CN102516196B - Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application - Google Patents
Alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application Download PDFInfo
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Abstract
The invention relates to an alpha, beta-unsaturated ketone compound containing thiazole heterocycle, its preparation method and application. The alpha, beta-unsaturated ketone compound containing thiazole heterocycle is shown by the general formula 8, wherein R1 represents hydrogen, methyl or chlorine, R2 represents methyl or chlorine, R3 represents methyl or ethyl, R4 represents hydrogen, phenyl, p-nitro phenyl, p-benzotrifluoride or naphthyl, R5 represents hydrogen, phenyl, p-nitro phenyl, p-benzotrifluoride or naphthyl. The invention also provides the preparation method and application of the compound. The compound has excellent activity for inhibiting GST Pi and activity for inhibiting HL-60 cell growth, and is used for preparing antitumor drugs.
Description
Technical field
The present invention relates to organic compound and medical applications field, relate in particular to preparation method and application containing thiazole heterocycle alpha, beta-unsaturated ketone compounds.
Background technology
Malignant tumour is one of principal disease threatening human health, and the molecular biological research that develops into antitumor drug provides new target spot.Thiadiazolidine isomerase (Glutathione transferases, GSTs) be the II phase metabolic enzyme extended familys that are extensively formed in the bodies of aminal and plant, its effect is catalysis gsh (glutathione, GSH) be combined with exogenous or endogenous electrophilic compound, form water-soluble large, the mixture that toxicity is low, be easy to by III phase metabolic enzyme metabolism inactivation, referring to: Townsend DM.Tew KD:The role of glutathione-S-transferase in anti-cancer drug resistance.Oncogene 2003, 22 (47): 7369-7375.GSTs can be divided into film in conjunction with the large class of microsome family and tenuigenin family two, mammalian cell matter GST has gene pleiomorphism, can be divided into seven hypotype: Alpha (α), Mu (μ), Pi (π), Sigma (σ), Theta (θ), Zeta (ζ) and Omega (ω), wherein, GST Pi is and the most closely-related isozyme of tumour, in kinds of tumor cells, all found the GST Pi of high expression level.
C-Jun nitrogen end kinases (JNK, c-Jun N-terminal kinase) be a member of mitogen activated protein kinase (mitogen-activated protein kinase) family, it plays an important role in cellular stress, apoptosis, differentiation and survival.Research shows, GST Pi can suppress JNK by protein-protein interaction, thereby inhibited apoptosis, referring to: Adler V, Yin Z, Fuchs SY, Benezra M, Rosario L, Tew KD, Pincus MR, Sardana M, Henderson CJ, Wolf CR et al:Regulation of JNK signaling by GSTp.EMBO J 1999, 18 (5): 1321-1334. in addition, GST Pi also can be by consuming intracellular active oxygen, suppress reactive oxygen species (ROS, reactive oxygen species) apoptosis causing, referring to: Yin Z, Ivanov VN, Habelhah H, Tew K, RonaiZ:Glutathione S-transferase p elicits protection against H
2o
2-induced cell death via coordinated regulation of stress kinases.Cancer Res 2000,60 (15): 4053-4057.
GST Pi accelerates the outer row of antitumor drug on the one hand as II phase metabolic enzyme, on the other hand as the endogenous regulatory factor of cell signaling path, suppress its activation with kinases and correlation factor interaction important in apoptosis pathway, thus blocking-up apoptosis path.
Ethacrynic Acid (Ethacrynic acid, write a Chinese character in simplified form EA, that first is for clinical GST Pi inhibitor likes I), but the toxic side effect such as the diuresis of EA, ototoxicity, and shortage isozyme specificity has all limited its clinical application, referring to: Zhao G.Wang X:Advance in antitumor agents targeting glutathione-S-transferase.Curr Med Chem 2006,13 (12): 1461-1471.
Take Ethacrynic Acid as lead compound, retain α in compound, alpha, beta-unsaturated ketone group, its structure is modified, with bioisostere 1,2, carboxylic acid group in 4-oxadiazole rings alternative compounds structure, GST Pi is suppressed to active to gained compound and effect all has raising in various degree to people's acute promyelocytic leukemia cell strain (HL-60) growth-inhibiting, referring to: a) Yang, X.; Liu, G.; Li, H.; Zhang, Y.; Song, D.; Li, C.; Wang, R.; Liu, B.; Liang, W.; Jing, Y.; Zhao, G.; Novel oxadiazole analogues derived from ethacrynic acid:design, synthesis, and structure-activity relationships in inhibiting the activity of glutathione S-transferase P1-1 and cancer cell proliferation.J.Med.Chem.2010,53,1015-1022; B) CN101108832A Chinese patent 200710015199.5 " five member ring heterocyclic compound, preparation method and application "; C) CN 101891697A Chinese patent 201010215382.1 " containing 1,2,4-oxadiazole heterocycle alpha, beta-unsaturated ketone compounds ".According to another report, thiazolidine compounds can be induced the apoptosis of the dependent colon cancer cell of GST π, referring to: Muller, J.; Sidler, D.; Nachbur, U.; Wastling, J.; Brunner, T.; Hemphill, A.Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells.Int.J.Cancer.2008,123,1797-1806.Therefore, take Ethacrynic Acid as lead compound, with the carboxylic acid group in bioisostere thiazole ring alternative compounds structure, the EA derivative of synthesizing new, measuring compound suppresses activity and to people's acute promyelocytic leukemia cell strain (HL-60) growth inhibitory activity, can obtain new antitumor drug candidate GST Pi.
Summary of the invention
Task of the present invention be to provide a kind of have anti-tumor activity containing thiazole heterocycle alpha, beta-unsaturated ketone compounds.
Another task of the present invention is to provide preparation method and the application of this compound.
Summary of the invention
α, beta-unsaturated ketone compound is the α of effective GST Pi inhibitor Han oxadiazole heterocycle, beta-unsaturated ketone compound significantly improves the growth inhibitory activity of HL-60 cell, referring to Chinese patent document CN101108832 and Chinese patent document CN101891697, the present invention is to α, beta-unsaturated ketone compound carries out composition optimizes, design, synthesized the α containing thiazole heterocycle, beta-unsaturated ketone compound, its innovative point is to introduce thiazole heterocycle, and activity experiment shows, this compounds has good HL-60 cell growth inhibiting activity.
Detailed Description Of The Invention
One,, containing thiazole heterocycle alpha, beta-unsaturated ketone compounds, there is the structure of general formula 8:
Wherein, R
1for hydrogen, methyl or chlorine; R
2for methyl or chlorine; R
3for methyl or ethyl; R
4for hydrogen, phenyl, substituted-phenyl, naphthyl or substituted naphthyl; R
5for hydrogen, phenyl, substituted-phenyl, naphthyl or substituted naphthyl.
Preferred in the compound of above-mentioned general formula 8, R
1for hydrogen, methyl or chlorine; R
2for methyl or chlorine; R
3for methyl or ethyl; R
4for phenyl, p-nitrophenyl, p-trifluoromethyl phenyl or naphthyl; R
5for hydrogen, phenyl, p-nitrophenyl, p-trifluoromethyl phenyl or naphthyl.
Further preferred in the compound of above-mentioned general formula 8, R
1for hydrogen or methyl; R
2for methyl or chlorine; R
3for methyl or ethyl; R
4for phenyl, p-nitrophenyl, p-trifluoromethyl phenyl or 2-naphthyl; R
5for hydrogen.
