CN102532052B - Thiazole amine compound and synthesis thereof - Google Patents
Thiazole amine compound and synthesis thereof Download PDFInfo
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Abstract
The invention relates to a novel thiazole amine compound and synthesis thereof, wherein a plurality of synthons containing thiazole amine frameworks are ingeniously developed by carrying out chemical conversion on a 4-bromomethyl-2-thiazole amine compound, a series of novel thiazole amine derivatives can be simply, conveniently and efficiently synthesized from the synthons, and the thiazole amine compound has the biological activity of inhibiting tumor cells.
Description
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 going on the market in the recent period.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 this three major types antitumour drug of regulating drug/cell growth inhibition have almost related to all types of tumours.2006, the front 12 powerful antitumor medicine sales volumes of global marketing all exceeded 1,000,000,000 dollars, became " cookle " level best-selling drugs, wherein had 2 product sales to break through respectively 3,000,000,000 dollars, and sales volume exceedes the product of 2,000,000,000 dollars and reaches 4.In addition, the product of sales volume more than 5,000 ten thousand dollars has 7, and the sales volume of other antitumour drugs (not comprising the medicine for the treatment of as the medicine of supportive treatment with for tumor complication) adds up to and exceedes 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 relating to reaches more than 1000.Approximately there are at present 800 molecular targeted agents in the clinical or preclinical study stage, wherein approximately have 403 in the clinical study stage.By following the tracks of nearest patent and the forward position report of developed country's drug development aspects such as the U.S., we find that thiazole sulfonamide derivatives is that a class has multi-direction bioactive compound, and the bioactive molecules that contains in a large number thiazole amine structure is synthesized and biological assessment.At present existing several micromolecular compounds that contain thiazole amine core skeleton are developed by u s company and Scientific Research in University mechanism, and what have enters clinical stage.
Sunesis company of the U.S. has developed SN-314 micromolecular compound (WO2007013964), and route is as follows:
Research finds that SNS-314 is Aurora protein kinase family, comprises Aurora-A, Aurora-B and Aurora-C selective depressant.Aurora protein kinase relates to the core enzyme of cancer cells division, aspect the improper hyperplasia of tumour cell, is playing the role of a nucleus.From organic chemistry angle, SNS-314 compound is a urea derivatives that contains thiazole amine skeleton and miazines thiophene phenol skeleton.
The MB07813 compound (WO2006023515) of American South California Metabasis Therapeutics company exploitation, compound MB07813 is a furan derivatives that the phosphonic amide that contains thiazole amine skeleton replaces.Route is as follows:
This compound is fructose-1，6-diphosphatase (Fructose-1,6-bisphosphatase, FBPase) two generations inhibitor, the effect that treatment diabetes B has been had.Research finds that MB07813 compounds can be used for equally treatment or prevents excessive glycogen storage diseases, cardiovascular disorder (comprising atherosclerosis, treating myocardial ischemia damage) and metabolic disturbance disease (as the hypercholesterolemia and the hyperlipidemia that worsen 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 for the research of anti-breast cancer disease (
cancer Research2008,68,8393; J. Med. Chem. 2009,52,1757.).
INH compounds directly acts on Hec1/Nek2 silk division complex compound.Hec1 (
highly
expressed in
cancer) be the oncogene of a high expression level in cancer cells, this gene expression amount in normal cell is relatively low.Hec1 modulates between kinetochore and centrosome (centrosome) and forms spindle body (Spindle) in cancer cells, and what is more important Nek2 kinases is most important to silk splitting function and the cancer cells survival of Hec1 to the phosphorylation of Hec1.INH small molecules just in time can be blocked Nek2 thereby the interaction of Hec1 is made to cancer cell death.At present, experimentation on animals shows that INH small molecules can stop the growth of animal in-vivo tumour effectively, and normal animal is not had to obvious toxicity.
In sum, the a lot of compounds that contain thiazole amine skeleton structure have broad application prospects at field of medicaments, and develop easy, efficient, diversity, novel thiazole aminated compounds and synthetic method thereof are the keys that high reactivity thiazole sulfonamide derivatives is researched and developed in current continuation on a large scale widely.
