CN105254585A - Thiazole amide compound and preparation method and application thereof - Google Patents
Thiazole amide compound and preparation method and application thereof Download PDFInfo
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- CN105254585A CN105254585A CN201510796748.1A CN201510796748A CN105254585A CN 105254585 A CN105254585 A CN 105254585A CN 201510796748 A CN201510796748 A CN 201510796748A CN 105254585 A CN105254585 A CN 105254585A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention relates to drugs, in particular to a thiazole amide compound and a preparation method and application thereof. The preparation method comprises the steps of firstly, preparing four-location or five-location 2-aminothiazole different in substitution, then, conducting nucleophilic substitution with chloroacetyl chloride or propionyl chloride, obtaining 2-halogenated acetaminothiazole or 3-halogenated propionyl aminothiazole derivatives, finally, conducting a reaction with amine, and obtaining 2-amido-substituted acetaminothiazole amide compounds and 3-amido-substituted propionyl aminothiazole derivatives. According to the thiazole amide compound and the preparation method and application thereof, the synthetic route is simple, convenient and easy to operate, production can be expanded, in-vitro growth inhibition tests are conducted on the human lung cancer cell H1299 and the human glioma cell SHG-44, and the high growth inhibition ratio is obtained under the low administration concentration.
Description
Technical field
The present invention relates to medicine, be specially thiazole amide compound and its preparation method and application.
Background technology
Compound containing thiazole heterocycle has multiple biological activity, has bibliographical information to be that the compound that female ring carries out structural modification transformation has anti-tumor activity, suppresses the effects such as quasi-eicosane acid metabolic, anti-schizotrypanum cruzi with thiazole.Thiazolamine (HeathEI, BibleK, etal.Investnewdrugs, 2008,26:59-65) compounds has good anti-tumor activity, is carrying out the I phase clinical study to refractory solid tumors at present.The most complex operation of existing synthetic route is unfavorable for the needs of industrial expanding production, and the thiazole amide compound anti-tumor activity of most report is not ideal.
Summary of the invention
For above-mentioned technical problem, of the present inventionly provide a kind of anti-tumor activity good thiazole amide compound.
Concrete technical scheme is:
Thiazole amide compound is formula I
In formula R be phenyl, benzyl, to methyl-benzyl, styroyl, furfuryl, thenyl, fragrant heterocycle; R ＇, thiazole ring 4 or 5, is methyl, phenyl, bromine cyclohexyl cyclopentyl; N=1,2.
The preparation method of this thiazole amide compound, comprises the following steps rapid:
(1) prepare 4 or 5 different thiazolamines replaced, then obtain the chloro-N-of 2-(4-replaces or 5-replaces-2-thiazole) ethanamide or the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide with chloroacetyl chloride or chlorpromazine chloride generation nucleophilic substitution;
(2) the chloro-N-of 2-(4-replaces or 5-replaces-2-thiazole) ethanamide, the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide and aliphatic amide or aromatic amine react 2-amido replaces acetylaminothiazole amides and 3-amido replaces propionamido thiazole derivative; Refine finally by column chromatography.
Wherein, acid binding agent used when the different thiazolamine that replaces of 4 or 5 and chloroacetyl chloride or chlorpromazine chloride react in step (1), acid binding agent used when reacting with the chloro-N-of 2-in step (2) (4-replaces or 5-replaces-2-thiazole) ethanamide, the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide and aliphatic amide or aromatic amine is all weakly alkaline organism or mineral alkali.
Acid binding agent is specially as one or more mixtures in pyridine, triethylamine, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
In step (2), reaction solvent used is aprotic solvent.Be specially tetrahydrofuran (THF), toluene, hexanaphthene.
This thiazole amide compound, has obvious anti-tumor activity, has good lethal effect to solid tumor cell, and being applied to medical aspect has as antitumor drug.
Thiazole amide compound provided by the invention and its preparation method and application, synthetic route is simple and easy to do and can expanding production, suppress test by carrying out growth in vitro to human lung carcinoma cell H1299 and human glioma cells SHG-44, under lower administration concentration, obtain higher growth inhibition ratio.
Embodiment
Below in conjunction with embodiment, the invention will be further described, but protection scope of the present invention is not limited to this.
Embodiment 1 prepares 2-(PhenethyIamino)-N-(5-methylthiazol-2-base) ethanamide
(1) preparation of the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide
2-amino-5-methylthiazol (34.2g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) are added in 500ml there-necked flask, ice bath, chloroacetyl chloride (40.6g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, steaming solvent is revolved by after methylene dichloride anhydrous magnesium sulfate drying, obtain white powder product 38.9g, productive rate 68%.
(2) 2-(PhenethyIamino)-N-(5-methylthiazol-2-base) ethanamide is prepared
Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), β-phenylethylamine (1.21g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow needle-like crystals sterling 1.3g by silicagel column, productive rate 46.6%, the sherwood oil that silicagel column is separated: ethyl acetate is 2:1, following examples are same.mp119.5-121℃；
1HNMR(MHz,ppm):δ7.332-7.191(m，5H，PhH)，7.088-7.085(s，1H,CH)，3.453(s，2H,CH
2)，2.963-2.929(m，2H,CH
2)2.850-2.816(m，2H,CH
2)，1.260(m，1H,NH)；
13CNMR(CDCl3)：δ11.703(CH
3)，36.291(PhCH
2)，51.256(NHCH
2),51.953(NHCH
2)，126.564(S-C＝),127.710(HC＝),128.757(2HC＝),134.418(N-HC＝),139.721(HC-HC＝),156.275(S-C＝N),169.721(C＝O)。
Embodiment 2 prepares 2-(4-methylbenzylamide)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow needle-like crystals sterling 1.3g by silicagel column, productive rate 48.3%, mp98.3-99.8 DEG C;
1hNMR (MHz, ppm): δ 7.261-7.128 (m, 4H, PhH), (7.030-7.028 s, 1H, CH), (3.788 s, 2H, CH2), (3.490 s, 2H, CH2), (2.388 s, 3H, CH3), (2.326 s, 3H, CH3);
13cNMR (CDCl3): δ 11.667 (CH3), 21.165 (PhCH2), 51.223 (NHCH2), 53.500 (NHCH2), 127.563 (S-C=), 128.266 (2HC=), 129.362 (2HC=), 134.162 (C-HC=), 135.889 (C-HC=), 137.194 (N-HC=), 156.640 (S-C=N), 169.690 (C=O).
Embodiment 3 prepares 2-(4-methoxybenzyl is amino)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), 4-Methoxybenzylamine (1.37g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow needle-like crystals sterling 1.5g by silicagel column, productive rate 53%, mp110.3-111 DEG C;
1hNMR (MHz, ppm): δ 7.265-7.222 (m, 2H, 2CH), 7.024 (s, 1H, CH), 6.874-6.853 (d, 2H, 2CH), 3.821-3.734 (m, 6H, 2CH
3), 2.391-2.377 (q, 4H, 2CH
2);
13cNMR (CDCl3): δ 11.680 (CH
3), 51.203 (NHCH
2), 53.282 (PhCH
2), 55.378 (OCH
3), 114.132 (2HC=), 127.166 (S-C=), 129.991 (2HC=), 131.007 (HC-HC=), 134.231 (N-HC=), 156.550 (O-C=), 159.111 (S-C=N), 169.685 (C=O).
