* 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] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 2, p. 450 - 453
2
[ 67-56-1 ]
[ 34604-60-9 ]
[ 13924-95-3 ]
Yield
Reaction Conditions
Operation in experiment
65%
Stage #1: at -20℃; for 0.5 h; Stage #2: for 2 h; Reflux
Preparation 405-Hvdroxy-pyrazine-2-carboxylic acid methyl esterThionyl chloride (152ml_, 2.08mol) was added dropwise at -20 °C to methanol (5L). After the addition was completed, the mixture was stirred at this temperature for 30 minutes. Then 5- hydroxy-pyrazine-2-carboxylic acid (100g, 714mmol) was added, and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was recrystallised from methanol (400ml_) to give 71 g (464mmol) of the title compound in 65percent yield.
61%
With hydrogenchloride In 1,4-dioxane; water at 60 - 80℃; for 4 h;
(62a) Methyl 5-hydroxypyrazine-2-carboxylate Commercially available 5-hydroxypyrazine-2-carboxylic acid (1.00 g, 7.14 mmol) was dissolved in methanol (5 mL), and a 4N hydrochloric acid/dioxane solution (25 mL) was added, followed by stirring at 60°C for 1.5 hours and heating to reflux at 80°C for 2.5 hours. The reaction solution was brought back to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate (20 mL) was added to the resulting residue to allow it to be suspended. The resulting precipitate was filtered off, and washed with ethyl acetate, followed by vacuum drying, to afford the desired compound (673 mg, yield 61percent) as an orange-brown solid. 1H-NMR (CD3OD, 400 MHz): δ 3.31 (1H, s), 3.85 (3H, s), 8.00 (1H, d, J=1.2 Hz), 8.13 (1H, d, J=1.2 Hz).
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 407 - 408
5
[ 82619-62-3 ]
[ 34604-60-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 407 - 408
6
[ 82619-63-4 ]
[ 34604-60-9 ]
Reference：
[1] Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 407 - 408
7
[ 34604-60-9 ]
[ 36070-80-1 ]
Yield
Reaction Conditions
Operation in experiment
93%
With thionyl chloride In N,N-dimethyl-formamide at 80℃; for 16 h;
Step 1: Preparation of 5-chloropyrazine-2-carboxylic acid [0170] To a solution 5-hydroxypyrazine-2-carboxylic acid (10 g, 71.42 mmol) in thionyl chloride (100 mL) was added N, N- dimethyl formamide (1 mL) and the reaction mixture was stirred at 80 °C for 16 h. Thionyl chloride was distilled off, the residue was diluted with ice water and extracted ethyl acetate (600 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was triturated with diethyl ether to afford the title compound 5-chloropyrazine-2-carboxylic acid (10.53 g, 93percent yield) as a brown solid. Calculated M+H: 158.99; Found M+H: 159.0.
75%
for 16 h; Reflux
Intermediate 44; 5-Chloropyrazine-2-carboxylic acid; 5-Hydroxypyrazine-2-carboxylic acid (1.0 g, 0.007 mol) was taken in thionyl chloride (10 mL), to this solution dimethylformamide (0.1 mL) was added which was heated to reflux for 16 h. After this period, excess thionyl chloride was distilled off to get crude compound, which was added to ice (20 g) and extracted with ethyl acetate (2 x 70 mL). The organic layers were combined and dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain brown solid which was triturated with diethyl ether (30 mL) to afford 600 mg (75percent) of 5-chloropyrazine-2-carboxylic acid.1H NMR (400 MHz, DMSO-d): δ 8.94 (s, IH), 9.04 (s, IH), 13.92 (s, IH). Mass (APCI): m/z 157.0 (M-H).
Reference：
[1] Patent: WO2015/48507, 2015, A1, . Location in patent: Paragraph 0170
[2] Patent: WO2010/67123, 2010, A1, . Location in patent: Page/Page column 183
[3] European Journal of Medicinal Chemistry, 2015, vol. 101, p. 692 - 704
8
[ 34604-60-9 ]
[ 36070-80-1 ]
Reference：
[1] Organic Process Research and Development, 2018, vol. 22, # 2, p. 241 - 246
9
[ 34604-60-9 ]
[ 21279-64-1 ]
Reference：
[1] Bioorganic and Medicinal Chemistry Letters, 2014, vol. 24, # 2, p. 450 - 453
With thionyl chloride;N,N-dimethyl-formamide; for 4h;Heating / reflux;Product distribution / selectivity;
Reflux a mixture of 5-Hydroxy-pyrazine-2-carboxylic acid (6.568 g, 46.88 mmol), thionyl chloride (51 mL, 703.2 mmol), and DMF (0.50 mL) for 4 h. Cool the mixture to room temperature, concentrate in vacuo, and pump on high vacuum for 3 h. Dilute the mixture with MeOH (25 mL) and add pyridine (4.5 mL, 55.7 mmol). Stir the mixture overnight at room temperature. Adsorb the reaction mixture onto silica gel and subject the mixture to flash column chromatography (330 g column, 25%-60% ethyl acetate/n-hexane) to yield the desired product (7.380 g, 91%). mass spectrum (m/e): 173.0 (M+l).
