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Structure of 102-52-3 * Storage: {[proInfo.prStorage]}
* 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.
EXAMPLE 4 2(1 H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25° C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23percent) of product; mp 186-188° C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
23%
With potassium carbonate In ethanol; water
EXAMPLE 4 2(1H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25° C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23percent) of product; mp 186-188° C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
Reference：
[1] Tetrahedron, 2001, vol. 57, # 20, p. 4397 - 4403
[2] Magnetic Resonance in Chemistry, 2011, vol. 49, # 8, p. 537 - 542
7
[ 4930-98-7 ]
[ 102-52-3 ]
[ 25700-11-2 ]
Yield
Reaction Conditions
Operation in experiment
70%
With hydrogenchloride In ethanol; water
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis (dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70percent) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) δ6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=l), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
70%
With hydrogenchloride In ethanol; water
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70percent) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) δ6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
70%
With hydrogenchloride In ethanol; water
Example 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70percent) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) δ6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
70%
With hydrogenchloride In ethanol; water
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70percent) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) δ6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=l), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
70%
With hydrogenchloride In ethanol; water
Example 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70percent) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) δ 6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
Reference：
[1] Journal of Medicinal Chemistry, 2004, vol. 47, # 19, p. 4645 - 4648
[2] Patent: US5604218, 1997, A,
[3] Patent: US5698547, 1997, A,
[4] Patent: US5607926, 1997, A,
[5] Patent: US5756493, 1998, A,
[6] Patent: US5593986, 1997, A,
[7] Patent: US5789584, 1998, A,
8
[ 102-52-3 ]
[ 102908-37-2 ]
Yield
Reaction Conditions
Operation in experiment
179.4mg
for 2 h; Reflux
a) 1-(2-Methoxyphenyl)-1H-pyrazol 200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 5 ml of ethanol, and 189 μl of malonaldehyde bisdimethylacetal was added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
a) 1-(2-Methoxyphenyl)-1H-pyrazole [0154] 200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 µl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR(CDCl3); δ (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); δ (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
for 2 h; Reflux
[0176] 200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 μl of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. [0177] 1H-NMR (CDCl3); δ (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). [0178] MS (FAB); m/z 175 (M+H)+
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89percent yield). 1H NMR (400 MHz, OMSO-Cl6): δl.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride In ethanol; waterReflux
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89percent). MS (ESI) m/z: 125 [M+H].
72%
Stage #1: With hydrogenchloride In ethanol; water at 50℃; for 2 h; Reflux; Industry scale Stage #2: With sodium hydroxide In water
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50°C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50°C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72percentyield) as a brown liquid (GC purity 99.70percenta/a).
72%
With hydrogenchloride In ethanol; water at 50℃; for 0.2 h; Reflux; Industrial scale
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50° C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0percent starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50° C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72percent yield) as a brown liquid (GC purity 99.70percent a/a).
21.9 g
With hydrogenchloride In ethanol for 2 h; Reflux
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
A. A solution of 3-amino-4-bromopyrazole (2.0 g, 12 mmol) and 1 ,1 ,3,3- tetramethoxypropane (4.1 mL, 25 mmol) in acetic acid (5 mL) was heated at reflux for 4 h. Water (2 mL) was added and the mixture heated at reflux for a further 0.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated in methanol. The solid thus obtained was washed with cold methanol, ethyl acetate, and hexanes to provide 3-bromopyrazolo[1 ,5-a]pyrimidine as a brownish solid in 39percent yield (0.953 g): 1H NMR (300 MHz, DMSO-d6) £9.13 (d, J = 6.5 Hz, 1 H), 8.61 (s, 1 H), 8.35 (s, 1 H), 7.19-7.02 (m, 1 H); MS (ES+) m/z 197.9 (M + 1), 199.9 (M + 1).
In the reaction flask with a stirrer was added 107 g of 2,6-diamino pyridine and 1070 ml phosphoric acid at room temperature was slowly added dropwise 241 g 1,1,3,3-tetramethoxypropane to the resulting solution, dropwise after an oil bath to heat up, control the internal temperature 70-75 ° C, for 40 minutes. Then the reaction mixture was poured into 5 liters of ice 5M aqueous sodium hydroxide solution, to ensure that pH> 10, the filter cake (200 ml × 2), and the filtrate was washed with methylene chloride and extracted with dichloromethane (300 ml × 2) the combined dichloromethane phases were washed with 100 g of anhydrous sodium sulfate, filtered, and concentrated to dryness, the resultant crude product was purified by column chromatography (packing agent is alumina, eluting with methylene chloride: methanol (v / v ) = 100: 1), to obtain 102 g of a red solid 1,8-naphthyridin-2-amine, yield 72percent, HPLC purity 96percent.
Reference：
[1] Patent: CN105399739, 2016, A, . Location in patent: Paragraph 0019; 0020
[2] Angewandte Chemie - International Edition, 2017, vol. 56, # 12, p. 3349 - 3353[3] Angew. Chem., 2017, vol. 129, p. 3397 - 3401,5
[4] Journal of Heterocyclic Chemistry, 1997, vol. 34, # 3, p. 765 - 771
13
[ 141-86-6 ]
[ 102-52-3 ]
[ 15936-09-1 ]
[ 15992-83-3 ]
Reference：
[1] New Journal of Chemistry, 2017, vol. 41, # 3, p. 1073 - 1081
Reference：
[1] Zhurnal Obshchei Khimii, 1957, vol. 27, p. 57,58,61;engl.Ausg.S.65,67,68
40
[ 102-52-3 ]
[ 2065-75-0 ]
Yield
Reaction Conditions
Operation in experiment
39%
Stage #1: With hydrogenchloride In water at 20℃; for 0.166667 h; Stage #2: With bromine In water at 20℃; for 1.16667 h;
A solution of 1,1,3,3-tetramethoxypropane (23) (10 g) and concentrated HCl (0.43 mL) in H2O (11 mL) was stirred at room temperature for 10 min. Br2 (3.1 mL) was added dropwise to the solution at room temperature for more than 50 min. The reaction mixture was stirred at room temperature for 20 min and concentrated in vacuo. The residual solid was washed with H2O to give 24 (3.6 g, 39percent) as a yellow solid. Mp 147–148 °C; 1H NMR (CDCl3) δ 4.73–4.80 (1H, m), 8.47 (2H, br s); FAB MS m/e (M−H)− 149.
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2004, vol. 14, # 1, p. 235 - 238
[2] Patent: US2005/85492, 2005, A1, . Location in patent: Page/Page column 25
[3] Bioorganic and Medicinal Chemistry, 2013, vol. 21, # 5, p. 1219 - 1233
[4] Organic and Biomolecular Chemistry, 2005, vol. 3, # 18, p. 3388 - 3398
[5] Patent: WO2004/67521, 2004, A1, . Location in patent: Page 68
41
[ 102-52-3 ]
[ 107953-75-3 ]
[ 6342-70-7 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6284 - 6286
42
[ 102-52-3 ]
[ 3943-73-5 ]
Reference：
[1] Journal of Organic Chemistry, 2007, vol. 72, # 16, p. 6284 - 6286
43
[ 1021178-39-1 ]
[ 102-52-3 ]
[ 52159-67-8 ]
Reference：
[1] Tetrahedron Letters, 2008, vol. 49, # 14, p. 2329 - 2332
[2] European Journal of Organic Chemistry, 2009, # 33, p. 5854 - 5867
44
[ 102-52-3 ]
[ 57-13-6 ]
[ 38353-09-2 ]
Reference：
[1] Organic Process Research and Development, 2007, vol. 11, # 2, p. 237 - 240
45
[ 102-52-3 ]
[ 2582-30-1 ]
[ 4023-02-3 ]
Reference：
[1] Journal of the American Chemical Society, 2010, vol. 132, # 32, p. 11223 - 11233
46
[ 102-52-3 ]
[ 1937-19-5 ]
[ 4023-02-3 ]
Reference：
[1] Journal of Medicinal Chemistry, 2008, vol. 51, # 24, p. 8168 - 8172
47
[ 102-52-3 ]
[ 31230-17-8 ]
[ 116834-96-9 ]
Reference：
[1] Journal of Medicinal Chemistry, 1997, vol. 40, # 17, p. 2706 - 2725
To a solution of ethyl 3,5-diamino-lH-pyrazole-4-carboxylate (5.00 g, 29.38 mmol) in DMF (80 mL) were added 1 , 1 ,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol) and AcOH (0.34 mL, 5.88 mmol). The reaction mixture was stirred at 100 °C for 14 h, and then concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (a solution of NH3in MeOH (7 M)/DCM (v/v) =1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1percent).MS (ESI, pos. ion) m/z: 207.1 [M+H]+;H NMR (400 MHz, CDC1 ): δ (ppm) 8.60 (dd, J= 4.40 Hz, 1.76 Hz, 1H), 8.46 (dd, J = 6.76 Hz, 1.76 Hz, 1H), 6.86 (dd, J = 6.72 Hz, 4.40 Hz, 1H), 4.50 (q, J = 7.08 Hz, 2H), 1.47 (t, J = 7.08 Hz, 3H).