Preferred compound is one of following:
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole (8a),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole (8b),
2-[3-methyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole (8c),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-p-nitrophenyl thiazole (8d),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-(2-naphthyl) thiazole (8e),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-p-trifluoromethyl phenyl thiazole (8f),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-p-nitrophenyl thiazole (8g),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-(2-naphthyl) thiazole (8h),
2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-p-trifluoromethyl phenyl thiazole (8i),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-p-nitrophenyl thiazole (8j),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-(2-naphthyl) thiazole (8k),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-p-trifluoromethyl phenyl thiazole (8l),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-p-nitrophenyl thiazole (8m),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-(2-naphthyl) thiazole (8n),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-p-trifluoromethyl phenyl thiazole (8o).
In bracket after above-mentioned preferred 15 compound titles, be its corresponding code name, in order to narrate convenient and to be concise in expression, the code name in above-mentioned bracket will directly be used in the following content of this specification sheets.
Further preferred compound is compound 8a, 8b, 8c, 8m, 8n or 8o.
Two, synthetic route
Above-mentioned general formula 8 containing thiazole heterocycle alpha, beta-unsaturated ketone compounds, synthetic route is as follows:
In above formula, reagent and reaction conditions: i.SOCl
2, 80 ℃; Ii. ammoniacal liquor, 0～5 ℃; Iii. thiophosphoric anhydride, tetrahydrofuran (THF), 50 ℃; Iv. aluminum chloride, dithiocarbonic anhydride, 50 ℃, hydrochloric acid; V. cupric bromide, ethyl acetate, chloroform, 60 ℃; Vi) CH
3oH, 66 ℃; Vii paraformaldehyde, dimethylamine hydrochloride, Glacial acetic acid, 100～150 ℃; Viii.10% sodium hydrogen carbonate solution, 85 ℃, hydrochloric acid.
Three, preparation method
The preparation method containing thiazole heterocycle alpha, beta-unsaturated ketone compounds of general formula 8 of the present invention, with R
1for hydrogen or methyl, R
2for methyl or chlorine, R
3for methyl or ethyl, R
4for phenyl, p-nitrophenyl, p-trifluoromethyl phenyl or 2-naphthyl, R
5for hydrogen is example, step is as follows:
(1) 2-(substituent phenoxy) acetic acid 1 and sulfur oxychloride are mixed for 1: 10 in molar ratio, be heated to 80 ℃, reaction 4h, remove sulfur oxychloride under reduced pressure, with dry toluene dilution, under condition of ice bath, the toluene solution of gained is added in ammoniacal liquor, and 1.5h is stirred in continuation, filter, filter cake alcohol-water recrystallization, obtains midbody compound 2:2-(substituent phenoxy) ethanamide 2;
(2) above-mentioned midbody compound 2 and thiophosphoric anhydride are joined in tetrahydrofuran (THF) for 1: 2 in molar ratio, 250 milliliters of every 1 mole of intermediate, 2 use tetrahydrofuran (THF)s, be heated to 50 ℃, reaction 1-1.5h, cooling, reaction solution is poured in frozen water, standing 2h, ethyl acetate extraction, removes ethyl acetate under reduced pressure, by re-crystallizing in ethyl acetate, obtain midbody compound 3:2-(substituent phenoxy) second sulphamide
(3) above-mentioned midbody compound 3, aluminum chloride and propionyl chloride or butyryl chloride are joined in dithiocarbonic anhydride for 1: 3: 1.5 in molar ratio, 3 liters of every 1 mole of intermediate, 3 use dithiocarbonic anhydride, room temperature reaction 0.5h, be warming up to 50 ℃, reaction 4h, cooling, incline and supernatant liquor, add wherein frozen water, be extracted with ethyl acetate, remove solvent under reduced pressure, with column chromatography purification, column chromatography sherwood oil: ethyl acetate=3: 1 volume ratio, obtains midbody compound 4:2-[4-(1-oxo-alkyl) substituent phenoxy] second sulphamide;
(4) substituent methyl ketone 5 and cupric bromide are joined in ethyl acetate and trichloromethane for 1: 2 in molar ratio, 750 milliliters of every 1 mole of substituent methyl ketone, 5 use ethyl acetate, 750 milliliters of every 1 mole of substituent methyl ketone, 5 use trichloromethanes, are heated to 60 ℃, reaction 5-12h, filtered while hot, filtrate is used 10wt% hydrochloric acid soln and distilled water wash, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, use dehydrated alcohol recrystallization, obtain midbody compound 6: alpha-brominated substituent methyl ketone;
(5) midbody compound 6 that the midbody compound 4 above-mentioned steps (3) being made and step (4) make joins in anhydrous methanol for 1: 1 in molar ratio, 1 liter of every 1 mole of midbody compound, 4 use anhydrous methanol, heating reflux reaction 24h, cooling, filter, be dried to obtain midbody compound 7:2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole.
(6) midbody compound 7, paraformaldehyde, dimethylamine hydrochloride and the Glacial acetic acid 1: 1.0 in molar ratio～1.5: 1.0～1.5: 0.06～1.0 above-mentioned steps (5) being made mixes, be heated to 100～150 ℃, decompression, reaction 1.5h, cooling, with the NaHCO of 10wt%
3solution is adjusted pH to 8.0, reacting by heating 40min at 80～85 ℃, cooling, be extracted with ethyl acetate, remove solvent under reduced pressure, with column chromatography purification, sherwood oil: acetone=20: 1 volume ratio, obtains target product 8:2-[replacement-4-(2-methylene radical-1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole.
Described 2-(substituent phenoxy) acetic acid 1 of above-mentioned steps (1) is 2-(2,3-dimethyl phenoxy) acetic acid, 2-(3-chlorophenoxy) acetic acid or 2-(3-methylphenoxy) acetic acid.
The substituent methyl ketone of above-mentioned steps (4) is selected from methyl phenyl ketone, to trifluoromethyl acetophenone, p-nitroacetophenone or 2-naphthyl methyl phenyl ketone.
Four, application
The major part that the present invention synthesizes has the GST of inhibition Pi activity and suppresses HL-60 cells growth activity containing the alpha, beta-unsaturated ketone compounds of thiazole heterocycle, for the preparation of antitumor drug.Particularly 8a, 8b, 8c, 8m, 8n or 8o have very excellent inhibition GST Pi activity and suppress HL-60 cells growth activity (experiment will be illustrated in embodiment 2 in detail).
Excellent results of the present invention compared with prior art:
The present invention design synthesized structure different containing thiazole heterocycle α, beta-unsaturated ketone compound, its innovative point is to α, alpha, beta-unsaturated ketone compound Ethacrynic Acid carries out structure of modification, introduce thiazole heterocycle, of the present invention containing thiazole heterocycle α, beta-unsaturated ketone compound has the growth inhibitory activity of the active and good HL-60 cell of certain inhibition GST Pi, wherein, 8a, 8b, 8c is when concentration is 1 μ M, to the inhibition percentage of GST Pi, be respectively 54.1%, 73.1%, 44.0%, 8m, 8n, 8o inhibition percentage when concentration is 5 μ M is 86.7%, 55.2%, 72.3%, compound of the present invention to the half growth inhibitory concentration of HL-60 cell all lower than 6.5 μ M.
