CN102603667B - N-(2-chloro-6-methyl phenyl)-2-(phenyl acrylamide)thiazole-5-formamide derivative, and preparation method and use thereof - Google Patents
N-(2-chloro-6-methyl phenyl)-2-(phenyl acrylamide)thiazole-5-formamide derivative, and preparation method and use thereof Download PDFInfo
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Abstract
The invention discloses an N-(2-chloro-6-methyl phenyl)-2-(phenyl acrylamide)thiazole-5-formamide derivative, and a preparation method of the derivative and use of the derivative, wherein the general structural formula of the N-(2-chloro-6-methyl phenyl)-2-(phenyl acrylamide)thiazole-5-formamide derivative is as follows: wherein R1, R2, R3 and R4 are independently selected from hydrogen, chlorine, fluorine, methyl, methoxyl or trifluoromethyl; at least two of R1, R2, R3 and R4 are hydrogen. In comparison with the existing anti-leukemia drug dasatinib, the compound disclosed by the invention has remarkable inhibitory effect on K562 leukemia cells and is suitable for being further chosen as an anti-leukemia drug; the condition required for synthesis of the compound is mild, and the yield of the compound is high.
Description
One, technical field
The present invention relates to a kind of medical compounds, is exactly a kind of N-(the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, Its Preparation Method And Use.
Two, background technology
Chronic myelocytic leukemia (chronic myeloid Leukemia, CML) is a kind of acquired hemopoietic stem cell malignant clone proliferative disease, by the day after tomorrow of a stem cell DNA in marrow changing, causes.This variation of stem cell DNA is to superiority condition that surpasses normal stem cell Growth and survival of malignant cell, and result makes the uncontrollable growth of white corpuscle, if do not add treatment, can cause the surge of white corpuscle in concentration.Annual nearly 100,000 CML patient's morbidities.CML can be divided into chronic phase clinically, acceleration period and acute transformation phase.There is the performances such as clinical and blood of acute leukemia in patient, is referred to as the CML sudden turn of events.Most of patients lifetime is 3-4, and poor prognosis after the sudden turn of events occurs CML.
Nineteen sixty, Nowell and Hungerford find to contain in CML patient's abnormal white cell a kind of abnormal " Philadelphia " karyomit(e) (Ph) that is named as.Subsequently, Rowley finds that Ph is the mutual transposition t (9 of gene that is named as BCR by the ABL-tyrosine kinase gene on No. 9 karyomit(e)s that split away off and No. 22 karyomit(e)s; 22) (q34; Q11) form.The eighties; the discoveries such as Witte; the species specific kinase gene of having encoded on the Philadelphia chromosome that this transposition forms; be BCR-ABL gene, produce BCR-ABL kinases in patient body, this kinases is by the phosphorylated of catalytic substrate; at intracellular delivery signal; excite the increment of patient's myeloid cell, cause CML[Leukemia Research 2004,28 (Supplement1): 29-38.].
At present, there are some research institutions to be engaged in the antitumor drug research that BCR-ABL Tyrosylprotein kinase is target both at home and abroad, and the medicine of invention anti-cell strain K562, thereby reach, cure chronic leukocytic object.Along with going deep into that BCR-ABL fusion rotein is studied, BCR-ABL also becomes the important target of clinical treatment.Tyrosine kinase inhibitor imatinib (STI-571) has brought revolutionary progress for the treatment of CML, become that in human history, first directly carries out the successful model of the antitumor drug of target treatment for Disease-causing gene, now become patient's CML first-line treatment medicine.Select again subsequently s-generation anti-leukemia medicine: nilotinib and Dasatinib.
Dasatinib is to select and obtain from the compound of patent WO0062778 report, in June, 2006, through U.S. FDA approval, goes on the market.In CML xenotransplantation mouse model, show potent activity in vivo and good pharmaco-kinetic properties, its action intensity is imatinib 325 times.
Cinnamic acid derivative or its analog are prevalent in occurring in nature, as coffic acid, forulic acid etc., have the multiple pharmacologically actives such as antibacterial, antiviral, antitumor and anti-oxidant; Also has cinnamophenone [Chinese pharmaceutical chemistry magazine, 2010,3 (20): 161-165], trans-resveratrol (Shenyang Pharmaceutical University's journal, 2008,10 (25): 51-53) and curcumine (Medical review, 2003,9:1-2) etc., they have similar phenylallene structure, are extensively present in multiple medicinal plant, and this compounds has the multiple pharmacological effect such as antitumor, anti-HIV, antibacterial, anti-inflammatory, antiulcer agent.Yao Sheng and Wu Shenghua etc. (Chinese invention patent 102225925) have invented a series of benzene acryloyl amino derivatives, and show that by pharmacological evaluation most compounds have obvious restraining effect to K562 cell.
Three, summary of the invention
The present invention aims to provide a kind of N-(the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, Its Preparation Method And Use, be by medicine principle of hybridization, thereby will there is the cinnamic acid structure of anti-leukocythemia liveness and the compound that the docking of Dasatinib intermediate obtains having higher anti-leukocythemia liveness.
Technical solution problem of the present invention adopts following technical scheme:
N-of the present invention (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that its structure is represented by general formula (I):
R in general formula (I)
1, R
2, R
3and R
4independently be selected from hydrogen, chlorine, fluorine, methyl, methoxyl group or trifluoromethyl, R
1, R
2, R
3and R
4in at least two be hydrogen.
R in general formula (I)
1and R
4be preferably-H R
2and R
3be preferably-CH
3.
R in general formula (I)
1, R
2and R
4be preferably-H R
3be preferably-Cl or methoxyl group.
R in general formula (I)
3and R
4be preferably-H R
1be preferably-CH
3, R
2for-F.
R in general formula (I)
2and R
3be preferably-H R
1and R
4be preferably methoxyl group.
R in general formula (I)
2and R
3be preferably-H R
1be preferably-CH
3, R
4for-F.
R in general formula (I)
1and R
3be preferably-H R
2and R
4be all methoxyl group or R
2and R
4be all-Cl.
R in general formula (I)
1, R
3and R
4be preferably-H R
2be preferably trifluoromethyl or for methoxyl group.
The preparation method of N-of the present invention (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, take substituted benzaldehyde as raw material, comprise the preparation of intermediate, synthetic and each unit process of aftertreatment of target product, difference with the prior art is:
The preparation of described intermediate be by substituted benzaldehyde and propanedioic acid according to mol ratio 1: 1-2 is placed in pyridine solvent, under the condition existing at the piperidines of substituted benzaldehyde 1-2% molar weight, at 80-100 ℃, react and within 5-8 hour, obtain intermediate (1) substituted benzene vinylformic acid, then intermediate (1) and chloride reagent under nitrogen protection according to mol ratio 1: 15-20 normal-temperature reaction obtains intermediate (2) substituted benzene acrylate chloride for 5-8 hour; Intermediate (2) and 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides are according to mol ratio 1-1.5: 1 is placed in tetrahydrofuran solvent, room temperature reaction 8-10 hour under the condition existing at the organic bases with intermediate (2) equimolar amount or carbonate;
Described aftertreatment is to boil off the tetrahydrofuran (THF) in reaction solution after reaction finishes, and then adds methylene dichloride and water, and organic phase is separated out solid, and suction filtration obtains target product;
The general structure of described substituted benzaldehyde is
r wherein
1, R
2, R
3and R
4independently be selected from hydrogen, chlorine, fluorine, methyl, methoxyl group or trifluoromethyl, R
1, R
2, R
3and R
4in at least two be hydrogen;
Described chloride reagent is selected from oxalyl chloride, triphosgene, thionyl chloride, phosphorus oxychloride or phosphorus trichloride;
Described organic bases is selected from triethylamine, Tributylamine, N, N-diisopropyl ethyl amine, DMA, N, N-Diethyl Aniline or pyridine;
Described carbonate is selected from sodium carbonate, salt of wormwood, calcium carbonate or magnesiumcarbonate.
The purposes of N-of the present invention (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: the application in preparing anti-leukocythemia liveness medicine.
Preparation method's of the present invention reaction process is as follows:
Compared with the prior art, beneficial effect of the present invention is embodied in:
1, the synthetic required mild condition of new compound of the present invention, productive rate is also higher, and its novel structure, has no report;
2, new compound of the present invention and the comparison of existing anti-leukemia medicine Dasatinib, fairly obvious to K562 leukemia cell's restraining effect, is applicable to further selecting it for anti-leukemia medicine.