Summary of the invention
The present invention has researched and developed several synthons that contain thiazole amine skeleton dexterously by 4-brooethyl-abadol compounds is carried out to chemical conversion, can synthesize simply, efficiently a class row novel thiazole amino derivative from these synthons.Find by preliminary biological activity test research, such thiazole amines compound has the biological activity of inhibition tumor cell growth and breeding.
The present invention's series compound mainly can carry out chemical conversion from 4-brooethyl-abadol compounds and obtain, general structure suc as formula (
1) shown in.In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3).
Compound (
1) can be under alkali effect and HP (O) (OEt)
2reaction prepared compound (
2), also can by similar reaction make compound (
2) other derivative (
3):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
In formula, organic solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o; The preferred THF of organic solvent and CH
3cN;
In formula, 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
3, pyridine etc.;
R in 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, generate 4-carboxylic oxygen methyl-2-thiazoamine compound (
4), wherein carboxylic acid (R
2cO
2h) comprise aliphatic carboxylic acid and aryl carboxylic acid:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
2can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
In formula, organic solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o; The preferred DMF of organic solvent, THF and CH
3cN.
In formula alkali include 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 alkali using
3n,
ipr
2nEt and K
2cO
3.;
In formula, temperature of reaction is 0
oc to 80
oc, the reaction times is 30 minutes to 72 hours.
Compound (
1)under the effect of alkali and a series of mercaptan and alcohol generation nucleophilic substitution reaction, 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:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
3can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
In formula, organic solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o; The preferred DMF of organic solvent, THF and CH
3cN.
Alkali include 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 alkali using
3n,
ipr
2nEt and K
2cO
3.;
In formula, temperature of reaction is 0
oc to 80
oc;
In formula, the reaction times is 30 minutes to 72 hours.
Compound (
1) and NaN
3reaction, generation 4-azido-methyl-abadol compound (
6), product further hydrogenation prepare 4-aminomethyl-abadol compound (
7):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
In formula, catalyzer is Pd/C, Pd (OH)
2/ C or Pt/C;
NaN in formula
3nucleophilic substitution reaction solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o;
In formula, catalytic hydrogenation solvent is methyl alcohol, ethanol, ethyl acetate, CH
3cN, Dioxane and their mixed solvent.
To compound (
1) under bromination condition, carry out bromination, can complete the bromo-4-brooethyl-abadol of 5-(
8) preparation:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
In formula, organic solvent includes but not limited to CHCl
3, CH
2cl
2, CCl
4, THF, CH
3cN, Dioxane, Et
2o, EtOAc, DMF; The preferred CHCl of organic solvent
3and CH
2cl
2;
In formula, bromide reagent includes but not limited to Br
2and NBS.Temperature of reaction is 0
oc to 100
oc; Reaction times is 10 minutes to 24 hours.
Compound (
8) under alkali exists, and there is SN in nucleophilic reagent
2reaction generate a series of 5 by the substituted product of bromine atoms (
9):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
In formula, organic solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o; The preferred THF of organic solvent and CH
3cN;
In formula, 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
3, pyridine etc.; The preferred NaH of alkali using, t-BuOK; The alkali using for compound (
8) 1.0-10 equivalent;
In formula, temperature of reaction is-30
oc to 100
oc, the reaction times is 10 minutes to 24 hours;
R in formula
1include but not limited to the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl.
Compound (
8) under alkali exists, and there is SN in nucleophilic reagent
2reaction generate a series of 5 by the substituted product of bromine atoms (
10)
:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
3can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
In formula, X includes but not limited to Sauerstoffatom, sulphur atom or NH;
In formula, organic solvent includes but not limited to THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF, H
2o; The preferred DMF of organic solvent, THF and CH
3cN;
Alkali include 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 alkali using
3n,
ipr
2nEt and K
2cO
3.;
In formula, temperature of reaction is 0
oc to 80
oc, the reaction times is 30 minutes to 72 hours.