Embodiment
Below in conjunction with embodiment, further describe the present invention, in order to more deep, understand the present invention and advantage and effect, but described embodiment is only for illustrating the present invention rather than restriction the present invention.
The preparation of embodiment 1. compound 8a～8o
(1) preparation of 2-(substituent phenoxy) ethanamide 2
2-(substituent phenoxy) acetic acid 1 (20mmol), sulfur oxychloride 15mL (200mmol) are added in 50mL round-bottomed flask, stirring and evenly mixing, oil bath is slowly heated to 80 ℃, back flow reaction 4h, remove sulfur oxychloride residual in reaction solution under reduced pressure, add dry toluene 10mL dilution to be directly used in the next step.
Get 100mL there-necked flask (band drying tube) and be placed in ice-water bath, add ammoniacal liquor 10mL, and the reaction solution after upper step processing is slowly dropped in ammoniacal liquor, drip and finish, in ice-water bath, continue stirring reaction 1.5h; Filter and discard filtrate.Filter cake is transferred in hot acetone, fully after dissolving, filters, and filter residue washs with hot acetone, merges washing lotion, filtrate, removes solvent under reduced pressure, and gained white solid alcohol-water recrystallization filters, is dried, and obtains midbody compound 2.
Above-mentioned 2-(substituent phenoxy) acetic acid 1 is selected respectively 2-(2,3-dimethyl phenoxy) acetic acid,, 2-(3-chlorophenoxy) acetic acid or 2-(3-methylphenoxy) acetic acid, obtain respectively following midbody compound 2.
2a:2-(2,3-dimethyl phenoxy) ethanamide, white crystal, yield 74.6%, mp:135～137 ℃.
1H-NMR(DMSO-d
6)δ(ppm)：7.34(s，1H)，7.35(s，1H)，7.01(t，J＝8.40Hz，1H)，6.78(d，J＝7.80Hz，1H)，6.67(d，J＝8.40Hz，1H)，4.39(s，2H，)，2.21(s，3H)，2.13(s，3H).MF：C
10H
13NO
2；MS(calcd/found)[M+H]
+：180.09/180.9。
2b:2-(3-chlorophenoxy) ethanamide, white crystal, yield 45.7%, mp:125～127 ℃.
1H-NMR(DMSO-d
6)δ(ppm)：7.56(s，1H)，7.41(s，1H)，7.32(t，J＝7.20Hz，1H)，7.01-7.03(m，2H)，6.92-6.94(m，1H)，4.46(s，2H)。MS(calcd/found)[M+H]+：185.61/185.3。
2c:2-(3-methylphenoxy) ethanamide, white crystal, yield 56.9%.
1H-NMR(DMSO-d
6)δ(ppm)：7.48(s，1H)，7.38(s，1H)，7.16(t，J＝8.40Hz，1H)，6.77-6.78(m，2H)，6.73(d，J＝9.00Hz，1H)，4.38(s，2H)，2.27(s，3H)。MS(calcd/found)[M+H]+：165.19/166.4。
(2) preparation of 2-(substituent phenoxy) second sulphamide 3
By 2-(substituent phenoxy) ethanamide 2, (20mmol joins in 50mL round-bottomed flask, add tetrahydrofuran (THF) 5mL, after stirring at room is dissolved, slowly be warming up to 50 ℃, at this temperature, add thiophosphoric anhydride 40mmol in batches, reaction 1-1.5h, be cooled to room temperature, reaction solution is poured standing 2h in the beaker that 100g mixture of ice and water is housed into, ethyl acetate extraction 3 times, each 50mL; Remove ethyl acetate under reduced pressure, be dried to obtain crude product.Crude product is dissolved in hot ethyl acetate, and filtered while hot, removes solvent under reduced pressure, obtains compound 3.
Above-mentioned 2-(substituent phenoxy) ethanamide 2 is selected respectively 2a, 2b or 2c, obtains respectively following compound 3a, 3b or 3c.
3a:2-(2,3-dimethyl phenoxy) second sulphamide, white crystal, yield 94.3%, 109～111 ℃ of mp.
1h-NMR (DMSO-d
6) δ (ppm): 10.00 (s, 1H), 9.17 (s, 1H), 7.01 (t, J=7.80Hz, 1H), 6.80 (d, J=7.80Hz, 1H), 6.64 (d, J=8.40Hz, 1H), 4.71 (s, 2H), 2.22 (s, 3H), 2.15 (s, 3H) .MS (calcd/found) [M+H]
+: 196.07/196.3.
3b:2-(3-chlorophenoxy) second sulphamide, white crystal, yield 75.5%, yield 75.5%, 119～122 ℃ of mp.
1h-NMR (DMSO-d
6) δ (ppm): 10.04 (s, 1H), 9.40 (s, 1H), 7.33 (t, J=8.40Hz, 1H), 7.03-7.06 (m, 2H), 7.01 (dd, J
1=2.40Hz, J
2=7.80Hz, 1H), 4.79 (s, 2H) .MS (calcd/found) [M+H]
+: 202.00/202.2.
3c:2-(3-methylphenoxy) second sulphamide, white crystal, yield 95.6%,
1h-NMR (DMSO-d
6) δ (ppm): 9.97 (s, 1H), 9.30 (s, 1H), 7.14 (t, J=7.80Hz, 1H), 6.75-6.77 (m, 2H), 6.72 (dd, J
1=7.80Hz, J
2=2.40Hz, 1H), 4.69 (s, 2H), 2.41 (s, 3H) .MS (calcd/found) [M+H]+: 182.06/182.3.
(3) 2-[4-(1-oxo-alkyl) substituent phenoxy] preparation of second sulphamide 4
2-(substituent phenoxy) second sulphamide 3 (10mmol) are added in 100mL there-necked flask, add CS
230mL under stirring at room, adds aluminum trichloride (anhydrous) powder 4.0g (30mmol) in batches, with constant pressure funnel, in reaction system, slowly drips acyl chlorides 2.78g (15mmol), produces dope, room temperature reaction 0.5h.Slowly be heated to 50 ℃, back flow reaction 4h, is cooled to room temperature, inclines and upper layer CS
2, there-necked flask is placed in to ice bath, in there-necked flask, add 50g mixture of ice and water, produce yellow sticky solid, ethyl acetate extraction, removes solvent under reduced pressure, and silica gel column chromatography obtains compound 4, and elution system is 3: 1 volume ratios of petrol ether/ethyl acetate.
Above-mentioned 2-(substituent phenoxy) second sulphamide 3 is selected respectively 3a, 3b, 3c, and acyl chlorides is selected respectively propionyl chloride or butyryl chloride, obtains following compound 4a, 4b, 4c, 4d or 4e.
4a:2-[2,3-dimethyl-4-(1-oxo-propyl group) phenoxy group] second sulphamide, faint yellow solid, yield 51.8%, mp139-141 ℃.
1h-NMR (DMSO-d
6) δ: 10.02 (s, 1H), 9.21 (s, 1H), 7.53 (d, J=8.40Hz, 1H), 6.71 (d, J=8.40Hz, 1H), 4.81 (s, 2H), 2.86 (q, J=7.80Hz, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.03 (t, J=7.80Hz, 3H) .MS (calcd/found) [M+H]
+: 252.10/252.4.