Embodiment 4 prepares 2-(benzylamino)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow needle-like crystals sterling 1.2g by silicagel column, productive rate 57.2%, mp109-110 DEG C;
1hNMR (MHz, ppm): δ 7.345-7.262 (m, 6H, PhH, CH), 7.028-7.022 (s, 1H, COCH), 3.837 (s, 2H, CH
2), 3.506 (s, 2H, CH
2), 2.390-2.364 (s, 3H, CH
3);
13cNMR (CDCl3): δ 11.629 (CH
3), 51.237 (NHCH
2), 53.701 (NHCH
2ph), 127.475 (S-C=), 127.557 (HC=), 128.274 (HC=), 128.661 (HC=), 134.048 (N-HC=), 138.931 (C=), 156.700 (S-C=N), 169.904 (C=O).
Embodiment 5 prepares 2-(4-Methoxyphenylaminol)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), P-nethoxyaniline (1.23g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain black solid sterling 1.8g by silicagel column, productive rate 64.2%, mp165.5-167 DEG C;
1hNMR (MHz, ppm): δ 10.236 (s, 1H, NH), 7.052-7.049 (s, 1H, CH), 6.795-6.733 (m, 2H, 2CH), 6.588-6.566 (m, 2H, 2CH), 3.962-3.953 (s, 2H, CH
2), 3.738 (s, 3H, CH
3), 2.403-2.401 (s, 3H, CH
3);
13cNMR (CDCl3): δ 11.765 (CH
3), 49.422 (NHCH
2), 55.874 (OCH
3), 114.472 (2HC=), 115.220 (2HC=), 128.112 (S-C=), 134.410 (N-HC=), 140.750 (N-C=), 153.648 (O-C=), 156.327 (S-C=N), 169.141 (C=O).
Embodiment 6 prepares 2-(camphoryl is amino)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), camphor amine (1.52g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow solid sterling 2.0g by silicagel column, productive rate 65.4%, mp154-155.4 DEG C;
1hNMR (MHz, ppm): δ 10.025 (s, 1H, CONH), 7.263-7.085 (s, 1H, CH), 3.448 (s, 2H, CH
2), 2.544-2.511 (q, 1H, NH), 2.403-2.400 (s, 3H, CH
3), 1.759-1.529 (m, 7H, C5H
7), 1.076 (s, 1H, CH), 1.027 (s, 3H, CH
3), 0.982 (s, 3H, CH
3), 0.841 (s, 3H, CH
3);
13cNMR (CDCl3): δ 11.734 (CH
3), 12.563 (C-CH
3), 20.603 (C-CH
3), 20.707 (C-CH
3), 27.227 (CH
2), 36.886 (CH
2), 39.244 (CH
2), 45.085 (CH), 46.648 (C), 48.765 (CH-N), 51.470 (C), 67.606 (CH-NH), 127.701 (S-C=), 134.553 (N-HC=), 156.108 (S-C=N), 170.165 (C=O).
Embodiment 7 prepares 2-(furfuryl is amino)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), 2-furylamine (0.97g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain orange solids sterling 1.9g by silicagel column, productive rate 74.9%, mp104-106 DEG C;
1hNMR (MHz, ppm): δ 7.358-7.269 (s, 1H, CH), 7.069-7.066 (s, 1H, CH), 6.302-6.690 (s, 1H, CH), 6.212-6.204 (s, 1H, CH), 3.830 (s, 2H, CH
2), 3.501 (s, 2H, CH
2), 2.278 (s, 3H, CH
3);
13cNMR (CDCl3): δ 11.589 (CH
3), 45.853 (NHCH
2), 50.875 (NHCH
2), 107.873 (HC=), 110.240 (HC=), 127.497 (S-C=), 134.089 (N-HC=), 142.233 (O-HC=), 152.506 (O-C=), 156.640 (S-C=N), 169.500 (C=O).
Embodiment 8 prepares 2-(N-methyl-2-thenyl is amino)-N-(5-methylthiazol-2-base) ethanamide
Under conditions similar to those of example 1, synthesis preparation 2-chloro-N-(5-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(5-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), N-methyl-2-thenylaminine (1.27g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid sterling 1.7 by silicagel column, productive rate 61.5%, mp94.1-96 DEG C;
1hNMR (MHz, ppm): δ 10.175 (s, 1H, CONH), 7.267-7.246 (m, 1H, CH), 7.098 (s, 1H, CH), 6.948-6.940 (d, 2H, 2CH), 3.872 (s, 2H, CH
2), 3.258 (s, 2H, CH
2), 2.425 (s, 3H, CH
3), 2.398 (s, 3H, CH
3);
13cNMR (CDCl3): δ 11.714 (CH
3), 43.410 (N-CH
3), 56.463 (NHCH
2), 59.186 (NHCH
2), 125.848 (S-C=), 126.824 (S-HC=), 126.908 (HC=), 127.812 (HC=), 134.665 (N-HC=), 140.503 (S-C=), 155.817 (S-C-N), 168.513 (C=O).
Embodiment 9 prepares 2-(benzylamino)-N-(5-bromo thiazole-2-base) ethanamide
(1) the chloro-N-of 2-(the bromo-2-thiazole of 5-) ethanamide is prepared
Take 2-amino-5-bromo thiazole (53.7g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) add in 500ml there-necked flask, ice bath, chloroacetyl chloride (40.6g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, steaming solvent is revolved by after methylene dichloride anhydrous magnesium sulfate drying, obtain solid product 45.4g, productive rate 70%.
(2) 2-(benzylamino)-N-(5-bromo thiazole-2-base) ethanamide is prepared
Take the chloro-N-of 2-(the bromo-2-thiazole of 5-) ethanamide (1.8g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain red brown solid sterling 1.8g by silicagel column, productive rate 67.9%, mp113.4-115.2 DEG C;
1hNMR (MHz, ppm): δ 7.344 (s, 3H, CH3), 7.220-7.137 (m, 4H, PhH), 3.797 (s, 2H, CH2), 3.504 (s, 2H, CH2), 2.329 (s, 3H, CH3);
13cNMR (CDCl3): δ 21.203 (Ph-CH3), 51.058 (CH2CO), 53.671 (NHCH2), 103.456 (S-CH-Br), 128.278 (2HC=), 129.501 (2HC=), 135.471 (H2C-C=), 137.460 (H3C-C=), 138.176 (N-HC=), 158.148 (S-C=N), 170.172 (C=O).
Embodiment 10 prepares 2-(4-methoxybenzyl is amino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), 4-Methoxybenzylamine (1.37g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow oily liquid 2.7g by silicagel column, productive rate 74.6%
1hNMR (MHz, ppm): δ 9.803 (s, 1H, CONH), 7.616 (s, 1H ,=CH), 7.493-7.473 (d, 2H, PhH), 6.995-6.974 (d, 2H, ArH), 4.159 (s, 2H, CH2), 4.000 (s, 2H, CH2), 3.769 (s, 3H, CH3), 2.531-2.506 (s, 1H, NH);
13cNMR (CDCl3): δ 47.070 (CH2CO), 50.080 (NHCH2), 55.776 (OCH3), 102.757 (S-CH-Br), 114.560 (2HC=), 123.757 (H2C-C=), 132.413 (2HC=), 139.439 (N-HC=), 157.906 (O-C=), 160.374 (S-C=N), 165.282 (C=O).
