ), 7.20 (d, 2H, J=8.08 ), 5.45 (s, 2H), 4.69 (s, 2H), 3.90 (br, 2H), 2.94 (s, 4H); 13C NMR (100 MHz, CDCl 3, δ, ppm):196.03, 164.07, 161.60, 144.33, 130.47, 130.44, 129.97, 129.88, 122.74, 116.21, 116.00, 53.41, 45.15, 31.7; HRMS (ESI) calcd for C 15H 19FN 5S 2 [M+H] +:352.1066, found: 352.1063.
Embodiment 19Shown in the general formula (II), R 2=p-CH 3, the derivative of n=1 ( II-3) preparation
With compound I-5(2.5mmol) with methylene dichloride (20mL) dissolving, add CF under the ice bath 3COOH(50mmol), finish and change the stirring at room reaction into, tracking monitor reacts.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-3Yield 94.0%, faint yellow solid, fusing point: 74-75 oC.IR ( KBr, cm -1) ν:3135, 2910, 1697, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 731, 695; 1H NMR (400 MHz, CDCl 3, δ, ppm): 7.56 (s, 1H), 7.16-7.33 (m, 4H), 5.43 (s, 2H), 4.67 (s, 2H), 4.31 (br, 2H), 3.92 (br, 2H), 2.96 (br, 4H), 2.35 (s, 3H); 13C NMR (100 MHz, CDCl 3, δ, ppm):195.82, 138.61, 131.59, 129.74, 128.08, 122.72, 53.96, 31.80, 29.68, 21.17; HRMS (ESI) calcd for C 16H 22N 5S 2 [M+H] +:348.1317, found: 348.1319.
Embodiment 20Shown in the general formula (II), R 2=p-Br, the derivative of n=1 ( II-4) preparation
With compound I-4(4mmol) with methylene dichloride (40mL) dissolving, add CF under the ice bath 3COOH(80mmol), finish and change the stirring at room reaction into, tracking monitor reacts.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (50mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-4Yield 95.1%, faint yellow solid, fusing point: 79-80 oC.IR ( KBr, cm -1) ν :3138, 2908, 1697, 1475, 1425, 1384, 1219, 1031, 996, 933, 785, 763, 731, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.63 (s, 1H), 7.30 (d, 2H, J=8.28 ), 7.21 (d, 2H, J=8.28 ), 5.47 (s, 2H), 4.70 (s, 2H), 3.91 (br, 2H), 2.95 (s, 4H); 13C NMR (100 MHz, CDCl 3, δ, ppm):195.63, 144.54, 134.71, 133.17, 129.35, 129.27, 122.81, 53.36, 45.61, 31.65; HRMS (ESI) calcd for C 15H 19ClN 5S 2 [M+H] +:368.0770, found: 368.0767.
Embodiment 21Shown in the general formula (II), R 2=p-OCH 3, the derivative of n=1 ( II-5) preparation
With compound I-6(4mmol) Isosorbide-5-Nitrae-dioxane solution (4mol/L, 30mL) with hydrogenchloride is dissolved under the ice bath, finishes to keep the ice bath stirring reaction tracking monitor reaction.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-5Yield 98.7%, faint yellow solid, fusing point: 95-96 oC.IR ( KBr, cm -1) ν :3138, 2910, 1693, 1474, 1425, 1383, 1219, 1031, 996, 933, 785, 763, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.55 (s, 1H), 7.24 (d, 2H, J=8.72), 6.91 (d, 2H, J=8.72), 5.42 (s, 2H), 4.68 (s, 2H), 4.31 (br, 2H), 3.95 (br, 2H), 3.80 (s, 3H), 2.96 (t, 4H, J=4.64); 13C NMR (100 MHz, CDCl 3, δ, ppm):195.75, 159.89, 144.12, 129.61, 126.61, 122.53, 114.45, 55.34, 53.69, 45.63, 31.79; HRMS (ESI) calcd for C 16H 22N 5OS 2 [M+H] +:364.1266, found: 364.1263。
Embodiment 22Shown in the general formula (II), R 2=m, p-diCl, the derivative of n=1 ( II-6) preparation
With compound I-8(5mmol) Isosorbide-5-Nitrae-dioxane solution (4mol/L, 40mL) with hydrogenchloride is dissolved under the ice bath, finishes to keep the ice bath stirring reaction tracking monitor reaction.After reacting end, with the reaction system concentrating under reduced pressure, enriched material is used respectively saturated sodium bicarbonate with methylene dichloride (30mL) dissolving, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates and to get product II-6Yield 95.5%, faint yellow solid, fusing point: 122-123 oC.IR ( KBr, cm -1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1163, 1031, 996, 933, 785, 763, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.65 (s, 1H), 7.45 (d, 1H, J=8.28 ), 7.35（d, 1H, J=1.92), 7.10 (dd, 1H, J 1=1.96, J 2=8.28), 5.44 (s, 2H), 4.70 (s, 2H), 4.31 (br, 2H), 3.92 (br, 2H), 2.95 (s, 4H); 13C NMR (100 MHz, CDCl 3, δ, ppm):195.62, 144.87, 134.79, 133.27, 133.07, 131.09, 129.86, 127.17, 122.92, 52.81, 45.63, 31.56; HRMS (ESI) calcd for C 15H 18Cl 2N 5S 2 [M+H] +:402.0381, found: 402.0369.
Embodiment 23Shown in the general formula (II), R 2=m, p, m-triOCH 3, the derivative of n=1 ( II-7) preparation
With compound I-9(2mmol) dissolve with the saturated ethyl acetate solution of hydrogenchloride (30mL) under the ice bath, finish and change the stirring at room reaction into, the tracking monitor reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product II-7Yield 96.0%, faint yellow solid, fusing point: 120-121 oC.IR ( KBr, cm -1) ν:3138, 2910, 1693, 1474, 1425, 1219, 1031, 996, 933, 785, 763, 694; 1H NMR (400 MHz, CDCl 3,δ, ppm): 7.64 (s, 1H), 6.47 (s, 2H), 5.40 (s, 2H), 4.69 (s, 2H), 4.30 (br, 2H), 3.91 (br, 2H), 3.83(s, 3H), 3.82(s, 6H), 2.93(s, 4H); 13C NMR (100 MHz, CDCl 3, δ, ppm):195.63, 153.66, 144.42, 138.23, 130.15, 122.83, 105.16, 60.85, 56.23, 54.35, 45.72, 31.68; HRMS (ESI) calcd for C 18H 26N 5O 3S 2 [M+H] +:424.1477, found: 424.1472.
Embodiment 24Shown in the general formula (II), R 2=o, o-diF, the derivative of n=1 ( II-8) preparation
With compound I-10(3mmol) with the saturated ethyl acetate solution of hydrogenchloride (40mL) dissolving, finish and change the stirring at room reaction into, the tracking monitor reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product II-8Yield 93.3%, faint yellow solid, fusing point: 144-145 oC. 1H NMR (400 MHz, CDCl 3,δ, ppm): 8.10 (s, 1H), 7.50-7.86（m, 3H）, 4.89 (s, 2H), 4.37 (br, 2H), 3.93 (br, 2H), 3.05(s, 4H); HRMS (ESI) calcd for C 15H 18F 2N 5S 2 [M+H] +:370.0792, found: 370.0795.
Embodiment 25Shown in the general formula (II), R 2=m, p-diBr, the derivative of n=1 ( II-9) preparation
With compound I-11(2.5mmol) with the saturated ethyl acetate solution of hydrogenchloride (30mL) dissolving, finish and change the stirring at room reaction into, the tracking monitor reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product II-9Yield 94.8%., faint yellow solid, fusing point: 187-188 oC. 1H NMR (400 MHz, CDCl 3,δ, ppm): 8.05 (s, 1H), 7.46-7.58（m, 3H）, 4.86 (s, 2H), 4.34 (br, 2H), 3.95 (br, 2H), 2.98(s, 4H);HRMS(ESI) calcd for C 15H 18Br 2N 5S 2 [M+H] +:489.9370, found: :489.9374
Embodiment 26Shown in the general formula (II), R 2=m--CF 3, the derivative of n=0 ( II-10) preparation
With compound I-17(4mmol) with the saturated ethyl acetate solution of hydrogenchloride (50mL) dissolving, finish and change the stirring at room reaction into, the tracking monitor reaction.Reaction is used respectively saturated sodium bicarbonate with reaction system after finishing, water, and the saturated common salt water washing, anhydrous sodium sulfate drying filters, and filtrate decompression concentrates to get product II-10Yield 94.0%, faint yellow solid, fusing point: 131-132 oC. 1H NMR (400 MHz, CDCl 3,δ, ppm): 8.20 (s, 1H), 8.01 (s, 1H),7.64-7.96（m, 3H）, 4.81 (s, 2H), 4.33 (br, 2H), 3.92 (br, 2H), 2.96(s, 4H); HRMS (ESI) calcd for C 15H 17F 3N 5S 2 [M+H] +:388.0877, found: 388.0880.
Embodiment 27The antitumor cytolytic activity of above-claimed cpd:
1. experimental technique:
Sample is that above-claimed cpd, the purifying that embodiment synthesized gets; The sample storing solution: take by weighing 3-5 mg sample and place 1.5 mL EP pipes, then being mixed with concentration with DMSO is 128 * 10 3The solution of μ g/mL, 4 ° of C preserve and place, and utilize the substratum dilution according to desired concn during experiment.
2. primary dcreening operation
The cell of taking the logarithm vegetative period, behind the digestion counting, adjust cell density with substratum, be seeded in 96 orifice plates with 4000-5000 cell/ hole, every hole 150 μ L, cultivate 24 h after, discard substratum, adding is diluted good medicine (50 μ g/mL, 100 μ g/mL) with substratum, and each concentration is established 6 multiple holes, and other establishes blank group and positive controls.Behind drug effect 72 h, every hole adds 20 μ L MTT, after continuing to cultivate 4 h, sucks liquid, adds the DMSO of 150 μ L, and vibration is even, and absorbance is detected at microplate reader 490 nm places, calculates inhibiting rate, and calculation formula is as follows:
Inhibiting rate (%)=(1-administration group absorbance/blank group absorbance) * 100%.
Inhibiting rate resets concentration and carries out dusting cover greater than 50% sample during 50 μ g/mL.Be about to testing sample and add in 96 orifice plates with 1 μ g/mL, 2 μ g/mL, 4 μ g/mL, 8 μ g/mL, 16 μ g/mL, 32 μ g/mL, 64 μ g/mL concentration, cultivate 72 h after, detect.Test-results adopts SPSS computed in software IC 50Value and relation conefficient.
3. experimental result:
Table 1Above-claimed cpd is to four kinds of human tumor cells' anti-tumor activity evaluating data:
Figure 940544DEST_PATH_IMAGE008
aHuman stomach cancer cell bThe mankind mastopathy cell cThe human benign prostatic cancer cells dThe human esophagus cancer cells
Experimental result shows: majority of compounds shows good anti-tumor activity, especially to MGC-803 and MCF-7.R in the general formula (I) 2=o-F; R 1=(CH 3) 3C-; The compound compound of n=1 has shown excellent broad-spectrum anti-tumor activity, and the activity of four kinds of tumour cells all is better than 5-fluor-uracil, can be used as candidate or the lead compound of further exploitation, is applied to prepare cancer therapy drug.

Claims (10)

1. a class contains the dithiocarbamates compound of triazolyl, it is characterized in that, has structure shown in the general formula (I):
Figure 626184DEST_PATH_IMAGE001
R wherein 1Alkyl, C1-C7 substituted alkyl for C1-C7; R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C5 of different positions; N=0-4.
2. a class as claimed in claim 1 contains the dithiocarbamates compound of triazolyl, it is characterized in that, and is preferred: R 1Alkyl for C1-C4; R 2Single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C3 for different positions; N=0-2.
3. a class as claimed in claim 1 contains the dithiocarbamates compound of triazolyl, it is characterized in that, is preferably as follows compound:
I-1:R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=1;
I-2:R 1=(CH 3) 3C-, R 2=p-Cl, the derivative of n=1;
I-3: R 1=(CH 3) 3C-, R 2=o-OH, the derivative of n=1;
I-4:R 1=(CH 3) 3C-, R 2=p-Br, the derivative of n=1;
I-5:R 1=(CH 3) 3C-, R 2=p-CH 3, the derivative of n=1;
I-6:R 1=(CH 3) 3C-, R 2=p-OCH 3, the derivative of n=1;
I-7:R 1=(CH 3) 3C-, R 2=o-CF 3, the derivative of n=1;
I-8:R 1=(CH 3) 3C-, R 2=m, p-diCl, the derivative of n=1;
I-9:R 1=(CH 3) 3C-, R 2=m, p, m-triOCH 3, the derivative of n=1;
I-10: R 1=(CH 3) 3C-, R 2=o, o-diF, the derivative of n=1;
I-11: R 1=(CH 3) 3C-, R 2=m, p-diBr, the derivative of n=1;
I-12:R 1=PhCH 2-, R 2=o-F, the derivative of n=1;
I-13:R 1=PhCH 2-, R 2=p-Cl, the derivative of n=1;
I-14:R 1=PhCH 2-, R 2=p-CH 3, the derivative of n=1;
I-15:R 1=PhCH 2-, R 2=p-OCH 3, the derivative of n=1;
I-16:R 1=(CH 3) 3C-, R 2=o-F, the derivative of n=0;
I-17: R 1=(CH 3) 3C-, R 2=p-CF 3, the derivative of n=0.
4. a class contains the dithiocarbamates compound of triazolyl, it is characterized in that, has structure shown in the general formula (II):
R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C5 of different positions; N=0-4.
5. a class as claimed in claim 4 contains the dithiocarbamates compound of triazolyl, it is characterized in that, and is preferred: R 2Single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C3 for different positions; N=0-2.
6. a class as claimed in claim 5 contains the dithiocarbamates compound of triazolyl, it is characterized in that, is preferably as follows compound:
II-1: R 2=o-F, the derivative of n=1;
II-2:R 2=p-Cl, the derivative of n=1;
II-3:R 2=p-CH 3, the derivative of n=1;
II-4: R 2=p-Br, the derivative of n=1;
II-5:R 2=p-OCH 3, the derivative of n=1;
II-6:R 2=m, p-diCl, the derivative of n=1;
II-7:R 2=m, p, m-triOCH 3, the derivative of n=1;
II-8:R 2=o-CF 3, the derivative of n=0;
II-9:R 2=o, o-diF, the derivative of n=0;
II-10:R 2=m, p-diBr, the derivative of n=0.
Preparation as claimed in claim 1 a class contain the dithiocarbamates compound method of triazolyl, it is characterized in that: realize as follows:
(1) in the solvent, take tertbutyloxycarbonyl list protection piperazine as starting raw material, under alkaline condition, with dithiocarbonic anhydride, propargyl bromide or propargyl chloride generation nucleophilic reaction, generates compound IV
Figure 191344DEST_PATH_IMAGE003
IV
Used alkali is a kind of in yellow soda ash, salt of wormwood, sodium phosphate, 11 water sodium phosphates, potassiumphosphate, saleratus, sodium bicarbonate, the triethylamine; Solvent for use is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane, distilled water one of them or any two or three mixture wherein;
(2) in the organic solvent, compound IVWith the compound shown in the logical formula V at CuI/ organic bases, CuSO 4/ sodium ascorbate or Cu/CuSO 41,3-cycloaddition reaction occurs under the condition, generates general formula (I) R 1=(CH 3) 3C-; R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C5 of different positions; Compound shown in during n=0-4;
Figure 310609DEST_PATH_IMAGE004
Used organic bases is triethylamine, diisopropyl ethyl amine; Used organic solvent is acetonitrile, butanol/water, tetrahydrofuran (THF)/water, DMF/water, ethanol/water; Temperature of reaction is at 0-90 0Between the C;
(3) in the general formula (I), R 1=(CH 3) 3C-, R 2Be R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C5 of different positions; Compound shown in during n=0-4 is sloughed tertbutyloxycarbonyl in organic solvent, under the acidic conditions, generate compound shown in the general formula (II); Used acid is trifluoroacetic acid hydrogenchloride or hydrogen bromide; Used organic solvent is methylene dichloride, chloroform, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane; Temperature of reaction is at-10-60 0Between the C;
(4) in the organic solvent, under the alkaline condition, the compound of general formula (II) and various chloro-formic ester generation acylation reaction generate compound shown in the general formula (I);
Figure 589985DEST_PATH_IMAGE006
Used organic solvent is acetone, DMF, acetonitrile, ethanol, methyl alcohol, Virahol, 1,2-ethylene dichloride, methylene dichloride, chloroform, tetrahydrofuran (THF), dioxane one of them or any two or three mixture wherein; Used alkali is pyridine, triethylamine, DMAP, diisopropyl ethyl amine, yellow soda ash, salt of wormwood, sodium hydroxide or potassium hydroxide; Reaction is at 0-90 0C.
Preparation as claimed in claim 4 a class contain the dithiocarbamates compound method of triazolyl, it is characterized in that: realize as follows:
In the general formula (I),
R 1=(CH 3) 3C-, R 2Be H, single alkyl, methoxyl group, hydroxyl, fluorine, chlorine, bromine, trifluoromethyl or polysubstituted fluorine, polysubstituted chlorine, polysubstituted bromine, polysubstituted methoxyl group that replaces C1-C5 of different positions; Compound shown in during n=0-4 is sloughed tertbutyloxycarbonyl in organic solvent, under the acidic conditions, generate compound shown in the general formula (II); Used acid is trifluoroacetic acid, hydrogenchloride or hydrogen bromide; Used organic solvent is methylene dichloride, chloroform, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane; Temperature of reaction is at-10-60 0Between the C.
9. such as one of them described dithiocarbamates compound application in the preparation medicine that contains a class triazolyl of claim 1-3, it is characterized in that, it as activeconstituents, is prepared into anti-cancer of the stomach, mammary cancer, the esophageal carcinoma, prostate cancer medicine.
10. such as one of them described application in the preparation medicine that contains the dithiocarbamates compound of a class triazolyl of claim 4-6, it is characterized in that, it as activeconstituents, is prepared into anti-cancer of the stomach, mammary cancer, the esophageal carcinoma, prostate cancer medicine.
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