Month: August 2021

These common heterocyclic compound, 77326-36-4, name is 2-Amino-6-fluorobenzonitrile, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route. Quality Control of 2-Amino-6-fluorobenzonitrile

[6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (250 g, 820 mmol) (dried with ethanol as described above) was dissolved in THF (3800 mL) in a 5000 mL flask fitted with a condenser, mechanical stirrer, temperature probe, and purged with argon. 2-Amino-6-fluoro-benzonitrile (95.3 g, 700 mmol) was added to the solution, and the internal temperature was raised to 40 C. When all the solids had dissolved and the solution temperature had reached 40 C., solid KHMDS (376.2 g, 1890 mmol) was added over a period of 5 minutes. When addition of the potassium base was complete, a heterogeneous yellow solution was obtained, and the internal temperature had risen to 62 C. After a period of 60 minutes, the internal temperature decreased back to 40 C., and the reaction was determined to be complete by HPLC (no starting material or uncyclized intermediate was present). The thick reaction mixture was then quenched by pouring i into H2O (6000 mL) and stirring the resulting mixture until it had reached room temperature. The mixture was then filtered, and the filter pad was washed with water (1000 mL 2×). The bright yellow solid was placed in a drying tray and dried in a vacuum oven at 50 C. overnight providing 155.3 g (47.9%) of the desired 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one.Procedure B A 5000 mL 4-neck jacketed flask was equipped with a distillation apparatus, a temperature probe, a N2 gas inlet, an addition funnel, and a mechanical stirrer. [6-(4-Methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-acetic acid ethyl ester (173.0 g, 570 mmol) was charged into the reactor, and the reactor was purged with N2 for 15 minutes. Dry THF (2600 mL) was then charged into the flask with stirring. After all the solid had dissolved, solvent was removed by distillation (vacuum or atmospheric (the higher temperature helps to remove the water) using heat as necessary. After 1000 mL of solvent had been removed, distillation was stopped and the reaction was purged with N2. 1000 mL of dry THF was then added to the reaction vessel, and when all solid was dissolved, distillation (vacuum or atmospheric) was again conducted until another 1000 mL of solvent had been removed. This process of adding dry THF and solvent removal was repeated at least 4 times (on the 4th distillation, 60% of the solvent is removed instead of just 40% as in the first 3 distillations) after which a 1 mL sample was removed for Karl Fischer analysis to determine water content. If the analysis showed that the sample contained less than 0.20% water, then reaction was continued as described in the next paragraph. However, if the analysis showed more than 0.20% water, then the drying process described above was continued until a water content of less than 0.20% was achieved. After a water content of less than or about 0.20% was achieved using the procedure described in the previous paragraph, the distillation apparatus was replaced with a reflux condenser, and the reaction was charged with 2-amino-6-fluoro-benzonitrile (66.2 g, 470 mmol)(in some procedures 0.95 equivalents is used). The reaction was then heated to an internal temperature of 38-42 C. When the internal temperature had reached 38-42 C., KHMDS solution (1313 g, 1.32 mol, 20% KHMDS in THF) was added to the reaction via the addition funnel over a period of 5 minutes maintaining the internal temperature at about 38-50 C. during the addition. When addition of the potassium base was complete, the reaction was stirred for 3.5 to 4.5 hours (in some examples it was stirred for 30 to 60 minutes and the reaction may be complete within that time) while maintaining the internal temperature at from 38-42 C. A sample of the reaction was then removed and analyzed by HPLC. If the reaction was not complete, additional KHMDS solution was added to the flask over a period of 5 minutes and the reaction was stirred at 38-42 C. for 45-60 minutes (the amount of KHMDS solution added was determined by the following: If the IPC ratio is <3.50, then 125 mL was added; if 10.0IPC ratio 3.50, then 56 mL was added; if 20.0IPC ratio 10, then 30 mL was added. The IPC ratio is equal to the area corresponding to 4-amino-5-fluoro-3-[6-(4-methyl-piperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one) divided by the area corresponding to the uncyclized intermediate). Once the reaction was complete (IPC ratio >20), the reactor was cooled to an internal temperature of 25-30 C., and water (350 mL) was charged into the reactor over a period of 15 minutes while maintaining the internal temperature at 25-35 C. (in one alternative, the reaction is conducted at 40 C. and water is added within 5 minutes. The quicker quench reduces the amount of impurity that forms over time). The reflux condenser was then replaced with a distillation apparatus and solvent was removed by distillation (vacuum or atmospheric) using heat as required. After 1500 mL of solvent had been removed, distillation was disc…

The synthetic route of 2-Amino-6-fluorobenzonitrile has been constantly updated, and we look forward to future research findings.

