CN101885709A - Novel thiazole amine compound and synthesis thereof - Google Patents

Novel thiazole amine compound and synthesis thereof Download PDF

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CN101885709A
CN101885709A CN2010102080125A CN201010208012A CN101885709A CN 101885709 A CN101885709 A CN 101885709A CN 2010102080125 A CN2010102080125 A CN 2010102080125A CN 201010208012 A CN201010208012 A CN 201010208012A CN 101885709 A CN101885709 A CN 101885709A
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carbonatoms
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邱小龙
赵勤
杨登贵
邹平
陈军
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Wisdom Pharmaceutical Co Ltd
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Wisdom Pharmaceutical Co Ltd
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Abstract

The invention relates to a novel thiazole amine compound and synthesis thereof, which skillfully develops a plurality of synthons containing a thiazole amine framework by carrying out chemical conversion on a 4-brooethyl-2-thiazole amine compound and synthesizes a series of novel thiazole amine derivates from the synthons simply and efficiently. The thiazole amine compound has bioactivity of restraining cancer cells.

Description

Novel thiazole amine compound and synthetic
Technical field
The present invention relates to novel thiazole amine compound and synthetic.
Background technology
Current, global pharmaceutical market is just representing huge commercial opportunities, and this point is had some idea of by the market manifestation of the antitumour drug of recent listing.The vitality in this field has also excited the research and development enthusiasm of enterprise to antitumour drug.The research and development of novel cell poison class medicine, immunotherapy/vaccine and adjusting medicine/this three major types antitumour drug of cell growth-inhibiting have almost related to all types of tumours.2006, the preceding 12 powerful antitumor medicine sales volumes of global marketing were all above 1,000,000,000 dollars, became " cookle " level best-selling drugs, wherein had 2 product sales to break through 3,000,000,000 dollars respectively, and sales volume exceedes 2,000,000,000 dollars product and reaches 4.In addition, sales volume has 7 at the product more than 5,000 ten thousand dollars, and the sales volume of other antitumour drugs (not comprising medicine and the medicine that is used for the tumor complication treatment as supportive treatment) adds up to above 32,000,000,000 dollars.In this field, molecular targeted agents is the pioneer in personalized medication epoch.This type of medicine has mechanism of action widely, and the malignant tumour molecular target that relates to reaches more than 1000.Have 800 molecular targeted agents to be in clinical or the preclinical study stage at present approximately, what wherein be in the clinical study stage has 403 approximately.By nearest patent and the forward position report of following the tracks of developed country drug development aspects such as the U.S., we find that the thiazole sulfonamide derivatives is that a class has multi-direction bioactive compound, and the bioactive molecules that contains the thiazole amine structure in a large number is synthesized and biological assessment.At present existing micromolecular compounds that several contain thiazole amine core skeleton are by u s company and the exploitation of scientific research institution of university, and what have enters clinical stage.
U.S. Sunesis company has developed SN-314 micromolecular compound (WO2007013964), and route is as follows:
Figure BSA00000165002700021
Discover that SNS-314 is an Aurora protein kinase family, comprises Aurora-A, Aurora-B and Aurora-C selective depressant.The Aurora protein kinase relates to cancer cells splitted core enzyme, is playing the role of a nucleus aspect the improper hyperplasia of tumour cell.From the organic chemistry angle, the SNS-314 compound is a urea derivatives that contains thiazole amine skeleton and miazines thiophene phenol skeleton.
The MB07813 compound (W02006023515) of American South California Metabasis Therapeutics company exploitation, compound MB07813 are furan derivatives that contains the phosphonic amide replacement of thiazole amine skeleton.Route is as follows:
Figure BSA00000165002700022
This compound be fructose-1 (Fructose-1,6-bisphosphatase, FBPase) two generation inhibitor, the treatment diabetes B is had good effect.Discover that the MB07813 compounds can be used for treatment equally or prevents excessive glycogen storage diseases, cardiovascular disorder (comprising atherosclerosis, treating myocardial ischemia damage) and metabolic disturbance disease (as hypercholesterolemia and the hyperlipidemia that worsens because of hyperinsulinemia and hyperglycemia).MB07813 plays a role by the pathways metabolism that stops liver, and these pathways metabolisms can cause the patient who suffers from II-type diabetes to produce too much glucose.
Recently, the Wen-Hwa Lee of California, USA university professor group development the one class Compound I NH that contains thiazole amine skeleton be used for the research of anti-breast cancer disease (Cancer Research 2008,68,8393; J.Med.Chem.2009,52,1757.).
