CN1291993C - N-substituted benzothiazolyl-1-substituted phenyl-O,O-dialkyl-α-amino phosphonate derivatives, preparation method and use - Google Patents
N-substituted benzothiazolyl-1-substituted phenyl-O,O-dialkyl-α-amino phosphonate derivatives, preparation method and use Download PDFInfo
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- CN1291993C CN1291993C CN 200510003041 CN200510003041A CN1291993C CN 1291993 C CN1291993 C CN 1291993C CN 200510003041 CN200510003041 CN 200510003041 CN 200510003041 A CN200510003041 A CN 200510003041A CN 1291993 C CN1291993 C CN 1291993C
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- Prior art keywords
- substituted
- fluorophenyl
- monofluoro
- aminophosphonate
- polyfluoro
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- 230000008659 phytopathology Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 201000008261 skin carcinoma Diseases 0.000 description 1
- 201000000498 stomach carcinoma Diseases 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000002769 thiazolinyl group Chemical group 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种抗植物病毒和抗肿瘤作用的药物——N-取代苯并噻唑基-1-取代苯基-O，O-二烷基-α-氨基膦酸酯类衍生物及制备方法和生物活性，是由下列通式表示的化合物及其制备方法。通式中R1、R2、R3、R4如说明书中所定义。本发明介绍了以取代2-氨基苯并噻唑、氟代苯甲醛、烷基膦酸酯为原料，反应溶剂为甲醇、乙醇、异丙醇、无水乙醇、苯、甲苯、二甲苯、N，N-二甲基甲酰胺、二氧六环、二甲亚砜、环己烷、正己烷或其混合物，经二步合成N-取代苯并噻唑基-1-取代苯基-O，O-二烷基-α-氨基膦酸酯类衍生物。本发明部分化合物对烟草花叶病(TMV)有良好的抑制活性，在药剂浓度为500ppm时，对活体钝化作用可达67.4%，对TMV侵染的活体治疗抑制率为39.8%，对活体保护作用为19.0%；同时部分混合物对人体前列腺癌细胞PC3有较好的抑制活性，在实验用药浓度为20μg/mL时，部分化合物对PC3细胞的抑制率可达50%以上。
The invention discloses a drug with anti-plant virus and anti-tumor effects - N-substituted benzothiazolyl-1-substituted phenyl-O, O-dialkyl-α-aminophosphonate derivatives and its preparation The method and biological activity are compounds represented by the following general formula and their preparation methods. In the general formula, R 1 , R 2 , R 3 , and R 4 are as defined in the specification. The present invention introduces substituted 2-aminobenzothiazole, fluorobenzaldehyde, and alkyl phosphonate as raw materials, and the reaction solvent is methanol, ethanol, isopropanol, dehydrated alcohol, benzene, toluene, xylene, N, N-Dimethylformamide, dioxane, dimethyl sulfoxide, cyclohexane, n-hexane or their mixture, through two-step synthesis of N-substituted benzothiazolyl-1-substituted phenyl-O, O- Dialkyl-α-aminophosphonate derivatives. Some compounds of the present invention have good inhibitory activity to tobacco mosaic disease (TMV). When the agent concentration is 500ppm, the passivation effect to living body can reach 67.4%, and the living body treatment inhibition rate to TMV infection is 39.8%. The protective effect was 19.0%. At the same time, some compounds had good inhibitory activity on human prostate cancer cell PC3. When the experimental drug concentration was 20 μg/mL, the inhibitory rate of some compounds on PC3 cells could reach more than 50%.
Description
Technical field
The present invention is the medicine N-substituted benzene benzothiazolyl-1-substituted-phenyl-O with Antiphytoviral and antitumor action, O-dialkyl-alpha-amino phosphonate ester derivatives and preparation method thereof.
Background technology
The α-An Jilinsuan ester separates in the sheep body at first and obtains, caused investigators' concern thereafter, synthetic, the bioactive research paper enormous amount of derivatives such as relevant α-An Jilinsuan ester, its biological activity also is extended to all respects of agricultural chemicals and medicine, see relevant α-An Jilinsuan ester and synthetic thereof summary document (as: Song Baoan etc., novel optical active alpha-amido phosphonate progress, organic chemistry for details, 2003,23 (9): 933; Song Baoan etc., the synthetic and bioactivity research progress of α-An Jilinsuan ester, organic chemistry, 2004,24 (8): 843.).
Yuan Cheng already waits the people to synthesize a series of α-An Jilinsuan derivative (Yuan, C.-Y. respectively at 1993,1998,2000 reports; Wang, G.-H.; Feng, H.-Z.Phosphors, Sulfur, Silicon Relt.Elem.1993,81,149.; Yuan, C.-Y.; Zhang, Y.-X.; Luo, W.-H.; Yao, Z.-P.Heteroatom Chem.1998,9,139.; Xiao, J-B, Zhang, X-M, Yuan, C-Y.Heteroatom Chem.2000,11,536.).
People such as Liu Xuejun had reported synthetic a series of 5-fluor-uracil-1-base phosphorus tripeptide compounds that contain the antitumour activity group in 2002, and had carried out Anticancer Activities.Find in the experiment, in the α-An Jilinsuan ester, the substituent volume of another of alpha-position is big more, alpha-amino nucleophilicity is more little, electron-withdrawing substituent will reduce the nucleophilicity of amido, when substituting group is that product yield is starkly lower than the yield of product under other situation when on aryl and the aryl nitro substituent being arranged, and when being nitro with the ortho position of aryl, the product that obtains expecting is failed in reaction.All target compounds are carried out external antitumour activity tentatively test, when production concentration is 1 * 10
-5During mol/L, the result shows that this compounds of part has certain anticancer (HL-60 and BEL-7404) effect.
