Structure of 34259-99-9
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Investigating the anticancer potential of 4-phenylthiazole derived Ru(II) and Os(II) metalacycles
Paul Getreuer ; Laura Marretta ; Emine Toyoglu ; Orsolya Dömötör ; Michaela Hejl ; Alexander Prado-Roller , et al.
Abstract: In this contribution we report the synthesis, characterization and in vitro anticancer activity of novel cyclometalated 4-phenylthiazole-derived ruthenium(II) (2a–e) and osmium(II) (3a–e) complexes. Formation and sufficient purity of the complexes were unambigiously confirmed by 1H-, 13C- and 2D-NMR techniques, X-ray diffractometry, HRMS and elemental analysis. The binding preferences of these cyclometalates to selected amino acids and to DNA models including G-quadruplex structures were analyzed. Additionally, their stability and behaviour in aqueous solutions was determined by UV-Vis spectroscopy. Their cellular accumulation, their ability of inducing apoptosis, as well as their interference in the cell cycle were studied in SW480 colon cancer cells. The anticancer potencies were investigated in three human cancer cell lines and revealed IC50 values in the low micromolar range, in contrast to the biologically inactive ligands.
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Purchased from AmBeed: 171364-79-7 ; 7652-46-2 ; 35671-83-1 ; 34259-99-9 ; 149104-88-1 ; 195062-57-8 ; 36097-48-0
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William F. Tracy ; Geraint H. M. Davies ; Lauren N. Grant ; Jacob M. Ganley ; Jesus Moreno ; Emily C. Cherney , et al.
Abstract: Immunomodulatory imide drugs form the core of many pharmaceutically relevant structures, but Csp2–Csp2 bond formation via metal-catalyzed cross coupling is difficult due to the sensitivity of the glutarimide ring ubiquitous in these structures. We report that replacement of the traditional alkali base with a fluoride source enhances a previously challenging Suzuki–Miyaura coupling on glutarimide-containing compounds with trifluoroborates. These enabling conditions are reactive enough to generate these derivatives in high yields but mild enough to preserve both the glutarimide and its sensitive stereocenter. Experimental and computational data suggest a mechanistically distinct process of π-coordination of the trifluoroborate enabled by these conditions.
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Purchased from AmBeed: 395083-14-4 ; 13472-85-0 ; 2093387-36-9 ; 2093536-12-8 ; 835616-62-1 ; 2527-99-3 ; 1010100-26-1 ; 2304513-76-4 ; 20493-60-1 ; 2229976-08-1 ; 153766-81-5 ; 15803-02-8 ; 2509137-01-1 ; 233664-53-4 ; 1334497-00-5 ; 34259-99-9 ; 131274-22-1 ; 92629-11-3 ; 906674-55-3 ; 13682-77-4 ; 1258323-45-3 ; 1111732-84-3 ; 1902198-18-8 ; 30318-99-1 ; 1186667-20-8 ; 166328-14-9 ; 26166-92-7 ; 1216805-49-0 ; 24674-39-3 ; 1111732-99-0
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CAS No. : | 34259-99-9 |
Formula : | C3H2BrNS |
M.W : | 164.02 |
SMILES Code : | C1=NC(=CS1)Br |
MDL No. : | MFCD06657592 |
InChI Key : | VDTIGYKLTROQAH-UHFFFAOYSA-N |
Pubchem ID : | 2763218 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 6 |
Num. arom. heavy atoms | 5 |
Fraction Csp3 | 0.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 1.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 29.81 |
TPSA ? Topological Polar Surface Area: Calculated from |
41.13 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.7 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
1.98 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
1.91 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.53 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
3.07 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
1.84 |
Log S (ESOL):? ESOL: Topological method implemented from |
-2.72 |
Solubility | 0.312 mg/ml ; 0.0019 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (Ali)? Ali: Topological method implemented from |
-2.47 |
Solubility | 0.556 mg/ml ; 0.00339 mol/l |
Class? Solubility class: Log S scale |
Soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-2.14 |
Solubility | 1.2 mg/ml ; 0.00729 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
Yes |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-5.89 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