To compound
(3)carry out direct bromination, can realize equally the bromo-abadol compounds of 5-(
9) preparation
:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
1can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
In formula, organic solvent includes but not limited to CHCl
3, CH
2cl
2, CCl
4, THF, CH
3cN, Dioxane, Et
2o, EtOAc, DMF; The preferred CHCl of organic solvent
3and CH
2cl
2;
In formula, bromide reagent includes but not limited to Br
2and NBS;
In formula, temperature of reaction is 0
oc to 100
oc;
In formula, the reaction times is 10 minutes to 24 hours.
To compound (
4) carry out direct bromination, can realize the bromo-abadol compounds of 5-(
11) preparation
:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
2can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
In formula, organic solvent includes but not limited to CHCl
3, CH
2cl
2, CCl
4, THF, CH
3cN, Dioxane, Et
2o, EtOAc, DMF; The preferred CHCl of organic solvent
3and CH
2cl
2;
In formula, bromide reagent includes but not limited to Br
2and NBS;
In formula, temperature of reaction is 0
oc to 100
oc;
In formula, the reaction times is 10 minutes to 24 hours.
To compound (
5) direct bromination, can realize equally the bromo-abadol compounds of 5-(
10) preparation:
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
3can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, comprise isocyclic aryl, heterocyclic aryl and biaryl group, all they can optionally be substituted, aryl can optionally be replaced by 1-6 substituting group);
In formula, organic solvent includes but not limited to CHCl
3, CH
2cl
2, CCl
4, THF, CH
3cN, Dioxane, Et
2o, EtOAc, DMF; The preferred CHCl of organic solvent
3and CH
2cl
2;
In formula, bromide reagent includes but not limited to Br
2and NBS;
In formula, temperature of reaction is 0
oc to 100
oc;
In formula, the reaction times is 10 minutes to 24 hours.
To compound (
9) carry out Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (
12):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
1can be the alkyl of C1-C5, preferable methyl, ethyl or sec.-propyl;
R in formula
2, R
3, R
4, R
5and R
6be independently 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, monomethyl di-t-butyl is silica-based, a tert-butyl diphenyl is silica-based, C
2-C
10hetero-aromatic ring, C
2-C
5alkyl, C
3-C
6cycloalkyl, C
4-C
15aryl, hydroxyl, the carboxyl with protecting group or the amino with protecting group with protecting group;
R in formula
7and R
8be independently H, methyl, ethyl, or be connected to
.
In formula, Suzuki linked reaction catalyzer used is Pd catalyzer; The consumption of described catalyzer be compound (
9) 0.01-0.2 times of equivalent.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)
2one or more in Pd; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
In formula, Suzuki linked reaction alkali used is DMF, 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 be compound (
9) 1.0-5.0 times of equivalent;
The temperature of reaction that in formula, Suzuki linked reaction adopts is 40-150 DEG C;
The organic solvent that in formula, Suzuki linked reaction is used is conventional solvent in existing Suzuki linked reaction, be preferably one or more in methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and DMF.
To compound (
11) carry out Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (
13):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
2can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, 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 formula
3, R
4, R
5, R
6and R
7be independently 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, monomethyl di-t-butyl is silica-based, a tert-butyl diphenyl is silica-based, C
2-C
10hetero-aromatic ring, C
2-C
5alkyl, C
3-C
6cycloalkyl, C
4-C
15aryl, hydroxyl, the carboxyl with protecting group or the amino with protecting group with protecting group;
R in formula
8and R
9be independently H, methyl, ethyl, or be connected to
.
In formula, Suzuki linked reaction catalyzer used is Pd catalyzer; The consumption of described catalyzer be compound (
11) 0.01-0.2 times of equivalent.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)
2one or more in Pd; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
In formula, Suzuki linked reaction alkali used is DMF, 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 be compound (
11) 1.0-5.0 times of equivalent;
The temperature of reaction that in formula, Suzuki linked reaction adopts is 40-150 DEG C;
The organic solvent that in formula, Suzuki linked reaction is used is conventional solvent in existing Suzuki linked reaction, be preferably one or more in methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and DMF.