Reports such as Song Baoan in 2002 contain synthetic and resisting tobacco mosaic virus (TMV) activity of trifluoromethyl-α-An Jilinsuan ester.Drug concentration is 5 * 10
-4G/L is 49.65～70.12% to the tobacco mosaic virus (TMV) inhibiting rate.(Song Baoan, Wu Yanglan, Huang Rongmao, CN02113256,2002.; Song, B.-A.; Wu, Y.L.; Yang, S.International Symposium on Frontiers in MolecularScience, Qingdao, 2002, p66.)
In recent years, inventor research group is in order to seek new high-efficiency anti-plant virus agent and antitumour activity new compound, the working foundation that synthesizes with original fluorine-containing amido phosphonate, introduce the benzothiazole group in the molecule, design with synthesized N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound, carry out have the design of anti-plant virus agent and antitumour activity heterocycle new compound, synthetic and biological screening.
Summary of the invention
Based on original work, derive design and the synthetic novel N-substituted benzene benzothiazolyl of a class-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound carries out novel pesticide and cancer therapy drug initiative research.Its general structure is as follows:
In the formula
R
1Be (1) halogen atom; (2) itrile group; (3) nitro; (4) hydroxyl; (5) sulfydryl; (6) C1-10 alkyl; C2-10 alkenyl or C2-10 alkynyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (7) C1-10 alkoxyl group; C2-10 alkenyloxy or C2-10 chain oxy-acetylene; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (8) C1-10 alkylthio; C2-10 alkenyl thio or C2-10 alkynes sulfenyl; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (9) substituted carbonyl; described substituting group is selected from (i) C1-10 alkyl; (ii) amino; (iii) C1-10 alkylamino; (iv) C1-10 alkyl oxy; (v) C1-10 alkyl sulfenyl; (vi) C3-8 cycloalkyl; (10) can be by the amino of 1 or 2 each substituting groups replacement; described substituting group is selected from (i) C1-10 alkyl; (ii) C2-10 alkenyl; (iii) C2-10 alkynyl group; (iv) C1-10 alkyl sulphonyl; (v) C2-10 alkenyl alkylsulfonyl; (vi) C2-10 alkynyl group alkylsulfonyl; (vii) C1-10 alkyl-carbonyl; (viii) C2-10 alkenyl carbonyl; (ix) C2-10 alkynyl group carbonyl; (11) C1-10 alkyl sulphonyl; (12) C2-10 alkenyl alkylsulfonyl; (13) C2-10 alkynyl group alkylsulfonyl; (14) C1-10 alkyl sulphinyl; (15) C2-10 alkenyl sulfinyl; (16) C2-10 alkynyl group sulfinyl; (17) formyl radical; (18) C3-8 cycloalkyl or C3-8 cycloalkenyl group; wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces; (19) C3-8 cycloalkyloxy or C3-8 cyclenes oxygen base, wherein each group all can be by at least one or a plurality of halogen atom; itrile group; nitro; hydroxyl; the sulfydryl substituting group replaces.
R
2Be (1) fluorine, (2) single fluorine or polyfluoro replace the C1-10 alkyl, the C2-10 alkenyl, the C2-10 alkynyl group, the C3-8 cycloalkyl, (3) single fluorine or polyfluoro replace the C1-10 alkoxyl group, the C2-10 alkenyloxy, the C2-10 chain oxy-acetylene, the C3-8 cycloalkyloxy, (4) single fluorine or polyfluoro replace the C1-10 alkylthio, the C2-10 alkenyl thio, C2-10 alkynes sulfenyl, (5) carbonyl of single fluorine or polyfluoro replacement, described substituting group is selected from (i) single fluorine or polyfluoro replaces the C1-10 alkyl, (ii) single fluorine or polyfluoro replace the C1-10 alkylamino, (iii) single fluorine or polyfluoro replace the C1-10 alkyl oxy, (iv) single fluorine or polyfluoro replace C1-10 alkyl sulfenyl, (v) single fluorine or polyfluoro replace the C3-8 cycloalkyl, (10) amino of single fluorine or polyfluoro replacement, described substituting group is selected from (i) single fluorine or polyfluoro replaces the C1-10 alkyl, (ii) single fluorine or polyfluoro replace the C2-10 alkenyl, (iii) single fluorine or polyfluoro replace the C2-10 alkynyl group, (iv) single fluorine or polyfluoro replace the C1-10 alkyl sulphonyl, (v) single fluorine or polyfluoro replace C2-10 alkenyl alkylsulfonyl, (vi) single fluorine or polyfluoro replace C2-10 alkynyl group alkylsulfonyl, (vii) single fluorine or polyfluoro replace the C1-10 alkyl-carbonyl, (viii) single fluorine or polyfluoro replace the C2-10 alkenyl carbonyl, (ix) single fluorine or polyfluoro replace C2-10 alkynyl group carbonyl, (11) single fluorine or polyfluoro replace the C1-10 alkyl sulphonyl, (12) single fluorine or polyfluoro replace C2-10 alkenyl alkylsulfonyl, (13) single fluorine or polyfluoro replace C2-10 alkynyl group alkylsulfonyl, (14) single fluorine or polyfluoro replace the C1-10 alkyl sulphinyl, (15) single fluorine or polyfluoro replace C2-10 alkenyl sulfinyl, and (16) single fluorine or polyfluoro replace C2-10 alkynyl group sulfinyl;
R
3, R
4Be respectively C1-10 alkyl, C3-8 cycloalkyl, C2-10 alkenyl, C2-10 alkynyl group.