2.5 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | a) Synthesis of 4-bromothiazol A solution of 10.0 g (41.2 mmol) 2,4-dibromothiazol in ether (210 ml) was cooled to -78° C. and 28.3 ml (45.3 mmol, 15percent in hexane) n-butyllithium was added in drops at this temperature. After 30 min of stirring, 3.3 ml (82.3 mmol) methanol was added at -78° C. to the reaction mixture. Heating was subsequently performed to RT over a period of 16 h. The reaction mixture was filtered over silica gel and washed with a n-hexane/AE mixture (2:1). The filtrate was concentrated in a vacuum, whereby 6.7 g (40.9 mmol, 99percent) 4-bromothiazol was obtained. | |
With sodium hydroxide; In dichloromethane; acetic acid; | Reference Example 2 4-Bromothiazole Following the procedure of M. Robba and R. C. Moreau, Annales pharm. franc. 22, #3, 201-210 (1965); 10 g of 2,4-dibromothiazole and 5 g of powdered zinc in 40 ml of glacial acetic acid is stirred at 60°-65° C. for 45 minutes. The mixture is cooled in an ice bath, as 40 ml of 10 N sodium hydroxide is added in portions. Stirring is continued for 30 minutes. Ten milliliters of 10 N sodium hydroxide is added and the reaction is extracted with diethyl ether followed by methylene chloride. The combined organic layers are dried over sodium sulfate, filtered and concentrated in vacuo to give 5.4 g of the product as a yellow oil. | |
2,4-Dibromothiazole (5.00 g, 20.7 mmol) is placed in a flask which has been back filled with Argon three times. Anhydrous ether (82 mL) is added and the solution is cooled to -78°C. n-Butyllithium (2.5 M in cyclohexane, 10.0 mL) is added and the reaction mixture is stirred for 90 minutes at -78°C before quenching with HCl/ether solution (2.0 m x 15 mL). The reaction mixture is warmed to room temperature. The mixture is washed with NaHCpsi3 (saturated aqueous solution, 60 mL) and the organic phase is dried with Na2SO4. After evaporation, 4-bromothiazole is obtained as a crude product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | With copper(l) iodide; triethylamine;bis-triphenylphosphine-palladium(II) chloride; at 75℃; for 5h;Inert atmosphere; | [544] Example 129 - 3-ri-Methyl-5-(4-methyl-cvclohexyl)-l,2,3,6-tetrahydro-pyridin-4-yl1-5-(4-HCl; [545] Bromothiazole (1 g, 6.10 mmol), copper (1) iodide (50 mg, 0.26 mmol), Pd(PPh3)2Cl2 (66 mg, 0.94 mmol), and trimethylsilylacetylene (1.04 mL, 7.36 mmol) in TEA (4 mL) were degassed, placed under N2, and stirred at 75 °C for 5 hr. The reaction mixture was cooled to RT and partitioned between DCM and water. The organic phase was dried over MgS04, concentrated, and column chromatography using 0-25percent EtOAc/hexane afforded 129A as a brown residue (1.05 g, 95 percent). MS calcd: (M+H)+ = 182. MS found: (M+H)+ = 182. |
79% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 80℃; for 3h;Inert atmosphere; | The mixture of 5a (5 g, 30.5 mmol), Trimethylsilylacetylene (3.6 g, 36.6 mmol), Pd(PPh3)2C12 (210 mg, 0.3 mmol) and Cul (85 mg, 0.45 mmol) in TEA (150 mE) was heated at 80° C. for 3 h under N2, then cooled, diluted with Et20 (100 mE) and washed with brine (100 mE). The organic phase was separated, dried over anhydrous Na2504 and concentrated under reduced pressure. The residue was purified by colunm chromatography (silica, EtOAc/petroleum ether 1:15) to provide Sb (4.3 g, 79percent yield) as a yellow oil. ?H-NMR (CDC13, 400 MHz): oe=8.74 (d, 1H), 7.53 (d, 1H), 0.26 (s, 9H) |
72% | Compound 11A was prepared following step 4A starting with 0.59 g of <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> and substituting 3-phenyl-1-propyne with trimethylsilyl acetylene. Yield: 0.475 g (72percent). |
72.4% | With bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; triethylamine; at 75℃; for 5h;Inert atmosphere; | 4- Bromothiazole (1 g, 6.1 mmol), Cul (58.1 mg, 0.3 mmol), Pd(PPh3)2Cl2 (128.4 mg, 0.18 mmol), and ethynyl(trimethyl)silane (898.2 mg, 9.15 mmol) in TEA (4 mL) were degassed, placed under N2, and stirred at 75 °C for 5 hr. The reaction mixture was cooled to RT and partitioned between DCM and water. The organic phase was dried over MgSC , concentrated, and column chromatography using 0-25percent EtOAc/hexane afforded the title product 800 mg (72.4percent) as a brown oil. ESI-MS m/z calcd for [C8Hi2NSSi]+ (M+H)+: 182.0; found: 182.1. |
With triethylamine;bis-triphenylphosphine-palladium(II) chloride; copper(l) iodide; at 75℃; for 5h; | Intermediate 4; 4-[(Trimethylsilyl)ethynyl]-1 ,3-thiazole; 4-Bromo-1 ,3-thiazole (1 g), copper (I) iodide (50 mg), Pd(PPh3)2CI2 (66 mg), trimethylsilyl acetylene (1.04 ml_), and triethylamine (4 ml.) were degassed and placed under a nitrogen atmosphere in a Reactivial.(TM). , then heated at 75°C for 5 h. The reaction mixture was allowed to cool, then partitioned between DCM and water. The organic phase was dried by using a hydrophobic frit, and the solvent removed under vacuum to give an oil. This was then purified by ISCO companion silica chromatography eluting with a gradient of EtOAc /cyclohexane (0percent to 25percent) to give the title compound MS calcd for (C8H11 NSiS+ H)+: 182MS found (electrospray): (M+H)+ = 182 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; copper(l) iodide; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 88℃; | After the mixture is cooled to room temperature, acetic acid (1.0 mL) is added and the mixture is filtered through a syringe filter (washed with DMF). The filtrate purified by reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90 percent CH3CN in 7.5 minutes, Ultro 120 5muM C18Q, 75x30mmID). The collected water/MeCN solution of the product is evaporated to remove the acetonitrile. NaHCO3 (saturated aqueous solution) is added to raise the pH to 9. DCM is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yielded the product as free base, N -(4- Methanesulfonyl-phenyl)-N2-pyridin-2-ylmethyl-9-thiazol-4-yl-9H-purine-2,6-diamine as a white powder; 1H NMR 400 MHz ( d-DMSO ) delta 10.21 (s, IH), 9.26 (s, IH), 8.53-7.70 ( m, 9H), 7.42 (d, IH, J = 8.0 Hz,), 7.24 (t, IH, J = 6.0 Hz), 4.67 (d, 2H, J = 5.6 Hz), 3.17 (s, 3H); MS m/z 479.3 (M+l). | |
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; potassium phosphate; copper(l) iodide; In DMF (N,N-dimethyl-formamide); at 88℃; | A mixture of 2-fluoro-6-chloropurine (17.26 g, 100 mmol), 3,4-dihydro-2H-pyran (12.62 g, 150 mmol) and p-toluenesulfonic acid monohydrate (1.90 g, 10 mmol) are dissolved in anhydrous dichloromethane (200 mL) and stirred at room temperature for 4 hours. The reaction mixture is filtered, washed with Na2CO3 (10percent aqueous solution, 100 mL) and water (100 mL) and the organic layer dried with Na2SO4. Evaporation of the solvent results in an oil which is triturated with ethyl acetate (10 mL) and hexanes (60 mL) which induces precipitate formation. The product, 2-fluoro-6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine, is collected by filtration. A mixture of 2-fluoro-6-chloro-9-(tetrahydro-pyran-2-yl)-9H-purine (2.56 g, 10 mmol), 4-(methylthio)aniline (1.39 g, 10 mmol) and DIEA (1.93 g, 15 mmol) in ethanol (20 ml) is stirred overnight at 78° C. The mixture is cooled down to room temperature. Evaporation of the solvent followed by column chromatography (EtOAc/DCM from 10percent to 30percent) yields [2-Fluoro-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-(4-methylsulfanyl-phenyl)-amine as a white solid. To a solution of the compound obtained above (3.33 g, 9.25 mmol) in DCM (10 ml) is added 3-chloroperoxybenzoic acid (6.22 g, 77percent maximum, 27.8 mmol) portion wise slowly (in an ice bath). After addition, the mixture is stirred at room temperature for another 2 hours. The mixture is diluted with DCM (50 ml) and the suspension is washed with saturated Na2S2O3 (50 ml) and saturated NaHCO3 (50 ml.x.2) until the organic phase is clear. The organic layer is further washed with water (50 ml) and brine (50 ml) and dried with MgSO4. Evaporation of the solvent followed by column chromatography (EtOAc/DCM from 30percent to 70percent) gives [2-fluoro-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-(4-methylsulfonyl-phenyl)-amine as a pale yellow solid. The mixture of the 2-fluoropurine substrate (4.6 g, 11.8 mmol) and 2-(aminomethyl) pyridine (15.0 g) is heated in an 84° C. oil bath, overnight. The mixture is distributed between ethyl acetate (200 mL) and water (200 mL). The organic phase is washed with NH4Cl (2.x.150 mL, saturated aqueous solution) and water (200 mL) and dried over Na2SO4. Evaporation of the solvent gives the crude product which is used in the next reaction without further purification. The compound obtained above (1.93 g, 4.02 mmol) is stirred with p-toluenesulfonic acid monohydrate (950 mg, 5.0 mmol) in methanol (20 mL) at 60° C. until the starting material is no longer be detected (monitored by TLC or LC-MS). Triethylamine (1.0 mL) is added. As the reaction mixture is cooled to room temperature precipitate forms which is collected by filtration to give the deprotected product. The deprotected 2,6-disubstituted purine (1.98 g, 5.0 mmol), Cul (475 mg, 2.50 mmol) and K3PO4 (3.18 g, 15 mmol) are combined in a flask (backfilled with argon). Trans-N,N'-dimethylcyclohexane-1,2-diamine (355 mg, 2.50 mmol) and <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> (932 mg, 88percent pure, 5.0 mmol) in DMF (9.0 mL) is added and the mixture is stirred at 88° C. overnight. After the mixture is cooled to room temperature, acetic acid (1.0 mL) is added and the mixture is filtered through a syringe filter (washed with DMF). The filtrate purified by reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90percent CH3CN in 7.5 minutes, Ultro 120 5 muM C18Q, 75.x.30 mmID). The collected water/MeCN solution of the product is evaporated to remove the acetonitrile. NaHCO3 (saturated aqueous solution) is added to raise the pH to 9. DCM is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yielded the product as free base, N6-(4-Methanesulfonyl-phenyl)-N2-pyridin-2-ylmethyl-9-thiazol-4-yl-9H-purine-2,6-diamine as a white powder; 1H NMR 400 MHz (d-DMSO) delta 10.21 (s, 1H), 9.26 (s, 1H), 8.53-7.70 ( m, 9H), 7.42 (d, 1H, J=8.0 Hz,), 7.24 (t, 1H, J=6.0 Hz), 4.67 (d, 2H, J=5.6 Hz), 3.17 (s, 3H); MS m/z 479.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With copper(l) iodide; caesium carbonate; trans-N,N'-dimethylcyclohexane-1,2-diamine; In N,N-dimethyl-formamide; at 88℃; | The deprotected 2,6-disubstituted purine (1.44 g, 3.71 mmol), CuI (352 mg, 1.86 mmol) and CS2CO3 (3.62 g, 3.0 eq) are combined in a flask (previously backfilled with argon). Trans-N,N'-dimethylcyclohexane-l,2-diamine (264 mg, 1.86 mmol) and 4- bromothiazole (691 mg, 88percent pure, 3.71 mmol) in DMF (8.0 mL) is added and the mixture is stirred at 880C, overnight. After the mixture is cooled to room temperature, acetic acid (1.0 mL) is added and the mixture is filtered through a syringe filter (washed with DMF). The filtrate purified by reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90 percent CH3CN in 7.5 minutes, Ultra 120 5uM C18Q, 75x30mmID). The collected water/MeCN solution of the product is evaporated to remove the acetonitrile. NaHCpsi3 (saturated aqueous solution) is added to raise the pH to 9. DCM is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yields R-(4- Metfaanesulfonyl-phenyl)-[2-(2-methyl-morpholin-4-yl)-9-tfaiazol-4-yl-9H-purin-6-vH- amine as free base/white powder; 1H NMR 400 MHz ( CDCl3 ) delta 9.69 (s, IH), 8.87 (d, IH, J = 2.4 Hz), 8.83 (s, IH), 8.26 (d, IH, J = 2.4 Hz), 8.07 (d, 2H, J = 8.8 Hz), 7.95 (d, 2H, J = <n="45"/>8.8 Hz), 4.53 (t, 2H, J = 10.8 Hz), 4.10-4.07 (m, IH), 3.74-3.65 (m, 2H), 3.25-3.10 ( m, IH), 3.08 (s, 3H), 2.90-2.84 (m, IH), 1.33 (d, 3H, J = 6.4 Hz); MS m/z 472.3 (M+l). | |
With trans-N,N'-dimethyl-1,2-cyclohexyldiamine; copper(l) iodide; caesium carbonate; In DMF (N,N-dimethyl-formamide); at 88℃; | N-Benzylethanolamine (9.06 g, 60 mmol) is stirred with (R)-(+)-propylene oxide (6.96 g, 99percent, 120 mmol) in a sealed tube at 45° C. overnight. Evaporation of the excess of propylene oxide in vacuo gives the diol residue which is used directly for the next step. The diol is dissolved in dioxane (60 mL, anhydrous). KOH (10.08 g, 180 mmol) and tris(3,6-dioxaheptyl)amine (200 mg, 0.62 mmol) are added and the mixture is cooled to 0° C. after which tosyl chloride (12.58 g, 66 mmol, in 60 mL anhydrous dioxane) is added dropwise. The reaction mixture is allowed to stir at 0° C. for 45 minutes after which it is warmed to room temperature and stirred for an additional 4 hours . The reaction mixture is filtered and the filtrate is evaporated in vacuo. HCl (2 N, 200 mL) is added to the product and the resulting acidic aqueous solution is washed with ethyl acetate (150 mL.x.2), the solution cooled to 0° C. and neutralized by adding NaOH. The product is then extracted with ethyl acetate. The organic phase is dried with Na2SO4 and then subjected to evaporation. The residue is chromatographed (520percent ethyl acetate in DCM) to give the cyclized product (6.66 g). The free base is converted to the HCl salt and recrystallized as follows: The free base obtained above is treated with HCl (2 M in ether, 50 mL) and subject to evaporation to yield the HCl salt. The salt (6.0 gram) is mixed with ethyl acetate (120 mL) and heated to reflux. EtOH is added dropwise cautiously until the entire solid has dissolved. Then it is cooled to room temperature and kept in the refrigerator overnight. The precipitate obtained is filtered to give pure product (2.8 g). A solution of the recrystallized salt (1.35 g, 5.94 mmol) in ethanol (30 mL) is hydrogenated over 10percent Pd/C (0.20 g) under pressure (55 psi) at room temperature overnight. The mixture is filtered through celite (washed with EtOH) and the filtrate is evaporated to give oil. Addition of ether and subsequent evaporation gives R-2-methylmorpholine hydrochloride as solid. The mixture of the 2-fluoropurine substrate (4.6 g, 11.8 mmol), R-2-methylmorpholine hydrochloride (1.78 g, 12.9 mmol) and DIEA (3.78 g, 29.4 mmol) in ethanol (20 ml) is refluxed overnight. Ethanol is evaporated and the residue is redissolved in DCM (100 ml). It is washed with saturated NaHCO3 (50 ml), water (50 ml), brine (50 ml) and dried over MgSO4. Evaporation of the solvent followed by column chromatography (EtOAc/DCM from 30percent to 50percent) yields R-4-methanesulfonyl-phenyl)-[2-(2-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-amine as pale brown solid. The compound obtained above (1.90 g, 4.02 mmol) is stirred with p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol) in methanol (20 mL) at 60° C. until the starting material is no longer detected (monitored by TLC or LC-MS). Triethylamine (0.5 mL) is added and ethanol is evaporated. Column chromatography (MeOH/DCM from 0 to 5percent) yields the deprotection product. 2,4-Dibromothiazole (5.00 g, 20.7 mmol) is placed in a flask which has been back filled with Argon three times. Anhydrous ether (82 mL) is added and the solution is cooled to -78° C. n-Butyllithium (2.5 M in cyclohexane, 10.0 mL) is added and the reaction mixture is stirred for 90 minutes at -78° C. before quenching with HCl/ether solution (2.0 m.x.15 mL). The reaction mixture is warmed to room temperature. The mixture is washed with NaHCO3 (saturated aqueous solution, 60 mL) and the organic phase is dried with Na2SO4. After evaporation, <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> is obtained as a crude product. The deprotected 2,6-disubstituted purine (1.44 g, 3.71 mmol), Cul (352 mg, 1.86 mmol) and Cs2CO3 (3.62 g, 3.0 eq) are combined in a flask (previously backfilled with argon). Trans-N,N'-dimethylcyclohexane-1,2-diamine (264 mg, 1.86 mmol) and <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> (691 mg, 88percent pure, 3.71 mmol) in DMF (8.0 mL) is added and the mixture is stirred at 88° C., overnight. After the mixture is cooled to room temperature, acetic acid (1.0 mL) is added and the mixture is filtered through a syringe filter (washed with DMF). The filtrate purified by reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90percent CH3CN in 7.5 minutes, Ultro 120 5 uM C18Q, 75.x.30 mmID). The collected water/MeCN solution of the product is evaporated to remove the acetonitrile. NaHCO3 (saturated aqueous solution) is added to raise the pH to 9. DCM is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yields R-(4-Methanesulfonyl-phenyl)-[2-(2-methyl-morpholin-4-yl)-9-thiazol-4-yl-9H-purin-6-yl]-amine as free base/white powder; 1H NMR 400 MHz (CDCl3 ) delta 9.69 (s, 1H), 8.87 (d, 1H, J=2.4 Hz), 8.83 (s, 1H), 8.26 (d, 1H, J=2.4 Hz), 8.07 (d, 2H, J=8.8 Hz), 7.95 (d, 2H, J=8.8 Hz), 4.53 (t, 2H, J=10.8 Hz), 4.10-4.07 (m, 1H), 3.74-3.65 (m, 2H), 3.25-3.10 (m, 1H), 3.08 (s, 3H), 2.90-2.84 (m, 1H), 1.33 (d, 3H, J=6.4 Hz); MS m/z 472.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In diethyl ether; cyclohexane; at -78 - 20℃; | N-Benzylethanolamine (9.06 g, 60 mmol) is stirred with (R)-(+)-propylene oxide (6.96 g, 99percent, 120 mmol) in a sealed tube at 45° C. overnight. Evaporation of the excess of propylene oxide in vacuo gives the diol residue which is used directly for the next step. The diol is dissolved in dioxane (60 mL, anhydrous). KOH (10.08 g, 180 mmol) and tris(3,6-dioxaheptyl)amine (200 mg, 0.62 mmol) are added and the mixture is cooled to 0° C. after which tosyl chloride (12.58 g, 66 mmol, in 60 mL anhydrous dioxane) is added dropwise. The reaction mixture is allowed to stir at 0° C. for 45 minutes after which it is warmed to room temperature and stirred for an additional 4 hours . The reaction mixture is filtered and the filtrate is evaporated in vacuo. HCl (2 N, 200 mL) is added to the product and the resulting acidic aqueous solution is washed with ethyl acetate (150 mL.x.2), the solution cooled to 0° C. and neutralized by adding NaOH. The product is then extracted with ethyl acetate. The organic phase is dried with Na2SO4 and then subjected to evaporation. The residue is chromatographed (520percent ethyl acetate in DCM) to give the cyclized product (6.66 g). The free base is converted to the HCl salt and recrystallized as follows: The free base obtained above is treated with HCl (2 M in ether, 50 mL) and subject to evaporation to yield the HCl salt. The salt (6.0 gram) is mixed with ethyl acetate (120 mL) and heated to reflux. EtOH is added dropwise cautiously until the entire solid has dissolved. Then it is cooled to room temperature and kept in the refrigerator overnight. The precipitate obtained is filtered to give pure product (2.8 g). A solution of the recrystallized salt (1.35 g, 5.94 mmol) in ethanol (30 mL) is hydrogenated over 10percent Pd/C (0.20 g) under pressure (55 psi) at room temperature overnight. The mixture is filtered through celite (washed with EtOH) and the filtrate is evaporated to give oil. Addition of ether and subsequent evaporation gives R-2-methylmorpholine hydrochloride as solid. The mixture of the 2-fluoropurine substrate (4.6 g, 11.8 mmol), R-2-methylmorpholine hydrochloride (1.78 g, 12.9 mmol) and DIEA (3.78 g, 29.4 mmol) in ethanol (20 ml) is refluxed overnight. Ethanol is evaporated and the residue is redissolved in DCM (100 ml). It is washed with saturated NaHCO3 (50 ml), water (50 ml), brine (50 ml) and dried over MgSO4. Evaporation of the solvent followed by column chromatography (EtOAc/DCM from 30percent to 50percent) yields R-4-methanesulfonyl-phenyl)-[2-(2-methyl-morpholin-4-yl)-9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]-amine as pale brown solid. The compound obtained above (1.90 g, 4.02 mmol) is stirred with p-toluenesulfonic acid monohydrate (380 mg, 2.0 mmol) in methanol (20 mL) at 60° C. until the starting material is no longer detected (monitored by TLC or LC-MS). Triethylamine (0.5 mL) is added and ethanol is evaporated. Column chromatography (MeOH/DCM from 0 to 5percent) yields the deprotection product. 2,4-Dibromothiazole (5.00 g, 20.7 mmol) is placed in a flask which has been back filled with Argon three times. Anhydrous ether (82 mL) is added and the solution is cooled to -78° C. n-Butyllithium (2.5 M in cyclohexane, 10.0 mL) is added and the reaction mixture is stirred for 90 minutes at -78° C. before quenching with HCl/ether solution (2.0 m.x.15 mL). The reaction mixture is warmed to room temperature. The mixture is washed with NaHCO3 (saturated aqueous solution, 60 mL) and the organic phase is dried with Na2SO4. After evaporation, 4-bromothiazole is obtained as a crude product. The deprotected 2,6-disubstituted purine (1.44 g, 3.71 mmol), Cul (352 mg, 1.86 mmol) and Cs2CO3 (3.62 g, 3.0 eq) are combined in a flask (previously backfilled with argon). Trans-N,N'-dimethylcyclohexane-1,2-diamine (264 mg, 1.86 mmol) and 4-bromothiazole (691 mg, 88percent pure, 3.71 mmol) in DMF (8.0 mL) is added and the mixture is stirred at 88° C., overnight. After the mixture is cooled to room temperature, acetic acid (1.0 mL) is added and the mixture is filtered through a syringe filter (washed with DMF). The filtrate purified by reverse-phase preparative LC-MS (acetonitrile/water/TFA gradient 10-90percent CH3CN in 7.5 minutes, Ultro 120 5 uM C18Q, 75.x.30 mmID). The collected water/MeCN solution of the product is evaporated to remove the acetonitrile. NaHCO3 (saturated aqueous solution) is added to raise the pH to 9. DCM is used to extract the product and the organic phase is dried with Na2SO4. Evaporation of the solvent yields R-(4-Methanesulfonyl-phenyl)-[2-(2-methyl-morpholin-4-yl)-9-thiazol-4-yl-9H-purin-6-yl]-amine as free base/white powder; 1H NMR 400 MHz (CDCl3 ) delta 9.69 (s, 1H), 8.87 (d, 1H, J=2.4 Hz), 8.83 (s, 1H), 8.26 (d, 1H, J=2.4 Hz), 8.07 (d, 2H, J=8.8 Hz), 7.95 (d, 2H, J=8.8 Hz), 4.53 (t, 2H, J=10.8 Hz), 4.10-4.07 (m, 1H), 3.74-3.65 (m, 2H), 3.25-3.10 (m, 1H), 3.08 (s, 3H), 2.90-2.84 (m, 1H), 1.33 (d, 3H, J=6.4 Hz); MS m/z 472.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With sodium carbonate;tetrakis(triphenylphosphine)palladium (0); In 1,2-dimethoxyethane; hexane; water; | Step A 2-Methoxy-5-(thiazol-4-yl)benzaldehyde (3-Formyl-4-methoxyphenyl)boronic acid (309 mg, 1.71 mmol), <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> (250 mg, 1.52 mmol, prepared as described by J. Trybulski and H. J. Brabander, U.S. Pat. No. 4,990,520, 1991), and tetrakis(triphenylphosphine)palladium(0) (88 mg, 0.076 mmol) were added to a mixture of water (3.5 mL), ethylene glycol dimethyl ether (3.5 mL), and sodium carbonate (805 mg, 7.6 mmol). The mixture was heated in an oil bath at 80° C. for 3 h, allowed to cool to 25° C., and partioned between ethyl acetate (40 mL) and water (20 mL). The aqueous layer was extracted with 2*40 mL of dichioromethane and the combined organic layers dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on silica gel, eluding with 10percent ethyl acetate in hexane to give 182 mg (55percent yield) of the title compound as a white solid. NMR (400 MHz, CDCl3): delta 10.51 (s, 1H), 8.88 (d, 1H, J=2 Hz), 8.32 (d, 1H, J=2 Hz), 8.24 (dd, 1H, J=9,2 Hz), 7.54 (d, 1H, J=2 Hz), 7.09 (d, 1H, J=9 Hz), 3.99 (s, 3H). Mass spectrum (NH3 /CI): 220 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
45% | With sodium carbonate;tetrakis(triphenylphosphine) palladium(0); In 1,4-dioxane; water; for 18h;Heating / reflux; | Procedure M: A suspension of <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> (1.13 g, 6.89 mmol), 4-methoxycarbonylphenylboronic acid (1.85 g, 10.3 mmol) and Tetrakis (triphenylphosphine) palladium (0) (0.35 g, 0.30 mmol) in dioxane (45 mL) and 2M Na2CC>3 (17.2 mL) is heated to reflux for 18h. The reaction is allowed to cool and filtered. The filtrate is evaporated in vacuo, and the residue is dissolved in ethyl acetate and washed with water (2X) and brine (2X). The combined organic layers are dried over Na2S04, and concentrated in vacuo. The crude material is purified by flash chromatography (100percent hexanes - 40percent ethyl acetate/hexanes) to give 4-thiazol-4-yl-benzoic acid methyl ester as a white solid (0.68g, 45percent) MS (ES+) 220.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | Example 112.; Preparation of 3-(3-chloro-5-thiazol-4-yl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl- imidazo[1,2-b]pyridazine.; To a 0 °C solution of 3-(5-bromo-3-chloro-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6- dimethyl-imidazo[1,2-b]pyridazine (0.60 g, 1.45 mmol) and THF (2 mL) is added 0.05 g/ mL of Reike Zn (3.80 mL, 2.91 mmol). The solution is heated at a reflux for 1 hour, and the excess Zn allowed to settle for 1 hour at ambient temperature. The solution is transferred to a flask of <strong>[34259-99-9]4-bromo-thiazole</strong> (Kelly, T. et al. Tetrahedron Lett. 1995, 51, 9293) (0.29 g, 1.74 mmol). PdCl2(dppf) (0.027 g, 0.036 mmol) is added and the solution heated at 65 °C overnight, diluted with EtOAc (40 mL), washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (15percent-20percent EtOAc/hexane gradient) followed by ISCO column chromatography (100percent Et2O) to furnish the title compound (0.098 g, 0.24 mmol, 16percent). 1H NMR (CDCl3) delta 0.88 (d, J = 7.5 Hz, 6H), 1.74-1.92 (m, 4H), 2.52 (s, 3H), 2.53 (s, 3H), 3.28-3.38 (m, 1H), 6.70 (s, 1H), 7.45 (s, 1H), 7.49 (d, J = 2.0 Hz, 1H), 8.85 (d, J = 2.0 Hz, 1H). LC/MS (m/z): calcd. for C20H2iClN4S2 (M+H)+: 417.1; found: 417.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-Bromosuccinimide; In water; acetic acid; | EXAMPLE 25 4-Bromothiazole A solution of 15 g of 3-(methylthio)thiophene in 60 ml of acetic acid is stirred and cooled 15° C. Twenty and four tenths grams of N-bromosuccinimide is added in portions at a rate so as to maintain the reaction temperature between 15°-17° C. and the reaction is stirred at room temperature for 2.5 hours. The reaction mixture is treated with 75 ml of water, extracted with 600 ml of diethyl ether, the diethyl ether portion is washed with water and then carefully shaken three times with saturated sodium bicarbonate. The diethyl ether layer is washed again with water, dried over sodium sulfate and concentrated in vacuo. The dark green oil was purified by Kugelrohr distillation to give 19.5 g of a pale yellow-green oil, by 74°-78° C. (0.15 mm Hg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | tris(dibenzylideneacetone)dipalladium(0) chloroform complex; johnphos; In tetrahydrofuran; at 70℃; for 24h; | Step 1. 4-Neopentylthiazole. <strong>[34259-99-9]4-Bromothiazole</strong> (1.98 g, 12.1 mmol) was covered with a 0.5 M solution of neopentylzinc iodide in THF (96 mL, 48.2 mmol). Pd2dba3.CHCI3 (624 mg, 0.603 mmol) and 2(-di-te/t-butylphosphine)biphenyl (720 mg, 2.41 mmol) were added and the reaction mixture was placed in an oil bath pre-heated to 70 °C. The resulting solution was allowed to stir for 24 h at 70 °C. The resulting mixture was cooled to room temperature and concentrated under vacuum and the residue was dissolved in ethyl acetate (100 mL) and subsequently washed with aqueous NaOH (2 x 40 mL, 3N). The organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified on a silica gel column (eluant hexane to hexane/ethyl acetate 8/2) to give 4-neopentylthiazole (1.42 g, 75percent), retention time (min) = 1.198, method [1], MS(ESI) 156.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
9% | at 100℃; for 20h; | b) Synthesis of (R)-4-(3-methylpiperazine-1-yl)thiazol 10.0 g (100 mmol) (R)-2-methylpiperazine were fused at 100 C. 2.7 g (16.8 mmol) <strong>[34259-99-9]4-bromothiazol</strong> was added in portions to this fusion over a period of 2 h. Stirring was subsequently performed for 18 h at 100 C. After cooling to RT, the residue was received in 10% aq. hydrochloric acid and washed with AE. Alkalic adjustment was subsequently performed with a 10% aq. NaOH sol. (pH>12) and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (SiO2, DCM/MeOH 9:1) was performed with the residue, whereby 277 mg (1.5 mmol, 9%) (R)-4-(3-methylpiperazine-1-yl)thiazol was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Prepared in a similar manner to Example 7 using <strong>[34259-99-9]<strong>[34259-99-9]4-bromothiazol</strong>e</strong> (Synthesis, 1986, 9, 757-60) to give the title compound (50 mg, 42percent). 1H NMR (400 MHz, CDCl3) ? 8.92 (1H, s), 8.52 (1H, d, J=1.1 Hz), 8.08 (1H, dd, J=8.0, 1.6 Hz), 7.67 (1H, d, J=1.9 Hz), 7.57-7.54 (2H, m), 7.47-7.40 (3H, m), 7.35 (1H, dd, J=8.2, 0.6 Hz), 4.05 (2H, s), 2.72 (3H, s), m/z (ES+) 398 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
8.13% | With caesium carbonate; 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene;tris-(dibenzylideneacetone)dipalladium(0); In 1,4-dioxane; at 100℃; for 12h;Inert atmosphere; | A screw-cap vial was charged with lambdaf-[(lS)-l-(5-Fluoropyrimidin-2-yl)ethyl]-6- morpholin-4-yl-l,3,5-triazine-2,4-diamine (Intermediate 18, 234 mg, 0.73 mmol), A- bromothiazole (100 mg, 0.61 mmol), CS2CO3 (497 mg, 1.52 mmol), Xantphos.(R). (35.3 mg, 0.06 mmol) and Pd2(dba)3 (27.9 mg, 0.03 mmol). The vial was flushed with nitrogen and dioxane (3048 mul) was added. The resulting mixture was heated to 100 0C for 12 hours. Evaporation of the volatiles under reduced pressure gave a residue that was purified by column chromatography (10percent-20percent-50percent-100percent EtOAc/hexanes) to give the title product (20.00 mg, 8.13 percent).1H NMR (300 MHz, MeOD) delta ppm 1.46 (d, 3 H), 3.38 - 3.73 (m, 8 H), 5.04 - 5.36 (m, 1 H), 7.37 (br. s., 0.5 H), 7.56 (br. s., 0.5 H), 8.59 (s, 2 H), 8.64 (br. s., 1 H). LCMS: 404 [M+H]+. |