Four, embodiment
With specific embodiment, technical scheme of the present invention is described below, but protection scope of the present invention is not limited to this:
Embodiment 1N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3,4-dimethyl benzene acrylamide) thiazole-5-methane amide
Synthetic route:
1, intermediate 1-3, the acrylic acid preparation of 4-dimethyl benzene
In 100mL there-necked flask, add respectively 3,4-dimethylbenzaldehyde 1.34g (10.0mmol), propanedioic acid 2.08g (20.0mmol), pyridine 8mL and piperidines 0.5mL, oil bath is heated to reflux temperature reaction, reacting after 6 hours uses thin-layer chromatography (TLC) to detect 3,4-dimethylbenzaldehyde react completely (developping agent is the solvent that ethyl acetate, sherwood oil and glacial acetic acid are mixed to get for 1: 6: 1 by volume), stopped reaction, in reaction system, add toluene 8mL, then add K
2cO
3solution, regulates pH to 9-10, and after stirring 30min, separatory is left and taken water layer, with the HCl of 1mol/L, regulates pH to 3, now has a large amount of white solids to separate out, and filters, and washing, is dried to obtain product 1.59g, productive rate 90.7%.
2, intermediate 2-3, the preparation of 4-dimethyl benzene acrylate chloride
Get 3; 4-dimethyl benzene vinylformic acid 1.2g (7.2mmol) is added in 100mL single port flask; then add methylene dichloride 40mL to dissolve, under room temperature nitrogen protection, add 6mL oxalyl chloride; after reaction for some time, detect; to raw material 3,4-dimethyl benzene vinylformic acid reacts completely, and then boils off solvent and excessive oxalyl chloride; prepare 3,4-dimethyl benzene acrylate chloride.
3, the preparation of target product-N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3,4-dimethyl benzene acrylamide) thiazole-5-methane amide
Add tetrahydrofuran (THF) and dissolve the acyl chlorides preparing, at 0-5 ℃, slowly drip the mixing solutions of tetrahydrofuran (THF), 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides 1.6g (6.0mmol) and triethylamine 0.73g (7.2mmol), after transfer room temperature reaction to, detect to 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides and react completely, boil off tetrahydrofuran (THF), add methylene dichloride and water, organic phase is separated out solid, suction filtration obtains target product 2.4g, fusing point is 315～317 ℃, productive rate 92.3%.
1H?NMR(400MHz，DMSO-d
6)δ：12.64(s，1H)，10.07(s，1H)，8.32(s，1H)，7.68-7.75(d，1H，J＝15.8Hz)，7.37-7.42(m，3H)，7.23-7.30(m，3H)，6.85-6.90(d，1H，J＝16.0Hz)，2.24-2.27(s，9H)。
Embodiment 2N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3,5-dimethoxy benzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 3,5-dimethoxy benzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 309～310 ℃, productive rate 92.1%.
1H?NMR(400MHz，DMSO-d
6)δ：12.64(s，1H)，10.07(s，1H)，8.32(s，1H)，7.68-7.75(d，1H，J＝15.8Hz)，7.24-7.43(m，3H)，6.82-6.96(m，3H)，6.6(d，1H，J＝4.4Hz)，3.8(s，6H)，2.27(s，3H)。
Embodiment 3N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3-trifluoromethylbenzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 3-trifluoromethylated benzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 284～286 ℃, productive rate 92.5%.
1H?NMR(400MHz，DMSO-d
6)δ：12.60(s，1H)，10.01(s，1H)，8.31(s，1H)，7.78-8.05(m，4H)，7.68-7.75(d，1H)，7.2-7.45(m，3H)，7.03-7.08(d，1H，J＝15.9Hz)，2.27(s，3H)。
Embodiment 4N-(the chloro-6-aminomethyl phenyl of 2-)-2-(5-fluoro-2-methylbenzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 5-fluoro-2-methylbenzene formaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 321～322 ℃, productive rate 90.5%.
1H?NMR(400MHz，DMSO-d
6)δ：12.71(s，1H)，10.07(s，1H)，8.31(s，1H)，7.86-7.90(d，1H，J＝16.5Hz)，7.12-7.47(m，6H)，6.84-6.89(d，1H，J＝15.8Hz)，2.41(s，3H)，2.25(s，3H)。
Embodiment 5N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3,5-dichlorobenzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 3,5-dichlorobenzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is pale solid, and fusing point is 306～307 ℃, productive rate 90.5%.
1H?NMR(400MHz，DMSO-d
6)δ：12.71(s，1H)，10.07(s，1H)，8.36(s，1H)，7.26-7.78(m，7H)，6.99-7.03(d，1H，J＝15.9Hz)，2.25(s，3H)。
Embodiment 6N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3-anisole acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use m-methoxybenzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 281～282 ℃, productive rate 92.3%.