To compound (
10) carry out Suzuki linked reaction, can successfully prepare 5-aryl-4-substituent methyl-abadol compounds (
14):
In formula, R can be tert.-butoxy, benzyloxy and other alkyl (carbonatoms is at the alkyl between 1-3) and other alkoxyl group (alkoxyl group of carbonatoms between 1-3);
R in formula
3can be that methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl between 3-10 (has the ring of 5-14 at least one conjugated pi electron system of annular atoms core, 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 formula
4, R
5, R
6, R
7and R
8be independently 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, monomethyl di-t-butyl is silica-based, a tert-butyl diphenyl is silica-based, C
2-C
10hetero-aromatic ring, C
2-C
5alkyl, C
3-C
6cycloalkyl, C
4-C
15aryl, hydroxyl, the carboxyl with protecting group or the amino with protecting group with protecting group;
R in formula
9and R
10be independently H, methyl, ethyl, or be connected to
.
In formula, Suzuki linked reaction catalyzer used is Pd catalyzer; The consumption of described catalyzer be compound (
10) 0.01-0.2 times of equivalent.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)
2one or more in Pd; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc represents acetate;
In formula, Suzuki linked reaction alkali used is DMF, 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 be compound (
10) 1.0-5.0 times of equivalent;
The temperature of reaction that in formula, Suzuki linked reaction adopts is 40-150 DEG C;
The organic solvent that in formula, Suzuki linked reaction is used is conventional solvent in existing Suzuki linked reaction, be preferably one or more in methyl alcohol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and DMF.
Embodiment
Can understand more specifically the present invention by the following examples, but it is to illustrate instead of limit the scope of the invention.
Embodiment 1:
Compound
(3)(R=OBu
t, R
1=OEt): NaH (60% in oil, 55mg, 1.375 mmol) is placed in reaction flask, adds anhydrous THF (1.5 mL) after frozen water is cooling.Then dropwise add THF (0.5 mL) solution of diethyl phosphite (diethyl phosphite) (0.188 mL) at 0 DEG C.Add rear system and stir 10min in 0 DEG C, stirring at room temperature 10min subsequently, then be cooled to 0 DEG C with frozen water.To reaction system dropwise add 4-brooethyl-abadol (
1) (R=OBu
t) THF (1.0 mL) solution of (75 mg, 0.26 mmol).Add rear 0 DEG C of reaction 5min, room temperature reaction 20min. frozen water cancellation reaction, CH
2cl
2(3 × 20mL) extraction, merges organic phase, anhydrous Na
2sO
4dry.Decompression removes solvent, and resistates column chromatography purification obtains compound
(3)(R=OBu
t, R
1=OEt): (63mg, 63%).
1h NMR (500 MHz, CDCl
3) δ 9.73 (s, 1H), 6.78 (d, J=4.0 Hz, 1H), 4.06 (q, J=7.0 Hz, 4H), 3.32 (d, J=21.0 Hz, 2H), 1.56 (s, 9H), 1.25 (t, J=7.0 Hz, 6H);
13c NMR (125 MHz, 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 Calcd for C
13h
23n
2o
5pSNa (M+Na
+), 373.0963 Found:373.0963.
[0121] embodiment 2:
Compound
(4)(R=OBu
t, R
2=Ph): 4-brooethyl-abadol (
1) (R=OBu
t) (50mg, 0.17 mmol), phenylformic acid (21mg, 0.17mmol) and Et
3n (23.8 μ L, 0.17 mmol) is dissolved in dry DMF (1.5 mL), and gained mixture was in stirring at room temperature 2 days.The shrend reaction of going out, CH
2cl
2(3 × 15mL) extraction, merges organic phase, anhydrous Na
2sO
4dry.Decompression removes solvent, and resistates column chromatography purification obtains compound
(4)(R=OBu
t, R
2=Ph) (35mg, 62%):
1h NMR (500 MHz, 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=0.5 Hz, 2H), 1.56 (s, 9H);
13c NMR (125 MHz, 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
+), 357.0885 Found:357.0887.
[0123] embodiment 3:
Compound
(5)(R=OBu
t, R
3=Ph, X=S): 4-brooethyl-abadol (
1) (R=OBu
t) (58 mg, 0.20 mmol), thiophenol (22mg, 0.20mmol) and Et
3n (28 μ L, 0.20 mmol) is dissolved in dry DMF (1.5 mL), and gained mixture shows that in stirring at room temperature to TLC raw material disappears.The shrend reaction of going out, CH
2cl
2(3 × 20 mL) extraction, merges organic phase, anhydrous Na
2sO
4dry.Decompression removes solvent, and resistates column chromatography purification obtains compound
(5)(R=OBu
t, R
3=Ph, X=S): (35mg, 53%):
1h NMR (400 MHz, 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 (100.5 MHz, 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
+), 345.0707 Found:345.0710.