Figure BSA00000165002700031
The INH compounds directly acts on Hec1/Nek2 silk division complex compound.Hec1 (Highly expressed incancer) is the oncogene of a high expression level in cancer cells, and this gene expression amount in normal cell is relatively low.Hec1 modulates in cancer cells between kinetochore and the centrosome (centrosome) and forms spindle body (Spindle), and even more important is that the Nek2 kinases is most important to silk splitting function and the cancer cells survival of Hec1 to the phosphorylation of Hec1.The INH small molecules just in time can be blocked Nek2 thereby the interaction of Hec1 is made cancer cell death.At present, experimentation on animals shows that the INH small molecules can stop growth of tumor in the animal body effectively, and normal animal is not had tangible toxicity.
In sum, the a lot of compounds that contain thiazole amine skeleton structure have wide application prospect at field of medicaments, and novel thiazole aminated compounds and synthetic method thereof are the keys that high reactivity thiazole sulfonamide derivatives is researched and developed in present continuation on a large scale widely and develop easy, efficient, diversity.
Summary of the invention:
The present invention has researched and developed several dexterously and has contained the synthon of thiazole amine skeleton by 4-brooethyl-abadol compounds being carried out chemical conversion, can synthesize a class row novel thiazole amino derivative simply, efficiently from these synthons.Discover that by preliminary biological activity test such thiazole amines compound has the biological activity that suppresses the growth of tumour cell breeding.
The present invention's series compound mainly can carry out chemical conversion from 4-brooethyl-abadol compounds and obtain, and general structure as the formula (1).R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3).
Compound (1) can be under the alkali effect and HP (O) (OEt) 2Reaction is prepared compound (2), also can make other derivative (3) of compound (2) by similar reaction:
Figure BSA00000165002700042
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
Organic solvent includes but not limited to THF in the formula, CH 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; Preferred THF of organic solvent and CH 3CN;
Alkali includes but not limited to NaH in the formula, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3, pyridine etc.;
R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl.
Compound (1) can be under the effect of alkali and a series of carboxylic acid generation nucleophilic substitution reactions, generates 4-carboxylic oxygen methyl-abadol compound (4), wherein carboxylic acid (R 2CO 2H) comprise aliphatic carboxylic acid and aryl carboxylic acid:
Figure BSA00000165002700051
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
Organic solvent includes but not limited to THF, CH in the formula 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; The preferred DMF of organic solvent, THF and CH 3CN.
Alkali includes but not limited to NaH, t-BuOK, n-BuLi, MeONa, EtONa, Et in the formula 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3With pyridine etc.; The preferred Et of alkali that uses 3N, iPr 2NEt and K 2CO 3
Temperature of reaction is 0 ℃ to 80 ℃ in the formula, and the reaction times is 30 minutes to 72 hours.
Nucleophilic substitution reaction takes place with a series of mercaptan and alcohol in compound (1) under the effect of alkali, generate thiazole amine compound (5), wherein mercaptan (R 3SH) comprise fragrant thiophenol and fatty mercaptan; Alcohol (R 3OH) comprise fragrant phenolic compound and Fatty Alcohol(C12-C14 and C12-C18):
Figure BSA00000165002700052
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
Organic solvent includes but not limited to THF, CH in the formula 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; The preferred DMF of organic solvent, THF and CH 3CN.
Alkali includes but not limited to NaH, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3With pyridine etc.; The preferred Et of employed alkali 3N, iPr 2NEt and K 2CO 3
Temperature of reaction is 0 ℃ to 80 ℃ in the formula;
The reaction times is 30 minutes to 72 hours in the formula.
Compound (1) and NaN 3Reaction generates 4-azido-methyl-abadol compound (6), and product further hydrogenation prepares 4-aminomethyl-abadol compound (7):
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
Catalyzer is Pd/C, Pd (OH) in the formula 2/ C or Pt/C;
NaN in the formula 3The nucleophilic substitution reaction solvent includes but not limited to THF, CH 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O;
The catalytic hydrogenation solvent is methyl alcohol, ethanol, ethyl acetate, CH3CN, Dioxane and their mixed solvent in the formula.
Compound (1) is carried out bromination under the bromination condition, can finish the preparation of 5-bromo-4-brooethyl-abadol (8):
Figure BSA00000165002700062
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
Bromide reagent includes but not limited to Br in the formula 2And NBS.Temperature of reaction is 0 ℃ to 100 ℃; Reaction times is 10 minutes to 24 hours.
