* 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.
To a 1000 ml dry-dried reaction flask, 60 g (0.416 mol) of methyl isobutyrylacetate was successively charged,120 g (1.288 mol) of aniline,6g 4-dimethylaminopyridine.Open slowly stirring,Heated to an internal temperature of 100 ° C,Incubated for 16 hours.The fractionator is fractionated to produce the reacted methanol.After the reaction,70 ° C under reduced pressure to recover aniline,74.7 g of aniline was recovered,Aniline recovery rate of 92percent; get concentrated 100G,And then at this temperature by adding water kg,Cooling to 30 ° C stirring crystallization for 5 hours or more, filtration, water rinse filter cake 3 times, the cake dried product was 82.3g,HPLC analysis of 99.8percent, the yield of 96.4percent
92.7%
at 80 - 125℃;
EXAMPLE-9; 4-Methyl-3-oxo-N-phenyl pentanamide; Methyl isobutyryl acetate (lOOg, 0.693 mol) is placed in a 4 neck RB flask equipped with a stirring rod, thermometer socket and a distillation condenser. Aniline (71 g, 0.762 mol) and triethylamine (15g, 0.148 mol) are added and the contents are heated to 80-85°C under agitation. The contents are maintained at 80-85°C for lhr and the temperature is gradually raised to 120-125°C. The reaction is maintained for 4-6 hours, during which period methanol formed in the reaction is collected (48 ml). The reaction is continued till methanol no longer distills out . the contents are cooled to 25-30°C. The reaction mixture is quenched with 2N hydrochloric acid (200ml) and extracted with methylene chloride (100ml). The aqueous layer is extracted twice with methylene chloride (2 xlOO ml). The combined methylene chloride extract (300 ml) is sequentially washed with IN hydrochloric acid (50ml), 5percent aqueous sodium bicarbonate (50 ml) and 5percent aq. sodium chloride (50 ml). The organic layer is concentrated to remove methylene chloride on a water bath at 50-55°C, traces of methlyene chloride are finally removed under vacuum. 4-Methyl-3-oxo-N-phenyl pentanamide (132 g, 92.7percent, HPLC purity 98.85percent) thus obtained is used in next step as such.
91.9%
With triethylamine In toluene at 70 - 120℃; for 6 h;
A mixture of compound 2 (5.00 g, 34.69 mmol), triethylamine(0.88 g, 8.70 mmol), and aniline (3.88 g, 41.62 mmol) in toluene (30 mL)was heated to 70 °C. The reaction mixture was stirred at 70 °C for 1 h and then gradually heated to 110–120 °C. The methanol formed during the reaction was distilled off together with some toluene for 5 h. After cooling to room temperature, the mixture was washed with 5 percent hydrochloric acid (30 mL) and water(2×30 mL). The organic phases were dried over anhydrous magnesium sulfate and then concentrated to give a red oil 3 (6.55 g, 91.9 percent yield). 1H NMR (600 MHz, CDCl3) δ: 9.23 (s,1H), 7.09–7.55 (m,5H), 3.59 (s,2H), 2.73(m,1H), 1.17(d, J6.6 Hz,6H). 13C NMR (150 MHz, CDCl3) δ: 210.4, 164.5, 137.6, 128.8, 124.5, 120.1, 47.7, 41.5, 17.6.
37 g
With ethylenediamine In 5,5-dimethyl-1,3-cyclohexadiene at 140 - 150℃; for 4 h; Inert atmosphere
The first intermediate prepared in the step (1) is subjected to a substitution reaction with the aniline under the action of the second catalyst,2-Methyl-3,5-dicarbonyl-5-anilino-butane (second intermediate) is obtained; the reaction scheme is as follows: A reaction flask with a thermometer and a stirrer in a 500 mL format is used as a reaction vessel.Adding the first intermediate 2-methyl-3-carbonyl-pentanoic acid methyl ester 30 g (0.2 mol), aniline 22.5 g (0.24 mol), adding solvent xylene 200 mL,2.5 g (0.04 mol) of a catalyst ethylenediamine was added, and the reaction was heated to a temperature of about 140 to 150 ° C under a nitrogen atmosphere.After the methanol formed is distilled off, the reflux reaction is continued for about 4 hours, and the TLC detection of the raw material reaction is complete; After the reaction is completed, it is cooled to room temperature, adjusted to neutral with dilute hydrochloric acid, stirred,Filtration, washing with 100 mL of a saturated sodium chloride solution, and separating the organic phase to remove xylene under reduced pressure.Further, acetone was added to carry out recrystallization to obtain white purified solid 2-methyl-3,5-dicarbonyl-5-anilino-butane (37 g).
