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CAS No. : | 259808-67-8 | MDL No. : | MFCD07371651 |
Formula : | C11H22N2O2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | LBAIYWWWORXVEQ-UHFFFAOYSA-N |
M.W : | 214.30 | Pubchem ID : | 22710387 |
Synonyms : |
|
Num. heavy atoms : | 15 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.91 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 68.15 |
TPSA : | 41.57 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.85 cm/s |
Log Po/w (iLOGP) : | 2.95 |
Log Po/w (XLOGP3) : | 1.07 |
Log Po/w (WLOGP) : | 0.84 |
Log Po/w (MLOGP) : | 1.15 |
Log Po/w (SILICOS-IT) : | 1.08 |
Consensus Log Po/w : | 1.42 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.64 |
Solubility : | 4.86 mg/ml ; 0.0227 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.53 |
Solubility : | 6.26 mg/ml ; 0.0292 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.05 |
Solubility : | 1.92 mg/ml ; 0.00897 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.37 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P280-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H332-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
96% | at 0 - 20℃; for 4 h; | To a solution of 2,2-dimethylpiperazine (400 mg) in dichloromethane (20 mL) at 0° C. was added di-tert-butyl dicarbonate (766 mg). The reaction was stirred at room temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2*40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give 3,3-diemethyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (720 mg, 96percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine In tetrahydrofuran at 20℃; Cooling with ice | Compound (I'-161): To a mixture of 6.02 g (0.01760 mole) of 2,2-dimethylpiperazine-2 trifluoroacetate, 7.8 ml (0.0563 mole) of triethylamine and 30 ml of tetrahydrofuran was added dropwise 4.2 ml (0.01848 mole) of di-tsrt-butyl dicarbonate under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and 1N-aqueous HCl and diisopropyl ether were added, and extracted. The aqueous layer was alkalified with 2N-aqueous NaOH, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 2.6 g (69percent) of 1-tert-butoxycarbonyl 3,3-dimethylpiperazine as a pale yellow liquid. 1H-NMR(CDCl3): δ(ppm) 1.11 (6H, s), 1.46 (9H, s), 2.87 (2H, t, J=5Hz), 3.16 (2H, s), 3.36 (2H, t, J=5Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In dichloromethane; at 0 - 20℃; for 16h; | To a solution of 3,3-diemethyl-piperazine-1-carboxylic acid tert-butyl ester (720 mg) and triethylamine (0.59 mL) in dichloromethane (10 mL) at 0 C. was added dropwise methanesulfonyl chloride (0.30 mL). The reaction mixture was stirred at room temperature for 16 h and then quenched with water (10 mL) and extracted into dichloromethane (2*20 mL). The combined organic layers were washed with saturated aqueous brine solution (2*20 mL), dried (MgSO4) and concentrated to give 4-methanesulfonyl-<strong>[259808-67-8]3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong> as a white solid (914 mg, 93%). |
88% | With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | To a solution of tert-butyl 3,3-dimethylpiperazine-l-carboxylate (500 mg, 2.333 mmol) in DCM (11 ml) at 0 C was added TEA (0.976 ml, 7.00 mmol) and methanesulfonyl chloride (321 mg, 2.80 mmol) and the resulting mixture was stirred RT for 3 h. The volatiles were removed under reduced pressure. The residue was purified via silica gel chromatography (5 - 100 % EtOAc in hexanes) to give tert-butyl 3,3-dimethyl-4-(methylsulfonyl)piperazine-l-carboxylate (600 mg, 2.052 mmol, 88 % yield) as a colorless liquid. MS (ES+) C^H^C^S requires: 292, found: 293 [M+H] +. |
With triethylamine; In dichloromethane; at 0 - 20℃; for 2h; | To a solution of 27 (1.00 g, 4.6 mmol) in CH2C12 (10 mL) at0C was charged with Et3N (2.30 g, 23 mmol) followed by MsC1 (0.59 mg, 7.0 mmol). The reaction mixture was stirred at room temperature for 2 h. Water (50 mL) was added to the reaction mixture and extracted with CH2C12 (2 x 50 mL). The organic phase was separated, dried over anhydrous Na2504, filtered and concentrated to afford 28 [1.20 g (cmde)j as a solid, whichwas used for the next step without further purification. |
With triethylamine; In dichloromethane; at 0 - 20℃; for 3h; | To a solution of the product from the previous step (1.0 g, 4.7 mmol) in CH2Cl2 (20 mL) at 0 C were added TEA (2.0 ml, 14 mmol) and methanesulfonyl chloride (0.641 g, 5.60 mmol) and the resulting mixture was stirred RT for 3 h. The mixture was concentrated under reduced pressure. The residue was purified via silica gel chromatography (5 - 100 % EtOAc in hexanes) to afford a colorless liquid. The residue was taken up in CH2CI2 (20 mL), 4 N HCl in dioxane (3.5 mL, 14 mmol) was added and the mixture was stirred at RT for 14 h. A white ppt was collected by vacuum filtration to afford the title compound (716 mg, 80 % yield). | |
270 mg | With potassium carbonate; In dichloromethane; at 20℃; for 4h; | To a stirring solution of <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (300 mg, 1.4 mmol) in DCM (3 mL) was added MsCl (321 mg, 2.8 mmol) and K2CO3(425 mg, 4.2 mmol). After being stirred at 20 C for 4 hrs, the resulting mixture was diluted with DCM (80 mL), then washed with water (30 mL) and brine (30 mL), dried over anhydrous Na2S04and concentrated in vacuo. The residue was purified by column chromatography (eluting with PE/EA=5/1, v:v) to give tert-butyl 3,3-dimethyl-4-methylsulfonyl-piperazine-l-carboxylate (270 mg) as a colorless oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; triethylamine; In dichloromethane; | [Referential Example 281] 4-(tert-Butoxycarbonyl)-1-[(6-chloronaphthalen-2-yl)sulfonyl]-2,2-dimethylpiperazine To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine (125 mg) in methylene chloride (3.0 ml) were added triethylamine (90 ml) and 6-chloronaphthalene-2-sulfonyl chloride (167 mg). The resulting mixture was stirred at room temperature for 84 hours. The reaction mixture was diluted with methylene chloride and added with a saturated aqueous solution of sodium chloride to form two layers. The organic layer obtained by separation was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crudely purified product was purified by chromatography on a silica gel column (hexane: ethyl acetate = 8:1), whereby the title compound (155 mg) was obtained as a colorless solid. 1H-NMR (CDCl3) delta: 1.31(6H,s), 1.44(9H,s), 3.22(2H,br s), 3.49-3.62(2H,br), 3.57-3.62(2H,br), 7.56(1H,dd,J=8.8,2.0Hz), 7.79(1H,d,J=8.8Hz), 7.86(1H,s), 7.87-7.92(3H,m), 8.36(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; sodium hydrogencarbonate; triethylamine; In N,N-dimethyl-formamide; | [Referential Example 283] 4-(tert-Butoxycarbonyl)-2,2-dimethyl-1-[4-(pyridin-4-yl)benzoyl]piperazine To a solution of 1-(tert-butoxycarbonyl)-3,3-dimethylpiperazine (173 mg) in a mixture of N,N-dimethylformamide (2.5 ml) and triethylamine (1.0 ml) was added (4-nirophenyl) 4-(4-pyridyl)benzoate (330 mg). The resulting mixture was stirred at 60°C for 5 days. The reaction mixture was diluted with methylene chloride and then added with a saturated aqueous solution of sodium chloride to form two layers. The organic layer obtained by separation was washed with a saturated aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crudely purified product was purified by chromatography on a silica gel column (methylene chloride: methanol = 50:1), whereby the title compound (199 mg) was obtained as colorless amorphous. 1H-NMR (CDCl3) delta: 1.49(9H,s), 1.61(6H,s), 3.45-3.56(6H,m), 7.50(2H,d,J=5.9Hz), 7.51(2H,d,J=7.8Hz), 7.67(2H,d,J=7.8Hz), 8.69(1H,d,J=5.9Hz). MS (FAB) m/z: 369 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | In dichloromethane; at 0 - 20℃; for 4h; | To a solution of 2,2-dimethylpiperazine (400 mg) in dichloromethane (20 mL) at 0 C. was added di-tert-butyl dicarbonate (766 mg). The reaction was stirred at room temperature for 4 h and then quenched with water (20 mL) and extracted into dichloromethane (2*40 mL). The combined organics were washed with saturated aqueous brine solution (40 mL), dried (MgSO4) and concentrated to give 3,3-diemethyl-piperazine-1-carboxylic acid tert-butyl ester as a white solid (720 mg, 96%). |
In dichloromethane; | [Referential Example 280] 1-(tert-Butoxycarbonyl)-3,3-dimethylpiperazine To a methylene chloride solution (5.0 ml) of 2,2-dimethylpiperazine (460 mg, 4.03 mmol) (J. Med. Chem., 1995, 38, 4389) was added di-tert-butyl dicarbonate (780 mul). The resulting mixture was stirred for 3 hours. The reaction mixture was diluted with methylene chloride and then added with saturated aqueous NaCl solution to separate into two layers. The water layer thus obtained was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crudely purified product was purified by chromatography on a silica gel column (methylene chloride: methanol = 10:1), whereby the title compound (360 mg) was obtained as a colorless oil. 1H-NMR (CDCl3) delta: 1.19(6H,s), 1.46(9H,s), 2.93(2H,t,J=4.9Hz), 3.23(2H,s), 3.42-3.48(2H,br), 3.95-4.01(1H,s). | |
In ethanol; at 9 - 15℃; for 2.5h;Inert atmosphere; | 2,2-dimethylpiperazine (1 1 .5 kg, 101 mol) was dissolved in ethanol (48.5 L) and the solution was cooled to approximately 9C. Di-tert-butyl dicarbonate (21 .9 kg, 100 mol) was dissolved in ethanol (41 .7 L). The solution of di-tertbutyl dicarbonate was added to the solution of dimethylpiperazine over a period of 2 h 30 min, keeping the temperature of the reaction below 15C. Ethanol (12.4 L) was added and the solution was stirred overnight at a temperature between 12-25C. The reaction was warmed to reflux and 75 L were distilled off. Ethanol (76 L) was added to the reaction and the solution was heated to 52C and transferred to a suspension of D,L-tartaric acid (7.5 kg, 50.0 mol) in ethanol (25.2 L), and warmed to 51 C. Ethanol (25.3 L ) was added and the reaction was kept at 20C overnight. The precipitate was filtered off and washed with ethanol (28.1 L). The solid was dried in a vacuum oven at 50C overnight to yield compound (XVIII) (27.1 kg, 93%) with 99% purity according to GC analysis. |
In dichloromethane; at 0 - 20℃; for 14h; | To a solution of 2,2-dimethylpiperazine (1.50 g, 13.1 mmol) in CH2Cl2 (119 mL) at 0 C was added BOC2O (2.8 mL, 12 mmol) and the resulting mixture was stirred at RT for 14 h. The mixture was concentrated under reduced pressure and taken on to the next step without purification |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With tetra-(n-butyl)ammonium iodide; potassium carbonate; In acetonitrile; at 60℃; for 18h; | Reference Example 46 2-(2,2-Dimethyl-piperazin-l-yl)-acetamideTo a solution of 3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester (0.55 g, 2.57 mmol) in acetonitrile (10 mL) were added 2-bromoacetamide (0.42 g, 3.08 mmol), potassium carbonate (1.06 g, 7.70 mmol) and tetrabutylammonium iodide (95 mg, 0.257 mmol). The reaction mixture was heated at 60 C for 18 h, then concentrated in vacuo. The resulting residue was partitioned between DCM and water. The organic layer was separated, dried (Na2SO4), and concentrated in vacuo to give 4-carbamoylmethyl-3,3-dimethyl- piperazine-1-carboxylic acid tert-butyl ester as a cream solid. 4-Carbamoylmethyl-3,3- dimethyl-piperazine-1-carboxylic acid tert-butyl ester was subsequently BOC-deprotected by using the general method to give the title compound as a white solid (0.43 g, 97 %). [M + H]+ 172.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With triethylamine; In tetrahydrofuran; at 20℃;Cooling with ice; | Compound (I'-161): To a mixture of 6.02 g (0.01760 mole) of 2,2-dimethylpiperazine-2 trifluoroacetate, 7.8 ml (0.0563 mole) of triethylamine and 30 ml of tetrahydrofuran was added dropwise 4.2 ml (0.01848 mole) of di-tsrt-butyl dicarbonate under ice-cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and 1N-aqueous HCl and diisopropyl ether were added, and extracted. The aqueous layer was alkalified with 2N-aqueous NaOH, and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give 2.6 g (69%) of 1-tert-butoxycarbonyl 3,3-dimethylpiperazine as a pale yellow liquid. 1H-NMR(CDCl3): delta(ppm) 1.11 (6H, s), 1.46 (9H, s), 2.87 (2H, t, J=5Hz), 3.16 (2H, s), 3.36 (2H, t, J=5Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (413 mg, 1.65 mmol) was dissolved in DCE (15 mL). TEA (1.148 mL, 8.23 mmol) was added, followed by cyclobutanone (231 mg, 3.29 mmol) and sodium triacetoxyborohydride (524 mg, 2.47 mmol). The reaction mixture was stirred for 5 h and a few drops of acetic acid were added. The reaction mixture was heated at 40 C. for 4 days, cooled to rt, washed with sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure to give a dark yellow oil. The crude title compound was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52.6% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Intermediate 14 was dissolved in DMF (20 mL). DIPEA (1.021 mL, 5.85 mmol) was added, followed by HOBT (395 mg, 2.92 mmol), EDC (561 mg, 2.92 mmol) and <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (587 mg, 2.34 mmol). The reaction mixture was stirred at rt overnight, concentrated under reduced pressure, redissolved in DCM, washed with 1M HCl and sat NaHCO3, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was purified on preparative HPLC UV using the long high pH shallow gradient method (Mobile phase: 30-50% B; A: H2O with 10 mM NH4CO3 and 0.375% NH4OH v/v, B: CH3CN, 30 min run) on XBridge Prep C18 OBD, 50×250 mm, 10 mum, Waters reverse phase column, giving 412 mg title compound (52.6%) as a solid. 1H NMR (400 MHz, CDCl3) delta ppm 1.22-1.35 (m, 1H) 1.38-1.55 (m, 9H) 1.71 (br. s., 1H) 1.94 (br. s., 1H) 2.47 (br. s., 1H) 2.88 (s, 3H) 2.96 (s, 3H) 3.32-3.59 (m, 4H) 3.65-3.85 (m, 2H) 5.77 (br. s., 1H) 6.16 (br. s., 1H) 7.17 (d, J=8.20 Hz, 2H) 7.75 (d, J=8.20 Hz, 2H); MS m/z 402.21 [M+H]+ (ESI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With triethylamine; In tetrahydrofuran; | To a solution of 1 ,1-dimethylethyl 3,3-dimethyl-1-piperazinecarboxylate (100mg, 0.467mol) in tetrahydrofuran (1 OmL) was added triethylamine (0.098ml_, 0.700 mmol) followed by dropwise addition of benzoyl chloride (0.06OmL, 0.513mmol). The reaction mixture was allowed to stir for 30 minutes. The reaction mixture was diluted with DCM (1OmL) and the solution was washed with saturated sodium bicarbonate solution (1OmL, twice), then (0.1 M, aq) HCI (1OmL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to yield 1 ,1-dimethylethyl 3,3-dimethyl-4- (phenylcarbonyl)-i-piperazinecarboxylate as a colourless oil (162mg, 100%), MS ES+ve m/z 319 (M+H)To 1 , 1 -dimethylethyl 3,3-dimethyl-4-(phenylcarbonyl)-1 -piperazinecarboxylate (162mg, 0.509 mmol) was added 1 M hydrochloric acid in 1 ,4 dioxane (1 OmL), followed by the addition of 3 drops of water. The reaction mixture was allowed to stir for 62hours. The reaction mixture was reduced in vacuo to yield colourless oil. The colourless oil was dissolved in methanol (1 OmL) and passed down a SCX-2 column washing with two column volumes methanol and eluting the product with three column volumes of 2N ammonia solution in methanol The fraction containing eluted product was reduced in vacuo to yield 2,2-dimethyl-1-(phenylcarbonyl)piperazine as a white solid (81 mg, 63%), MS ES+ve m/z 219 (M+H). To a solution of 2,2-dimethyl-1-(phenylcarbonyl)piperazine (81 mg, 0.318 mmol) in DCM (5m L) was added DIPEA (0.172mL, 0.986 mmol), followed by gradual addition of 4-cyanobenzenesulfonyl chloride (70.5mg, 0.350 mmol). The reaction mixture was allowed to stir for 1 hour.The reaction mixture was diluted with DCM (1 OmL) and the solution was washed with saturated sodium bicarbonate solution (1 OmL, twice), then with distilled water (1OmL). The organic layer was dried (MgSO4), filtered and reduced in vacuo to yield a transparent oil (160mg).The oil was then dissolved in 1 :1 MeCN/DMSO (0.9ml) and purified using MDAP (over 3 batches). The fractions containing product were combined and reduced in vacuo to yield the title compound as a white solid (48mg, 32%)1H-NMR (CDCI3) 51.58 (6H, s), 3.00 (2H, s), 3.15 (2H, t, J=5.6Hz), 3.47 (2H, t, J=5.6Hz), 7.31-7.48 (5H, m), 7.84-7.93 (4H, m).MS ES+ve m/z 384 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | (a) 4-[6-(2-Fluoro-4-Hydroxy-phenyl)-3-methyl-1 -(tetrahydro-pyran-2-yl)-1 H-pyrazo- lo[3,4-b]pyridine-4-carbonyl]-3,3-dimethyl-piperazine-1 -carboxylic acid tert-butyl ester To a suspension of 6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1 -(tetrahydro-pyran-2-yl)- 1 H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg) in dry dichloromethane (3 ml_), N,N-diisopropylethylamine (70 ??_), 2-bromo-1 -ethylpyridinium tetrafluoroborate (221 mg) and 1 -Boc-3,3-dimethylpiperazine (87 mg) were added. The solution was stirred for 30 min. Upon complete conversion, the solution is evaporated in vacuo and 3 ml_ of 30% sodium methoxide in methanol were added. The mixture was stirred for 30 min, the pH was adjusted to 5 by addition of 2M hydrochloric acid. Ethyl acetate was added and the organic layer was extracted with saturated sodium bicarbonate, 20% aqueous ammonium chloride solution and multiple times with water. The organic layer was dried over sodium sulfate and evaporated to dryness to give 132 mg (58%) of the title compound.LC/MS (Method LC1 ): Rt = 1 .34 min; m/z = 568.32 [M+H]+. | |
58% | With 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In dichloromethane; for 0.5h; | To a suspension of 6-(2-fluoro-4-Hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (150 mg) in dry dichloromethane (3 mL), N,N-diisopropylethylamine (70 muL), 2-bromo-1-ethylpyridinium tetrafluoroborate (221 mg) and <strong>[259808-67-8]1-Boc-3,3-dimethylpiperazine</strong> (87 mg) were added. The solution was stirred for 30 min. Upon complete conversion, the solution is evaporated in vacuo and 3 mL of 30% sodium methoxide in methanol were added. The mixture was stirred for 30 min, the pH was adjusted to 5 by addition of 2M hydrochloric acid. Ethyl acetate was added and the organic layer was extracted with saturated sodium bicarbonate, 20% aqueous ammonium chloride solution and multiple times with water. The organic layer was dried over sodium sulfate and evaporated to dryness to give 132 mg (58%) of the title compound. LC/MS (Method LC1): Rt=1.34 min; m/z=568.32 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27% | With tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 24h;Inert atmosphere; | Example 125a tert-Butyl 3,3-Dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 125a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-2-nitropyridine (5.6 g, 28.0 mmol), <strong>[259808-67-8]tert-butyl 3,3-dimethyl-piperazine-1-carboxylate</strong> (3.0 g, 14.0 mmol), cesium carbonate (9.1 g, 28 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting solution for 30 min, Binap (870 mg, 1.4 mmol) and tris(dibenzylideneacetone)dipalladium(0) (1.2 g, 1.4 mmol) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and stirred at 120 C. for 24 h. After this time the reaction was cooled to room temperature it was filtered and the filtrate was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3*50 mL). The combined organic layer was washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 125a (1.27 g, 27%). LCMS: [M+H]+ 337.2. |
27% | With tris-(dibenzylideneacetone)dipalladium(0); caesium carbonate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In 1,4-dioxane; at 120℃; for 24h;Inert atmosphere; | Example 190a tert-Butyl 3,3-Dimethyl-4-(6-nitropyridin-3-yl)piperazine-1-carboxylate 190a A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 5-bromo-2-nitropyridine (5.6 g, 28.0 mmol), tert-butyl 3,3-dimethyl-4-piperazine-1-carboxylate (3.0 g, 14.0 mmol), cesium carbonate (9.1 g, 28 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting solution for 30 min, Binap (870 mg, 1.4 mmol) and tris(dibenzylideneacetone)-dipalladium(0) (1.2 g, 1.4 mmol) were added. The reaction mixture was subjected to three cycles of vacuum/argon flush and stirred at 120 C for 24 h. After this time the reaction was cooled to room temperature, filtered and the filtrate was partitioned between ethyl acetate (200 mL) and water (50 mL). The aqueous layer was separated and extracted with ethyl acetate (3 * 50 mL). The combined organic layers were washed with brine (50 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 190a (1.27 g, 27%). LCMS: [M+H]+ 337.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | Intermediate 20: l-Cyclopropylmethyl-lH-[l ,2,4]triazole-3-carboxylic acid 20.1 : 3,3-Dimethyl-4-(l -phenyl- 1Eta-[ 1 ,2,4]triazole-3-carbonyl)-piperazine- 1 -carboxylic acid tert-butyl ester A mixture of 420 mg (2.22 mmol) l-phenyl-lH-[l ,2,4]triazole-3-carboxylic acid, 500 mg (2.22 mmol) 3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester, 750 mg (2.22 mmol) TBTU and 500 mu (2.91 mmol) DIPEA in 5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water. The precipitate was filtered off, taken up in EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. yield: 850 mg (99 %) ESI-MS: m/z = 386 (M+H)~ Rt(HPLC): 1.20 min (method 23) |
99% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; for 2h; | 20.1: 3,3-Dimethyl-4-(1-phenyl-1H-[1,2,4]triazole-3-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester A mixture of 420 mg (2.22 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carboxylic acid, 500 mg (2.22 mmol) <strong>[259808-67-8]3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong>, 750 mg (2.22 mmol) TBTU and 500 muL (2.91 mmol) DIPEA in 5 mL DMF was stirred at RT for 2 h. The reaction mixture was poured into ice water. The precipitate was filtered off, taken up in EtOAc, dried over sodium sulfate, filtered and concentrated in vacuo. yield: 850 mg (99%) ESI-MS: m/z=386 (M+H)- Rt(HPLC): 1.20 min (method 23) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | Intermediate 9: 2,2-Dimethyl-piperazine-l-carboxylic acid benzyl ester trifluoro acetate 9.1 : 2,2-Dimethyl-piperazine- 1 ,4-dicarboxylic acid 1 -benzyl ester 4-tert-butyl ester To a solution of 18.5 g (82.0 mmol) 3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester in 150 mL DCM at RT was added 30.0 mL (174 mmol) DIPEA. The mixture was cooled with ice and a solution of 14.0 mL (93.2 mmol) benzyl chloroformate in 60 mL DCM was added drop wise. The reaction mixture was stirred at RT over night and quenched with saturated aqueous sodium bicarbonate solution. The product was extracted with DCM. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Yield: 23.0 g (81%) ESI-MS: m/z = 249 (M-BOC+H)+ Rt(HPLC): 1.60 min (method 1) |
81% | With N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | 9.1: 2,2-Dimethyl-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester To a solution of 18.5 g (82.0 mmol) <strong>[259808-67-8]3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong> in 150 mL DCM at RT was added 30.0 mL (174 mmol) DIPEA. The mixture was cooled with ice and a solution of 14.0 mL (93.2 mmol) benzyl chloroformate in 60 mL DCM was added dropwise. The reaction mixture was stirred at RT over night and quenched with saturated aqueous sodium bicarbonate solution. The product was extracted with DCM. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo. Yield: 23.0 g (81%) ESI-MS: m/z=249 (M-BOC+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Intermediate 28 : (2,2-Dimethyl-piperazin- lyl)-[ 1 -(3-fluoro-phenyl)- 1Eta-[ 1 ,2,4]triazol-3yl]- methanone A mixture of 460 mg (2.22 mmol) l-(3-fluoro-phenyl)-lH-[l,2,4]triazole-3-carboxylic acid and 330 (2.49 mmol) l-chloro-N,N,2-trimethylpropylamine in 10 mL THF was stirred at RT for 30 min, 500 mg (2.22 mmol) 3,3-dimethyl-piperazine-l-carboxylic acid tert-butyl ester and 620 (4.45 mmol) TEA were added and the mixture was stirred at RT for 1 h. The solvent was removed by distillation and the residue was purified by HPLC. yield: 205 mg (30 %) ESI-MS: m/z = 304 (M+H)+ Rt(HPLC) : 1.24 min (method 3) | |
30% | Intermediate 28: (2,2-Dimethyl-piperazin-1yl)-[1-(3-fluoro-phenyl)-1H-[1,2,4]triazol-3yl]-methanone A mixture of 460 mg (2.22 mmol) 1-(3-fluoro-phenyl)-1H-[1,2,4]-triazole-3-carboxylic acid and 330 muL (2.49 mmol) 1-chloro-N,N,2-trimethylpropylamine in 10 mL THF was stirred at RT for 30 min, 500 mg (2.22 mmol) <strong>[259808-67-8]3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester</strong> and 620 muL (4.45 mmol) TEA were added and the mixture was stirred at RT for 1 h. The solvent was removed by distillation and the residue was purified by HPLC. yield: 205 mg (30%) ESI-MS: m/z=304 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.1 kg | In ethanol; at 20 - 52℃;Inert atmosphere; | 2,2-dimethylpiperazine (1 1 .5 kg, 101 mol) was dissolved in ethanol (48.5 L) and the solution was cooled to approximately 9C. Di-tert-butyl dicarbonate (21 .9 kg, 100 mol) was dissolved in ethanol (41 .7 L). The solution of di-tertbutyl dicarbonate was added to the solution of dimethylpiperazine over a period of 2 h 30 min, keeping the temperature of the reaction below 15C. Ethanol (12.4 L) was added and the solution was stirred overnight at a temperature between 12-25C. The reaction was warmed to reflux and 75 L were distilled off. Ethanol (76 L) was added to the reaction and the solution was heated to 52C and transferred to a suspension of D,L-tartaric acid (7.5 kg, 50.0 mol) in ethanol (25.2 L), and warmed to 51 C. Ethanol (25.3 L ) was added and the reaction was kept at 20C overnight. The precipitate was filtered off and washed with ethanol (28.1 L). The solid was dried in a vacuum oven at 50C overnight to yield compound (XVIII) (27.1 kg, 93%) with 99% purity according to GC analysis. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium fluoride; triethylamine; In N,N-dimethyl-formamide; at 80 - 140℃; for 25h;Inert atmosphere; Microwave irradiation; | Tert-butyl 3,3-dimethylpiperazine-1-carboxylate (CAS 259808-67-8, 300 mg, 1.40 mmol), 2- chloropyrimidine (CAS 1722-12-9, 240 mg, 2.10 mmol), potassium fluoride (122 mg, 2.10 mmol) and TEA (0.389 mL, 2.80 mmol) were dissolved in DMF (3 mL). After flushing with argon, the solution was heated in a microwave reactor for 3 h at 80C, 6h at 100C, 6 h at 120C and 10 h at 140C.After cooling to rt the crude mixture was extracted with EtOAc (2x10mL) and water. The combined organic phases were washed with 1M HCI (aq), dried over Mg504 and evaporated to give crude tert-butyl 3,3-dimethyl-4-(pyrimidin-2-yl)piperazine-1- carboxylate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 2h; | 6-(4-Fluorophenyl)-8-( 1 -methylcyclopropyl)imidazo[ 1 ,2-b]pyridazine-2- carboxylic acid (150 mg, 0.48 mmol) was dissolved in DMF (4.5 mL) and HATU (238 mg, 0.63 mmol), <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (113.6 mg, 0.53 mmol) and DIPEA (249 mg, 336 .iL, 1.93 mmol) were added. The solution was stirred at r. t. for 3h and then aqueous NH4C1 was added and the aqueous phase was extracted twice with EtOAc. The combined organic layers were washed with iN HC1 aqueous, saturated aqueous NaHCO3 and brine, dried over anhydrous Mg504, filtered and the filtrate evaporated under reduced pressure affording the title compound (245 mg, quantitative) as a yellow solid which was used in the subsequent step without further purification. LC-MS: mlz = 508.17 (M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; for 1h; | 6-Chloro-8-isopropyl-imidazo [1 ,2-b]pyridazine-2-carboxylic acid (2.3 g, 9.5 mmol) was solubilized in N,N-dimethylformamide (37.8 mL) and DIPEA (3.06 g, 4.12 mL, 23.65 mmol). HATU (3.95 g, 10.4 mmol) was added followed by tert-butyl 3,3- dimethylpiperazine-1-carboxylate (2.23 g, 10.4 mmol). The solution was allowed to stir for 1 hour. Upon completion, a saturated aqueous solution of NH4C1 was added to the reaction mixture. The layers were partitioned and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography using 0-100% ethyl acetate: hexanes to afford the title compound (2.13 g, 51% yield). ?HNMR (400 MHz, Chloroform-d) oe 8.27 (s, 1H), 6.89 (s, 1H), 4.31 -4.17 (m, 2H), 3.67 - 3.45 (m, 5H), 1.63 - 1.58 (m, 6H), 1.51 - 1.46 (m, 9H), 1.44 - 1.37 (m, 6H). LCMS: mlz = 436.45 (M+Hj |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To a solution of Intermediate E (59 mg, 0.20 mmol) in DMF (3 mL) were added <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (50.7 mg, 0.24 mmol), HATU (97.4 mg, 0.26 mmol) and DIPEA (51 mg, 69 .iL, 0.39 mmol) and the resulting mixture was stirred at rt ON. The reaction mixture was then diluted with EtOAc, washed with water and brine consecutively, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash chromatography eluting with EtOAc/Hexanes 0-50% in 20 CV to obtain tert-butyl 4- [6-(4-fluorophenyl)-8-isopropyl-imidazo[ 1 ,2-b]pyridazine-2-carbonyl] - 3,3-dimethyl-piperazine-1-carboxylate (58 mg) as a white solid. ?H NMR (400 MHz, CDC13) oe 8.33 (s, 1H), 8.11 -7.87 (m, 2H), 7.24-7.10 (m, 3H), 4.28 (s, 2H), 3.77 -3.43 (m, 5H), 1.61 (s, 6H), 1.51 - 1.40 (m, 15H). LC-MS: 497.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
j00268j 8-Cyclopropyl-6-(4-fluorophenyl)imidazo[ 1 ,2-b]pyridazine-2-carboxylic acid (80 mg, 0.27 mmol) was dissolved in DMF (3.4 mL) and DIPEA (121.7 mg, 164 tL, 0.94 mmol) followed by <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (69.20 mg, 0.3229 mmol) were successively added at r. t. After 2 mi HATU (153.5 mg, 0.40 mmol) was added and the reaction mixture was stirred at r.t. ON. Water was added and the reaction mixture and the mixture was extracted with EtOAc. The resulting organic phase was washed twice with a 1:1 mixture of water and brine, dried over anhydrous Mg504, filtered and evaporated under reduced pressure. The resulting crude product was used as such in the next reaction. LC-MS:mlz = 494.26 (M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
235 mg | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To a solution of Intermediate H (190 mg, 0.67 mmol) in DMF (3 mL) were added <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (171.3 mg, 0.80 mmol), HATU (329.2 mg, 0.87 mmol) and DIPEA (232 tL, 1.3 mmol) and the mixture was stirred at rt ON. The reaction mixture was then diluted with EtOAc, washed with water and brine consecutively, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The residue was purified by flash chromatography eluting with EtOAc/hexanes 0-50% in 20 CV to obtain tertbutyl 4- [8-ethyl-6-(4-fluorophenyl)imidazo[ 1 ,2-b]pyridazine-2-carbonyl] -3,3 -dimethylpiperazine-1-carboxylate (235 mg) as a white solid. ?H NMR (400 MHz, CDC13) oe 8.32 (s, 1H), 8.04-7.86 (m, 2H), 7.26 (s, 1H), 7.22-7.11 (m, 2H), 4.39-3.92 (m, 2H), 3.73 -3.40 (m, 4H), 3.09 (m, 2H), 1.65 - 1.59 (m, 6H), 1.50 - 1.40 (m, 12H). LC-MS: 482.5 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.5% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | General procedure: The appropriate carboxylic acid (1.0 equiv) is dissolved in DMF or NMP (0.15 to 0.3 M) before HATU (1.1 to 1.5 equiv), the corresponding amine (1.1-1.2 equiv) and Huenig? s base (2.5 to 3.5 equiv) are added. The mixture is stirred at room temperature between 45 mm. and 16h. Either one of these 4 work-up procedures can be employed j00237j The intermediate was prepared according to general procedure 1 using Intermediate P (1.0 equiv), DMF (0.3M), HATU (1.1 equiv), tert-butyl 3,3- dimethylpiperazine-1-carboxylate (1.1 equiv) and Huenig?s base (2.5 equiv) affording tertbutyl 4-(8-(tert-butyl)-6-(4-fluorophenyl)imidazo [1 ,2-b]pyridazine-2-carbonyl)-3 ,3 - dimethylpiperazine-1-carboxylate (47.6g, 93.5 mmol, 97.5%). ?H NMR (400 MHz, DMSOd6) oe 8.52 (s, 1H), 8.18 -8.11 (m, 2H), 7.49 (s, 1H), 7.45 -7.37 (m, 2H), 4.17-4.05 (m, 2H), 3.59 - 3.44 (m, 4H), 1.59 (s, 9H), 1.50 (s, 6H), 1.43 (s, 9H). LC-MS: 510.13 (M+H), retention time: 2.18 minutes using method C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96.85% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | The product was prepared according to General Procedure 1 using 8-tert-butyl- 6-(4,4-difluorocyclohexyl)imidazo [1 ,2-b]pyridazine-2-carboxylic acid (500 mg, 1.482 mmol), DMF (10 mL), HATU (845.3 mg, 2.223 mmol), Huenig?s base (775 tL, 4.449 mmol) and <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (476.4 mg, 2.223 mmol Purification by flash chromatography on silica gel was carried out under standard condition to afford title compound tert-butyl 4-[8-tert-butyl-6-(4,4-difluorocyclohexyl)imidazo [1 ,2-b]pyridazine-2- carbonyl]-3,3-dimethyl-piperazine-1-carboxylate (766 mg, 1.435 mmol, 96.85%) as a white solid. ?H NMR (400 MHz, Chloroform-cl) oe 8.23 (s, 1H), 6.72 (s, 1H), 4.31 (t, J= 6.3 Hz, 2H), 3.68-3.34 (m, 4H), 2.81 (t, J= 10.9 Hz, 1H), 2.24 (dt, J= 12.3, 7.2 Hz, 2H), 2.12 -1.72 (m, 6H), 1.59 (s, 6H), 1.52 (t, J= 1.9 Hz, 9H), 1.47 (d, J= 1.7 Hz, 9H). LC-MS: 534.26 (M+Hj. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 155℃; for 12h;Microwave irradiation; | A vial was charged with 5-amino-3,6-dichloro-l,2,4-triazine (736 mg, 4.46 mmol), diisopropylethylamine (2.0 mL, 11.48 mmol), tert-butyl 2-(3,3-dimethylpiperazin-l- yl)acetate (1.0875 g, 4.52 mmol) in dioxane (8 mL). The mixture was heated at 155 C for 12 h using microwave. The mixture was concentrated to remove all of solvent. The residue was treated with saturated sodium bicarbonate solution, extracted with dichloromethane (4 x 50 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, concentrated. The residue was separated with flash column chromatography on silica gel using 1-10% methanol in dichloromethane, and 30-100% ethyl acetate/Hexane to afford product (201.8 mg) in 13% yield. NMR (500 MHz, Chloroform-*/) delta 5.12 (s, 2H), 4.06 - 4.02 (m , 2H), 3.52 - 3.46 (m, 2H), 1.50 (s, 6H), 1.44 (s, 9H). MS for C 14H23CIN6O2: 343.2 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37.2% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | A mixture of 7-methoxy-8- (1-methyl-1H-pyrazol-3-yl) -1- (thiophen-3-yl) -1, 4-dihydrochromeno [4, 3-c] pyrazole-3-carboxylic acid (50 mg, 0.123 mmol) , HATU (51 mg, 0.135 mmol) , tert-butyl 3, 3-dimethylpiperazine-1-carboxylate (34 mg, 0.135 mmol) and DIPEA (48 mg, 0.369 mmol) in DMF (3 ml) was was stirred at RT overnight. Then the mixture was purified by Combi-Flash (mobile phase: acetonitrile/water (10 mM NH4HCO3) to afford tert-butyl 4- (7-methoxy-8- (1-methyl-1H-pyrazol-3-yl) -1- (thiophen-3-yl) -1, 4-dihydrochromeno [4, 3-c] pyrazole-3-carbonyl) -3, 3-dimethylpiperazine-1-carboxylate (55 mg, 37.2) as a white solid. LCMS m/z605 [M+H] +. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86.26% | With 4-methyl-morpholine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In N,N-dimethyl-formamide; at 20℃; for 0.5h; | To a solution of 7-bromo-5-chloro-furo[3,2-b]pyridine-2-carboxylic acid (200 mg, 0.723 mmol) and <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (164.3 mg, 0.767 mmol) in DMF (2.13 mL) was added N-methyl morpholine (329.2 mg, 357.8 muL, 3.26 mmol) at ambient temperature. T3P (575.4 mg, 0.904 mmol) 50% W/W in DMF was added dropwise and the solution was stirred at room temperature for 30 minutes. NaHCO3 was added and the aqueous phase was extracted with EtOAc 3 times. The combined organic phase was washed with sat aq. ammonium chloride and brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography affording the title compound, tert-butyl 4-(7-bromo-5-chloro-furo[3,2- b]pyridine-2-carbonyl)-3,3-dimethyl-piperazine-1-carboxylate (295 mg, 0.6240 mmol, 86.26%). ESI-MS m/z calc.471.05606, found 472.24 (M+1)+; Rt: 2.05 min using Method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | Scheme 2 [00253] 7-Chloro-5-(4-fluorophenyl)furo[3,2-b]pyridine-2-carboxylic acid (Intermediate A) (390 mg, 1.34 mmol) was dissolved in DMF (6 mL) before HATU (661 mg, 1.74 mmol), <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (287 mg, 1.34 mmol) and Huenig's base (932 muL, 5.35 mmol) were added. The solution was stirred at room temperature for 3h, and then saturated aqueous NH4Cl is added. The aq. phase was extracted twice with EtOAc. The combined organic phase was washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic phase was then dried over MgSO4, filtered and the filtrate evaporated under reduced pressure. The crude product was used in the subsequent step without further purification. tert-Butyl 4-[7-chloro-5-(4- fluorophenyl)furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazine-1-carboxylate (170 mg, 24% yield). ESI-MS m/z calc.487.16742, found 488.39 (M+1)+; Retention time: 2.16 minutes using method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 72h; | Scheme 6 Step I: tert-Butyl 4-[5-(4-fluorophenyl)-7-isopropyl-furo[3,2-b]pyridine-2-carbonyl]- 3,3-dimethyl-piperazine-1-carboxylate The product was prepared according to General Procedure 1 using Intermediate D (750 mg, 2.51 mmol), HATU (1.24 g, 3.26 mmol), DMF (12 mL), Huenig's base (1.31 mL, 7.52 mmol) and tert-butyl 3,3-dimethylpiperazine- 1-carboxylate (591 mg, 2.76 mmol) affording the title compound. tert-Butyl 4-[5-(4- fluorophenyl)-7-isopropyl-furo[3,2-b]pyridine-2-carbonyl]-3,3-dimethyl-piperazine-1- carboxylate (1.24 g, 100% yield). An aliquot of the crude product was purified by mass- directed reverse phase HPLC affording the title compound, the remaining product was used in the subsequent step without further purification.1H NMR (400 MHz, DMSO-d6) 8.23 - 8.14 (m, 2H), 7.88 (s, 1H), 7.50 (s, 1H), 7.33 (t, J = 8.9 Hz, 2H), 3.86 (s, 2H), 3.58 - 3.39 (m, 5H), 1.49 (s, 6H), 1.42 (d, J = 7.7 Hz, 15H). ESI-MS m/z calc.495.25333, found 496.79 (M+1)+; Retention time: 2.02 minutes using method C General Procedure 1: Amide Formation The appropriate carboxylic acid (1.0 equiv) is dissolved in DMF or NMP (0.03 to 0.4M) before HATU (1.1 to 1.5 equiv), or T3P (1 to 5 equiv) the corresponding amine (1.0 to 1.5 equiv) and Huenig?s base (3.0 to 5.0 equiv) are added (the addition order of the reagents may vary) The mixture is stirred at room temperature for 45 min. to 72h. Either one of these 3 work-up procedures can be employed: 1. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with brine, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification. 2. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with 1N HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification. 3. The volatiles are removed under reduced pressure and the residue is purified by flash chromatography on silica gel or by mass-directed reverse phase HPLC, affording the title compound |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | To a solution of Intermediate M (27 mg, 0.090 mmol) in DMF (1.5 mL) were added <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (30 mg, 0.13 mmol), HATU (51 mg, 0.13 mmol) and Huenig?s base (63 muL, 0.36 mmol) and the solution was stirred at room temperature overnight. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography on silica gel eluting with 0-25% EtOAc: Hexanes affording the title compound. tert-Butyl 4-[2-(4-fluorophenyl)-4-isopropyl- furo[3,2-d]pyrimidine-6-carbonyl]-3,3-dimethyl-piperazine-1-carboxylate (32 mg, 72% yield).1H NMR (400 MHz, Chloroform-d) 8.63 - 8.37 (m, 2H), 7.27 (s, 1H), 7.19 - 6.95 (m, 2H), 3.79 (dd, J = 6.6, 4.8 Hz, 2H), 3.66 - 3.40 (m, 5H), 1.59 (s, 6H), 1.47 (d, J = 6.5 Hz, 15H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (19.90 g, 92.86 mmol) and (2,2-dimethylpiperazin-1-yl)methanone hydrochloride (Intermediate II) (27.87 g, 84.60 mmol) were dissolved in DMF (300 mL) before HATU (35.45 g, 93.23 mmol) and DIPEA (27.72 g, 37.36 mL, 214.5 mmol) were added. The solution was stirred at room temperature for 3h, and then water was added dropwise. The aq. phase was extracted three times with EtOAc. The combined organic phase was washed with water and brine. The organic phase was then dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure. The crude product was purified passing through a pad of silica gel (25%-33% EtOAc/hexanes affording the title product (34.28 g, 91% yield) as a yellow orange foamy solid, which was used directly in the next step. 1H NMR (400 MHz, Chloroform-d) 7.34 (s, 1H), 7.06 (s, 1H), 3.84 (dd, J = 6.6, 4.8 Hz, 2H), 3.67 - 3.45 (m, 4H), 2.71 (tt, J = 10.3, 5.5 Hz, 1H), 1.85 - 1.77 (m, 4H), 1.77 - 1.71 (m, 1H), 1.57 - 1.51 (m, 2H), 1.49 (s, 9H), 1.49 (s, 9H), 1.43 - 1.31 (m, 3H), 1.01 (s, 3H), 0.97 (s, 3H). ESI-MS m/z calc.525.3567, found 526.61 (M+1)+; Retention time: 3.15 minutes using method A |
91% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; for 3h; | <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (19.90 g, 92.86 mmol) and (2,2- dimethylpiperazin-1-yl)methanone hydrochloride (Intermediate C) (27.87 g, 84.60 mmol) are dissolved in DMF (300 mL) before HATU (35.45 g, 93.23 mmol) and DIPEA (27.72 g, 37.36 mL, 214.5 mmol) are added. The solution is stirred at room temperature for 3h, and then water is added dropwise. The aq. phase is extracted three times with EtOAc. The combined organic phase is washed with water and brine. The organic phase is then dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure. The crude product is purified passing through a pad of silica gel (25%-33% EtOAc/hexanes affording the title product (34.28 g, 91% yield) as a yellow orange foamy solid, which is used directly in the next step. 1H NMR (400 MHz, Chloroform-d) 6 7.34 (s, 1H), 7.06 (s, 1H), 3.84 (dd, J = 6.6, 4.8 Hz, 2H), 3.67 - 3.45 (m, 4H), 2.71 (tt, J = 10.3, 5.5 Hz, 1H), 1.85 - 1.77 (m, 4H), 1.77 - 1.71 (m, 1H), 1.57 - 1.51 (m, 2H), 1.49 (s, 9H), 1.49 (s, 9H), 1.43- 1.31 (m, 3H), 1.01 (s, 3H), 0.97 (s, 3H). ESI-MS m/z calc. 525.3567, found 526.61 (M+1) Retention time: 3.15 minutes using method A. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; | To a solution of <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (152.4 mg, 0.711 mmol) in dry DMF (2.5 mL) was added 7-tert-butyl-5-(4,4-dichlorocyclohexyl)furo[3,2- b]pyridine-2-carboxylic acid (240 mg, 0.6482 mmol), DIPEA (212.3 mg, 286.1 muL, 1.64mmol) and HATU (271.6 mg, 0.7143 mmol). After 30 min, H2O (20 mL) was added. The mixture was extracted with EtOAc (X3), dried (MgSO4), and the solvent was removed under reduced pressure to afford tert-butyl 4-[7-tert-butyl-5-(4,4- dichlorocyclohexyl)furo[3,2- b]pyridine-2-carbonyl]- 3,3-dimethyl-piperazine-1- carboxylate (235 mg, 64%). To the N-Boc intermediate in dioxane (4.94 mL) was added HCl in dioxane (810.2 muL 4 M, 3.24 mmol). The mixture was stirred for 24 h, and MeOH (0.05 mL) was added and stirring continued for 3 h. The solvent was removed in vacuo to give 7-tert-butyl-5-(4,4- dichlorocyclohexyl)furo[3,2-b]pyridin-2-yl]-(2,2- dimethylpiperazin-1-yl)methanone (Hydrochloride salt) (210 mg, 101%). ESI-MS m/z calc.465.19498, found 466.3 (M+1)+; Rt: 1.27 minutes using Method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
66% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; | 7-tert-butyl-5-(4,4-difluorocyclohexyl)furo[3,2-b]pyridine-2-carboxylic acid (910 mg, 2.697 mmol) and <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (578.0 mg, 2.697 mmol) was dissolved in DMF (3.3 mL). HATU (1.33 g, 3.51 mmol) and DIPEA (1.64 mL, 9.44 mmol) were successively added at RT. The reaction mixture was stirred overnight. EtOAc along with water were added. The phases were separated, and concentrated in vacuo to afford the title compound (950 mg, 66%). ESI-MS m/z calc. 533.3065, found 534.21. Rt: 2.48 min using Method C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In dichloromethane; at 0 - 20℃; for 3h; | A solution of 21 (200 mg, 0.93 mmol) in CH2C12 (5.0 mL) was charged with TFA (1.0 mL) at 0C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to afford 22 [100 mg (cmde), 94%j as a liquid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | With N-ethyl-N,N-diisopropylamine; In 1-methyl-pyrrolidin-2-one; at 20℃; for 2h; | General procedure: In a 1 L round-bottom flask with a magnetic stir bar, compound 7 (46 g, 0.2014 mol, 1.0 eq.) was diluted in DIEA (41.64 mL, 0.2416 mol, 1.2 equivalents) and THF (700 mL). Solid N-Boc piperazine (39.38 g, 0.2114 mol, 1.05 eq.) was slowly added in portions. A mild exothermic reaction was observed. The reaction mixture was allowed to stir at room temperature for 2 hours then was quenched with saturated NaCl solution (100 mL), water (400 mL), and EtOAc (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were dried (Na2SO4) and concentrated to give a gray solid. The crude solid was stirred in 2:1 TBME/hexanes (300/150 mL) overnight. The solids were filtered then washed with hexane (250 mL) to recover 52 g of impure product. The TBME/hexanes slurry was repeated to recover 46 g (59%) of compound 8. All remaining impure material was combined and purified via silica gel chromatography (4:1 hexane/EtOAc) to recover another 11.2 g (14%) of 8 for a total combined yield of 57.2 g (74%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With potassium carbonate; In N,N-dimethyl-formamide; at 20℃; for 14h; | To a stirred solution of 4-(bromomethyl)pyridin-2-amine hydrobromide (2.50 g, 9.33 mmol) in DMF (30 mL) was added potassium carbonate (5.16 g, 37.3 mmol) and <strong>[259808-67-8]tert-butyl 3,3-dimethylpiperazine-1-carboxylate</strong> (2.409, 11.2 mmol). The mixture was stirred at r.t. for 14 h. Water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with half-saturated sodium chloride solution, dried (sodium sulfate) and the solvent was removed in vacuum. Aminophase-silicagel chromatography followed by silicagel chromatography gave 2.20 g (74 % yield) of the title compound.LC-MS (Method 2): Rt = 1.16 mm; MS (ESIpos): m/z = 321 [M+H]1H-NMR (400 MHz, DMSO-d6) 6 [ppm]: 1.004 (9.22), 1.027 (0.55), 1.042 (0.53), 1.390 (16.00),2.276 (0.67), 3.126 (0.69), 3.335 (3.19), 5.788 (1.25), 6.414 (0.98), 6.423 (0.68), 6.435 (0.58),7.775 (0.78), 7.777 (0.73), 7.788 (0.73), 7.790 (0.73). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis(tri-t-butylphosphine)palladium(0); sodium t-butanolate; In toluene; at 110℃; for 2h;Inert atmosphere; | Step 1 : tert-butyl 4-(4-fluorophenyl)-3,3-dimethyl-piperazine-l-carboxylate [00400] A32-1 (200.0 mg, 0.933 mmol, 1.00 eq), A32-2 (310.8 mg, 1.40 mmol, 0. 16 mL, (1153) 1.50 eq), f-BuONa (179.4 mg, 1.87 mmol, 2.00 eq) and bis(tri-tertbutylphosphine) Palladium(O) (47.69 mg, 0.093 mmol, 0. 10 eq) were taken up into toluene (6.00 mL). The reaction mixture was stirred at 1 10 C for 2 hour under N2. LCMS and TLC (Petroleum ether: Ethyl acetate=10/l) showed desired compound was found and the starting material was consumed completely. The reaction mixture was concentrated to give a crude product. The residue was purified by Prep- TLC (Petroleum ether: Ethyl acetate= 10/1) to give the A32-3 (260.0 mg, 0.776 mmol, 83. 1 1% yield, 92% purity) as a yellow oil. LCMS (ESI): RT =0.630 min, mass calcd. for C17H25FN2O2 308.19, m/z found 308.9 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 110℃; for 4h;Microwave irradiation; | A 2OmL microwave reaction vessel is charged with methyl 4-42-[44[2-4[3- (chloromethyl)benzoyl]amino14, 5,6,7tetrahydrobenzothiophene3 -carbonyi1aminoi2,6 difiuoro-phenyI]ethyijhenzoate (1 .85 g, 2.97 mmol), tert-hutyi 3,3dimethylpiperazine-icarboxylate (0.91 g, 416 mmol), and DllEA (207 mL, 11.9 mmol)in 15 mL of ACN. The resulting yellow suspension is heated in a BIOTAGE Initiator microwave synthesizer at 110C for 4 hr. The reaction mixture is concentrated in vacuo and the residue is partitionedbetween 5% aqueous NaHCO3 (150 mL) and DCM (50 ml,). The organic layer is separated, the aqueous layer is extracted with DCM (2 x 25 rnL). The combined organic layers arewashed with saturated aqueous NaC1 (50 ml.), dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The resulting residue is purified by chromatography over silica, eluting with a gradient of 0 100% of a mixture of 9: 1 I)CM/acetone in hexane, to afford the title compound as a yellow solid (163 g, 69% yield) after solvent evaporation. ?HMvR(400.i MHz, DMSOd6) oe 1.04 (s, 6H), 1.38 (s, 9H),1.81-1.74 (m, 4H), 2.28 (t, J 5.0 Hz, 2H), 2.70 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide; at 20℃; | General procedure: The appropriate carboxylic acid (1.0 equiv) is dissolved in DMF or NMP (0.03 to 0.4M) before HATU (1.1 to 1.5 equiv), or T3P (1 to 5 equiv) the corresponding amine (1.0 to 1.5 equiv) and Hunig?s base (3.0 to 5.0 equiv) are added (the addition order of the reagents may vary) The mixture is stirred at room temperature for 45 mm. to 72h. Any one of these 3 work-up procedures can be employed:1. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with brine, dried over MgSO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification.2. Water or aq. ammonium chloride is added and the aq. phase is extracted with EtOAc. The combined organic phase is washed with iN HCI, sat. aq. NaHCO3 and brine, dried over Na2SO4, filtered and the filtrate evaporated under reduced pressure affording the title compound which is used in the subsequent step without further purification.3. The volatiles are removed under reduced pressure and the residue is purified by flash chromatography on silica gel or by mass-directed reverse phase HPLC, affording the title compound; The intermediate is prepared according to General Procedure 1 using a solution of Intermediate A (10.0 g, 28.3 mmol) in DMF (110 mL), HATU (12.0 g, 31.6 mmol), tert-butyl 3,3- dimethylpiperazine-1-carboxylate (6.64, 31.0 mmol) and DIPEA (12.5 ml, 71.8 mmol) affording the title compound (15.38 g, quantitative yield) as a pale yellow solid, which is used directly in the next step. 1H NMR (400 MHz, DMSO-d6) 6 8.16 (dd, J = 11.0, 2.0 Hz, 1H), 8.07 - 7.97 (m, 1H), 7.82 (s, 1H), 7.76 - 7.64 (m, 1H), 7.51 (s, 1H), 3.85 (s, 2H), 3.57 - 3.38 (m, 4H), 1.52 (s, 1OH), 1.48 (s, 6H), 1.42 (s, 9H). ESI-MS m/z calc. 543.2300, found 546.10 (M+1) Retention time: 1.23 minutes using method J. |
Tags: 259808-67-8 synthesis path| 259808-67-8 SDS| 259808-67-8 COA| 259808-67-8 purity| 259808-67-8 application| 259808-67-8 NMR| 259808-67-8 COA| 259808-67-8 structure
[ 129779-30-2 ]
(3R,5S)-rel-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 180975-66-0 ]
tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 639068-43-2 ]
tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 438049-91-3 ]
(3R,5R)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 129779-30-2 ]
(3R,5S)-rel-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 180975-66-0 ]
tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 639068-43-2 ]
tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 438049-91-3 ]
(3R,5R)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 129779-30-2 ]
(3R,5S)-rel-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 180975-66-0 ]
tert-Butyl cis-2,6-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 639068-43-2 ]
tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
[ 438049-91-3 ]
(3R,5R)-tert-Butyl 3,5-dimethylpiperazine-1-carboxylate
Similarity: 0.96
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Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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