Compound (8) in the presence of alkali and nucleophilic reagent SN takes place 2Reaction generate a series of 5 by the substituted product of bromine atoms (9):
Figure BSA00000165002700071
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
Organic solvent includes but not limited to THF in the formula, CH 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; Preferred THF of organic solvent and CH 3CN;
Alkali includes but not limited to NaH in the formula, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3, pyridine etc.; The preferred NaH of employed alkali, t-BuOK; Employed alkali is the 1.0-10 equivalent of compound (8);
Temperature of reaction is-30 ℃ to 100 ℃ in the formula, and the reaction times is 10 minutes to 24 hours;
R in the formula 1Include but not limited to the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl.
Compound (8) in the presence of alkali and nucleophilic reagent SN takes place 2Reaction generate a series of 5 by the substituted product of bromine atoms (10):
Figure BSA00000165002700072
R can be a tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
X includes but not limited to Sauerstoffatom, sulphur atom or NH in the formula;
Organic solvent includes but not limited to THF, CH in the formula 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; The preferred DMF of organic solvent, THF and CH 3CN;
Alkali includes but not limited to NaH, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3With pyridine etc.; The preferred Et of employed alkali 3N, iPr 2NEt and K 2CO 3
Temperature of reaction is 0 ℃ to 80 ℃ in the formula, and the reaction times is 30 minutes to 72 hours.
Compound (3) is carried out direct bromination, can realize the preparation of 5-bromo-abadol compounds (9) equally:
Figure BSA00000165002700081
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
Bromide reagent includes but not limited to Br in the formula 2And NBS;
Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
The reaction times is 10 minutes to 24 hours in the formula.
Compound (4) is carried out direct bromination, can realize the preparation of 5-bromo-abadol compounds (11):
Figure BSA00000165002700082
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
Bromide reagent includes but not limited to Bt in the formula 2And NBS;
Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
The reaction times is 10 minutes to 24 hours in the formula.
To the direct bromination of compound (5), can realize the preparation of 5-bromo-abadol compounds (10) equally:
Figure BSA00000165002700091
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
In the formula, can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
Bromide reagent includes but not limited to Br in the formula 2And NBS;
Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
The reaction times is 10 minutes to 24 hours in the formula.
Compound (9) is carried out the Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (12):
Figure BSA00000165002700092
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
R in the formula 2, R 3, R 4, R 5And R 6Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
R in the formula 7And R 8Be H, methyl, ethyl independently, or be connected to
Figure BSA00000165002700093
The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (9).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh3) 2, PdCl 2(dppf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (9);
The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
Compound (11) is carried out the Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (13):
Figure BSA00000165002700101
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
R in the formula 3, R 4, R 5, R 6And R 7Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
R in the formula 8And R 9Be H, methyl, ethyl independently, or be connected to
Figure BSA00000165002700102
The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (11).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh3) 2, PdCl 2(dpPf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (11);
The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
Compound (10) is carried out the Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (14):
R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
R in the formula 4, R 5, R 6, R 7And R 8Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
Figure BSA00000165002700112
R in the formula 9And R 10Be H, methyl, ethyl independently, or be connected to.
The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (10).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh3) 2, PdCl 2(dppf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (10);
The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
Embodiment
Can understand the present invention more specifically by the following examples, but it is to illustrate rather than limit the scope of the invention.
Embodiment 1:
Compound (3) (R=OBu t, R 1=OEt): (60%in oil, 55mg 1.375mmol) place reaction flask to NaH, and frozen water cooling back adds anhydrous THF (1.5mL).Dropwise add diethyl phosphite (diethyl phosphite) THF (0.5mL) solution (0.188mL) under 0 ℃ then.Add the back system in 0 ℃ of stirring 10min, stirring at room 10min is cooled to 0 ℃ with frozen water more subsequently.Dropwise add 4-brooethyl-abadol (1) (R=OBu to reaction system t) (75mg, THF 0.26mmol) (1.0mL) solution.Add back 0 ℃ of reaction 5min, room temperature reaction 20min. frozen water cancellation reaction, CH 2Cl 2(3 * 20mL) extractions merge organic phase, anhydrous Na 2SO 4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound (3) (R=OBu t, R 1=OEt): (63mg, 63%). 1H NMR (500MHz, CDCl 3) δ 9.73 (s, 1H), 6.78 (d, J=4.0Hz, 1H), 4.06 (q, J=7.0Hz, 4H), 3.32 (d, J=21.0Hz, 2H), 1.56 (s, 9H), 1.25 (t, J=7.0Hz, 6H); 13C NMR (125MHz, CDCl 3) δ 160.4,152.6,141.4,141.3,110.1,110.0,83.0,62.4,62.3,30.2,29.1,28.4,16.6,16.5; MS (ESI) m/z 351 (M+H +), 373 (M+Na +); ESI-HRMS Calcdfor C 13H 23N 2O 5PSNa (M+Na +), 373.0963Found:373.0963.