Above-described a kind of medicine that is used for Antiphytoviral and antitumor action, R in its compound general formula
1Be methyl, methoxyl group, ethyl, oxyethyl group, n-propyl, positive propoxy, sec.-propyl, isopropoxy, normal-butyl, n-butoxy, isobutyl-, isobutoxy, the tertiary butyl, tert.-butoxy, vinyl, vinyloxy group, propenyl, propenyloxy group, butenyl, butenyloxy, ethynyl, second alkynyloxy group, proyl, third alkynyloxy group, butynyl, fourth alkynyloxy group, halogen atom, itrile group, nitro, hydroxyl, sulfydryl.
The above-described a kind of antitumor and medicine Antiphytoviral effect of being used for, R in its compound general formula
2Be fluorine, trifluoromethyl.
The above-described a kind of antitumor and medicine Antiphytoviral effect of being used for, R in its compound general formula
3, R
4Be respectively hydrogen, methyl, ethyl, propyl group, butyl, allyl group, propenyl, 1-butylene base, crotyl, propargyl, proyl, ethyl acetylene base, 2-butyne base.
In the content of the present invention, the C1-6 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, uncle's hexyl, new hexyl.
In the content of the present invention, the C2-6 alkenyl can be vinyl, propenyl, allyl group, (two keys are at 1 for butenyl, two or three-digit), isobutenyl (two keys are at 1 or 2), (two keys are at 1 for pentenyl, 2,3 or 4), (two keys are at 1 for isopentene group, two or three-digit), new pentenyl (two keys are at 1 or 2), (two keys are at 1 for hexenyl, 2,3,4 or 5), (two keys are at 1 for dissident's thiazolinyl, 2, in the content of the present invention, the C2-6 alkynyl group can be ethynyl, proyl, propargyl, (three key is at 1 for butynyl, two or three-digit), isobutyl alkynyl (three key is at 1 or 2), (three key is at 1 for pentynyl, 2,3 or 4), (three key is at 1 for the isoamyl alkynyl, two or three-digit), new pentynyl (three key is at 1 or 2), (three key is at 1 for the hexin base, 2,3,4 or 5), (three key is at 1 for dissident's alkynyl, 2,3 or 4), (three key is at 1 for new hexin base, two or three-digit).
In the content of the present invention, halogen atom can be fluorine, chlorine, bromine, iodine.
In the content of the present invention; can be a kind of pharmaceutical composition; it is characterized in that comprising formula (I) compound of significant quantity, its purposes is to be used to prevent and treat plant virus, weeds, the insect that appears in husbandry, the forestry, and stores the animal pest on product, material protection, the health.The compounds of this invention also can be used as defoliating agent, weedicide, anti-plant virus agent as activeconstituents.Particularly The compounds of this invention has better activity to tobacco mosaic disease (TMV) as anti-plant virus agent the time.
Described pharmaceutical composition contains the mixture as formula at least (I) compound of activeconstituents itself or itself and one or more pharmaceutically useful inert non-toxic vehicle or carrier.
The compounds of this invention also can be used as treatment and prevents various optimum or malignant tumours as activeconstituents.Wherein said tumour comprises prostate cancer, leukemia, skin carcinoma, cancer of the stomach, mammary cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, lymphatic cancer, large bowel cancer, nasopharyngeal carcinoma, oral carcinoma, wherein is meant prostate cancer especially.
The present invention is to be raw material to replace 2-aminobenzothiazole, Fluorobenzaldehyde, phosphonate ester, and synthetic through two steps, synthetic route is as follows:
R wherein
1, R
2, R
3, R
4As previously mentioned, reaction solvent is methyl alcohol, ethanol, Virahol, dehydrated alcohol, benzene,toluene,xylene, N, dinethylformamide, dioxane, methyl-sulphoxide, hexanaphthene, normal hexane or its mixture.
The first step: N-substituted benzene benzothiazolyl-1-substituted-phenyl imines synthetic
At the bottom of having three mouthfuls of gardens of water segregator capable, drop in the flask and replace 2-aminobenzothiazole, Fluorobenzaldehyde, solvent, reflux, azeotropic dehydration, follow the tracks of (sherwood oil: ethyl acetate=2: 1 volume ratios) with TLC, 0.5-5h reaction finishes, and is N-substituted benzene benzothiazolyl-1-substituted-phenyl imines.
This step is applicable to the synthetic of all above-mentioned N-substituted benzene benzothiazolyl-1-substituted-phenyl imines.
Second step: N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonic acid ester synthetic
The product of the first step is dissolved in the solvent, adds phosphorous acid ester, react 0.5-5h under the stirring and refluxing condition, underpressure distillation removes and desolvates, and thick product ethyl alcohol recrystallization gets clear crystal, be N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonic acid ester.
This step is applicable to all above-mentioned N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonic acid ester synthetic.