[0125] embodiment 4:
Compound (
6) (R=OBu
t): 4-brooethyl-abadol (
1) (R=OBu
t) (100 mg, 0.34 mmol), NaN
3(45 mg, 0.69 mmol) is dissolved in dry DMF (2.0 mL), and gained mixture is just heated to 80 DEG C and reacts to the disappearance of TLC demonstration raw material.The shrend reaction of going out, CH
2cl
2(3 × 25 mL) extraction, merges organic phase, anhydrous Na
2sO
4dry.Decompression removes solvent, resistates column chromatography purification obtain compound (
6) (R=OBu
t) (65mg, 75%):
1h NMR (500 MHz, CDCl
3) δ 10.72 (br, 1H), 6.82 (s, 1H), 4.44 (s, 2H), 1.27 (s, 9H);
13c NMR (125 MHz, 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-HRMS Calcd for C
9h
13n
5o
2sNa (M+Na
+), 278.0688 Found:278.0692.
[0127] embodiment 5:
Compound (
7) (R=OBu
t): compound (
6) (R=OBu
t) (49 mg, 0.19 mmol) be dissolved in EtOH (2mL), adds Pd (OH)
2/ C (5% Pd, 20mg). system room temperature normal pressure hydrogenation, reacts to TLC and shows that raw material disappears.Decompression removes solvent, resistates column chromatography purification obtain compound (
7) (R=OBu
t) (29 mg, 67%):
1h NMR (500 MHz, 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
+), 230.0963 Found:230.0969.
[0129] embodiment 6:
Compound (
8) (R=OBu
t): 4-brooethyl-abadol (
1) (R=OBu
t) (102 mg, 0.35 mmol) be dissolved in CHCl
3(1mL), in, in system, dropwise add Br
2the CHCl of (72 mg, 0.4 mmol)
3(0.1 ml) solution.Adding rear system reflux 10min disappears to reaction raw materials.Naturally cool to room temperature, remove all solvents obtain yellow solid (
8) (R=OBu
t) (127 mg, 98%):
1h NMR (500 MHz, CDCl
3) δ 4.52 (s, 2H), 1.56 (s, 9H);
13c NMR (125 MHz, 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
+), 394.8863 Found:394.8866.
Embodiment 7:
Compound
(10)(R=OBu
t, R
3=Ph, X=S), method
a: compound
(8)(R=OBu
t) (53 mg, 0.14 mmol), Et
3n (24 μ L, 0.17 mmol), THF (4mL) the solution stirred overnight at room temperature of PhSH (16mg, 0.15 mmol).All solvents are shifted out in decompression, and resistates column chromatography purification obtains compound
(10)(R=OBu
t, R
3=Ph, X=S) (50 mg, 88%);
1h NMR (600 MHz, 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 (150 MHz, 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 Calcd for C
15h
17brN
2o
2s
2na (M+Na
+), 422.9813 Found: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) (55 mg, 0.17 mmol) be dissolved in CHCl
3(0.6 mL), adds Br
2the CHCl of (33 mg, 0.21 mmol)
3(0.1 mL) solution.Add rear system reflux and show that to TLC raw material disappears.Decompression removes all solvents, and resistates column chromatography purification obtains compound
(10)(R=OBu
t, R
3=Ph, X=S) (55 mg, 81%).