Embodiment 2:
Compound (4) (R=OBu t, R 2=Ph): 4-brooethyl-abadol (1) (R=OBu t) (50mg, 0.17mmol), phenylformic acid (21mg, 0.17mmol) and Et 3(23.8 μ tL 0.17mmol) are dissolved in the dry DMF (1.5mL) N, and the gained mixture was in stirring at room 2 days.The shrend reaction of going out, CH 2Cl 2(3 * 15mL) extractions merge organic phase, anhydrous Na 2SO 4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound (4) (R=OBu t, R 2=Ph) (35mg, 62%): 1H NMR (500MHz, CDCl 3) δ 9.95 (br, 1H), 8.08-8.06 (m, 2H), 7.58-7.54 (m, 1H), 7.45-7.41 (m, 2H), 6.95 (s, 1H), 5.39 (t, J=0.5Hz, 2H), 1.56 (s, 9H); 13C NMR (125MHz, CDCl 3) δ 166.4,161.2,152.6,146.1,133.3,130.1,129.9,128.6,110.9,83.2,62.5,28.4; MS (ESI) m/z 357 (M+Na +); ESI-HRMS Calcd for C 16H 18N 2O 4SNa (M+Na +), 357.0885Found:357.0887.
Embodiment 3:
Compound (5) (R=OBu t, R 3=Ph, X=S): 4-brooethyl-abadol (1) (R=OBu t) (58mg, 0.20mmol), thiophenol (22mg, 0.20mmol) and Et 3(28 μ L 0.20mmol) are dissolved in the dry DMF (1.5mL) N, and the gained mixture shows that in stirring at room to TLC raw material disappears.The shrend reaction of going out, CH 2Cl 2(3 * 20mL) extractions merge organic phase, anhydrous Na 2SO 4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound (5) (R=OBu t, R 3=Ph, X=S): (35mg, 53%): 1H NMR (400MHz, CDCl 3) δ 10.7 (br, 1H), 7.32-7.30 (m, 2H), 7.23-7.19 (m, 2H), 7.15-7.11 (m, 1H), 6.61 (s, 1H), 4.19 (s, 2H), 1.53 (s, 9H); 13C NMR (100.5MHz, CDCl 3) δ 161.4,152.8,147.5,135.8,130.4,129.0,126.7,109.3,82.9,34.6,28.4; MS (ESI) m/z 323 (M+H +), 345 (M+Na +); ESI-HRMS Calcd for C 15H 18N 2O 2S 2Na (M+Na +), 345.0707Found:345.0710.
Embodiment 4:
Compound (6) (R=OBu t): 4-brooethyl-abadol (1) (R=OBu t) (100mg, 0.34mmol), NaN 3(45mg 0.69mmol) is dissolved in the dry DMF (2.0mL), and the gained mixture just is heated to 80 ℃ and reacts to the disappearance of TLC demonstration raw material.The shrend reaction of going out, CH 2Cl 2(3 * 25mL) extractions merge organic phase, anhydrous Na 2SO 4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound (6) (R=OBu t) (65mg, 75%): 1H NMR (500MHz, CDCl 3) δ 10.72 (br, 1H), 6.82 (s, 1H), 4.44 (s, 2H), 1.27 (s, 9H); 13C NMR (125MHz, CDCl 3) δ 162.2,152.7,145.6,110.1,83.2,50.2,28.4; MS (ESI) m/z 256 (M+H +), 278 (M+Na +); ESI-HRMSCalcd for C 9H 13N 5O 2SNa (M+Na +), 278.0688Found:278.0692.
Embodiment 5:
Compound (7) (R=OBu t): compound (6) (R=OBu t) (49mg 0.19mmol) is dissolved among the EtOH (2mL), adds Pd (OH) 2/ C (5%Pd, 20mg). system room temperature normal pressure hydrogenation, react to the disappearance of TLC demonstration raw material.Decompression removes solvent, and the resistates column chromatography purification gets compound (7) (R=OBu t) (29mg, 67%): 1H NMR (500MHz, CDCl 3) δ 6.65 (s, 1H), 4.50 (br, 2H), 3.88 (s, 2H), 3.63 (s, 1H), 1.54 (s, 9H); MS (ESI) m/z 230 (M+H +), 252 (M+Na +); ESI-HRMS Calcd for C 9H 16N 3O 2S (M+H +), 230.0963Found:230.0969.
Embodiment 6:
Compound (8) (R=OBu t): 4-brooethyl-abadol (1) (R=OBu t) (102mg 0.35mmol) is dissolved in CHCl 3(1mL), in system, dropwise add Br 2(72mg, CHCl 0.4mmol) 3(0.1ml) solution.Adding back system reflux 10min disappears to reaction raw materials.Naturally cool to room temperature, remove all solvents and get yellow solid (8) (R=OBu t) (127mg, 98%): 1H NMR (500MHz, CDCl 3) δ 4.52 (s, 2H), 1.56 (s, 9H); 13C NMR (125MHz, CDCl 3) δ 160.7,160.6,152.4,144.2,102.5,84.3,28.4,25.4,25.3; MS (ESI) m/z 372.9 (M+H +), 394.8 (M+Na +); ESI-HRMS Calcd for C 9H 12Br 2N 2O 2SNa (M+Na +), 394.8863Found:394.8866.
Embodiment 7:
Compound (10) (R=OBu t, R 3=Ph, X=S), method A: compound (8) (R=OBu t) (53mg, 0.14mmol), Et 3N (24 μ L, 0.17mmol), PhSH (16mg, THF 0.15mmol) (4mL) solution stirred overnight at room temperature.All solvents are shifted out in decompression, and the resistates column chromatography purification gets compound (10) (R=OBu t, R 3=Ph, X=S) (50mg, 88%); 1H NMR (600MHz, CDCl 3) δ 10.29 (br, 1H), 7.38-7.36 (m, 2H), 7.20-7.13 (m, 3H), 4.13 (s, 2H), 1.54 (s, 9H); 13C NMR (150MHz, CDCl 3) δ 160.4,152.7,145.9,135.0,132.2,129.0,127.5,100.0,83.6,33.4,28.4; MS (ESI) m/z 402 (M+H +), 423 (M+Na +); ESI-HRMS Calcdfor C 15H 17BrN 2O 2S 2Na (M+Na +), 422.9813Found:422.9809.
Embodiment 8:
Compound (10) (R=OBu t, R 3=Ph, X=S), method B: compound (5) (R=OBu t, R 3=Ph, X=S) (55mg 0.17mmol) is dissolved in CHCl 3(0.6mL), add Br 2(33mg, CHCl 0.21mmol) 3(0.1mL) solution.Add back system reflux and show that to TLC raw material disappears.Decompression removes all solvents, and the resistates column chromatography purification gets compound (10) (R=OBu t, R 3=Ph, X=S) (55mg, 81%).
Embodiment 9:
Compound (9) (R=OBu t, R 1=Et): (60%in oil, 31mg 0.78mmol) place reaction flask to NaH, and frozen water cooling back adds anhydrous THF (1.0mL).Dropwise add diethyl phosphite (diethyl phosphite) (101 μ L, THF 0.79mmol) (0.5mL) solution under 0 ℃ then.Add the back system in 0 ℃ of stirring 10min, stirring at room 10min is cooled to 0 ℃ with frozen water more subsequently.Dropwise add compound (8) (R=OBu to reaction system t) (73mg, THF 0.19mmol) (3.0mL) solution.Add back 0 ℃ of reaction 20min to TLC and show that raw material disappears.Frozen water cancellation reaction, CH 2Cl 2(3 * 20mL) extractions merge organic phase, anhydrous Na 2SO 4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound (9) (R=OBu t, R 1=Et) (89mg, quant.): 1H NMR (400MHz, CDCl 3) δ 10.3 (br, 1H), 4.07-3.99 (m, 4H), 3.35 (d, J=21.6Hz, 2H), 1.55 (s, 9H), 1.20 (t, J=7.2Hz, 6H); MS (ESI) m/z 429 (M+H +), 451 (M+Na +); ESI-HRMS Calcd for C 13H 22BrN 2O 5PSNa (M+Na +), 451.0068Found:451.0072.
Embodiment 10:
Compound (11) (R=OBu t, R 2=Ph): compound (4) (R=OBu t, R 2=Ph) (15mg 0.045mmol) is dissolved in CHCl 3(1.0mL), add Br 2(25mg, CHCl 0.16mmol) 3(0.1mL) solution.Add back system reflux and show that to TLC raw material disappears.Decompression removes all solvents, and the resistates column chromatography purification gets compound (11) (R=OBu t, R 2=Ph) (12mg, 65%): 1H NMR (600MHz, CDCl 3) δ 9.36 (br, 1H), 8.04-8.03 (m, 2H), 7.56-7.53 (m, 1H), 7.42-7.40 (m, 2H), 5.34 (s, 2H), 1.54 (s, 9H); MS (ESI) m/z 435 (M+Na +); ESI-HRMSCalcd for C 16H 17BrN 2O 4SNa (M+Na +), 434.9990Found:434.9997.
Embodiment 11:
Compound (12) (R=OBu t, R 4=Me, R 2=R 3=R 5=R 6=H): compound (9) (R=OBu t, R 1=Et) (62mg 0.14mmol) is dissolved among the Benzene (1.5mL), add successively to methylphenylboronic acid (30mg, 0.22mmol), Pd (PPh 3) 4(17mg, 0.014mmol) and K 2CO 3(62mg, H 0.45mmol) 2O (0.18mL) solution.Gained reaction mixture reflux is spent the night.Decompression removes all solvents, and the resistates column chromatography purification gets compound (13) (R=OBu t, R 4=Me, R 2=R 3=R 5=R 6=H) (8mg, 13%): 1H NMR (500MHz, CDCl 3) δ 9.91 (and br, 1H), 7.46 (d, J=8.0Hz, 2H), 7.22 (d, J=8.0Hz, 2H), 7.04 (q, J=7.0Hz, 4H), 3.36 (d, J=21.5Hz, 2H), 2.37 (s, 3H), 1.55 (s, 9H) .1.22 (t, J=7.0Hz, 6H); MS (ESI) m/z 463 (M+Na +); ESI-HRMSCalcd for C 20H 29N 2O 5PSNa (M+Na +), 463.1432Found:463.1434.
Embodiment 12:
Compound (13) (R=OBu t, R 2=Ph, R 5=OMe, R 3=R 4=R 6=R 7=H): compound (11) (R=OBu t, R 2=Ph) (12mg 0.029mmol) is dissolved in the glycol dimethyl ether (2.0ml), add successively to methoxyphenylboronic acid (11.0mg, 0.072mmol), Pd (PPh 3) 4(3.0mg, 0.0026mmol) and CsF (16.0mg, 0.11mmol).Gained reaction mixture reflux is spent the night.Decompression removes all solvents, and the resistates column chromatography purification gets compound (13) (R=OBu t, R 2=Ph, R 5=OMe, R 3=R 4=R 6=R 7=H) (4.0mg, 30%): 1H NMR (400MHz, CDCl 3) δ 8.08-8.05 (m, 2H), 7.57-7.53 (m, 1H), 7.45-7.40 (m, 4H), 6.95 (d, J=8.8Hz, 2H), 5.30 (s, 2H), 3.84 (s, 3H), 1.56 (s, 9H); MS (ESI) m/z 463.1 (M+Na +); ESI-HRMS Calcd forC 23H 24N 2O 5SNa (M+Na +), 463.1304Found:463.1306.
Embodiment 13:
Compound (14) (R=OBu t, R 3=Ph, X=S, R 6=OMe, R 4=R 5=R 7=R 8=H): compound (10) (R=OBu t, R 3=Ph, X=S) (50mg 0.125mmol) is dissolved in the glycol dimethyl ether (2.0mL), add successively to methoxyphenylboronic acid (95.0mg, 0.63mmol), Pd (PPh 3) 4(14.0mg, 0.012mmol) and CsF (95.0mg, 0.63mmol).Gained reaction mixture reflux is spent the night.Decompression removes all solvents, and the resistates column chromatography purification gets compound (14) (R=OBu t, R 3=Ph, X=S, R 6=OMe, R 4=R 5=R 7=R 8=H) (8.0mg, 15%): 1H NMR (400MHz, CDCl 3) δ 7.32-7.29 (m, 2H), 7.26-7.18 (m, 5H), 6.90 (d, J=8.8Hz, 2H), 4.12 (s, 2H), 3.84 (s, 3H), 1.55 (s, 9H); MS (ESI) m/z 429.1 (M+H +), 451.1 (M+Na +); ESI-HRMS Calcd forC 22H 25N 2O 3S 2(M+H +), 429.1307Found:429.1299.