Embodiment
Embodiment one, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, (compound number is a) for O-dimethyl-α-An Jilinsuan ester synthetic
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic
In flask at the bottom of three mouthfuls of gardens of the 25mL that has water segregator capable, drop into 2-amino-6-methoxyl group benzo thiazole (4mmol), 4-fluorobenzaldehyde (4mmol) and 15mL toluene, the stirring at room post-heating refluxes, azeotropic dehydration, (sherwood oil: ethyl acetate=2: 1 volume ratios), about 1-2h afterreaction raw material point disappears, stopped reaction with the TLC tracking, directly go next step reaction, gained solution is N-(6-methoxy benzothiazole-2-yl)-1-(4-fluorophenyl) imide liquor.Through purifying, obtain light yellow crystal, productive rate 82.4%, m.p.110～112 ℃,
1H NMR δ: 3.70 (s, 3H, OCH
3), 4.05-4.10 (m, 1H, CH), 7.01-7.53 (m, 7H, Ar-H).
With same synthetic method, select different solvent (as benzene, dimethylbenzene, N, dinethylformamide, methyl-sulphoxide, dioxane) for use, obtain identical experimental result.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-dimethyl-α-An Jilinsuan ester synthetic
1 (4mmol) added dimethylphosphite (4mmol), react 1-2h under the stirring and refluxing condition, underpressure distillation removes and desolvates, thick product ethyl alcohol recrystallization, get clear crystal, be N-(6-methoxy benzothiazole-2-yl)-1-(4-fluorophenyl)-O, O-dimethyl-α-An Jilinsuan ester, productive rate 45.9%, m.p.177～179 ℃.
Embodiment two, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is b) of O-diethyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-diethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to diethyl phosphite, productive rate 72.3%, m.p.198～200 ℃.
Embodiment three, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is c) of O-di-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-di-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to di-n-propyl phosphite, productive rate 71.6%, m.p.130～131.5 ℃.
Embodiment four, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is d) of O-di-isopropyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-di-isopropyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to diisopropyl phosphite, productive rate 69.2%, m.p.201.5～203 ℃.
Embodiment five, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is e) of O-di-n-butyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-di-n-butyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to di-n-butyl phosphite, productive rate 60.7%, m.p.95～97 ℃.
Embodiment six, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is f) of O-diisobutyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-diisobutyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to the phosphorous acid diisobutyl ester, productive rate 50.2%, m.p.115～117 ℃.
Embodiment seven, N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, synthetic (compound number is g) of O-di-t-butyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl) imines is synthetic synthetic as embodiment one (1) method and condition.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(4-fluorophenyl)-O, O-di-t-butyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only dimethylphosphite is changed to the phosphorous acid di tert butyl carbonate, productive rate 30.41%, m.p.167～169 ℃.
According to organic chemist common thinking and simple repeated experiment, the embodiment (1) of embodiment one to embodiment seven is fit to the synthetic of following product equally:
N-[4 (or 5, or 7)-methoxyl group benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethoxyl benzo thiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-positive propoxy benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isopropoxy benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-n-butoxy benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isobutoxy benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-tert.-butoxy benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-vinyloxy group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-propenyloxy group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butenyloxy benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-second alkynyloxy group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-third alkynyloxy group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-Ding alkynyloxy group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-halo benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-itrile group benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-nitrobenzene thiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-mercaptobenzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-hydroxybenzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 7)-methylbenzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-n-propyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-sec.-propyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-normal-butyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isobutyl-benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-tertiary butyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-vinyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-propenyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butenyl benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethynyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-proyl benzothiazole-2-yl]-1-(4-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butynyl benzo thiazol-2-yl]-1-(4-fluorophenyl) imines.
Above-mentioned each product all can synthesize corresponding target product N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound with compounds such as dimethylphosphite, diethyl phosphite, di-n-propyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, phosphorous acid diisobutyl ester, phosphorous acid di tert butyl carbonates according to embodiment one to embodiment seven embodiment (2) respectively.
Embodiment eight, N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is h) of O-dimethyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, O-dimethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, productive rate 49.3%, m.p.180-182 ℃.
Embodiment nine, N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is i) of O-diethyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, O-diethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to diethyl phosphonate, productive rate 83.1%, m.p.147-148 ℃.
Embodiment ten, N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is j) of O-di-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, O-di-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di phosphonic acid ester, productive rate 85.7%, m.p.160～162 ℃.
Embodiment 11, N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is k) of O-di-n-butyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(2-fluorophenyl)-O, O-di-n-butyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di-n-butyl phosphonic acid ester, productive rate 68.3%, m.p.107～109 ℃.
According to organic chemist common thinking and simple repeated experiment, the embodiment (1) of embodiment eight to embodiment 11 is fit to the synthetic of following product equally:
N-[5 (or 6, or 7)-methylbenzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-n-propyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-sec.-propyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-normal-butyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isobutyl-benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-tertiary butyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-vinyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-propenyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butenyl benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethynyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-proyl benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butynyl benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-halo benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-itrile group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-nitrobenzene thiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-mercaptobenzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-hydroxybenzothiazole-2-yl]-1-(2-fluorophenyl) imines;
Above-mentioned each product all can synthesize corresponding target product N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound with compounds such as dimethylphosphite, diethyl phosphite, di-n-propyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, phosphorous acid diisobutyl ester, phosphorous acid di tert butyl carbonates according to embodiment eight to embodiment 11 embodiments (2) respectively.
Embodiment 12, N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, synthetic (compound number is 1) of O-dimethyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, O-dimethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, productive rate 63.9%, m.p.190～192 ℃.