The chloro-4-of 4b:2-[3-(1-oxo-propyl group) phenoxy group] second sulphamide, white solid, yield 36.6%, 116～119 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 10.05 (s, 1H), 9.43 (s, 1H), 7.73 (d, J=9.00Hz, 1H), 7.13 (d, J=9.00Hz, 1H), 7.02 (dd, J
1=8.40Hz, J
2=1.80Hz, 2H), 4.87 (s, 2H), 2.92 (q, J=7.20Hz, 2H), 1.05 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 257.74/258.2.
4c:2-[3-methyl-4-(1-oxo-propyl group) phenoxy group] second sulphamide, yellow solid, yield 51.5%,
1h-NMR (DMSO-d
6) δ: 10.04 (s, 1H), 9.40 (s, 1H), 7.84 (d, J=8.40Hz, 1H), 6.89 (s, 1H), 6.87 (d, J=7.20Hz, 1H), 4.82 (s, 2H), 2.91 (q, J=7.20Hz, 2H), 2.42 (s, 3H), 1.04 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 238.08/238.2.
4d:2-[2,3-dimethyl-4-(1-oxo-butyl) phenoxy group] second sulphamide, faint yellow solid, yield 73.5%, mp147～149 ℃.
1H-NMR(DMSO-d
6)δ：10.02(s，1H)，9.21(s，1H)，7.52(d，J＝8.40Hz，1H)，6.72(d，J＝8.40Hz，1H)，4.81(s，2H)，2.82(t，J＝7.20Hz，2H)，2.26(s，3H)，2.19(s，3H)，1.55-1.59(m，2H)，0.89(t，J＝7.20Hz，3H).MS(calcd/found)[M+H]
+：265.37/266.4。
The chloro-4-of 4e:2-[3-(1-oxo-butyl) phenoxy group] second sulphamide, white solid, yield 54.6%, 115～117 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 10.05 (s, 1H), 9.43 (s, 1H), 7.71 (d, J=8.40Hz, 1H), 7.13 (d, J=3.00Hz, 1H), 7.02 (dd, J
1=9.00Hz, J
2=2.4Hz, 1H), 4.87 (s, 2H), 2.89 (t, J=7.20Hz, 2H), 1.57-1.61 (m, 2H), 0.90 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 271.76/272.4.
(4) preparation of alpha-brominated substituent methyl ketone 6
Substituent methyl ketone 5 (20mmol), ethyl acetate 15mL, trichloromethane 15mL are joined in 100mL bis-neck flasks, be warming up to 60 ℃, add cupric bromide 8.92g (40mmol) in batches, back flow reaction 5-12h, filtered while hot, filtrate is successively respectively washed respectively 3 times with 10% hydrochloric acid soln 30mL, distilled water 30mL, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, dehydrated alcohol recrystallization obtains compound 6.
Above-mentioned substituent methyl ketone is selected respectively methyl phenyl ketone, p-trifluoromethyl acetophenone, and p-nitro-acetophenone or 2-naphthyl methyl phenyl ketone, obtain respectively following compound 6a, 6b, 6c or 6d.
6a:2-bromoacetophenone, white crystals, mp 46-51 ℃.
The bromo-1-of 6b:2-(4-nitrophenyl) ethyl ketone, faint yellow solid, yield 75.6%, mp:73～76 ℃.
1H-NMR(DMSO-d
6)δ：8.37(d，J＝9.00Hz，2H)，8.23(d，J＝9.00Hz，2H)，5.05(s，2H)。
The bromo-1-of 6c:2-(2-naphthyl) ethyl ketone, purple crystals, yield 82.6%, mp:76～77 ℃.
1H-NMR(DMSO-d
6)δ：8.76(s，1H)，8.12(d，J＝8.40Hz，1H)，8.05(d，J＝8.40Hz，1H)，8.00(m，2H)，5.07(s，2H)。
The bromo-1-of 6d:2-(4-trifluoromethyl) ethyl ketone, clear crystal, yield 52.7%, mp:50～52 ℃.
1H-NMR(DMSO-d
6)δ：8.19(d，J＝8.40Hz，2H)，7.94(d，J＝7.80Hz，2H)，5.03(s，2H)。
(5) 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene] preparation of-4-aryl thiazole 7
Compound 4 (10mmol), compound 6 (10mmol), anhydrous methanol 10mL are joined in 50mL round-bottomed flask, and back flow reaction 24h, is cooled to room temperature, filters, dry, obtains compound 7.
Above-mentioned compound 4 is 4a, 4b, 4c, 4d or 4e, compound 6 is 6a, 6b, 6c or 6d, compound 4 and compound 6 various combinations, obtain respectively following compound 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j, 7k, 7l, 7m, 7n or 7o.
7a:2-[2,3-dimethyl-4-(1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, faint yellow solid, yield 53.4%, 81～83 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.17 (s, 1H), 7.98 (d, J=7.80Hz, 2H), 7.57 (d, J=8.40Hz, 1H), 7.46 (t, J=7.80Hz, 2H), 7.36 (t, J=7.80Hz, 1H), 7.06 (d, J=8.40Hz, 1H), 5.57 (s, 2H), 2.88 (q, J=7.20Hz, 2H), 2.28 (s, 3H), 2.22 (s, 3H), 1.04 (t, J=7.20Hz, 3H) .HRMS (ESI) m/zfor C
21h
22nO
2s[M+H]
+: calculated 352.1366 found 352.1391.
The chloro-4-of 7b::2-[3-(1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, yellow solid, yield 48.1%..
1H-NMR(DMSO-d
6)δ：8.19(s，1H)，7.97(d，J＝7.20Hz，2H)，7.74(d，J＝9.00Hz，1H)，7.46(t，J＝7.80Hz，2H)，7.36(t，J＝7.80Hz，1H)，7.32(d，J＝2.40Hz，1H)，7.17(dd，J＝8.40Hz，J＝2.40Hz，1H)，5.62(s，2H)，2.93(q，J＝7.20Hz，2H)，1.05(t，J＝7.20Hz，3H).MS(calcd/found)[M+H]
+：358.06/358.2。
7c:2-[3-methyl-4-(1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, yellow solid, yield 27.4%.
1H-NMR(DMSO-d
6)δ：8.17(s，1H)，7.97(d，J＝7.80Hz，2H)，7.86(d，J＝9.00Hz，1H)，7.46(t，J＝7.80Hz，2H)，7.36(t，J＝7.20Hz，1H)，7.02(d，J＝7.20Hz，2H)，5.58(s，2H)，2.92(q，J＝7.20Hz，2H)，2.44(s，3H)，1.04(t，J＝7.20Hz，3H).MS(calcd/found)[M+H]
+：338.11/338.5。
7d:2-[2,3-dimethyl-4-(1-oxo-butyl) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, light yellow solid, yield 67.6%, 155～156 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.54 (s, 1H), 8.33 (d, J=9.60Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.57 (d, J=9.00Hz, 1H), 7.07 (d, J=9.00Hz, 1H), 5.60 (s, 2H), 2.84 (t, J=7.20Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.56-1.60 (m, 2H), 0.90 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 410.39/411.4.
7e:2-[2,3-dimethyl-4-(1-oxo-butyl) benzene Oxymethylene]-4-naphthyl thiazole, light yellow solid, yield 68.9%, 119～122 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 8.12 (dd, J
1=8.40Hz, J
2=1.20Hz, 1H), 7.99-8.02 (m, 2H), 7.94 (d, J=7.80Hz, 1H), 7.52-7.59 (m, 3H), 7.09 (d, J=8.40Hz, 1H), 5.61 (s, 2H), 2.85 (t, J=7.20Hz, 2H), 2.29 (s, 3H), 2.24 (s, 3H), 1.57-1.61 (m, 2H), 0.90 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 415.55/416.5.
7f:2-[2,3-dimethyl-4-(1-oxo-butyl) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 68.5%, 114～117 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.42 (s, 1H), 8.20 (d, J=7.80Hz, 2H), 7.83 (d, J=7.80Hz, 2H), 7.56 (d, J=8.40Hz, 1H), 7.067 (d, J=8.40Hz, 1H), 5.60 (s, 2H), 2.84 (t, J=7.2Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.56-1.60 (m, 2H), 0.90 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 433.49/434.4.
7g:2-[2,3-dimethyl-4-(1-oxo-propyl group) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, white powder, yield 65.6%, 144～147 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.54 (s, 1H), 8.33 (d, J=9.60Hz, 2H), 8.26 (d, J=9.00Hz, 2H), 7.57 (d, J=9.00Hz, 1H), 7.06 (d, J=9.00Hz, 1H), 5.60 (s, 2H), 2.88 (q, J=7.20Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.04 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 396.46/397.4.
7h:2-[2,3-dimethyl-4-(1-oxo-propyl group) benzene Oxymethylene]-4-naphthyl thiazole, buff powder, yield 56.0%, 107～109 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 8.12 (dd, J
1=9.00Hz, J
1=1.80Hz, 1H), 7.99-8.02 (m, 2H), 7.94 (d, J=7.80Hz, 1H), 7.58 (d, J=8.40Hz, 1H), 7.55 (m, 2H), 7.09 (d, J=9.00Hz, 1H), 5.61 (s, 2H), 2.88 (q, J=7.20Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.05 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 401.52/402.4.
7i:2-[2,3-dimethyl-4-(1-oxo-propyl group) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, light yellow solid, yield 58.5%, 107～110 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.41 (s, 1H), 8.20 (d, J=8.40Hz, 2H), 7.83 (d, J=8.40Hz, 2H), 7.57 (d, J=8.40Hz, 1H), 7.06 (d, J=9.00Hz, 1H), 5.59 (s, 2H), 2.88 (q, J=7.2Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 1.04 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 419.46/420.4.
The chloro-4-of 7j:2-[3-(1-oxo-butyl) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, yellow solid, yield 68.2%, 149～151 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.56 (s, 1H), 8.33 (d, J=9.00Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.73 (d, J=9.00Hz, 1H), 7.32 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 5.65 (s, 2H), 2.89 (t, J=7.20Hz, 2H), 1.57-1.61 (m, 2H), 0.90 (t, J=7.80Hz, 3H) .MS (calcd/found) [M+H]
+: 416.88/417.4.
The chloro-4-of 7k:2-[3-(1-oxo-butyl) benzene Oxymethylene]-4-naphthyl thiazole, white solid, yield 69.5%, 88～90 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.34 (s, 1H), 8.12 (dd, J
1=9.00Hz, J
2=1.80Hz, 1H), 7.99-8.01 (m, 2H), 7.94 (d, J=7.20Hz, 1H), 7.74 (d, J=8.40Hz, 1H), 7.52-7.57 (m, 2H), 7.35 (d, J=3.00Hz, 1H), 7.19 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 5.67 (s, 2H), 2.90 (t, J=7.20Hz, 2H), 1.56-1.63 (m, 2H), 0.91 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 421.94/422.3.
The chloro-4-of 7l:2-[3-(1-oxo-butyl) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 67.6%, 86～88 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.43 (s, 1H), 8.20 (d, J=8.40Hz, 2H), 7.83 (d, J=8.40Hz, 2H), 7.73 (d, J=8.40Hz, 1H), 7.32 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 5.64 (s, 2H), 2.90 (t, J=7.20Hz, 2H), 1.57-1.61 (m, 2H), 0.90 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 439.88/440.4.
The chloro-4-of 7m:[3-(1-oxo-propyl group) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, yellow powder, yield 69.6%, 148～150 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.56 (s, 1H), 8.33 (d, J=8.40Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.75 (d, J=8.40Hz, 1H), 7.32 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=9.00Hz, J
2=2.40Hz, 1H), 5.66 (s, 2H), 2.93 (q, J=7.20Hz, 2H), 1.05 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 402.85/403.4.
The chloro-4-of 7n:2-[3-(1-oxo-propyl group) benzene Oxymethylene]-4-naphthyl thiazole, light red powder, yield 50.0%, mp109～111 ℃.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.34 (s, 1H), 8.11 (dd, J
1=8.40Hz, J
2=1.80Hz, 1H), 7.99-8.01 (m, 2H), 7.94 (d, J=7.20Hz, 1H), 7.76 (d, J=9.00Hz, 1H), 7.55 (m, 2H), 7.35 (d, J=2.40Hz, 1H), 7.19 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 5.67 (s, 2H), 2.93 (q, J=7.20Hz, 2H), 1.06 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 407.91/408.4.
The chloro-4-of 7o:2-[3-(1-oxo-propyl group) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 58.5%, 88～90 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.43 (s, 1H), 8.20 (d, J=7.80Hz, 2H), 7.83 (d, J=7.80Hz, 2H), 7.75 (d, J=8.40Hz, 1H), 7.32 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
1=2.40Hz, 1H), 5.65 (s, 2H), 2.93 (q, J=7.20Hz, 2H), 1.06 (t, J=7.20Hz, 3H) .MS (calcd/found) [M+H]
+: 425.85/426.2.
(6) 2-[replacement-4-(2-methylene radical-1-oxo-alkyl) benzene Oxymethylene] preparation of-4-aryl thiazole 8
By 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole 7 (9.6mmol), paraformaldehyde 0.38g (11.5mmol), dimethylamine hydrochloride 0.91g (10.4mmol) join in 50mL flask, add one, Glacial acetic acid, mix, oil bath is heated to 100～150 ℃, after solid all liquefies, Depressor response 1.5h, is cooled to room temperature, adds wherein appropriate 10wt%NaHCO
3solution, adjusts pH to 8.0, and reacting by heating 40min at 80～85 ℃, is cooled to room temperature, and ethyl acetate extraction, removes solvent under reduced pressure, obtains oily matter, silica gel column chromatography separated target compound 8, elution system is 20: 1 volume ratios of sherwood oil/acetone.
Above-mentioned 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole 7 selects respectively midbody compound 7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h, 7i, 7j, 7k, 7l, 7m, 7n or 7o, obtains target compound 8 as follows:
8a:2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, white powder, yield 39.5%, 69～70 ℃ of mp.
1h-NMR (CDCl
3-d
3) δ: 7.90 (d, J=7.80Hz, 2H), 7.51 (s, 1H), 7.44 (t, J=7.80Hz, 2H), 7.35 (t, J=7.80Hz, 1H), 7.09 (d, J=7.80Hz, 1H), 6.81 (d, J=7.80Hz, 1H), 5.92 (s, 1H), 5.57 (s, 1H), 5.45 (s, 2H), 2.29 (s, 3H), 2.21 (s, 3H), 2.04 (s, 3H) .IR (KBr, cm
-1) υ
=CH: 3113.78,3068.66,3025.33; υ
cH: 2976.26,2922.56; υ
c=O: 1653.48; υ
c=C: 1624.97,1589.43,1516.50; δ
cH: 1444.25,1357.02,1324.59; υ
c-O: 1266.54,1230.89; γ
=CH: 1090.84,947.82,803.22,741.60.MS (calcd/found) [M+H]
+: 363.47/364.3.