With thionyl chloride; N,N-dimethyl-formamide; In toluene; for 1h;Reflux;
General procedure: 5-Chloropyrazine-2-carboxamide (1). 5.0 g of <strong>[34604-60-9]5-hydroxypyrazine-2-carboxylic acid</strong> (0.036 mol) was suspended in 50 mL of dry toluene and treated with thionyl chloride (3 eq., 7.9 mL, 0.108 mol). DMF (10 drops) was added to the reaction mixture as a catalyst. The reaction mixture was heated to reflux for about 1 h. The excess of thionyl chloride was removed by repeated evaporation with dry toluene in vacuo.
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 100℃; for 1h;
5-Hydroxypyrazine-2-carboxylic acid (5-OH-POA, 300 mg, 2.14 mmol) was dispersed in dry toluene (approx. 30 mL). Thionyl chloride (SOCl2, approximately 1.0 mL, 14 mmol) was added to the reaction mixture, followed by a catalytic amount (1-2 drops) of N,N-dimethylformamide (DMF). The reaction mixture was heated and stirred in an oil bath under a condenser at 100 C for approx. 1 h. During the course of reaction the starting solid 5-OH-POA dissolved (chemically changed) and the reaction mixture turned brown-red. When no further conversion of the solid could be observed (usually there was a small amount of dark solid particles left), the solvents were decanted from the dark residue and concentrated in vacuo. To remove the unreacted SOCl2, the residue was azeotroped with dry toluene (3 × 20 mL). The crude 5-chloropyrazine-2-carbonyl chloride product , obtained in the form of brown-red viscous liquid, was diluted with dry acetone (10 mL) and added dropwise to the stirred solution of respective aniline (1.71 mmol, 0.8 molar equivalents) and triethylamine (433 mg, 4.18 mmol, 2 molar equivalents) in dry acetone (20 mL). The product precipitated from the reaction mixture. The mixture was stirred at laboratory temperature for 30 min and the completeness was checked by TLC (silica 60 F254, hexane-EtOAc 3:1). The reaction mixture was adsorbed to silica by removing the solvents in vacuo and the product was purified by flash chromatography (silica, 0%-25% EtOAc in hexane gradient elution) and recrystallized from EtOH/H20 if needed. Note: For compounds with higher polarity, e.g., compounds 2-4 and 30, it was necessary to increase the strength of the mobile phase for flash chromatography. Usually gradient elution 0%-60% EtOAc in hexane was sufficient, although for compound 30 we had to use EtOAc with 10% of MeOH.
With thionyl chloride; N,N-dimethyl-formamide; at 75℃; for 4h;
5-Hydroxypyrazine-2-carboxylic acid (2 mmol) was suspended in 6 mL of thionyl chloride and 200 muL of N,N-dimethylformamide (DMF) was added. The mixture was heated at 75 C for 4 h. After this period, excess of thionyl chloride was distilled off to get crude compound and the reaction intermediate was hydrolysed according to previously described procedure [33] to obtain 5-chloropyrazine-2-carboxylic acid 1.
With thionyl chloride; N,N-dimethyl-formamide; In toluene; at 100℃; for 1.16667h;
General procedure: A suspension of 0.308 g (2.2 mmol) 5-hydroxy-2-pyrazine carboxylic acid, 1.666 g (14.0 mmol)thionyl chloride, and 2 drops of DMF in 30 ml of drytoluene was heated at 100 C 70 min. The reaction mixturewas cooled, filtrated, and evaporated under reduced pressure.The red oil residue was dissolved in 10 ml of drydichloromethane and added dropwise to a cold solution(0 C) of corresponding amine (1.7 mmol) and 0.404 g(4.0 mmol) TEA in 20 ml of dry dichloromethane. Thereaction mixture was stirred 30 min and evaporated underreduced pressure. Products 4a-f were purified by columnchromatography or by crystallization.
1,2-diamino-1,2-dicyanoethylene (25 g) and glyoxylic acid monohydrate (21.3 g) were dissolved in 2N-hydrochloric acid (240 ml), and the solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure. To the residue, an aqueous 10% sodium hydroxide solution (600 ml) was added and, after heating at reflux for 13 hours, the reaction solution was ice-cooled and neutralized with concentrated hydrochloric acid. The resulting ocher precipitate was collected by filtration and then washed with water and acetone. The crude product was suspended in acetic acid (800 ml) and heated at reflux at 120C for 2 hours. The reaction mixture was returned to room temperature and filtered, and then the filtrate was concentrated. The resulting precipitate was collected by filtration and washed with ether. After ice cooling methanol (600 ml), thionyl chloride (60 ml) was added dropwise, followed by stirring at room temperature for one hour, the addition of the crude product and further stirring at 80C. The reaction solution was concentrated and then purified by silica gel column chromatography (chloroform:methanol = 10:1 to 5:1) to obtain the objective product (8.0 g).
Preparation 405-Hvdroxy-pyrazine-2-carboxylic acid methyl esterThionyl chloride (152ml_, 2.08mol) was added dropwise at -20 C to methanol (5L). After the addition was completed, the mixture was stirred at this temperature for 30 minutes. Then 5- hydroxy-pyrazine-2-carboxylic acid (100g, 714mmol) was added, and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was recrystallised from methanol (400ml_) to give 71 g (464mmol) of the title compound in 65% yield.
61%
With hydrogenchloride; In 1,4-dioxane; water; at 60 - 80℃; for 4h;
(62a) Methyl 5-hydroxypyrazine-2-carboxylate Commercially available 5-hydroxypyrazine-2-carboxylic acid (1.00 g, 7.14 mmol) was dissolved in methanol (5 mL), and a 4N hydrochloric acid/dioxane solution (25 mL) was added, followed by stirring at 60C for 1.5 hours and heating to reflux at 80C for 2.5 hours. The reaction solution was brought back to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate (20 mL) was added to the resulting residue to allow it to be suspended. The resulting precipitate was filtered off, and washed with ethyl acetate, followed by vacuum drying, to afford the desired compound (673 mg, yield 61%) as an orange-brown solid. 1H-NMR (CD3OD, 400 MHz): delta 3.31 (1H, s), 3.85 (3H, s), 8.00 (1H, d, J=1.2 Hz), 8.13 (1H, d, J=1.2 Hz).
With thionyl chloride; at 80℃;
1,2-diamino-1,2-dicyanoethylene (25 g) and glyoxylic acid monohydrate (21.3 g) were dissolved in 2N-hydrochloric acid (240 ml), and the solution was stirred at room temperature for 4 hours and then concentrated under reduced pressure. To the residue, an aqueous 10% sodium hydroxide solution (600 ml) was added and, after heating at reflux for 13 hours, the reaction solution was ice-cooled and neutralized with concentrated hydrochloric acid. The resulting ocher precipitate was collected by filtration and then washed with water and acetone. The crude product was suspended in acetic acid (800 ml) and heated at reflux at 120C for 2 hours. The reaction mixture was returned to room temperature and filtered, and then the filtrate was concentrated. The resulting precipitate was collected by filtration and washed with ether. After ice cooling methanol (600 ml), thionyl chloride (60 ml) was added dropwise, followed by stirring at room temperature for one hour, the addition of the crude product and further stirring at 80C. The reaction solution was concentrated and then purified by silica gel column chromatography (chloroform:methanol = 10:1 to 5:1) to obtain the objective product (8.0 g).
The 5-chloro-N- 5- [ (cyclopropylamino) carbonyl]-2-methylphenyl}-2- pyrazinecarboxamide used as starting material was prepared as follows:- To <strong>[34604-60-9]5-hydroxypyrazine-2-carboxylic acid</strong> (1 g, 1.14 mmol) was added phosphorous oxychloride (10 mL) and phosphorous pentachloride (4.91 g). After the initial reaction had subsided the mixture was heated to 100C and stirred for 16h. The mixture was cooled and formic acid (347 mL, 9.19 nunol) was added to convert all excess phosphorous pentachloride to phosphorous oxychloride then the excess phosphorous oxychloride was carefully evaporated off to give a residue which was dissolved in DCM (50 mL). Triethylamine (10 mL) and 3-amino-N-cyclopropyl-4-methylbenzamide (1.307 g) were added and the resulting mixture stirred at room temperature for 16h. The solvent was evaporated under reduced pressure and the residue purified on a 20 g silica chromatography column, eluting with 20 % methanol/1% ammonium hydroxide SG 0.88 in ethyl acetate. The crude product was dissolved in DCM and washed with saturated aqueous sodium bicarbonate and evaporated to dryness to give the title compound as a solid (1.24g, 52.6%) ; NMR Spectrum: (DMSOd6) 0.62 (m, 2H), 0.74 (m, 2H), 2.37 (s, 3H), 2.91 (m, 1H), 7.41 (m, 1H), 7. 70 (m, 1H), 8.05 (m, 1H), 8.44 (m, 1H), 9.02 (m, 1H), 9.18 (m, 1H), 10.44 (s, 1H) ; Mass Spectrum : M-H-329.
With thionyl chloride; In N,N-dimethyl-formamide; at 80℃; for 16h;
Step 1: Preparation of 5-chloropyrazine-2-carboxylic acid [0170] To a solution 5-hydroxypyrazine-2-carboxylic acid (10 g, 71.42 mmol) in thionyl chloride (100 mL) was added N, N- dimethyl formamide (1 mL) and the reaction mixture was stirred at 80 C for 16 h. Thionyl chloride was distilled off, the residue was diluted with ice water and extracted ethyl acetate (600 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude was triturated with diethyl ether to afford the title compound 5-chloropyrazine-2-carboxylic acid (10.53 g, 93% yield) as a brown solid. Calculated M+H: 158.99; Found M+H: 159.0.
75%
With thionyl chloride;N,N-dimethyl-formamide; for 16h;Reflux;
Intermediate 44; 5-Chloropyrazine-2-carboxylic acid; 5-Hydroxypyrazine-2-carboxylic acid (1.0 g, 0.007 mol) was taken in thionyl chloride (10 mL), to this solution dimethylformamide (0.1 mL) was added which was heated to reflux for 16 h. After this period, excess thionyl chloride was distilled off to get crude compound, which was added to ice (20 g) and extracted with ethyl acetate (2 x 70 mL). The organic layers were combined and dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain brown solid which was triturated with diethyl ether (30 mL) to afford 600 mg (75%) of 5-chloropyrazine-2-carboxylic acid.1H NMR (400 MHz, DMSO-d): delta 8.94 (s, IH), 9.04 (s, IH), 13.92 (s, IH). Mass (APCI): m/z 157.0 (M-H).
Et3N (4.17 mL, 29.9 mmol) and mesyl chloride (1.57 mL, 20.3 mmol) were added to a solution of (5-chloro-2-pyrazinyl)methanol (45) (obtained by chlorination and reduction of 5-hydroxypyrazine-2-carboxylic acid, as reported by Kiener et al., 1994) (1.443 g, 9.98 mmol) in anhydrous THF (20 mL) at 0 0C. The mixture was stirred at 0 0C for 0.5 h, then partitioned between EtOAc and water. The organic fraction was dried (MgSO4) and the solvent was removed under reduced pressure to give the crude mesylate. The mesylate was dissolved in acetone (40 mL), sodium iodide (7.5 g, 50 mmol) was added, and the mixture was refluxed for 1 h. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic fraction was concentrated under reduced pressure and the residue was chromatographed on silica gel (eluting with CH2Cl2) to give 2-chloro-5- (iodomethyl)pyrazine (46) (1.54 g, 61%), which was used immediately due to its instability
Stepl: Synthesis of 1-16.A solution of R14 (2.0 g, 14.3mmol) and thionyl chloride (10.0 mL) with a catalytic amount of DMF is refluxed for 4 hours. The solvent is removed under reduced pressure, MeOH (10.0 mL) and pyridine (1.4 mL, 17.1 mmol) are slowly added and the mixture is stirred overnight at room temperature. The solvent is removed under reduced pressure, the crude is purified via silica gel column chromatography to afford 1-16 (1.12 g); m/z 173 [M+H].
Synthesis of (5-{3-ri-(6-Chloro-pyridin-3-yl)-cvclobutyl1-l,2,4-oxadiazol-5-yl}- pyrazin-2-yl)-(2-methoxy-ethyl)-amine (Intermediate 1-4.12)Step 1: synthesis of 5-chloro-pyrazine-2-carboxylic acid methyl ester (R24)R23 (2.00 g, 14.3 mmol) is treated with R12 (10.0 mL) and to the resulting mixture is added DMF (0.1 mL) dropwise. The reaction mixture is then heated at reflux for 4 hours.The solvent is removed in vacuo and the residue is treated with methanol (10.0 mL) and pyridine (1.39 mL, 17.1 mmol) and the resulting mixture is stirred overnight. The solvent is removed in vacuo and the residue is purified by flash chromatography (Si02, 20% ethyl acetate/cyclohexane) to give R24 (1.12 g); m/z 173 [M+H].
Example 121 Step-1 : 5-Chloro-N-(2,6-difluorophenyl)pyrazine-2-carboxamide: A mixture of 5- hydroxypyrazine-2-carboxylic acid (500 mg, 3.57 mmol, 1.0 eq), thionyl chloride (5 mL) and DMF (0.3 mL) was refluxed for 15 h. The excess of thionyl chloride was removed under vacuum and the residue was taken in THF (5 mL). The resulting mixture was cooled to 0 C and a solution of 2,6-difluoroaniline (0.58 mL, 5.35 mmol, 1.5 eq) was added to the above mixture followed by triethyl amine (0.75 mL, 5.35 mmol, 1.5 eq). After stirring for 3 h at room temperature, the reaction was diluted with ethyl acetate (15 mL). The organic layer was washed with water (10 mL), 2N HC1 (10 mL), dried (Na2S04) and filtered. The filtrate was concentrated under vacuum. The crude product was purified with flash column chromatography (silica gel, ethyl acetate and hexane system as eluent) to afford 500 mg of the title product as a white solid. 1HNMR (400 MHz, DMSO-c¾) delta 10.67 (s, 1H, D20 exchangeable), 9.1 1 (s, 1H), 9.98 (s, 1H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 2H); ESI-MS (m/z) 270, 272 [(MH)+, CI 35> 37]
Example 45 Preparation of (S)-2-[5-(3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-3-[(5-hydroxy-pyrazine-2-carbonyl)-amino]-propionic acid (S)-3-amino-2-[5-(3-hydroxy-benzylcarbamoyl)-3-methyl-thiophene-2-carbonyl]-amino}-propionic acid methyl ester (HCl salt) (100 mg, 0.23 mmol) was dissolved in DMF (2.5 ml) and the following reagents were successively added at rt: <strong>[34604-60-9]5-hydroxy-pyrazine-2-carboxylic acid</strong> (33 mg, 0.23 mmol), triethylamine (0.10 ml, 0.70 mmol), HOBT (38 mg, 0.28 mmol), and HBTU (110 mg, 0.28 mmol). The mixture was stirred at rt for 0.5 h, then quenched with pH 7 buffer and extracted with EtOAc. The layers were separated. The organic layer was successively washed with water and brine, then dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 100% EtOAc and then 10% MeOH in EtOAc to afford the desired methyl ester (32 mg, 27% yield), This ester was dissolved in THF/water (2 ml/1 ml) and treated with LiOH.H2O (26 mg, 0.6 mmol) at 40 C. for 1.5 h. The mixture was quenched with 1N HCl and concentrated. The crude was purified by reverse phase HPLC to afford the desired product (5 mg, 17% yield). MS m/e 499.9 (M+H+).
Intermediate 95-Ch[oro-N-methy[pyrazine-2-carboxamide 5-Hydroxypyrazine-2-carboxy[ic acid [CAS RN: 34604-60-9] (500 mg, 3.57 mmo[,1.0 eq) was treated with thiony[ ch[oride (3.90 mL, 53.5 mmo[, 15 eq) and 0.04 mLDMF. Then, the reaction mixture was heated to ref[ux temperature for 4 h. On coo[ing, the vo[ati[e components were removed in vacuo. The crude materia[ remaining was di[uted with to[uene and the resu[ting so[ution was concentrated by the use of a rotary evaporator. This procedure was repeated two more times. Then, the remaining materia[ was treated with 4 m[ DMF and with 2-methoxy-N-methy[ethanamine [CAS-RN: 38256-93-8] (795 mg, 8.92 mmo[, 2.5 eq). The reactionmixture was stirred at rt overnight. The vo[ati[e components were removed invacuo and the crude materia[ was purified via preparative MPLC (Biotage Iso[era;25 g SNAP cartridge: hexane -> hexane/ethy[ acetate 2/1 -> ethy[ acetate ) to give300 mg (49% yie[d of theory) of the tit[e compound.UPLC-MS (Method 1): R = 0.64 mm; MS (EI0): m/z = 172 [M+H]÷.1H-NMR (400 MHz, DMSO-d6): oe [ppm] = 2.82 (d, 3H), 8.85 (d, 1H), 8.89 (m, 1H),8.98 (d, 1H).
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