Embodiment 13, N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, synthetic (compound number is m) of O-diethyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, O-diethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to diethyl phosphonate, productive rate 72.1%, m.p.148-150 ℃.
Embodiment 14, N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, synthetic (compound number is n) of O-di-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, O-di-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di phosphonic acid ester, productive rate 80.1%, m.p.127～129 ℃.
Embodiment 15, N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, synthetic (compound number is o) of O-di-isopropyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, O-di-isopropyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di-isopropyl phosphonic acid ester, productive rate 75.4%, m.p.168～170 ℃.
Embodiment 16, N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, synthetic (compound number is p) of O-di-n-butyl-α-An Jilinsuan ester
(1) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only 2-amino-6-methoxyl group benzo thiazole is changed to 2-amino-4-methylbenzothiazole, the 4-fluorobenzaldehyde is changed to the 4-trifluoromethylated benzaldehyde.
(2) N-(4-methylbenzothiazole-2-yl)-1-(4-trifluoromethyl)-O, O-di-n-butyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di-n-butyl phosphonic acid ester, productive rate 60.3%, m.p.106～108 ℃.
According to organic chemist common thinking and simple repeated experiment, the embodiment (1) of embodiment 12 to embodiment 16 is fit to the synthetic of following product equally:
N-[5 (or 6, or 7)-methylbenzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-ethyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-n-propyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-sec.-propyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-normal-butyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-isobutyl-benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-tertiary butyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-vinyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-propenyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-butenyl benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-ethynyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-proyl benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-butynyl benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-halo benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-itrile group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-nitrobenzene thiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-mercaptobenzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-hydroxybenzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[5 (or 6, or 7)-methoxyl group benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-ethoxyl benzo thiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-positive propoxy benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-isopropoxy benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-n-butoxy benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-isobutoxy benzo thiazol-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-tert.-butoxy benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-vinyloxy group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-propenyloxy group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-butenyloxy benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-second alkynyloxy group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-third alkynyloxy group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines;
N-[4 (or 5, or 6, or 7)-Ding alkynyloxy group benzothiazole-2-yl]-1-(4-trifluoromethyl) imines.
Above-mentioned each product all can synthesize corresponding target product N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound with compounds such as dimethylphosphite, diethyl phosphite, di-n-propyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, phosphorous acid diisobutyl ester, phosphorous acid di tert butyl carbonates according to embodiment 12 to embodiment 16 embodiments (2) respectively.
Embodiment 17, N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is q) of O-dimethyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, O-dimethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, productive rate 63.1%, m.p.157-159 ℃.
Embodiment 18, N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is r) of O-diethyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, O-diethyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to diethyl phosphonate, productive rate 90.1%, m.p.150～151 ℃.
Embodiment 19, N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is s) of O-di-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, O-di-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di phosphonic acid ester, productive rate 85.6%, m.p.171～173 ℃.
Embodiment 20, N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is t) of O-di-isopropyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, O-di-isopropyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di-isopropyl phosphonic acid ester, productive rate 84.2%, m.p.215～216 ℃.
Embodiment 21, N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, synthetic (compound number is u) of O-di-n-butyl-α-An Jilinsuan ester
(1) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl) imines is synthetic
Synthetic as embodiment one (1) method and condition, only the 4-fluorobenzaldehyde is changed to the 2-fluorobenzaldehyde.
(2) N-(6-methoxyl group benzo thiazol-2-yl)-1-(2-fluorophenyl)-O, O-di-n-butyl-α-An Jilinsuan ester synthetic
Synthetic as embodiment one (2) method and condition, only the dimethyl phosphine acid esters is changed to the di-n-butyl phosphonic acid ester, productive rate 72.1%, m.p.100～101 ℃.
According to organic chemist common thinking and simple repeated experiment, the embodiment (1) of embodiment 17 to embodiment 21 is fit to the synthetic of following product equally:
N-[4 (or 5, or 7)-methoxyl group benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-ethoxyl benzo thiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-positive propoxy benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isopropoxy benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-n-butoxy benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-isobutoxy benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-tert.-butoxy benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-vinyloxy group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-propenyloxy group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-butenyloxy benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-second alkynyloxy group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-third alkynyloxy group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-Ding alkynyloxy group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-halo benzo thiazol-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-itrile group benzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-nitrobenzene thiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-mercaptobenzothiazole-2-yl]-1-(2-fluorophenyl) imines;
N-[4 (or 5, or 6, or 7)-hydroxybenzothiazole-2-yl]-1-(2-fluorophenyl) imines.
Above-mentioned each product all can synthesize corresponding target product N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, O-dialkyl-alpha-amino phosphonate ester compound with compounds such as dimethylphosphite, diethyl phosphite, di-n-propyl phosphite, diisopropyl phosphite, di-n-butyl phosphite, phosphorous acid diisobutyl ester, phosphorous acid di tert butyl carbonates according to embodiment 17 to embodiment 21 embodiments (2) respectively.
Utilize similar synthetic method and reaction conditions synthetic N-substituted benzene benzothiazolyl-1-substituted-phenyl-O, the O-dialkyl-alpha-amino phosphonate ester derivatives is as shown in table 1.The N-substituted benzene benzothiazolyl-1-substituted-phenyl-O of partial synthesis, O-dialkyl-alpha-amino phosphonate ester derivatives proton nmr spectra (
1H NMR) data are as shown in table 1, and physico-chemical property and ultimate analysis data are as shown in table 2, and infrared spectra (IR) data are as shown in table 3, carbon-13 nmr spectra (
13C NMR) data are as shown in table 4.
