* 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.
Reference：
[1] Patent: US2006/293366, 2006, A1, . Location in patent: Page/Page column 13-14
[2] Journal of Medicinal Chemistry, 2011, vol. 54, # 12, p. 4119 - 4132
3
[ 34846-90-7 ]
[ 100-63-0 ]
[ 876-93-7 ]
Yield
Reaction Conditions
Operation in experiment
85.7%
for 6 h; Reflux
To three reaction bottles were added 10.8 g (100 mmol) of phenylhydrazine, 11.6 g (100 mmol) of methyl methacrylate,100 mL of methanol. The temperature of the reaction mixture was raised to reflux for about 6 hours. The reaction liquid was quantified by liquid chromatography, and 1-phenyl-5-hydroxypyrazoleYield 85.7percent.
3-Methoxyacrylic acid methyl ester (4 g, 34.45 mmol) was dissolved in methanol (50 ml) and cooled to O0C. Methyl hydrazine (1.75 g, 37.9 mmol) in methanol (20ml) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 10 minutes then heated to reflux for 4 hours. The reaction was then concentrated and purified by silica gel column chromatography eluted with ethyl acetate/methanol = 100/0 to 80/20 to recover the title product as a white solid (2.5 g, 73percent yield). 1H NMR (400 MHz, DMSO-de) δ 3.463.47(3H s) 5.28-5.29(1H d) 7.06-7.08(1 H d) 10.75-10.81(1H bs)
Reference：
[1] Patent: WO2008/59370, 2008, A2, . Location in patent: Page/Page column 49
[2] European Journal of Medicinal Chemistry, 2016, vol. 108, p. 730 - 740
5
[ 67-56-1 ]
[ 60778-73-6 ]
[ 34846-90-7 ]
Yield
Reaction Conditions
Operation in experiment
81%
at 0℃; for 0.5 h;
87.6 g of methoxyacryloyl chloride was slowly added dropwise to a solution of triethylamine (89 g, 0.88 mol) in methanol (67.2 g, 2.1 mol) at 0 ° C, and stirred for 30 min.After distilling off the methanol solvent, distillation under reduced pressure tomethoxyacrylic acid methyl ester was 68.6 g, and the yield was 81percent (85 torr, 99 to 100 ° C).
Reference：
[1] Patent: CN108129304, 2018, A, . Location in patent: Paragraph 0044; 0050; 0054; 0058; 0062; 0063; 0066; 0070
6
[ 7424-91-1 ]
[ 34846-90-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
at 160℃; for 6 h;
Example 2: Preparation of methyl 3-methoxyprop-2-enoate Under an atmosphere of nitrogen, 0.2 g (2 mmol) of methanesulfonic acid (Fluka) was added to 150 g of a filtrate, analogously obtained as described in example 1 (about 85percent, 0.86 mol of methyl 3,3-dimethoxypropionate), in a distillation apparatus with round-bottomed flask. Under constant flow of nitrogen, the mixture was slowly heated to 160 °C, and the methanol formed was directly distilled off. After 6 hours, the heat supply was stopped. The methyl 3-methoxy- prop-2-enoate obtained in this manner was 88percent pure (GC) and was purified by rectification at 10 kPa. The yield was 85 g (85percent) of methyl 3-methoxyprop-2-enoate (Ki0 kpa = 950C) with a purity of 99percent (GC).; Example 6: Preparation of methyl 3-methoxyprop-2-enoate After distillative removal of the unreacted trimethyl ortho formate from example 1, 4.4 t (30 kmol) of the methyl 3,3-dimethoxypropionate thus obtained were reacted under an atmosphere of nitrogen with 6 kg (62 mol) of methanesulfonic acid analogously to example 2. <n="10"/>Rectification at 10 kPa gave 2.4 t (21 kmol, 69percent based on trimethyl orthoformate employed) of methyl 3-methoxyprop-2-enoate (Ki0 kpa = 95 °C) in a purity of 93percent (GC).
82%
at 150 - 160℃; for 4 h;
In a 100 ml three-necked flask, 97 g of BJ02, 5 g of potassium bisulfate and 50 g were addedPolyethylene glycol dimethyl ether, Heated to 150 ~ 160 , 4 hours of stirring insulation, vacuum pump distillation was 46.5gMethyl 3-methoxyacrylate, Yield 82percent, GC normalized content of 98.7percent
535 g
at 190℃; for 20 h;
Raw material composition of this embodiment: methyl acrylate 560g, methanol 716g, cobalt oxide 2.24g, indium oxide 8.96g, concentrated sulfuric acid 17.6g;Preparation Process: Methyl acrylate, methanol and synthetic catalyst were added to the reactor and stirred well to keep the reaction liquid warm to 50°C.The reactor was filled with nitrogen and oxygen so that the partial pressures of nitrogen and oxygen were 0.4 MPa and the reaction was started. The reaction time was 16 h.When the content of methyl acrylate in the reaction solution was 3percent, the reaction was completed and the etherification reaction product was added.The etherification reaction product is filtered to recover the catalyst, petroleum ether is added to the filtrate, and the mixture is evenly stirred and allowed to stand for stratification.The upper layer is a petroleum ether layer. Atmospheric distillation recovers petroleum ether to give intermediate product methyl 3,3-dimethoxypropionate 703g.From the lower aqueous phase, methanol and methyl acrylate are recovered and applied.Separated methyl 3,3-dimethoxypropionate into the cracking kettle, then slowly added 17.6 g of concentrated sulfuric acid,The temperature was further increased to 190° C., the cleavage reaction was carried out for 20 h, and all lysates were collected to obtain 430 g of crude MAME.The crude MAME was added to the rectification vessel to recover the distillation product by vacuum distillation and weighed to obtain 478 g of the target product methyl 3-methoxyacrylate.The target product obtained in this example was 535 g, and the yield based on methyl acrylate was 82.4percent. The product purity was 95.8percent.