Biological activity test: standard x TT experiment (experiment in 4 days) is used for test compounds (12) (R=OBu t, R 6=Me, R 4=R 5=R 7=R 8=H), compound (13) (R=OBu t, R 2=Ph, R 6=OMe, R 4=R 5=R 7=R 8=H) and compound (14) (R=OBu t, R 3=Ph, X=S, R 6=OMe, R 4=R 5=R 7=R 8=H) to breast cancer cell MDA-MB231, breast cancer cell MDA-MB468, cervical cancer cell HeLa and erythroleukemia cell line k562.Each test is parallelly done results averaged three times.Cancer cells was carried before adding compound and being cultivated the day before yesterday in standard 96 orifice plates, added the compound of different concns, carried out XTT and test in the 5th day in second day.On microplate reader, measure absorbance, wavelength 595nm, the result is converted into cancer cells survival per-cent, and the result shows that these compounds have restraining effect in various degree, IC to the growth of test cancer cells 50Between 25 μ M～200 μ M.

Claims (13)

  1. The present invention relates to novel thiazole amine compound and synthetic.
    1. compound as the formula (8).
    Figure FSA00000165002600011
    R is a tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3).
  2. 2. compound as the formula (12).
    Figure FSA00000165002600012
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
    R in the formula 2, R 3, R 4, R 5And R 6Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group.
  3. 3. compound as the formula (13).
    Figure FSA00000165002600013
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (alkyl of carbonatoms between 1-3) and other alkoxyl group;
    R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    R in the formula 3, R 4, R 5, R 6And R 7Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group.
  4. 4. compound as the formula (14).
    Figure FSA00000165002600021
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    R in the formula 4, R 5, R 6, R 7And R 8Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based ,-silica-based, the C of tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group.
  5. 5. the preparation method of a compound as the formula (8).It is characterized in that comprising the following steps: in organic solvent, making the reaction of compound (1) and bromide reagent, can obtain the compound shown in the formula (8).
    Figure FSA00000165002600022
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
    Bromide reagent includes but not limited to Br in the formula 2And NBS.Temperature of reaction is 0 ℃ to 100 ℃; Reaction times is 10 minutes to 24 hours.
  6. 6. the preparation method of a compound as the formula (10).It is characterized in that comprising the following steps: in organic solvent and under the effect of alkali, making compound (8) and compound R 3The XH reaction can obtain the compound shown in the formula (10).
    Figure FSA00000165002600031
    R can be a tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group).
    X includes but not limited to Sauerstoffatom, sulphur atom or NH in the formula.
    Organic solvent includes but not limited to THF, CH in the formula 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; The preferred DMF of organic solvent, THF and CH 3CN;
    Alkali includes but not limited to NaH, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3With pyridine etc.; The preferred Et of employed alkali 3N, iPr 2NEt and K 2CO 3Temperature of reaction is 0 ℃ to 80 ℃ in the formula, and the reaction times is 30 minutes to 72 hours.
  7. 7. the preparation method of a compound as the formula (9).It is characterized in that comprising the following steps: in organic solvent and under the effect of alkali, make the reaction of compound (8) and compound dialkyl phosphite, can obtain the compound shown in the formula (9).
    Figure FSA00000165002600032
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    Organic solvent includes but not limited to THF in the formula, CH 3CN, Dioxane, CH 2Cl 2, Et 2O, EtOAc, DMF, H 2O; Preferred THF of organic solvent and CH 3CN;
    Alkali includes but not limited to NaH in the formula, t-BuOK, n-BuLi, MeONa, EtONa, Et 3N, iPr 2NEt, NaHCO 3, K 2CO 3, Na 2CO 3, NaHCO 3, pyridine etc.; The preferred NaH of employed alkali, t-BuOK; Employed alkali is the 1.0-10 equivalent of compound (8);
    Temperature of reaction is-30 ℃ to 100 ℃ in the formula, and the reaction times is 10 minutes to 24 hours;
    R in the formula 1Include but not limited to the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl.
  8. 8. the preparation method of a compound as the formula (11).It is characterized in that comprising the following steps: in organic solvent, making the reaction of compound (4) and bromide reagent, can obtain the compound shown in the formula (11).
    Figure FSA00000165002600041
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
    Bromide reagent includes but not limited to Br in the formula 2And NBS;
    Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
    The reaction times is 10 minutes to 24 hours in the formula.
  9. 9. the compound as the formula (10) of right 6 requirements can also be by the following method from the compound shown in the formula (5).It is characterized in that comprising the following steps: in organic solvent, making the reaction of compound (5) and bromide reagent, can obtain the compound shown in the formula (10).
    Figure FSA00000165002600042
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
    Bromide reagent includes but not limited to Br in the formula 2And NBS;
    Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
    The reaction times is 10 minutes to 24 hours in the formula.
  10. 10. the compound as the formula (9) of right 7 requirements can also be by the following method from the compound shown in the formula (3).It is characterized in that comprising the following steps: in organic solvent, making the reaction of compound (3) and bromide reagent, can obtain the compound shown in the formula (9).