Embodiment 11 prepares 2-(phenyl amino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), aniline (0.93g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain brown solid 1.3g by silicagel column, productive rate 54.9%, mp177.3-178.6 DEG C;
1hNMR (MHz, ppm): δ 7.330 (s, 1H,=CH), 7.280-7.208 (m, 2H, PhH), 6.883-6.846 (t, 1H, PhH), 6.636-6.617 (d, 2H, PhH), 4.266 (s, 1H, NH) 4.003 (s, 2H, CH
2);
13cNMR (CDCl3): δ 48.783 (CH
2cO), 103.985 (S-CH-Br), 113.659 (2HC=), 120.273 (HC=), 129.828 (2HC=), 138.343 (N-HC=), 146.512 (HN-C=), 157.995 (S-C=N), 169.440 (C=O).
Embodiment 12 prepares 2-(4-Methoxyphenylaminol)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), aniline (0.93g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain black solid 1.5g by silicagel column, productive rate 58.5%, mp143.3-145 DEG C;
1hNMR (MHz, ppm): δ 7.258 (s, 1H ,=CH), 6.755-6.754 (d, 2H, PhH), 6.667-6.645 (d, 2H, PhH), 3.867-3.672 (m, 3H, CH
2, NH), 2.928 (s, 3H, CH
3);
13cNMR (CDCl3): δ 49.541 (CH
2cO), 55.950 (OCH
3), 103.818 (S-CH-Br), 115.023 (2HC=), 116.715 (2HC=), 138.443 (N-HC=), 139.909 (HN-C=), 153.176 (O-C=), 157.843 (S-C=N), 169.734 (C=O).
Embodiment 13 prepares 2-(4-chlorphenylamino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), p-Chlorobenzoic acid amide (1.27g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow solid 1.7g by silicagel column, productive rate 60.4%, mp189.4-190.6 DEG C;
1hNMR (MHz, ppm): δ 9.837 (s, 1H, CONH), 7.332 (s, 1H ,=CH), (7.260-7.177 d, 2H, PhH), (7.657-7.652 d, 2H, PhH), (4.349 s, 1H, NH), 4.022-4.008 (s, 2H, CH
2);
13cNMR (CDCl3): δ 48.798 (CH
2cO), 104.058 (S-CH-Br), 114.187 (2HC=), 129.748 (3HC=), 138.485 (N-C=), 144.981 (HN-C=), 157.508 (S-C=N), 168.732 (C=O).
Embodiment 14 prepares 2-(beta-phenyl ethylamino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), β-phenylethylamine (1.21g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain orange solids 1.2g by silicagel column, productive rate 45.2%, mp130.3-132 DEG C;
1hNMR (MHz, ppm): δ 7.361 (s, 1H ,=CH), 7.336-7.300 (t, 2H, PhH), 7.259-7.253 (d, 2H, PhH), 7.206-7.188 (d, 2H, PhH), 3.469 (s, 2H, COCH
2), 2.968-2.934 (m, 2H, CH
2), 2.847-2.814 (s, 2H, CH
2);
13cNMR (CDCl3): δ 36.148 (Ph-CH
2), 51.194 (NHCH
2), 51.681 (CH2CO), 103.432 (S-CH-Br), 126.615 (HC=), 128.699 (2HC=), 128.776 (2HC=), 138.259 (N-HC=), 138.906 (-C=), 157.964 (S-C=N), 170.258 (C=O).
Embodiment 15 prepares 2-(furans-2-methylamino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), furylamine (0.97g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain brown solid 1.4g by silicagel column, productive rate 54%, mp92.4-95.3 DEG C;
1hNMR (MHz, ppm): δ 7.357-7.266 (m, 2H ,=CH), 6.301-6.288 (m, 1H ,=CH), 6.219-6.206 (d, 1H ,=CH), 3.870-3.836 (s, 2H, CH
2), 3.540-3.518 (s, 2H, CH
2);
13cNMR (CDCl3): δ 46.061 (NHCH
2), 50.797 (CH
2cO), 103.477 (S-CH-Br), 108.319 (HC=), 110.419 (HC=), 138.227 (N-HC=), 142.658 (O-HC=), 152.054 (O-C=), 158.142 (S-C=N), 170.021 (C=O).
Embodiment 16 prepares 2-(N-methyl-2-thenyl is amino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), N-methyl-2-thenylaminine (1.27g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain orange oily liquids 1.4g by silicagel column, productive rate 49.4%
1hNMR (MHz, ppm): δ 11.253 (s, 1H, CONH), (7.742-7.729 m, 1H ,=CH), (7.629 s, 1H ,=CH), (7.409-7.401 m, 1H ,=CH), (7.155-7.133 m, 1H ,=CH), 4.697 (s, 2H, CH
2), 4.240 (s, 2H, CH
2), 2.870 (s, 3H, CH
3);
13cNMR (CDCl3): δ 53.227 (N-CH
2), 54.530 (CH
2cO), 103.107 (S-CH-Br), 128.302 (S-HC=), 130.497 (HC=), 130.771 (HC=), 133.526 (N-HC=), 139.591 (S-C=), 157.890 (S-C=N), 164.714 (C=O).
Embodiment 17 prepares 2-(camphoryl is amino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), camphor amine (1.52g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain red solid 1.6g by silicagel column, productive rate 50.6%, mp110.9-112 DEG C;
1hNMR (MHz, ppm): δ 7.361 (s, 1H ,=CH), 3.471 (s, 2H, CH
2), 2.540-2.506 (m, 1H, CH), 1.765-1.688 (m, 2H, CH
2), 1.078-0.845 (m, 14H, C
9h
14);
13cNMR (CDCl3): δ 12.579,20.686,27.179,36.860,39.252,45.024,46.945,48.777,51.219 (C
10h
15), 67.705 (CH
2cO), 103.435 (S-CH-Br), 138.360 (N-HC=), 157.799 (S-C=N), 170.703 (C=O).
Embodiment 18 prepares 2-(adamantylamino)-N-(5-bromo thiazole-2-base) ethanamide
Under the condition similar to embodiment 9, synthesis preparation 2-chloro-N-(5-bromo thiazole-2 base) ethanamide.Take the chloro-N-of 2-(5-bromo thiazole-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), amantadine (1.51g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain orange solids 1.6g by silicagel column, productive rate 53.4%, mp134-135.6 DEG C;
1hNMR (MHz, ppm): δ 7.364 (s, 1H ,=CH), 3.473 (s, 2H, CH
2), 2.087-2.044 (s, H, NH), 1.664-1.603 (m, 15H, C
10h
15);
13cNMR (CDCl3): δ 29.490,36.441,42.632,43.573 (C
10h
15), 51.437 (CH
2cO), 103.382 (S-CH-Br), 138.308 (N-HC=), 157.859 (S-C=N), 171.637 (C=O).
Embodiment 19 prepares 2-(benzylamino)-N-(4-methylthiazol-2-base) ethanamide
(1) the chloro-N-of 2-(4-methyl-2-thiazole) ethanamide is prepared
Take 2-amino-4-methylthiazol (34.2g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) add in 500ml there-necked flask, ice bath, chloroacetyl chloride (40.6g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, steaming solvent is revolved by after methylene dichloride anhydrous magnesium sulfate drying, obtain solid product 38.9g, productive rate 68%.
(2) 2-(benzylamino)-N-(4-methylthiazol-2-base) ethanamide is prepared
Take the chloro-N-of 2-(4-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid 1.6g by silicagel column, productive rate 61.1%, mp196.2-197.5 DEG C;
1hNMR (MHz, ppm): δ 9.854 (s, 1H, CONH), 7.592-7.569 (m, 2H, PhH), 7.422-7.407 (m, 3H, PhH), 6.668 (s, 1H, CH), 4.245 (s, 2H, CH
2), 3.993 (s, 2H, CH
2), 2.295 (s, 3H, CH
3);
13cNMR (CDCl3): δ 17.356 (CH
3), 47.790 (NHCH
2), 51.017 (NHCH
2), 108.540 (S-HC=), 129.197 (HC=), 129.643 (HC=), 130.912 (HC=), 131..898 (HC=), 147.245 (N-C=), 157.368 (S-C=N), 164.995 (C=O).
Embodiment 20 prepares 2-(4-methoxybenzyl is amino)-N-(4-methylthiazol-2-base) ethanamide
Under the condition similar to embodiment 19, synthesis preparation 2-chloro-N-(4-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(4-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), 4-Methoxybenzylamine (1.38g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid 2.1g by silicagel column, productive rate 73.2%, mp201.7-203 DEG C;
1hNMR (MHz, ppm): δ 9.781 (s, 1H, CONH), 7.509-7.481 (d, 2H, PhH), 6.942-6.921 (d, 2H, PhH), 6.737-6.717 (s, 1H, CH), 4.179-4.169 (s, 2H, CH
2), 3.986-3.976 (s, 2H, CH
2), 3.797 (s, 3H, CH
3), 2.563-2.554 (s, 1H, NH), 2.326-2.311 (s, 3H, CH
3);
13cNMR (CDCl3): δ 16.651 (CH
3), 47.691 (CH
2-C=O), 50.640 (Ph-CH
2), 55.871 (NHCH
2), 109.252 (S-HC=), 114.719 (2HC=), (123.608-C=), 132.572 (2HC=), 145.976 (N-C=), 160.758 (O-C=), 164.961 (S-C=N), 165.845 (C=O).
Embodiment 21 prepares 2-(4-methylbenzylamide)-N-(4-methylthiazol-2-base) ethanamide
Under the condition similar to embodiment 19, synthesis preparation 2-chloro-N-(4-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(4-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid 1.9g by silicagel column, productive rate 71.2%, mp207.2-208.6 DEG C;
1hNMR (MHz, ppm): δ 9.680 (s, 1H, CONH), 7.439-7.420 (d, 2H, PhH), 7.229-7.209 (d, 2H, PhH), 6.694 (s, 1H, CH), 4.186 (s, 2H, CH
2), 3.961 (s, 2H, CH
2), 2.351 (s, 3H, CH
3), 2.290 (s, 3H, CH
3);
13cNMR (CDCl3): δ 17.421 (CH
3), 21.604 (CH
3), 47.645 (NHCH
2), 50.753 (NHCH
2), 108.618 (S-HC=), 128.845 (2HC=), 129.835 (2HC=), 130.965 (CH2-C=), 139.272 (CH
3-C=), 147.313 (N-C=), 157.343 (S-C=N), 164.635 (C=O).
Embodiment 22 prepares 2-(furfuryl is amino)-N-(4-methylthiazol-2-base) ethanamide
Under the condition similar to embodiment 19, synthesis preparation 2-chloro-N-(4-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(4-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), furylamine (0.97g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain gray solid 1.7g by silicagel column, productive rate 68.7%, mp179.9-181.2 DEG C;
1hNMR (MHz, ppm): δ 9.969 (s, 1H, CONH), (7.770-7.764 s, 1H, CH), (6.839-6.836 s, 1H, THF), (6.674-6.666 s, 1H, THF), (6.527-6.515 s, 1H, THF), 4.302 (s, 2H, CH
2), 4.002 (s, 2H, CH
2), 2.267-2.265 (s, 3H, CH
3);
13cNMR (CDCl3): δ 17.548 (CH
3), 43.181 (NHCH
2), 47.631 (NHCH
2), 109.146 (S-HC=), 111.867 (HC=), 113.414 (HC=), 145.040 (CHO-C=), 146.362 (N-C=), 147.368 (O-C-C=), 157.445 (S-C=N), 164.985 (C=O).
Embodiment 23 prepares 2-(adamantylamino)-N-(4-methylthiazol-2-base) ethanamide
Under the condition similar to embodiment 19, synthesis preparation 2-chloro-N-(4-methylthiazol-2 base) ethanamide.Take the chloro-N-of 2-(4-methylthiazol-2 base) ethanamide (1.9g0.01mol), triethylamine (3.0g0.03mol), amantadine (1.51g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow solid 2.6g by silicagel column, productive rate 84.5%, mp113.4-115 DEG C;
1hNMR (MHz, ppm): δ 6.524-6.519 (s, 1H, CH), 3.457 (s, 2H, CH
2), 2.363-2.361 (s, 3H, CH
3), 1.689-1.557 (m, 14H, C
10h
14);
13cNMR (CDCl3): δ 17.231 (CH
3), 29.511,36.527,42.679,43.844 (C
10h
15), 51.385 (NHCH
2), 108.111 (S-HC=), 147.339 (N-C=), 157.051 (S-C=N), 171.400 (C=O).
Embodiment 24 prepares 3-(amino to methoxybenzyl)-N-(4-methylthiazol-2-base) propionic acid amide
(1) the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide is prepared
Take 2-amino-4-methylthiazol (34.2g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) add in 500ml there-necked flask, ice bath, chlorpromazine chloride (45.4g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, steaming solvent is revolved by after methylene dichloride anhydrous magnesium sulfate drying, obtain solid product 42.9g, productive rate 70%.
(2) 3-(amino to methoxybenzyl)-N-(4-methylthiazol-2-base) propionic acid amide is prepared
Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), 4-Methoxybenzylamine (1.37g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow oily liquid 1.43g by silicagel column, productive rate 47.8%
1hNMR (MHz, ppm): δ 10.957 (s, 1H, CONH), 7.606-7.584 (d, 2H, PhH), 7.032-7.011 (d, 2H, PhH), 6.775-6.773 (d, 1H ,=CH), 4.330 (s, 2H, CH
2), 3.790 (s, 3H, CH
3), 3.366-3.330 (t, 2H, CH
2), 3.104-3.086 (t, 2H, CH
2), 2.257 (s, 3H, CH
3);
13cNMR (CDCl3): δ 17.159 (CH
3), 29.888 (CH
2cO), 47.707 (NHCH
2), 55.807 (Ph-CH
2), 56.531 (OCH3), 108.518 (S-HC=), 114.785 (2HC=), 121.921 (-C=), 133.473 (2HC=), 146.567 (O-C=), 157.704 (N-C=), 160.672 (S-C=N), 168.459 (C=O).
Embodiment 25 prepares 3-(PhenethyIamino)-N-(4-methylthiazol-2-base) propionic acid amide
Under the condition similar to embodiment 24, synthesis preparation 3-chloro-N-(4-methyl-2-thiazole) propionic acid amide.Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), β-phenylethylamine (1.20g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid 1.3g by silicagel column, productive rate 45.8%, mp150.2-151.8 DEG C;
1hNMR (MHz, ppm): δ 11.882 (s, 1H, CONH), 7.196-7.058 (m, 5H, PhH), 6.464-6.462 (s, 1H ,=CH), 3.043-3.012 (t, 2H, CH
2), 2.842-2.761 (t, 2H, CH
2), 2.630-2.601 (t, 2H, CH
2), 2.357-2.355 (s, 3H, CH
3);
13cNMR (CDCl3): δ 17.143 (CH
3), 32.856 (CH
2cO), 33.949 (Ph-CH
2), 50.762 (NHCH
2), 55.852 (NHCH
2), 107.999 (S-CH=), 126.394 (HC=), 128.634 (2HC=), 128.744 (2HC=), 139.195 (-C=), 147.455 (N-C=), 157.532 (S-C=N), 170.017 (C=O).
Embodiment 26 prepares N-(4-methylthiazol-2-base)-3-(4-methylbenzylamine base) propionic acid amide
Under the condition similar to embodiment 24, synthesis preparation 3-chloro-N-(4-methyl-2-thiazole) propionic acid amide.Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid by silicagel column, productive rate 52.3%, mp131.56-132.8 DEG C;
1hNMR (MHz, ppm): δ 11.831 (s, 1H, CONH), 7.212-7.192 (d, 2H, PhH), 7.043-7.025 (d, 2H, PhH), 6.449-6.439 (s, 1H ,=CH), 3.670-3.661 (t, 2H, CH
2), 2.986-2.935 (t, 2H, CH
2), 2.615-2.585 (t, 2H, CH
2), 2.350-2.336 (d, 6H, 2XCH
3);
13cNMR (CDCl3): δ 17.136 (CH
3), 21.144 (Ph-CH
3), 33.427 (CH
2cO), 49.775 (NHCH
2), 58.512 (Ph-CH
2), 107.908 (S-CH=), 129.342 (2HC=), 129.518 (2HC=), 133.213 (-C=), 137.492 (CH
3-C=), 147.146 (N-C=), 157.589 (S-C=N), 169.876 (C=O).
Embodiment 27 prepares 3-(camphoryl is amino)-N-(4-methylthiazol-2-base) propionic acid amide
Under the condition similar to embodiment 24, synthesis preparation 3-chloro-N-(4-methyl-2-thiazole) propionic acid amide.Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), camphor amine (1.53g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow oily liquid 1.8g by silicagel column, productive rate 56.4%
1hNMR (MHz, ppm): δ 7.747 (s, 1H, CONH), 6.650 (s, 1H ,=CH), 3.807-3.731 (t, 2H, CH
2), 3.526-3.429 (t, 2H, CH
2), 3.241-3.124 (t, 1H, CH), 2.526-2.250 (s, 3H, CH
3), 2.265-0.894 (m, 16H, C
9h
16);
13cNMR (CDCl3): δ 12.873 (CH
3), 14.390,18.641,19.472,20.207,20.973,26.222,27.580,28.300,32.952,36.739 (C
10h
15), 108.690 (S-CH=), 138.750 (N-C=), 160.791 (S-C=N), 170.818 (C=O).
Embodiment 28 prepares 3-(adamantylamino)-N-(4-methylthiazol-2-base) propionic acid amide
Under the condition similar to embodiment 24, synthesis preparation 3-chloro-N-(4-methyl-2-thiazole) propionic acid amide.Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), amantadine (1.51g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain white solid 2.0g by silicagel column, productive rate 63.9%, mp166.5-167.7 DEG C;
1hNMR (MHz, ppm): δ 9.061 (s, 1H, CONH), 6.776 (s, 1H ,=CH), 3.166 (s, 2H, CH
2), 2.970-2.935 (m, 2H, CH
2), 2.511-1.588 (m, 15H, C
10h
15);
13cNMR (CDCl3): δ 17.377 (CH
3), 36.111 (CH
2cO), 29.314,32.655,35.234,38.370,39.822,40.031,40.241,40.450,40.660,40.866 (C
10h
15), 57.172 (NHCH
2), 108.774 (S-CH=), 146.580 (N-C=), 158.200 (S-C=N), 169.002 (C=O).
Embodiment 29 prepares 3-(2-phenelyl is amino)-N-(4-methylthiazol-2-base) propionic acid amide
Under the condition similar to embodiment 24, synthesis preparation 3-chloro-N-(4-methyl-2-thiazole) propionic acid amide.Take the chloro-N-of 3-(4-methyl-2-thiazole) propionic acid amide (2.0g0.01mol), triethylamine (3.0g0.03mol), 2-phenetidine (1.37g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stirs, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming and remove tetrahydrofuran (THF) and obtain crude product, crude product is separated to obtain yellow oily liquid 1.4g by silicagel column, productive rate 47.2%
1hNMR (MHz, ppm): δ 10.431 (s, 1H, CONH), 6.787-6.765 (m, 2H, PhH), 6.643-6.620 (m, 2H, PhH), 6.516 (s, 1H ,=CH), 3.985-3.933 (m, 2H, CH
2), 3.503-3.473 (m, 2H, CH
2), 2.715-2.685 (m, 2H, CH
2), 2.305 (s, 3H, CH
3), 1.391-1.357 (t, 3H, CH
3);
13cNMR (CDCl3): δ 15.118 (OCH
2-CH
3), 17.202 (CH
3), 35.581 (CH
2cO), 41.071 (NHCH
2), 64.183 (OCH
2), 108.439 (S-CH=), 115.440 (2HC=), 115.906 (2HC=), 141.323 (HN-C=), 146.904 (O-C=), 152.329 (N-C=), 158.060 (S-C=N), 169.878 (C=O).
Embodiment 30 prepares 2-(N-methyl-2-thenyl is amino)-N-(4-phenyl thiazole-2-base) ethanamide
(1) the chloro-N-of 2-(4-phenyl-2-thiazole) ethanamide is prepared
Take 2-amino-4-phenyl thiazole (52.9g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) add in 500ml there-necked flask, ice bath, chloroacetyl chloride (40.6g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, revolve steaming solvent by after methylene dichloride anhydrous magnesium sulfate drying, obtain solid product D
142.5g, productive rate 65%.
(2) preparation preparation 2-(N-methyl-2-thenyl is amino)-N-(4-phenyl thiazole-2-base) ethanamide takes 2-amino-4-phenyl thiazole (2.5g0.01mol), triethylamine (3.0g0.03mol), N-thiotolene methylamine (1.27g0.01mol) adds in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 1.6g, productive rate 46.5%,
1hNMR (MHz, ppm): δ 11.196 (s, 1H, CONH), 7.914-7.895 (m, 2H, 2=CH), 7.745 (m, 2H, 2=CH), 7.464-7.417 (m, 5H, PhH), 4.719 (s, 2H, CH
2), 4.418 (s, 2H, CH
2), 2.895 (s, 3H, CH
3),
13cNMR (CDCl3): δ 53.410 (NHCH
2), 54.789 (CH
2cO), 109.633 (S-HC=), 126.519 (2HC=), 128.427 (HC=), 128.755 (HC=), 129.567 (2HC=), 130.565 (HC=), 130.923 (HC=), 133.601 (-C=), 134.782 (S-C=), 149.843 (N-C=), 157.528 (S-C=N), 164.428 (C=O).