The proton nmr spectra data of table 1 part institute synthetic compound
| Numbering | Product structure | Molecular formula | 1H NMR，δ(ppm，DMSO-d 6) (TMS marks in doing) |
The physico-chemical property and the ultimate analysis of table 2 part institute synthetic compound
| Compd. | Physical State | m.p./℃ | Yield ％ | Elemental analysis(Calcd.，％) | ||
| C | H | N | ||||
| a b c d | Colorless crystal Colorless crystal Colorless crystal Colorless crystal | 177～179 198～200 130～131.5 201.5～203 | 45.9 72.3 71.6 69.2 | 51.41(51.50) 53.67(53.80) 55.61(55.70) 55.80(55.70) | 5.27(4.58) 5.27(5.22) 6.02(5.79) 5.59(5.79) | 6.49(7.07) 6.49(6.60) 6.06(6.19) 6.09(6.19) |
| e f g h i j k l m n o p q r s t u | Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal Colorless crystal | 95～97 115～117 167～169 180～182 147～148 160～162 107～109 190～192 148-150 127～129 168～170 106～108 157～159 150～151 171～173 215～216 100～101 | 60.7 50.2 30.4 49.3 83.1 85.7 68.3 63.9 72.1 80.1 75.4 60.3 63.1 90.1 85.6 84.2 72.1 | 57.48(57.49) 57.51(57.49) 57.45(57.49) 53.55(53.68) 55.77(55.87) 57.60(57.79) 59.34(59.47) 50.42(50.36) 52.52(52.40) 54.61(54.32) 54.48(54.32) 56.12(56.03) 51.70(51.50) 53.47(53.34) 55.74(55.64) 55.74(55.74) 57.49(57.35) | 658(6.29) 6.56(6.29) 6.51(6.29) 4.81(4.77) 5.01(5.43) 5.88(6.00) 6.44(6.51) 4.20(4.23) (4.534.84) 5.40(5.39) 5.03(5.39) 5.90(5.88) 4.77(4.58) 5.22(5.18) 5.79(5.56) 5.79(5.94) 6.29(6.37) | 5.63(5.83) 5.80(5.83) 5.71(5.83) 7.31(7.36) 6.85(6.86) 6.32(6.42) 6.13(6.03) 6.71(6.53) 5.73(6.11) 5.62(5.76) 5.54(5.76) 5.42(5.45) 6.88(7.07) 6.46(6.32) 6.19(6.00) 6.19(6.09) 5.83(5.63) |
The IR data of table 3 part institute synthetic compound
| Compd | IR，ν max/cm -1 |
| a b c d e f g | 785，1029，1051，1213，1240，1510，1546，1604，3045，3244 966，1018，1049，1222，1236，1436，1469，1544，1604，3242 995，1056，1222，1267，1436，1469，1543，1571，1604，2964，3242 987，1006，1222，1469，1544，1573，1604，2358，2980，3043，3248 756，1023，1062，1217，1438，1470，1542，1605，2970，3255 827，1014，1224，1247，1436，1469，1508，1543，1604，2960，3037，3228 956，1031，1222，1469，1508，1541，1614，2974，3234 |
| h i j k l m n o p q r s t u | 1034，1055，1211，1242，1456，1489，1539，1591，2940，3036，3223 1028，1049，1213，1236，1487，1539，1591，3211 1006，1062，1219，1230，1492，1533，1577，1591，2966，3034，3230 1004，1024，1060，1213，1234，1539，1593，2958，3090，3246 1018，1035，1058，1215，1244，1325，1537，3236 1020，1051，1068，1215，1238，1327，1537，3230 1006，1066，1124，1166，1220，1234，1325，1534，1541，1600，2968，3018，3228 995，1068，1122，1163，1215，1234，1325，1537，1589，2981，3035，3221 1022，1053，1066，1126，1168，1251，1244，1323，1539，1591，3010，3250 1043，1219，1255，1541，1604，2951，3253 945，1051，1225，1267，1542，1602，3221 1064，1215，1259，1541，1608，2951，3253 1004，1265，1546，1604，3248 997，1022，1217，1267，1541，1602，3251 |
Table 4 part institute synthetic compound
13C NMR data
| Compd. | 13C NMR，δ(CDCl 3) |
| a b c d f g h i j k l m | 52.9，54.5，55.5，62.4，105.5，113.0，115.0，118.7，130.0，132.2，145.5，154.6，160.4，162.9， 163.8 52.9，54.5，55.5，62.4，105.5，113.0，115.0，118.7，130.0，132.2，145.5，154.6，160.4，162.9， 163.8 54.3，55.5，67.6，68.0，105.5，113.0，114.9，115.2，118.7，130.0，131.2，145.5，154.6，163.6 53.4，55.0，71.0，105.5，113.0，114.8，115.0，118.7，130.1，132.5，145.6，154.6，160.4，162.8， 163.8 53.8，55.4，55.7，72.9，73.0，73.1，73.4，105.1，113.2，115.2，115.4，119.5，130.0，130.1， 132.0，146.1，155.2，161.2，163.8，164.0 9.1，9.2，9.48，9.51，9.6，9.67，9.72，20.70，20.75，20.79，20.8，21.3，21.6，21.9，29.2，29.4， 29.6，29.8，30.0，30.2，30.4，30.55，30.57，30.60，30.63，30.90，30.97，31.16，31.20，31.33， 31.34，31.37，55.9，105.8，114.00，114.03，115.5，115.8，120.1，131.31，131.37，131.45， 133.2，133.88，133.97，147.1，156.22，156.23，162.0，164.4 17.8，38.9，39.5，45.8，47.4，53.3 53.8，115.1，118.6，121.6，123.4，124.7，126.3，127.8， 129.5，130.0，150.2，158.4，160.9，164.4 164.6，130.8，129.8，129.35，129.27，126.5，124.4，123.1，122.9，121.7，118.1，115.4，115.2， 63.7，63.64，63.56，49.9，48.4，18.2，16.44，16.39，16.15，16.09 164.5，164.4，161.9，151.0，130.9，129.7，129.6，129.4，129.3，126.4，124.3，123.4，123.2， 121.6，118.0，115.3，115.1，69.1，69.0，68.93，68.85，49.6，48.0，23.8，23.8，23.7，23.6，18.1， 9.9，9.7 164.6，164.4，161.9，161.8，159.5，159.4，1509，130.9，129.72，129.67，129.3，126.4，124.7， 124.4，123.3，123.1，118.1，115.3，115.1，67.4，67.3，67.2，67.1，49.7，48.2，32.51，32.45， 32.3，32.2，18.6，18.4，18.1，13.50，13.46 139.3，130.8，129.4，128.54，128.48，126.6，125.6，122.1，118.2，55.8，54.24，54.16，54.09， 54.04，53.97，18.2 139.6，130.7，129.3，128.61，128.55，126.6，125.4，122.0，118.2，109.8，63.7，56.4，54.9， 18.2，16.5，16.4，16.22，16.16 |
| n o p r s t u | 164.43，164.31，150.8，140.0，130.9，129.2，128.76，128.71，126.5，125.3，121.8，118.1， 69.29，69.21，69.0，68.9，56.0，54.5，23.9，23.8，23.7，23.6，18.2，9.9，9.8 142.4，131.7，130.13，130.07，129.4，127.1，125.8，122.5，119.0，72.7，57.0，55.5，30.4， 30.2，29.99，29.80，29.60，29.41，29.22，24.3，23.9，23.5，18.2 164.4，164.3，150.9，140.0，130.9，129.2，128.77，128.72，126.5，125.3，121.8，118.1，67.56， 67.49，67.23，67.15，56.0，54.5，32.53，32.48，32.30，32.24，18.60，18.46，18.2，13.5，13.4 16.07，16.12，16.24，16.29，38.86，39.08，39.50，39.70，39.91，40.12，52.92，54.45，55.52， 62.47，62.54，62.75，62.82，105.57，113.09，115.01，115.22，118.78，130.04，130.10，130.10， 130.12，130.18，132.288，132.318，145.58，154.66，160.48，160.51，162.90，163.73，163.83 9.98，9.84，23.21，23.27，23.35，23.40，38.87，39.08，39.29，39.50，39.70，39.92，40.12， 54.36，55.51，67.64，67.71，68.03，68.10，105.55，113.06，114.98，115.19，1118.74，130.05， 131.85，132.28，145.56，154.62，163.68，163.77 22.91，22.96，23.43，23.82，23.85，23.93，23.96，38.87，39.08，39.28，39.50，39.7，39.91， 4012，46.87，55.51，71.22，71.28，71.50，71.57，105.56，113.08，115.01，115.22，118.89， 123.69，123.84，124.45，129.55，129.82，131.90，145.50，154.66，163.76，163.86 13.35，18.00，18.14，31.80，31.86，31.99，32.04，38.87，39.08，39.29，39.5，39.7，39.9， 40.13，46.29，47.88，55.50，65.89，65.97，66.42，66.48，105.53，113.09，115.08，115.30， 118.93，123.44，123.59，124.54，129.99，131.92，145.51，154.70，158.28，163.65，163.74 |
Embodiment 22, compound i are to the inhibition activity test of tobacco mosaic disease (TMV)
(1) test method
1.1 virus is purified
Adopt Gooding method (Gooding G V jr, Hebert T T.A simple technique forpurification of tobacco mosaic virus in large quantities[J] .Phytopathology, 1967,57:1285.), choose more than 3 weeks of inoculation, TMV systemic infection host Nicotiana tabacum.L plant upper blade, homogenate in phosphoric acid buffer, double gauze filters, 1000g is centrifugal, handles through 2 polyoxyethylene glycol, and is centrifugal again, precipitation suspends with phosphoric acid buffer, promptly obtains slightly guiding and supporting of TMV.Whole experiment under 4 ℃, carry out (see deeply along one, last China fir Kang Yan (day), Japanese plum just, the king is sincere withered, Jiao Shumei translates. agricultural chemicals laboratory method---a sterilant piece of writing [M]. Beijing: agriculture press, 1991,93-94.).Absorbance with ultraviolet spectrophotometer mensuration 260nm wavelength calculates virus concentration according to formula.
Virus concentration (mg/mL)=(A
260* extension rate)/E
0.1% 1cm 260nm
Wherein E represents optical extinction coefficient, and promptly during wavelength 260nm, concentration is the suspension of 0.1% (1mg/mL), the photoabsorption when light path is 1cm (optical density(OD)) value.The E of TMV
0.1% 1cm 260nmBe 3.1.
1.2 the stripped therapeutic action that medicament infects TMV
With phosphoric acid buffer TMV is diluted to 6 * 10
-3Mg/ml, artificial inoculation is in the of the right age blade that spreads silicon carbide (500 order), and inoculation back water washes the blade that connects.Treat that the blade face receive to do, cut, along arteries and veins in the blade to cuing open, about half leaf immerse respectively in test compound solution and the aqua sterilisa, represent treatment group and blank group respectively, take out after 30 minutes.Place the cultivation of preserving moisture under optimal temperature and the illumination, observed and recorded incidence after 3～4 days.
1.3 the live body provide protection that medicament infects TMV
Select the Nicotiana glutinosa of growing way unanimity, spread medicament at Zuo Banye gently with writing brush, right half leaf spreads aqua sterilisa and compares, 12 hours, treat that blade is done after, virus inoculation.Dip in writing brush and to get viral juice, concentration is 6 * 10
-3Mg/mL, artificial frictional inoculation are on the blade that spreads silicon carbide, and (full leaf) wiped 1～2 time gently along its offshoot direction on the blade face.The blade below is supported with palm or multilayer filter paper.The blade that the inoculation back connects with flowing water (or wash bottle) flushing.Promptly occur scab after 3～4 days, when scab is counted easily, add up.
1.4 medicament is to the live body passivation of TMV
With medicament and isopyknic viral juice mixing passivation 30min, a frictional inoculation Nicotiana glutinosa left side half leaf, right half leaf of aqua sterilisa and viral juice combined inoculation.Write down withered spot number after 3～4 days.
1.5 the live body therapeutic action that medicament infects TMV
Select the Nicotiana glutinosa of growing way unanimity, dip in writing brush earlier and get viral juice, full leaf virus inoculation, the water flushing of inoculation back.After treating that blade is done, spread medicament at Zuo Banye, right half leaf spreads aqua sterilisa and compares.Write down withered spot number after 3～4 days.
Calculate inhibiting rate:
Wherein, the average withered spot number that does not spread the average withered spot number of medicament half leaf and spread medicament half leaf all adopts and respectively organizes multiple mean number three times.
(2) test-results
After tested; being 8.52% to the therapeutic action of exsomatizing when the compound i drug concentration is 500ppm, is 54.05% to the live body passivation, and the live body treatment inhibiting rate that TMV is infected is 39.87%; to the live body provide protection is 18.98%, shows good anti-phytoviral activity.
Embodiment 23, compound j are to the inhibition activity test of tobacco mosaic disease (TMV)
(1) test method
Test method is with embodiment 22 (1) test methods.
(2) test-results
After tested, be 18.03% to the therapeutic action of exsomatizing when compound j drug concentration is 500ppm, be 67.36% to the live body passivation, the live body treatment inhibiting rate that TMV is infected is 10.55%, shows good anti-phytoviral activity.
Embodiment 24, compound m are to the inhibition activity test of tobacco mosaic disease (TMV)
(1) test method
Test method is with embodiment 22 (1) test methods.
(2) test-results
After tested, be 26.11% to the therapeutic action of exsomatizing when compound m drug concentration is 500ppm, be 48.39% to the live body passivation, show certain anti-phytoviral activity.
Embodiment 25, compound o are to the inhibition activity test of tobacco mosaic disease (TMV)
(1) test method
Test method is with embodiment 22 (1) test methods.
(2) test-results
After tested, when compound o drug concentration is 500ppm, be 63.66% to the live body passivation, show certain anti-phytoviral activity.
Embodiment 26, compound f are to the inhibition of proliferation experiment in 72 hours of prostate cancer cell strain PC3 cell
Test method
Compound f is mixed with 0 μ g/mL, 2 μ g/mL, 5 μ g/mL, 10 μ g/mL, 20 μ g/mL 5 concentration altogether, every concentration triplicate with the DMSO solvent.Suspension 4 * 10 will be made behind the PC3 cell dissociation
4Individual/mL, get 10mL and add in the big culture dish, treat that 24h is adherent after, dosing is handled.Get 2 wares behind the 24h at random and take pictures, the record cell state.The former substratum of sucking-off changes pastille substratum (10%FBS 1640) and handles 72h, and cell is added 1.5mL pancreatin (37 ℃) digestion 4min, adds former pastille substratum 2mL again and stops digestion, beat even, set 20 at random by same people and look eye, the numeration cell number is averaged.Get pastille substratum 3mL in the culture dish lid, play 20 of even numerations and look a cell number, record dead cell number; Get pastille substratum 100 μ L and add trypan blue working fluid 20 μ L, 37 ℃, the cell count of being killed is write down in the 5min numeration.
Necrocytosis number=(total cell count-viable count)/total cell count
Inhibiting rate=(control group viable count-treatment group viable count)/control group viable count
Test-results
After tested, compound f is 84.3% to the PC3 cell inhibitory rate when drug concentration 20 μ g/mL, shows the good anticancer activity.
Embodiment 27, compound d are to the inhibition of proliferation experiment in 72 hours of prostate cancer cell strain PC3 cell
Test method is with embodiment 26.
Test-results
After tested, compound d is 69.1% to the PC3 cell inhibitory rate when drug concentration 20 μ g/mL, shows the good anticancer activity.
Embodiment 28, compound g are to the inhibition of proliferation experiment in 72 hours of prostate cancer cell strain PC3 cell
Test method is with embodiment 26.
Test-results
After tested, compound g is 59.7% to show the good anticancer activity to the PC3 cell inhibitory rate when drug concentration 20 μ g/mL.
The embodiment of the invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Claims (9)
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