1H?NMR(400MHz，DMSO-d
6)δ：12.65(s，1H)，10.09(s，1H)，8.35(s，1H)，7.75-7.79(d，1H，J＝15.9Hz)，7.38-7.42(m，2H)，7.22-7.31(m，4H)，7.03-7.06(m，1H)，6.93-6.97(d，1H，J＝15.8Hz)，3.82(s，3H)，2.25(s，3H)。
Embodiment 7N-(the chloro-6-aminomethyl phenyl of 2-)-2-(2,5-dimethoxy benzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 2,5-dimethoxy benzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is yellow solid, and fusing point is 301～302 ℃, productive rate 91.5%.
1H?NMR(400MHz，DMSO-d
6)δ：12.62(s，1H)，10.08(s，1H)，8.34(s，1H)，7.91-7.95(d，1H，J＝15.9Hz)，7.40-7.42(m，1H)，7.26-7.31(m，2H)，7.15-7.16(d，1H，J＝2.5Hz)，7.03-7.09(m，3H)，3.85(s，3H)，3.77(s，3H)，2.25(s，3H)。
Embodiment 8N-(the chloro-6-aminomethyl phenyl of 2-)-2-(3-fluoro-2-methylbenzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 3-fluoro-2-methylbenzene formaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 325～326 ℃, productive rate 91.7%.
1H?NMR(400MHz，DMSO-d
6)δ：12.75(s，1H)，10.09(s，1H)，8.36(s，1H)，7.96-8.00(d，1H，J＝15.6Hz)，7.46-7.48(m，1H)，7.40-7.42(m，1H)，7.24-7.37(m，4H)，6.87-6.91(d，1H，J＝15.8Hz)，2.34(s，3H)，2.25(s，3H)。
Embodiment 9N-(the chloro-6-aminomethyl phenyl of 2-)-2-(to chlorobenzene acrylamide) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use 4-chloro-benzaldehyde to replace 3,4-dimethylbenzaldehyde.Target product is faint yellow solid, and fusing point is 320～321 ℃, productive rate 90.5%.
1H?NMR(400MHz，DMSO-d
6)δ：12.85(s，1H)，10.22(s，1H)，8.34(s，1H)，7.73-7.80(m，3H)，7.53-7.55(m，2H)，7.41-7.43(m，1H)，7.29-7.31(m，2H)，6.90-6.94(d，1H，J＝16.3Hz)，2.25(s，3H)。
Embodiment 10N-(the chloro-6-aminomethyl phenyl of 2-)-2-(estragole acid amides) thiazole-5-methane amide
Operation steps is with embodiment 1, and different is in step 1, to use aubepine to replace 3,4-dimethylbenzaldehyde.Target product is white solid, and fusing point is 328～329 ℃, productive rate 92.8%.
1H?NMR(400MHz，DMSO-d
6)δ：12.57(s，1H)，10.05(s，1H)，8.34(s，1H)，7.73-7.77(d，1H，J＝15.8Hz)，7.63(s，1H)，7.61(s，1H)，7.40-7.42(m，1H)，7.25-7.31(m，2H)，7.05(s，1H)，7.03(s，1H)，6.78-6.82(d，1H，J＝15.8Hz)，3.82(s，3H)，2.25(s，3H)。
Leukemia shaker test, tests with K562 leukemia cell, adopts MTT (tetrazolium bromide) method [Chinese Chinese materia medica academic periodical, 2011,29 (8): 1790-1795].
Collect logarithmic phase cell, adjusting concentration of cell suspension is 5 * 10
4mL
-1cell suspension, be inoculated in 96 orifice plates, every hole 200 μ L, in CO
2volumetric concentration is the CO of 5% (surplus is air)
2in incubator, hatch for 37 ℃, at the bottom of being paved with hole to cell monolayer, add the medicine of different concns, establish 3 multiple holes, the control wells that does not add medicine is set simultaneously, do not add the blank well of cell and medicine, in CO
2volumetric concentration is the CO of 5% (surplus is air)
2in incubator, hatch 48h for 37 ℃, then discard former substratum, every hole adds 200 μ L freshly prepared containing 0.5gL
-1the serum free medium of MTT, hatches 4～6h in incubator, discard substratum, and every hole adds 150 μ L DMSO to dissolve first a ceremonial jade-ladle, used in libation precipitation, measures light absorption value (OD value) by microplate reader under wavelength 492nm condition.
Inhibiting rate/%=1-(administration group average absorption degree value-blank group average absorption degree value)/(control group average absorption degree value-blank group average absorption degree value).
With above formula, calculate the inhibiting rate of medicine to tumour cell, and calculate IC by improvement bandit formula method
50.Improvement bandit formula method calculation formula: lgIC
50=Xm-I (P-(3-Pm-Pn)/4).
Xm:lg maximal dose wherein, I:lg (maximal dose/face mutually dosage), P: positive reaction rate sum, Pm: maximum positive reaction rate, Pn: minimum positive reaction rate.
Table 1 N-of the present invention (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives
IC to K562 leukemia cell
50value
* the positive contrast of Dasatinib.
As shown in Table 1, the compound of embodiment 1,2,5,8 has good restraining effect to K562 leukemia cell, and the compound of embodiment 3,4,6,7 has restraining effect to K562 leukemia cell.Show that most compound of the present invention has obvious restraining effect to K562 leukemia cell.
With the comparison of existing anti-leukemia medicine Dasatinib, the compound of synthesized of the present invention is fairly obvious to K562 leukemia cell's restraining effect.
Claims (10)
1. N-(the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that its structure represents by leading to formula I:
R in logical formula I
1, R
2, R
3and R
4independently be selected from hydrogen, chlorine, fluorine, methyl, methoxyl group or trifluoromethyl, R
1, R
2, R
3and R
4in at least two be hydrogen.
2. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
1and R
4for-H, R
2and R
3for-CH
3.
3. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
1, R
2and R
4for-H, R
3for-Cl or methoxyl group.
4. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
3and R
4for-H, R
1for-CH
3, R
2for-F.
5. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
2and R
3for-H, R
1and R
4for methoxyl group.
6. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
2and R
3for-H, R
1for-CH
3, R
4for-F.
7. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
1and R
3for-H, R
2and R
4be all methoxyl group or R
2and R
4be all-Cl.
8. N-according to claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: R in logical formula I
1, R
3and R
4for-H, R
2for trifluoromethyl or be methoxyl group.
9. the preparation method of a N-claimed in claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, take compound of benzaldehyde category as raw material, comprise the preparation of intermediate, synthetic and each unit process of aftertreatment of target product, it is characterized in that:
The preparation of described intermediate is that compound of benzaldehyde category and propanedioic acid are placed in to pyridine solvent according to mol ratio 1:1-2, under the condition existing at the piperidines of compound of benzaldehyde category 1-2% molar weight, react and within 5-8 hour, obtain intermediate (1) substituted benzene vinylformic acid at 80-100 ℃, then intermediate (1) 5-8 hour obtains intermediate (2) substituted benzene acrylate chloride according to mol ratio 1:15-20 normal-temperature reaction with chloride reagent under nitrogen protection; Intermediate (2) is placed in tetrahydrofuran solvent with 2-amino-N-(the chloro-6-aminomethyl phenyl of 2-)-5-thiazole carboxamides according to mol ratio 1-1.5:1, room temperature reaction 8-10 hour under the condition of the organic bases with intermediate (2) equimolar amount or carbonate existence;
Described aftertreatment is to boil off the tetrahydrofuran (THF) in reaction solution after reaction finishes, and then adds methylene dichloride and water, and organic phase is separated out solid, and suction filtration obtains target product;
The general structure of described compound of benzaldehyde category is
r wherein
1, R
2, R
3and R
4independently be selected from hydrogen, chlorine, fluorine, methyl, methoxyl group or trifluoromethyl, R
1, R
2, R
3and R
4in at least two be hydrogen;
Described chloride reagent is selected from oxalyl chloride, triphosgene, thionyl chloride, phosphorus oxychloride or phosphorus trichloride;
Described organic bases is selected from triethylamine, Tributylamine, N, N-diisopropyl ethyl amine, DMA, N, N-Diethyl Aniline or pyridine;
Described carbonate is selected from sodium carbonate, salt of wormwood, calcium carbonate or magnesiumcarbonate.
10. a purposes for N-claimed in claim 1 (the chloro-6-aminomethyl phenyl of 2-)-2-(phenylallene acid amides) thiazole-5-carboxamides derivatives, is characterized in that: the application in preparing anti-leukocythemia liveness medicine.
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| CN106674150A (en) * | 2016-12-28 | 2017-05-17 | 上海应用技术大学 | Dasatinib derivative with anti-tumor activity and application thereof |
| CN108033930A (en) * | 2017-12-29 | 2018-05-15 | 湖北广辰药业有限公司 | A kind of synthesis technique of Dasatinib analog |
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| CN101578275A (en) * | 2006-10-31 | 2009-11-11 | 先灵公司 | Anilinopiperazine derivatives and methods of use thereof |
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