CN102532052A - Novel thiazolamine compound and synthesis thereof - Google Patents
Novel thiazolamine 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
The present invention be directed to patent application document (application number: 201010208012.5; The applying date is 2010.06.24; Denomination of invention is a novel thiazole amine compound and synthetic) divide an application.
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 type 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.Through 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 one type and has multi-direction bioactive compound, and the bioactive molecules that contains the thiazole amine structure in a large number is synthesized and biological assessment.The existing at present micromolecular compound that several contain thiazole amine core skeleton is by u s company and the exploitation of scientific research institution of university, the clinical stage of entering that has.
U.S. Sunesis company has developed SN-314 micromolecular compound (WO2007013964), and route is following:
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.See that from the 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 substituted furan derivatives of phosphonic amide that contains thiazole amine skeleton.Route is following:
This compound be fructose-1 (Fructose-1,6-bisphosphatase, FBPase) two generation suppressor factor, 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 (like hypercholesterolemia and the hyperlipidemia that worsens because of hyperinsulinemia and hyperglycemia).MB07813 plays a role through the pathways metabolism that stops liver, and these pathways metabolisms can cause the patient who suffers from II-type mellitus to produce too much glucose.
Recently, the Wen-Hwa Lee of California, USA university professor group development one type of compound I NH that contains thiazole amine skeleton be used for the anti-breast cancer disease research (
Cancer Research2008,68,8393; J. Med. Chem. 2009,52, and 1757.).
The 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 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.Thereby the INH small molecules just in time can block N ek2 makes cancer cell death to the interaction of Hec1.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 compound 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 and has contained the synthon of thiazole amine skeleton through 4-brooethyl-abadol compounds being carried out chemical conversion, can synthesize one type of row novel thiazole amino derivative simply, efficiently from these synthons.Discover that through 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 (1) and obtain.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).
Concrete steps are following:
A, 4-brooethyl-abadol compounds are under the alkali effect and R
1-H compound reaction production (2):
B, formula (2) is carried out direct bromination, preparation 5-bromo-abadol compounds (3):
C, compound (3) is carried out the Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (4):
In the formula, R can be tert.-butoxy, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R1 can be phosphate dialkyl ester base, alkyl ester group, benzyl, substituted benzyl, and R-X-; Wherein X is Sauerstoffatom, sulphur atom or NH;
R
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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base;
R
7And R
8Be H, methyl, ethyl independently, or be connected to
Compound (
1) can be under the alkali effect and HP (O) (OEt)
2The reaction be able to prepare compound (
5), also can through similar reaction make compound (
5) other verivate (
6):
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
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
9Can 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-abadol compound (
7), carboxylic acid (R wherein
10CO
2H) comprise aliphatic carboxylic acid and aryl carboxylic acid:
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is 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.
In the 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 that uses
3N,
iPr
2NEt and K
2CO
3.
Temperature of reaction is 0 in the formula
oC to 80
oC, the reaction times is 30 minutes to 72 hours.
Compound (
1)Under the effect of alkali with a series of mercaptan and alcohol nucleophilic substitution reaction takes place, generation thiazole amine compound (
8), mercaptan (R wherein
10SH) comprise fragrant thiophenol and fatty mercaptan; Alcohol (R
10OH) comprise fragrant phenolic cpd and Fatty Alcohol(C12-C14 and C12-C18):
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is 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 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 employed alkali
3N,
iPr
2NEt and K
2CO
3.
Temperature of reaction is 0 in the formula
oC to 80
oC, the reaction times is 30 minutes to 72 hours.
To compound
(6)Carry out direct bromination, can realize equally 5-bromo-abadol compounds (
9) preparation
:
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
9Can 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 in the formula
oC to 100
oC, the reaction times is 10 minutes to 24 hours.
To compound (
7) carry out direct bromination, can realize 5-bromo-abadol compounds (
11) preparation
:
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is 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 in the formula
oC to 100
oC, the reaction times is 10 minutes to 24 hours.
To compound (
8) direct bromination, can realize equally 5-bromo-abadol compounds (
10) preparation:
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is 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 in the formula
oC to 100
oC, the reaction times is 10 minutes to 24 hours.
To compound (
9) carry out the Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (
12):
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
9Can 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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base;
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 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)
2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc representes 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 be compound (
9) 1.0-5.0 times of equivalent;
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, THF, glycol dimethyl ether, SL 1332, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
To compound (
11) carry out the Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (
13):
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is replaced by 1-6 substituting group);
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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base;
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 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)
2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc representes 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 be compound (
11) 1.0-5.0 times of equivalent;
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, THF, glycol dimethyl ether, SL 1332, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
To compound (
10) carry out the Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (
14):
R can be tert.-butoxy in the formula, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R in the formula
10It can be methyl, ethyl, other carbonatoms alkyl, aryl and substituted aryl (ring between 3-10 with 5-14 at least one conjugated pi electron system of annular atoms nuclear; Comprise isocyclic aryl, heterocyclic aryl and biaryl group; All they can optionally be substituted, what aryl can be optional is replaced by 1-6 substituting group);
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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base;
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 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)
2Among the Pd one or more; Wherein, dppf representative two (phenylbenzene see base) ferrocene; Dba represents dibenzalacetone; OAc representes 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 be compound (
10) 1.0-5.0 times of equivalent;
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, THF, glycol dimethyl ether, SL 1332, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
Embodiment
Can understand the present invention more specifically through following embodiment, but just illustrate and do not limit the scope of the invention.
Embodiment 1:
Compound
(6)(R=OBu
t, R
9=OEt): NaH (60% in oil, 55mg, 1.375 mmol) places reaction flask, and frozen water cooling back adds anhydrous THF (1.5 mL).THF (0.5 mL) solution that dropwise adds diethyl phosphite (diethyl phosphite) (0.188 mL) then under 0 ℃.Add the back system in 0 ℃ of stirring 10min, stirring at room 10min is cooled to 0 ℃ with frozen water more subsequently.To reaction system dropwise add 4-brooethyl-abadol (
1) (R=OBu
t) THF (1.0 mL) solution of (75 mg, 0.26 mmol).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
(6)(R=OBu
t, R
9=OEt): (63mg, 63%).
1H NMR (500 MHz, CDCl
3) d 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) d 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.
Embodiment 2:
Compound
(7)(R=OBu
t, R
10=Ph): 4-brooethyl-abadol (
1) (R=OBu
t) (50mg, 0.17 mmol), phenylformic acid (21mg, 0.17mmol) and Et
3N (23.8 L, 0.17 mmol) is dissolved in the dry DMF (1.5 mL), 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
(7)(R=OBu
t, R
10=Ph) (35mg, 62%):
1H NMR (500 MHz, CDCl
3) d 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) d 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.
Embodiment 3:
Compound
(8)(R=OBu
t, R
10=Ph, X=S): 4-brooethyl-abadol (
1) (R=OBu
t) (58 mg, 0.20 mmol), thiophenol (22mg, 0.20mmol) and Et
3N (28 L, 0.20 mmol) is dissolved in the dry DMF (1.5 mL), 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 * 20 mL) extraction merges organic phase, anhydrous Na
2SO
4Dry.Decompression removes solvent, and the resistates column chromatography purification gets compound
(8)(R=OBu
t, R
10=Ph, X=S): (35mg, 53%):
1H NMR (400 MHz, CDCl
3) d 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) d 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.
Embodiment 4:
Compound (
10) (R=OBu
t, R
10=Ph, X=S), compound (
8) (R=OBu
t, R
10=Ph, X=S) (55 mg, 0.17 mmol) is dissolved in CHCl
3(0.6 mL) adds Br
2The CHCl of (33 mg, 0.21 mmol)
3(0.1 mL) 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
10=Ph, X=S) (55 mg, 81%).
Embodiment 5:
Compound (
11) (R=OBu
t, R
10=Ph): compound
(4)(R=OBu
t, R
10=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 back system reflux and show that to TLC raw material disappears.Decompression removes all solvents, the resistates column chromatography purification get compound (
11) (R=OBu
t, R
10=Ph) (12 mg, 65%):
1H NMR (600 MHz, CDCl
3) d 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 6:
Compound
(12)(R=OBu
t, R
4=Me, R
2=R
3=R
5=R
6=H): compound (
9) (R=OBu
t, R
9=Et) (62 mg, 0.14 mmol) be dissolved among the 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 the resistates column chromatography purification gets compound
(12)(R=OBu
t, R
4=Me, R
2=R
3=R
5=R
6=H) (8mg, 13%):
1H NMR (500 MHz, CDCl
3) d 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.
Embodiment 7:
Compound (
13) (R=OBu
t, R
10=Ph, R
4=OMe, R
2=R
3=R
5=R
6=H): compound (
11) (R=OBu
t, R
10=Ph) (12 mg, 0.029 mmol) be dissolved in the 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 the resistates column chromatography purification gets compound
(13)(R=OBu
t, R
10=Ph, R
4=OMe, R
2=R
3=R
5=R
6=H) (4.0 mg, 30%):
1H NMR (400 MHz, CDCl
3) d 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 8:
Compound (
14) (R=OBu
t, R
10=Ph, X=S, R
4=OMe, R
2=R
3=R
5=R
6=H): compound (
10) (R=OBu
t, R
10=Ph, X=S) (50 mg, 0.125 mmol) is dissolved in the glycol dimethyl ether (2.0 mL), adds 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, the resistates column chromatography purification get compound (
14) (R=OBu
t, R
10=Ph, X=S, R
4=OMe, R
2=R
3=R
5=R
6=H) (8.0 mg, 15%):
1H NMR (400 MHz, CDCl
3) d 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) be 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
10=Ph, R
4=OMe, R
2=R3
5=R
5=R
6=H) and compound (
14) (R=OBu
t, R
10=Ph, X=S, R
4=OMe, R
2=R
3=R
5=R
6=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 previous day in standard 96 orifice plates, added the compound of different concns, carried out XTT and test in the 5th day in second day.On ELIASA, 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
5025
uM ~ 200
uBetween the M.
Claims (10)
1. novel thiazole amine compound (4):
In the formula, R can be tert.-butoxy, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R
1Can be phosphate dialkyl ester base, alkyl ester group, benzyl, substituted benzyl, and R-X-; Wherein X is Sauerstoffatom, sulphur atom or NH;
R
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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base.
2. the preparation method of a synthetic compound (4) is characterized in that this method may further comprise the steps:
A, 4-brooethyl-abadol compounds are under the alkali effect and R
1-H compound reaction production (2):
B, formula (2) is carried out direct bromination, preparation 5-bromo-abadol compounds (3):
C, compound (3) is carried out the Suzuki linked reaction, can prepare 5-aryl-4-substituent methyl-abadol compounds (4):
;
In the formula, R can be tert.-butoxy, the alkyl of C1-C3 and the alkoxyl group of C1-C3;
R
1Can be phosphate dialkyl ester base, alkyl ester group, benzyl, substituted benzyl, and R-X-; Wherein X is Sauerstoffatom, sulphur atom or NH;
R
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
6Naphthenic base, C
4-C
15The amino of the carboxyl of the hydroxyl of aryl, band protection base, band protection base or band protection base;
R
7And R
8Be H, methyl, ethyl independently, 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, one or more in the pyridine; Reacting used organic solvent is THF, CH
3CN, Dioxane, CH
2Cl
2, Et
2O, EtOAc, DMF, H
2Among the O one or more.
4. method as claimed in claim 2 is characterized in that wherein the temperature of reaction of step a is 0
oC to 80
oC, the reaction times is 30 minutes to 72 hours.
5. method as claimed in claim 2 is characterized in that the bromide reagent that wherein step b reaction is used can be Br2 or NBS; Reacting used organic solvent is CHCl
3, CH
2Cl
2, CCl
4, THF, CH
3CN, Dioxane, Et
2O, EtOAc, one or more among the DMF.
6. 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.
7. method as claimed in claim 2 is characterized in that wherein the used catalyzer of step c reaction is the Pd catalyzer; Its consumption be compound (
3) 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(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 representes acetate.
8. method as claimed in claim 2 is characterized in that wherein the used alkali of step c reaction is N, 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 be compound (
3) 1.0-5.0 times of equivalent.
9. the method for claim 1 is characterized in that wherein it is 40-150 ℃ that step c reacts used temperature of reaction.
10. the method for claim 1; It is characterized in that wherein step c reaction organic solvent is a solvent commonly used in the existing Suzuki linked reaction; That preferable is methyl alcohol, Virahol, benzene, THF, glycol dimethyl ether, SL 1332, dioxane, toluene, ethanol and N, one or more in the dinethylformamide.
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| CN101628898A (en) * | 2008-07-18 | 2010-01-20 | 上海合力惠邦生物医药有限公司 | Method for preparing N-aroyl-4-aryl-2-thiazolamines and intermediates of N-aroyl-4-aryl-2-thiazolamines |
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| Title |
|---|
| XIAO-LONG QIU，ET AL.: "Synthesis and Biological Evaluation of a Series of Novel Inhibitor of Nek2/Hec1 Analogues", 《J.MED.CHEM.》, vol. 52, no. 6, 25 February 2009 (2009-02-25), pages 1757 - 1767, XP055067651, DOI: doi:10.1021/jm8015969 * |
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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 |