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Structure of 109-01-3
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 109-01-3 |
Formula : | C5H12N2 |
M.W : | 100.16 |
SMILES Code : | CN1CCNCC1 |
MDL No. : | MFCD00005966 |
InChI Key : | PVOAHINGSUIXLS-UHFFFAOYSA-N |
Pubchem ID : | 53167 |
GHS Pictogram: |
![]() ![]() ![]() |
Signal Word: | Danger |
Hazard Statements: | H225-H303-H312+H332-H314 |
Precautionary Statements: | P241-P242-P264-P270-P271-P272-P280-P304+P340-P305+P351+P338-P310-P330-P331-P363-P370+P378-P403+P233-P501 |
Class: | 3(8) |
UN#: | 2924 |
Packing Group: | Ⅱ |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 0 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 1.0 |
Molar Refractivity | 37.56 |
TPSA ? Topological Polar Surface Area: Calculated from |
15.27 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.66 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.39 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-1.24 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.62 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.1 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.22 |
Solubility | 61.0 mg/ml ; 0.609 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.53 |
Solubility | 342.0 mg/ml ; 3.41 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.69 |
Solubility | 20.7 mg/ml ; 0.207 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
Low |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
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 |
-7.19 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 |
1.0 |
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) |
1.1 |
* 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 |
---|---|---|
44.1% | With sodium hydroxide In acetone at 20℃; for 24 h; Cooling with ice | N-methylpiperazine (30 mmol, 3.3 ml), 4 ml of 25percent NaOH solution and 40 ml of acetone were added to a 100 ml round-bottomed flask under ice-cooling, then 1-bromo-3-chloropropane (30 mmol, 3 ml) After completion of ice bath stirring to insoluble material dissolved, and then at room temperature for 24h.The solvent was concentrated under reduced pressure, 20 ml of water-soluble concentrate was added, extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated to give a clear oil. The reaction flask was placed in an ice bath and 50 ml of ethyl acetate was added. 2.5 ml of concentrated hydrochloric acid was added dropwise slowly until a large amount of white solid was formed. The pH was controlled to about 2 during the reaction. The solvent was concentrated under reduced pressure, recrystallized from 100 ml of anhydrous ethanol, filtered and dried to obtain 3.3 g of a white solid, |
25% | Stage #1: With sodium hydroxide In water; acetone at 0 - 20℃; for 24 h; Stage #2: With hydrogenchloride In ethanol |
A modified procedure of Mahesh et al, Pharmazie, 2005, 60, 6, 411-414, was used. After cooling a stirred solution of N-methylpiperazine (50 mmol, 5.55 ml) in 100 ml acetone to 0 °C, 10 ml of an aqueous 25 percent NaOH-solution and l-bromo-3-chloropropane (50 mmol, 7.87 g = 4.92 ml) were added cautiously. The reaction was stirred at RT for 24 hours. After concentrating the mixture under reduced pressure, the residue was diluted with water and extracted with dichloromethane. The collected organic phases were dried over Na2S04, filtered and concentrated. The residue was diluted with ethanol and after adding 2.3 M ethanolic HC1 l-(3-chloropropyl)-4-methylpiperazin-dihydrochloride crystallized as white crystals(12.5 mmol, 25 percent). Mp = 257 °C. ]H NMR (300 MHz, DMSO) 3.74 (t; 2H; 3J = 6.4 Hz; NCH7CH7CH7CI); 3.37 (m; 12H: NCH7CH7CH7Cl+4xpiperazin-CH7+2x H); 2.81 (s; 3H; CH3); 2.19 (d; 2H; J = 6.8 Hz; NCH2CH2CH2CI). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With sodium tetrahydroborate; acetic acid In chloroform at 0 - 20℃; for 13 h; | General procedure: AcOH (100percent) (140 mL, 2.44 ml) was added over 1 h to a flask containing stirred NaBH4 (20.0 g, 0.53 ml) and CHCl3 (220 mL) at 0-5 °. The resulting mixture was stirred at 0-5 ° for 1.5 h and 1-methylpiperazine (1) (28.0 ml, 0.25 ml) and a solution of methyl 4-formylbenzoate (2a) (43.4 g, 0.26 ml) in CHCl3 (60 mL) were added. The resulting mixture was stirred at 0-5 ° for 1 h and then for 12 h at rt. the mixture was treated with H2O (150 mL) and Na2CO3 until pH 8.0-9.0. The aqueous phase was extracted with EtOAc (2 .x. 100 ml) then both organic layers were combined, washed with H2O (1 .x. 100 ml), and dried over anhydrous Na2SO4. Filtration and evaporation of the solvents gave methyl 4-[(4-methylpiperazin-1-yl)methyl]benzoate (4a): yellowish oil; yield: 61.6 g, 99percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With potassium carbonate; potassium iodide In acetonitrile for 5 h; | 4-nitrobenzylbromide (4.30 g, 20 mmol) was dissolved in 40 ml of acetonitrile solvent,Then K2CO3 (5.52 g, 40 mmol) was added,KI (0.33 g, 2 mmol),Then, 4-methylpiperazine (2.20 g, 22 mmol) was added thereto,After 5 h, the reaction was complete.The reaction