The chloro-4-of 8b:2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, yield 75.0%, 138～139 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.20 (s, 1H), 7.97 (d, J=7.80Hz, 2H), 7.46 (t, J=7.80Hz, 2H), 7.39 (d, J=8.40Hz, 1H), 7.36 (t, J=7.20Hz, 1H), 7.34 (dd, J
1=7.80Hz, J
2=2.40Hz, 1H), 7.15-7.18 (m, 1H), 6.12 (s, 1H), 5.61 (s, 1H), 5.52 (s, 2H), 1.95 (s, 3H) .IR (KBr, cm
-1) υ
=CH: 3099.94,3070.24; υ
cH: 2976.32,2922.48,2880.86; υ
c=O: 1650.91; υ
c=C: 1598.16,1559.57,1507.16,1495.80; δ
cH: 1470.24,1456.71,1445.02,1369.65,1335.97,1298.32; υ
c-O: 1243.95,1230.95; γ
=CH: 1061.94,917.04,841.17,758.00.MS (calcd/found) [M+H]
+: 369.86/370.3.
8c:2-[3-methyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-phenyl thiazole, white powder, yield 31.3%, 129～131 ℃ of mp.
1h-NMR (CDCl
3-d
3) δ: 7.91 (d, J=7.80Hz, 2H), 7.52 (s, 1H), 7.44 (t, J=7.80Hz, 2H), 7.36 (t, J=7.20Hz, 1H), 7.29 (d, J=8.40Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 5.91 (s, 1H), 5.55 (s, 1H), 5.47 (s, 2H), 2.34 (s, 3H), 2.04 (s, 3H) .IR (KBr, cm
-1) υ
=CH: 3095.89,3059.71; υ
cH: 2983.90,2956.19,2921.15; υ
c=O: 1633.70; υ
c=C: 1599.79,1508.37; δ
cH: 1445.40,1367.85,1336.32,1309.41; υ
c-O: 1248.35,1232.96; γ
=CH: 1011.83,957.11,847.16,762.30.MS (calcd/found) [M+H]
+: 349.44/350.4.
8d 2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, white solid, yield 62.3%, 145～152 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.54 (s, 1H), 8.33 (d, J=9.00Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.10 (d, J=8.40Hz, 1H), 7.05 (d, J=8.40Hz, 1H), 5.95 (s, 1H), 5.58 (s, 2H), 5.49 (s, 1H), 2.38 (q, J=7.20Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.07 (t, J=7.20Hz, 3H) .IR (KBr, cm
-1): υ
=CH: 3120.10; υ
cH: 2963.22,2921.64,2873.38; υ
c=O: 1641.89; υ
c=C: 1599.36,1578.59,1522.28,1509.61,1482.03; υ
nO2: 1341.16; υ
c-O: 1276.62; γ
=CH: 1099.88,857.00,847.12,744.80.MF:C
23h
22n
2o
4s.MS (calcd/found) [M+H]
+: 422.50/423.4.
8e:2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-naphthyl thiazole, white solid, yield 72.6%, 134～136 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.33 (s, 1H), 8.12 (dd, J
1=8.40Hz, J
2=1.20Hz, 1H), 7.99-8.02 (m, 2H), 7.94 (d, J=7.20Hz, 1H), 7.52-7.56 (m, 2H), 7.10 (q, J=8.40Hz, 2H), 5.95 (s, 1H) 5.59 (s, 2H), 5.50 (s, 1H), 2.38 (q, J=7.20Hz, 2H), 2.25 (s, 3H), 2.15 (s, 3H), 1.07 (t, J=7.20Hz, 3H) .IR (KBr, cm
-1): υ
=CH: 3103.45,3058.86; υ
cH: 2965.60,2919.85,2872.20; υ
c=O: 1651.76; υ
c=C: 1590.94,1519.59,1483.20,1445.57; δ
cH: 1353.74; υ
c-O: 1268.86; γ
=CH: 1087.32,943.79,802.25,760.07.MF:C
27h
25nO
2s.MS (calcd/found) [M+H]
+: 427.56/428.4.
8f:2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 78.5%, 86～87 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.42 (s, 1H), 8.20 (d, J=7.80Hz, 2H), 7.83 (d, J=7.80Hz, 2H), 7.10 (d, J=8.40Hz, 1H), 7.05 (d, J=8.40Hz, 1H), 5.95 (s, 1H), 5.57 (s, 2H), 5.49 (s, 1H), 2.38 (q, J=7.20Hz, 2H), 2.23 (s, 3H), 2.14 (s, 3H), 1.07 (t, J=7.20Hz, 3H) .IR (KBr, cm
-1): υ
=CH: 3114.66; υ
cH: 2966.08,2918.55,2874.16; υ
c=O: 1649.55; υ
c=C: 1617.86,1590.25,1508.20; δ
cH: 1329.14; υ
c-O: 1271.02; γ
=CH: 1069.70,854.25,765.93.MF:C
24h
22f
3nO
2s.MS (calcd/found) [M+H]
+: 445.50/446.3.
8g:2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, white powder, yield 75.6%, 158～160 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.54 (s, 1H), 8.33 (d, J=9.00Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.11 (d, J=8.40Hz, 1H), 7.05 (d, J=8.40Hz, 1H), 6.04 (s, 1H), 5.58 (s, 2H), 5.48 (s, 1H), 2.23 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3094.47; υ
cH: 2922.45,2848.60; υ
c=O: 1687.43,1653.48; υ
c=C: 1597.22,1579.44,1507.98,1482.34; υ
nO2: 1336.32; υ
c-O: 1267.42; γ
=CH: 1088.68,862.79,844.75,795.59,753.79.MF:C
22h
20n
2o
4s.MS (calcd/found) [M+H]
+: 408.47/409.4.
8h:-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-naphthyl thiazole, white powder, yield 66.0%, 116～118 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.32 (s, 1H), 8.12 (dd, J
1=8.40Hz, J
2=1.80Hz, 1H), 8.02 (s, 1H), 8.00 (d, J=840Hz, 1H), 7.94 (d, J=7.20Hz, 1H), 7.54 (m, 2H), 7.12 (d, J=8.40Hz, 1H), 7.07 (d, J=8.40Hz, 1H), 6.04 (s, 1H), 5.59 (s, 2H), 5.49 (s, 1H), 2.25 (s, 3H), 2.14 (s, 3H), 1.96 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3111.49,3051.20; υ
cH: 2972.96,2919.32,2842.02; υ
c=O: 1693.46,1655.22; υ
c=C: 1593.12,1584.01,1520.90,1484.39,1446.79; δ
cH: 1354.34; υ
c-O: 1268.09; γ
=CH: 1085.37,943.38,858.61,808.86,769.40,761.59.MF:C
26h
23nO
2s.MS (calcd/found) [M+H]
+: 413.53/414.4.
8i:2-[2,3-dimethyl-4-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 68.5%, 104～106 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.42 (s, 1H), 8.20 (d, J=8.40Hz, 2H), 7.83 (d, J=8.40Hz, 2H), 7.11 (d, J=8.40Hz, 1H), 7.06 (d, J=9.00Hz, 1H), 6.04 (s, 1H), 5.57 (s, 2H), 5.48 (s, 1H), 2.23 (s, 3H), 2.13 (s, 3H), 1.96 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3116.46,3088.72; υ
cH: 2919.31,2868.88; υ
c=O: 1683.15,1653.13; υ
c=C: 1617.62,1591.85,1579.96,1508.90,1449.19; δ
cH: 1329.73; υ
c-O: 1272.48; γ
=CH: 1069.72,854.17,766.14.MF:C
23h
20f
3nO
2s.MS (calcd/found) [M+H]
+: 431.47/432.5.
The chloro-4-of 8j:2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, white crystal, yield 76.9%, 111～112 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.56 (s, 1H), 8.33 (d, J=9.00Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.38 (d, J=8.40Hz, 1H), 7.34 (d, J=9.00Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 6.04 (s, 1H), 5.65 (s, 2H), 5.54 (s, 1H), 2.37 (q, J=7.2Hz, 2H), 0.90 (t, J=7.2Hz, 3H) .IR (KBr, cm
-1): υ
=CH: 3097.71; υ
cH: 2969.51,2935.62,2875.13,2851.09; υ
c=O: 1653.84; υ
c=C: 1599.22,1566.07,1522.36,1514.60,1492.26; υ
nO2: 1344.80; υ
c-O: 1294.67; γ
=CH: 1066.83,981.27,903.61,863.04,844.37,749.09.MF:C
21h
17clN
2o
4s.MS (calcd/found) [M+H]
+: 428.89/429.3.
The chloro-4-of 8k:2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-naphthyl thiazole, white crystal, yield 50.0%, 101～102 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.34 (s, 1H), 8.12 (dd, J
1=8.40Hz, J
2=1.20Hz, 1H), 8.01 (s, 1H), 8.00 (d, J=2.40Hz, 1H), 7.94 (d, J=7.80Hz, 1H), 7.55 (m, 2H), 7.41 (d, J=8.40Hz, 1H), 7.37 (d, J=2.40Hz, 1H), 7.18 (dd, J=9.00Hz, J=2.40Hz, 1H), 6.12 (s, 1H) 5.67 (s, 2H), 5.54 (s, 1H), 1.96 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3108.01,3055.33; υ
cH: 2971.25,2935.43,2873.26; υ
c=O: 1664.80; υ
c=C: 1599.45,1559.55,1506.87,1490.74,1453.91; δ
cH: 1356.55; υ
c-O: 1298.58,1236.76; γ
=CH: 1060.17,1043.76,979.66,905.48,861.42,831.20,773.77,751.80.MF:C
25h
20clNO
2s.MS (calcd/found) [M+H]
+: 433.95/434.4.
The chloro-4-of 8l:-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, white solid, yield 58.5%, 104～106 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.43 (s, 1H), 8.20 (d, J=7.80Hz, 2H), 7.83 (d, J=7.80Hz, 2H), 7.73 (d, J=9.00Hz, 1H), 7.38 (d, J=9.00Hz, 1H), 7.33 (dd, J
1=13.60Hz, J
1=2.4Hz, 1H), 6.04 (s, 1H), 5.64 (s, 2H), 5.54 (s, 1H), 1.59 (q, J=7.20Hz, 2H), 1.07 (t, J=7.20Hz, 3H) .IR (KBr, cm
-1): υ
=CH: 3115.44; υ
cH: 2968.58,2935.49,2879.43; υ
c=O: 1697.71,1661.06; υ
c=C: 1599.30,1565.92,1511.10,1492.97,1456.72; δ
cH: 1324.07; υ
c-O: 1242.93; γ
=CH: 1070.64,943.38,980.57,909.75,852.56,843.13,760.57,733.83.MF:C
22h
17clF
3nO
2s.MS (calcd/found) [M+H]
+: 451.89/452.2.
The chloro-4-of 8m:22-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-, light red crystal, yield 76.9%, 88～91 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.56 (s, 1H), 8.33 (d, J=9.60Hz, 2H), 8.25 (d, J=9.00Hz, 2H), 7.40 (d, J=2.40Hz, 1H), 7.34 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
1=2.40Hz, 1H), 6.12 (s, 1H), 5.64 (s, 2H), 5.53 (s, 1H), 1.95 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3106.73; υ
cH: 2924.34,2850.22; υ
c=O: 1665.75; υ
c=C: 1598.82,1521.78,1493.18,1449.99; υ
nO2: 1346.38; υ
c-O: 1294.13; γ
=CH: 1061.96,918.06,861.24,845.77,742.48.MF:C
20h
15clN
2o
4s.MS (calcd/found) [M+H]
+: 414.86/415.3.
The chloro-4-of 8n:2-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene]-4-naphthyl thiazole, light red crystal, yield 50.0%, 105～107 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.55 (s, 1H), 8.34 (s, 1H), 8.12 (dd, J
1=8.40Hz, J
2=1.20Hz, 1H), 8.01 (s, 1H), 8.00 (d, J=2.40Hz, 1H), 7.94 (d, J=7.80Hz, 1H), 7.55 (m, 2H), 7.41 (d, J=8.40Hz, 1H), 7.37 (d, J=2.40Hz, 1H), 7.18 (dd, J
1=9.00Hz, J
2=2.40Hz, 1H), 6.12 (s, 1H) 5.67 (s, 2H), 5.54 (s, 1H), 1.96 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3114.67,3088.31,3055.47; υ
cH: 2982.74,2925.09,2865.53; υ
c=O: 1700.54,1664.62; υ
c=C: 1596.16,1565.31,1499.09; δ
cH: 1344.43; υ
c-O: 1295.92; γ
=CH: 1058.32,940.78,862.87,832.42,753.65.MF:C
24h
18clNO
2s.MS (calcd/found) [M+H]
+: 419.92/420.3.
The chloro-4-of 8o:22-[3-(2-methylene radical-1-oxo-propyl group) benzene Oxymethylene] the p-trifluoromethyl thiazole of-4-, light yellow solid, yield 58.5%, 87～90 ℃ of mp.
1h-NMR (DMSO-d
6) δ: 8.43 (s, 1H), 8.20 (d, J=7.80Hz, 2H), 7.83 (d, J=7.80Hz, 2H), 7.40 (d, J=8.40Hz, 1H), 7.34 (d, J=2.40Hz, 1H), 7.17 (dd, J
1=8.40Hz, J
2=2.40Hz, 1H), 6.12 (s, 1H) 5.63 (s, 2H), 5.53 (s, 1H), 1.82 (s, 3H) .IR (KBr, cm
-1): υ
=CH: 3112.45; υ
cH: 2931.62,2882.16; υ
c=O: 1708.82,1663.30; υ
c=C: 1614.86,1599.73,1565.84,1492.42; δ
cH: 1323.72; υ
c-O: 1292.58; γ
=CH: 1070.57,917.65,852.17,841.66,759.65.MF:C
21h
15clF
3nO
2s.MS (calcd/found) [M+H]
+: 437.86/438.3.
Embodiment 2: compound suppresses determination of activity to GST Pi and the growth inhibitory activity of HL-60 cell is measured
Compound 8a～the 8o of embodiment 1 preparation is suppressed to determination of activity by the following method, and acquired results is listed in table 1.
GST Pi suppresses activity determination method, by prior art, referring to CN1706789 " alpha, beta-unsaturated ketone compounds and preparation method thereof and inhibition GST π thereof are active " the 11st page of embodiment 5 of (200510043573.3) specification sheets.
HL-60 cell growth inhibiting activity measuring method, by prior art, referring to CN101108832 " five member ring heterocyclic compound, preparation method and application " (200710015199.5) Instructions Page 3.
Table 1. compound suppresses GST Pi activity and suppresses HL-60 cells growth activity determination data
Experimental result shows, in table 1,15 kinds of alpha, beta-unsaturated ketone compounds containing thiazole heterocycle are all less than 6.5 μ M to HL-60 cell half growth inhibitory concentration; Wherein, 8a, 8b, 8c are 54.1%, 73.1%, 44.0% to the inhibition percentage of GST Pi when concentration is 1 μ M, apparently higher than lead compound EA; 8m, 8n, 8o inhibition percentage when concentration is 5 μ M is 86.7%, 55.2%, 72.3%; Apparently higher than or approach lead compound EA.Experiment shows that the alpha, beta-unsaturated ketone compounds containing thiazole heterocycle of the present invention has good inhibition GST Pi activity and suppresses HL-60 cells growth activity.
Claims (1)
1. containing thiazole heterocycle alpha, beta-unsaturated ketone compounds, it is characterized in that, is one of following compounds:
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-p-nitrophenyl thiazole (8j),
The chloro-4-of 2-[3-(2-methylene radical-1-oxo-butyl) benzene Oxymethylene]-4-(2-naphthyl) thiazole (8k).
2. the preparation method containing thiazole heterocycle alpha, beta-unsaturated ketone compounds claimed in claim 1, step is as follows:
(1) 2-(substituent phenoxy) ethanamide
2preparation
By 20 mmol 2-(substituent phenoxy) acetic acid
1, 200 mmol sulfur oxychloride 15 mL are added in 50 mL round-bottomed flasks, stirring and evenly mixing, oil bath is slowly heated to 80 ° of C, back flow reaction 4 h, remove sulfur oxychloride residual in reaction solution under reduced pressure, add the 10 mL dilutions of dry toluene to be directly used in the next step;
Get 100 mL and be placed in ice-water bath with the there-necked flask of drying tube, add ammoniacal liquor 10 mL, and the reaction solution after upper step is processed slowly drops in ammoniacal liquor, drip and finish, in ice-water bath, continue stirring reaction 1.5 h; Filter and discard filtrate, filter cake is transferred in hot acetone, fully after dissolving, filters, and filter residue washs with hot acetone, merges washing lotion, filtrate, removes solvent under reduced pressure, and gained white solid alcohol-water recrystallization filters, is dried, and obtains midbody compound
2;
Above-mentioned 2-(substituent phenoxy) acetic acid
1select 2-(3-chlorophenoxy) acetic acid to obtain compound
2b: 2-(3-chlorophenoxy) ethanamide;
(2) 2-(substituent phenoxy) second sulphamide
3preparation
By 20 mmol 2-(substituent phenoxy) ethanamides
2join in 50 mL round-bottomed flasks, add tetrahydrofuran (THF) 5 mL, after stirring at room is dissolved, slowly be warming up to 50 ° of C, at this temperature, add thiophosphoric anhydride 40 mmol in batches, reaction 1-1.5 h, be cooled to room temperature, reaction solution is poured standing 2 h in the beaker that 100 g mixture of ice and water are housed into, ethyl acetate extraction 3 times, each 50 mL; Remove ethyl acetate under reduced pressure, be dried to obtain crude product, crude product is dissolved in hot ethyl acetate, filtered while hot, removes solvent under reduced pressure, obtains compound
3,
Above-mentioned 2-(substituent phenoxy) ethanamide
2select
2bobtain compound
3b: 2-(3-chlorophenoxy) second sulphamide;
(3) 2-[4-(1-oxo-alkyl) substituent phenoxy] second sulphamide
4preparation
By 10 mmol 2-(substituent phenoxy) second sulphamides
3be added in 100 mL there-necked flasks, add CS
230 mL, under stirring at room, add 30 mmol aluminum trichloride (anhydrous) powder 4.0 g in batches, with constant pressure funnel, in reaction system, slowly drip 15 mmol acyl chlorides 2.78 g, produce dope, room temperature reaction 0.5 h, slowly be heated to 50 ° of C, back flow reaction 4 h, are cooled to room temperature, incline and upper layer CS
2, there-necked flask is placed in to ice bath, in there-necked flask, add 50 g mixture of ice and water, produce yellow sticky solid, ethyl acetate extraction, removes solvent under reduced pressure, and silica gel column chromatography obtains compound
4,elution system is petrol ether/ethyl acetate 3:1 volume ratio;
Above-mentioned 2-(substituent phenoxy) second sulphamide
3select
3b,acyl chlorides is selected butyryl chloride, obtains compound
4e: the chloro-4-of 2-[3-(1-oxo-butyl) phenoxy group] second sulphamide
;
(4) alpha-brominated substituent methyl ketone
6preparation
By 20 mmol substituent methyl ketone
5, ethyl acetate 15mL, trichloromethane 15 mL join in 100 mL bis-neck flasks, are warming up to 60
oc adds 40 mmol cupric bromide 8.92 g, back flow reaction 5-12 h in batches, filtered while hot, filtrate is successively respectively washed respectively 3 times with 10% hydrochloric acid soln 30 mL, distilled water 30 mL, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, dehydrated alcohol recrystallization obtains compound
6;
Above-mentioned substituent methyl ketone is selected respectively p-nitro-acetophenone or 2-naphthyl ethyl ketone, obtains respectively compound
6b or 6c:
6b: the bromo-1-of 2-(4-nitrophenyl) ethyl ketone,
6c: the bromo-1-of 2-(2-naphthyl) ethyl ketone,
(5) 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole
7preparation
By 10 mmol compounds
4, 10 mmol compounds
6, anhydrous methanol 10 mL join in 50 mL round-bottomed flasks, back flow reaction 24 h, are cooled to room temperature, filter, dry, obtain compound
7,
Above-mentioned compound
4for
4e, compound
6for
6b or 6c,obtain respectively compound
7jor
7k:
7j: the chloro-4-of 2-[3-(1-oxo-butyl) benzene Oxymethylene] the p-nitrophenyl thiazole of-4-;
7k: the chloro-4-of 2-[3-(1-oxo-butyl) benzene Oxymethylene]-4-naphthyl thiazole;
(6) 2-[replacement-4-(2-methylene radical-1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole
8preparation
By 9.6 mmol 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylenes]-4-aryl thiazole
7, 11.5 mmol paraformaldehyde 0.38 g, 10.4 mmol dimethylamine hydrochloride 0.91 g join in 50 mL flasks, add one, Glacial acetic acid, mix, oil bath is heated to 100 ~ 150 ° of C, after solid all liquefies, and Depressor response 1.5 h, be cooled to room temperature, add wherein appropriate 10wt% NaHCO
3solution, adjusts pH to 8.0, and under 80 ~ 85 ° of C, reacting by heating 40 min, are cooled to room temperature, and ethyl acetate extraction, removes solvent under reduced pressure, obtains oily matter, the separated target compound that obtains of silica gel column chromatography
8, elution system is sherwood oil/acetone 20:1 volume ratio,
Described 2-[replacement-4-(1-oxo-alkyl) benzene Oxymethylene]-4-aryl thiazole
7select respectively midbody compound
7jor
7k, obtain target compound 8j or 8k.
3. the application containing thiazole heterocycle alpha, beta-unsaturated ketone compounds claimed in claim 1, for the preparation of antitumor drug.
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