Reference:
Patent; Novartis AG; US2008/293738; (2008); A1;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Electric Literature of 32446-66-5,Some common heterocyclic compound, 32446-66-5, name is 4,4′-Dicyanobenzophenone, molecular formula is C15H8N2O, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

Compound III-2 (3.51 g, 8 mmol) was dissolved in 50 mL of dry THF and stirred.Cooled to -20 C in a nitrogen atmosphere,Then, 1.6 M of n-BuLi n-hexane solution (5 mL, 8 mmol) was slowly added dropwise with a syringe, and after the addition was completed,The reaction mixture was stirred at this temperature for an additional 1 hour.A solution of V-2 (1.86 g, 8 mmol) dissolved in 5 mL of dry THF was slowly added dropwise with a syringe.After the dropwise addition was completed, the reaction mixture was stirred at the same temperature for half an hour, and then warmed to room temperature and stirred for 1 hour.Finally, it was stirred under reflux overnight. The reaction mixture was carefully poured into 300 mL of ice water and stirred.The extract was extracted with 50 mL of EtOAc (3 mL).The desiccant was removed by suction filtration, and the filtrate was evaporated to dryness on a rotary evaporator.Compound VI-2 is obtained

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 4,4′-Dicyanobenzophenone, its application will become more common.

Reference:
Patent; Tianjin Xiaoxin Pharmaceutical Technology Co., Ltd.; Zeng Huaxian; (7 pag.)CN108129370; (2018); A;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Researchers who often do experiments know that organic synthesis is a process of preparing more complex target molecules from simple raw materials through one or more chemical reactions. Generally, it requires fewer steps, and cheap raw materials. 6330-25-2, name is 2-Cyano-N-methyl-acetamide, A new synthetic method of this compound is introduced below., SDS of cas: 6330-25-2

0.394 g (9.95 mmol) of sodium hydride at 60% in mineral oil is added, in small amounts, to a solution, cooled to 0-5 C., of 0.483 g (4.93 mmol) of N-methylcyanoacetamide in 7 ml of anhydrous dimethylformamide. Stirring is continued at this temperature for ten minutes and then a solution of 1.0 g (4.93 mmol) of 2-(aminoethyl)-6-chloronicotinic acid fluoride in 5 ml of dimethylformamide is added. The medium is stirred overnight at ambient temperature and then 0.197 g (4.93 mmol) of sodium hydride at 60% is added in small amounts. Stirring is continued at this temperature for 10 minutes and then 0.56 ml (9.78 mmol) of acetic acid is added. 60 ml of water are then added and the solid is spin-filter-dried, rinsed with water, and then dried in an oven. 1.30 g of the expected product are obtained. Melting point: 283-284 C. MH+=281. Yield=94%. 1H NMR (DMSO-d6, 400 MHz): delta 11.75 (s, <1H, very broad); 11.00 (q, 1H, broad); 8.45 (d, 1H); 8.10 (s, 1H broad); 7.40 (d, 1H); 4.40 (q, 2H); 2.80 (d, 3H); 1.25 (t, 3H). The synthetic route of 6330-25-2 has been constantly updated, and we look forward to future research findings. Reference:
Patent; SANOFI-AVENTIS; US2010/144757; (2010); A1;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Electric Literature of 17626-40-3, In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 17626-40-3 as follows.

Step 1 : 1 H-Benzo[dlimidazole-5-carbonitrile3,4-Diaminobenzonitrile (5.0 g; 37 mmol) was dissolved in 5 N HCI (200 ml). After addition of formic acid (20 ml) the mixture was heated to reflux for 3 h. After cooling to room temperature, the mixture was basified by means of aqueous NH3-solution and put into a fridge. The precipitated solid was collected by filtration, washed with water and used without further purification. Yield: 3.6 g (67.6%) MS m/z: 144.2 [M+H]+

According to the analysis of related databases, 17626-40-3, the application of this compound in the production field has become more and more popular.