Embodiment 9:
Compound (
9) (R=OBu
t, R
1=Et): NaH (60% in oil, 31 mg, 0.78 mmol) is placed in reaction flask, adds anhydrous THF (1.0 mL) after frozen water is cooling.Then dropwise add THF (0.5 mL) solution of diethyl phosphite (diethyl phosphite) (101 μ L, 0.79 mmol) at 0 DEG C.Add rear system and stir 10min in 0 DEG C, stirring at room temperature 10min subsequently, then be cooled to 0 DEG C with frozen water.To reaction system dropwise add compound (
8) (R=OBu
t) THF (3.0 mL) solution of (73 mg, 0.19 mmol).Add rear 0 DEG C of reaction 20min to TLC and show that raw material disappears.Frozen water cancellation reaction, CH
2cl
2(3 × 20mL) extraction, merges organic phase, anhydrous Na
2sO
4dry.Decompression removes solvent, and resistates column chromatography purification obtains compound
(9)(R=OBu
t, R
1=Et) (89 mg, quant.):
1h NMR (400 MHz, CDCl
3) δ 10.3 (br, 1H), 4.07-3.99 (m, 4H), 3.35 (d, J=21.6 Hz, 2H), 1.55 (s, 9H), 1.20 (t, J=7.2 Hz, 6H); MS (ESI) m/z 429 (M+H
+), 451 (M+Na
+); ESI-HRMS Calcd for C
13h
22brN
2o
5pSNa (M+Na
+), 451.0068 Found:451.0072.
Embodiment 10:
Compound (
11) (R=OBu
t, R
2=Ph): compound
(4)(R=OBu
t, R
2=Ph) (15 mg, 0.045 mmol) be dissolved in CHCl
3(1.0 mL), adds Br
2the CHCl of (25 mg, 0.16 mmol)
3(0.1mL) solution.Add rear system reflux and show that to TLC raw material disappears.Decompression removes all solvents, resistates column chromatography purification obtain compound (
11) (R=OBu
t, R
2=Ph) (12 mg, 65%):
1h NMR (600 MHz, 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-HRMS Calcd for C
16h
17brN
2o
4sNa (M+Na
+), 434.9990 Found: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) (62 mg, 0.14 mmol) be dissolved in Benzene (1.5 mL), add successively methylphenylboronic acid (30mg, 0.22 mmol), Pd (PPh
3)
4(17mg, 0.014 mmol) and K
2cO
3the H of (62mg, 0.45 mmol)
2o (0.18 mL) solution.Gained reaction mixture reflux is spent the night.Decompression removes all solvents, and resistates column chromatography purification obtains compound
(13)(R=OBu
t, R
4=Me, R
2=R
3=R
5=R
6=H) (8mg, 13%):
1h NMR (500 MHz, CDCl
3) δ 9.91 (br, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.04 (q, J=7.0 Hz, 4H), 3.36 (d, J=21.5 Hz, 2H), 2.37 (s, 3H), 1.55 (s, 9H). 1.22 (t, J=7.0 Hz, 6H); MS (ESI) m/z 463 (M+Na
+); ESI-HRMS Calcd for C
20h
29n
2o
5pSNa (M+Na
+), 463.1432 Found:463.1434.
[0141] 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) (12 mg, 0.029 mmol) be dissolved in glycol dimethyl ether (2.0 ml), add successively methoxyphenylboronic acid (11.0 mg, 0.072 mmol), Pd (PPh
3)
4(3.0 mg, 0.0026 mmol) and CsF (16.0 mg, 0.11 mmol).Gained reaction mixture reflux is spent the night.Decompression removes all solvents, and resistates column chromatography purification obtains compound
(13)(R=OBu
t, R
2=Ph, R
5=OMe, R
3=R
4=R
6=R
7=H) (4.0 mg, 30%):
1h NMR (400 MHz, 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=8.8 Hz, 2H), 5.30 (s, 2H), 3.84 (s, 3H), 1.56 (s, 9H); MS (ESI) m/z 463.1 (M+Na
+); ESI-HRMS Calcd for C
23h
24n
2o
5sNa (M+Na
+), 463.1304 Found: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) (50 mg, 0.125 mmol) be dissolved in glycol dimethyl ether (2.0 mL), add successively methoxyphenylboronic acid (95.0 mg, 0.63 mmol), Pd (PPh
3)
4(14.0 mg, 0.012 mmol) and CsF (95.0 mg, 0.63 mmol).Gained reaction mixture reflux is spent the night.Decompression removes all solvents, resistates column chromatography purification obtain compound (
14) (R=OBu
t, R
3=Ph, X=S, R
6=OMe, R
4=R
5=R
7=R
8=H) (8.0 mg, 15%):
1h NMR (400 MHz, CDCl
3) δ 7.32-7.29 (m, 2H), 7.26-7.18 (m, 5H), 6.90 (d, J=8.8 Hz, 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 for C
22h
25n
2o
3s
2(M+H
+), 429.1307 Found:429.1299.