Embodiment 31 prepares 2-(benzylamino)-N-(4-phenyl thiazole-2-base) ethanamide
Under the condition similar to embodiment 30, preparation 2-amino-4-phenyl thiazole.Take 2-amino-4-phenyl thiazole (2.5g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow solid 1.4g, productive rate 47.9%, mp97.5-98.9 DEG C;
1hNMR (MHz, ppm): δ 10.626 (s, 1H, CONH), 7.847-7.829 (d, 2H, PhH), 7.429-7.248 (d, 8H, PhH), 7.132 (s, 1H ,=CH), 3.842 (s, 2H, CH
2), 3.498 (s, 2H, CH
2), 1.978-1.929 (s, H, NH);
13cNMR (CDCl3): δ 51.276 (CH
2cO), 53.909 (NHCH
2), 107.835 (S-HC=), 126.172,127.635,128.100,128.248,128.786,128.828 (2C
5h
5), 134.501 (-C=), 138.718 (-C=), 150.060 (N-C=), 157.372 (S-C=N), 170.074 (C=O).
Embodiment 32 prepares 2-(4-xylyl is amino)-N-(4-phenyl thiazole-2-base) ethanamide
Under the condition similar to embodiment 30, preparation 2-amino-4-phenyl thiazole.Take 2-amino-4-phenyl thiazole (2.5g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 1.7g, productive rate 50.1%
1hNMR (MHz, ppm): δ 9.885 (s, 1H, CONH), 7.910-7.891 (d, 2H, PhH), 7.729 (s, 1H ,=CH), 7.470-7.424 (m, 4H, PhH), 7.358-7.321 (m, 1H, PhrH), (7.259-7.239 d, 2H, PhH), 4.210-4.186 (s, 2H, CH
2), 4.034-4.009 (s, 2H, CH
2), 2.325 (s, 3H, CH
3);
13cNMR (CDCl3): δ 21.642 (Ph-CH
3), 47.629 (CH
2cO), 50.658 (NHCH
2), 109.526 (S-CH-Br), 126.568 (HC=), 128.770 (2HC=), 129.307 (2HC=), 129.597 (2HC=), 130.020 (2HC=), (131.105-C=), 134.908 (CH
2-C=), 139.331 (CH
3-C=), 149.926 (N-C=), 157.744 (S-C=N), 165.231 (C=O).
Embodiment 33 prepares 3-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide
(1) the chloro-N-(4 of 3-is prepared, 5, 6, 7-tetrahydro benzo-2-thiazole) propionic acid amide takes 2-amino-4, 5, 6, the synthesis (46.3g0.3mol) of 7-tetrahydro benzothiazol, methylene dichloride (100ml), pyridine (23.7g0.3mol) adds in 500ml there-necked flask, ice bath, chlorpromazine chloride (45.4g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, three times are washed after completion of the reaction with water 50ml, steaming solvent is revolved by after methylene dichloride anhydrous magnesium sulfate drying, obtain white solid product E
248.6, productive rate 66%.
(2) 3-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide is prepared
Take the chloro-N-(4 of 3-, 5,6,7-tetrahydro benzo-2-thiazole) propionic acid amide (2.5g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to emilium tosylate (1.37g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 2.8g, productive rate 79.8%
1hNMR (MHz, ppm): δ 9.455 (s, 1H, CONH), 7.516-7.495 (s, 2H, PhH), 6.993-6.972 (s, 2H, PhH), 4.094-4.066 (s, 2H, CH), 3.772 (s, 3H, CH
3), 3.151-3.122 (m, 2H, CH
2), 2.974-2.940 (m, 2H, CH
2), 2.628-2.514 (d, 4H, 2CH), 1.761 (s, 4H, 2CH);
13cNMR (CDCl3): δ 23.707 (CH
2), 23.332 (CH
2), 23.740 (CH
2), 26.403 (CH
2), 32.255 (CH
2-C=O), 40.870 (NHCH
2), 50.440 (NHCH
2), 56.220 (OCH
3), 114.935 (2HC=), 122.562 (HC=), 124.665 (HC=), 132.727 (-C=), 143.273 (N-C=), 156.109 (O-C=), 160.639 (S-C=N), 169.093 (C=O).
Embodiment 34 prepares 3-(4-xylyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide
Under the condition similar to embodiment 32, preparation 3-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) propionic acid amide.Take 3-(4-methoxybenzyl is amino)-N-(4, 5, 6, 7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide (2.5g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methylbenzylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitors extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow solid 2.1g, productive rate 64.1%, mp88.9-100.2 DEG C,
1hNMR (MHz, ppm): δ 7.263-7.258 (d, 2H, PhH), 7.153-7.134 (d, 2H, PhH), 3.852-3.848 (s, 2H, CH
2), 2.980-2.951 (s, 2H, CH
2), 2.667-2.549 (d, 4H, 2CH
2), 2.333 (s, 3H, CH
3), 1.851-1.845 (s, 4H, 2CH
2), 1.255 (s, 1H, NH),
13cNMR (CDCl3): δ 22.937 (CH
2), 23.118 (CH
2), 23.395 (CH
2), 26.477 (CH
2), 29.725 (PhCH
3), 34.689 (CH
2-C=O), 43.821 (NHCH
2), 52.801 (NHCH
2ph), 122.510 (S-C=), 128.416 (2HC=), 129.308 (2HC=), 135.587 (-C=), 137.608 (-C=), 144.118 (N-C=), 155.257 (S-C=N), 170.157 (C=O).
Embodiment 35 prepares 3-(2-thenyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide
Under the condition similar to embodiment 32, preparation 3-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) propionic acid amide.Take 3-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide (2.5g0.01mol), triethylamine (3.0g0.03mol), thiophene methyl amine (1.35g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains brown solid 1.7g, productive rate 48.1%, mp103.7-104.6 DEG C;
1hNMR (MHz, ppm): δ 7.263-7.222 (t, 1H, CH), 6.977-6.950 (m, 2H, 2CH), 4.085 (s, 2H, CH
2), 3.019-2.911 (t, 2H, CH
2), 2.700-2.647 (m, 4H, 2CH
2), 2.572-2.543 (t, 2H, CH
2), 1.852-1.836 (m, 4H, 2CH
2);
13cNMR (CDCl3): δ 22.995 (CH
2), 23.182 (CH
2), 23.436 (CH
2), 26.605 (CH
2), 35.011 (CH
2-C=O), 43.754 (NHCH
2), 47.476 (NHCH
2), 122.700 (S-C=), 124.926 (S-HC=), 125.797 (HC=), 126.942 (HC=), 142.440 (S-C=), 144.204 (N-C=), 155.326 (S-C=N), 170.024 (C=O).
Embodiment 36 prepares 3-(benzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide
Under the condition similar to embodiment 32, preparation 3-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) propionic acid amide.Take 3-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide (2.5g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 1.4g, productive rate 45.6%
1hNMR (MHz, ppm): δ 7.376-7.257 (m, 5H, PhH), 3.881 (s, 2H, CH
2), 2.986-2.957 (t, 2H, CH
2), 2.676-2.644 (m, 4H, 2CH
2), 2.566-2.537 (t, 2H, CH
2), 1.85.-1.836 (s, 4H, 2CH
2), 1.256 (s, 1H, NH);
13cNMR (CDCl3): δ 22.942 (CH
2), 23.131 (CH
2), 23.398 (CH
2), 26.530 (CH
2), 34.764 (CH
2-C=O), 43.925 (NHCH
2), 53.139 (NHCH
2ph), 122.543 (S-C=), 127.417 (HC=), 128.433 (2HC=), 128.628 (2HC=), 138.774 (-C=), 144.151 (N-C=), 155.248 (S-C=N), 170.104 (C=O).
Embodiment 37 prepares 3-(furfuryl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide
Under the condition similar to embodiment 32, preparation 3-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) propionic acid amide.Take 3-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) propionic acid amide (2.5g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 1.8g, productive rate 55.4%
1hNMR (MHz, ppm): δ 9.521 (s, 1H, CONH), 7.781-7.777 (s, 1H, CH), 6.674-6.540 (s, 1H, CH), 6.535-6.527 (s, 1H, CH), 4.304-4.223 (s, 2H, CH
2), 3.193-3.145 (m, 2H, CH
2), 3.941-3.905 (t, 2H, CH
2), 2.630-2.506 (m, 4H, 2CH
2), 1.763 (s, 4H, 2CH
2), 1.074-1.039 (s, 1H, NH);
13cNMR (CDCl3): δ 27.605 (CH
2), 27.708 (CH
2), 28.127 (CH
2), 30.760 (CH
2), 36.650 (CH
2-C=O), 46.869 (NHCH
2), 47.669 (NHCH
2), 116.422 (HC=), 117.707 (HC=), 127.011 (S-C=), 147.573 (O-HC=), 149.524 (O-HC=), 151.139 (N-C=), 160.576 (S-C=N), 173.469 (C=O).
Embodiment 38 prepares 2-(4-Methoxyphenylaminol)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
(1) the chloro-N-of 2-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide is prepared
Take 2-amino-4,5,6,7-tetrahydro benzothiazol (46.3g0.3mol), methylene dichloride (100ml), pyridine (23.7g0.3mol) add in 500ml there-necked flask, ice bath, chloroacetyl chloride (40.6g0.36mol) is dissolved in 50ml methylene dichloride and slowly drops to reaction flask, 2h dropwises, continue reaction 2h, TLC monitors extent of reaction, wash three times with water 50ml after completion of the reaction, revolve steaming solvent by after methylene dichloride anhydrous magnesium sulfate drying, obtain white solid product E
147.8g, productive rate 69%.
(2) preparation preparation 2-(4-Methoxyphenylaminol)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to methyl oxyaniline (1.23g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow solid 1.7g, productive rate 53.5%, mp149.9-151.3 DEG C;
1hNMR (MHz, ppm): δ 9.912 (s, 1H, CONH), 6.786-6.764 (d, 2H, PhH), 6.571-6.549 (d, 2H, PhH), 4.147-4.130 (s, 1H, NH), 3.934 (s, 2H, CH
2), 3.735 (s, 3H, CH
3), 2.697-2.692 (s, 2H, CH
2), 2.607-2.602 (s, 2H, CH
2), 1.847-1.818 (m, 4H, 2CH
2);
13cNMR (CDCl3): δ 23.085 (CH
2), 23.111 (CH
2), 23.451 (CH
2), 26.470 (CH
2), 49.572 (CH
2-C=O), 55.846 (CH
3-O), 114.691 (2HC=), 115.193 (2HC=), 123.395 (S-C=), 140.637 (-C=), 144.484 (O-C=), 153.689 (N-C=), 154.478 (S-C=N), 169.103 (C=O).
Embodiment 39 prepares 2-(furfuryl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Under the condition similar to embodiment 38, preparation 2-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide.Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), 2-furylamine (0.97g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow solid 1.9g, productive rate 66.7%, mp101.6-103.3 DEG C;
1hNMR (MHz, ppm): δ 10.198 (s, 1H, CONH), 7.360-7.353 (m, 1H, CH), 6.307-6.294 (m, 1H, CH), 6.207-6.194 (m, 1H, CH), 3.808 (s, 2H, CH
2), 3.488 (s, 2H, CH
2), 2.695-2.656 (m, 4H, 2CH
2), 1.851-1.254 (m, 5H, 2CH
2, NH);
13cNMR (CDCl3): δ 23.002 (CH
2), 23.093 (CH
2), 23.400 (CH
2), 26.435 (CH
2), 46.003 (NHCH
2), 50.846 (NHCH
2), 107.957 (HC=), 110.292 (HC=), 122.954 (S-C=), 142.424 (O-HC=), 144.338 (O-C=), 152.236 (N-C=), 154.558 (S-C=N), 169.376 (C=O).
Embodiment 40 prepares 2-(N-methyl-2-thenyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Under the condition similar to embodiment 38, preparation 2-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide.Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), N-methyl-2-thenylaminine (1.27g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 1.9g, productive rate 61.6%
1hNMR (MHz, ppm): δ 11.108 (s, 1H, CONH), 7.743-7.727 (d, 1H,=CH), 7.395-7.387 (m, 1H ,=CH), 7.156-7.134 (m, 1H ,=CH), 4.685 (s, 2H, CH
2), 4.188 (m, 2H, CH
2), 2.860 (s, 3H, CH
3), 2.652-2.507 (m, 4H, 2CH
2), 1.772 (s, 4H, 2CH
2);
13cNMR (CDCl3): δ 23.145 (CH
2), 23.301 (CH
2), 23.675 (CH
2), 26.483 (CH
2), 41.113 (N-CH
3), 53.343 (N-CH
2), 55.004 (CH
2cO), 122.905 (S-C=), 128.460 (S-HC=), 130.551 (HC=), 131.035 (HC=), 133.603 (S-C=), 143.962 (N-C=), 155.453 (S-C=N), 164.464 (C=O).
Embodiment 41 prepares 2-(benzylamino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Under the condition similar to embodiment 38, preparation 2-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide.Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), benzylamine (1.07g0.01mol) add in 100ml reaction flask, add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow solid 1.9g, productive rate 65.4%, mp101.4-103 DEG C;
1hNMR (MHz, ppm): δ 7.365-7.263 (m, 5H, PhH), 3.825 (s, 2H, CH
2), 3.484 (s, 2H, CH
2), 2.707-2.615 (m, 4H, 2CH
2), 1.870-1.833 (m, 5H, 2CH
2, NH);
13cNMR (CDCl3): δ 21.139 (CH
2), 23.109 (CH
2), 23.402 (CH
2), 26.458 (CH
2), 51.215 (CH
2cO), 53.607 (NHCH
2), 122.967 (S-C=), 128.187 (2HC=), 129.368 (2HC=), 135.708 (HC=), 137.190 (-C=), 144.337 (N-C=), 154.540 (S-C=N), 169.517 (C=O).