Reference：
[1] Patent: CN106397241, 2017, A, . Location in patent: Paragraph 0014; 0015; 0016; 0017; 0018; 0019; 0020; 0021
[2] Patent: WO2012/143933, 2012, A1, . Location in patent: Page/Page column 21-22
[3] Organic and Biomolecular Chemistry, 2016, vol. 14, # 7, p. 2291 - 2296
[4] Synthetic Communications, 2015, vol. 45, # 24, p. 2832 - 2840
[5] Journal of Heterocyclic Chemistry, 2007, vol. 44, # 4, p. 923 - 926
[6] Patent: US2009/298907, 2009, A1, . Location in patent: Page/Page column 7
[7] Patent: WO2009/144736, 2009, A1, . Location in patent: Page/Page column 19
[8] Chemistry - A European Journal, 2017, vol. 23, # 45, p. 10773 - 10776
[9] Patent: CN108218759, 2018, A, . Location in patent: Paragraph 0014; 0015
2
[ 62-53-3 ]
[ 7152-15-0 ]
[ 124401-38-3 ]
Yield
Reaction Conditions
Operation in experiment
81%
for 3 h; Reflux
10 g of ethylisobutyrylacetate (63.2 mmol) was dissolved in 30 ml of toluene, and6.5 g of aniline (70 mmol) was added to the resulting mixture and refluxed for 3 hours. When the reaction was completed, 50 ml of IN HCl was added to the resulting reaction mixture, and stirred to separate an organic phase. The organic phase was diluted with 50 ml of ethylacetate, washed with distilled water and saturated saline, and then concentrated under a reduced pressure to obtain brown oil. The resultant brown oil was washed with nucleic acid to obtain 10.5 g of brown oil (Yield: 81percent).[92] IH-NMR (CDC13)δ: 1.14 (d, 6H), 2.71 (m, IH), 3.58 (s, 2H), 7.09 (m, IH),7.24-7.31 (m, 2H), 7.53 (d, 2H), 9.20 (b, IH)[93] Mass (M+l): 206
Reference：
[1] Angewandte Chemie - International Edition, 2017, vol. 56, # 15, p. 4277 - 4281[2] Angew. Chem., 2017, vol. 129, p. 4341 - 4345,5
[3] Patent: WO2009/84827, 2009, A2, . Location in patent: Page/Page column 9
[4] Journal of Medicinal Chemistry, 1990, vol. 33, # 1, p. 61 - 70
[5] Patent: WO2016/16316, 2016, A1, . Location in patent: Page/Page column 292
3
[ 7152-15-0 ]
[ 124401-38-3 ]
Yield
Reaction Conditions
Operation in experiment
66%
With aniline In acetic acid; ethyl acetate; toluene
EXAMPLE 19.1 3-Oxo-4-methylpentananilide A solution of 47.4 g (0.3 mol) of ethyl 3-oxo-4-methylpentanoate, 27.93 g (0.3 mol) of aniline and 0.6 ml of glacial acetic acid in 360 ml of toluene is boiled under reflux with a water trap for 4 hours. The reaction mixture is cooled and then washed twice with 0.5 N hydrochloric acid, then twice with saturated sodium bicarbonate solution and then with saturated brine, and is dried and concentrated in vacuo. The residue is chromatographed on 1 kg of silica gel using toluene/ethyl acetate 10:1. 40.5 g (66percent yield) of pale pink-colored oil. 1 H NMR (CDCl3): δ=1.2 (d, 6H), 2.8 (s, 2H), 3.65 (s, 2H), 7.0-7.75 (m, 5H, 9.1-9.4 (s, br., 1H). MS: C12 H15 NO2 (205) m/e=205 (M+), 93.
Reference：
[1] Patent: US5055484, 1991, A,
4
[ 5650-76-0 ]
[ 62-53-3 ]
[ 124401-38-3 ]
Yield
Reaction Conditions
Operation in experiment
67 g
With triethylamine In toluene at 85℃; for 4 h;
The compound 1 (50.0 g), aniline (38.8 g), triethylamine (8.8 g) is added to the toluene (300 ml) in, heating to 85 °C, reaction 1 hour, the reaction system is heated up to reflux 4 hours. TLC (PE:EA=4:1) display the completion of reaction, the reaction system after cooling to room temperature, adding ethyl acetate (500 ml), respectively water (100 ml) washing, 5percent hydrochloric acid aqueous solution (150 ml) washing, saturated salt water washing 3 times after drying, turns on lathe does to obtain compound 2 (67.0 g).
Reference：
[1] Patent: CN108373437, 2018, A, . Location in patent: Paragraph 0022-0034; 30051-0052
5
[ 42558-54-3 ]
[ 124401-38-3 ]
Reference：
[1] Patent: US5998633, 1999, A,
[2] Patent: US5003080, 1991, A,
6
[ 42558-54-3 ]
[ 124401-38-3 ]
Reference：
[1] Patent: US5155251, 1992, A,
7
[ 42558-54-3 ]
[ 124401-38-3 ]
Reference：
[1] Patent: US5103024, 1992, A,
8
[ 1236069-48-9 ]
[ 124401-38-3 ]
Reference：
[1] Synlett, 2010, # 8, p. 1273 - 1275
9
[ 62-53-3 ]
[ 124401-38-3 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 3, p. 261 - 270
10
[ 563-80-4 ]
[ 124401-38-3 ]
Reference：
[1] Synthetic Communications, 2015, vol. 45, # 24, p. 2832 - 2840
[2] Patent: CN108218759, 2018, A,
11
[ 563-80-4 ]
[ 103-71-9 ]
[ 124401-38-3 ]
Reference：
[1] Chemistry - A European Journal, 2012, vol. 18, # 20, p. 6152 - 6157
12
[ 124401-38-3 ]
[ 100-52-7 ]
[ 125971-57-5 ]
Yield
Reaction Conditions
Operation in experiment
46 g
With acetic acid; glycine In n-heptane for 8 h; Inert atmosphere; Reflux
The second intermediate prepared in the step (2) is subjected to a condensation reaction with benzaldehyde under the action of a third catalyst.4-methyl-3-oxo-N-benzene-2-(benzylidene)pentanamide (third intermediate); the reaction scheme is as follows: A reaction flask with a thermometer and a stirrer in a size of 1000 mL was used as a reaction vessel under a nitrogen atmosphere.The second intermediate 2-methyl-3,5-dicarbonyl-5-anilino-butane 41 g (0.2 mol) was added to 250 mL of n-heptane, heated to reflux to separate water, and the reaction was about 6 h.At room temperature, 4 g of catalyst glycine and 6 g of glacial acetic acid were added, followed by benzaldehyde 24 g (0.22 mol).The temperature is raised to reflux and the water is reacted for about 8 hours. The TLC test ensures that the reaction is complete; After the reaction was completed, the temperature was lowered to room temperature, and washed with 50 mL of a saturated sodium chloride solution.After adding 100 mL of n-heptane, the organic phase was separated, and the organic phase was dried over anhydrous sodium sulfate and filtered.The filtrate was evaporated under reduced pressure to give 4-methyl-3-oxo-N-benzene-2-(phenylmethylene)pentanamide 46 g.
40 g
With piperidine; acetic acid In hexane; tolueneReflux
The compound 2 (67.0 g), benzaldehyde (38.6 g), piperidine (5.0 g), acetic acid (10.0 g), toluene (40 ml), hexane (350 ml) are added to a reaction flask, heated to reflux overnight. TLC (PE:EA=4:1) display the completion of reaction, the temperature of the after-treatment. The reaction system after cooling to room temperature, adding ethyl acetate (700 ml), saturated sodium bicarbonate respectively (150 ml) washing, saturated salt water (100 ml) washing, anhydrous sodium sulfate drying, turns on lathe does it is crude compound 3 (100.0 g). The obtained crude product added to ethyl acetate (100 ml), heated to 80 °C after dissolving, slowly dropping petroleum ether (600 ml), the temperature of the crystallization to obtain compound 3 (40.0 g, white solid).
Reference：
[1] Organic and Biomolecular Chemistry, 2016, vol. 14, # 7, p. 2291 - 2296
[2] Tetrahedron Letters, 1992, vol. 33, # 17, p. 2283 - 2284
[3] RSC Advances, 2014, vol. 4, # 63, p. 33175 - 33183
[4] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 3, p. 261 - 270
[5] Journal of the Indian Chemical Society, 2010, vol. 87, # 4, p. 495 - 499
[6] Chemistry - A European Journal, 2017, vol. 23, # 45, p. 10773 - 10776
[7] Patent: CN108218759, 2018, A, . Location in patent: Paragraph 0016; 0017
[8] Patent: CN108373437, 2018, A, . Location in patent: Paragraph 0022; 0034; 0053-0054
13
[ 124401-38-3 ]
[ 107-95-9 ]
[ 125971-57-5 ]
Reference：
[1] Patent: US5998633, 1999, A,
14
[ 124401-38-3 ]
[ 134395-00-9 ]
Reference：
[1] Journal of Labelled Compounds and Radiopharmaceuticals, 2000, vol. 43, # 3, p. 261 - 270
To a 1000 ml dry-dried reaction flask, 60 g (0.416 mol) of methyl isobutyrylacetate was successively charged,120 g (1.288 mol) of aniline,6g 4-dimethylaminopyridine.Open slowly stirring,Heated to an internal temperature of 100 C,Incubated for 16 hours.The fractionator is fractionated to produce the reacted methanol.After the reaction,70 C under reduced pressure to recover aniline,74.7 g of aniline was recovered,Aniline recovery rate of 92%; get concentrated 100G,And then at this temperature by adding water kg,Cooling to 30 C stirring crystallization for 5 hours or more, filtration, water rinse filter cake 3 times, the cake dried product was 82.3g,HPLC analysis of 99.8%, the yield of 96.4%
92.7%
With triethylamine; at 80 - 125℃;
EXAMPLE-9; 4-Methyl-3-oxo-N-phenyl pentanamide; Methyl isobutyryl acetate (lOOg, 0.693 mol) is placed in a 4 neck RB flask equipped with a stirring rod, thermometer socket and a distillation condenser. Aniline (71 g, 0.762 mol) and triethylamine (15g, 0.148 mol) are added and the contents are heated to 80-85C under agitation. The contents are maintained at 80-85C for lhr and the temperature is gradually raised to 120-125C. The reaction is maintained for 4-6 hours, during which period methanol formed in the reaction is collected (48 ml). The reaction is continued till methanol no longer distills out . the contents are cooled to 25-30C. The reaction mixture is quenched with 2N hydrochloric acid (200ml) and extracted with methylene chloride (100ml). The aqueous layer is extracted twice with methylene chloride (2 xlOO ml). The combined methylene chloride extract (300 ml) is sequentially washed with IN hydrochloric acid (50ml), 5% aqueous sodium bicarbonate (50 ml) and 5% aq. sodium chloride (50 ml). The organic layer is concentrated to remove methylene chloride on a water bath at 50-55C, traces of methlyene chloride are finally removed under vacuum. 4-Methyl-3-oxo-N-phenyl pentanamide (132 g, 92.7%, HPLC purity 98.85%) thus obtained is used in next step as such.
91.9%
With triethylamine; In toluene; at 70 - 120℃; for 6h;
A mixture of compound 2 (5.00 g, 34.69 mmol), triethylamine(0.88 g, 8.70 mmol), and aniline (3.88 g, 41.62 mmol) in toluene (30 mL)was heated to 70 C. The reaction mixture was stirred at 70 C for 1 h and then gradually heated to 110-120 C. The methanol formed during the reaction was distilled off together with some toluene for 5 h. After cooling to room temperature, the mixture was washed with 5 % hydrochloric acid (30 mL) and water(2×30 mL). The organic phases were dried over anhydrous magnesium sulfate and then concentrated to give a red oil 3 (6.55 g, 91.9 % yield). 1H NMR (600 MHz, CDCl3) delta: 9.23 (s,1H), 7.09-7.55 (m,5H), 3.59 (s,2H), 2.73(m,1H), 1.17(d, J6.6 Hz,6H). 13C NMR (150 MHz, CDCl3) delta: 210.4, 164.5, 137.6, 128.8, 124.5, 120.1, 47.7, 41.5, 17.6.
With pyridine; at 110 - 115℃; for 12h;Neat (no solvent);
Preparation of 4-methyl -3-oxo-N-phenylpentamideEXAMPLE 7 Reaction mixture containing 100 g methyl isobutyryl acetate and 100 ml of pyridine is heated at temperature of 110-115 C. 77.5 g aniline is added slowly in about two hrs keeping reaction mass at 110-115 C. for 12 hrs. Completion of the reaction is monitored by TLC. Mixture of pyridine and methanol is distilled out at 85-90 C. under reduced pressure. Contents are cooled to 35-40 C. and water is added followed by pH adjustment to 1-1.5. Mass is cooled further to 10-20 C. and product is filtered off. Wet cake obtained as 125-150 g (moisture content 20%, assay 98.5% by HPLC). Product is further dried to get 138 g product.
With pyridine; at 110 - 115℃; for 14h;
EXAMPLE 7:Reaction mixture containing 100 g methyl isobutyryl acetate and 100 ml of pyridine is heated at temperature of 110-115C. 77.5g aniline is added slowly in about two hrs keeping reaction mass at 110-115C for 12 hrs. Completion of the reaction is monitored by TLC. Mixture of pyridine and methanol is distilled out at 85-90C under reduced pressure. Contents are cooled to 35-400C and water is added followed by pH adjustment to l-1.5.Mass is cooled further to 10-200C and product is filtered off. Wet cake obtained as 125-150 g (moisture content 20%, assay 98.5% by HPLC). Product is further dried to get 138 g product.
37 g
With ethylenediamine; In 5,5-dimethyl-1,3-cyclohexadiene; at 140 - 150℃; for 4h;Inert atmosphere;
The first intermediate prepared in the step (1) is subjected to a substitution reaction with the aniline under the action of the second catalyst,2-Methyl-3,5-dicarbonyl-5-anilino-butane (second intermediate) is obtained; the reaction scheme is as follows: A reaction flask with a thermometer and a stirrer in a 500 mL format is used as a reaction vessel.Adding the first intermediate 2-methyl-3-carbonyl-pentanoic acid methyl ester 30 g (0.2 mol), aniline 22.5 g (0.24 mol), adding solvent xylene 200 mL,2.5 g (0.04 mol) of a catalyst ethylenediamine was added, and the reaction was heated to a temperature of about 140 to 150 C under a nitrogen atmosphere.After the methanol formed is distilled off, the reflux reaction is continued for about 4 hours, and the TLC detection of the raw material reaction is complete; After the reaction is completed, it is cooled to room temperature, adjusted to neutral with dilute hydrochloric acid, stirred,Filtration, washing with 100 mL of a saturated sodium chloride solution, and separating the organic phase to remove xylene under reduced pressure.Further, acetone was added to carry out recrystallization to obtain white purified solid 2-methyl-3,5-dicarbonyl-5-anilino-butane (37 g).
With potassium carbonate; In isopropyl alcohol; at 10 - 45℃;Product distribution / selectivity;
Preparation of 4-fluoro-alpha-[2-methyl-1-oxopropyl]-gamma-oxo-N-beta-diphenylbenzenebutanamideEXAMPLE 1 The mixture containing 300 ml isopropanol and 100 g of the formula III is cooled to 10-15 C. Potassium carbonate 94 g is charged into the above contents keeping the temperature 10-15 C. A solution of 128 gm of formula II in 125 ml isopropanol is then added slowly in 2-3 hrs keeping temperature at 10-15 C. Temperature is allowed to reach at 25-30 C. Temperature is further raised to 40-45 C. and then maintained for 8-10 hrs with simultaneous monitoring on HPLC. After HPLC complies, isopropanol is removed under vacuum keeping temperature below 55 C. followed by the addition of 600 ml ethyl acetate at 40-45 C. 600 ml water is charged and the organic layer is collected. Solvent is removed under vacuum when a solid mass is seen. This solid is purified by using isopropanol and methanol. Purity 99.69% with 0.047% of DESFLUORO impurity, Difluoro almost nil and O-alkylated impurity to be 0.1% with yield of 73%.
40 C. and a further 1.0 L of water is charged. Seven hundred milliliters of toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate mp 46.5-58.8 C. HPLC: 98.8%--retention time 3.56 min. 65/35 acetonitrile/water on a dry basis.
40
[ 124401-38-3 ]
[ 807361-46-2 ]
Yield
Reaction Conditions
Operation in experiment
92%
With N-Bromosuccinimide; In acetone; for 3h;
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol)in acetone 100 mL), N-bromosuccinimide (8.5 g, 0.048 mol) was added. Afterstirring for 3 hours, the reaction mixture was concentrated and product was isolatedby crystallization from Pet. Ether/ethyl acetate.Yield: 12.5 g, 92%
80%
With bromine; In chloroform; for 0.5h;
To a solution of 4-Methyl-3-oxo-pentanoic acid phenylamide (10 g, 0.048 mol)in chloroform (100 mL), liquid bromine (7.8 g, 0.048 mol) was added. After stirringfor 30 minutes, the reaction mixture was concentrated and product was isolated bycolumn chromatography(silica gel: 60-120 mesh, eluent: Pet. Ether/ethyl acetate-60:40)Yield: 11.0g,80%
Step 6: (Z)-2-((2-methoxypyrimidin-4-yl)methylene)-<strong>[124401-38-3]4-methyl-3-oxo-N-phenylpentanamide</strong>, 62 is prepared as follows: To a mixture of 2-methoxypyrimidine-4-carbaldehyde, 61 (0.833 g) and <strong>[124401-38-3]4-methyl-3-oxo-N-phenylpentanamide</strong> (1.23 g) are added piperidine (4 drops) and acetic acid (4 drops). The mixture is heated to 65 C. for 3 h after which time it is partitioned between water and dichloromethane. The aqueous layer is extracted with further dichloromethane and the combined organics dried (magnesium sulfate), filtered and concentrated. Purification by flash chromatography followed by trituration with toluene affords the title compound (0.221 g) as a powder. The compound obtained in this step shows the following mass spectral data: LC/MS: C18H19N3O3 requires 325.1; observed M/Z 326.1 [M+H]+, 324.2 [M-H]-. RT 4.02 min.
EXAMPLE A 4-Methyl-3-oxo-N-phenylpentanamide A three-necked, 12 L round bottom flask equipped with a mechanical stirrer, a thermometer, and set up for distillation was charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylenediamine. The mixture was heated to 80 C. and charged with 0.49 kg of aniline. The mixture was brought to reflux and distillation was started. After 40 minutes, a further 0.245 kg of aniline was charged and, at 40 minute intervals, a further two portions of aniline (0.245 and 0.25 kg) were charged. Distillation was continued for a further 1 to 5 hours until a total of 985 mL of solvent was removed. The solution was stirred at room temperature for 16 hours, and a further 550 mL of solvent was removed by vacuum distillation (at approximately 85 mm Hg). The mixture was cooled, and 2 L of water was charged to provide an oil. The mixture was warmed to 40 C., and a further 1.0 L of water was charged. Seven hundred milliliters of toluene/water mixture was removed by vacuum distillation (approximately 20 mm Hg). Two liters of water were charged, and the mixture allowed to stand for 10 days. The product was isolated by filtration and washed with three portions of hexane. Drying in vacuo gave 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate; mp 46.5-58.8 C. HPLC: 98.8%--retention time 3.56 minutes, acetonitrile/water 65:35 on a dry basis.
With aniline; In water; ethylenediamine; toluene;
EXAMPLE B 4-Methyl-3-oxo-N-phenylpentanamide A three-necked, 12-L round-bottom flask equipped with a mechanical stirrer, a thermometer and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylene diamine. The mixture is heated to 80 C. and charged with 0.49 kg of aniline. The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 40 minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours and a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to
EXAMPLE A 4-Methyl-3-oxo N phenylpentamide A three-necked, 12-L round-bottom flask equipped with a mechanical stirrer, a thermometer, and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylenediamine. The mixture is heated to 80 C. and charged with 0.49 kg of aniline. The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 40-minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours and a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to 40 C. and a further 1.0 L of water is charged. Seven hundred milliliters of toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate; mp 46.5 C.-58.8 C. HPLC: 98.8%--retention time 3.56 minutes. 65/35 acetonitrile/water on a dry basis.
Step A: Preparation of 4-Methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide. A suspension of 100 kg of <strong>[124401-38-3]4-methyl-3-oxo-N-phenylpentanamide</strong> (Example B) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of beta-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. An additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for one hour. The reaction mixture is cooled to 20-25 C. and the product is isolated by filtration. The product is purified by slurrying in hexanes at 50-60 C., cooling, and filtration. The product is slurried twice with water at 20-25 C., filtered, and dried in vacuo to yield 110 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7-154.4 C. Vapor Phase Chromatography (VPC): 30 meter DB 5 capillary column 50-270 C. at 15 C./min. 19.33 min, 99.7% (area). Gas Chromatography/Mass Spectrometry (GC/MC): M/Z 293 [M]+.
With benzaldehyde; In acetic acid;
Step A: Preparation of 4-Methyl-3-oxo-N-phenyl-2(phenylmethylene)pentanamide A suspension of 100 kg of <strong>[124401-38-3]4-methyl-3-oxo-N-phenylpentanamide</strong> (Example A) in 660 kg of hexanes is treated with agitation under nitrogen with 8 kg of beta-alanine, 47 kg of benzaldehyde, and 13 kg of glacial acetic acid. The resulting suspension is heated to reflux with removal of water for 20 hours. An additional 396 kg of hexanes and 3 kg of glacial acetic acid is added and reflux continued with water removal for 1 hour. The reaction mixture is cooled to 20 to 25 C., and the product is isolated by filtration. The product is purified by slurrying in hexanes at 50-60 C., cooling, and filtration. The product is slurried twice with water at 20 to 25 C., filtered, and dried in vacuo to yield 100 kg of 4-methyl-3-oxo-N-phenyl-2-(phenylmethylene)pentanamide, mp 143.7-154.4 C. Vapor Phase Chromatography (VPC): 30 meter DB-5 capillary column 50 to 270 C. at 15 C./min. 19.33 min., 99.7% (area). Gas Chromatography/Mass Spectrometry (GC/MC): M/Z 293 [M]+.
EXAMPLE A 4-Methyl-3-oxo-N-phenylpentamide A three-necked, 12-L round-bottom flask equipped with a mechanical stirrer, a thermometer, and set up for distillation is charged with 2.6 L of toluene, 1.73 kg (12 mol) of methyl 4-methyl-3-oxopentanoate and 72 g (1.18 mol) of ethylenediamine. The mixture is heated to 80 C. and charged with 0.49 kg of aniline. The mixture is brought to reflux and distillation started. After 40 minutes a further 0.245 kg of aniline is charged and at 40-minute intervals a further two portions of aniline (0.245 and 0.25 kg) are charged. Distillation is continued for a further one to five hours until a total of 985 mL of solvent is removed. The solution is stirred at room temperature for 16 hours and a further 550 mL of solvent is removed by vacuum distillation (using approximately 85 mm Hg). The mixture is cooled and 2 L of water is charged to provide an oil. The mixture is warmed to 40 C. and a further 1.0 L of water is charged. Seven hundred milliliters of toluene-water mixture is removed by vacuum distillation (approximately 20 mm Hg). Two liters of water is charged and the mixture is allowed to stand for 10 days. The product is isolated by filtration and washed with three portions of hexane. Drying in vacuo gives 1.7 kg of 4-methyl-3-oxo-N-phenylpentanamide as a hydrate; m.p. 46.5-58.8 C. HPLC: 98.8%--retention time 3.56 minutes. 65/35 acetonitrile/water on a dry basis.
With aniline; In acetic acid; ethyl acetate; toluene;
EXAMPLE 19.1 3-Oxo-4-methylpentananilide A solution of 47.4 g (0.3 mol) of ethyl 3-oxo-4-methylpentanoate, 27.93 g (0.3 mol) of aniline and 0.6 ml of glacial acetic acid in 360 ml of toluene is boiled under reflux with a water trap for 4 hours. The reaction mixture is cooled and then washed twice with 0.5 N hydrochloric acid, then twice with saturated sodium bicarbonate solution and then with saturated brine, and is dried and concentrated in vacuo. The residue is chromatographed on 1 kg of silica gel using toluene/ethyl acetate 10:1. 40.5 g (66% yield) of pale pink-colored oil. 1 H NMR (CDCl3): delta=1.2 (d, 6H), 2.8 (s, 2H), 3.65 (s, 2H), 7.0-7.75 (m, 5H, 9.1-9.4 (s, br., 1H). MS: C12 H15 NO2 (205) m/e=205 (M+), 93.
5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
81%
With ammonium acetate; In acetic acid; at 110 - 120℃; for 2h;
3 g of the 4-methyl-3-oxo-N-phenylpentaneamide derivative (14.6 mmol) prepared inExample 2 was dissolved in 50 ml of acetic acid, and 3.3 g of the l-(4-fluorphenyl)-2-hydroxy-2-phenylethanone derivative (14.6 mmol)prepared in Example 1 was then added to the resulting mixture. Also, 12 g of ammonium acetate (146 mmol) was added to the mixture, and the resulting mixture was refluxed at a temperature of 110 to 12O0C for 2 hours. When the reaction was completed, the resulting reaction solution was cooled, diluted with distilled water, and extracted three times with ethylacetate. The extracted reaction solution was washed with distilled water and saturated saline, and concentrated under a reduced pressure. The resulting derivative was purified with column chromatography to obtain 4.7 g of a white solid title derivative (Yield: 81%).[97] IH-NMR (CDC13)delta: 1.40 (d, 6H), 4.08 (m, IH), 6.90-7.23 (m, 10H), 7.38-7.51 (m,5H), 8.38 (b, IH),[98] Mass (M+l): 399
With potassium carbonate; In acetone; at 10 - 45℃;Product distribution / selectivity;
EXAMPLE 4 The mixture containing 300 ml acetone and 100 g of the formula III is cooled to 10-15 C. Potassium carbonate 94 g is charged into the above contents keeping the temperature 10-15 C. A solution of 128 gm of formula II in 125 ml acetone is then added slowly in 2-3 hrs keeping temperature at 10-15 C. Temperature is allowed to reach at 25-30 C. Temperature is further raised to 40-45 C. and then maintained for 8 hrs with simultaneous monitoring on HPLC. HPLC revealed the progress of the reaction to be 65%, unreacted compound of formula III to be 10.0%, 8.1% of formula II and O-alkylated impurity to be 14.7%. Looking at the unreacted starting material reaction is pursued but it results in enhancing the O-alkylated impurity.
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