biological activity test:standard x TT experiment (experiment in 4 days) 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 parallel to be done three times, results averaged.Cancer cells was carried and being cultivated the day before yesterday in standard 96 orifice plates before adding compound, within second day, added the compound of different concns, within the 5th day, carried out XTT experiment.In microplate reader, measure absorbance, wavelength 595nm, result is converted into cancer cells survival per-cent, and result shows that these compounds have restraining effect in various degree, IC to the growth of tested cancer cells
5025
μm ~ 200
μbetween M.
Claims (9)
1. a class thiazole amines compound (4):
In formula, R is tert.-butoxy, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R
1for di(2-ethylhexyl)phosphate ethyl ester group [(EtO)
2p (O) O-];
R
2, R
3, R
4, R
5and R
6be independently H, NH
2, OH, F, Cl, Br, C
2-C
5alkyl.
2. a preparation method for compound as claimed in claim 1 (4), is characterized in that the method comprises the following steps:
A, 4-brooethyl-abadol compounds is under alkali effect and R
1-H compound reaction production (2):
；
B, formula (2) is carried out to direct bromination, the preparation bromo-abadol compounds of 5-(3):
；
C, compound (3) is carried out to Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (4):
;
In formula, R, R
1, R
2, R
3, R
4, R
5and R
6as claim 1 defines;
R
7and R
8be independently H, methyl, ethyl, or be connected to
.
3. method as claimed in claim 2, is characterized in that the alkali that wherein step a reaction is used is NaH, t-BuOK, n-BuLi, MeONa, EtONa, Et
3n,
i pr
2nEt, NaHCO
3, K
2cO
3, Na
2cO
3, pyridine; Reacting organic solvent used is THF, CH
3cN, Dioxane, CH
2cl
2, Et
2o, EtOAc, DMF.
4. method as claimed in claim 2, is characterized in that the bromide reagent that wherein step b reaction is used can be Br
2or NBS; Reacting organic solvent used is CHCl
3, CH
2cl
2, CCl
4, THF, CH
3cN, Dioxane, Et
2o, EtOAc, DMF.
5. method as claimed in claim 2, is characterized in that wherein the temperature of step b reaction is 0
oc to 100
oc, the reaction times is 10 minutes to 24 hours.
6. method as claimed in claim 2, is characterized in that the catalyzer that wherein step c reacts used is Pd catalyzer; Its consumption be compound (
3) 0.01-0.2 times of equivalent.
7. method as claimed in claim 2, is characterized in that the alkali that wherein step c reacts used is 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 be compound (
3) 1.0-5.0 times of equivalent.
8. method as claimed in claim 2, is characterized in that wherein it is 40-150 DEG C that step c reacts temperature of reaction used.
9. method as claimed in claim 2, it is characterized in that the reaction of step c wherein organic solvent is one or more in solvent methanol, Virahol, benzene, tetrahydrofuran (THF), glycol dimethyl ether, methyl-2-pyrrolidone, dioxane, toluene, ethanol and DMF conventional in existing Suzuki linked reaction.
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Address after: No. 601, Xiushan East Road, Haimen City, Nantong City, Jiangsu Province, 226100 Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee after: Qiu Xiaolong Address before: No. 601, Xiushan East Road, Haimen City, Nantong City, Jiangsu Province, 226100 Patentee before: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee before: Qiu Xiaolong Address after: No. 601, Xiushan East Road, Haimen City, Nantong City, Jiangsu Province, 226100 Patentee after: Jiangsu Huiju Pharmaceutical Co.,Ltd. Patentee after: Qiu Xiaolong Address before: No. 601, Xiushan East Road, Haimen City, Nantong City, Jiangsu Province, 226100 Patentee before: WISDOM PHARMACEUTICAL Co.,Ltd. Patentee before: Qiu Xiaolong |