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CAS No. : | 4637-24-5 | MDL No. : | MFCD00008482 |
Formula : | C5H13NO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | ZSXGLVDWWRXATF-UHFFFAOYSA-N |
M.W : | 119.16 | Pubchem ID : | 78373 |
Synonyms : |
|
Num. heavy atoms : | 8 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 1.0 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 31.22 |
TPSA : | 21.7 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.86 cm/s |
Log Po/w (iLOGP) : | 1.63 |
Log Po/w (XLOGP3) : | 0.23 |
Log Po/w (WLOGP) : | 0.12 |
Log Po/w (MLOGP) : | 0.16 |
Log Po/w (SILICOS-IT) : | -0.6 |
Consensus Log Po/w : | 0.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.53 |
Solubility : | 35.5 mg/ml ; 0.298 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.25 |
Solubility : | 67.7 mg/ml ; 0.568 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -0.24 |
Solubility : | 67.8 mg/ml ; 0.569 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.41 |
Signal Word: | Danger | Class: | 3 |
Precautionary Statements: | P210-P261-P280-P305+P351+P338 | UN#: | 3271 |
Hazard Statements: | H225-H302+H312+H332-H315-H319-H335 | Packing Group: | Ⅱ |
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 |
---|---|---|
5.7% | Stage #1: With pyrrolidine In DMF (N,N-dimethyl-formamide) at 20 - 115℃; Stage #2: With hydrogen In methanol at 50℃; |
Example S40; Preparation of 6-fluoro-1H-indole-7-carboxylic acid; A solution of 70.3 g of 4-fluoro-1-methyl-2-nitro-benzene (453 mmol) in 330 ml DMF was treated at rt with 87.5 ml of N,N-dimethylformamide dimethylacetal (DMFDMA, 589 mmol) and 50 ml of pyrrolidine (544 mmol) and then heated in an oil bath at 115° C. under argon. The dark red solution was then cooled down to rt, and poured into 1500 ml brine, extracted twice with diethylether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo, leading to 106 g residue. About half of this residue (51.5 g) were dissolved in 800 ml methanol, treated with 12.5 g 10percent Pd/C and hydrogenated at 50° C. After removal of the catalyst by filtration, the residue was purified by silicagel chromatography (800 g silicagel, heptane/EtOAc 9:1) leading to 3.5 g of 6-fluoro-1H-indole as a light green solid (5.7percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
36% | Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 110℃; for 1.5 h; Stage #2: With acetic acid; zinc In water at 75 - 85℃; for 5.5 h; |
Step A: To a solution of 4-bromo-2-nitrotoluene (7.9 g, 36.6 mmol) in dimethylformamide (73 mL) were added N,N-dimethylformamide dimethylacetal (14.5 mL, 110 mmol) and pyrrolidine (4.7 mL), and the mixture was heated at 110° C. for 90 minutes. The cooled reaction mixture was diluted with diethyl ether, and washed with water. The aqueous layer was re-extracted with diethyl ether twice, and the combined organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained was dissolved in aqueous acetic acid (245 mL, 80percent), and heated to 75° C. Zinc powder (20.8 g, 318 mmol) was added to the hot solution in small portions over 2 hours. The reaction mixture was then heated at 85° C. for 3 hours and 30 minutes, cooled to room temperature and then to 0° C. The precipitate formed was removed by filtration, and the filtrate was diluted with ethyl acetate and washed with water twice. The organic extract was dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown oil. The crude product was purified by flash column chromatography (95:5 hexanes/ethyl acetate, then 90:10 hexanes/ethyl acetate) to give 6-bromoindole as a grey solid (2.61 g, 36percent): 1H NMR (500 MHz, CDCl3) δ 8.14 (br s, 1H), 7.53 (s, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.21 (dd, J=8.4, 1.7 Hz, 1H), 7.17-7.15 (m, 1H), 6.53-6.51 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
32% | Stage #1: at 50℃; for 2 h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h; |
[0621] A mixture of XI-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,N-dimethylformamide dimethyl acetal was heated at 50° C. for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,N-dimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80° C. for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5° C. overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=7.0. After storage at 0-5° C. for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give XI-3 (3 g, 32percent yield). 1H NMR (DMSO-d6, 300 MHz): δ 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J=7.6 Hz, 1H). |
32% | Stage #1: at 50℃; for 2 h; Stage #2: With sodium hydride In N,N-dimethyl-formamide; mineral oil at 80℃; for 2.5 h; |
A mixture of X-2 (13 g, 95.6 mmol, 1 eq) and 18.2 mL of N,Ndimethylformamide dimethyl acetal was heated at 50°C for 2 hrs. During the second hour, all the volatiles was removed. The residue was cooled to rt., diluted with 100 mL of anhydrous N,Ndimethylformamide, and then treated carefully with batch wise portions of sodium hydride (5 g, 124.3 mmol, 1.3 eq, 60percent oil dispersion; caution: vigorous evolution of hydrogen). The mixture was heated at 80°C for 2.5 hrs, and then ice-cooled, treated cautiously with 25 mL of 2-propanol, and then maintained at 0-5°C overnight. The solid were collected, and then dissolved in 10 mL of hot water. The solution was filtered, the filtrate was ice-cooled and then treated dropwise with concentrated hydrochloric acid to pH=-7.0. After storage at 0-5°C for 3 hrs, the precipitated solids were collected, washed with ice-cold water, and dried in vacuum to give X-3 (3 g, 32percent yield). ‘H NMR (DMSO-d6, 300 MHz): ö 8.90 (s, 1H), 8.49 (d, J=7.6 Hz, 1H), 7.51-7.43 (m, 2H), 6.61 (d, J =7.6 Hz, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | Stage #1: for 23 h; Reflux Stage #2: at 20℃; for 24 h; |
2-Aminopyridine (1.88 g, 20 mmol) in 1,1-dimethoxyN,N-dimethylmethanamine (3.82 g, 32 mmol) was refluxed for 23 h and then evaporated. The resulting residue was dissolved in EtOH (35 mL), 1-bromoacetone (3.12 g, 22.75 mmol) was added and the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated and the residue was purified by column chromatography (eluent: dichloromethane/methanol = 40:1) to afford 12s as a pale yellow solid (2.06 g, 64percent). Mp: 95-96 °C (Lit.Mp [20] 98-99 °C). 1H NMR (400 MHz, CDCl3): δ = 2.61 (s, 3H), 7.08 (t, J = 6.80 Hz, 1H), 7.50 (t, J = 8.00 Hz, 1H), 7.76 (d, J = 9.00 Hz, 1H), 8.34 (s, 1H), 9.65 (d, J = 6.84 Hz, 1H). |
12% | Stage #1: at 90℃; for 3 h; Stage #2: at 20℃; for 4 h; |
A solution of intermediate 1 (20 g, 0.21 mol) and DMF-DMA (38 g, 0.32 mol) was stirred at 90° C. for 3 hrs. The mixture was concentrated in vacuum, the residue was dissolved in EtOH (200 ml), 1-bromopropan-2-one (32 g, 0.23 mol) was added dropwise, and the mixture was stirred at room temperature for 4 hrs. The solvent was concentrated in vacuum and purified by flash column chromatography to give intermediate 23 (4.1 g, 12percent) as a yellow solid. (0384) 1H NMR (CDCl3, 400 MHz): δ (ppm) 9.649.66 (m, 1H), 8.35 (s, 1H), 7.76 (d, 1H, J=8.8 Hz), 7.487.52 (m, 1H), 7.077.11 (m, 1H), 2.62 (s, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: at 100℃; for 0.166667 h; Stage #2: With hydrogenchloride In dichloromethane; water at 40℃; for 0.5 h; |
Example 10A 7-methoxy-4H-1-benzopyran-4-one 1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated to >100° C. in a sand bath for 10 minutes, at which point a solid mass had formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a frilled funnel. The solid material was crushed with a pestle and then washed with heptanes. The solid was then dried on the filter to give about 60 g of the crude intermediate. This intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40° C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2*100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was then precipitated from 500 mL of 1:1 cyclopentyl methyl ether:heptanes to give the title compound (35 g, 70percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
70% | Stage #1: at 100℃; for 0.166667 h; Stage #2: With hydrogenchloride In dichloromethane at 40℃; for 0.5 h; |
1-(2-Hydroxy-4-methoxyphenyl)ethanone (47 g, 283 mmol) was dissolved in N,N-dimethylformamide dimethyl acetal (47 mL, 351 mmol), and the solution was heated at >100° C. in a sand bath for 10 minutes, at which point a solid mass formed. The flask was cooled to ambient temperature, and 200 mL of heptanes were added. The solids were broken up with a spatula and collected by filtration with a fritted funnel. The solid material was crushed with a pestle and washed with heptanes. The solid was dried on the filter to give about 60 g of the crude intermediate. The intermediate was dissolved in dichloromethane (1 L) and stirred with 150 mL of concentrated HCl at 40° C. for 30 minutes. The flask was cooled to ambient temperature, and about 100 mL of water was added. The layers were separated, and the aqueous layer was extracted with dichloromethane (2×100 mL). The combined organic extracts were washed with saturated sodium bicarbonate (100 mL) and brine (100 mL) and dried over sodium sulfate. The mixture was filtered, and the filtrate was concentrated in vacuo to give a solid. The solid was taken into 500 mL of 1:1 cyclopentyl methyl ether:heptanes and the precipitate was collected to provide the title compound (35 g, 70percent yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.11 (d, J=8.9 Hz, 1H), 7.77 (d, J=6.0 Hz, 1H), 6.97 (dd, J=8.9, 2.4 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.28 (d, J=6.0 Hz, 1H), 3.90 (s, 3H); MS(ESI+) m/z 176.9 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | for 1 h; Reflux | A mixture of 2,3-Dihydro-1H-carbazol-4(9H)-one (1.0 mmol)and DMF-DMA (10 mmol) in DMF (5.0 mL) was refluxed for 1.0 h.The reaction mixture was cooled and extracted with ethyl acetate(2 25 mL). The organic layer was separated and washed with brine solution. The organic layer was dried over anhydrous Na2SO4.The solvent was removed under reduced pressure and the solidobtained was recrystallized from ethanol.White needles, yield 71percent, m.p. 188–90 C. IR (cm1) 1695(CO), 1H NMR (400 MHz, CDCl3) d 2.24–2.27 (t, 2H, CH2,J = 6.28 Hz), 2.56–2.59 (t, 2H, CH2, J = 6.0 Hz), 2.91–2.94 (t, 2H,CH2, J = 6.21 Hz), 3.70 (s, 3H, NCH3), 7.27–7.30 (m, 3H, Ph), 8.24–8.26 (m, 1H, Ph). Anal. Calc. for C13H13NO: C, 78.36; H, 6.58, N,7.03percent. Found: C, 78.29; H, 6.49; N, 6.92percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71% | at 120℃; for 4 h; | Ethyl 3- (2-aminophenyl) -3-oxopropionate (20.7 g, 0.1 mol) was dissolved in 100 mL of N, N-dimethylformamide,N, N-dimethylformamide dimethyl acetal (24.0 g, 0.2 mol) was added thereto, and the reaction was carried out at 120 ° C for 4 hours.The reaction solution was cooled to 20 ° C and the solvent was concentrated under reduced pressure. The residue was added to 200 g of ice water and stirred for 2 h.Ethanol and water volume (30mLx2 times), 50 drying, with 160mL ethyl acetate and petroleum ether equal volume mixedWas purified by recrystallization to obtain 15.4 g of ethyl 4-hydroxyquinoline-3-carboxylate in 71percent yield as an off-white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | at 90℃; for 12 h; | A solution of 4.0 g (33.0 mmol, 1.0 eq.) of 1-(pyridin-2-yl)ethan-1-one in 13.1 mL (99.1 mmol, 3.0 eq,) of DMF dimethylacetal was stirred at 90 °C for 12 h. The mixture wasallowed to cool to room temperature, and the resulting precipitate was collected by filtration. The solids were washed with 2 x 5 mL of ethyl acetate and dried under high vacuum to provide, 3.0 g (17.0 mmol, 51percent) of (E)-3 -(dimethylamino)- 1 -(pyridin-2-yl)prop-2-en- 1-one. |
13 g | for 24 h; Reflux | 12.1 g of 2-acetylpyridine was dissolved in 150 ml of toluene, 30 ml of DMF-DMA was added while stirring, and the mixture was heated to reflux for 24 hours, cooled to room temperature, concentrated to dryness under reduced pressure, and 150 ml of petroleum ether was added to the residue for stirring. Disperse, filter, filter cake washed with petroleum ether to give intermediate 13g, yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85.4% | Stage #1: at 20 - 70℃; for 4 h; Stage #2: at 25℃; for 2 h; |
A process for the synthesis of N, N-dimethylformamide dimethylacetal comprising the steps of:(1) N, N-dimethylformamide was heated to 70 ° C, incubated with dimethyl sulfate, and reacted at the end of the dropwise addition for 4 hours to obtain an imine complex,Cooled to room temperature, and the molar ratio of N, N-dimethylformamide and dimethyl sulfate is 1: 1;(2) the solid sodium methoxide added to 200 solvent oil, ultrasonic dispersion, adjust the temperature to 25 ,Insulation, dropping imine complex, after the end of the reaction for 2h, filtration, the filtrate under normal pressure fractionation,A fraction of 105-108 ° C was collected to give N, N-dimethylformamide dimethyl acetal in a yield of 75.3percentPurity of 97percent; where the molar ratio of sodium methoxide to imine complex is 1: The synthesis method of N, N-dimethylformamide dimethyl acetal of Example 6 was the same as in Example 2 except that the organic solvent of this example was a mixed solvent oil: D40 solvent oil, D60 solvent oil, 260 (Volume ratio: 2: 1: 1) to give N, N-dimethylformamide dimethylacetal as a yield of 85.4percent and a purity of 97percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59% | at 0 - 20℃; for 20 h; Inert atmosphere | Separately, 440 g of anhydrous methanol and 111 g (2.05 mol) of sodium methoxide are added to a 1-liter three-necked flask under a nitrogen atmosphere and cooled to 0 to 5 ° C. 400.4 g (2.01 mol) of the immune complex was dropped for 3 hours while maintaining the temperature at 5 DEG C or lower, and the mixture was stirred at room temperature for 20 hours. The methanol was removed by distillation under atmospheric pressure and distilled under vacuum to obtain 141.3 g (yield 59percent) of colorless liquid dimethylformamide dimethylacetal. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93.5% | at 80℃; for 2 h; | To 2-nitro-(1H)-imidazole (2.0 g, 17.7 mmol)N,N-dimethylformamide dimethyl acetal (8.4 g, 70.7 mmol) was added dropwise to a solution of DMF (10 ml).The reaction was carried out at 80 ° C for 2 h. Add water (30ml) and ethyl acetate (25ml),The mixture was extracted with ethyl acetate (25×2 mL).Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure.The crude product was separated by column chromatography (eluent: dichloromethane: anhydrous methanol = 30:1).A pale yellow solid (2.1 g, 93.5percent) was obtained.The product purity is 99.7percent (mass fraction) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: With acetic acid In N,N-dimethyl-formamide at 25℃; for 1 h; Stage #2: With hydrazine hydrate In N,N-dimethyl-formamide at 50℃; for 2 h; |
To a solution of 25 g of ethyl cyanoacetate (1, 0.221 mol)in 25 cm3 dimethylformamide was added 37.5 cm3 glacialacetic acid (0.077 mol) followed by 47.40 g of N,N-dimethylformamidedimethyl acetal (0.397 mol) dropwise at room temperature and stirred for 1 h. To the resultant pale yellow color solution was added 25 cm3 hydrazine hydrate (0.42 mol) drop wise at 0°C and the reaction medium was stirred for 2 h 50 °C. After completion of the reaction, the reaction medium was diluted with 2.5 dm3 of water and extracted with 2 9 700 cm3 of ethyl acetate. The combined organic layer was dried over sodium sulfate,filtered, and concentrated under reduced pressure to obtain the crude product as pale brown liquid. The crude product was further purified by column chromatography over silicagel, eluted with chloroform/methanol (95:5, v/v) to afford the compound 2 as a white solid (29 g, 85 percent). M.p.: 106.7–108.9 °C; TLC: Rf = 0.22 (CHCl3–MeOH 8:2); IR (ATR):v = 3193 (–NH), 2972 (=C–H), 1662 (ester –C=O), 1551(–C–C), 1496 (ester –C–O), 1337 (C–N) cm-1; 1H NMR(400 MHz, CDCl3): d = 1.23 (3H, t, J = 8 Hz, CH3), 4.15(2H, q, J = 8 Hz, OCH2CH3), 5.98 (2H, bs, ArNH2), 7.45(1H, bs, ArH), 12.04 (1H, bs, pyrazole NH) ppm; 13C NMR(100 MHz, DMSO-d6): d = 14.9, 59.1, 94.0, 139.9, 151.8,164.2 ppm; LC–MS: m/z = 156.7 [M+H]+. |
70% | at 20℃; for 2.5 h; Inert atmosphere | To a solution of ethylcyanoacetate (3) (25 g, 221.0 mmol)in dimethylformamide (25 mL) and acetic acid(37.5 mL), dimethyl formamide dimethyl acetal(47.40 g, 397.8 mmol) was added drop wise at roomtemperature under nitrogen atmosphere over a period of30 min. The reaction medium was stirred at room temperaturefor 2 h. The reaction mixture was cooled to 0 °Cand hydrazine hydrate (80percent, 25 mL) was added drop wiseto it over a period of 45 min and then heated to 50 °C for2 h. Completion of the reaction was monitored by TLC.After completion of the reaction, the reaction mixture wasdiluted with ice cold water (1L) and then extracted to ethylacetate (2 × 250 mL). The combined ethyl acetate layerwas dried over anhydrous sodium sulfate, filtered andevaporated under reduced pressure. The crude materialobtained was purified by column chromatography oversilica gel, eluted with 2–5percent methanol in chloroform to getthe product (4) as off-white solid (24 g, 70percent). MP:106.7–108.9 °C. IR (ATR, cm−1) υ: 1125.41 (C–O),1337.61 (C–N), 1496.40 (C–C), 1615.86 (N–H bend),1662.37 (ester C=O), 2972.92 (C–H), 3193.79(N–H stretch). 1H NMR (DMSO-d6, 400 MHz) δ (ppm):1.23 (3H, t, J = 7.2 Hz, ester–CH3), 4.16 (2H, q, J = 6.9Hz, ester–CH2), 5.99 (2H, bs, pyrazole–NH2), 7.47 (1H,bs, pyrazole–CH), 11.84 (1H, bs, pyrazole–NH). 13CNMR (DMSO-d6, 100 MHz) δ (ppm): 14.92 (ester–CH3),59.10 (ester–CH2), 94.00 (pyrazole–C-3), 139.93(pyrazole–C-4), 151.86 (pyrazole–C-5), 164.27 (carbonylfrom ester). LC-MS (ESI, m/z): 153.7 (M-H) and 156.7(M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
68% | Stage #1: at 110℃; for 4 h; Stage #2: at 25℃; |
4-bromoacetophenone (20.0 g; 0.10 mole) and N,N-dimethylformamide dimethylacetal (28.5 mL; 0.20 mole) were mixed together in DMF (12 mL) and heated to 1100C for 4 hours. The methanol and water that were generated during the reaction were distilled (6.2 mL). The mixture was cooled to 25°C. Methyl t-butyl ether (100 mL) and methylhydrazine (21.2 mL; 0.40 moles) <n="70"/>were added and the mixture was stirred over night. The reaction mixture was washed with 1 M aqueous ammonium chloride (3 x 40 ml_) and water (40 ml_). The organic phase was dried by azeotropic distillation using a Dean-Stark apparatus. As an alternative to distillation, the solution was dried through an anhydrous magnesium sulfate cartridge. The solution was filtered through a silica gel cartridge (60 g). The product was flushed from the cartridge with methyl t-butyl ether. The fraction(s) containing product were combined and concentrated to about 70 ml_ by distillation. Heptane (120 ml_) was added and distillation was continued until the pot temperature reached 98.4 0C. About 100 ml_ of distillate was collected. The mixture was cooled to 40 0C. The mixture was seeded and the temperature was maintained at 40 0C for 30 minutes while crystallization was initiated. The mixture was slowly chilled to 0 0C over 90 minutes. The mixture was held at 0 0C for 30 minutes. The mixture was filtered and the solid was washed (3 x) with chilled (00C) heptane. The solid was dried on the filter. A cream-colored, crystalline solid (16.3 g; 68percent yield) was obtained. The NMR data of the title compound are as per alternative 1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
80% | Stage #1: at 80℃; Stage #2: With hydrazine hydrate In ethanol at 80℃; for 2 h; |
(1) 3-(4-bromophenyl)-1H-pyrazole 5 g (25.0 mmol) of 4-bromoacetophenone and 3.59 g (30.1 mmol) of 1,1-dimethoxy-N,N-dimethylmethanamine were added to 40 ml of DMF. The mixture was heated to 80° C. for overnight. After cooling, the mixture was poured to water (150 mL) and extracted with EA (100 mL*3). The combined organic phase was washed with brine, concentrated to give red liquid (6 g). The thus obtained product was redissolved in 50 ml of ethanol and treated with hydrazine monohydrate (3.5 ml, 75 mmol). After the reaction was stirred at 80° C. for 2 h, it was cooled to 23° C. and poured to ice-water. Solid was precipitated out of the solution and filtered, washed with water, and dried to give 3.6 g of compound 3-(4-bromophenyl)-1H-pyrazole as yellow solid (yield: 80percent). 1H NMR (400 MHz, CDCl3): δ=7.58-7.62 (m, 3H), 7.49-7.51 (m, 2H), 6.58 (d, J=2.4, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 140℃; for 12 h; | In a 100 mL dry round bottom flask, acetophenone 1.08 g (9 mmol) of N,N-Dimethylformamide dimethyl acetal 3.9 mL (30 mmol) and 30 mL of xylene were added as a solvent. The mixture was refluxed at 140 ° C for 12 hours. After the TLC detection reaction was completed, the heating was stopped, the solvent was removed under reduced pressure, and the crude product was separated by flash column chromatography to give a pale yellow solid N,N-(dimethylamino)-1-phenyl enaminoketones 1.48 g (97percent yield). |
92% | Reflux | 2-1 1: Preparation of 3-dimethylamino-1- Yield: 92percent. Appearance: yellow solid. phenylprop-2-en-1-one (Protocol SA and 1H NMR: 2.93-3.14 (m, 6H); 5.73 (d, 1H, PC) J = 12.4 Hz); 7.38-7.49 (m, 3H); 7.82 (d, 1H, J = 12.4 Hz); 7.89 (d, 2H, J = 7.9 Hz).; Protocol SA:The appropriate ketone (acetophenone for Ex. 2-1; 4-trifluoroacetophenone for Ex. 2-2; 2-phenylacetophenone for Ex. 2-3; 2-acetylfuran for Ex. 2-5; para-acetylbiphenyl for Example 2-6; 3-trifluoromethylacetophenone 2.7) is dissolved in dimethyl acetal of N,N-dimethylformamide (1.2 to 1.5 eq.). The reaction mixture is stirred under reflux. The estimated reaction time varies between 24 and 48 hours. Satisfactory results were obtained in 24 hours. |
83% | at 115℃; for 20 h; | To a 100 mL round bottom flask, was added acetophenone (1.0 g, 0.0083 mol) followed by NN-dimethylformamide dimethyl acetal (1.48 g, 0.012 mol). The reaction mixture was stirred at 115 °C for 20 h. The reaction mixture was cooled to room temperature and ether was added to get the solid. The solid was collected by filtration to get the title compound [1.2 g, 83 percent]. JH NMR (300 MHz, CDC13): δ 7.89-7.86 (m, 2H), 7.80 (d, = 12.3 Hz, 1H), 7.44-7.39 (m, 3H), 5.72 (d, = 12.6 Hz, 1H), 3.11 (s, 3H), 2.91 (s, 3H); LC-MS: 176.0 [M+H]+. |
82% | at 150℃; for 20 h; Inert atmosphere | A mixture of acetophenone 1 (5.0 g, 41.66 mmol) and DMF-DMA (17.71 mL, 49.9 mmol) in DMF (10 mL) was heated to 150 0C under N2 atmosphere. After stirring for 2Oh at 150 0C, the reaction mixture was concentrated in vacuo. The resulting residue was triturated with diethyl ether, filtered and dried under high vacuum to obtain compound 2 (6 g, 82percent) as a yellow solid. TLC Rf = 0.5 (CHCl3 - MeOH, 7:3); 1H NMR (CDCl3) δ 7.88 (dd, J= 7.8, 1.5 Hz, 2H), 7.8 (d, J= 12.3 Hz, IH), 7.42 (m, 3H), 5.71 (d, J= 12.3 Hz, IH), 3.1 (s, 6H); MS (ES) mlz 176 (M + H)+. |
82% | at 150℃; for 20 h; Inert atmosphere | General procedure: A mixture of acetophenone 7a-7d (41.66 mmol) and DMF-DMA (49.9 mmol) in DMF (10 mL) was heated to 150 oC under N2 atmosphere. After being stirred for 20h at this temperature, the reaction mixture was concentrated in vacuo and the residue obtained was triturated with diethyl ether, filtered and dried under high vacuum to obtain compound 2a-2d (70-85percent) as a yellow solid. |
81% | for 14 h; Reflux | General procedure: To a mixture of acetone 14b (5.8 g, 100 mmol), inxylene (200 mL), was added dimethylformamide dimethylacetal (DMF-DMA, 11.9 g, 100 mmol)and the reaction refluxed for 15 h (monitored by TLC). The xylene was distilled off and the resultingsolid residue was purified by column chromatography using PE and EtOAc (6:1) as eluent to afford4-(dimethylamino)but-3-en-2-one 15b (4.3 g, 38percent) as a yellow oil. |
62% | for 21 h; Reflux | 5 g of acetophenone, 15 g of N, N-dimethylformamide dimethylacetal, and 60 ml of xylene were refluxed overnight (21 hours), a little raw material was not reacted and the reaction was stopped. The reaction solution was cooled and concentrated to remove xylene. 150 ml of petroleum ether was added to the residue, and a solid precipitated under stirring, followed by filtration to obtain 4.5 g of 3-dimethylamino-1-phenyl-prop-2-en-1-one as a yellow solid, 62percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | Stage #1: at 140℃; for 16 h; Stage #2: With sodium periodate In tetrahydrofuran; water at 0 - 20℃; for 5.16667 h; |
Example 110; This example concerns the synthesis of Aldehyde 5: To a stirred solution of 2 (5.248 g, 30.59 mmol) in dry DMF (172 mL) was added N,N-dimethylformamide dimethyl acetal (DMFDMA) (13.7 g, 12.0 mL, 88.5 mmol). After heating at 1400C for 16 h, the dark red solution was cooled to 0°C and added slowly, over 20 min via cannula, to a rapidly stirred solution OfNaIO4 (18.7 g, 87.4 mmol) in H2O (69 mL) and DMF (23 mL) at 0°C. The reaction flask was washed with DMF (20 mL) at 0°C and added to NaIO4 mixture. The reaction was stirred at 0°C for 30 min then allowed to warm to rt. After an additional 4 h, the orange solution was filtered and rinsed with PhMe (200 mL). The filtrate was then washed with H2O (2 x 200 mL) and sat. aq. NaCl (2 x 100 mL). The dried (MgSO4) extract was filtered, concentrated in vacuo to a dark red oil, and purified by flash chromatography over silica gel, eluting with 20-50percent EtOAc / Hexanes to give known aldehyde 5 (4.737 g, 25.53 mmol, 84percent). 1H NMR (400 MHz, CDCl3) δ 10.41 (s, IH), 8.13 (d, J- 2.0 Hz, IH), 7.97 (dd, J= 8.3 Hz, IH), 7.78 (dd, J= 2.0, 8.3 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 186.9, 150.1, 140.2, 134.2, 130.9, 129.3, 124.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
23% | Stage #1: at 135℃; for 12 h; Stage #2: With sodium periodate In water; N,N-dimethyl-formamide at 20℃; for 3 h; |
A mixture of l-fluoro-2-methyl-3-nitrobenzene and Λ/,Λ/-dimethylformamide dimethyl acetal (2.75 eq.) was heated to 135°C for 12 h. The reaction mixture was cooled to RT and added dropwise to a solution Of NaIO4 (2.75 eq.) in water/DMF (1 :1, 1.1 M). After the addition is finished, the reaction mixture was stirred at RT for 3 h. Then, it was filtered, and the solid was washed with toluene. The filtrate was transferred to a separatory funnel, and the layers were separated. The organic layer was washed with water and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave a crude that was purified by flash chromatography on silica using a gradient of EtO Ac/Petroleum ether (1 :30) to afford (23percent) the title compound. MS (ES+) C7H4FNO3 required: 169, found: 170 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Stage #1: at 140℃; for 16 h; Stage #2: With sodium periodate In water; N,N-dimethyl-formamide at 0 - 20℃; for 9 h; |
Example 109; This example concerns the synthesis of Aldehyde 4: To a stirred solution of1 (18.53 g, 108.0 mmol) in dry DMF (240 mL) was added N,JV-dimethylformamide dimethyl acetal (DMF'DMA) (39.5 g, 44.0 mL, 331 mmol). After heating at 140°C for 16 h, the dark red solution was cooled to 0°C and added slowly, over 1 h via cannula, to a rapidly stirred solution OfNaIO4 (83.0 g, 388.0 mmol) in H2O (291 mL) and DMF (77 mL) at 0°C. The reaction flask was washed with DMF (20 mL) at 0°C and added to NaIO4 mixture. The reaction was stirred at 0°C for 2 h then allowed to warm to rt. After an additional 6 h, the orange solution was filtered and rinsed with PhMe/EtOAc (1 : 1 , 200 mL). The filtrate was then washed with H2O (3 x 150 mL) and sat. aq. NaCl (3 x 150 mL). The dried (MgSO4) extract was concentrated in vacuo to a dark red oil, and hexanes (40 mL) were added. Solids were isolated and recrystalized in PhMe to give the known aldehyde 4 (17.23 g, 92.88 mmol, 86percent). 1H NMR (400 MHz, CDCl3) δ 10.42 (s, IH), 8.01 (dd, J= 1.0, 8.2 Hz, IH), 7.79 (dd, J= 1.0, 8.1 Hz5 IH), 7.65 (t, J= 8.1 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 188.6, 148.4, 138.6, 132.9, 132.4, 123.4, 121.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | at 110℃; for 3 h; | 1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and 1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at 110° C. for 3 hours. The produced methanol was removed by a Dean-Stark apparatus. After the solution was cooled to room temperature, the remaining volatile materials were removed in vacuo to provide 130 g of the crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 143 g theoretical, 91percent). LC-MS m/z 283 (M+1). Reference: WO 2006/0097341A1 (incorporated by reference), pg 67. |
68% | for 20 h; Reflux | (3E)-4-(Dimethylamino)-1,1-dimethoxybut-3-en-2-one (C10) A solution of N,N-dimethylformamide dimethyl acetal (147 g, 1.23 mol) and 1,1-dimethoxyacetone (146 g, 1.24 mol) in 2-butanol (1 L) was heated at reflux for 20 hours. After removal of solvent in vacuo, the residue was distilled under vacuum to provide the product as an oil. Yield: 145 g, 0.837 mol, 68percent. Boiling point: 132-140° C./0.15 torr. NMR and MS data were obtained using the product of a reaction run under similar conditions. LCMS m/z 174.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.77 (br s, 3H), 3.02 (br s, 3H), 3.30 (s, 6H), 4.47 (s, 1H), 5.23 (br d, J=12.6 Hz, 1H), 7.63 (d, J=12.6 Hz, 1H). |
68% | at 110℃; for 3 h; Inert atmosphere | A stuffed solution of 1,1-dimethoxy-N,N-dimethylmethanamine (5 g, 42 mmol) was mixed with 1,1-dimethoxypropan-2-one (4.95 g, 42 mmol) under nitrogen atmosphere. The reaction mixture was heated to 110 °C for 3 h. The methanol produced was removed by Dean-Stark apparatus. After completion the solution was cooled to rt and volatiles were removed under reduced pressure to obtain oily residue. The crude material was purified by column chromatography (60-120 silica gel, 0-5percent Methanol/DCM) to afford 2.3g of the title compound (68percent). LCMS: mlz=174 [M+1]. ‘H-NMR (400MHz, CDC13) ö: 7.6 1-7.58 (d, 1H), 5.19-5.16 (d, 1H), 4.43 (s, 1H), 3.26 (s, 6H), 3.10-3.08 (d, 3H), 2.79 (s, 3H), 1.15 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | Stage #1: at 135℃; for 16 h; Stage #2: With sodium periodate In water; N,N-dimethyl-formamide at 0 - 20℃; for 22 h; |
Example 35; This example describes the synthesis of Aldehyde 10: To a stirred solution of 9 (4.94 g, 22.3 mmol) and DMF (22.3 mL) was added DMF'DMA (8.18 g, 9.59 mL, 68.6 mmol). After heating at 135°C for 16 h, the dark red solution was cooled to 0°C and added to a rapidly stirred solution OfNaIO4 (14.7 g, 68.6 mmol) in H2O (46 mL) and DMF (23 mL) at 0°C. The reaction flask was washed with DMF (23 mL) at 0°C and added to NaIO4 mixture. The reaction was stirred at O0C for 4 h then allowed to warm to rt. After an additional 18 h, the orange solution was filtered over a pad of celite-.(R). and rinsed with EtOAc (200 mL) to remove precipitate. The filtrate was then washed with H2O (3 x 150 mL) and sat. aq. NaCl (3 x 150 mL). The dried extract (MgSO4) was concentrated in vacuo and purified by chromatography over silica gel, eluting with 40percent EtOAc / Hexanes to give the known aldehyde 10 (3.44 g, 14.8 mmol, 67percent). 1H NMR (400 MHz, CDCl3) δ 10.3 (s, IH), 8.04 (dd, J= 1.0, 8.2 Hz, IH), 7.95 (dd, J= 1.0, 8.0 Hz, IH), 7.55 (t, J= 8.0 Hz, IH); 13C NMR (100 MHz, CDCl3) δ 188.6, 148.4, 138.6, 132.9, 132.4, 123.4, 121.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | Stage #1: at 100℃; for 16 h; Reflux Stage #2: With hydrazine hydrate In ethanol at 60℃; for 0.5 h; |
A mixture of N-dimethoxymethyl-N,N-dimethylamine(10 mL) and 2-acetylpyridine (40 mL) was refluxed at 100 °C for 16 h, then concentrated by rotating evaporationto give dark brown solid. This was washed with hexane(100 mL) and diethyl ether (100 mL) to give the pure and bright yellow crystalline product. Hydrazine monohydrate (40 mL) and ethanol (15 mL) were mixed with the previously obtained solid, and the mixture was stirred at 60 °C for 30 min. After cooling, distilled water (75 mL) was added to the solution, which was kept at 0 °C for 24 h to produce a light yellow precipitate. This was recrystallized from a mixture of dichloromethane and hexane. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 110℃; for 4 h; Stage #2: With hydrogenchloride; titanium(III) chloride In water; N,N-dimethyl-formamide at 0℃; for 3 h; |
6-Iodoindole (4): Starting material 3 (5.00 g, 19.0 mmol, 1.0 equiv) was dissolved in DMF (50 mL). DMFDMA (3.05 mL, 22.8 mmol, 1.2 equiv) was added, followed by pyrrolidine (1.90 mL, 23.1 mmol, 1.2 equiv). The mixture was heated to 110 °C for 4 h until complete consumption of starting material as monitored by TLC, and allowed to cool to rt. DMF (100 mL) and 4 M aqueous NH4OAc buffer (83 mL, 17.5 equiv) were added and the solution was cooled with an ice bath. An aqueous solution of 20percent TiCl3 in 3percent HCl (73.3 mL, 114.06 mmol, 6.0 equiv) was added via a dropping funnel. The reaction mixture was stirred for 3 h followed by extraction with TBME (3 × 100 mL). The organic phase was washed with 2 M NaOH (100 mL), H2O (100 mL) and dried with MgSO4. After evaporation of the solvent the raw material was prepurified by short column chromatography [PE/EA (15:1)] to be sublimated in HV at 110–115 °C to give the product as a slightly yellowish solid (2.83 g, 11.6 mmol, 61percent). TLC [PE/EA (10:1)]: Rf = 0.25. Mp.: 103-105 °C. 1H NMR (400 MHz, CDCl3): = 8.10 (sbr, 1H, NH), 7.75 (dd, 1H, J = 2.0 Hz, J = 1.0 Hz, 4-H), 7.40-7.39 (m, 2H, 5-H and 7-H), 7.13 (dd, 1H, J = 3.2 Hz, J = 2.5 Hz, 2-H), 6.52 (ddd, 1H, J = 3.1 Hz, J = 2.0 Hz, J = 0.9 Hz, 3-H). 13C NMR (100 MHz, CDCl3): = 137.1 (1C, C-7a), 128.7 (1C, C-7), 127.2 (1C, C-3a), 124.5 (1C, C-2), 122.4 (1C, C-5), 120.0 (1C, C-4), 102.9 (1C, C-3), 85.8 (1C, C-6). IR (ATR): = 3888 (w), 3410 (s), 3094 (w), 3073 (w), 2925 (w), 1884 (w), 1726 (w), 1624 (w), 1597 (w), 1563 (w), 1493 (w), 1449 (m), 1392 (m), 1331 (m), 1309 (m), 1270 (w), 1232 (w), 1199 (w), 1090 (m), 1059 (w), 1043 (w), 998 (m), 944 (w), 878 (m), 858 (m), 802 (s), 759 (m), 727 (s), 651 (w), 607 (m), 586 (m), 565 (w). UV-Vis (MeOH): max (lg ) = 202 (4.32), 227 (4.62), 279 (3.86), 285 (3.86). MS (EI, 70 eV): m/z (percent) = 243 [M]+ (100), 116 [M–I]+ (56), 89 (26), 63 (12) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | at 100℃; for 9 h; | A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100°C for 9 hours. After cooling as it was, the reaction mixture was concentrated. To the residue were added diethyl ether and hexane. The resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J= 12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J = 0.8, 3.4 Hz), 7.68 (1H, d, J = 12.6 Hz), 7.79 (1H, dd, J = 0.8, 2.0 Hz). |
97% | at 100℃; for 9 h; | Reference Example 5 3-(Dimethylamino)-1-(2-furyl)-2-propen-1-one A mixture of 2-acetylfuran (25.0 g, 0.227 mmol) and N,N-dimethylformamide dimethylacetal (40 ml) was stirred at 100° C. for 9 hours. After cooling as it was, the reaction solution was concentrated. Diethyl ether and hexane were added to the residue, and the resulting solid was collected by filtration and washed with hexane, to give the title compound (36.5 g, 97percent) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm; 2.88 (3H, br s), 3.14 (3H, br s), 5.65 (1H, d, J=12.6 Hz), 6.60 (1H, dd, J=2.0, 3.4 Hz), 7.10 (1H, dd, J=0.8, 3.4 Hz), 7.68 (1H, d, J=12.6 Hz), 7.79 (1H, dd, J=0.8, 2.0 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
5.5% | Stage #1: With pyrrolidine In 1,4-dioxane at 100℃; for 18 h; Inert atmosphere Stage #2: at 110℃; for 4 h; |
ep 2: A mixture of 298 (3.0 g, 13.04 mmol), pyrrolidine (926 mg, 13.04 mmol), and DMF-DMA (7.76 g, 65.22 mmol) in 1,4-dioxane (20 mL) under nitrogen atmosphere was heated at 100 °C for 18 h. The reaction was concentrated under to dryness in vacuo and to the residue was added iron (3.65 g, 65.22 mmol) and HO Ac (40 mL). The resulting mixture was heated at 110 °C for 4 h, cooled to RT and filtered. The filtrate was concentrated in vacuo. The crude was purified by S1O2 chromatography eluting with petroleum ether/EtOAc (10:1) to afford 150 mg (5.5percent) of 4-bromo-5-methyl-lH-indole (300) as a yellow solid: MS (ESI) m/z = 210.1 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | Stage #1: at 110℃; for 15 h; Stage #2: With sodium hydroxide In water; N,N-dimethyl-formamide at 110℃; for 36 h; |
Pyruvic aldehyde dimethyl acetal (10 g, 84 mmol) and N, N’-dimethyl formamide dimethyl diacetal (10 g, 84 mmol) in DMF (30 ml) were heated in a round bottom flask at 110 °C for 15 h. Guanidine hydrochloride (12 g, 127 mmol) and NaOH (6.7 g, 169 mmol) in water were then added to the reaction mixture. The mixture was refluxed for further 36 h. The reaction mass was then cooled and filtered. The product was recrystallized from hot ethyl acetate to yield white crystalline solid 2 (10 g, 70percent). |
36% | Stage #1: at 100℃; for 16 h; Stage #2: With sodium hydroxide In water at 20℃; for 48 h; |
Procedure H: Intermediate 8 (1-8) - 2-Aminopyrimidine-4-carboxaldehyde dimethylacetal.; [0093] A solution of 5.5 mL (41 mmol, 1.0 eq.) of dimethylformamide dimethyl acetal and 5.0 mL (41 mmol, 1.0 eq.) pyruvric aldehyde dimethyl acetal was heated at 100 0C for 16 h. Methanol was removed in vacuo to afford a brown oil. A solution of 1.8 g (45 mmol, 1.1 eq.) of sodium hydroxide in 5 mL of water was added to a solution of 4.3 g (45 mmol, 1.1 eq.) of guanidine HCl in 10 mL of water. The resulting solution was added to the above described oil. The resulting mixture was stirred at room temperature for 48 h. The mixture was filtered to provide 2.5 g (15 <n="38"/>mmol, 36percent) of 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (1-8). |
50% | With sodium hydroxide In water | a) 2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h. Methanol was removed in vacuo to afford an oil. A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl (43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil. The resulting mixture was stirred at 23° for 48 h. Filtration afforded 25 g (50percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With sodium hydroxide In water | a 2-Aminopyrimidine-4-carboxaldehyde dimethyl acetal Dimethylformamide dimethyl acetal (55 mL, 0.41 mol), and pyrrhic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 100° for 18 h. Methanol was removed in vacuo to afford an oil. A solution of NaOH (18 g, 0.45 mol) in H2 O (50 mL) was added to guanidine HCl(43 g, 0.45 mol) in H2 O (100 mL), and the resulting solution was added to the above described oil. The resulting mixture was stirred at 23° for 48 h. Filtration afforded 25 g (50percent) of the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium methylate; thiourea; methyl iodide In methanol | a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil. |
93% | With sodium methylate; thiourea; methyl iodide In methanol | a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3 X 100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil. |
93% | With sodium methylate; thiourea; methyl iodide In methanol | a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask and heated at 100° C. After 4.5 h the flask was removed from the heat, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried over Na2 SO4 and concentrated to give the title compound (26.8 g, 93percent) as a brown oil. |
93% | With sodium methylate; thiourea; methyl iodide In methanol | a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2 O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2 SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium methylate; thiourea In methanol | a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mnL, 459 mmol) were stirred together at 100° C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H). |
82% | With sodium methylate; thiourea In methanol | a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 milliliter (hereinafter "mL"), 459 millimole (hereinafter "mmol")) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 hours (hereinafter "h"). The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4), and concentration to yield the title compound as a brown oil (75.5 gram (hereinafter "g"), 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H). |
82% | With sodium methylate; thiourea In methanol | a 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvic aldehyde dimethyl acetal (60 mL, 459 mmol) and N,N-dimethyl formamide dimethyl acetal (60 mL, 459 mmol) were stirred together at 100° C. for 18 h. The mixture was cooled. Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 mL, 25 wt percent in MeOH) were added to the above mixture and stirred at 70° C. for 2 h. After cooling, iodomethane (144 mL) was added dropwise and the mixture was stirred 3 h. at room temp. After diluting with EtOAc and H2 O, the organic phase was separated, dried (Na2 SO4),and concentrated to yield the title compound as a brown oil (75.5 g, 82percent yield). 1 H NMR (CDCl3): d 8.17 (d, 1H), 6.77 (d, 1H), 5.15 (s, 1H), 3.40 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With sodium methylate; thiourea; methyl iodide In methanol; water | a) 2-Methylthiopyrimidine-4-carboxaldehyde dimethyl acetal Pyruvaldehyde dimethyl acetal (19.2 mL, 159.1 mmol) and N,N-dimethylformamide dimethyl acetal (21.12 mL, 159.1 mmol) were combined in a 500 mL flask. After heating at 100° C. 4.5 h, thiourea (11.0 g, 144.5 mmol), NaOMe (25 wt. percent solution in MeOH, 39.7 mL, 173 mmol) and 30 mL of MeOH were added and heating was continued at 65° C. After 18 h, the solution was cooled to 25° C. and MeI (10.8 mL, 173 mmol) was added over 5 min (exothermic). After 3 h, the solution was diluted with 250 mL of H2O and extracted with EtOAc (3*100 mL). The organics were combined, dried (Na2SO4) and concentrated to give the title compound (26.8 g, 93percent) as a brown oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | at 140℃; for 12 h; | In a 250 mL round bottom flask was added 16.5 g (100 mmol) of 3-nitroacetophenone, 26.5 mL of N,N-dimethylformamide dimethyl acetal (200 mmol) and 100 mL of xylene. The mixture was heated to 140°C for 12 hours. Then the reaction mixture was cooled to room temperature and the formed precipitate was filtered off, washed with petroleum ether and diethyl ether followed by purification by chromatography using ethyl acetate/cyclohexene (25/75) to afford 19.6 g of a yellow solid. Yield: 89percent. 1H NMR (200 MHz, DMSO-d6) δ 8.59 (t, 1H), 8.42 – 8.23 (m, 1H), 7.81 (d, J = 12.1 Hz, 1H), 7.70 (t, J = 7.9 Hz, 1H), 5.89 (d, J = 12.1 Hz, 1H), 3.17 (s, 1H), 2.95 (s, 1H). 13C NMR (50 MHz, DMSO-d6) δ 182.8, 155.2, 147.9, 141.6, 133.4, 129.8, 125.1, 121.5, 90.3, 44.7, 37.3. |
79% | Heating / reflux; Neat (no solvent) | 3-Nitroacetophenone (5.0 g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) is heated at reflux overnight. The reaction mixture is cooled to room temperature and evaporated to remove the volatiles. The residue is slurried in ethyl ether and the suspension is filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C. |
79% | Heating / reflux | 3-Nitroacetophenone (5.0g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated to remove the volatiles. The residue was slurried in ethyl ether and the suspension was filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C. |
79% | Heating / reflux | 3-Nitroacetophenone (5.0g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and evaporated to remove the volatiles. The residue was slurried in ethyl ether and the suspension was filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C. |
79% | Heating / reflux | Step 1: 3-(Dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one 3-Nitroacetophenone (5.0 g, 30.3 mmol) in dimethylformamide-dimethylacetal (10 mL) is heated at reflux overnight. The reaction mixture is cooled to room temperature and evaporated to remove the volatiles. The residue is slurried in ethyl ether and the suspension is filtered and washed with ether to give 10.5 g (79percent) of 3-(dimethylamino)-1-(3-nitrophenyl)-2-propen-1-one, 104-105° C. |
11.34 g | for 21 h; Reflux | 10 g of 3-nitroacetophenone (60.6 mmol, 1 equiv.), 35.63 g of N, N-dimethylformamide dimethylacetal (181 mmol, 3 equiv.), and 50 ml of xylene were refluxed overnight (21 hours), a little raw material was not reacted and the reaction was stopped. The reaction solution was cooled and concentrated to remove xylene. 150 ml of petroleum ether was added to the residue, and a solid precipitated under stirring, followed by filtration to obtain 11.34 g of 3-dimethylamino-1-(3-nitrophenyl)-prop-2-en-1-one as a yellow solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62% | Stage #1: With acetic acid In toluene at 105℃; for 2 h; Stage #2: at 125℃; for 3 h; |
Compound 2-amino-4-fluoro-5-nitrobenzonitrile (7.2 g, 40 mmol) was dissolved into toluene (70 mL), DMF-DMA (N,N-dimethylformamide dimethyl acetal, 4.7 g, 40 mmol) and acetic acid (1 mL) was added, stirring to react at 105°C for 2 h, after concentration by evaporation, acetic acid (140 mL) and 3-chloro-4-fluoroaniline (6.9 g, 48 mmol) were added, stirring toreact at 125°C for 3 h. The reaction mixture was cooled to room temperature, poured into ice-water, after the pH value was adjusted to 9 with ammonia, then ethyl acetate 40 mL was added, stirred for 1 h, filtrated, dried to deliver the product N-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitro-4-quinazolinamine (8.3 g, 62percent yield). 1H-NMR (d-DMSO, 400 MHz, δ ppm): 10.61 (br, 1 H), 9.68 (d, J = 10.8 Hz, 1 H), 8.81 (s, 1 H), 8.10-8.13 (d, J= 7.6 Hz, 1 H), 8.05-8.07 (d, J = 8 Hz, 1 H), 7.81-7.85 (m, 1 H), 7.50-7.54 (d, J = 8 Hz, 1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 90℃; for 18 h; Stage #2: for 1 h; Reflux Stage #3: With sodium carbonate In water |
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitro-benzene (31 g, 0.126 mol) in DMF (150 mL) was added dimethylformamide dimethylacetal (27 mL) and pyrrolidine (10.5mL, 0.127 mol). The mixture was heated at 90°C for 18h and cooled to r.t. The mixture was diluted with water and extracted with CH2CI2. The organic phase was dried over Na2S04i filtered and concentrated. The residue was dissolved into HOAc (50 mL) and added dropwise to a solution of Fe (20.5 g, 0.37 mol) in boiling HOAc (150 mL). The mixture was refluxed for 1h and cooled to r.t., water added and the mixture was neutralised with Na2C03, and extracted with CH2CI2.The organic phase was dried over Na2S04, filtered and concentrated. The residue was purified by Prep-TLC (PE/EtOAc =5/1) to give the title compound (13 g, 44percent). H NMR CDCI3400 MHz δ: 8.41 (brs, 1 H), 7.18-7.08 (m, 2H), 6.49-6.43 (m, 2H), 3.86 (s, 3H). |
44% | Stage #1: With pyrrolidine In N,N-dimethyl-formamide at 90℃; for 18 h; Stage #2: for 1 h; Reflux |
To a solution of 1-bromo-4-methoxy-2-methyl-3-nitro-benzene (31 g, 0.126 mol) in DMF (150 mL) was added dimethylformamide dimethylacetal (27 mL) and pyrrolidine (10.5 mL, 0.127 mol). The mixture was heated at 90° C. for 18 h and cooled to r.t. The mixture was diluted with water and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was dissolved into HOAc (50 mL) and added dropwise to a solution of Fe (20.5 g, 0.37 mol) in boiling HOAc (150 mL). The mixture was refluxed for 1 h and cooled to r.t., water added and the mixture was neutralised with Na2CO3, and extracted with CH2Cl2. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by Prep-TLC (PE/EtOAc=5/1) to give the title compound (13 g, 44percent). 1H NMR CDCl3400 MHz δ: 8.41 (brs, 1H), 7.18-7.08 (m, 2H), 6.49-6.43 (m, 2H), 3.86 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58% | Stage #1: at 150℃; for 1 h; Stage #2: at 150℃; for 5 h; |
In a 1000 ml three-necked flask, 6.3 g (0.05 mmol) of 2-acetylthiophene was added,(N, N-dimethylbutyl) benzylammonium chloride (202 g, 0.5 mmol)Dimethylformamide dimethylacetal (22 g, 0.15 mmol) was added, and the mixture was stirred at 150 ° C for 1 hour.Then, 1.7 g (0.05 mmol) of hydroxylamine was added, and the reaction was stirred at 150 ° C for 5 hours.6.8 g (0.05 mmol) of aminoguanidine hydrochloride and the appropriate amount of water were added and the reaction was stirred at 150 ° C for 1 hour,12.3 g (0.05 mmol) of N- [3- [3- (dimethylamino) -1-oxo-2-propenyl] -phenyl] -N-methylacetamide was added,The reaction was stirred at 100 ° C for 5 hours, cooled to 10 ° C,Add 100 ml of dichloromethane to extract, dry over anhydrous magnesium sulfate, filter,The methylene chloride was evaporated to give an oil which was recrystallized from methanol to give 11 g of product as a yellow needle, yield 58percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | at 105℃; for 1 h; | [00377] Step 1: Synthesis of tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine– 1-carboxylate. A suspension of tert-butyl 3-oxopyrrolidine-1-carboxylate (10 g, 54.05 mmol) in 1,1-dimethoxy-N,N-dimethylmethanamine (120 mL) was stirred at 105°C for 1 h., cooled down to room temperature, the solvent was removed in vacuo and the residue was purified by chromatographic column on silicagel (DCM/MeOH = 60/1 to 20/1) to give tert-butyl 3-((di-methyl- amino)methylene)-4-oxopyrrolidine-1-carboxylate (10.78 g, 83percent yield). ESI-LCMS (m/z): 241.2[M+1]+;1HNMR (400 MHz, CDCl3) δ ppm: 7.26 (s, 1H), 4.57 (s, 2H), 3.86 (s, 2H), 3.09 (s, 6H), 1.48 (s, 9H). |
46% | at 100℃; for 17 h; | Preparation 31 3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2*80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent). |
46% | at 100℃; for 17 h; | Preparation 31 3-Dimethylaminomethylene-4-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (25.0 g, 135 mmol), dimethylformamide dimethylacetal (27 mL, 202 mmol) and 1,4-dioxane (170 mL) was heated at 100° C. for 17 hours. The dioxane was removed in vacuo. The resulting red solid was triturated with hexanes (180 mL) for one hour, and filtered. The solid was rinsed with hexanes (2*80 mL) and air dried. Chromatography on silica gel eluting with dichloromethane:methanol 39:1 then 19:1 to give the title compound (15.04 g, 46percent). |
41 g | at 105℃; for 0.666667 h; | The 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (40g, 216mmol) was dissolved in 300ml DMF-DMA was heated at 105 deg. C 40 minutes. The solution was cooled and evaporated under reduced pressure, hexane was added, and filtered to give an orange solid 41g, and dried, it was used for the next reaction without purification. |
41 g | at 105℃; for 0.666667 h; | (0086) 3-oxopyrrolidine-1-tert-butyl carboxylate (40g, 216mmol) was dissolved in 300mL DMF-DMA, heated for 40 minutes at 105°C. Cooled and concentrated to dry under vacuum, treated with hexane, filtered to obtain orange solid 41g, dried, the product can be used in the reaction of the next step without purification. |
4.7 g | at 100℃; for 1.5 h; | A solution of N-Boc-3-pyrrolidinone (CAS Number 101385-93-7; 5.0 g, 27.0 mmol) in DMF- DMA (32.17 g, 270 mmol) was heated at 100°C for 1.5 h. The resulting mixture was cooled to rt and concentrated under reduced pressure. The obtained residue was triturated with n-pentane (100 ml). The resulting solid was dried under high vacuum yielding tert-butyl 3-((dimethylamino)methylene)-4- oxopyrrolidine-l-carboxylate (4.700 g, 19.58 mmol). LCMS: Method 1, 1.556 min, MS: ES+ 241.43. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | at 80℃; for 24 h; | A mixture of N,N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and l-(tert-butoxycarbonyl)piperidin-4-one (30 g, 151 mmol) in DMF (240 mL) was stirred at 80 °C for 24 h. The mixture was concentrated in vacuo to give the title compound as a yellow solid (38.4 g, 100percent). MS (ESI, pos. ion) m/z: 255 [M + H]+. |
100% | at 80℃; for 24 h; | N, N-dimethylformamide dimethyl acetal (18 g, 20 mL, 151 mmol) and1- (tert-butoxycarbonyl) piperidin-4-one (30 g, 151 mmol)N, N-dimethylformamide (240 mL)The mixture was heated and stirred at 80 ° C for 24 hours.The reaction was complete and concentrated under reduced pressure to give the title compound as a yellow solid (38.4 g, 100percent). |
94.4% | at 95℃; for 1.5 h; | S1. Add N- t-butoxycarbonyl-4-piperidone (1) (12g, 60mmol) in 250ml flask, 150ml DMF-DMA, reaction at 95 1.5h, TLC showed the reaction was complete, concentrated to give 3 - ((N, N- dimethylamino) - methylene) -N- tert-butoxycarbonyl-4-piperidone (2) (white solid, 14.4g), yield 94.4percent. |
82% | for 20 h; Reflux | Preparation 21 t-Butyl-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate A solution of N-Boc-4-piperidone (10 g, 50.19 mmol) and DMF-dimethylacetal (20.16 ml, 150.57 mmol) in 1,4-dioxane (100 ml) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7percent MeOH in EtOAc) to give the title compound as an orange oil which crystallized on standing (10.51 g, 82percent). |
82% | for 20 h; Reflux | Preparation 21 t-Butyl-3-[(dimethylamino)methylidene]-4-oxopiperidine-1-carboxylate A solution of N-Boc-4-piperidone (10 g, 50.19 mmol) and DMF-dimethylacetal (20.16 ml, 150.57 mmol) in 1,4-dioxane (100 ml) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 7percent MeOH in EtOAc) to give the title compound as an orange oil which crystallized on standing (10.51 g, 82percent). |
76% | at 80℃; for 18 h; Inert atmosphere | Step 1DMF dimethyl acetal (5.82 mL, 0.044 mol) was added to a stirred solution of tert-butyl 4-oxopiperidine-l-carboxylate (8.73 g, 0.044 mol) in DMF (80 mL) and the reaction mixture was heated to 80 °C under N2 for 18 h. After cooling, the DMF was removed under reduced pressure and the residue was partitioned between EtOAc and H20. The organic layer was washed with H20 and saturated brine, then dried over MgS04 and evaporated to afford tert- butyl 3-((dimethylamino)methylene)-4-oxopiperidine-l-carboxylate (8.44 g, 76percent). |
63.8% | for 1.5 h; Reflux | N-tert-butoxycarbonyl-4-piperidone (58, 5.8 g, 31.4 mmol) wasdissolved in N,N-dimethylformamide dimethyl acetal (45.0 mL),and the solution was heated under reflux for 1.5 h and concentrated.The residue was triturated with hexane, filtered, andwashed with hexane to give 59 as a yellow powder (5.1 g, 63.8percent):mp 135e136 C; To a solution of 59 (5.0 g, 20.8 mmol) in EtOH(200.0 mL) were added guanidine carbonate (15.0 g, 84.0 mmol)and sodium acetate (13.7 g, 167.0 mmol), and the solution washeated under reflux for 48 h. The reaction mixturewas filtered, andthe insoluble material was extracted with CHCl3 and washed withwater. The organic layer was dried over anhydrous MgSO4 andevaporated. The resultant solid was triturated with 2-propanol,filtered, and washed with 2-propanol and Et2O to give a colorlesspowder. It was dissolved in TFA (50.0 mL) at 0 C, and the solutionwas stirred at room temperature for 1 h and concentrated. Theresidue was dissolved in 2-propanol and treated with concentrated HCl (4.0 mL). The precipitated solidwas filtered andwashed with 2-propanol and Et2O to give 60a (4.2 g, 81.6percent) as a colorless powder: Mp 258e260 C; Compound 57g was obtained from 60a in thesame way as 57f. |
60% | for 15 h; Reflux | A solution of N-t-Butoxycarbonyl-4-piperidone (10.0 g, 50.19 mmol) and N,N-dimethylformamide dimethylacetal (20.16 mL, 150.57 mmol) in 1,4-dioxane (100 mL) was heated at reflux for 15 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8percent MeOH in EtOAc) to obtain the title compound as an orange oil which crystallized on standing (7.64 g, 60percent). |
40% | for 6 h; Reflux | Stage 1: tert-Butyl 3-((dimethylamino)methylene)-4-oxopiperidine-1-carboxylate A mixture of tert-butyl 4-oxopiperidine-1-carboxylate (20.0 g, 100.38 mmol, 1.0 eq.) and N,N-dimethylformamide dimethylacetal (80 ml) was refluxed for 6 hours. After monitoring by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure and the residue was taken up in DCM (300 ml), washed with water (200 ml) and sat. NaCl solution (200 ml), dried over sodium sulfate, concentrated and purified by column chromatography (silica gel, 2.5percent MeOH in DCM). Yield: 40percent (10.2 g, 40.16 mmol) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | Stage #1: at 100℃; for 48 h; Stage #2: With sodium methylate In methanol for 118 h; Heating / reflux |
1) 4-Acetyl-2-methylthiopyrimidine A mixture of 3, 3-dimethylbutan-2-one (25.15 g) and N, N-dimethylformamide dimethylacetal (126 mL) was stirred at an external temperature of 100°C for 48 hours. After air cooling, the low boiling point components generated during the reaction were evaporated under reduced pressure, and methanol (400 mL), thiourea (28.92 g) and sodium methoxide (15.39 g) were added to the residue thus obtained. The mixture was heated to reflux for 118 hours. After air cooling, sodium methoxide (10.26 g) was added to the reaction solution, methyl iodide (17.8 mL) was added dropwise to the mixture over 5 minutes under ice cooling, and the mixture was stirred for 5 hours. Water and ethyl acetate were added to a residue obtained by evaporating the reaction solvent under reduced pressure, and the mixture was partitioned. The organic layer was washed with water and saturated saline, and then dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and an aqueous 3 N hydrochloric acid solution (400 mL) was added to the residue thus obtained and stirred for 15 hours at room temperature. Ethyl acetate was added to the reaction solution and the mixture was partitioned, and the organic layer was dried over anhydrous sodium sulfate. After separation by filtration, a residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (ethyl acetate-hexane), to obtain 4-acetyl-2-methylthiopyrimidine (26.34 g, 82percent) as a solid. 1H-NMR(400MHz, CDCl3)δ: 2.63(3H, s), 2.70(3H, s), 7.51(1H, d, J=4.9Hz), 8.74(1H, d, J=4.9Hz). ESI-MSm/z: 169(M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
16% | With hydrazine hydrate In tetrahydrofuran; methanol; N,N-dimethyl-formamide | 6-Bromo-5-fluoroindole N,N-Dimethylformamide dimethylacetal (8.5 mL, 60 mmol) was added in one portion to a stirred solution of 3-bromo-4-fluoro-6-methylnitrobenzene (11.8 g, 50 mmol) in N,N-dimethylformamide (30 mL) at room temperature under Ar. The mixture was heated to 120° C., stirred for 16 h then concentrated in vacuo to leave a crude oil. The oil was crystallized [methanol-dichloromethane (4:1)] to give a purple solid (4.5 g). The solid was dissolved in methanol/tetrahydrofuran (1:1; 30 mL) and Raney Nickel.(R). (1 g) was added. The mixture was cooled to 0° C. and hydrazine hydrate (0.8 mL, 16 mmol) was added in one portion. The mixture was stirred at 0° C. for 90 min then a further aliquot of hydrazine hydrate (0.8 mL) was added. The mixture was stirred at 0° C. for 30 min then filtered through celite.(R). and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated in vacuo and purified by column chromatography [SiO2; heptane-dichloromethane (4:1)] to give the product (1.7 g, 16percent) as an off-white solid: IR νmax (nujol)/cm-1 3395, 2925, 2855, 1570, 1469, 1451, 1408, 1314, 1145, 1105, 865, 763 and 502; NMR δH (400 MHz, CDCl3) 7.85 (1H, br. s), 7.55 (1H, d, J 5.5 Hz), 7.34 (1H, d, J 9 Hz), 7.23 (1H, t, J 2.8 Hz), 6.49-6.51 (1H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | Stage #1: at 50℃; for 4 h; Stage #2: With toluene-4-sulfonic acid In toluene at 100℃; for 18 h; |
To a solution of 9.0 g of 4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (see reference WO 9703986 A1 19970206) (37 mmoles, 1 eq.) in 40 ml of THF, were added 8.1 ml of dimethylformamide dimethyl acetal (55.4 mmoles, 1.5 eq.). The reaction mixture was then stirred at 50° C. for 4 hours under nitrogen. The solvent was removed under reduced pressure, the residue dissolved in 40 ml of toluene, and 400 mg of para toluene sulfonic acid were added. The mixture was then heated at 100° C. under nitrogen for 18 hours, the volatiles were removed under reduced pressure and the residue was partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic phase was dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the residue was purified by column chromatography on silica gel using methylene chloride/methanol as eluant (98:2 v/v to 95:5 v/v) to afford 8.07 g of the title compound as a white solid (81percent). 1H NMR (400 MHz, CD3OD): δ 1.42 (s, 9H), 1.70 (m, 2H), 2.05 (m, 2H), 2.50 (s, 3H), 3.00 (m, 2H), 3.15 (m, 1H), 4.05 (m, 2H); LCMS: m/z APCl+, 268 [MH]+; Found; C, 58.26percent; H, 7.96percent; N, 15.78percent; C13H21N3O3 requires C, 58.41percent, H, 7.92percent, N, 15.72percent |
81% | Stage #1: at 50℃; for 4 h; Stage #2: at 100℃; for 18 h; |
To a solution of ferf-butyl 4-(hydrazinocarbonyl)-1-piperidinecarboxylate (see WO 00/39125, preparation 27) (9.0 g, 37 mmol), in tetrahydrofuran (40 ml), was added dimethylformamide dimethyl acetal (8.1 ml, 55.4 mmol). The reaction mixture was stirred at 500C for 4 hours, under nitrogen. The solvent was then removed under reduced pressure, the residue was dissolved in toluene (40 ml), and para-toluenesulfonic acid (400 mg, 2.1 mmol) was added. The reaction mixture was heated at 1000C, under nitrogen, for 18 hours, after which time the cooled reaction EPO <DP n="48"/>mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (200 ml) and an aqueous solution of sodium bicarbonate (150 ml). The organic phase was separated and dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol as eluant (98:2 v/v to 95:5 v/v) to yield the title compound (8.07 g, 81percent) as a white solid.1H NMR (400MHz1 CD3OD): δ 1.42 (s, 9H), 1.70 (m, 2H), 2.05 (m, 2H1), 2.50 (s, 3H), 3.00 (m, 2H), 3.15 (m, 1 H), 4.05 (m, 2H); LCMS: m/z APCI+ 268 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3.6 g | at 60℃; for 3 h; | To a solution of ethyl acetoacetate (2.6 g, 20 mmol) in ethanol (10 mL) was added N,N-Dimethylformamide dimethyl acetal (2.5 g, 21 mmol). The mixture was allowed to stir at 60 °C for 3 h, then cooled to room temperature and concentrated to give a crude product (3.6 g, 97percent), which was used without further purification. |
A1638647[ 61853-18-7 ]
1,1-Dimethoxy-N,N-dimethylmethanamine-13C
Reason: Stable Isotope
[ 1188-33-6 ]
1,1-Diethoxy-N,N-dimethylmethanamine
Similarity: 0.79
[ 1188-33-6 ]
1,1-Diethoxy-N,N-dimethylmethanamine
Similarity: 0.79
[ 1188-33-6 ]
1,1-Diethoxy-N,N-dimethylmethanamine
Similarity: 0.79