Embodiment 42 prepares 2-(4-xylyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Under the condition similar to embodiment 38, preparation 2-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide.Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to xylylamine (1.21g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains orange solids 2.0g, productive rate 64.6%, mp114.3-116 DEG C;
1hNMR (MHz, ppm): δ 7.189-7.129 (m, 4H, PhH), 3.776 (s, 2H, CH
2), 3.464 (s, 2H, CH
2), 2.692-2.643 (m, 4H, 2CH
2), 2.330 (s, 3H, CH
3), 1.869-1.842 (m, 4H, 2CH
2);
13cNMR (CDCl3): δ 21.139 (CH
2), 23.006 (CH
2), 23.109 (CH
2), 23.402 (CH
2), 26.458 (Ph-CH
3), 51.215 (CH
2cO), 53.607 (NHCH
2), 122.967 (S-C=), 128.187 (2HC=), 129.368 (2HC=), 135.708 (HC=), 137.190 (-C=), 144.337 (N-C=), 154.540 (S-C=N), 169.517 (C=O).
Embodiment 43 prepares 2-(4-methoxybenzyl is amino)-N-(4,5,6,7-tetrahydro benzo [d] thiazol-2-yl) ethanamide
Under the condition similar to embodiment 38, preparation 2-chloro-N-(4,5,6,7-tetrahydro benzo-2-thiazole) ethanamide.Take the chloro-N-(4 of 2-, 5,6,7-tetrahydro benzo-2-thiazole) ethanamide (2.3g0.01mol), triethylamine (3.0g0.03mol), add in 100ml reaction flask to emilium tosylate (1.37g0.01mol), add tetrahydrofuran (THF) (50ml), backflow, stir, reaction 4h, TLC monitor extent of reaction, after completion of the reaction, revolve steaming to remove tetrahydrofuran (THF) and obtain crude product, crude product is separated (sherwood oil: ethyl acetate=3:1) by silicagel column and obtains yellow oily liquid 2.1g, productive rate 63.6%
1hNMR (MHz, ppm): δ 9.676 (s, 1H, CONH), 7.478-7.457 (m, 2H, PhH), 6.993-6.971 (m, 2H, PhH), 4.144-4.132 (s, 2H, CH
2), 3.947-3.936 (s, 2H, CH
2), 3.770 (s, 3H, CH
3), 2.647-2.497 (m, 4H, 2CH
2), 1.769 (m, 4H, 2CH
2);
13cNMR (CDCl3): δ 23.228 (CH
2), 23.430 (CH
2), 23.781 (CH
2), 26.676 (CH
2), 47.673 (CH
2cO), 50.389 (NHCH
2), 56.207 (OCH
3), 114.953 (2HC=), 122.954 (S-C=), (124.264-C=), 132.960 (2HC=), 144.358 (N-C=), 155.258 (S-C=N), 160.733 (O-C=), 165.088 (C=O).
Embodiment above describes ultimate principle of the present invention, principal character and advantage; the technician of the industry should understand; the present invention is not restricted to the described embodiments; what describe in above-described embodiment and specification sheets just illustrates principle of the present invention; under the scope not departing from the principle of the invention; the present invention also has various changes and modifications, and these changes and improvements all fall in the scope of protection of the invention.
Embodiment 44 thiazole amide compound is to the restraining effect of tumour cell
The human lung carcinoma cell H1299 taken the logarithm vegetative period and human glioma cells SHG-44 is suspended in the DMEM substratum containing 10% foetal calf serum, blows and beats into single cell suspension gently with glass dropper, blood cell counting plate living cell counting under microscope.96 orifice plate every hole inoculating cell suspension 180 μ L, cell concn is 10000 cells/well, 37 DEG C, 100% relative humidity, containing the incubator preculture of 5%CO2 after 24 hours, every hole adds 20 μ L sample solutions, and final concentration is set to 5 μm of ol/L.And establish negative control (isoconcentration DMSO) and blank background, do not add cell, all establish 3 multiple holes for each group.Cultured continuously 48 hours, then measures with mtt assay again.Every hole adds the MTT solution of 20 μ L5mg/mL, continues cultivation after 4 hours, carefully sucks supernatant liquor.Every hole adds 100 μ LDMSO, puts micro oscillator vibration 5min and crystallization is dissolved completely, in microplate reader 492nm Single wavelength colorimetric, measure OD value.Calculate the inhibiting rate of cell proliferation: inhibiting rate (%)=(OD value control wells-OD is worth dosing holes)/OD value control wells × 100%.Result is as shown in table 1, show R in formula 1 be to xylyl, R ＇ is 4,5 and the compound of cyclohexyl, n=2 to human lung carcinoma cell H1299 and human glioma cells SHG-44 inhibition better.
Table 1 sample to the growth inhibition ratio of H1299, SHG-44 (%,
)
| R＇ | R | n | H1299 inhibiting rate | SHG-44 inhibiting rate |
| 5 bromines | To xylyl | 1 | 84.60±3.97 | 57.16±0.666 |
| 5 bromines | To methoxybenzyl | 1 | 70.03±14.34 | 43.24±9.67 |
| 5 bromines | Phenyl | 1 | 60.04±1.42 | 39.13±6.79 |
| 5 bromines | Rubigan | 1 | 64.18±4.34 | 40.94±3.36 |
| 4,5 and cyclohexyl | To xylyl | 2 | 81.09±9.70 | 92.74±13.06 |
| 4,5 and cyclohexyl | 2-thenyl | 2 | 77.77±0.32 | 69.55±0.02 |
| 4,5 and cyclohexyl | Benzyl | 2 | 79.35±15.40 | 68.66±8.06 |
| 4,5 and cyclohexyl | P-methoxyphenyl | 1 | 45.35±0.86 | 57.85±4.61 |
Claims (7)
1. thiazole amide compound, is characterized in that, the chemical formula of this compound is:
In formula, R is phenyl, benzyl, styroyl, furfuryl, thenyl, fragrant heterocycle; R ＇, thiazole ring 4 or 5, is methyl, phenyl, bromine, cyclohexyl; N=1,2.
2. thiazole amide compound according to claim 1, is characterized in that, preparation method comprises the following steps:
(1) prepare 4 or 5 different thiazolamines replaced, then obtain the chloro-N-of 2-(4-replaces or 5-replaces-2-thiazole) ethanamide or the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide with chloroacetyl chloride or chlorpromazine chloride generation nucleophilic substitution;
(2) the chloro-N-of 2-(4-replaces or 5-replaces-2-thiazole) ethanamide, the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide and aliphatic amide or aromatic amine react 2-amido replaces acetylaminothiazole amides and 3-amido replaces propionamido thiazole derivative; Refine finally by column chromatography.
3. thiazole amide compound according to claim 2, it is characterized in that, acid binding agent used when the different thiazolamine that replaces of 4 or 5 and chloroacetyl chloride or chlorpromazine chloride react in step (1), acid binding agent used when reacting with the chloro-N-of 2-in step (2) (4-replaces or 5-replaces-2-thiazole) ethanamide, the chloro-N-of 3-(4-replaces or 5-replaces-2-thiazole) propionic acid amide and aliphatic amide or aromatic amine is all weakly alkaline organism or mineral alkali.
4. thiazole amide compound according to claim 3, is characterized in that, described acid binding agent is one or more mixtures in pyridine, triethylamine, sodium carbonate, sodium bicarbonate, salt of wormwood, saleratus.
5. thiazole amide compound according to claim 2, is characterized in that, in step (2), reaction solvent used is aprotic solvent.
6. thiazole amide compound according to claim 5, is characterized in that, described solvent is tetrahydrofuran (THF), toluene, hexanaphthene.
7. the thiazole amide compound according to any one of claim 1 to 6, is characterized in that, has as antitumor drug for medical aspect.
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