solution was concentrated and dried,And further adding 100 ml of H2O thereto,Extracted with ethyl acetate (150 ml x 3)The organic layer was collected, concentrated,4.32 g of a solid was obtained in 92percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | at 20℃; for 24 h; | The First Step: Preparation of 1-methyl-4-(4-nitrobenzyl)-piperazine (F652-01) Monomethylpiperazine (15 mL) and tetrahydrofuran (60 mL) were placed in a 200 mL eggplant shaped flask, and a solution of 4-nitrobenzylchloride (8.58 g, 50 mmol) in tetrahydrofuran was added dropwise to the mixture at room temperature while stirring. After finishing the instillation, the mixture was stirred at room temperature for 24 hours. The reaction mixture was mixed with distilled water, and the precipitated solids were collected by filtration and dried under reduced pressure to obtain the title compound (5.9 g, 50percent). LC/MS (Method 3): m/z (ESI, POS): 236[M+H]+; retention time: 1.28 minutes. |
59% | With sodium carbonate; triethylamine In ethylene glycol | A. 1-methyl-4-[(4-nitrophenyl)methyl]piperazine To a solution of p-nitrobenzyl chloride (5.2 g, 10mM) and 3.2 g of triethylamine in 30 ml of ethylene glycol is added a solution of N-methylpiperazine (3 g, 30 mM) in 20 ml of ethylene glycol. After complete addition, the resulting solution is heated to 80° C. under nitrogen for 30 minutes. The reaction mixture is quenched into aqueous 10percent sodium carbonate solution and extracted with methylene chloride. The methylene chloride solution is washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to give 4.15 g (59percent) of 1-methyl-4-[(4-nitrophenyl)methyl]piperazine. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 90℃; for 18 h; | 31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of 1-methyl-piperazine are combined and stirred for 18 hours at 90° C. Then the solution is poured onto ice water and the precipitate formed is suction filtered, washed with water and recrystallised from ethanol/water (1:1). The residue is dried in vacuo at 75° C. [00369] Yield: 44.0 g (99percent of theory), [00370] Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) [00371] Melting point: 108-112° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | at 100℃; for 2 h; | Step 3 1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95percent) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam. MS (ISP): 311 (M+H+, 100), 254 (62). |
95% | at 100℃; for 2 h; | Step 3: (0177) 1.0 g (4.05 mMol) 6-Chloro-4-o-tolyl-nicotinamide in 9.0 ml 1-methyl-piperazine was heated to 100° C. for 2 hours. The excess N-methyl-piperazine was removed under high vacuum and the residue was filtered on silica gel (eluent: dichloromethane) to yield 1.2 g (95percent) 6-(4-methyl-piperazin-1-yl)-4-o-tolyl-nicotinamide as a light yellow crystalline foam. (0178) MS (ISP): 311 (M+H+, 100), 254 (62). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.52% | With potassium carbonate; In N,N-dimethyl-formamide; at 80℃; for 4.5h; | 200 g of the compound 4-chloromethyl-N- [4-methyl-3- (4-pyridin-3-pyrimidin-2-amino) phenyl] benzamide was added to1.8 L of N, N-dimethylformamide,86.9 g of potassium carbonate (d (0.5) was 20 mum) and 51 g of N-methylpiperidine were added with stirring,80 reaction,4.5 hours TLC detection reaction was complete,Drop to room temperature,Add 10.8L of purified water,filter,dry,Get 228.9g crude imatinib, the yield of 99.2%Purity 98.76%.Refined imatinib crude:228.5 g of imatinib obtained was added to 800 ml of ethanol,Reflux dissolved,Cooled to 0 ~ 5 ,filter,dry,Get imatinib 224.3g,Yield 97.52%. |
91% | In 1,4-dioxane; at 135℃; for 3h;Conversion of starting material; | Example 9 A flask containing a mixture of 4-chloromethyl-N-{4-methyl-3- [(4-pyridin-3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide obtained in the previous step (56.072 g; 0.130 M), N-methylpiperazine (84 mL; 75.852 g; 0.757 M) and dioxane (56 mL) was placed in an oil bath at temperature 135C and the reaction mixture was heated for 3 hours. After that time the oil bath was taken away and after cooling the reaction mixture, acetone (150 mL) was added and stirring was continued until the mixture was cooled down to room temperature. The precipitated product was filtered off, washed with cold acetone EPO <DP n="29"/>(50 mL) and dried in the air to afford 59.2 g (yield 91%) of the title compound in the form of a cream-coloured, crystalline solid. M.p. 167-1700C. iH NMR (DMSO-d6): 10.16 (IH, s), 9.27 (IH, d, J=2.2), 8.98 (IH, s), 8.68 (IH, dd, J=4.8-1.6), 8.51 (IH, d, J=5.3), 8.48 (IH, dt, J=8.2-2.0), 8.08 (IH, d, J=I.8), 7.90 (2H, d, J=8.2), 7.45 (5H, m), 7.20 (IH, d, J=8.6), 3.52 (2H, s), 2.35 (8H, m), 2.22 (3H, s), 2.15 (3H,s). |
91 - 96% | at 120 - 130℃; for 1.5h;Conversion of starting material; | Example 10 A flask containing a mixture of 4-chloromethyl-N-{4-methyl-3- [(4-pyridin-3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide (55.276 g; 0.129 M) and N-methylpiperazine (83 mL; 74.949 g; 0.748 M) was placed in an oil bath at temperature 120-1250C and the reaction mixture was heated for 90 minutes. After that time the oil bath was taken away, isopropanol (300 mL) was added to the hot mixture and stirring was continued until the mixture was cooled down to room temperature. The precipitated product was filtered off, washed with cold isopropanol (50 mL) and dried in the air to afford 58.7 g (92%) of the product. Example 11 A flask containing a mixture of 4-chloromethyl-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide (54.953 g; 0.129 M) and N-methylpiperazine (83 mL; 74.949 g; 0.748 M) was placed in an oil bath at temperature 120-1250C and the reaction mixture was heated for 90 minutes. After that time the oil bath was taken away, isopropanol (200 mL) was added to the hot mixture and stirring was continued until the mixture was cooled down to room temperature. The precipitated product was filtered off, washed with a mixture of isopropanol and water (1: 1, 100 mL) and dried in the air to afford 57.7g (91%) of the product. EPO <DP n="30"/>Example 12 A flask containing a mixture of 4-chloromethyl-N-{4-methyl-3- [(4-pyridin-3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide (54.949g; 0.129 M) and N-methylpiperazine (83 mL; 74.949 g; 0.748 M) was placed in an oil bath at temperature 120-1250C and the reaction mixture was heated for 90 minutes. After that time the oil bath was taken away, water (100 mL) was added to the hot mixture and stirring was continued until the mixture was cooled down to room temperature. The precipitated product was filtered off and the residue was taken from the flask with water (80 mL). The whole precipitate was washed with water (3x 100 mL) to afford 60.2g (95%) of the product. Example 13 A flask containing a mixture of 4-chloromethyl-N-{4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-ylamino]-phenyl}-benzamide (55.00Og; 0.128 M) and N-methylpiperazine (83 mL; 74.949 g; 0.748 M) was placed in a cold oil bath and the reaction mixture was heated until the bath temperature has reached 1300C. Heating at that temperature was continued for 90 minutes. After that time the oil bath was taken away, and when temperature of the reaction mixture dropped to 95C, water (100 mL) was added. Stirring was continued until the mixture was cooled down to room temperature. A solution of sodium hydroxide (5.12g) in water (100 mL) was added and the mixture was stirred for 30 min. The precipitated product was filtered off, washed with water (300 mL) to afford 60.6g (96%) of the product. |
89% | With calcium carbonate; In N,N-dimethyl-formamide; | <strong>[404844-11-7]4-(chloromethyl)-N-(4-methyl-3-(4-(pyridin-3-yl)pyrimidin-2-ylamino)phenyl)benzamide</strong>(4) (0.5 g, 1.16 mmol) and 1-methylpiperazine (0.23 g, 2.33 mmol) were reacted with CaCO3 (0.23 g, 2.33mmol) in 5 mL of DMF. The mixture was stirred at 90 oC for 12 h. Thereaction mixture was filtered, and removed the solvent under vacuum. And theresulting solid was washed with water and dried to produce solid with 89% yield (0.51 g, 1.03 mmol). 1HNMR (300 MHz, DMSO) delta 10.16 (s, 1H), 9.27 (d, J = 1.5 Hz, 1H), 8.97(s, 1H), 8.68 (dd, J = 3.3 Hz, 1H), 8.52-8.46 (m,2H), 8.08 (d, J = 1.8 Hz, 1H), 7.90 (d, J =8.4 Hz, 2H), 7.5-7.42 (m, 5H), 7.20 (d, J= 8.4 Hz, 1H), 3.52 (s, 2H), 2.36 (bs, 8H), 2.20 (s, 3H), 2.15(s, 3H). 13C NMR (75 MHz, DMSO): delta165.2, 161.6, 161.2, 159.5, 151.4, 148.2, 142.1, 137.8, 137.2, 134.4, 133.8,132.2, 130.0, 128.6, 127.56 (2C), 123.8, 117.2, 116.7, 107.5, 61.6, 54.7, 52.6,45.7, 17.6. HRMS (ESI) calcd. for C29H32N7O[M+H]+ 494.2668,found 494.2668. |
61% | In DMF (N,N-dimethyl-formamide); at 20 - 40℃; for 4.25h; | Into the reactor 40 L Dimethyl formamide is charged (DMF) into thereactor 19.7 Kgs of N-methyl piperazine is charged. It is stirred for 15 minutes. 13.9Kg of compound of formula (II)is charged to the reaction mass slowly during four hoursat 20-40C. Reaction mass is poured into 400 L DM water and stirred for 15 minutes.Reaction mass is extracted with 3 x 100 L chloroform. All chloroform layers arecombined and washed with 2 x 100 L 5% aq. Sodium hydroxide solution 2 x 100 Lts DMwater. Carbon treatment is given to the chloroform layer. Organic layer Dried oversodium sulfate and distilled off completely under vacuum. 100 Lts Ethyl acetate ischarged to the residue and stirred for 15 minutes at 25-35C. The product of the formula(la)is centrifuged and washed with 40 L Ethyl Acetate. It is dried in oven at 60-70CDrywt. : 9.8 Kg (61%)MR: 202-206C.Purity by HPLC : 99.8% |
In N,N-dimethyl-formamide; at -6 - 5℃; for 2h;Product distribution / selectivity; | Nu,Nu-Dimethylformamide (250 ml) was added to N-methylpiperazine (1750 ml) and the mixture was cooled to -6C to -1C. 4-Chloromethyl-N-[4-methyl-3-[[4-(3-pyridinyl)-2- pyrimidinyl] amino ]phenyl]benzamide (250 g) was added to the resulting mass at -6C to - 1C and then stirred for 2 hours at -5C to 5C. The reaction mass was quenched into a mixture of water (7 L), ethyl acetate (875 ml) and aqueous ammonia (500 ml) at 20-30C, and the resulting mass was stirred for 3 hours at 20-30C. The resulting solid was filtered and washed with water (1250 ml).[0213] The resulting wet solid (content of 4-methylbenzamide impurity at 2.94 RRt: 1.5% as measured by HPLC) was placed in another reaction flask, followed by the addition of water (2500 ml) and adjusting the pH of the mixture to 3.0 to 4.0 with acetic acid (125 ml). The resulting mixture was filtered through hyflow bed, washed the hyflow bed with water (250 ml) and the resulting aqueous layer was washed with ethyl acetate (1000 ml x 3). The aqueous layer was separated and followed by the addition of ethyl acetate (750 ml) and aqueous ammonia (500 ml) and stirring the resulting mixture for 3 hours at 20-30C. The separated solid was filtered, washed with water (1250 ml) and then dried the material in air oven at 55-65C to give 240 g of crude imatinib free base (Purity by HPLC: 99.7%).Content of Impurities measured by HPLC:1. 4-Methylbenzamide impurity at 2.94 RRt: 0.06%2. '2.24 RRt' impurity: 0.06%3. Formamide impurity at 1.20 RRt: 0.01 %4. Desmethyl impurity at 0.9 RRt: 0.06%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With potassium carbonate; In 1,4-dioxane; for 1h;Heating / reflux; | PREPARATION 14; EPO <DP n="71"/>4-Methyl-3,4,5,6-tetrahvdro-2H-?,2'lbipyrazinyl-3'-carbaldehvde;.S-Chloro-pyrazine^-carb-aldehyde (Turck, et al., Synthesis 1988, 881-4) (6.01 g, -40 mmol), N-methylpiperazine (6.6 mL, 59.4 mmol) and K2CO3 (8.3g, 60.0 mmol) were refluxed for 1h in dioxane (250 mL). After cooling, the mixture was filtered and concentrated to an orange oil. This was dissolved in EtOAc (500 mL) and washed with water (4x150 mL) and brine, dried (MgSO4) and concentrated. Chromatography with 5% MeOH/ CH2CI2 gave 3.34 g (40%) of PP14 as a dark red oil : NMR (CDCI3) 9.94 (s, 1 H), 8.18 (d, J= 2.1 Hz, 1 H), 8.08 (d, J = 2.1 Hz, 1 H), 3.59 (t, J= 5.2 Hz, 4H), 2.53 (t, J = 5.0 Hz, 4H), 2.32 (s, 3H). |
With potassium carbonate; In 1,4-dioxane; at 100℃; for 1.5h; | Preparation 1; 4-Methyi-3,4,5,6-tetrahydro-2H-[1,2'lbip(at)rrazinyl-3'-carbaldehyde; n-BuLi (56 mmol, 22.4 mL, 2.5 M in hexanes) was added to tetrahydrofuran (300 mL) cooled to-78 C followed by the addition of 2,2-6,6-tetramethylpiperidine (52 mmol, 8.71 mL). The solution was removed from the cooling bath and stirred for 30 minutes and then cooled back to -78C. 2-chloropyrazine (40 mmol, 3.65 mL) was added dropwise, and the solution turned a reddish-brown color. After stirring 30 minutes, methylformate (60 mmol, 3.7 mL) was added and the reaction mixture was stirred for 2.25 hrs at -78C. Acetic acid (8 mL) was added and the mixture was warmed to 0C, was washed 3 times with 1: 1 brine-water, dried over sodium sulfate, and then concentrated in vacuo. The residue was dissolved in 1,4- dioxane (250 mL) and 1-methylpiperazine (60 mmol, 6.6mL) and potassium carbonate solution (8.28g in 60 mL of water) were added and the mixture was heated at 100C for 1.5 hours. After cooling to room temperature, the mixture was filtered through a Celite pad which was then washed with chloroform. The filtrate was concentrated in vacuo and purified by silica gel chromatography (100: 1:1 chloroform-methanol-ammonium hydroxide) to yield 3.3 g (40% yield for two steps) of 4-methyl-3,4,5,6-tetrahydro-2H-[1,2']bipyrazinyl-3'-carbaldehyde; ¹3C NMR (100 MHz, CDC13) d 191.7,154.3, 145.3,134.5, 133.2, 55.1, 48.7, 46.3; MS (AP/CI) 207.2 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 20h; | 5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition Of K2CO3 (1.3g, 9.6 mmol) and 1 -methyl piperazine (1.4 ml, 12.8 mmol). The reaction mixture was heated at 80 0C for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl- rhoirhoerazin-l-yl)-benzonitrile (1.4g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M + H]+ 236, acidic method). |
93% | With potassium carbonate; In dimethyl sulfoxide; at 80℃; for 20h; | 18A. Synthesis of 3-Cmoro-5-(4-methyl^iperazm-l-ylVbeiizomtrile; 5-Fluoro-3-chloro-benzonitrile (Ig, 6.4 mmol) was dissolved in DMSO (20 ml) followed by addition OfK2CO3 (1.3g, 9.6 mmol) and 1-methyl piperazine (1.4 ml, 12.8 mmol). The reaction <n="215"/>mixture was heated at 80 0C for 20 hours. Diethyl ether was added to the crude material (10 ml) then acidified with IN HCl. A precipitate was filtered off from the crude reaction mixture to give 3-chloro-5-(4-methyl-piperazin-l-yl)-benzonitrile (1.4g, 93% yield) as a white solid (LC/MS: Rt 1.83 [M + H]+ 236, acidic method). |
61% | With potassium carbonate; In dimethyl sulfoxide; at 100℃; | STEP A A mixture of <strong>[327056-73-5]3-chloro-5-fluoro-benzonitrile</strong> (1.1 g, 7.07 mmol), 1-methyl-piperazine (1.18 ml, 10.6 mmol), and K2CO3 (2.92 g, 21.21 mmol) in DMSO (25 ml) was heated to 100C overnight and then partitioned between water and Et2O. The aqueous phase was extracted with Et2O and the collected organic phases were dried over Na2SO4 and evaporated under vacuum. The residue was dissolved in Et2O and extracted with 0.5 M HCl. The aqueous phase was basified with NH4OH and extracted with DCM. The organic phase was dried over Na2SO4 and evaporated to give 1.01 g of 3-chloro-5-(4-methyl-piperazin-1-yl)-benzonitrile. Y=61% |
With potassium carbonate; In N,N-dimethyl-formamide; at 140℃; for 0.666667h;microwave irradiation; | Preparation 4: 1 -[3-ChIoro-5-(4-methyI-piperazin-1 -yl)-phenyl]-ethanone; STEP A; A mixture of <strong>[327056-73-5]3-chloro-5-fluoro-benzonitrile</strong> (1 g, 6.45 mmol), 1-methyl-piperazine (0.715 ml, 6.45 mmol), and K2CO3 (2.64 g, 19.3 mmol) in DMF (5 ml) was heated to 1400C for 40 min in a microwave apparatus. The resulting slurry was filtered and the solvent was removed in vacuo to give 1 g of 3-chloro-5-(4-methyl- piperazin-1-yl)-benzonitrile. The crude reaction mixture was used in the next step without any further purification. | |
With potassium carbonate; In dimethyl sulfoxide; at 20 - 80℃; | 3-Chloro-5-fluorobenzonitrile (0.50 g, 3.21 mmol) in dimethyl sulfoxide (10 ml.) was stirred at room temperature under an atmosphere of argon (following a similar method to that of WO200670195). Potassium carbonate (0.67 g, 4.82 mmol) and then 1-methylpiperidine (0.71 ml_, 6.42 mmol) were added. The reaction mixture was heated at 80 0C overnight. The reaction mixture was cooled to room temperature and diethyl ether (5 ml.) was added. A white precipitate formed which was filtered off. The filtrate was acidified using 1 M hydrochloric acid to pH 5. The white precipitate was filtered. Further product precipitated out in the filtrate and was collected. This was repeated twice to give the title compound. LC/MS (ES+ve): [M+H]+ at m/z 236, 238 (Ci2H14CIN3 requires [M+H]+ at m/z 236, 238). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium phosphate; In tetrahydrofuran; | e [3-(4-Methyl-piperazin-1-yl)-5,6,7,8-tetrahydro-naphthalen-1-yl]-acetic Acid Ethyl Ester To a solution of compound of step d) (0.5 g, 1.36 mmol) in dry THF (10 ml) K3PO4 (405 mg, 1.90 mmol), N-methylpiperazine (180 mul, 163 mmol), tris(dibenzylideneacetoneacetone)-dipalladium(0) (60 mg, 0.07 mmol) and 2-(di-t-butylphosphino)biphenyl (21 mg, 0.07 mmol) are added under argon. The reaction is kept under argon at 80° C. for 24 hours. After filtration DMF is removed under reduced pressure and the crude residue is purified on silica gel (methylene chloride/methanol 95/5) affording the pure compound. 1H NMR (400 MHz, CDCl3) delta 6.68 (d, 1H, J=2.44 Hz), 6.59 (d, 1H, J=2.20 Hz), 4.15 (q, 2H, J=7.34 Hz), 3.55 (s, 2H), 3.17 (t, 4H, J=5.13 Hz), 2.75 (t, 2H, J=5.87 Hz), 2.60 (t, 2H, J=6.11 Hz), 2.57 (t, 4H, J=4.90 Hz), 2.35 (s, 3H), 1.77 (m, 4H), 1.25 (t, 3H, J=7.10 Hz) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy) cyclopenta [c]-pyrane-4-carboxylic acid; | Example 9 A dichloromethane solution containing 400 mg of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid described in Example 1 was cooled with ice followed by addition of 0.20 ml of 1-methylpiperazine, 2 ml of triethylamine and 301 mg of <strong>[37091-73-9]2-chloro-1,3-dimethylimidazolinium chloride</strong> and stirring for 15 hours at room temperature. The reaction mixture was then extracted with dichloromethane. After washing the organic phase with saturated aqueous sodium bicarbonate and brine, it was dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel chromatography to obtain a colorless powder from the dichloromethane-methanol elude in the form of (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid 4-methylpiperazylamide (264 mg, yield: 50percent). The physicochemical properties of this compound are described in Table 5, Compound No. 20. (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid cyclohexylester was produced in the same manner from (1S,4aS,6S,7R,7aR)-6,7-epoxy-1,4a,5,6,7,7a-hexahydro-7-methyl-1-(methylcarbamoyloxy)cyclopenta[c]-pyrane-4-carboxylic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine; In ethanol; for 1.25h;Reflux; | General procedure: To a solution of absolute ethanol (5 mL) and dichlorodiazine (3.36 mmol) in a 50mL round-bottom flaskwas added triethylamine (5.03 mmol), followed by the amine (5.03 mmol). The mixture was stirred either under reflux of ethanol (for dichloropyridazine and for dichloropyrazine) or at room temperature (for dichloropyrimidines). The reaction was monitored by GC. Once the starting dichlorodiazinewas completely consumed, the mixture was poured into a saturated NH4Cl solution (20 mL), then extracted with CH2Cl2 (320 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under vacuum. The crude solid was triturated in petroleum ether, filtered through a Buchner to afford the pure product. |
80% | In dichloromethane; | Example 295-Cyano-furan-2-carboxylic acid [4-methyl-6.-(4-methyl-piperidin- 1 -yl)-3 ,4,5 ,6- tetrahydro-2H- [1,2'] -bipyrazinyl-5 -yl] -amide a) 6'-Chloro-4-methyl-3,4,5,6-tetrahydro-2H-[l,2']bipyrazinyl; To a solution of 2,6-dichloropyrazine (400 mg, 2.68 mmol) in 6 mL of CH2Cl2 was added 4-methylpiperidine (1.2 eq, 3.2 mmol) and allowed to stir overnight. The reaction was diluted with CH2Cl2 (50 mL) washed with H2O (2x50 mL) and dried (K2CO3) to give 450 mg (80%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for CnH15ClN2, 211.0 (M+H), found 211.1. |
80% | General procedure: To the N,N-dimethylformamide (DMF) (4 mL) solution of N,N-dimethylethylenediamine (95 mL, 0.87 mmol) was added K2CO3 (0.19 g, 1.3 mmol). After the reaction mixture was stirred at room temperature (RT) for 30 min, 2,6-dichloropyrazine (0.10 g, 0.67 mmol) was added and the resulting reaction mixture was further stirred at RT for 12 h. After removal of solvent in vacuo, the residue was treated with dichoromethane. Insoluble impurities were removed by filtration. Removal of solvent in vacuo gave the product 0.095 g in 71 % yield; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 37 Using the method of Example 35, 4-methyl-piperazine was reacted with 4-amino-6-chloro-2-methylthio-pyrimidine to provide white solid 4-amino-6-[1-(4-methyl-piperazino)]-2-methylthiopyrimidine, m.p. 165°-167° C. The structural assignment was supported by infrared and nuclear magnetic resonance spectral analyses. |
Yield | Reaction Conditions | Operation in experiment |
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With 1,8-diazabicyclo[5.4.0]undec-7-ene; In pyridine; | EXAMPLE L 4-(4-Methylpiperazinyl)-1,8-naphthalic anhydride 4-Methylpiperazine (0.6 g, 6.6 mmol) and DBU (1 mL) were added to <strong>[21563-29-1]4-bromo-1,8-naphthalic anhydride</strong> (1.5 g, 5.4 mmol) in pyridine (10 mL). The solution was refluxed for 8 hours, concentrated in vacuo, and the residue was triturated with water. The separated solid was filtered and dried to give 0.8 g of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In water; acetonitrile; | EXAMPLE 137 6-methyl-3-[(4-methyl-1-piperazinyl)carbonyl]-2-pyridinol The desired product was prepared by substituting <strong>[38116-61-9]2-hydroxy-6-methylnicotinic acid</strong> for 6-methylnicotinic and 1-methylpiperazine for 2-methylpyrrolidine in Example 1. After workup the crude compound was purified by HPLC on a C-18 column with a solvent system increasing in gradient over 50 minutes from 5% to 100% acetonitrile/water containing 0.01% TFA to provide the desired product as the trifluoroacetate salt. MS m/e 236 (M+H)+; 1H NMR (DMSO-d6) delta 2.19 (s, 3H), 2.20 (s, 3H), 2.31 (br d, 4H), 3.21 (br t, 2H), 3.54 (br t, 2H), 6.04 (dd, 1H), 7.36 (d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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In tetrahydrofuran; methanol; dichloromethane; toluene; | EXAMPLE 15 A mixture of 8-chloro-2-[3-(4-phenyl-3,6-dihydro-1 (2H)-pyridinyl)propyl]-4(3H)-quinazolinone (50 mg), 1-methylpiperazine (19.8 mg), palladium (II) acetate (2.96 mg), 2-(di-t-butylphosphino)biphenyl (7.86 mg), sodium t-butoxide (23 mg) in toluene (0.4 ml and tetrahydrofuran (0.2 ml) was stirred at 80° C. under nitrogen atmosphere overnight. The mixture was cooled, diluted with water and extracted with dichloromethane twice. The combined extracts were dried over magnesium sulfate and concentrated. The residue was purified by preparative thin layer chromatography on silica gel using 10percent methanol in dichloromethane to give the 8-(4-methyl-1-piperazinyl)-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone. Mass (APCI): 444.3 (M++H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With potassium carbonate; In dimethyl sulfoxide; at 120℃; for 18h; | 2-Fluoro-5-nitroanisole (1.0 mmol) and N-methyl-piperazine (1.0 mmol)It was added to a 25 ml dry eggplant-shaped flask and dissolved in 4 ml of dry dimethyl sulfoxide.Potassium carbonate (2.0 mmol) was then added, and the mixture was heated to 120 C for 18 h, and the reaction was completely converted by TLC.Add water after cooling to room temperature.It was extracted three times with ethyl acetate and the organic phases were combined.Wash the organic phase with saturated brine.It was then dried over anhydrous sodium sulfate.Concentrated under reduced pressure to obtain crude product and then purified by column chromatography(dichloromethane: methanol = 100:1 ? dichloromethane: methanol = 50:1),A yellow solid S5 was obtained (yield 93%). |
69% | In dimethyl sulfoxide; at 120℃; for 12h; | A mixture of scheme 2 compound 1 (2.00 g, 11.68 mmol) and scheme 2 compound 2 (1.17 g, 11.68 mmol) in dry DMSO (5 mL) was heated to 120 C for 12 h. After TLC showed the starting material was consumed completely, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (5 x 50 mL). The organic layer was dried over Na2S04, filtered and concentrated to give scheme 2 compound 3 (2.00 g, 69% yield) as a brown solid which was used without further purification. *H NMR (400 MHz, CDCls): delta 7.87 (dd, J= 8.8, 2.6 Hz, 1H), 7.71 (d, J= 2.5 Hz, 1H), 6.90 (d, J= 8.8 Hz, 1H), 3.95 (s, 3H), 3.26 (d, J= 4.9 Hz, 4H), 2.61 (t, J= 4.9 Hz, 4H), 2.37 (s, 3H). MS [ESI, MH+] = 252.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; In trifluoroethanol; for 2h; | Step A: Methyl-6-[1-(4-methylpiperazin-1-yl)-2-(2-naphthylamino)-2-oxoethyl]nicotinate. Methyl 6-formylnicotinate (50.0 mg, 0.303 mmol), acetic acid (19.0 muL, 0.333 mmol), N-methylpiperizine (40.4 muL, 0.364 mmol), and 2-napthylisocyanide (51.0 mg, 0.333 mmol) were dissolved in 100 muL of TFE. The solution was allowed to stir for 2 h then purified by reverse phase HPLC to give the desired product MS cal'd 419 (MH+), exp 419 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate; In toluene; at 75℃; | General procedure: A solution of the corresponding lithium reagent (10 mmol) in THF (10 mL) was stirredat 50 C and treated dropwise with a solution of 2-chloropyrimidine, 2-chloro-5-propylpyrimidine or2-chloroquinazoline (12 mmol) in THF (15 mL). The mixture was allowed to reach 0 C within 2 h, thenquenched with a solution of water in THF (1:5, 6 mL), stirred at 0 C and treated with a solution of DDQ(2.3 g, 10 mmol) in THF (5 mL). After stirring for an additional 10 min at 0 C, the mixture was treatedwith a cold solution of sodium hydroxide (4 M, 5 mL, 20 mmol), stirred and extracted immediatelywith ether/hexanes (1:1, 3 x 10 mL). The combined extracts were dried with anhydrous sodium sulfate,decolorized by filtration through a pad of silica gel (5 g) and concentrated on a rotary evaporator. Theresultant crude 4-substituted 2-chloropyrimidine or 2-chloroquinazoline was treated with a primaryor secondary amine (30 mmol) in toluene (20 mL) in the presence of anhydrous potassium carbonateand the mixture was heated at 75 C for 5-10 h, after which time a TLC analysis on silica gel elutingwith ether/triethylamine (9:1) showed the absence of the substrate. Preparative chromatography wasconducted eluting with ether/triethylamine/hexanes (9:5:5) to give product 1, 2, 21, 23, 24, 26, 29, 30,32, 36-46 (Scheme 1) and 48 (Scheme 2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; catacxium A;palladium diacetate; In 1-methyl-pyrrolidin-2-one; at 160℃; for 16.0h;Inert atmosphere; | Example 2[00417] Isoquinolinone 5 was prepared from compound 3 according to the following procedure:[00418] (S)-3-(l-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-l(2H)-one (3) (200 mg, 0.48 mmol) and 1 -methylpiperazine (0.267 mL, 2.4 mmol) were dissolved in anhydrous NMP (8 mL) and the resulting solution was degassed and back-filled with argon (two cycles). To this mixture, Na2C03 (102 mg, 0.96 mmol), Pd(OAc)2 (11 mg, 0.048 mmol) and di-(l-adamantyl)-n-butylphosphine (52 mg, 0.144 mmol) were added sequentially. The resulting mixture was degassed and back-filled with argon (two cycles) and then stirred at 160 C under argon for 16 h. The reaction mixture was allowed to cool to RT and then partitioned between water and ethyl acetate. The organic layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was purified by ISCO (silica gel cartridge, 0-10% MeOH-DCM with 0.1 % TEA) to afford the product, (S)-3-(l-((9H-purin-6-yl)amino)ethyl)- 8-(4-methylpiperazin-l-yl)-2-phenylisoquinolin-l(2H)-one (5) as a yellowish solid. ESI-MS m/z: 481.2 [M +H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | In ethanol; at 78℃; for 1.75h; | General procedure: Cyclic secondary amine (2.5 equiv) was treated with 2-halobenzaldehyde (1 mmol) and active methylidene compound (1 mmol) in EtOH (2 mL) or DMF (2 mL). The mixture was stirred and heated to reflux. After the reaction was completed, the mixture was cooled down to r.t. and poured into H2O (10 mL). Crude products were filtered off and purified by recrystallization in EtOH or by column chromatography on silica gel; 52?88percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | a3.1) tert-butyl 6-(4-methylpiperazin-l-yl)-2-azaspiro[3.3]heptane-2-carboxylate 1-Methylpiperazin (4.73 mmol, 0.47 g) and concentrated acetic acid (0.5 mL) were added to a solution of <strong>[1181816-12-5]tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate</strong> (4.73 mmol, 1.0 g) in EtOH (15 mL). It was stirred for lh and NaCNBH3 (5.68 mmol, 0.36 g) was added portionswise, and the reaction mixture was further stirred over night at rt. The mixture was poured onto cold 5percent aq. K2CO3 (15 mL) and extracted three-times with ethyl acetate (15 mL); the organic phases were combined, washed with water three-times (15 mL), dried on Na2S04, filtered and evaporated in vacuo. It was passed through a silicagel column [eluent: l .)EtOAc:MeOH 17:3 and 2.) CH2Cl2:MeOH 1 : 1]. Yield: 1.1 g (78percent). ESI-MS: [M+H+] = 296.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 20℃; for 4h; | Methyl 5-[(4-methylpiperazin-1-yl)methyl]pyridine-2-carboxylate In a 50-mL round bottom flask with magnetic stir bar, <strong>[55876-84-1]methyl 5-(bromomethyl)pyridine-2-carboxylate</strong> (940 mg, 4.09 mmol, 1.00 equiv) and 1-methylpiperazine (449.6 mg, 4.49 mmol, 1.10 equiv) were dissolved in ACN (10 mL), to which DIEA (790.8 mg, 6.12 mmol, 1.50 equiv) was added at room temperature. The resulting solution was stirred for 4 h at room temperature. After the reaction was done, the reaction mixture was concentrated under reduced pressure. The residue was purified in a silica gel column eluting with methanol in dichloromethane (1percent to 10percent gradient) to afford methyl 5-[(4-methylpiperazin-1-yl)methyl]pyridine-2-carboxylate (500 mg, 49percent) as brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79.3% | With tris-(dibenzylideneacetone)dipalladium(0); 4,5-bis(diphenylphos4,5-bis(diphenylphosphino)-9,9-dimethylxanthenephino)-9,9-dimethylxanthene; sodium t-butanolate; In toluene; at 60℃; for 24.0h;Inert atmosphere; | Pd2(dba)3 (229 mg, 0.25 mmol), Xantphos (290 mg, 0.5 mmol) and sodium tert-butoxide (2.88 g, 30 mmol) were added to 2-bromo-5-iodopyridine (3.41 g, 12 mmol)And a solution of 1-methylpiperazine (1.0 g, 10 mmol) in toluene (50 ml), heated to 60 degrees Celsius under the protection of argon, and stirred for 24 hours.After the reaction solution was cooled to room temperature, the solid was filtered off, the filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by Combi-flash column chromatography [DCM: MeOH = 100: 0 to 90:10] The compound 1-(6-bromopyridin-3-yl)-4-methylpiperazine was obtained (2.68 g, 79.3%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
77.1% | With potassium carbonate; In 1,4-dioxane; at 70℃; | Compound 1-3 (2.6 g, 10 mmol) was dissolved in 1,4-dioxane (50 mL), followed by addition of N-methylpiperazine 15-1 (3 g, 30 mmol), and potassium carbonate (2.76 g, 20 mmol) was added under stirring, followed by stirring the reaction overnight under conditions of 70° C. and a closed reaction system, TLC monitoring showed that the starting material 1-3 was completely reacted. The solvent was removed under reduced pressure to obtain a concentrated residue. The concentrated residue was dispensed with dichloromethane (20 mL), an appropriate amount of silica gel was added and the sample was stirred, spin-dried under reduced pressure and directly placed on a silica gel column for column chromatographic purification, with an eluent (dichloromethane:methanol=20/1-5/1) to obtain the target product 15-2 (1.45 g, 77.1percent) as a pale yellow oil, LC-MS: m/z=189[M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With copper(l) iodide; sodium acetate; N-ethyl-N,N-diisopropylamine; In 1,4-dioxane; at 100℃; for 4h;Inert atmosphere; | Under nitrogen, 10 mmol of 4- (3-pyridyl) -2-aminopyrimidine (CAS: 66521-66-2)10 mmol of 4-chloromethylbenzoyl (3-bromo-4-methylphenyl) amine (CAS: 1072105-05-5), 10 mmol of N-methylpiperazine (CAS: 109-01-3 ) And 0.2 mmol of cuprous iodide,0.2 mmol of N, N'-diisopropylethylenediamine,110 mmol of sodium acetate in 20 mL of 1,4-dioxane,The reaction was carried out under heating at a temperature of 100 ° C for 4 hours.After completion of the reaction, the solvent was evaporated to dryness with a rotary evaporator and the residue was separated by column chromatography,Obtain 4.2 grams of imatinib in 86percent yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With cesiumhydroxide monohydrate; In dimethyl sulfoxide; at 120℃; for 20h; | <strong>[7499-66-3]6-bromo-2-aminonaphthalene</strong> (500 mg, 2.25 mmol),N-methylpiperazine (270 mg, 2.7 mmol),cesium hydroxide hydrate(760 mg, 4.5 mmol)A solution of dimethyl sulfoxide (5.0 mL) was stirred at 120 ° C for 20 hours.The reaction system was then cooled to room temperature.Dilute with ice water (10 mL).The aqueous phase was extracted with dichloromethane (20 mL×2).Organic phase in turn,Washed with saturated saline,Dry over anhydrous sodium sulfate,filter,concentrate,The residue was purified by flash column chromatography ( petroleum ether / ethyl acetate = 1/3)Compound 21.1 (70 mg, yield: 13percent) was obtained as a brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.7% | With water; dicyclohexyl-carbodiimide; 1-butyl-3-methylimidazolium Tetrafluoroborate; In chloroform; at 0 - 35℃; for 8h;Inert atmosphere; | Compound 4 (120 g, 587.8 mmol) and the condensing agent N,N'-diisopropylcarbodiimide (DIC) (0.1 eq) were dissolved in chloroform (1.2 L) under nitrogen atmosphere. To a temperature below 0 C, a catalytic amount of water was added followed by 1.2 eq of a six-membered azacyclic amine.Continue to add the ionic solution [BMIM]+[BF4]- recovered in Example 7.After heating to 35 C for 120 minutes, the temperature was slowly raised to room temperature and the reaction was continued for 6 hours. The organic phase and the ionic liquid were separated by phase separation. The organic phase was concentrated and then recrystallized from ethanol to obtain the product furanose derivative 5 (yield 83.7). %); the ionic liquid is washed three times with ethyl acetate (20 mL) and can be recycled for reuse; |
Tags: 109-01-3 synthesis path| 109-01-3 SDS| 109-01-3 COA| 109-01-3 purity| 109-01-3 application| 109-01-3 NMR| 109-01-3 COA| 109-01-3 structure
A245391 [934-98-5]
2-(4-Methylpiperazin-1-yl)ethanamine
Similarity: 1.00
A177323 [34885-02-4]
3-(Piperazin-1-yl)propan-1-amine
Similarity: 0.76
A115956 [5845-28-3]
1-(2-Bromoethyl)-4-methylpiperazine dihydrobromide
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P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
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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