58.1%
With acetic acid In N,N-dimethyl-formamide at 100℃; for 14 h;
To a solution of ethyl 3,5-diamino-1 -hydro-pyrazole-4-carboxylate (5.00 g, 29.38 mmol)In N, N-dimethylformamide ((80 mL)1,1,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol)And acetic acid (0.34 mL, 5.88 mmol).After the reaction mixture was stirred at 100 ° C for 14 hours,Concentrate under reduced pressure. The resulting residue was dispersed in a mixed system of dichloromethane (50 mL) and water (50 mL), the organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH3 in methanol (7M) / methylene chloride (v / v) = 1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1percent).
35.3%
With triethylamine In N,N-dimethyl-formamide at 100℃; for 14 h;
ethyl 2-aminopyrazolo[l ,5-a]pyrimidine-3-carboxylateA mixture of ethyl 3,5-diamino-l H-pyrazole-4-carboxylate (1.0 g, 5.9 mmol), 1,1,3,3- tetramethoxypropane (2.9 mL, 18 mmol), triethylamine (2 mL, 10 mmol), and DMF (15 mL) was heated at 100 0C for 14 hrs, then a further 2 mL of 1,1,3,3-tetramethoxypropane was added. After adding the additional 1,1,3,3-tetramethoxypropane, a significant by-product was noted and heating was stopped immediately. The reaction was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between DCM and water, then the organic layer was concentrated and the residue purified by silica chromatography, eluting with 95:5 DCM: 2M methanolic ammonia solution to afford 420 mg (35percent) of ethyl 2-aminopyrazolo[l,5- a]pyrimidine-3-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.57 (dd, J = 4.3, 1.6, IH), 8.43 (dd, J = 6.7, 1.6, IH), 6.84 (dd, J = 6.7, 4.4, IH), 5.52 (s, 2H), 4.48 (q, J= 7.1, 2H), 1.45 (t, J= 7.1, 3H).
Stage #1: acetamidine hydrochloride With hydrogenchloride In methanol at 5 - 10℃; for 0.75h;
Stage #2: malonaldehydebis(dimethylacetal) In methanol at 5 - 20℃; for 53h;
To a solution of <strong>[15108-18-6]2-hydrazinobenzimidazole</strong> (750 mg;5mmol) in a mixture of 10mL of water and 0.75mL of concentrated HCl was gradually added 1,1,3,3-tetramethoxypropane(820mL; 5mmol). The resulting mixture was heated at reflux for 2 h, then was allowed to cool and filtered.The filtrate was neutralised with solid potassium carbonate,causing the product to precipitate as a pale tan solid, which was filtered and dried in vacuo. Yield 650mg (71%). m.p. 233-2358C; dH(500MHz, d6-DMSO) 6.66 (m, br, 1H,H2), 7.19-7.21 (m, 2H, H6 H7), 7.46 (d, 1H, J 6.1 Hz,H5), 7.58 (d, 1H, J 7.7 Hz, H8), 7.94 (d, 1H, J 1.5 Hz,H3), 8.59 (d, 1H, J 2.9 Hz, H1), 13.10 (s, br, 1H, H4);dC(125MHz, d6-DMSO) 109.2, 111.6, 118.4, 122.2, 122.5,129.1, 133.7, 141.7, 142.9, 146.1; m/z (HR-ES-MS)185.0821 ([M H], calculated for C10H9N4 185.0822);y max(KBr)/cm21 2943m br, 1628m, 1574s, 1479m, 1460s,1387m, 1324m, 1273m, 1226m, 1076s, 927s, 740s.
5-Amino-1H-pyrazole-4-carboxylic acidEthyl ester (3.0 g, 19.3 mmol)In acetic acid (40 mL) and ethanol (10 mL)1,1,3,3-Tetramethoxypropane (3.48 g, 21.4 mmol) was added,The resulting reaction was stirred at 90 C overnight,Cool to room temperature,Concentrate under reduced pressure.The resulting residue was diluted with ethyl acetate (100 mL). The resulting solution was washed with saturated aqueous sodium bicarbonate (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DCM / EA v / v) = 6/1) to give the title compound as a light yellow solid (3.2 g, 85%).
In acetic acid;
EXAMPLE 53 4,5,6,7-Tetrahydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester A stirred mixture of 10.88 g of 5-amino-4-pyrazolecarboxylic acid, ethyl ester, 11.51 g of malonaldehyde bis(dimethyl acetal) and 100 ml of glacial acetic acid was heated at reflux for 16 hours, then worked up as described in Example 50 to give 7.8 g of pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, ethyl ester.
With acetic acid; In ethanol; at 90.0℃;
To a solution of ethyl 5-amino-lH-pyrazole-4-carboxylate (3.0 g, 19.3 mmol) in acetic acid (40 mL) and ethanol (10 mL) was added 1,1,3,3-tetramethoxypropane (3.48 g, 21.4 mmol). The reaction mixture was stirred at 90 C overnight and cooled down to room temperature and then concentrated in vacuo. The residue was diluted with ethyl acetate (100 mL) and washed with saturated NaHC03aqueous solution (20 mL) and then dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EA (v/v) = 6/1) to give the title compound as a light yellow solid (3.2 g, 85%).LC-MS (ESI, pos. ion) m/z: 192.3 [M+H]+; H NMR (600 MHz, CDC1 ): delta (ppm) 8.81 (m, 1H), 8.78 (m, 1H), 8.61 (s, 1H), 7.04 (dd, J = 6.9, 4.1 Hz, 1H), 4.47 (q, J= 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).
In the reaction flask with a stirrer was added 107 g of 2,6-diamino pyridine and 1070 ml phosphoric acid at room temperature was slowly added dropwise 241 g 1,1,3,3-tetramethoxypropane to the resulting solution, dropwise after an oil bath to heat up, control the internal temperature 70-75 C, for 40 minutes. Then the reaction mixture was poured into 5 liters of ice 5M aqueous sodium hydroxide solution, to ensure that pH> 10, the filter cake (200 ml × 2), and the filtrate was washed with methylene chloride and extracted with dichloromethane (300 ml × 2) the combined dichloromethane phases were washed with 100 g of anhydrous sodium sulfate, filtered, and concentrated to dryness, the resultant crude product was purified by column chromatography (packing agent is alumina, eluting with methylene chloride: methanol (v / v ) = 100: 1), to obtain 102 g of a red solid 1,8-naphthyridin-2-amine, yield 72%, HPLC purity 96%.
2 g (14.63 mmol) of compound (1) (<strong>[18202-73-8]2,2,2-trimethylacetamidine hydrochloride</strong>), and 4.85 mL (29.27 mmol) of compound (2) (1,1,3,3-tetramethoxypropane) were added into a reaction bottle. Next, the reaction bottle was disposed into a high-pressure autoclave, and heated at 200 C. for 2.5 hr. After cooling, the result was washed by dichloromethane-methanol co-solvent (with a small amount of triethylamine). After concentrating and purification by column chromatography, a compound (3) (2-t-Butyl-pyrimidine) was obtained with a yield of 71%.
With triethylamine; In dichloromethane;
Step 1: Synthesis of 2-tert-Butylpyrimidine 1,1,3,3-Tetramethoxypropane was sparged with N2 for ?5 minutes. Under nitrogen, a 50-mL Schlenk tube was charged with 1,1,3,3-tetramethoxypropane (23.5 g, 143 mmol) and <strong>[18202-73-8]pivalamidine hydrochloride</strong> (10.2 g, 75.0 mmol). The viscous mixture was stirred and heated at 195 C. for 3.5 h. The reaction was black. The solvent level appeared to have diminished by ?20-30%. From the reaction mixture, about 15 g of a mixture of dark brown oil and sludge was obtained and transferred to an Erlenmeyer flask by dichloromethane and a small amount of methanol. There was a significant amount of sludge that was dissolved by stirring in dichloromethane. Triethylamine (1 mL) was added to the mixture. The mixture was passed through a plug of silica (150 g), rinsed with dichloromethane (1 L), and concentrated under reduced pressure to give 9.4 g of a brown liquid. The product was purified by vacuum distillation to give a clear colorless liquid (5.2 g, 51%). 1H NMR (CD2Cl2, 499.8 MHz) delta 8.67 (d, J=4.8 Hz, 2H), 7.09 (t, J=4.8 Hz, 1H), 1.40 (s, 9H).
8,16-methano-16H-dinaphtho[2,1-d:1',2'-g][1,3]dioxocine-2,14-diol[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
83%
With polystyrene-bound p-toluenesulfonic acid In neat (no solvent) at 80℃; for 4h; Green chemistry; regioselective reaction;
General experimental procedure for the synthesis of 7
To a 25 mL round-bottomed flask was added 2,7-dihydroxynaphthalene 6 (1 mmol, 0.16 g), 1,1,3,3-tetramethoxypropane 2 (1equiv, 0.166 mL), and polystyrene-bound p-TSA (25 mg) (25 mg) and then capped. The reaction mixture was stirred at 80 °C under solvent-free conditions for 4 h. Finally, the completion of the reaction was confirmed by TLC and the reaction mixture was cooled to room temperature. Then, the reaction mixture was washed twice with ethyl acetate (2×5 mL) and filtered to recover the catalyst. The combined filtrate was evaporated under reduced pressure to obtain the crude product, which was further purified by recrystallization from a mixed solvent (EtOH/water, 5/1,v/v) to give the pure desired product.