Reference：
[1] Patent: WO2009/56293, 2009, A1, . Location in patent: Page/Page column 8-9
[2] Patent: CN105418421, 2016, A, . Location in patent: Paragraph 0020; 0023
[3] Patent: WO2009/56293, 2009, A1, . Location in patent: Page/Page column 8
[4] Patent: WO2009/56293, 2009, A1, . Location in patent: Page/Page column 8
[5] Patent: WO2009/56293, 2009, A1, . Location in patent: Page/Page column 8
[6] Patent: CN107879936, 2018, A, . Location in patent: Paragraph 0016-0020
7
[ 616-38-6 ]
[ 74-86-2 ]
[ 34846-90-7 ]
Reference：
[1] Journal of the American Chemical Society, 1949, vol. 71, p. 1259
[2] Journal of the American Chemical Society, 1949, vol. 71, p. 1259
(Step B-4) Synthesis of methyl 3-(4-chloromethylphenyl)isoxazole-4-carboxylate N-Hydroxy-4-chloromethylbenzenecarboxyimidoyl chloride (15.27 g, 74.82 mmol) was dissolved in dichloromethane (300 ml), methyl 3-methoxyacrylate (10.43 g, 89.82 mmol) was added, and triethylamine (21 ml, 151 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (9.67 g, 51percent). 1H-NMR(300 MHz, CDCl3) delta=3.84(3H, s), 4.63(2H, s), 7.49(2H, d, J=6.9 Hz), 7.70(2H, d, J=6.9 Hz), 9.01(1H, s).
(Step 4) Synthesis of methyl 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate N-Hydroxy-4-(2-chloroethyl)benzenecarboxyimidoyl chloride (2.07 g, 9.48 mmol) was dissolved in dichloromethane (5 ml), methyl 3-methoxyacrylate (1.32 g, 11.37 mmol) was added, and triethylamine (1.92 g, 18.97 mmol) was slowly added dropwise. The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (hexane:ethyl acetate=5:1) to give the title compound (1.46 g, 58percent). MS(ESI) m/z 266 (M+H)+.
4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
96%
With sodium chloride; sodium t-butanolate; In tetrahydrofuran;
Example 3 4-(2-BROMO-PHENYL)-4-CYANO-BUT-3-ENOIC ACID METHYL ESTER A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2*80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96percent). Major isomer 1H NMR (400 MHz, CDCl3) delta7.59 (dd, 1H, J =7.6, 1.2), 7.57-719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) delta169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm-1. Minor isomer 1H NMR (400 MHz, CDCl3) delta7.61 (dd, 1H, J=7.6, 1.0), 7.57-7.19 (m, 3H), 6.9 (t,1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5).
With hydrogenchloride; sodium methylate; sodium hydrogencarbonate; In water;
EXAMPLE 2 The toluene solution of 3-mercapto-2-butanone from the previous step (613 g of ca. 25 wt percent solution) was placed in a clean, dry reactor along with 15 g of methyl-3-methoxyacrylate. The mixture was warmed to 25° C., stirred vigorously, and treated with solid sodium methoxide (8.5 g, ca. 0.1 equiv.) all at once. The remaining methyl-3-methoxyacrylate (151 g) was added in at a rate to keep the temperature at or below 35° C. (2 h). The resulting mixture was allowed to reach room temperature and stir for 21 h. Concentrated hydrochloric acid (88 g) was added to the mixture over 30 min such that the temperature did not exceed 35° C. The resulting mixture was stirred vigorously for 2 h, then treated with 73 g of water, and stirred for 10 min more. The phases were allowed to separate. After standing for 10 min, the aqueous phase was drained from the reactor, and the upper, product phase was washed with 100 g of 5percent sodium bicarbonate solution. After being stirred for 15 min, the phases were allowed to separate. The lower, aqueous phase was drained from the reactor, and the upper, product phase was transferred to a distilling flask. The toluene was distilled through a 5-plate distillation column at 100 mmHg. After a small fraction containing toluene and other low boiling impurities was collected, the product, 3-carbomethoxy-4,5-dimethylthiophene, was distilled through the column at 50 mmHg.
With hydrogenchloride; sodium methylate; sodium hydrogencarbonate; In water;
Example 2 The toluene solution of 3-mercapto-2-butanone from the previous step (613 g of ca. 25 wtpercent solution) was placed in a clean, dry reactor along with 15 g of methyl-3-methoxyacrylate. The mixture was warmed to 25°C, stirred vigorously, and treated with solid sodium methoxide (8.5 g, ca. 0.1 equiv.) all at once. The remaining methyl-3-methoxyacrylate (151 g) was added in at a rate to keep the temperature at or below 35°C (2 h). The resulting mixture was allowed to reach room temperature and stir for 21 h. Concentrated hydrochloric acid (88 g) was added to the mixture over 30 min such that the temperature did not exceed 35°C. The resulting mixture was stirred vigorously for 2 h, then treated with 73 g of water, and stirred for 10 min more. The phases were allowed to separate. After standing for 10 min, the aqueous phase was drained from the reactor, and the upper, product phase was washed with 100 g of 5percent sodium bicarbonate solution. After being stirred for 15 min, the phases were allowed to separate. The lower, aqueous phase was drained from the reactor, and the upper. product phase was transferred to a distilling flask. The toluene was distilled through a 5-plate distillation column at 13.3 kPa [100 mmHg]. After a small fraction containing toluene and other low boiling impurities was collected, the product, 3-carbomethoxy-4,5-dimethylthiophene, was distilled through the column at 6.665 kPa [150 mmHg].
With N-iodo-succinimide; acetic acid; triethylamine; In di-isopropyl ether;
Preparation 1 methyl 2-iodo 3-methoxy 2-propenoate A solution containing 12.95 g of methyl 3-methoxy 2-propenoate and 50 ml ofacetic acid is introduced into a solution containing 37 g of N-iodosuccinimide and 150 ml of acetic acid. The reaction medium is agitated for 4 hours at ambient temperature. It is concentrated under reduced pressure and taken up in isopropyl ether. Filtration and rinsing with isopropyl ether are carried out. After concentrating and taking up inmethylene chloride, a sufficient quantity of triethylamine is added to ensure the conversion to the acrylic derivative. After washing, drying andconcentrating, an oil is obtained which crystallizes spontaneously at ambient temperature. The crystals obtained are recrystallized from isopropanol. 17 g of desired product is obtained melting at 50.9° C.
30.5 g
A mixture of methyl-3-methoxypropenoate, 37-f, (13.92 g, 120 mmol), N- iodosuccinimid (32g, 140mmol), glacial acetic acid (18 mL, 240 mmol), and dichloromethane(150 mL) was stirred at room temperature for 24h. Triethylamine (50 mL, 36 mmol) was added, and the reaction mixture was stirred at room temperature for 12h before water was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and water, and were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1 :5) to afford compound, 37-g (30.5 g, crude) . 1H NMR (300 MHz, CDCI3) delta 7.69 (s, 1H), 4.01 (s, 3H), 3.80 (s, 3H); LC-MS (ESI): 243 [M+H]+
In methanol; at 0℃; for 4.66667h;Heating / reflux;
3-Methoxyacrylic acid methyl ester (4 g, 34.45 mmol) was dissolved in methanol (50 ml) and cooled to O0C. Methyl hydrazine (1.75 g, 37.9 mmol) in methanol (20ml) was added dropwise over 30 minutes. The reaction was stirred at room temperature for 10 minutes then heated to reflux for 4 hours. The reaction was then concentrated and purified by silica gel column chromatography eluted with ethyl acetate/methanol = 100/0 to 80/20 to recover the title product as a white solid (2.5 g, 73% yield). 1H NMR (400 MHz, DMSO-de) delta 3.463.47(3H s) 5.28-5.29(1H d) 7.06-7.08(1 H d) 10.75-10.81(1H bs)
In methanol; for 8h;Reflux; Inert atmosphere;
A magnetically stirred solution of methyl 3-methoxyacrylate (20.0g, 172.2mmol) in methanol (100mL) was treated slowly with N-methylhydrazine (10.0mL, 189.4mmol) then heated at reflux for 8h. The resulting mixture was cooled to room temperature then concentrated under a stream of nitrogen followed by high vacuum pump to afford an orange solid that was dissolved in DMF (19.9mL, 258.4mmol) and cooled to 0C. The resulting mixture was treated dropwise with phosphoryl chloride (48.1mL, 516.6mmol) then heated at 80C for 12h before being cooled and neutralised via the slow addition of ice cold NaOH (10M, 300mL). The aqueous solution was then extracted with a dichloromethane/isopropanol mixture (9:1, 5×100mL) and the combined organic phases were washed with chilled water (3x100mL), brine (1×100mL) before being dried (MgSO4), filtered and concentrated under reduced pressure to afford an orange solid. Recrystallisation (dichloromethane/hexane) afforded the title pyrazole 8 (16.31g, 66%) as yellow crystals
In methanol; water; for 2h;Cooling with ice;
To a 1000 mL four-necked flask was placed 170 g of methanol under ice-water bath.At the same time, 116 g of methyl 3-methoxyacrylate and 262.8 g (35%) of an aqueous methylhydrazine solution were added dropwise to the flask.After the addition was completed, the reaction was continued for 2 hours.After the reaction was completed, methanol, water and methylhydrazine were distilled off under reduced pressure.That is, the product 1-methyl-5-hydroxypyrazole.
Montmorillonite K10; at 0℃;Product distribution / selectivity;
Example 1: Preparation of methyl 3,3-dimethoxypropionate Simultaneously, but separately, 150 kg/h (1.413 kmol/h) of trimethyl ortho formate (Fluka), comprising 1.5percent by weight of montmorillonite KlO (Sd-Chemie), and 84 kg/h of ketene (ketene content about 70percent, remainder inert gases, such as N2, CO and CO2, i.e. neat ketene about 59 kg/h, that is about 1.4 kmol/h) were fed into a 620 L jet reactor (see figure 1), which had been inertized and cooled to an internal temperature of 0 0C. Under an atmosphere of nitrogen, the reaction mixture was kept at a temperature of about 0 °C and circulated in the loop via a circulating pump. Corresponding to the amount of starting materials added, and also continuously, a corresponding part of the reaction mixture flowed over into a collecting tank. After filtration, the purity of the filtrate was determined by GC as 80percent methyl 3,3-dimethoxypropionate, 8percent unreacted trimethyl orthoformate, 4percent methyl 3-methoxyprop-2-enoate and 4percent methyl acetate.By virtue of its low boiling point, it was easy to remove trimethyl orthoformate by distillation. The recovered starting material was subsequently re-cycled into the reaction mixture. <n="9"/>The yield of methyl 3,3-dimethoxypropionate was 82percent (based on conversion).
methanesulfonic acid; at 160℃; for 6h;Product distribution / selectivity;
Example 2: Preparation of methyl 3-methoxyprop-2-enoate Under an atmosphere of nitrogen, 0.2 g (2 mmol) of methanesulfonic acid (Fluka) was added to 150 g of a filtrate, analogously obtained as described in example 1 (about 85percent, 0.86 mol of methyl 3,3-dimethoxypropionate), in a distillation apparatus with round-bottomed flask. Under constant flow of nitrogen, the mixture was slowly heated to 160 °C, and the methanol formed was directly distilled off. After 6 hours, the heat supply was stopped. The methyl 3-methoxy- prop-2-enoate obtained in this manner was 88percent pure (GC) and was purified by rectification at 10 kPa. The yield was 85 g (85percent) of methyl 3-methoxyprop-2-enoate (Ki0 kpa = 950C) with a purity of 99percent (GC).; Example 6: Preparation of methyl 3-methoxyprop-2-enoate After distillative removal of the unreacted trimethyl ortho formate from example 1, 4.4 t (30 kmol) of the methyl 3,3-dimethoxypropionate thus obtained were reacted under an atmosphere of nitrogen with 6 kg (62 mol) of methanesulfonic acid analogously to example 2. <n="10"/>Rectification at 10 kPa gave 2.4 t (21 kmol, 69percent based on trimethyl orthoformate employed) of methyl 3-methoxyprop-2-enoate (Ki0 kpa = 95 °C) in a purity of 93percent (GC).
82%
With potassium hydrogensulfate; at 150 - 160℃; for 4h;
In a 100 ml three-necked flask, 97 g of BJ02, 5 g of potassium bisulfate and 50 g were addedPolyethylene glycol dimethyl ether, Heated to 150 ~ 160 , 4 hours of stirring insulation, vacuum pump distillation was 46.5gMethyl 3-methoxyacrylate, Yield 82percent, GC normalized content of 98.7percent
toluene-4-sulfonic acid; In water; at 160℃; for 6h;Product distribution / selectivity;
Example 3: Preparation of methyl 3-methoxyprop-2-enoate The reaction was carried out analogously to example 2 using 5 g (content 99percent, 34 mmol) of pure-distilled methyl 3,3-dimethoxypropionate and 25 mg (0.13 mmol) of/?-toluenesulfonic acid monohydrate (Fluka). The resulting crude product had a content of 91percent (GC) of methyl 3- methoxyprop-2-enoate.
4-aminobenzene sulfonic acid; at 160℃; for 6h;Product distribution / selectivity;
Example 4: Preparation of methyl 3-methoxyprop-2-enoate The reaction was carried out analogously to example 2 using 5 g (content 99percent, 34 mmol) of pure-distilled methyl 3,3-dimethoxypropionate and 47 mg (0.27 mmol) of sulfanilic acid (Fluka). The resulting crude product had a content of 92percent (GC) of methyl 3-methoxyprop-2- enoate.
phosphoric acid; at 160℃; for 6h;Product distribution / selectivity;
Example 5: Preparation of methyl 3-methoxyprop-2-enoate The reaction was carried out analogously to example 2 using 5 g (content 99percent, 34 mmol) of pure distilled methyl 3,3-dimethoxypropionate and 31 mg (0.31 mmol) of orthophosphoric acid (Fluka). The resulting crude product had a content of 88percent (GC) of methyl 3-methoxyprop-2- enoate.
535 g
With sulfuric acid; at 190℃; for 20h;
Raw material composition of this embodiment: methyl acrylate 560g, methanol 716g, cobalt oxide 2.24g, indium oxide 8.96g, concentrated sulfuric acid 17.6g;Preparation Process: Methyl acrylate, methanol and synthetic catalyst were added to the reactor and stirred well to keep the reaction liquid warm to 50°C.The reactor was filled with nitrogen and oxygen so that the partial pressures of nitrogen and oxygen were 0.4 MPa and the reaction was started. The reaction time was 16 h.When the content of methyl acrylate in the reaction solution was 3percent, the reaction was completed and the etherification reaction product was added.The etherification reaction product is filtered to recover the catalyst, petroleum ether is added to the filtrate, and the mixture is evenly stirred and allowed to stand for stratification.The upper layer is a petroleum ether layer. Atmospheric distillation recovers petroleum ether to give intermediate product methyl 3,3-dimethoxypropionate 703g.From the lower aqueous phase, methanol and methyl acrylate are recovered and applied.Separated methyl 3,3-dimethoxypropionate into the cracking kettle, then slowly added 17.6 g of concentrated sulfuric acid,The temperature was further increased to 190° C., the cleavage reaction was carried out for 20 h, and all lysates were collected to obtain 430 g of crude MAME.The crude MAME was added to the rectification vessel to recover the distillation product by vacuum distillation and weighed to obtain 478 g of the target product methyl 3-methoxyacrylate.The target product obtained in this example was 535 g, and the yield based on methyl acrylate was 82.4percent. The product purity was 95.8percent.
Example 6; N-[(2E)-1-(difluoromethyl)-3-methoxy-2-(methoxycarbonyl)prop-2-en-1-ylidene]-N-methyl-methanaminium tetrafluoroborate; 8.7 g (60 mmol) of N-1,1,2,2-tetrafluoroethyldimethylamine were initially charged in 50 ml of dichloromethane under argon, and 8.2 g (60 mmol) of boron trifluoride-diethyl ether complex were added at RT. The mixture was stirred for 30 min and then admixed with 6.38 g (55 mmol) of methyl methoxyacrylate. After stirring at RT for 2 h and removing the dichloromethane under reduced pressure, 12.4 g of the product (100percent yield) were obtained as a yellow oil.19F NMR (CDCl3) delta=-121.55, (d, 2F, J=51 Hz); -150.2 (s, 4F) ppm.
Methyl 3-methoxyacrylate (4) (13.36 g, 0.114 mol) and hydrazine hydrochloride (8.08 g, 0.117 mol)) were refluxed in methanol (200 mL) for 48 hours. The solvent were removed under reduced pressure, the residue was dispersed in water (500 mL) and slowly made basic by the addition of solid sodium hydrogencarbonate. The aqueous phase was saturated with salt, extracted with dichloromethane; this organic phase was washed with a 1 N solution of sodium hydrogencarbonate three times, dried over sodium sulfate and concentrated to dryness. The residue was boiled in water (50 mL) in the presence of potassium hydroxide (3.8 g) for 6 hours. This was extracted with ethyl acetate; the organic phase was washed with brine dried over sodium sulfate and concentrated to dryness to yield compound 15 as an oil (0.85 g, 7.5 percent). 1H (CDCl3): 3.92 (s, 3H); 5.73 (d, 1H, J = 2.5); 7.37 (d, 1H, J = 2.5). 13C (CDCl3): 56.6; 89.6; 130.4; 164.4.
methyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68%
To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (96percent, 46 g, 305 mmol) in acetonitrile (100 ml) was added dropwise, at 25° C. under Argon, BF3-etherate (38.9 g, 274 mmol). Subsequently, under reflux conditions (approx. 70° C.), a solution of methyl 3-methoxyacrylate (95percent, 33.5 g, 274 mmol) in acetonitrile (75 ml) was added dropwise to the reaction mixture within 1 h. After stirring under reflux conditions for 21 h, the reaction mixture was cooled to 25° C. The resulting reaction mixture was added dropwise to a solution of methylhydrazine (21 g, 457 mmol) in acetonitrile (48 ml) at 0 to 15° C. within 1.5 h. After stirring at 25° C. for 0.5 h, water (100 ml) was added. The reaction mixture was extracted once with 150 ml and once with 90 ml of methylene chloride. The combined organic phases were washed with water (1.x.200 ml). The resulting organic phase (530 g) contained, according to GC area percent analysis, methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate and methyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate in a ratio of 6.8:1. According to quantitative HPLC analysis, the organic phase comprised 6.7percent by weight of methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate. This corresponds to a yield of 68percent (based on methyl 3-methoxyacrylate).
To a solution of 1,1,2,2-tetrafluoroethyldimethylamine (96percent, 46 g, 305 mmol) in acetonitrile (100 ml) was added dropwise, at 25° C. under argon, BF3-etherate (36.8 g, 259 mmol). Subsequently, under reflux conditions (approx. 70° C.), a solution of methyl 3-methoxyacrylate (95percent, 31.6 g, 259 mmol) in acetonitrile (75 ml) was added dropwise to the reaction mixture within 1 h. After stirring under reflux conditions for a further 26 h, the reaction mixture was cooled to 25° C. The resulting reaction mixture was added dropwise at 0 to 15° C. to a solution of hydrazine hydrate (66.5 g, 850 mmol) in acetonitrile (100 ml) within 1 h. After stirring at 25° C. for a further hour, a sample of the solution was taken and analyzed by HPLC analysis. According to HPLC analysis, the reaction mixture comprised, as the main product (53 area percent) methyl 3-difluoromethyl-1H-pyrazole-4-carboxylate (retention time: 10 min; HPLC-MS: (m/z)=177).
[1-13C]-Methyl phenyl sulfoxide (2.5 g, 0.014 mol) and anhydrous THF (20 mL) were mixed in a 100 mL round bottom equipped with a magnetic stir bar and a rubber septum fitted to a nitrogen inlet. This mixture was stirred under a constant flow of nitrogen for a period of 10 minutes, after which it was then equilibrated at -78° C. in an ethanol dry ice bath. After about 10 minutes of equilibration, lithium diisopropylamide (17.7 mL, 1.8 eq) was added slowly for a period of 2 minutes. The resultant mixture was stirred for a period of 45 minutes to ensure complete anion formation. At that point, <strong>[34846-90-7]3-methoxy acrylic acid methyl ester</strong> (2.09 mL, 0.015 mol) was added neat to the reaction mixture still at -78° C. Initial 13CNMR in CDCl3 showed the formation of a new peak at 59 ppm and some starting material at 44 ppm (a ratio of 80percent to 20percent product starting material). The reaction mixture was allowed to go for an additional 3.0 hours and 13CNMR analysis of an aliquot in CDCl3 at that point showed 85percent conversion of starting material to product. After about 30 minutes of stirring, the reaction mixture was poured into a separatory funnel containing dichloromethane (75 mL) and deionised water (30 mL). This mixture was acidified to a pH of 2 and the organic layer was extracted (2.x.50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and then concentrated using a rotary evaporator to afford 4.2 g of a red fluid. This crude product was purified by dry column chromatography (using 80percent EtoAc/20percent hexane as the eluent) to afford 2.74 g, 86.9percent of the titled compound light red oil, which immediately solidified on standing.The spectra data are as follows:1HNMR delta: 7.58-7.52 (m 5H); delta: 6.73-6.65 (m unresolved multiplet 1H); delta: 5.93-5.86 (ddd J 15.44, 6.98, 6.25, 1.1); delta: 3.99-3.31 (two sets of ddd J 149.28, 12.87, 7.72, 2H); delta: 3.72 (s 3H).13CNMR (75 MHz in CDCl3) delta: 138.60, 131.66, 129.43, 128.48, 59.04 and 55.13 (the carbonyl peak was not seen).
boron trifluoride diethyl etherate; In dichloromethane; at 20 - 75℃;
To a solution of 2-(5-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-lH-indol-3-yl)ethanol (0.1 g, 0.248 mmol) in DCM (1.0 mL) were added methyl 3-methoxyacrylate (0.086 g, 0.744 mmol) and boron trifiuoride etherate (2.324 muL, 0.018 mmol). The reaction was stirred for 1 d at room temperature, warmed to 50 0C and stirred an additional 24 h, and then warmed to 75 0C and stirred 24 h. The mixture was concentrated to an oil, dissolved in dioxane (3 mL) and added 1.0 M LiOH (600 muL). The mixture was stirred for 2 h and then acidified to pEta 4 with 1 M HCl. The mixture was diluted with water and extracted twice with EtOAc. The combined extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by EtaPLC to provide the title compound (1.0 mg). LCMS m/z = 474.43 [M+Eta]+; 1H NMR (400 MHz, CDCl3) delta ppm 1.54-1.65 (m, 2H), 1.67-1.78 (m, 2H), 1.81-2.16 (m, 4H), 2.68-2.76 (m, IH), 2.86-2.98 (m, 2H), 3.04 (dd, J= 16.9, 5.2 Hz, IH), 3.33-3.43 (m, IH), 3.84-3.93 (m, IH), 4.19-4.27 (m, IH), 5.09 (s, 2H), 5.19-5.24 (m, IH), 6.91 (dd, J = 8.7, 2.4 Hz, IH), 7.04 (d, J= 2.4 Hz, IH), 7.24 (d, J = 8.8 Hz, IH), 7.48 (d, J= 8.3 Hz, IH), 7.60 (d, J= 7.7 Hz, IH), 7.70 (s, IH), 8.33 (bs, IH).
methyl 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
89%
Example 5; Preparation of methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate from 1,1,2,2-tetrafluoroethyldimethylamine, methyl 3-methoxyacrylate and N-methyl-benzaldehyde hydrazoneTo a solution of 96percent pure 1,1,2,2-tetrafluoroethyldimethylamine (48.1 g, 318 mmol) in acetonitrile (97 g) under argon were added dropwise, at 25° C., 38.4 g (270 mmol) of BF3 etherate. After the addition had ended, the mixture was heated to reflux (70° C.). At this temperature, a solution of 95percent pure methyl 3-methoxyacrylate (33.1 g, 271 mmol) in acetonitrile (61 g) was added dropwise to the reaction mixture within 1 h. After stirring under reflux for 20 h, the reaction mixture was cooled to 25° C. and 99.8 g of a 38percent solution of N-methylbenzalde hydrazone in toluene (287 mmol) were added at 25° C. within 15 min. After a further stirring phase of 0.5 h, 10.4 g of a 50percent by weight solution of water in acetonitrile (289 mmol) were added. 32.7 g (287 mmol) of 32percent hydrochloric acid were then added and the mixture was heated to reflux with stirring for 3 h. Subsequently, the mixture was cooled to 25° C. and 100 ml of water were added. The organic phase was removed; the water phase was extracted once with 100 ml of methylene chloride. The combined organic phases were washed once with 100 ml of water. 391 g of organic phase were obtained. Gas chromatography analysis showed that the undesired 1,5-isomer (methyl 5-difluoromethyl-1-methylpyrazole-4-carboxylate) had been formed only in traces in addition to the methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate. The isomer ratio was 141:1. The organic phase was concentrated. 63.6 g of residue were obtained, which, as well as benzaldehyde, according to quantitative HPLC analysis, comprised 71.7percent by weight of methyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate. This corresponds to 89percent yield based on methyl 3-methoxyacrylate. The benzaldehyde can be removed easily by fractional distillation or after hydrolysis of the title compound as described in examples 1 to 4.
A mixture of Intermediate-8C (1 equiv) and methyl 3-methoxyacrylate (3 equiv) was stirred at 90 °C for 6 h. The solvent was removed in vacuo and purification by silica gel chromatography (0-7percent methanol/dicloromethane) delivered the desired compound as a colorless solid (41percent). Intermediate-11: 1H NMR (400 MHz, CDC13) delta 10.46 (br s, 1H), 8.51 (d, 1H), 7.96 (d, 1H), 7.31 (s, 1H), 7.31-7.24 (m, 1H), 7.07-7.02 (m, 3H), 6.60 (d, 1H), 6.38 (d, 1H), 5.89 (s, 2H).
Methyl 2-iodo-3-methoxyacrylate (37-g) A mixture of methyl-3-methoxypropenoate, 37-f, (13.92 g, 120 mmol), N- iodosuccinimid (32g, 140mmol), glacial acetic acid (18 mL, 240 mmol), and dichloromethane (150 mL) was stirred at room temperature for 24h. Triethylamine (50 mL, 36 mmol) was added, and the reaction mixture was stirred at room temperature for 12h before water was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, and water, and were dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography (PE:EA=1 :5) to afford compound, 37-g (30.5 g, crude) . NMR (300 MHz, CDCI3) delta 7.69 (s, 1H), 4.01 (s, 3H), 3.80 (s, 3H); LC-MS (ESI): 243 [M+H]+.
With hydrazine hydrate; In methanol; for 2h;Reflux;
Reference Production Example 1 (0548) A mixture of 21.1 g of methyl 3-methoxyacrylate, 10.0 g of hydrazine hydrate, and 20 mL of methanol was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain 11.0 g of 1H-pyrazol-3-ol. 1H-pyrazol-3-ol (0549) (0550) 1H-NMR (DMSO-d6) delta (ppm): 10.22 (1H, s), 7.35 (1H, d, J=2.2 Hz), 5.43 (1H, d, J=2.2 Hz)
11 g
With hydrazine hydrate; In methanol; for 2h;Reflux;
The 21.1g of 3-methoxy-acrylate, and a mixture of 10.0g of hydrazine hydrate in 20mL of methanol was heated under reflux for 2 hours with stirring. The reaction mixture was concentrated under reduced pressure to obtain 11.0 g of 1H- pyrazol-3-ol.
A magnetically stirred solution of methyl 3-methoxyacrylate (20.0g, 172.2 mmol) in MeOH (100 mL) was treated slowly with Nmethylhydrazine(10.0 mL, 189.4 mmol) and then heated at refluxfor 16 h. The resulting mixture was cooled to r.t. then concentratedunder reduced pressure to afford an orange solid that was dissolvedin DMF (19.9 mL, 258.4 mmol) and cooled to 0 °C. The resultingmixture was treated slowly with POCl3 (48.1 mL, 516.6 mmol) andthen heated at 80 °C for 7 h. It was cooled and poured slowly intoice-cold 20percent aq Na2CO3 soln (600 mL). The aqueous solution wasthen extracted with CHCl3 (5 × 100 mL); the combined organicphases were washed with brine (1 × 100 mL) and then dried(MgSO4), filtered, and concentrated under reduced pressure to affordan orange solid. Recrystallization (CH2Cl2?hexane) afforded55 (X = Cl, 12.87 g, 52percent) as yellow crystals, mp 77?78 °C;Rf = 0.44 (EtOAc?hexane, 1:1).
General procedure: Sodium hydride (60percent), (1.88 g, 0.047 mol), washed twice withhexane to remove the paraffin oil, was added to a clean well driedRB flask. Traces of solvent were removed by applying nitrogenusing evacuated carousel or ampoules. To the dried sodiumhydride, dry DMF (30 mL) was added under nitrogen atmosphere,followed by trimethylsulfoxonium iodide (10.35 g, 0.047 mol) insingle lot and the contents were stirred for 60 min at 40?45 C.This solution was added to a mixture of the compound 3a (10 g,0.046 mol) in DMF (5 mL) at 0 C under nitrogen atmosphere overa period of 15 min. The completion of reaction was checked by TLC.Then the reaction mixture was maintained for a period of 1?2 h atroom temperature and quenched by adding the reaction mixtureinto a solution of aqueous hydroiodic acid (10percent) solution at 0 C.The aqueous mixture was extracted with chloroform and theorganic layer was washed with 10percent sodium thiosulfate solutionto remove the excess iodine. The organic layer was concentratedand purified using column chromatography on silica gel (hexane/EtOAc) to afford the iodo compound 5a, as pale yellow colouroily liquid.
With pyridine; iodine; In tetrachloromethane; at 0 - 20℃; for 72h;Inert atmosphere;
(Z) -3- methoxy-2-iodo-Preparation of methacrylate: reactor, 3-methoxy-acrylate (1.00g, 8.62mmol) was dissolved in carbon tetrachloride / pyridine ( 1: 1v / v) 20mL mixed solution while the iodine (6.57g, 25.86mmol) was dissolved in carbon tetrachloride / pyridine (1: 1v / v) 60mL mixed solution, and placed in the dropping funnel , N2Protection under 0 to start dropping and stirring, the reaction was completed after 72h, during the natural temperature to room temperature.After completion of the reaction, diluted with water, then ethyl acetate (100mL), 37percent hydrochloric acid solution (8mL), and the organic layer was separated.The organic layer again with water (50 mL) and sodium thiosulfate (5.00 g) shock, the organic layer was separated again.Concentrated under reduced pressure, recovering the organic solvent, to VAcetic acidEthyl: VHexane= 1:10 as eluant column chromatography to give a white solid was finally 1.48 g, yield 70.9percent.
17.5 g (100 mmol) of 4-methoxyphenylhydrazine hydrochloride, 11.6 g (100 mmol) of methoxyMethyl acrylate, and 100 mL of methanol. The reaction mixture was heated to reflux for about 6 hours. The reaction solution was quantified by liquid chromatography,and 1- (4-methoxyphenyl) -5-hydroxypyrazole Yield 79.3percent
1-(5-fluoro-2-methylphenyl)-5-hydroxypyrazole[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.9%
In methanol; for 6h;Reflux;
Added to the three-port reaction bottle 1.77 g (10 mmol) of 5-fluoro-2-methylphenylhydrazine hydrochloride, 1.16 g (10 mmol) of methanesulfonyl chlorideMethoxyacrylic acid methyl ester, 10 mL of methanol. The reaction mixture was heated to reflux for 6 hours. The reaction solution was quantified by liquid chromatography. 1- (5-Fluoro-2-methylphenyl) -5-hydroxypyrazole. Yield 75.9percent
1.70 g (10 mmol) of 4-cyanophenylhydrazine hydrochloride, 1.16 g (10 mmol) of methoxypropan-2-ol were added to a three-necked reaction flaskMethylene chloride, 10 mL of methanol. The temperature of the reaction mixture was raised to reflux for about 6 hours. The reaction solution was quantitated by liquid chromatography, and 1- (4-cyanoPhenyl) -5-hydroxypyrazole Yield 64.2percent
To three reaction bottles were added 17.9 g (100 mmol) of p-chlorophenylhydrazine hydrochloride, 11.6 g (100 mmol) of methoxypropylMethyl ester, l00mL methanol. The temperature of the reaction mixture was raised to reflux for about 6 hours. The reaction liquid was quantitated by liquid chromatography, and 1-p-chlorophenyl-The yield of 5-hydroxypyrazole was 81.3percent.
To three reaction bottles were added 10.8 g (100 mmol) of phenylhydrazine, 11.6 g (100 mmol) of methyl methacrylate,100 mL of methanol. The temperature of the reaction mixture was raised to reflux for about 6 hours. The reaction liquid was quantified by liquid chromatography, and 1-phenyl-5-hydroxypyrazoleYield 85.7percent.
(100 mmol) of 2-nitrophenylhydrazine, 11.6 g (100 mmol) of methacrylic acidMethyl ester, 100 mL of methanol. Heating to 40 ° C reaction for about 6 hours, the reaction liquid by liquid chromatography quantitative, 1-(2-nitrophenyl)-5-hydroxypyrazole.The yield of the title compound was 52.6percent
With potassium carbonate; In ethanol; at 85℃; for 10h;
The mixture of methyl 3-methoxyacrylate (4.0g, 34.4mmol), isobutyrimidamide hydrochloride (12.64g, 103.2 mmol) and potassium carbonate (15.2g, 110.1 mmol) in ethanol (50 mL) was stined at 85 °C for 10h. The reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to get 2-isopropylpyrimidin-4(3H)-one (4.0g,84percent). ?H NMR (400 MHz, DMSO-d6): oe 12.37 (br s, 1H), 7.84 (d, J= 6.6 Hz, 1H), 6.14 (d, J=6.6 Hz, 1H), 2.71 ? 2.83 (m, 1H), 0.97 (d, J= 6.9 Hz, 6H)); LC-MS: 138.9 [M+H].
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