Category: Pyrazines

Synthetic Route of 33332-28-4, As we all know, there are many different methods for the synthesis of a compound, and people can choose the synthesis method that suits their own laboratory according to the actual situation. 33332-28-4 name is 2-Amino-6-chloropyrazine, This compound is widely used in many fields, so it is necessary to find a new synthetic route. The downstream synthesis method of this compound is introduced below.

Example 29: Preparation of:2-(4-Ch]oro-2-mophiholin-4-yl-1.24hiazol-5-yl)-5-(dicvcloprorhoyImethylV3,7-dimethyl-5H-pyitauolof2.3- ipyrazine; Part A: 2-Amino-6-methy] pyrazine; A solution of zinc chloride (2.0M in THF, 96.5 mL, 48.2 mmol, 5.0 equiv.) is treated dropwise with methylmagnesium bromide (3.0 M in Et2O, 32.2 mL, 96.5 mmoi, 10.0 equiv.) at 0 °C. The mixture is wanned to room temp and stirred for 45 min. A solution of 2-amino-6-chloro pyrazine (1.25 g. 9.65 mmol, 1.0 equiv) and NiC12(dppp) (157 mg, 0.29 mmol, 0.03 equiv) in THF (15 mL) is added to the freshly prepared dimethylzinc reagent. The reaction mixture is stirred under for 3h and cooied to room temp. The reaction is quenched carefully with sat’d NH4CI solution and allowed to stir overnight. The layers are separated and the aqueous layer is extracted with EtOAc (2 X 30 mL). The combined organic extracts are washed with brine, dried over Na2Spsi4 and concentrated under reduced pressure to give a cream-colored solid that is used without further purification. MS = 110.08 (M +1). 1H NMR (400 MHz, CDCI3) delta 7.78 (IH, s), 7.72 (IH, s), 4.59 (2H, bs), 2.35 (3H, s).

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

Reference:
Patent; NEUROGEN CORPORATION; WO2008/83070; (2008); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

These common heterocyclic compound, 762240-92-6, name is 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride, 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. HPLC of Formula: C6H8ClF3N4

General procedure: A solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4]triazolo[4,3-a]pyrazine hydrochloride salt 9 (1.0 eq.) in dimethylformamide (DMF, 2e3 mL) was added potassium carbonate (2.5eq.) at 5 C and stirred for 15 min at room temperature. To this,various chloride derivatives (1.0 eq.) in DMF was added to reaction mixture at same temperature. The resultant reaction mixture was allowed to stir at room temperature for 24 h. The completion of the reaction was monitored on TLC (using 10% MeOH: DCM and ammonia as a modifier as mobile phase). The reaction mixture was poured into ice-cold water and extracted with ethyl acetate(2 x 15 mL). Organic layers were combined and the combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford crude material and crystallized it from methanol to get 3-(trifluoromethyl)-5,6,7,8-tetrahydro [1,2,4]triazolo [4,3-a]pyrazine derivatives (12f-12j) in good practical yield.

The synthetic route of 3-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride has been constantly updated, and we look forward to future research findings.

Reference:
Article; Jethava, Divya J.; Acharya, Prachi T.; Vasava, Mahesh S.; Bhoi, Manoj N.; Bhavsar, Zeel A.; Rathwa, Sanjay K.; Rajani, Dhanji P.; Patel, Hitesh D.; Journal of Molecular Structure; vol. 1184; (2019); p. 168 – 192;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Some common heterocyclic compound, 5049-61-6, name is Pyrazin-2-amine, molecular formula is C4H5N3, 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. Application In Synthesis of Pyrazin-2-amine

To a three-necked flask equipped with 2-aminopyrazine (14.27 g, 0.15 mol) was added dichloromethane (200 mL) and pyridine(25.3 mL, 0.315 mol); immersed in water at 40 C, slowly added dropwise bromine (16.2 mL,0.315 mol) in dichloromethane (100 mL). After the reaction, the solution changed from orange to orange to orange1h was added dropwise; reflux was continued at 40 C for 30 min; cooling to room temperature, adding distilled water (50 mL) to the reaction system,Stirring for 10 min, standing on the stratified layer; collecting the lower liquid, the collected liquid was washed twice with distilled water (100 mL); the organic phaseWas transferred to a flask equipped with silica gel (10 g) and activated carbon (1 g), boiled and refluxed for 30 min. The filtrate was collected by filtration and distilled under reduced pressure,The solid obtained after the distillation was transferred to a flask equipped with n-hexane (45 mL) and refluxed at 80 C for 2 h. The filtrate was filtered while hotThe solid product was dried and weighed to give 18.15 g of a pale yellow solid, i.e., 3,5-dibromo-2-aminopyrazine, in a yield of 47.8%.

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 5049-61-6, its application will become more common.

Reference:
Patent; Jiangxi Science and Technology Normal University; Zhu Wufu; Zheng Pengwu; Sun Chengyu; Chen Chen; Xu Shan; Tang Qidong; Wang Wenhui; Wang Qinqin; Wang Caolin; (23 pag.)CN106831812; (2017); A;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Each compound has different characteristics, and only by selecting the characteristics of the compound suitable for a specific situation can the compound be applied on a large scale. 87486-34-8, name is 3,5-Dibromo-1-methylpyrazin-2(1H)-one, This compound has unique chemical properties. The synthetic route is as follows., Product Details of 87486-34-8

Example 114a (R)-5-bromo-3-(4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenylamino)-1-methylpyrazin -2(1H)-one 114a A sealed tube equipped with a magnetic stirrer was charged with (R)-3-(4-aminophenyl)-1,4-dimethylpiperazin-2-one (1.08 g, 5 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.47 g, 5.5 mmol), diisopropylethylamine (1.94 g, 15 mmol), and iPrOH (20 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110 °C overnight. After cooling down to room temperature, water (20 mL) was added to, and the mixture was extracted with ethyl acetate (50 mL X 2). The organic layer was separated, combined, dried over anhydrous sodium sulfate, and concentrated. The resulting residue was purified by silica gel column chromatography eluting with dichloromethane/methanol (10:1, V/V) to afford 114a (1.8 g, 90percent) as a red solid. LCMS: [M+H]+ 406

Chemical properties determine the actual use. Each compound has specific chemical properties and uses. We look forward to more synthetic routes in the future to expand reaction routes of 87486-34-8.

Reference:
Patent; F.Hoffmann-La Roche AG; CRAWFORD, James John; ORTWINE, Daniel Fred; WEI, BinQing; YOUNG, Wendy B.; EP2773638; (2015); B1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Electric Literature of 113305-94-5,Some common heterocyclic compound, 113305-94-5, name is 5-Aminopyrazine-2-carbonitrile, molecular formula is C5H4N4, 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.

ii) 5-Aminopyrazine-2-carbonitrile (0.208 mmol) in acetonitrile (1 mL) was added portionwise to a stirred solution of copper (II) bromide (0.25 mmol) and t-butylnitrite (0.31 mmol) in acetonitrile (2 mL) and the reaction mixture was maintained at 60 C. for 1 h. The reaction was diluted with ethyl acetate (15 mL) and washed twice with 1N HCl (aqueous). Purification was done by chromatography (silica, hexane; ethyl acetate) to yield the title compound (49%). 1H NMR (CDCl3) delta (ppm): 8.83 (s, 1H); 8.71 (s, 1H).

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 5-Aminopyrazine-2-carbonitrile, its application will become more common.

Reference:
Patent; AstraZeneca AB; NPS PHARMACEUTICALS, INC.; US2007/37820; (2007); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Related Products of 4774-14-5,Some common heterocyclic compound, 4774-14-5, name is 2,6-Dichloropyrazine, molecular formula is C4H2Cl2N2, 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.

2,6-Dichloropyrazine (360 mg, 2.4 mmol), phenylboronic acid (295 mg, 2.4 mmol), tetrakis(triphenylphosphine)palladium(0) (290 mg, 0.25 mmol), potassium carbonate (333 mg, 2.4 mmol), ethanol (1 mL), and toluene (5 mL) were combined and the mixture degassed with nitrogen for 2 minutes before heating to 80C for one hour. The reaction was partitioned between ethyl acetate and water. The aqueous layer was washed with ethyl acetate (3x), the organics were combined, dried over magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (0-30% ethyl acetate in hexanes) to give the title compound as a solid (108 mg, 0.56 mmol, 23% yield); MS (ESI) MS (ESI) m/z 191.2 [M+l]+.

These compound has a wide range of applications. It is believed that with the continuous development of the source of the synthetic route 2,6-Dichloropyrazine, its application will become more common.

Reference:
Patent; SIGNAL PHARMACEUTICALS, LLC; WO2009/89042; (2009); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Related Products of 5521-55-1, As we all know, there are many different methods for the synthesis of a compound, and people can choose the synthesis method that suits their own laboratory according to the actual situation. 5521-55-1 name is 5-Methylpyrazine-2-carboxylic acid, This compound is widely used in many fields, so it is necessary to find a new synthetic route. The downstream synthesis method of this compound is introduced below.

Weigh 3.0g (7.38mmol) GK and 1.22g (8.86mmol, 1.2eq)The 5-methylpyrazine-2-carboxylic acid was dissolved in 50 mL of acetonitrile and mixed in an ice bath with stirring.Then 0.09 g (1.48 mmol, 0.1 eq) of 4-dimethylaminopyridine (DMAP) and1.84 g (9.59 mmol, 1.3 eq) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl),After stirring in an ice bath for 1 hour, the mixture was reacted at 20C for 4 hours, and the solvent was removed by rotary evaporation.The crude product was dissolved in ethyl acetate and washed twice with 5% NaHCO3 and once with saturated brine.The organic phase is dried, filtered and concentrated.Column chromatography (V petroleum ether: V EtOAc = 2:1) gave 1.82 g of GKC as a white solid.Yield 46.91%, HPLC purity 98.96%

At the same time, in my other blogs, there are other synthetic methods of this type of compound, 5-Methylpyrazine-2-carboxylic acid, and friends who are interested can also refer to it.

Reference:
Patent; Chengdu Baiyu Pharmaceutical Co., Ltd.; Li Daxiong; Ke Hong; Fan Xiaobo; Sun Yi; (17 pag.)CN108069980; (2018); A;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Application of 4744-50-7,Some common heterocyclic compound, 4744-50-7, name is 2,3-Pyrazinecarboxylic anhydride, molecular formula is C6H2N2O3, 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.

Example 10 5-(5,7-Dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-2-(oxalyl-amino)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid; In a 4-ml scintillating vial, a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (148 mg, 0.5 mmol) in tetrahydrofuran (1.0 ml) was treated with a solution of pyrazine phthtalic acid anhydride (85 mg, 0.56 mmol) in tetrahydrofuran (1.0 ml) and N,N-dimethylformamide (0.5 ml). The reaction mixture was allowed to stir at room temperature for 1 h. Diisopropylethylamine (220 mul, 0.13 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (121 mg, 0.6 mmol) were then added. The reaction mixture was shaken vigorously for 10 seconds before being stirred at room temperature for 14 h. The volatiles were evaporated in vacuo and the residue purified by silica gel chromatography using a mixture of dichloromethane/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 25 mg (12%) of the 2-amino-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.1H NMR (300 MHz, CDCl3) delta 8.97 (s, 2H), 4.62-4.49 (m, 2H), 4.21-4.04 (m, 2H), 3.94 (dd, J=14, 4, 1H), 2.91 (d, J=17, 1H), 2.63 (dd, J=17, 10, 1H), 1.68 (s, 9H).In a 4 ml scintillating vial a solution of the above 2-amino-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (25 mg, 0.06 mmol) in tetrahydrofuran (3 ml) was treated with midazol-1-yl-oxo-acetic acid tert-butyl ester (0.36 mmol). After stirring for 3 hours at room temperature the reaction solution was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of hexanes/ethyl acetate (3:1) as eluant. Pure fractions were collected and the solvent evaporated in vacuo affording 31 mg (95%) of 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.1H NMR (300 MHz, CDCl3) delta 12.49 (s, 1H), 8.96 (s, 2H), 4.80-4.61 (m, 2H), 4.21-4.04 (m, 2H), 3.96 (dd, J=14, 4, 1H), 3.03 (d, J=16, 1H), 2.70 (dd, J=17, 10, 1H), 1.60 (s, 9H), 1.59 (s, 9H).In a 25 ml round bottom flask the above 2-(tert-butoxyoxalyl-amino)-5-(5,7-dioxo-5,7-dihydro-pyrrolo[3,4-b]pyrazin-6-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester, (31 mg, 0.06 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (4 ml). The solution was left open to the atmosphere without stirring for 24 h. A precipitate was filtered off and washed with diethyl ether, affording after drying 22 mg (90%) of the title compound as a solid.1H NMR (300 MHz, DMSO-d6) delta 12.31 (s, 1H), 9.02 (s, 2), 4.81-4.59 (m, 2H), 3.97-3.81 (m partially obscured by water, 3H), 3.08 (d, J=18, 1H), 2.74-2.53 (m partially obscured by DMSO, 1H).HPLC (254.4 nm) Rt=2.97 min, 89%.MS (APCI) [M-H] 432.4

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-Pyrazinecarboxylic anhydride, its application will become more common.

Reference:
Patent; Novo Nordisk A/S; US7115624; (2006); B1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Reference of 61655-72-9, A common heterocyclic compound, 61655-72-9, name is 6-Chloro-N,N-dimethylpyrazin-2-amine, molecular formula is C6H8ClN3, 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.

EXAMPLE 24 6-(N,N-dimethylamino)-2-(1-piperazinyl)pyrazine dihydrochloride Twenty millimoles (3.14 g.) of 6-(N,N-dimethylamino)-2-chloropyrazine and piperazine (3 g.) are fused under N2 at 135° for 6 hours. The mixture is digested with water and after filtering to remove insolubles, is basified with 10 N sodium hydroxide and extracted with chloroform. The combined chloroform extracts are washed with 2 N sodium hydroxide, dried (sodium sulfate, anhyd.), filtered, and concentrated to an oil under reduced pressure. The product is isolated as the dihydrochloride salt, m.p. 249°-250°, from isopropanol.

The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.

Reference:
Patent; Merck & Co., Inc.; US4081542; (1978); A;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem

Synthetic Route of 22047-25-2, 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 22047-25-2 as follows.

1) 1-(6-Chloro-3-pyridazinyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid methyl ester Under cooling to -78C, lithium bis(trimethylsilyl) amide(a 1.0 M solution in tetrahydrofuran, 55.0 mL) was added to a solution of 1-(2-pyrazinyl)-1-ethanone (6.10 g) in tetrahydrofuran (50 mL), and the resultant mixture was stirred for 45 minutes. Dimethyl oxalate (8.85 g) was added to the reaction solution, and the mixture was stirred for 10 minutes. Then, while slowly returning the temperature of the mixture to room temperature, the mixture was stirred for 2.5 hours. Diethyl ether and water were added to the reaction solution, and the mixture was partitioned. An aqueous 1 N hydrochloric acid solution (55 mL) was added to the aqueous layer, and the aqueous layer was further saturated with sodium chloride, and then extracted with diethyl ether. The organic layers were combined and dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and 4-(2-pyrazinyl)-2, 4-dioxobutanoic acid methyl ester (10.0 g, 96%) was obtained as a solid. To a suspension of a crude product of this butanoic acid methyl ester product (6.27 g) in methanol (150 mL), 3-chloro-6-hydrazinopyridazine (4.35 g) was added, and the mixture heated to reflux for 18.5 hours. Concentrated hydrochloric acid (0. 750 mL) was further added to the reaction solution, and the mixture was heated to reflux for 2 hours. After air cooling, ethyl acetate and a saturated aqueous solution of sodium hydrogen carbonate were added to the reaction solution, and the mixture was partitioned. The organic layer was dried over anhydrous sodium sulfate. After separation by filtration, the solvent was evaporated under reduced pressure, and methanol was added to the residue thus obtained. The precipitated solid was filtered, and 1-(6-chloro-3-pyridazinyl)-5-(2-pyrazinyl)-1H-pyrazole-3-carboxylic acid methyl ester (5.74 g, 60%) was obtained as a solid. 1H-NMR(400MHz, CDCl3)delta: 4. 02 (3H, s), 7.33(1H, s), 7.72(1H, d, J=9.3Hz), 8.16(1H, d, J=9.0Hz), 8.42(1H, dd, J=2.4, 1.5Hz), 8.57(1H, d, J=2.7Hz), 8.90(1H, d, J=1.5Hz). ESI-MSm/z: 317[(M+H)+, 35Cl], 319[(M+H)+, 37Cl].

According to the analysis of related databases, 22047-25-2, the application of this compound in the production field has become more and more popular.

Reference:
Patent; DAIICHI PHARMACEUTICAL CO., LTD.; EP1785418; (2007); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem