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CAS No. : | 3616-56-6 | MDL No. : | MFCD00009232 |
Formula : | C8H19NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SSFAUOAQOOISRQ-UHFFFAOYSA-N |
M.W : | 161.24 | Pubchem ID : | 77163 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 6 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 45.64 |
TPSA : | 21.7 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) : | -6.67 cm/s |
Log Po/w (iLOGP) : | 2.74 |
Log Po/w (XLOGP3) : | 0.87 |
Log Po/w (WLOGP) : | 0.95 |
Log Po/w (MLOGP) : | 0.82 |
Log Po/w (SILICOS-IT) : | 0.6 |
Consensus Log Po/w : | 1.2 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.99 |
Solubility : | 16.4 mg/ml ; 0.102 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.91 |
Solubility : | 19.9 mg/ml ; 0.123 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -1.5 |
Solubility : | 5.12 mg/ml ; 0.0318 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.26 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | 1993 |
Hazard Statements: | H225-H315-H319-H335 | Packing Group: | Ⅲ |
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 |
---|---|---|
89.6% | Stage #1: With hydrogenchloride In water at 40℃; for 3 h; Stage #2: With sodium metabisulfite In water for 1 h; |
40 g of dimethylaminoacetaldehyde diethylacetal are heated to 400C in a mixture of 48 g cone, hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 00C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45C in vacuo. Yield: 42.5 g (89.6 percent of theoretical) decomp.: from 180C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In water; at 0 - 40℃; for 5h; | Sodium 2-Dimethylamino-1-hydroxy-ethanesulfonate To a 5 L jacket reactor, (Dimethylamino)acetaldehyde diethyl acetal (400 g) and Water (200 mL) is charged at room temperature. Start agitation and cool the system down to 0 C., then Conc. HCl aqueous solution (37 wt %, 480 g) is added within 1 h, followed by stirring at 40 C. for 4 h. At this point, a solution of sodium metasulphite (424 g) in water (720 mL) is added into the above system within 40 min, and keep stirring at 40 C. for 2 h. The ethanol (2 L) is added and cool the mixture to 0 C., followed by filteration and washing with ethanol to get a white cake, which is dried in vacuo at 45 C. for 6 h to give desired compound 1 in 84% yield (474 g) and >98% NMR purity. | |
With hydrogenchloride; In water; at 0 - 40℃; for 12h;Inert atmosphere; | Under the protection of N2, 6mol /l of HCl 11.7mL L of (0.07mol), cooled to 0 C, then dropwise added solution of (dimethylamino)acetaldehyde diethyl acetal 9.1mL (0. 05mol) then hydrolysis at 40 C for 12h, cooled to 0 C, the standby (stand by liquid A) | |
With hydrogenchloride; In water; at 30℃; | 1 Concentrated hydrochloric acid plus purified water (1) after dilution,Transfer to a 10L reactorWarm up to about 30C. Under nitrogen protection,The dimethylamino acetaldehyde diethyl acetal was slowly added dropwise to the diluted hydrochloric acid,About 2 hours after the addition,The reaction was stirred overnight at about 30C. MakeBefore use, neutralize to neutral with solid sodium carbonate,Inorganic salts are filtered away. |
With hydrogenchloride; In water; at 40℃; | Concentrated hydrochloric acid (5 mL) and water (2 mL) were added to a 50mL of flask and then heated to 40C. N,N-<strong>[3616-56-6]dimethylaminoacetaldehyde diethyl acetal</strong> was added to the reaction flask and the mixture was stirred at 40C overnight. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With acetic acid; at 118℃; for 8h;Inert atmosphere; | Under a nitrogen atmosphere, 14.1 g (0.061 mol) of the intermediate A, 11.4 g (0.071 mol) ofN,N'-<strong>[3616-56-6]dimethylaminoacetaldehyde diethyl acetal</strong>, and 110.0 g of acetic acid were stirred for 8 hours while being heated at 118°C to reflux. After the reaction solution was cooled to room temperature, the precipitated crystal was collected by filtration and washed with acetic acid (30 ml) . The resultant crystal was subjected to purification by reslurrying to afford 10.4 g (67percent yield) of IC-2 as a white crystal. |
67% | With acetic acid; at 118℃; for 8h;Inert atmosphere; | Under a nitrogen atmosphere, 14.1 g (0.061 mol) of Intermediate C, 11.4 g (0.071 mol) of N,N?-<strong>[3616-56-6]dimethylaminoacetaldehyde diethyl acetal</strong>, and 110.0 g of acetic acid were stirred for 8 hr while being refluxed under heat at 118° C. After the reaction solution had been cooled to room temperature, the precipitated crystal was taken by filtration and washed with acetic acid (30 ml). The resultant crystal was subjected to re-slurry purification to provide 10.4 g (0.041 mol, yield: 67percent) of 5,12-dihydroindolo[3,2-a]carbazole (IC-5) as a white crystal. |
60% | With acetic acid; at 130℃;Inert atmosphere; | (3) 1H,1'H-2,3'-biindole (16.4 g, 70.6 mmol) and 2,2-diethoxy-N,N-dimethylethanamine (14.18 ml, 78 mmol) in glacial acetic acid (160 mL) were refluxed at 130 °C overnight under nitrogen. The reaction solution was cooled to room temperature and filtered. The filtrate was washed with small amount of acetic acid and excess of water. The filtrate was dried in the oven at 65°C overnight affording 10.79 g (60percent) of the 5,12-dihydroindolo[3,2-a]carbazole as gray solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With acetic acid; at 100℃; for 1h; | General procedure: Dimethylaminoacetaldehyde diethyl acetal (5 mmol) was added to a solution of 7 (0.5 mmol) in AcOH (5mL) at room temperature, and the mixture was heated at 100 °C. After 1 h, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 3, 4 and 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With acetic acid; at 100℃; for 2h; | The mixture of homocoupling product 2i (0.5 mmol), NaOEt (340.25 mg, 5.0 mmol) and DMSO (1.0 mL) was added into a 35 ml pressure-resistant vial under air atmosphere. The mixture was heated to 120oC and stirred for 5h. After being cooled to ambient temperature, the reaction mixture was diluted with EtOAc (60 mL) and washed with H2O (2×30 mL). The aqueous phase was extracted with EtOAc (2×30 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under the reduced pressure. The residue was purified by silica gel column directly to give the product 3i (Yield 82%). The spectra of 3i were in accordance with those reported in the literature3. Then 16.1mg (1.0 mmol) (dimethylamino)acetaldehyde diethyl acetal was added in the refluxing mixture of 30 mg (0.10 mmol) biindole 3i with the 3ml of AcOH solvent. The resulting mixture was refluxed for 2 h, then cooled to room temperature, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give tjipanazole D (4i) with 65% yield (21.1 mg). The spectra of 4i were in accordance with those reported in the literature3,4,5. |
60% | With acetic acid; at 100℃; for 1h; | General procedure: Dimethylaminoacetaldehyde diethyl acetal (5 mmol) was added to a solution of 7 (0.5 mmol) in AcOH (5mL) at room temperature, and the mixture was heated at 100 C. After 1 h, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 3, 4 and 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
6% | Step 8B: Compound 8-2; To a flask containing (R)-1-{4-[2-((S)-l-amino-2-methyl-propyl)-6-fluoro-phenyl]- piperazin-l-yl}-3- (4-chloro-phenyl)-2-methyl-propan-l-one (43 mg, 0. 10 mmol) and (2,2- diethoxy-ethyl) -dimethyl-amine (100 pL, 0.50 mmol), TFA (30011L, 4.0 mmol) was added via syringe. After-5 min. , NaCNBH3 (95 mg, 1.5 mmol) was added and the resulting mixture was heated to 120 °C overnight. The resulting brown reaction mixture was concentrated in vacuo and purified via preparative HPLC/MS to furnish 8-2 (3.8 mg, 0.006 mmol, 6percent) as the TFA salt. LCMS-tR (method 4) 1.596 min. m/z 502.8 (M+ + H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tetrahydroborate; toluene-4-sulfonic acid; In isopropyl alcohol; | EXAMPLE 43 N,N-Diethyl-5-[[2-(dimethylamino)ethyl]amino]-2H-[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine A mixture of 5.0 g (0.015 mol) of 5-amino-N,N-diethyl-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine, 2.4 g (0.015 mol) of 2,2-diethoxy-N,N-dimethyl ethanamine, and 0.001 g of p-toluenesulfonic acid in 100 ml of 2-propanol was heated under reflux for four hours, allowed to cool to room temperature, and treated portionwise with 1.0 g (0.026 mol) of NaBH4 over a two hour period. The mixture was stirred at room temperature for 16 hours and poured into 1 l of H2 O. The precipitate that formed was collected, washed with H2 O, dried, and recrystallized to give the product. An example of another 5-(monoalkylated or acylated)-2-(substituted)benzothiopyrano[4,3,2-cd]-indazole, prepared in the manner of Examples 5-11, is as follows: N-[2-[2-(diethylamino)ethyl]-2H[1]benzothiopyrano[4,3,2-cd]indazol-5-yl]-1,3-propanediamine, hydrochloride salt, mp 222° C. dec. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
900 g (73.3%) | With trichlorophosphate; In N-methyl-acetamide; hexane; chloroform; water; | EXAMPLE 5 Preparation of N-(3-(dimethylamino)-2-ethoxy-2-propenylidene)-N-methylmethanaminium perchlorate A solution of 1293 g (17.7 mol) dimethylformamide and 1800 ml chloroform was cooled to 3° C. and 910 ml (9.76 mol) phosphorus oxychloride was added at the rate of 10 ml/minute. The resulting mixture was stirred for 30 minutes. N,N-Dimethylaminoacetaldehyde diethyl acetal, 727.9 g (4.51 mol), was added at the rate of 12-15 ml per minute, maintaining the temperature between 6° to 15° C. The mixture was heated at reflux for 31/2 hours, then allowed to stir overnight. The mixture was poured into 4800 g of ice and 3 l hexane and this mixture was agitated, and the organic phase separated and washed with 500 ml cold water. The combined aqueous phases were treated with 1091 g sodium perchlorate, monohydrate, and dissolved in 750 ml distilled water. Combination of the first and second crops gave 900 g (73.3percent) of N-(3-(dimethylamino)-2-ethoxy-2-propenylidene)-N-methylmethanaminium perchlorate, which could be purified by recrystallization from ethanol. M.p. 117°-120° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium borohydrid; In ethanol; water; | EXAMPLE 269 2-[3-(2-Dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine A mixture of 1.1 g., (0.005 mole) of 2-(3-aminophenyl)oxazolo[4,5-b]pyridine and 50 ml. of ethanol is reacted with dimethylaminoacetaldehyde [from 0.96 g. (0.006 mole) dimethylaminoacetaldehyde diethylacetal]by gentle heating to complete the intermediate Schiff base formation. The mixture is then cooled and 60 mg., (0.0015 mole) of sodium borohydride is added, and the mixture allowed to stir overnight at room temperature. Water is added, the solvents are removed in vacuo, and the residue is distributed between water and methylene chloride. The organic layer is dried and concentrated in vacuo to give crude 2-[3-(2-dimethylaminoethyl)aminophenyl]oxazolo[4,5-b]pyridine, purified via column chromatography using an alumina column with an ethylacetate-ether mixture (v/v 0-60percent ethylacetate) as eluant. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | A solution of the higher running product of (trans,trans)-tert-butyl 4-(3-fluoro-2- methylphenyl)-3-(3-hydroxybenzoyl)-5-((S)-2-(trifluoromethyl)pyrrolidine-l- carbonyl)piperidine-l-carboxylate (29 mg, 0.050 mmol) in THF (0.5 mL) was treated with HCl/dioxane solution (4 M, 5 mL) at room temperature and the mixture stirred overnight. The solvents were evaporated and the residue partitioned between EtOAc and saturated NaHCO3. The layers were separated and the organic phase was extracted with EtOAc. The combined organic layers were combined, dried over Na2SO4, and concentrated under vacuum to give 24 mg of a glassy solid, hi a separate flask, (dimethylamino)acetaldehyde diethyl acetal (1 g) was dissolved in 4 M HCl/dioxane solution (50 mL). Water (15 mL) was added and the resulting mixture stirred at 60 C for 30 min. The organic solvent was removed under vacuum and the pH of the remaining aqueous phase was adjusted with 1 M KOH to pH15. The mixture was extracted with dichloromethane, dried over Na2SO4, and concentrated under vacuum until -20 mL remained. The piperidine (24 mg) from above was treated with 1 mL of the above aldehyde/dichloromethane solution followed by NaBH(OAc)3 (75 mg, excess) in dichloromethane (3 mL). After stirring 30 min at room temperature, the reaction was quenched with NaHCpsi3 and the layers separated. The organic phase was washed with NaHCpsi3, dried over Na2SO4 and evaporated to dryness. The residue was purified over silica gel using 10percent <n="105"/>MeOH/dichloromethane to give pure desired ((trans, trans)- l-(2-(dimethylamino)ethyl)-4-(3- fluoro-2-methylphenyl)-5-((S)-2-(trifluoromethyl)pyrrolidine-l-carbonyl)piperidin-3-yl)(3- hydroxyphenyl)methanone (11 mg, 40percent yield) (characterized by LCMS and 1H NMR, LRMS (M+H+) m/z = 550.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.6% | 40 g of dimethylaminoacetaldehyde diethylacetal are heated to 400C in a mixture of 48 g cone, hydrochloric acid and 20 ml of water for 3 h. Then a solution of 42.4 g sodium pyrosulphite in 72 ml of water (sodium hydrogen sulphite solution) is added dropwise and the mixture is stirred for 1 h. 200 ml of ethanol are added and then the mixture is stirred for 2 h at 00C. The suspension is suction filtered, washed with 160 ml of ethanol and dried at 45C in vacuo. Yield: 42.5 g (89.6 percent of theoretical) decomp.: from 180C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
0.027 g (20%) | With sodium cyanoborohydride; In water; acetic acid; | EXAMPLE 64 {2-Chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethyl-amine To a stirring solution of 2-chloro-5-[5-(3-chlorothiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenylamine (0.121 g, 0.386 mmol), (dimethylamino)acetaldehyde diethyl acetal (0.720 mL, 3.94 mmol), glacial acetic acid (24.0 mL) and water (0.100 mL, 5.55 mmol) was added sodium cyanoborohydride (0.140 g, 2.22 mmol). The solution was heated at 60° C. for 5 days and then the solution was stirred at room temperature until a precipitate formed. The suspension was filtered, the filter cake was washed with EtOAc (10 mL) and then the filtrate was concentrated by rotary evaporation. The residue was purified by flash column chromatography (silica gel, elution with EtOAc:hexanes, 1:3.5), gave 0.027 g (20percent) of the title compound as a white solid. 1H NMR (CDCl3): 7.60 (d, 1H, J=5.2 Hz), 7.44-7.35 (m, 3H), 7.13 (d, 1H, J=5.2 Hz), 4.33 (br s, 1H), 3.37-3.28 (m, 2H), 1.36 (t, 3H, J=7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97.7% | To a 50 ml single-neck round-bottom flask equipped with magnetic needle and nitrogen balloon was charged 5.0 ml (46.9 mmol) concentrated HCl, 5.0 ml water and the mixture was stirred at 30 °C. After 15 min, 5.3 ml (27.1 mmol) (dimethylamino)- acetaldehyde-diethyl acetal was added over a period of 5 min at 30 °C. The mixture was stirred at room temperature in an inert atmosphere overnight. The solution thus obtained was designated as reagent "A".A 250 ml two-neck round-bottom flask equipped with magnetic needle, thermometer and nitrogen balloon was charged with 6.0 g (10.85 mmol) diethyl (4-(3-chloro-4- fluorophenylam o)-7-(S)-(tetrahyc ^methyl)-phosphonate, 0.47 g (10.85 mmol), lithium chloride anhydrous and 25 ml THF. The mixture was cooled to -8 °C in an ice-salt bath and a cold solution of potassium hydroxide (4.7 g, 82.7 mmol dissolved in 24 ml water kept at -18°C) was added over the period of 15 min. Reagent "A" was added dropwise over the course of 30 min to the reaction mixture which was maintained at -7 °C and stirred at the same temperature for 1 h. The reaction was slowly allowed to come to 20 °C and stirred at this temperature for 45 min. 20 ml water were added and the mixture was extracted with 3 x 50 ml ethyl acetate. The combined extract was dried on sodium sulphate, evaporated and the resulting residue dried at 45 °C under vacuum to give a yellow solid. 200 ml water were added to the solid, the mixture was stirred for 1 h, filtered, washed with 200 ml water, dried on a rotary evaporator at 45 °C for 2 h to give 5.1 g (97.7percent, 10.6 mmol) of an off- white solid. DSC shows two endothermic peaks at 95.9 °C and 138.6 °C.IR (cm"1): 3547.4, 2980.2, 2947.8, 2865.7, 2774, 1673.1, 1626.9, 1575.8, 1536.1,1500.1, 1455.7, 1430.5, 1397.0, 1233.4, 1147.1, 981.9, 852.1, 778.5 and 660.9. | |
78% | Example 2 (E)-4-Dimethylamino-But-2-Enoic acid-[4-(3-Chloro-4-Fluoro-Phenylamino)-7-((S)-Tetrahydrofuran-3-Yloxy)-Quinazolin-6yl]-Amide 5.6 litres of 30percent hydrochloric acid (53.17 mol) are added to 4.4 litres of water. Then 4.28 kg of 95percent (dimethylamino)-acetaldehyde-diethylacetal (26.59 mol) are added dropwise within 20 minutes at 30° C. The reaction solution is stirred for 8 hours at 35° C. stirred, cooled to 5° C. and stored under argon. This solution is referred to as solution B. 4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 litres of water and cooled to -5° C. This solution is referred to as solution C. 5.88 kg (10.63 mol) of diethyl ((4-(3-chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3-yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 litres of tetrahydrofuran and cooled to -7° C. The cold solution C is added within 10 minutes. Then solution B is added at -7° C. within 1 hour. After stirring for a further hour at -5° C. the reaction mixture is heated to 30° C. and combined with 15 litres of water. After cooling to 3° C. the suspension is suction filtered, the precipitate is washed with water and dried. Yield: 5.21 kg of crude product, 100percent, water content: 6.7percent The crystallisation of the crude product is carried out with butyl acetate/methylcyclohexane Yield: 78percent purity HPLC 99.4Fl percent, water content 5.4percent | |
5.6 litres of 30percent hydrochloric acid (53.17 mol) was added to 4.4 liters of water. Then 4.28 kgof 95percent (dimethylamino)-acetaldehyde-diethyl-acetal (26.59 mol) was added dropwise within20 minutes at 30 deg C. The solution is stined for 8 hours at 35 deg C. stined, cooled to 5 deg C. and stored under argon. This solution is refened to as solution B.4.55 kg (68.06 mol) of Potassium hydroxide was dissolved in 23.5 liters of water and cooledto -5 deg C. This solution is referred to as solution C.5.88 kg (10.63 mol) of diethyl ((4-(3-Chloro-4-fluoro-phenylamino)-7-(tetrahydrofuran-3 - yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) were placed in 23.5 liters of tetrahydrofuran and cooled to -7 deg C. The coldsolution C was added within 10 minutes. Then solution B was added at -7 deg. C within 1 hour. Stined for a further hour at -5 deg C, heated to 30 deg C. and combined with 15 litres of water. After cooling to 3deg C. the suspension was suction filtered, washed with water and dried. Yield: 5.21 kg of crude product, 100percent, water content: 6.7percentThe crystallisation of the crude product is canied out with butylacetate/methylcyclohexane Yield: 78percent purity HPLC 99.4F1 percent, water content 5.4percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | To a stirred mixture of 2,2-diethoxy-IV,JV-dimemylcthanapiiine (15.7 g, 97.5 mmol) and water (16.4 mL) at room temperature under a nitrogen atmosphere was added aq. 37percent HCl (16.4 mL, 195 mmol). After addition the mixture was stirred at 40°C (bath) for 25 hours. It was then cooled to 0 °C (bath) to give Solution A. KOH (14.0 g, 250 mmol) was dissolved in water (75 mL) at room temperature under a nitrogen atmosphere. It was then cooled to 0 °C (bath) to give Solution B. To a stirred heterogeneous mixture of compound 160 (19.97 g, 39.0 mmol) at room temperature under a nitrogen atmosphere was added a rninirnurn amount of DMA (60 mL) to give a homogeneous solution. LiCl (1.65 g, 39.0 mmol) was then added and the resulting mixture was stirred atO °C (bath) for 15 min. The cold Solution B was then added and the reaction was stirred at 0 °C for 2 min. Cold Solution A was then added and the final reaction mixture was stirred further at 0 °C under a nitrogen atmosphere. The reaction was monitored by TLC (DCM/MeOH=10:l). After 30 min more KOH (s) (5.0 g, 89 mmol) was added and the reaction was stirred further at 0 °C for 1.5 hours. It was then poured into water (1,000 mL). Petroleum ether (1,000 mL) was added and the mixture was stirred at room temperature for 20 min. The petroleum ether layer was decanted before more petroleum ether (600 mL) was added and the mixture was again stirred for 15 min. The solid was collected by filtration, washed with water (5x200 mL) and dried under reduced pressure over silica gel/KOH to give (2J3)-iV-[4-(3-bromo-4-fluoroanilino)pyrido[3,4-Lambda(|pyrimidin-6-yl]-4- (dimethykmino)-2-butenamide (161) (16.9 g, 97percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With acetic acid;Reflux; | Synthesis example B2: Synthesis of 12H-benzofuranyl[2,3-a]carbazole (compound 2); Compound 1 (2.0 g, 1 eq.) is added to acetic acid (90 ml) and heated to reflux. (Dimethylamino)acetaldehyde diethyl acetal (95percent; 14.6 g, 10 eq.) is added dropwise in portions to the solution. The reaction is stirred at reflux until no reactant is present any longer. Subsequently, the flask contents are diluted with CH2CI2 at room temperature and washed in a separating funnel with distilled water and NaCI (saturated). Organic phase is dried with Na2S04 and concentrated. LC (Si02, 15:85 CH2CI2/n-hex) gives the product 2 (0.85 g, 39percent yield).1H NMR (CD2CI2, 400 MHz): "5 = 8.68 (br s, 1 H), 8.15 (d, 1 H), 8.06 (dd, 2H), 7.83 (d, 1 H), 7.67 (d, 1 H), 7.59 (d, 1 H), 7.47 (dd, 2H), 7.41 (dd, 1 H), 7.30 (dd, 1 H). |
39% | With acetic acid; sodium chloride; In dichloromethane; water; | Synthesis Example B2Synthesis of 12H-benzofuranyl[2,3-a]carbazole (compound 2)Compound 1 (2.0 g, 1 eq.) is added to acetic acid (90 ml) and heated to reflux. (Dimethylamino)acetaldehyde diethyl acetal (95percent; 14.6 g, 10 eq.) is added dropwise in portions to the solution.The reaction is stirred at reflux until no reactant is present any longer.Subsequently, the flask contents are diluted with CH2Cl2 at room temperature and washed in a separating funnel with distilled water and NaCl (saturated).Organic phase is dried with Na2SO4 and concentrated. LC (SiO2, 15:85 CH2Cl2/n-hex) gives the product 2 (0.85 g, 39percent yield).1H NMR (CD2Cl2, 400 MHz): delta=8.68 (br s, 1H), 8.15 (d, 1H), 8.06 (dd, 2H), 7.83 (d, 1H), 7.67 (d, 1H), 7.59 (d, 1H), 7.47 (dd, 2H), 7.41 (dd, 1H), 7.30 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.2% | With acetic acid;Reflux; | Synthesis example B6: Synthesis of 12H-benzofuranyl[3,2-a]carbazole (compound 6); (6); Compound 5 (2.8 g, 1 eq.) is added to acetic acid (30 ml) and heated to reflux. (Dimethylamino)acetaldehyde diethyl acetal (95percent; 20.3 g, 10 eq.) is added dropwise in portions to the solution. The reaction is stirred at reflux overnight. Then further (dimethylamino)acetaldehyde diethyl acetal (95percent; 2.0 g) is added and stirred further at reflux after 3 h. Subsequently, the flask contents are diluted with CH2CI2 at room temperature and washed in a separating funnel with distilled water and NaCI (saturated). Organic phase is dried with Na2S04 and concentrated. LC (Si02, 15:85 ethyl acetate/cyclohexane) gives the product 6 (1 .92 g, 62.2percent yield).1 H NMR (CD2CI2, 400 MHz): "5 = 8.88 (br s, 1 H), 8.16 (d, 1 H), 8.12 (d, 2H), 7.66 (d, 1 H), 7.62 (d, 1 H), 7.42-7.53 (m, 4H), 7.31 (dd, 1 H). |
62.2% | With acetic acid; sodium chloride; In water; | Synthesis Example B6Synthesis of 12H-benzofuranyl[3,2-a]carbazole (compound 6)Compound 5 (2.8 g, 1 eq.) is added to acetic acid (30 ml) and heated to reflux. (Dimethylamino)acetaldehyde diethyl acetal (95percent; 20.3 g, 10 eq.) is added dropwise in portions to the solution.The reaction is stirred at reflux overnight.Then further (dimethylamino)acetaldehyde diethyl acetal (95percent; 2.0 g) is added and stirred further at reflux after 3 h.Subsequently, the flask contents are diluted with CH2Cl2 at room temperature and washed in a separating funnel with distilled water and NaCl (saturated).Organic phase is dried with Na2SO4 and concentrated. LC (SiO2, 15:85 ethyl acetate/cyclohexane) gives the product 6 (1.92 g, 62.2percent yield).1H NMR (CD2Cl2, 400 MHz): delta=8.88 (br s, 1H), 8.16 (d, 1H), 8.12 (d, 2H), 7.66 (d, 1H), 7.62 (d, 1H), 7.42-7.53 (m, 4H), 7.31 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With acetic acid; at 20℃;Reflux; Inert atmosphere; | Synthesis of 3-bromo-12H-benzofuranyl[2,3-a]carbazole (compound 9); (9); Under nitrogen, compound 8 (1 .3 g, 1 eq.) is initially charged and dissolved with acetic acid (55 ml) while heating to reflux. Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 7.1 g, 10 eq.) is added dropwise to the reaction within 1 .5 h and the mixture is stirred at reflux for a further 7 h. It is stirred at room temperature overnight. The next day, it is heated back to reflux and a further 2 g of (dimethylamino)acetaldehyde diethyl acetal are added dropwise. After 6 h at reflux, a further 4 g (dimethylamino)acetaldehyde diethyl acetal are added dropwise and it is stirred for a further 7.5 h. The mixture is cooled to room temperature and diluted with methylene chloride. Washed in a separating funnel with distilled water and then with saturated NaCI. The organic phase is dried with sodium sulfate and concentrated. LC (C18-Si02, acetonitrile) gives 0.33 g of product (24percent yield). 1H NMR (CD2CI2, 400 MHz): "5 = 8.7 (br s, 1 H), 8.15 (d, 2H), 8.06 (d, 1 H), 7.78 (d, 1 H), 7.60 (m, 3H), 7.48 (dd, 1 H), 7.32 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.6% | With acetic acid; for 49h;Reflux; Inert atmosphere; | Synthesis of 3-bromo-12H-benzofuranyl[3,2-a]carbazole (compound 13); (13); Under nitrogen, compound 12 (3.2 g, 1 eq) is initially charged and dissolved with acetic acid (30 ml) while heating to reflux. Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 21 .9 g, 10 eq.) is added dropwise to the reaction within 1 h and the mixture is stirred at reflux for 48 h. The mixture is cooled to room temperature and diluted with methylene chloride. Washed in a separating funnel with distilled water and then with saturated NaCI solution. The organic phase is dried with sodium sulfate and concentrated. LC (Si02, 3: 1 cyclohexane/methylene chloride) gives 0.98 g of product (28.6percent yield). 1H NMR (CD2CI2, 400 MHz): "5 = 8.75 (s, 1 H), 8.24 (s, 1 H), 8.1 (dd, 2H), 7.67 (d, 1 H), 7.48-7.55 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With acetic acid; for 8h;Reflux; Inert atmosphere; | Synthesis example B17: Synthesis of 8-bromo-12H-benzofuranyl[2,3-a]carbazole (compound 17); (1 7); Under nitrogen, compound 16 (4.6 g, 1 eq) is initially charged and dissolved with acetic acid (185 ml) while heating to reflux. Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 25 g, 10 eq.) is added dropwise to the reaction within 1 h and the mixture is stirred at reflux for 7 h. The mixture is cooled to room temperature and diluted with methylene chloride. In a separating funnel, the organic phase is washed with distilled water and then with saturated NaCI solution. The organic phase is dried with sodium sulfate and concentrated. LC (reverse phase, acetonitrile) gives 1 .35 g of product (27.3percent yield).1 H N MR (CD2CI2; 400 MHz): "5 = 8.73 (s, 1 H), 8.17 (s, 1 H), 8.16 (d, 1 H), 8.08 (d, 1 H), 7.78 (d, 1 H), 7.60 (d, 1 H), 7.56 (m, 2H), 7.49 (dd, 1 H), 7.31 (dd, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
24% | With acetic acid; In water; | Synthesis Example B9Synthesis of 3-bromo-12H-benzofuranyl[2,3-a]carbazole (compound 9)Under nitrogen, compound 8 (1.3 g, 1 eq.) is initially charged and dissolved with acetic acid (55 ml) while heating to reflux.Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 7.1 g, 10 eq.) is added dropwise to the reaction within 1.5 h and the mixture is stirred at reflux for a further 7 h.It is stirred at room temperature overnight.The next day, it is heated back to reflux and a further 2 g of (dimethylamino)acetaldehyde diethyl acetal are added dropwise.After 6 h at reflux, a further 4 g (dimethylamino)acetaldehyde diethyl acetal are added dropwise and it is stirred for a further 7.5 h.The mixture is cooled to room temperature and diluted with methylene chloride.Washed in a separating funnel with distilled water and then with saturated NaCl.The organic phase is dried with sodium sulfate and concentrated. LC (C18-SiO2, acetonitrile) gives 0.33 g of product (24percent yield).1H NMR (CD2Cl2, 400 MHz): delta=8.7 (br s, 1H), 8.15 (d, 2H), 8.06 (d, 1H), 7.78 (d, 1H), 7.60 (m, 3H), 7.48 (dd, 1H), 7.32 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28.6% | With acetic acid; In water; | Synthesis Example B13Synthesis of 3-bromo-12H-benzofuranyl[3,2-a]carbazole (compound 13)Under nitrogen, compound 12 (3.2 g, 1 eq) is initially charged and dissolved with acetic acid (30 ml) while heating to reflux.Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 21.9 g, 10 eq.) is added dropwise to the reaction within 1 h and the mixture is stirred at reflux for 48 h.The mixture is cooled to room temperature and diluted with methylene chloride.Washed in a separating funnel with distilled water and then with saturated NaCl solution.The organic phase is dried with sodium sulfate and concentrated. LC (SiO2, 3:1 cyclohexane/methylene chloride) gives 0.98 g of product (28.6percent yield).1H NMR (CD2Cl2, 400 MHz): delta=8.75 (s, 1H), 8.24 (s, 1H), 8.1 (dd, 2H), 7.67 (d, 1H), 7.48-7.55 (m, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
27.3% | With acetic acid; | Synthesis Example B17Synthesis of 8-bromo-12H-benzofuranyl[2,3-a]carbazole (compound 17)Under nitrogen, compound 16 (4.6 g, 1 eq) is initially charged and dissolved with acetic acid (185 ml) while heating to reflux.Then (dimethylamino)acetaldehyde diethyl acetal (95percent; 25 g, 10 eq.) is added dropwise to the reaction within 1 h and the mixture is stirred at reflux for 7 h.The mixture is cooled to room temperature and diluted with methylene chloride.In a separating funnel, the organic phase is washed with distilled water and then with saturated NaCl solution.The organic phase is dried with sodium sulfate and concentrated. LC (reverse phase, acetonitrile) gives 1.35 g of product (27.3percent yield).1H NMR (CD2Cl2; 400 MHz): delta=8.73 (s, 1H), 8.17 (s, 1H), 8.16 (d, 1H), 8.08 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.56 (m, 2H), 7.49 (dd, 1H), 7.31 (dd, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Preparation of the Afatinib base starting material:Afatinib base was prepared according to WO2005/037824 example 2.5.6 litres of 30percent hydrochloric acid (53.17 mol) are added to 4.4 liters of water. Then 4.28 kg of 95percent (dimethylamino)-acetaldehyde-diethyl- acetal (26.59 mol) are added dropwise within 20 mmutes at 30° C. The reaction solution is stirred for 8 hours at 35° C. stirred, cooled to 5. degree. C. and stored under argon. This solution is referred to as solution B.4.55 kg (68.06 mol) of potassium hydroxide are dissolved in 23.5 liters of water and cooled to -5. degree. C. This solution is referred to as solution C.5.88 kg (10.63 mol) of diethyl ((4-(3-cMoro-4-fluoro-phenylamino)-- 7-(tetrahydrofuran- 3-yloxy)-quinazoline-6-ylcarbamoyl)-methyl)-phosphonate and 0.45 kg of lithium chloride (10.63 mol) are placed in 23.5 liters of tetrahydrofuran and cooled to -7°C. The cold solution C is added within 10 minutes. Then solution B is added at -7° C. within 1 hour. After stirring for a further hour at -5. degree. C. the reaction mixture is heated to 30° C. and combined with 15 litres of water. After cooling to 3° C. the suspension is suction filtered, the precipitate is washed with water and dried. Yield:5.21 kg of crude product, 100percent, water content: 6.7percentThe crystallisation of the crude product is carried out with butylacetate/methylcyclohexane Yield: 78percent purity HPLC 99.4F1 percent, water content 5.4percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15.9 g | With acetic acid; at 140℃; for 16h; | 26.0 g (111 mmol) of the intermediate (A-5), 22.5 g (139 mmol) of (dimethylamino)acetaldehyde diethylacetal, and 50 ml of acetic acid were loaded and the mixture was stirred for 16 hr while being heated at 140C. The reaction solution was cooled to room temperature and then the solvent was removed by evaporation under reduced pressure. The resultant residue was purified by silica gel column chromatography to give 15.9 g (61.8 mmol, yield: 55 mol%) of an intermediate (A-6). APCI-TOFMS, m/z 257 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.3 g | With acetic acid; at 140℃; for 96h; | 5.0 g (20.0 mmol) of the intermediate (A-8), 5.2 g (32.1 mmol) of (dimethylamino)acetaldehyde diethylacetal, and 65 ml of acetic acid were loaded and the mixture was stirred for 96 hr while being heated at 140°C. The reaction solution was cooled to room temperature and then the solvent was removed by evaporation under reduced pressure. The resultant residue was purified by silica gel column chromatography to give 1.3 g (4.9 mmol, yield: 25 molpercent) of an intermediate (A-9). FD-MS, m/z 258 [M] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.3 g | With acetic acid; at 140℃; for 96h; | 5.0 g (20.0 mmol) of the intermediate (A-11), 4.8 g (30.0 mmol) of (dimethylamino)acetaldehyde diethylacetal, and 78 ml of acetic acid were loaded and the mixture was stirred for 96 hr while being heated at 140°C. The reaction solution was cooled to room temperature and then the solvent was removed by evaporation under reduced pressure. The resultant residue was purified by silica gel column chromatography to give 2.3 g (8.4 mmol, yield: 42 molpercent) of an intermediate (A-12). FD-MS, m/z 274 [M] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | With acetic acid; at 100℃; for 1h; | General procedure: Dimethylaminoacetaldehyde diethyl acetal (5 mmol) was added to a solution of 7 (0.5 mmol) in AcOH (5mL) at room temperature, and the mixture was heated at 100 °C. After 1 h, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 3, 4 and 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With acetic acid; at 100℃; for 1h; | General procedure: Dimethylaminoacetaldehyde diethyl acetal (5 mmol) was added to a solution of 7 (0.5 mmol) in AcOH (5mL) at room temperature, and the mixture was heated at 100 °C. After 1 h, the mixture was gradually cooled to room temperature. The mixture was diluted with AcOEt (100 mL), washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed, and the residue was separated by silica gel column chromatography with hexane/AcOEt (5:1) to give 3, 4 and 8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 1) three-neck flask, concentrated hydrochloric acid (120g), water (50ml). Low temperature dropwise addition of dimethylamino diethanol (100g) heated to 30-40 reaction 3h, To the room temperature, below 20 drop dropping 106g aqueous sodium bisulfite solution, The mixture was stirred at this temperature for 1 h, then 500 ml of ethanol was added, stirred and filtered. The filter cake was rinsed with ethanol and dried to give compound 9. 107g, yield 90percent, dried and sealed. | |
84% | To a 5 L jacket reactor, (Dimethylamino)acetaldehyde diethyl acetal (400 g) and Water (200 ml_) is charged at room temperature. Start agitation and cool the system down to 0°C, then Cone. HCI aqueous solution (37 wtpercent, 480 g) is added within 1 h, followed by stirring at 40°C for 4h. At this point, a solution of sodium metasulphite (424 g) in water (720 ml_) is added into the above system within 40 min, and keep stiring at 40°C for 2h. The ethanol (2 L) is added and cool the mixture to 0°C, followed by filteration and washing with ethanol to get a white cake, which is dried in vacuo at 45°C for 6 h to give desired compound 1 in 84percent yield (474 g) and > 98percent NMR purity. | |
84% | A stirred solution of 2,2-diethoxy-N,N-dimethylethan-l -amine (15 g, 93.16 mmol. 1.0 eq), cone, hydrochloric acid (15.5 ml) and water (7.5 ml) heated at 40 °C for about 3 hours. Then a solution of sodium pyro sulphite (15.93 g, 83.84 mmol, 0.9 eq) dissolved in water (27 ml) was added dropwise and the mixture was stirred for about 1 hour. Then 90 ml of ethanol was added to reaction mixture and stirred for about 2 hours at 0 °C. The suspension was filtered and washed with ethanol (20 ml), then dried under vacuum at 40 °C for about 30 minutes to afford the desired product (15 g, yield: 84percent) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.0 g | To the solution of 45.2 ml of cone. HC1 (aq) and 25.1 ml of water at 20 °C - 25 °C, 50.0 g of 2,2-diethoxy-N,N-dimethylethanamine was added dropwise. After stirring for 2.5 hours at about 40 °C, solution of 53.1 g of a2S205 in 89.0 ml of water was added dropwise at about 40 °C. The reaction mixture was stirred for 1 hour at 40 °C when 251 ml of ethanol was added. The suspension was cooled down to 0 °C - 5 °C and stirred for 1.5 hours. Crystals were filtered off, washed with 100.0 ml of ethanol and dried at 45 °C/ 15 mbar for about 17 hours. 48.0 g of 2- (dimethylamino)-l -hydroxy ethanesulfonic acid was obtained. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In a round bottom flask, 2,2-diethoxy-N,N-dimethylethanamine (Formula III, 200 g) and deionized water (100 mL) were added at about 20°C to about 25°C. To the solution, concentrated hydrochloric acid (240 mL) was added at about 25°C to about 50°C. The temperature of the reaction mixture was raised to about 70°C. The reaction mixture was stirred at about 60°C to about 70°C for about 12 hours. The reaction mixture was cooled to about 0°C. To the reaction mixture, about 200 mL of aqueous potassium hydroxide (240 g in 250 mL water) was added at about 0°C to about 10°C to attain a pH of 9.0. To the reaction mixture, ethyl(diethoxyphosphoryl) acetate (200 g) and 2- methyltetrahydrofuran (600 mL) were added at about 0°C to about 5°C. Further, 50 mL of aqueous potassium hydroxide was added to the reaction mixture at about -5°C to about 0°C to attain a pH of about 13.5. The reaction mixture was stirred at about -5°C to about 0°C for about 1 hour. The reaction mixture was filtered, and then the filtrate was recovered under vacuum at about 45°C to about 50°C to obtain ethyl-4- (dimethylamino)crotonate as an oily mass. Yield: 89percent |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 81% | 2, Preparation of intermediate IIUnder the protection of nitrogen, take 6mol / L sulfuric acid 10.0ml, down to 0 , drop compound III ((dimethyl ammoniaYl) -acetaldehyde-diethyl acetal) was hydrolyzed at 45 ° C and cooled to 0 ° C for standby (A).To 200 ml of absolute ethanol was added to the above-mentioned intermediate IV20.00g, lithium chloride 1.60g, cooling to 0And 8.0 g of sodium ethoxide was added thereto. The mixture was stirred for 30 minutes, and the stock solution A was added dropwise. All the prepared liquid A was added dropwise.After the reaction was continued for 50 min, 500 ml of ethyl acetate was added, stirred for 1.0 hr, filtered, and 250 ml of water was added to the filtrate. In ThereThe organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give intermediate II. The yield in this step was about 81percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Ca. 84% | Under the protection of nitrogen, take 6mol / L hydrochloric acid 10.0ml, down to 0 ,9.0 ml of compound III ((dimethylamino) -acetaldehyde-diethyl acetal) was added dropwise, hydrolyzed at 40 ° C and cooled to 0 ° C for standby (A).To 100 ml of absolute ethanol, 10.00 g of the intermediate IV, 0.80 g of lithium chloride were added in this order, and the temperature was lowered to 04.0 g of sodium ethoxide was added, and the mixture was stirred for 30 minutes. The stock solution A was added dropwise, and the prepared liquid A was added dropwise.After the reaction was continued for 40 min, 250 ml of ethyl acetate was added, stirred for 1.0 hr, filtered, and 125 ml of water was added to the filtrate. In ThereThe organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to give intermediate II. The yield in this step was about 84percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In sodium hydroxide; | (a) 2-(N,N-dimethylaminomethyl)chroman-4-one Dimethylaminoacetaldehyde diethyl acetal (40 g) was treated below -5° C. with conc. hydrochloric acid (196 ml) and then stirred at room temperature for 2 hours. After the solution had been neutralised with sodium bicarbonate, 2 N sodium hydroxide (80 ml) was added followed by 2-hydroxyacetophenone (34 g) in 2 N sodium hydroxide (80 ml) and sufficient dioxane to give a single phase reaction mixture. The solution was heated at 70°-80° C. with stirring for 21/2 hours and left at ambient temperature overnight. Extraction with diethyl ether was followed by extraction of the organic phase with dilute hydrochloric acid. The aqueous acid solution was basified with sodium hydroxide solution and extracted into diethyl ether to give the title compound (3.4 g) as an oil. 1 H nmr (CDCl3) delta: 8.1-6.9 (m, 4H); 4.9-4.4 (m, 1H); 3.0-2.5 (m, 4H); 2.3 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48.7% | Intermediate IV andBromo-2,3-dihydro-1H-pyrrolo (2,3-b) pyridine to give d,React with (S) -3-hydroxytetrahydrofuran,A dark yellow solid VId was obtained.The intermediate d with activated carbon,Ferric chloride and hydrazine hydrate reduction,Obtained as an off-white solid VIId.Then VIId and diethyl phosphoric acid condensation,Compound VIIId is obtained,In the condensation with (dimethylamino) acetaldehyde diethyl acetal,The target compound was obtained. Yield: 48.7percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With 5percent silver supported on titanium oxide; at 25℃; for 10h;Inert atmosphere; Sealed tube; UV-irradiation; | General procedure: In a glass reaction vessel, 2 mmol of benzylamine,45 mg of catalyst D,20 mL of dehydrated methanol,And a magnetic stirrer.Then, an argon gas is introduced into the sealed reaction system,Under the condition of 25 ° C.,While stirring the reaction system, ultraviolet rays were irradiated for 10 hours.Analysis of the reaction liquid showed that as a reaction product,Only N, N-dimethylbenzylamine was obtained(Yield 99percent or more, see Table 5). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With acetic acid; for 6h; | 1) 1H, 1'H-2, 3'-twoversus(dimethylamino)Acetaldehyde acetalAccording to the molar ratio of 1:1 to 3,Stir in acetic acid for 6 hours.Rearrangement to obtain an intermediate with a yield of 91% |
Tags: 3616-56-6 synthesis path| 3616-56-6 SDS| 3616-56-6 COA| 3616-56-6 purity| 3616-56-6 application| 3616-56-6 NMR| 3616-56-6 COA| 3616-56-6 structure
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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 |
Sorry,this product has been discontinued.
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