Reference:
Patent; PROBIODRUG AG; HEISER, Ulrich; RAMSBECK, Daniel; HOFFMANN, Torsten; BOEHME, Livia; DEMUTH, Hans-Ulrich; WO2011/107530; (2011); A2;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Adding a certain compound to certain chemical reactions, such as: 79463-77-7, name is Diphenyl N-cyanocarbonimidate, belongs to nitriles-buliding-blocks compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 79463-77-7, Product Details of 79463-77-7

DIPEA (1.52 mL, 8.82 mmol) then diphenyl cyanocarbonimidate (1.08 g, 4.41 mmol) in DCM (11 mL) were added to a sol. of intermediate 12 (1 g, 4.41 mmol) in DCM (39 mL). The r.m. was stirred at r.t. for 1 h. The solvent was evaporated. Yield: 0.5 g of intermediate 13 (34 %).

In the field of chemistry, the synthetic routes of compounds are constantly being developed and updated. I will also mention this compound in other articles, Diphenyl N-cyanocarbonimidate, other downstream synthetic routes, hurry up and to see.

Reference:
Patent; JANSSEN PHARMACEUTICALS, INC.; BISCHOFF, Francois, Paul; VELTER, Adriana, Ingrid; VAN BRANDT, Sven, Franciscus, Anna; BERTHELOT, Didier, Jean-Claude; WO2012/126984; (2012); A1;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Electric Literature of 658-99-1,Some common heterocyclic compound, 658-99-1, name is 2-(3,4-Difluorophenyl)acetonitrile, molecular formula is C8H5F2N, traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

Step 1: Methyl 4-cyano-4-(3,4-difluorophenyl)-3-(3-fluorophenyl)butanoate Under protective gas (Ar), 3.828 g (25.0 mmol) of (3,4-difluorophenyl)acetonitrile and 0.281 mg of potassium tert-butoxide were added to 4.099 g (22.7 mmol) of methyl 3-(3-fluorophenyl)acrylate in 25.0 ml of toluene, and the mixture was stirred in a closed vessel at 65 C. for 5 h. The solvent was removed under reduced pressure, the residue was taken up in ethyl acetate and the mixture was washed twice with in each case 25 ml of water. The combined organic phases were dried over sodium sulphate and the solvent was removed under reduced pressure. Chromatography of the residue on silica gel (ethyl acetate/heptane=20:80) gave 7.3 g (87% of theory) of the diastereomeric methyl 4-cyano-4-(3,4-difluorophenyl)-3-(3-fluorophenyl)butanoate (erythro:threo=65:35 according to integration of the methyl singlets in the 1H-NMR in CDCl3 at 3.68 and 3.59 ppm).

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 2-(3,4-Difluorophenyl)acetonitrile, its application will become more common.

Reference:
Patent; BAYER INTELLECTUAL PROPERTY GMBH; Mosrin, Marc; Jakobi, Harald; Angermann, Alfred; Gatzweiler, Elmar; Haeuser-Hahn, Isolde; Heinemann, Ines; Rosinger, Christopher Hugh; Lehr, Stefan; Schnatterer, Stefan; US2014/235446; (2014); A1;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Adding a certain compound to certain chemical reactions, such as: 75279-55-9, name is 2-Chloro-6-fluorophenylacetonitrile, belongs to nitriles-buliding-blocks compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 75279-55-9, HPLC of Formula: C8H5ClFN

General procedure: A mixture of 15.3 g (100 mmol) of 2-(2,6difluorophenyl)acetonitrile, 152.5 g (70 mL, 812 mmol) of dibromoethane, and 32.7 g (144 mmol) of Et3BnN+Cl- was isolated from moisture and carbon dioxide and vigorously stirred at 60. A solution prepared from 95 g (1430 mmol, ?84.5%) of KOH and 95 mL of water was then added dropwise; the mixture was stirred during 6 h at 60-65C, and left overnight. On the next day, the reaction mixture was extracted with t-BuOMe (3×100 mL), the combined organic fractions were evaporated, and residual water was removed via azeotropic distillation with toluene. Then 60 mL of water and 40 mL of concentrated sulfuric acid were added to the obtained 1-(2,6-difluorophenyl)cyclopropanecarbonitrile, and the mixture was refluxed during 4 h. The reaction mass was cooled to ambient; the precipitate was filtered off and dried. Yield 17.82 g (90%), mp 156-157 (toluene).

At the same time, in my other blogs, there are other synthetic methods of this type of compound, 2-Chloro-6-fluorophenylacetonitrile, and friends who are interested can also refer to it.