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis (dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70%) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) delta6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=l), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
3.10 g (70%)
With hydrogenchloride; In ethanol; water;
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70%) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) delta6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
3.10 g (70%)
With hydrogenchloride; In ethanol; water;
Example 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70%) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) delta6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
3.10 g (70%)
With hydrogenchloride; In ethanol; water;
EXAMPLE 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70%) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) delta6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=l), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
3.10 g (70%)
With hydrogenchloride; In ethanol; water;
Example 176 (7R)-7-[(phenylacetyl)amino]-3-(1-(pyrid-2-yl)pyrazol-5-ylthio)-3-cephem-4-carboxylate, 4-methoxybenzyl ester To a stirring solution of 2-pyridylhydrazine (3.30 g, 30.2 mmol) and malonaldehyde bis(dimethylacetal) (4.96 g, 30.2 mmol) in absolute ethanol (60 mL) at room temperature was added concentrated HCl until the mixture was acidic (3 mL). The mixture was heated at reflux for 3 h, and was allowed to cool to room temperature. The mixture was concentrated with a rotary evaporator, and the residue was triturated with ether and filtered. The remaining solid was dissolved in water, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were washed with water and brine, dried (sodium sulfate), and concentrated with a rotary evaporator to afford 3.10 g (70%) of 1-(pyrid-2-yl)pyrazole. 1 H NMR (CDCl3) delta 6.48 (dd, 1, J=1, 2), 7.20 (dd, 1, J=8, 10), 7.75 (d, 1, J=1), 7.82 (dt, 1, J=2, 10), 8.00 (d, 1, J=10), 8.42 (dd, 1, J=2, 8), 8.59 (d, 1, J=2).
With hydrogenchloride; In ethanol;Heating / reflux;
A mixture of 1 , 1 ,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and cone HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-lH-pyrazole (25 g, 89% yield). 1H NMR (400 MHz, OMSO-Cl6): deltal.n (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
89%
With hydrogenchloride; In ethanol; water;Reflux;
A mixture of 1,1,3,3-tetramethoxypropane (3.7 g, 22.6 mmol), tert-butylhydrazinehydrochloride (2.8 g, 22.6 mmol), and conc. HCl (6 mL, 72 mmol) in EtOH (30 mL) was heated at reflux overnight. The reaction mixture was poured into water and the resulting mixture wasextracted with ether (30 mL x 3). The combined organics was washed with brine (20 mL), dried over MgSO4, and concentrated under reduced pressure to afford 1-tert-butyl-1H-pyrazole as awhite solid (2.5 g, 89%). MS (ESI) m/z: 125 [M+H].
72%
To a mixture of 1 ,1 ,3,3-tetramethoxypropane (3.82kg, 23.27mol) and tert- butylhydrazine hydrochloride (2.9kg, 23.27mol) in ethanol (24.54kg), cone HCI (4.72kg ,46.55mol) was added, keeping the temperature below 50C. The reaction mixture was then rapidly heated to reflux. After ca. 2h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29kg) and evaporated in vacuo (T<50C, p<-0.08MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (1 1 .1 1 kgx2) and the organic phase washed with saturated ammonium chloride solution (4.3ml/g x 2) and brine (4.3ml/g), then evaporated to give the title compound (2.08kg, 72%yield) as a brown liquid (GC purity 99.70%a/a).
72%
With hydrogenchloride; In ethanol; water; at 50℃; for 0.2h;Reflux; Industrial scale;
Stage a) Preparation of 1-(1,1-Dimethylethyl)-1H-pyrazole (Intermediate 9) To a mixture of 1,1,3,3-tetramethoxypropane (3.82 kg, 23.27 mol) and tert-butylhydrazine hydrochloride (2.9 kg, 23.27 mol) in ethanol (24.54 kg), conc HCl (4.72 kg, 46.55 mol) was added, keeping the temperature below 50 C. The reaction mixture was then rapidly heated to reflux. After ca. 2 h the reaction was sampled and analysed by NMR. Pass criteria was <3.0% starting material remaining. On receipt of a pass result the solution is cooled, diluted with water (8.29 kg) and evaporated in vacuo (T<50 C., p<-0.08 MPa) until approximately all of the original ethanol was removed. The solution was basified with 10M NaOH(aq), extracted with EtOAc (11.11 kg*2) and the organic phase washed with saturated ammonium chloride solution (4.3 ml/g*2) and brine (4.3 ml/g), then evaporated to give the title compound (2.08 kg, 72% yield) as a brown liquid (GC purity 99.70% a/a).
21.9 g
With hydrogenchloride; In ethanol; for 2.0h;Reflux;
To a stirred mixture of 34.48 g of 1,1,3,3-tetramethoxy-propane and 26.20 g tert.butyihydrazine hydrochloride in 230 mL ethanol was added 40.0 mL conc. hydrochloric acid dropwise below 50 00, then the mixture was stirred under reflux for 2 h. The reaction mixture was diluted with water. The solvent was almost removed by destillation and the aqueous residue extracted with diethylether. The combined aqueous phases were basified with iON sodium hydroxide solution and extracted with diethylether. The combined organic phases were washed with saturated brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 21.90 g of 1-tert-butyl-pyrazole as oil.Analysis: HPLC-MS: R1 = 0.412 mm (method A), M+H = 125
With hydrogenchloride; In ethanol; water; for 0.24h;Reflux;
5.71 g (34.80 mmol) of 1,3,3-tetramethoxypropane was dissolved.50mL ethanol solution,About 3mL hydrochloric acid solution was injected with stirring.To the above solution, 100 mL of an ethanol solution of 5.0 g (31.63 mmol) of <strong>[40594-29-4]2,4-difluorophenylhydrazine hydrochloride</strong> was slowly added dropwise.The addition is complete, heated to reflux for about 24 hours.After the reaction was completed, the resulting mixture was washed with water and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and then evaporated.Get a black viscous liquid. The resulting black viscous liquid sand, column chromatography purification, with petroleum ether: dichloromethane 10: 1 elution, spin-dry,A colorless oily liquid was obtained in a yield of 75%.
Stage #1: malonaldehydebis(dimethylacetal) With acetic acid at 55℃; for 5.5h;
Stage #2: 1-Ethyl-2,3,3-Trimethylindolenineninium 5-Sulfone With acetic acid at 80℃; for 1h;
Stage #3: 1-(5-carboxypentyl)-2,3,3-trimethyl-3H-indolium-5-sulfonate With pyridine; acetic anhydride at 110℃; for 0.25h; Further stages.;
1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene[ No CAS ]
[ 606-45-1 ]
Yield
Reaction Conditions
Operation in experiment
32%
Stage #1: malonaldehydebis(dimethylacetal); 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene With trimethylsilyl trifluoromethanesulfonate In dichloromethane at -78 - 20℃;
Stage #2: With hydrogenchloride In dichloromethane Further stages.;
25%
Stage #1: malonaldehydebis(dimethylacetal); 1,3-bis(trimethylsiloxy)-1-methoxybuta-1,3-diene With titanium tetrachloride In dichloromethane at -78 - 20℃; for 14h;
Stage #2: With hydrogenchloride; water In dichloromethane at 20℃;
To chloroacetoamidine hydrochloride (19.7 g) was added 1,1,3,3-tetramethoxypropane (50 ml), and the mixture was stirred for 16 hours at 100°C. After cooling to room temperature, the mixture was added to water, extracted with methylene chloride, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2-(chloromethyl)pyrimidine (2.0 g). 1H-NMR (200 MHz, CDCl3) delta 4.76 (2H, s), 7.27 to 7.30 (1H, m), 8.78 (1H, d, J = 5.2 Hz)
at 100℃; for 16h;
Step A: 2-(Chloromethyl)pyrimidineA suspension of Chloroacetamidine HCl (5 g, 38.76 mmol) in 1 ,1 ,3,3-tetramethoxy propane (12.5 mL) was heated at 100°C for 16 h. Reaction mixture was diluted with H20 (50 mL), the pH adjusted to ~8 using NaHC03and extracted with DCM (2x 50 mL). The organic layer was washed with brine (50 mL), then 4N Dioxane-HCI (2 mL) was added to the organic layer and stirred for 10 min. The organic layer was dried (Na2S0 ), filtered and evaporated in vacuo to give the crude product (10 g) which was employed in the next step without further purification.
With hydrogenchloride In 2-methoxy-ethanol at 10 - 25℃; for 12h;
2 EXAMPLE 2[Synthesis of Example Compound No. (2-a-2); Sulfur-containing compound represented by formula (2) in which "a" is 1, R1 is a methylene group, "k" and "l" are each 1, and X1 and X2 are each an oxygen atom]
A glass-made reactor (inside volume: 2L) equipped with a condenser, thermometer, gas-blowing tube and stirrer was charged with 500 g of 2-methoxy ethanol, into which 36.5 g (1.00 mol) of hydrogen chloride gas was blown at 15°C in 1 hour to be dissolved therein, and then 82.0 g (0.50 mol) of malondialdehyde bisdimethylacetal(1,1,3,3-tetramethoxypropane) was added at 10°C. Then, 137.0 g (1.10 mols) of 2,3-dimercapto-1-propanol was added immediately to the above mixture at the same temperature, and the resultant mixture was stirred at 25°C for 12 hours. After the starting compound was confirmed to disappear by gas chromatography, the reaction mixture was added, with stirring, to 1000 g of water in 30 minutes. The resultant mixture was subjected to extraction with chloroform and washing with water, and separation to obtain an organic phase. Chloroform was distilled at 45°C under a vacuum to obtain a singly yellowish, transparent liquid crude product. The crude product thus prepared was purified by silica gel column chromatography (developing solvent: using mixed solvent of toluene/ethyl acetate: 60/40), to obtain 92.4 g (0.325 mol) of the dihydroxy compound represented by the following formula, which was a lightly yellowish crystal, as Example Compound No. (2-a-2). Its yield was 65% on malondialdehyde bisdimethylacetal as the starting compound. • 270MHz 1H-NMR δ (CDCl3); 2.18 to 2.33 (m, 2H), 3.15 to 3.38 (m, 4H), 3.42 to 3.68 (m, 4H), 3.72 to 3.88 (m, 2H), 4.47 (dq, 2H), 4.72 to 4.78 (m, 2H) • EI-MS: 284(M)
1,3-dimethyl-2,3-dihydro-2-oxopyrimidinium sulfate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
69%
With sulfuric acid In methanol at 20 - 50℃; for 0.5h;
2 Synthesis of 1,3-dimethyl-2,3-dihydro-2-oxopyrimidinium sulfate (1-2)
82.1 g (0.5 mol) of 1, 1, 3, 3-tetramethoxypropane and 39.7 g (0.45 mol) of 1,3-dimethylurea were dissolved in 400 ml of methanol, 49.0 g (0.5 mol) of concentrated sulfuric acid was added dropwise thereto at room temperature, and the mixture was allowed to undergo the reaction at 50°C for 30 minutes. After completion of the reaction, this was cooled to room temperature, and the precipitated crystals were collected by filtration to obtain 59.7 g (yield 69%) of the title compound (purity 99.8%, melting point 203 - 205°C).
14.2 g (87 mmol) of 1,1,3,3-tetramethoxypropane, 10 g (83 mmol) of 4-acetylpyridine, 30 ml (500 mmol) of acetic acid and 39 g (500 mmol) of ammonium acetate were dissolved in 160 ml of 2-propanol, and the reaction solution was allowed to undergo the reaction at 80C for 9 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 3.2 g (yield 27.6%) of the title compound (purity 98.2%).
12.3 g (79 mmol) of 1,1,3,3-tetramethoxypropane, 0.12 g (0.8 mmol) of 1-methyl-3-phenylurea, 9,6 g (79 mmol) of 4-acetylpyridine, 30 ml (500 mmol) of acetic acid and 39 g (500 mmol) of ammonium acetate were dissolved in 160 ml of 2-propanol, and the reaction solution was allowed to undergo the reaction at 80C for 9 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodiumhydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 7.8 g (yield 63.2%) of the title compound (purity 99.2%, melting point 55 - 57C).
With hydrogenchloride; In water; isopropyl alcohol; for 1h;Heating / reflux;
15. 0 g (92 mmol) of 1,1,3,3-tetramethoxypropane and 20.5 g (119 mmol) of 1,3-di(n-butyl)urea were dissolved in 20 ml of 2-propanol, 13.0 g (125 mmol) of 35% hydrochloric acid was added thereto, and the mixture was refluxed for 1 hour. The reaction solution was cooled to room temperature, and 10.0 g (83 mmol) of 4-acetylpyridine and 7.1 g (89.8 mmol) of pyridine were added thereto. After 30 minutes of stirring at room temperature, 19 ml (416 mmol) of formic acid and 31.5 g (500 mmol) of ammonium formate were added to the reaction solution to carry out the reaction at 100C for 8 hours. After completion of the reaction, this was cooled to room temperature, neutralized with 200 g (1.2 mol) of 25% sodium hydroxide aqueous solution and then extracted three times with 200 ml of toluene. The organic layer was concentrated and then purified by distillation under a reduced pressure to obtain 9.9 g (yield 76.5%) of the title compound (purity 99.9%, melting point 55 - 57C).
EXAMPLE 4 2(1 H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25 C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23%) of product; mp 186-188 C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
22.9 g (23%)
With potassium carbonate; In ethanol; water;
EXAMPLE 4 2(1H)-Pyrimidinethione, 1-methyl To a stirred mixture of 1-methyl-2-thiourea (76.6 g, 0.85 mol) and malonaldehyde bis(dimethyl acetal) (126.8 g, 0.77 mol) in EtOH (1.5 L) was added 10 M HCI (76.6 mL, 0.77 mol) in one portion. The resulting mixture was stirred at 25 C. for 18 h, then spin-evaporated in vacuo. The residue was dissolved in H2O (1.25 L). The solution was made alkaline by the portionwise addition of K2CO3 and extracted with CH2Cl2 (4*500 mL). The combined extracts were dried over MgSO4 and spin-evaporated in vacuo to a solid. The crude product was recrystallized from EtOH (600 mL) then dried to constant weight in vacuo at room temperature to give 22.9 g (23%) of product; mp 186-188 C. (uncorrected). An additional reaction was performed to give a total of 40.7 g.
2-cyano-5-methoxy-N, N-dimethyl-2,4-pentadienamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
16 g (44.3%)
With acetic anhydride; acetic acid
1 Preparation of 2-cyano-5-methoxy-N, N-dimethyl-2,4-pentadienamide
EXAMPLE 1 Preparation of 2-cyano-5-methoxy-N, N-dimethyl-2,4-pentadienamide To a 250 ml 3-necked R.B. flask was charged 50 g malonodialdehyde bis(dimethylacetal), 22.5 g N,N-dimethyl-2-cyanoacetamide, 60 g acetic anhydride, 0.5 g zinc chloride and 100 ml acetic acid. It was heated to reflux to distill off low boilers until the pot temperature reached 125° C. and head reached 110° C. and a total of 60 ml distillate was collected. GC analysis of the pot content showed disappearance of N,N-dimethyl-2-cyanoacetamide. The reaction mixture was filtered to remove zinc catalyst and then rotovapped. The pot residue was crystallized from a methanol in dry ice-acetone bath to afford 16 g (44.3%) of the title compound.
2-amino-4-methoxypyrido[2,3-d]pyrimidine[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
2.5 gm (40.5%)
With sodium hydrogencarbonate; In water; acetic acid;
EXAMPLE 73 2-Amino-4-methoxypyrido[2,3-d]pyrimidine A quantity of 4.94 gm of <strong>[3270-97-1]2,4-diamino-6-methoxypyrimidine</strong> is heated to boiling in 120 ml of glacial acetic acid and, after the addition of 6.4 ml of 1,1,3,3-tetramethoxypropane, left for a further 45 minutes at boiling temperature. Then, the glacial acetic acid is distilled off and evaporated several times with water, and the residue is taken up in 400 ml of water. After the addition of 5 gm of sodium bicarbonate, the residue is removed by suction filtration and discarded. The filtrate is extracted several times with chloroform, and the combined extracts are washed with sodium bicarbonate solution and then dried over sodium sulfate. The residue remaining after evaporation is purified on silica gel with chloroform and a chloroform/methanol mixture and then recrystallized from water. Yield: 2.5 gm (40.5%) of 2-amino-4-methoxy-pyrido[2,3-d]pyrimidine in the form of crystals, m.p.: 178-180 C. Elementary analysis Calc.: C 54.54 H 4.58 N 31.80. Found: 54.42 4.56 31.77.
A solution of <strong>[78583-82-1]3-(4-bromophenyl)-1H-pyrazol-5-amine</strong> (5.00 g) in AcOH (80 mL) was treated with 1 ,1 ,3,3-tetramethoxypropane (4.13 g) and the mixture heated at 110C for 1.5 h. On cooling to room temperature the precipitated solid was isolated by filtration, washed with water (3 x 10 mL) and dried in vacuo at 40C. This was recrystallised from acetic acid and dried in vacuo at 400C to give the title compound. MS calcd for (C12H8BrN3+ H)+: 274/276 MS found (electrospray): (M+H)+ = 274/276
With acetic acid; at 110℃; for 1.5h;
A solution of 3-(4-bromophenyl)-1 H-pyrazol-5-amine (5.00 g) in AcOH (80 ml.) was treated with 1 ,1 ,3,3-tetramethoxypropane (4.13 g) and the mixture heated at 11O0C for 1.5 h. On cooling to room temperature, the precipitated solid was isolated by filtration, washed with water (3 x 10 ml.) and dried in vacuo at 400C. This was recrystallised from acetic acid and dried in vacuo at 400C to give the title compound. MS calcd for (C12H8BrN3+ H)+: 274/276MS found (electrospray): (M+H)+ = 274/276
With acetic acid; at 40 - 110℃; for 2.91667h;
Intermediate 5 2-(4-Bromophenyl)pyrazolo[1,5-a]pyrimidineA solution of 5-(4-bromophenyl)-2H-pyrazol-3-ylamine (20.2 g, 84.8 mmol) in glacial acetic acid (300 mL) was treated with 1 ,1 ,3,3-tetramethoxypropane (15.4 mL, 93.3 mmol) and the mixture heated to around 1100C over approximately 25 mins. Further heating was continued at 11O0C for 60 mins, then the temperature was cooled to around 4O0C over 90 mins. The resulting solid was filtered off, washed with water and dried at 4O0C under vacuum to give the title compound. MS calcd for (C28H8BrN3 + H)+: 275/277 MS found (electrospray): (M+H)+ = 275/277
With acetic acid; at 110℃; for 1.5h;
Intermediate 422-(4-Bromophenyl)pyrazolo[1,5-a]pyrimidineA solution of <strong>[78583-82-1]3-(4-bromophenyl)-1H-pyrazol-5-amine</strong> (1.19 g) in acetic acid (20 ml_) was treated with 1 ,1 ,3,3-tetramethoxypropane (615 mg) and the mixture heated at 11O0C for 1.5 h. On cooling to room temperature the precipitated solid was isolated by filtration, washed with water and allowed to dry in air to give the title compound. MS calcd for (C12H8BrN3+ H)+: 274/276 MS found (electrospray): (M+H)+ = 274/276
With acetic acid; at 110℃; for 1.5h;
Intermediate 6 2-(4-Bromopheϖyl)pyrazolo[1,5-a]pyrimidineA solution of 3-(4-bromophenyl)-1 H-pyrazol-5-amine (1.19 g) in acetic acid (20 mL) was treated with 1 ,1 ,3,3-tetramethoxypropane (615 mg) and the mixture heated at 11 O0C for 1.5 h. On cooling to room temperature the precipitated solid was isolated by filtration, washed with water and allowed to dry in air to give the title compound. MS calcd for (C12H8BrN3+ H)+: 274/276 MS found (electrospray): (M+H)+ = 274/276
With acetic acid; at 110℃; for 1.5h;
[231] Example 5 - 3-ri-Methyl-5-(4-methyl-cvclohexyl)-l,2,3,6-tetrahydro-pyridin-4-yl1-5-(4- pyrazolof 1 ,5-alpyrimidin-2-yl-phenyl)-thiophene-2-carboxylic acid; [232] A solution of 3-(4-bromophenyl)-lH-pyrazol-5-amine (5.00 g) in acetic acid (80 mL) was treated with 1,1,3,3-tetramethoxypropane (4.13 g) and the mixture heated at 110 C for 1.5 hr. On cooling to RT, the precipitated solid was isolated by filtration, washed with water (3x10 mL) and dried in vacuo at 40 C. The residue was recrystallized from acetic acid and dried in vacuo at 40 C to give 005A. MS calcd: (M+ +: 274/276. MS found: (M+H)+ = 274/276.
With acetic acid; at 110℃; for 1.5h;Neat (no solvent);
Intermediate 1 2-(4-Bromophenyl)pyrazolo[1 ,5-a]pyrimidineA solution of 3-(4-bromophenyl)-1 /-/-pyrazol-5-amine (5.00 g) in AcOH (80 mL) was treated with 1 ,1 ,3,3-tetramethoxypropane (4.13 g) and the mixture heated at 11 O0C for 1.5 h. On cooling to room temperature the precipitated solid was isolated by filtration, washed with water (3 x 10 mL) and dried in vacuo at 400C. This was recrystallised from acetic acid and dried in vacuo at 400C to give the title compound. MS calcd for (Ci2H8BrN3+ H)+: 274/276 MS found (electrospray): (M+H)+ = 274/276
A. A solution of 3-amino-4-bromopyrazole (2.0 g, 12 mmol) and 1 ,1 ,3,3- tetramethoxypropane (4.1 mL, 25 mmol) in acetic acid (5 mL) was heated at reflux for 4 h. Water (2 mL) was added and the mixture heated at reflux for a further 0.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was triturated in methanol. The solid thus obtained was washed with cold methanol, ethyl acetate, and hexanes to provide 3-bromopyrazolo[1 ,5-a]pyrimidine as a brownish solid in 39% yield (0.953 g): 1H NMR (300 MHz, DMSO-d6) £9.13 (d, J = 6.5 Hz, 1 H), 8.61 (s, 1 H), 8.35 (s, 1 H), 7.19-7.02 (m, 1 H); MS (ES+) m/z 197.9 (M + 1), 199.9 (M + 1).
With hydrogenchloride; In ethanol; water; at 20 - 71℃;
A solution of the amino-bromo-pyrazole obtained above, dissolved in EtOH (23OmL) was treated with cone. HCl (13.6mL) followed by tetra-methoxypropane (3 ImL) at rt. The resulting turbid solution was heated to 71C for 2h, during this time, the reaction mixture turned into a suspension and a solid started separating out. The reaction mixture was cooled to rt, the precipitated solid was collected by filtration, washed with EtOH (min vol.) and dried to obtain the desired compound. The crude compound (C) was used as such for the next step without further purification (26.8 g, 74.1%). (M + H): 198.0.
Stage #1: malonaldehydebis(dimethylacetal) With acetic acid at 55℃; for 5.5h;
Stage #2: 1-Ethyl-2,3,3-Trimethylindolenineninium 5-Sulfone With acetic acid at 80℃; for 2h;
Stage #3: 1-(5-carboxypentyl)-2,3,3-trimethyl-3H-indolium-5-sulfonate With pyridine; acetic anhydride at 110℃; for 0.25h;
Stage #1: malonaldehydebis(dimethylacetal) With acetic acid at 55℃; for 5.5h;
Stage #2: 1-Ethyl-2,3,3-Trimethylindolenineninium 5-Sulfone With acetic acid at 80℃; for 2h;
Stage #3: 1-methyl-2,3,3-trimethyl-3H-indolium-5-sulfonate With pyridine; acetic anhydride at 110℃; for 0.25h;
Stage #1: 1-methyl-4-nitropyrrole-2-carboxylic acid methyl ester With ammonium formate In ethyl acetate for 2h; Heating / reflux;
Stage #2: malonaldehydebis(dimethylacetal) With hydrogenchloride In water for 16h; Heating / reflux;
4 Synthesis of 1-methyl-1H-pyrrolO[3,2-b]pyridine-2-carboxylic acid; 2-methoxycarbonyl-1-methylpyrrolO[3,2-b]pyridine
A SOLUTION of methyl 1-methyl-4-nitropyrrole-2-carboxylate (10.02 g, 54.4 MMOL) and HCO2NH4 (17.2 g, 272.0 MMOL) in ethyl acetate (250 mL) was added 20% Pd (OH) 2/C. The mixture was heated to reflux for 2 h, then the catalyst was removed by filtration.The filtrate was EVAPORATED IN VACUO, then MALONALDEHYDE bis (dimethyl acetal) (26.8 g, 163.2 MMOL) and concentrated HCI (5 mL) were added, and the mixture was heated to reflux for 16 hours. After evaporation of the METHANOL IN VACUO, a saturated aqueous solution of NA2CO3 (150 mL) was added, and the mixture was extracted with ethyl acetate (200 mL x 2). The combined extracts were washed with saturated NaCl (150 mL), dried over NA2SO4, concentrated, and purified by chromatography with hexane-acetone (3: 1) to afford 2.81 g (27.2%) of the desired product as a yellow SOLID. 1H NMR (300 MHz, CDCl3) 6 8.50 (dd, J=4.5 Hz, J=1.2 Hz, 1H), 7.61 (dd, J=5.5 Hz, J=1.2 Hz, 1H), 7.37 (s, 1H), 7.17 (dd, J=8.55 Hz, J=4.5 Hz, 1 H), 4.00 (s, 3H), 3.89 (s, 3H) ; 13C NMR (75 MHz, CDCI3) # 162. 2,145. 0,143. 4,132. 6,130. 0,117. 7,110. 1,51. 8,31. 5. Anal.Calc'd. for C10H10N2O2: C, 63.15 ; H, 5.30 ; N, 14.73. Found: C, 63.21 ; H, 5.30 ; N, 14.63.
5.1 Preparation of 1- (4-methoxyphenyl) -1H-pyrazole
Take 17.40 g (0.1 mol) of 4-methoxyphenylhydrazine hydrochloride with16.4 g (0 · lmol) of 1,1,3,3-tetramethoxypropane in a 250 ml three-necked flask,100 ml of a 95% aqueous solution of ethanol as a solvent, and the temperature was raised to reflux for 3-5 hours.After the TLC monitoring reaction was completed, most of the ethanol was distilled off under reduced pressure. The aqueous solution of the aqueous solution was extracted with the aqueous solution of the aqueous solution. The aqueous phase was extracted with (3? 100 ml) of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and dissolved.The residue was subjected to column chromatography (eluent, ethyl acetate and petroleum ether, volume ratio 1:10) to give 15.25 g of a gray solid in 82.6% yield.
To a solution of ethyl 3,5-diamino-lH-pyrazole-4-carboxylate (5.00 g, 29.38 mmol) in DMF (80 mL) were added 1 , 1 ,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol) and AcOH (0.34 mL, 5.88 mmol). The reaction mixture was stirred at 100 C for 14 h, and then concentrated in vacuo. The residue was partitioned between DCM (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (a solution of NH3in MeOH (7 M)/DCM (v/v) =1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1%).MS (ESI, pos. ion) m/z: 207.1 [M+H]+; H NMR (400 MHz, CDC1 ): delta (ppm) 8.60 (dd, J= 4.40 Hz, 1.76 Hz, 1H), 8.46 (dd, J = 6.76 Hz, 1.76 Hz, 1H), 6.86 (dd, J = 6.72 Hz, 4.40 Hz, 1H), 4.50 (q, J = 7.08 Hz, 2H), 1.47 (t, J = 7.08 Hz, 3H).
58.1%
With acetic acid; In N,N-dimethyl-formamide; at 100℃; for 14.0h;
To a solution of ethyl 3,5-diamino-1 -hydro-pyrazole-4-carboxylate (5.00 g, 29.38 mmol)In N, N-dimethylformamide ((80 mL)1,1,3,3-tetramethoxypropane (14.50 mL, 88.15 mmol)And acetic acid (0.34 mL, 5.88 mmol).After the reaction mixture was stirred at 100 C for 14 hours,Concentrate under reduced pressure. The resulting residue was dispersed in a mixed system of dichloromethane (50 mL) and water (50 mL), the organic phase was separated and the aqueous phase was extracted with dichloromethane (100 mL x 3). The combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH3 in methanol (7M) / methylene chloride (v / v) = 1/100) to give the title compound as a pale yellow solid (3.52 g, 58.1%).
35.3%
With triethylamine; In N,N-dimethyl-formamide; at 100℃; for 14.0h;
ethyl 2-aminopyrazolo[l ,5-a]pyrimidine-3-carboxylateA mixture of ethyl 3,5-diamino-l H-pyrazole-4-carboxylate (1.0 g, 5.9 mmol), 1,1,3,3- tetramethoxypropane (2.9 mL, 18 mmol), triethylamine (2 mL, 10 mmol), and DMF (15 mL) was heated at 100 0C for 14 hrs, then a further 2 mL of 1,1,3,3-tetramethoxypropane was added. After adding the additional 1,1,3,3-tetramethoxypropane, a significant by-product was noted and heating was stopped immediately. The reaction was cooled to room temperature and the DMF was removed in vacuo. The residue was partitioned between DCM and water, then the organic layer was concentrated and the residue purified by silica chromatography, eluting with 95:5 DCM: 2M methanolic ammonia solution to afford 420 mg (35%) of ethyl 2-aminopyrazolo[l,5- a]pyrimidine-3-carboxylate. 1H NMR (500 MHz, CDCl3) delta 8.57 (dd, J = 4.3, 1.6, IH), 8.43 (dd, J = 6.7, 1.6, IH), 6.84 (dd, J = 6.7, 4.4, IH), 5.52 (s, 2H), 4.48 (q, J= 7.1, 2H), 1.45 (t, J= 7.1, 3H).
With acetic acid; at 25 - 95℃;
Another exemplary study was carried out as follow: Compound J and AcOH (7.5 volumes) were charged to an appropriately sized jacketed reactor. Mixing was started and the jacket was set to maintain an internal temperature of 25 C . Tetramethoxypropane (1.01 equivalents) was charged to the reactor and the j acket was set to maintain an internal temperature of 95 C. Once at temperature, the reaction continued mixing for 1.5 hours and then an IPC sample was taken. The passing criteria for this IPC was 60 C to prevent premature precipitation. Once the target volume was reached the jacket was set to maintain an internal temperature of 50 C. A 4 M solution of NaOH was then charged to the reactor via cannula to neutralize the remaining AcOH. This typically required approximately 10 volumes of the base solution. The neutralization was monitored by pH probe. Solids began to precipitate during the course of the charge. Once neutralized, the slurry was cooled to 20 C and held at that temperature for 1 hour prior to isolation via Buchner funnel. The cake was washed twice with 2 volumes of water and once with 2 volumes of MeOH. The solids were then dried to constant weight in a vacuum oven to provide Compound H. This procedure had been performed on 110 g scale to produce a granular light brown solid.
Step 1; 5-Bromo-2-nitrobenzaldehyde 1 (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HC1 (10 mL). The mixture was heated to 70 C and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. Upon completion (by TLC) the reaction was cooled and DCM (200 mL) was added before filtering through a pad of celite. The filtrate was concentrated under reduced pressure to 150 mL. To this material, a solution of 1,1,3, 3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HC1 (10 mL) pre- mixed for 45 min was added. The reaction mixture was stirred at 80 C for 60 min. Toluene (100 mL) and acetic acid (40 mL) were added and the solution was heated to 110 C for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to give 6-bromoquinoline-3-carbaldehyde 2.
Example A4 Preparation of the Compound of Formula 70.67 grams of piperidine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 59.72 grams of 2-ethoxyethyl cyanoacetate cyanoacetate in the presence of an organic base and a solvent. [0228] The following base/solvent combinations are used:The desired product (104) is obtained in yields of 91% (96.5 grams) as an orange powder. [0230] After silica gel column chromatography (eluent: toluene/acetone) the pure product (104) is obtained yielding dark yellow crystals. [0231] Melting point: 66-67 C.
With acetic acid; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example A4: Preparation of the compound of formula 70.67 grams of piperidine are condensed with 1 ,1 ,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 59.72 grams of 2-ethoxyethyl cyanoacetate cyanoacetate in the presence of an organic base and a solvent. The following base/solvent combinations are used: Example Base Solvent Example A4.1 DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) dimethylformamide Example A4.2 DBN (1 ,5-diazabicyclo[ 4.3.0]non-5-ene) dimethylacetamide Example A4.3 DBN (1 ,5-diazabicyclo[ 4.3.0]non-5-ene) 1 -methylpyrrolidone Example A4.4 DBN (1 ,5-diazabicyclo[ 4.3.0]non-5-ene) dimethylsulfoxide Example A4.5 DBU (1 ,8-diazabicyclo[5.4.0]undec-7-ene) dimethylformamide Example A4.6 piperidine dimethylacetamide Example A4.7 piperidine 1 -methylpyrrolidone Example A4.8 sodium methylate dimethylsulfoxide The desired product (104) is obtained in yields of 91 % (96.5 grams) as an orange powder. After silica gel column chromatography (eluent: toluene/acetone) the pure product (104) is obtained yielding dark yellow crystals. Melting point: 66-67C.
70.67 grams of piperidine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 59.72 grams of 2-ethoxyethyl cyanoacetate cyanoacetate in the presence of an organic base and a solvent. After silica gel column chromatography (eluent: toluene/acetone) the pure product is obtained yielding dark yellow crystals. Melting point: 66-67 C.
With acetic acid; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example A12: Preparation of the com ound of formula 83.40 grams of morpholine are condensed with 1 ,1 ,3,3-tetramethoxypropane in acetic acid and treated with 47.15 grams of 2-ethoxyethyl cyanoacetate in the presence of the organic base and a solvent. The following base/solvent combinations are used: 32.58 grams of the compound (1 12) are obtained yielding yellow crystals. Melting point: 81.5C.
32.58 g
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetic acid; N,N-dimethyl-d6-formamide;
8 3. 4 0 grams of morpho line are condensed with 1, 1, 3, 3-tetramethoxypropane in acetic acid and treated with 47.15 grams of 2-ethoxyethyl cyanoacetate in thepresence of the organic base and a solvent.32. 58 grams of the compound ( 10) are obtained yieldingyellow crystals.Melting point: 81.5C.
32.58 g
Example A12 Preparation of the Compound of Formula [0269] [0270] 83.40 grams of morpholine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid and treated with 47.15 grams of 2-ethoxyethyl cyanoacetate in the presence of the organic base and a solvent. [0271] The following base/solvent combinations are used: [0272] 32.58 grams of the compound (112) are obtained yielding yellow crystals. [0273] Melting point: 81.5 C.
83.40 grams of morpholine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid and treated with 47.15 grams of 2-ethoxyethyl cyanoacetate in the presence of the organic base and a solvent. 32.58 grams of the compound (10) are obtained yielding yellow crystals. Melting point: 81.5 C.
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetic acid; N,N-dimethyl-d6-formamide;
55.33 grams of bis- (2-methoxyethyl) amine are condensedwith 1,1,3,3-tetramethoxypropane in acetic acid,10 concentrated and treated with 29.85 grams of 2-ethoxyethyl-cyanoacetate in the presence of an organicbase and a solvent.After the reaction, the product (103) is obtained fromthe reaction mixture through ordinary product isolationby liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to thereaction mixture.The desired product (103) is obtained in yields of 66 %(39. 99 grams) as beige crystals (melting point:58.3C).
66%
Example A3 Preparation of the Compound of Formula] 55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 29.85 grams of 2-ethoxyethyl-cyanoacetate in the presence of an organic base and a solvent [0223] The following base/solvent combinations are used:After the reaction, the product (103) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. [0225] The desired product (103) is obtained in yields of 66% (39.99 grams) as beige crystals (melting point: 58.3 C.).
With acetic acid; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example A3: Preparation of the com ound of formula (103) 55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1 ,1 ,3,3- tetramethoxypropane in acetic acid, concentrated and treated with 29.85 grams of 2- ethoxyethyl-cyanoacetate in the presence of an organic base and a solvent The following base/solvent combinations are used: After the reaction, the product (103) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. The desired product (103) is obtained in yields of 66 % (39.99 grams) as beige crystals (melting point: 58.3C).
55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 29.85 grams of 2-ethoxyethyl-cyanoacetate in the presence of an organic base and a solvent. After the reaction, the product (103) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. The desired product (103) is obtained in yields of 66% (39.99 grams) as beige crystals (melting point: 58.3 C.)
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetic acid; N,N-dimethyl-d6-formamide;
55.33 grams of bis-(2-methoxyethyl)amine are reactedwith 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 21.48 grams of ethylcyanoacetate in the presence of an organic base and a solvent.The reaction temperature is between 0C and the boilingpoint of the solvent.The reaction end point is confirmed by thin layer chromatography chromatography.or high performance liquidAfter the reaction, the product ( 101) is obtained from the reaction mixture through ordinary product isolationby liquid-liquid separation, column chromatography orcrystallization by addition of a poor solvent to thereaction mixture. The desired product (1) is obtained in yields of 66 %(36 grams) as a dark brownish oil which crystallized asyellow crystals (Melting point: 76.9C).
66%
[0210] 55.33 grams of bis-(2-methoxyethyl)amine are reacted with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 21.48 grams of ethyl cyanoacetate in the presence of an organic base and a solvent. [0211] The following base/solvent combinations are used [0212] The reaction temperature is between 0 C. and the boiling point of the solvent. [0213] The reaction end point is confirmed by thin layer chromatography or high performance liquid chromatography. [0214] After the reaction, the product (101) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. [0215] The desired product (101) is obtained in yields of 66% (36 grams) as a dark brownish oil which crystallized as yellow crystals (Melting point: 76.9 C.).
With acetic acid; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide; at 0℃;Heating;
Example A1 : Preparation of the com ound of formula N 55.33 grams of bis-(2-methoxyethyl)amine are reacted with 1 ,1 ,3,3-tetramethoxypropane acetic acid, concentrated and treated with 21.48 grams of ethyl cyanoacetate in the presence of an organic base and a solvent. The following base/solvent combinations are used: The reaction temperature is between 0C and the boiling point of the solvent. The reaction end point is confirmed by thin layer chromatography or high performance liquid chromatography. After the reaction, the product (101 ) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. The desired product (101 ) is obtained in yields of 66 % (36 grams) as a dark brownish oil which crystallized as yellow crystals (Melting point: 76.9C).
55.33 grams of bis-(2-methoxyethyl)amine are reacted with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 21.48 grams of ethyl cyanoacetate in the presence of an organic base and a solvent. The reaction temperature is between 0 C. and the boiling point of the solvent. [0338] The reaction end point is confirmed by thin layer chromatography or high performance liquid chromatography. [0339] After the reaction, the product (101) is obtained from the reaction mixture through ordinary product isolation by liquid-liquid separation, column chromatography or crystallization by addition of a poor solvent to the reaction mixture. [0340] The desired product (1) is obtained in yields of 66% (36 grams) as a dark brownish oil which crystallized as yellow crystals (Melting point: 76.9 C.)
Example A2 Preparation of the Compound of Formula[0217] 55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 27.18 grams of 2-methoxyethyl-cyanoacetate in the presence of an organic base and a solvent. [0218] The following base/solvent combinations are used: After the reaction, the product (102) is obtained from the reaction mixture through silica gel column chromatography (eluent: toluene/acetone). [0220] The desired product (102) is obtained in yields of 75% (45.44 grams) as a yellow powder (melting point: 92.2 C.).
With acetic acid; 1,8-diazabicyclo[5.4.0]undec-7-ene; In N,N-dimethyl-formamide;
Example A2: Preparation of the com ound of formula 55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1 ,1 ,3,3- tetramethoxypropane in acetic acid, concentrated and treated with 27.18 grams of 2- methoxyethyl-cyanoacetate in the presence of an organic base and a solvent. The following base/solvent combinations are used: After the reaction, the product (102) is obtained from the reaction mixture through silica gel column chromatography (eluent: toluene/acetone). The desired product (102) is obtained in yields of 75 % (45.44 grams) as a yellow powder (melting point: 92.2C).
55.33 grams of bis-(2-methoxyethyl)amine are condensed with 1,1,3,3-tetramethoxypropane in acetic acid, concentrated and treated with 27.18 grams of 2-methoxyethyl-cyanoacetate in the presence of an organic base and a solvent. After the reaction, the product (102) is obtained from the reaction mixture through silica gel column chromatography (eluent: toluene/acetone). [0345] The desired product (2) is obtained in yields of 75% (45.44 grams) as a yellow powder (melting point: 92.2 C.)
With hydrogenchloride In water at 50℃; for 0.5h; Inert atmosphere;
2.9 N-((1E,3E)-3-(phenylimino)prop-1-enyl)benzenamine hydrochloride (12)
A solution of propanedial bis(dimethyl acetal) (11, 5.25mL, 0.03mol) and HCl (4.25mL) in distilled water (90mL) was treated with a solution of distilled water (70mL), HCl (5mL) and aniline (3.7mL, 0.04mol) at 50°C. The resulting solution was stirred at 50°C for 30min, cooled, and the resulting precipitate was isolated by vacuum filtration and dried in vacuo to yield 12 as an orange solid (6.35g, 24.5mmol, 81.8%) [24]. Mp=charring at 150°C; 1H NMR (400MHz, CDCl3) d 8.72 (d, J=12Hz, 2H), 7.45-7.38 (m, 9H), 7.24 (t, J=8Hz, 2H), 6.28 (t, J=12Hz, 1H); 13C NMR (100MHz, DMSO-d6) d 159.6, 139.8, 131.1, 131.0, 127.6, 118.8, 118.7, 99.5, 99.4.
77%
With hydrogenchloride In water at 70℃; for 17h;
Synthetic procedure JIntermediate 66: (E)-N-((E)-3-(phenylamino)allylidene)benzenaminium chloride
To a solution of Malonaldehydebis(dimethylacetal) (0.03 mol) and concentrated HCI (4.25 mL) in water(85.5 mL), a solution of aniline (0.060 mol) and concentrated HCI (5 mL) in water (70 mL) was addeddrop wise. This mixture was allowed to stir at 7000 for 17 hours. A precipitate was formed and filteredThe product was obtained as an orange solid.Yield: 77%, MS (ESI): m/z 223.6 [M]+ en 221.6 [M - 2H]-; Rt: 1.36 mm (UPLC)1 H NMR (DMSO-d6, 400 MHz): 56.24 (t, 1 H, J = 11.6), 7.27 (t, 2H, J = 7.4), 7.36 (d, 4H, J = 8.0), 7.50 (t, 4H,J = 7.7), 8.74 (br d, 2H, J = 6.7), 12.09 (br s, 2H)
73%
Stage #1: malonaldehydebis(dimethylacetal) With hydrogenchloride In water at 50℃;
Stage #2: aniline With hydrogenchloride In water at 50℃;
46%
With hydrogenchloride In water at 0 - 20℃; for 0.25h;
200 mg of <strong>[6971-45-5]2-methoxyphenylhydrazine hydrochloride</strong> was dissolved in 5 ml of ethanol and 189 mul of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); delta (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
In ethanol; for 2h;Reflux;
[0176] 200 mg of <strong>[6971-45-5]2-methoxyphenylhydrazine hydrochloride</strong> was dissolved in 5 ml of ethanol and 189 mul of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. [0177] 1H-NMR (CDCl3); delta (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). [0178] MS (FAB); m/z 175 (M+H)+
(2-methoxyphenyl)hydrazine hydrochloride[ No CAS ]
[ 102908-37-2 ]
Yield
Reaction Conditions
Operation in experiment
179.4mg
In ethanol; for 2h;Reflux;
a) 1-(2-Methoxyphenyl)-1H-pyrazol 200 mg of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 5 ml of ethanol, and 189 mul of malonaldehyde bisdimethylacetal was added and heated at reflux for 2 hours. To the reaction mixture was added 50 ml of water, neutralized with a saturated aqueous solution of sodium carbonate, and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to yield 179.4 mg of the title compound. 1H-NMR (CDCl3); delta (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
In ethanol; for 2h;Reflux;
200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 mul of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR (CDCl3); delta (ppm) 3.87 (3H, s), 6.42 (1H, d, J=2.4 Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4 Hz). MS (FAB); m/z 175 (M+H)+
179.4 mg
In ethanol; for 2h;Reflux;
a) 1-(2-Methoxyphenyl)-1H-pyrazole [0154] 200 mg of 2-methoxyphenylhydrazine hydrochloride was dissolved in 5 ml of ethanol and 189 mul of malonaldehyde bisdimethylacetal was added, followed by heating to reflux for 2 hours. To the reaction mixture was added 50 ml of water, followed by neutralizing with a saturated aqueous sodium carbonate solution and extracting with 60 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and subsequently the solvent was distilled off under reduced pressure to afford 179.4 mg of the title compound. 1H-NMR(CDCl3); delta (ppm) 3.87 (3H,s), 6.42 (1H, d, J=2.4Hz), 7.02-7.07 (2H, m), 7.27-7.32 (1H, m), 7.68-7.72 (2H, m), 8.01 (1H, d, J=2.4Hz). MS (FAB); m/z 175 (M+H)+
With 1,8-diazabicyclo[5.4.0]undec-7-ene; In acetic acid; N,N-dimethyl-d6-formamide;
7 0. 67 grams of piperidine are condensed with 1, 1, 3, 3-tetramethoxypropane in acetic acid, concentrated andtreated with 59.72 grams of 2-ethoxyethyl cyanoacetatecyanoacetate in the presence of an organic base and a solvent.After silica gel column chromatography (eluent:toluene/acetone) the pure product is obtained yieldingdark yellow crystals. Melting point: 66-67C.
With hydrogenchloride In ethanol; water for 1h; Reflux;
Step 4: Synthesis of 1 -(4,4-difluorocyclohexyl)pyrazole
Step 4: Synthesis of 1 -(4,4-difluorocyclohexyl)pyrazoleTo a mixture of 2.04 g of (4,4-difluoro-cyclohexyl)-hydrazine hydrochlorid in 15 mL ethanol was added 3.50 mL cone, hydrochloric acid followed by 1 .80 g 1 ,1 ,3,3-tetramethoxypropane, then the mixture was refluxed for 1 h. The reaction mixture was diluted with water, ethanol was removed by destination. The residue was alkalized with aqueous sodium hydroxid solution (30%) and extracted with diethylether. The combined organic phases were dried over magnesium sulfate, filtered and concentrated in vacuo to yield 2.02 g of 1 -(4,4- difluorocyclohexyl)pyrazole as oil.Analysis: HPLC-MS: Rt = 0.46 min (method C), M+H = 187
b- Synthesis of intermediate 48: To a solution of 47 (161 mg, 1.00 mmol) in acetic acid (2.8 mL) was added 1,1,3,3- tetramethoxypropane (0.199 mL, 1.21 mmol). The solution was heated at 110C for 1 6h, then, evaporated in vacuo and co-evaporated with toluene twice. The residue wasdissolved in DCM and neutralized with a saturated aqueous solution of NaHCO3. The organic layer was separated, dried over MgSO4, filtered off and evaporated in vacuo to give 189 mg of intermediate 48, beige solid (96%).
1,1,3,3-tetramethoxypropane (16.4 g, 0.1 mol) was added to a suspension of <strong>[5446-18-4]2,4-dichlorophenyl hydrazine hydrochloride</strong> (21.35 g, 0.1 mol) in 95% ethanol aqueous solution (100 mL) and the resulting mixture was heated to reflux for 3-5 h. After the reaction was over by Thin-Layer Chromatography monitoring, the reaction mixture was concentrated under reduced pressure to remove most of the ethanol, and then poured into sodium carbonate solution. The water phase was extracted with ethyl acetate (3*100 mL), the organic phases were emerged, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was purified through silica column (ethyl acetate/petroleum ether=1:10, as an eluent) to get 18.06 g 1-(2,4-dichlorophenyl)-1H-pyrazole as yellow solid with yield of 84.8%.
84.8%
In ethanol; water;Reflux;
Take 21 · 35g (0 · lmol) of <strong>[5446-18-4]2,4-dichlorophenylhydrazine hydrochloride</strong> with16.4 g (0 · lmol) 1,1,3,3-tetramethoxypropane in 250 ml three-necked flask, 100 ml of a 95% aqueous ethanol solution was used as the solvent and the temperature was raised to reflux for 3-5 hours.After the TLC monitoring reaction was completed, most of the ethanol was distilled off under reduced pressure. The aqueous solution was added to the residue, and the aqueous phase was extracted with (3? 100 ml) of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and dissolved. The residue was subjected to column chromatography (eluent: ethyl acetate and petroleum ether in a volume ratio of 1:10) to give 18.06 g of a yellow solid in 84.8% yield.
84.8%
In ethanol; water;Reflux;
Taking 21.35 g (0.1 muM) phenyl-dichloride jing hydrochloride with 2, 4 - 16.4 g (0.1 muM) 1, 1, 3, 3 - tetramethoxy propane in 250 ml three-mouth bottle, 100 ml 95% ethanol aqueous solution as the solvent, heating to reflux reaction for 3 - 5 hours. TLC monitoring after the reaction, reducing pressure and most of the ethanol, to the remnants in the fluid adds sodium carbonate aqueous solution, the aqueous phase is (3 × 100 ml) ethyl acetate extraction, the combined organic phase, anhydrous magnesium sulfate drying, filtering, desolvation. The residue column chromatography (eluting agent is ethyl acetate with petroleum ether, the volume ratio of 1:10) to separate the yellow solid 18.06 g, yield 84.8%.
Stage #1: malonaldehydebis(dimethylacetal) With acetic anhydride; zinc(II) chloride at 100℃; for 0.5h; Inert atmosphere;
Stage #2: 2-(ethanesulfonyl)acetonitrile In toluene for 3h;
Stage #3: With hydrogen bromide; acetic acid at 30℃; for 1h;
1
1.2 g of acetic anhydride, 16.3 mg of zinc chloride and 980 mg of 1,1,3,3-tetramethoxypropane were added to a three-neck eggplant-shaped flask at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100°C. for 30 minutes. To the resulting mixture, 531.0 mg of (ethylsulfonyl) acetonitrile and 1.0 g of toluene were added. The resulting mixture was stirred for 3 hours, cooled to room temperature and concentrated in vacuo. 3.2 g of hydrogen bromide in 20% acetic acid solution was added to the obtained mixture, and the mixture was stirred at 30°C. for 1 hour. To the resulting mixture was added a mixture of water and hexane-diethyl ether (1:1). The obtained mixture was adjusted to pH=7 with saturated sodium bicarbonate water and separated. The obtained organic layer was washed with saturated brine and concentrated under reduced pressure to obtain 90 mg of 2-bromo-3-ethanesulfonylpyridine.
With trifluoroacetic acid In ethylbenzene for 3h; Reflux;
6 Example 6, Preparation of Compound 1
Take 28.1 g (0.107 mol) of compound 4 in 400 mL of ethylbenzene, add 17.6 g (0.107 mol)1,1,3,3-tetramethoxypropane and 14.6 g (0.128 mol) of trifluoroacetic acid were added and heated to reflux for 3 hours. The solvent was evaporated under reduced pressureThe residue was added with 200 mL of water, extracted with ethyl acetate (100 mL × 3), and then washed with 50 mL of saturated brine,Dried over sodium sulfate, suction filtered and concentrated to give 26.1 g of light yellow solid, yield 81.7%
2.1
1) Will be 2.89 g (0.02 µM) phenyl hydrazine hydrochloride and 3.28 g (0.02 µM) 1, 1, 3, 3 - tetramethoxy propane is added to the 50 ml95% in alcohol. Raising the temperature to 80 °C reflux, the reaction 3 - 6 hours, TLC monitoring after the reaction, reducing pressure and solvent, adding (3 × 50 ml) ethyl acetate extraction, the organic phase with saturated salt water 50 ml washing, desolvation residue after column chromatography (eluting agent is ethyl acetate with petroleum ether (reflux 60 - 90 °C), the volume ratio of 1:6), shall be 2.45 g oily liquid, yield 85.0%.
1-[2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]pyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
85%
Stage #1: 2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline With sulfuric acid; acetic acid; sodium nitrite In water at 0 - 5℃; for 0.75h;
Stage #2: ascorbic acid In water at 0 - 20℃; for 2h;
Stage #3: malonaldehydebis(dimethylacetal) In water at 65℃; for 5h;
4.4-2 Example 4-2) 1-[2,6-dichloro-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-1H-pyrazole (from Precursor of the General Formula (II): One-Pot Method with Step 1, Step 2 and Step 3) (I-1)
27.9 g (68.0 mmol, 1.0 eq) of 2,6-dichloro-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline were initially charged in 150 ml of glacial acetic acid and 75 ml of sulfuric acid (50% by weight) and admixed with a solution of 5.4 g of sodium nitrite (78.2 mmol, 1.15 eq) in 10.0 ml of water over 30 min at 0-5°C. After addition was complete, the reaction mixture was stirred for 15 min at this temperature and then 14.0 g (78.2 mmol, 1.15 eq) of ascorbic acid were added in one portion. The reaction mixture was warmed to room temperature over 2 h, then heated to 65°C., and 11.3 g (68.0 mmol, 1.0 eq) of 1,1,3,3-tetramethoxypropane were added at this temperature. The reaction was stirred at this temperature for a further 5 h. After cooling to room temperature and addition of 250 ml of water, the mixture was extracted once with 200 ml of n-heptane and once with 100 ml of n-heptane, the combined organic phases were washed with 150 ml of 10% by weight aqueous NaOH and the product was obtained, after removal of the solvent under reduced pressure, as an orange-red oil: yield 22.6 g (85% of theory).
With acetic anhydride; glacial acetic acid at 110℃; for 2h; Sealed tube;
1 Preparation of compound 3a:
The operation was as follows: 1a (17.9 mg, 0.1 mmol), Ac2O (95 uL, 1.0 mmol), AcOH (0.4 mL)and 1,1,3,3-tetramethoxypropane 2a (20uL, 0.12mmol) were sequentially added to a 25mL glass sealed tube,The caps in the sealed tubes were tightly closed and the reaction mixture was stirred in a parallel reactor at 110°C for 2 hours.After the reaction is completed, cool down to room temperature, transfer the reaction solution to a 25mL round-bottomed flask, evaporate and concentrate the reaction solution in a vacuum diaphragm pump in a water bath at 30°C for 5 min, and spin dry the reaction solution directly through the Separation and purification by column chromatography, using THF as eluent,to isolate the target product,Then the target product is evaporated and concentrated to a solid,Product 3a was obtained (20.9 mg, 97% yield). Yellow solid, mp
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