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
    Organic solvent includes but not limited to CHCl in the formula 3, CH 2Cl 2, CCl 4, THF, CH 3CN, Dioxane, Et 2O, EtOAc, DMF; The preferred CHCl of organic solvent 3And CH 2Cl 2
    Bromide reagent includes but not limited to Br in the formula 2And NBS;
    Temperature of reaction is 0 ℃ to 100 ℃ in the formula;
    The reaction times is 10 minutes to 24 hours in the formula.
  11. 11. the preparation method of a compound as the formula (12).It is characterized in that comprising the following steps: that the Suzuki linked reaction takes place for compound (9) and boric acid (or boric acid ester), can obtain the compound shown in the formula (12).
    Figure FSA00000165002600061
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 1Can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
    R in the formula 2, R 3, R 4, R 5And R 6Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
    R in the formula 7And R 8Be H, methyl, ethyl independently, or be connected to
    The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (9).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh 3) 2, PdCl 2(dppf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
    The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (9);
    The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
    The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
  12. 12. the preparation method of a compound as the formula (13).It is characterized in that comprising the following steps: that the Suzuki linked reaction takes place for compound (11) and boric acid (or boric acid ester), can obtain the compound shown in the formula (13).
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 2Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    R in the formula 3, R 4, R 5, R 6And R 7Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
    R in the formula 8And R 9Be H, methyl, ethyl independently, or be connected to
    Figure FSA00000165002600072
    The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (11).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh 3) 2, PdCl 2(dppf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
    The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (11);
    The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
    The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
  13. 13. the preparation method of a compound as the formula (14).It is characterized in that comprising the following steps: that the Suzuki linked reaction takes place for compound (10) and boric acid (or boric acid ester), can obtain the compound shown in the formula (14).
    Figure FSA00000165002600081
    R can be tert.-butoxy in the formula, benzyloxy and other alkyl (carbonatoms is at the alkyl between the 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
    R in the formula 3Can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring that 5-14 annular atoms examined at least one conjugated pi electron system, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
    R in the formula 4, R 5, R 6, R 7And R 8Independently be H, NH 2, CN, NO 2, CO 2H, OH, F, CHF 2, CF 3, C 2-C 15Perfluoroalkyl, Cl, Br, I, vinyl, ethynyl, trimethyl silicon based, triethyl is silica-based, the monomethyl di-t-butyl is silica-based, silica-based, the C of a tert-butyl diphenyl 2-C 10Hetero-aromatic ring, C 2-C 5Alkyl, C 3-C 6Cycloalkyl, C 4-C 15The amino of the carboxyl of the hydroxyl of aryl, band protecting group, band protecting group or band protecting group;
    R in the formula 9And R 10Be H, methyl, ethyl independently, or be connected to
    The used catalyzer of Suzuki linked reaction is the Pd catalyzer in the formula; Described catalyst consumption is a 0.01-0.2 times of equivalent of compound (10).Preferred Pd catalyzer is Pd (OAc) 2, Pd (PPh 3) 4, PdCl 2, [3-(1,3-(MeO) 2-C 6H 3-) C 6H 4-Cy 2P] 2PdCl 2, CuI/PdCl 2(PPh 3) 2, PdCl 2(dppf) CH 2Cl 2, Pd 2(dba) 3, Pd 2(dba) 3CHCl 3(t-Bu 3P) 2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
    The used alkali of Suzuki linked reaction is N in the formula, dinethylformamide, NaHCO 3, KF, KHCO 3, K 2CO 3, Na 2CO 3, Et 3N, CsF, Cs 2CO 3, NaOH, KOH, LiOH, (i-Pr) 2NEt and K 3PO 4In one or more; The consumption of described alkali is a 1.0-5.0 times of equivalent of compound (10);
    The temperature of reaction that the Suzuki linked reaction is adopted in the formula is 40-150 ℃;
    The employed organic solvent of Suzuki linked reaction is a solvent commonly used in the existing Suzuki linked reaction in the formula, that preferable is methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
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US3592904A (en) * 1968-07-05 1971-07-13 Lilly Industries Ltd Method of treating inflammatory diseases
JPH1087629A (en) * 1996-09-18 1998-04-07 Fujisawa Pharmaceut Co Ltd New isoquinoline derivative, and its medicinal use

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JPH1087629A (en) * 1996-09-18 1998-04-07 Fujisawa Pharmaceut Co Ltd New isoquinoline derivative, and its medicinal use

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