Reference:
Article; Novakov; Yablokov; Navrotskii; Mkrtchyan; Vernigora; Babushkin; Kachala; Ruchko; Russian Journal of General Chemistry; vol. 87; 2; (2017); p. 224 – 230; Zh. Obshch. Khim.; vol. 87; 2; (2017); p. 247 – 254,8;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

These common heterocyclic compound, 10412-93-8, name is N-Benzyl-2-cyanoacetamide, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route. COA of Formula: C10H10N2O

General procedure: A mixture of N-alkyl-2-cyano-acetamides 1a-c (2 mmol), aldehydes 2a-f (2 mmol),malononitrile (3) (2 mmol), K2CO3 (2 mmol), and EtOH (2 mL) in a 10 mL septum-capped microwavevials was irradiated under microwave conditions at 90 C, 500 W, 200 rpm, for 10-15 min. Aftercompletion of the reaction, as indicated by TLC, each vial was de-capped and the contents were left tocool to room temperature. Then, the reaction mixture was worked up as described in method I to givecompounds 4a-q. Analytical samples were obtained by recrystallization from MeOH.

The synthetic route of N-Benzyl-2-cyanoacetamide has been constantly updated, and we look forward to future research findings.

Reference:
Article; Mekheimer, Ramadan Ahmed; Al-Sheikh, Mariam Abdullah; Medrasi, Hanadi Yousef; Alsofyani, Najla Hosain Hassan; Molecules; vol. 23; 3; (2018);,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

Reference of 10365-94-3, A common heterocyclic compound, 10365-94-3, name is 1,3,5-Benzenetricarbonitrile, molecular formula is C9H3N3, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.

REFERENCE EXAMPLE 1 In an autoclave of a 300-ml content fitted with an electromagnetic agitator was placed for tight sealing a mixture of 15 g of 1,3,5-tricyanobenzene (MTN), 15 g of Raney-nickel.chromium catalyst prepared according to the conventional method (atomic ratio of Ni_Cr=49:1), 27 ml of methanol, 63 ml of m-xylene and 0.18 g of caustic soda, and hydrogen was charged at an initial pressure of 100 kg/cm2 G to conduct the reaction at 100 C., resulting in the absorption of 0.59 mole of hydrogen over a 35-minute period. The catalyst was filtrated out and the solvent was distilled off, followed by conducting vacuum distillation, thus resulting in 12.8 g of 1,3,5-tris(aminomethyl)benzene (MTA).

The synthetic route of 10365-94-3 has been constantly updated, and we look forward to future research findings.

Reference:
Patent; Takeda Chemical Industries, Ltd.; US4338256; (1982); A;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts

In the chemical reaction process, reaction time, type of solvent, can easily affect the result of the reaction, thereby determining the yield and properties of the reaction product. An updated downstream synthesis route of 120315-65-3 as follows. Formula: C8H6BrNO

Intermediate S: 3-Methoxy-4-(4,4,5,5-tetramethyl-ri ,3,21dioxaborolan-2ylbenzonitrile 4-Bromo-3-methoxy-benzonitrile (300 mg, 1.4 mmol) was dissolved in dioxane (2.5 mL) and the solution was flushed with argon. Bis-pinacolatodiboron (719 mg, 2.8mmol), Pd(dppf)CI2 (58 mg, 0.07 mmol) and KOAc (417 mg, 4.2 mmol) were added and the reaction mixture was heated to 100 C and stirred at this temperature for 19 h. It was then allowed to cool to rt and diluted with EtOAc. The organic phase was washed with brine, dried (Na2S04) and concentrated. The residual crude product was purified by flash chromatography (25g silica gel cartridge, hexanes/EtOAc, 100:0? 60:40) to give the title compound as a white solid; H-NMR (DMSO-c 6, 400 MHz) delta ppm 7.68 (d, 1 H), 7.42 (s, 1 H), 7.39 (d, 1 H), 3.82 (s, 3H), 1.32 (s, 12H).

According to the analysis of related databases, 120315-65-3, the application of this compound in the production field has become more and more popular.

Reference:
Patent; NOVARTIS AG; FURET, Pascal; GUAGNANO, Vito; HOLZER, Philipp; KALLEN, Joerg; LIAO, Lv; MAH, Robert; MAO, Liang; MASUYA, Keiichi; SCHLAPBACH, Achim; STUTZ, Stefan; VAUPEL, Andrea; WO2013/111105; (2013); A1;,
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts