Structure of 642459-09-4
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CAS No. : | 642459-09-4 |
Formula : | C7H5ClN4 |
M.W : | 180.59 |
SMILES Code : | ClC1=NC(N2N=CC=C2)=CN=C1 |
MDL No. : | MFCD09800958 |
InChI Key : | WGFZJZXNZJZULL-UHFFFAOYSA-N |
Pubchem ID : | 10035227 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With potassium carbonate; In N,N-dimethyl acetamide; at 50℃; for 2h;Sealed tube; | To a 40 mL vial was added 2,6-dichloropyrazine (4.0 g, 26.9 mmol), lH-pyrazole (1.8 g, 26.9 mmol), potassium carbonate (7.4 g5 53.7 mmol), and 10 mL of N,N-dimethylacetamide. The reaction was capped and shaken at 50C for 2 hours, then cooled to room temperature and diluted with ethyl acetate. The organic was then washed with water, and concentrated under reduced pressure. The crude product was purified by flash column (10-35% Ethyl Acetate : Heptanes) yielding title compound as a white solid (1.51 g, 31%). 1H NMR (400 MHz, DMSO- d6) δ 9.24 - 9.12 (m, 2H), 8.80 - 8.68 (m, 2H), 8.68 - 8.54 (m, 2H)5 7.96 (dd, J = 1.7, 0.7 Hz, 2H), 6.74 - 6.63 (m, 2H), 3.38 - 3.24 (m, 1H). LCMS M/Z (M+H) 281. |
EXAMPLE 30 General Synthetic Procedure H Preparation of 2-Chloro-6-pyrazol-1-yl-pyrazine To NaH (0.15 mg, 3.70 mmol, 1.1 eq. ) in DMSO (1.5 ml) was added the pyrazole (0.23 ml, 3.36 mmol) in DMSO (1.5 ml) and the reaction mixture was stirred for 30 minutes. 2,6-dichloropyrazine (0.5 g, 3.36 mmol, 1 eq. ) was then added and the reaction was allowed to stir at room temperature for 30 minutes before being heated to 100 C for 5 hours. The reaction was quenched with water and the product extracted with EtOAc (x2). The combined organic layers were washed again with water, then brine and dried over MgS04. The product was filtered, evaporated to dryness and purified by column chromatography to yield the product. LCMS 3.20 min, m/z [M+H] + 181. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
7% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃;Microwave irradiation; Inert atmosphere; | Example 64N- (3,4-Dif [uoropheny[)-3-methy[-5-[6- (1 H-pyrazo[- 1 -y[)pyrazin-2-y[]aminol- 1 ,2- thiazo[e-4-carboxamide A mixture of 5-amino-N-(3,4-dif[uoropheny[)-3-methy[-1 ,2-thiazo[e-4-carboxamide [Intermediate 3] (150 mg, 0.56 mmo[, 1.0 eq), 2-ch[oro-6-(1H-pyrazo[-1-y[)- pyrazine [CAS RN: 642459-09-4; for the synthesis, see a[so: WO 2004/4730, 2004 (Astex Techno[ogy, Ltd.)] (80 mg, 0.45 mmo[, 0.8 eq) and cesium carbonate (417mg, 1.28 mmo[, 2.3 eq) in 4.5 mL dioxane/DMF (7/1) was p[aced in a microwave via[ and f[ushed with argon. Then, pa[[adium(II) acetate (13 mg, 0.06 mmo[, 0.1 eq) and Xantphos (32 mg, 0.06 mmo[, 0.1 eq) were added. The via[ was capped and the reaction mixture was stirred at an environmenta[ temperature of 110 C overnight. On coo[ing, the vo[ati[e components were removed in vacuo. The crude materia[was disso[ved in a sma[[ amount DM50 and fi[tered. Purification was conducted via preparative HPLC (method A) to give 18 mg (7 % yie[d of theory) of the tit[e compound.UPLC-MS (Method 2): R = 0.83 mm; MS (Elneg) m/z = 402 [M-H].1H-NMR (400 MHz, DMSO-d6): ö [ppm] = 2.47 (s, 3H), 6.75 (t, 1H), 7.39-7.51 (m,2H), 7.89-8.02 (m, 2H), 8.63 (s, 1H), 8.67-8.73 (m, 2H), 10.54 (s br, 1H), 11.23 (s br, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
3% | With palladium diacetate; caesium carbonate; 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; In 1,4-dioxane; N,N-dimethyl-formamide; at 110℃;Microwave irradiation; Inert atmosphere; | Example 67N- (4-Ch[oro-3-f [uoropheny[)-3-methy[-5-[6- (1 H-pyrazo[- 1 -y[)pyrazin-2-y[]aminol- 1 ,2-thiazo[e-4-carboxamide A mixture of 5-amino-N-(4-ch[oro-3-f[uoropheny[)-3-methy[-1 ,2-thiazo[e-4-carbox- amide [Intermediate 4] (150 mg, 0.53 mmo[, 1.0 eq), 2-ch[oro-6-(1H-pyrazo[-1-y[)- pyrazine [for the synthesis, p[ease see: WO 20044730, 2004 (Astex Techno[ogy Ltd.)] (95 mg, 0.53 mmo[, 1.0 eq) and cesium carbonate (393 mg, 1.21 mmo[, 2.3 eq) in 5.4 mL dioxane/DMF (7/1) was p[aced in a microwave via[ and f[ushedwith argon. Then, pa[[adium(II) acetate (12 mg, 0.05 mmo[, 0.1 eq) and Xantphos (30 mg, 0.05 mmo[, 0.1 eq) were added. The via[ was capped and the reaction mixture was stirred at an environmenta[ temperature of 110 C overnight. On coo[ing, the vo[ati[e components were removed in vacuo. The crude materia[ was treated with DM50 and fi[tered. The crude materia[ was purified via preparativeHPLC (method A) to give 6 mg (3 % yie[d of theory) of the tit[e compound.UPLC-MS (Method 1): R = 1.34 mm; MS (ESIneg) m/z = 428 [M-H].1H-NMR (400 MHz, DMSO-d6): ö [ppm] = 2.46 (s, 3H), 6.75 (dd, 1H), 7.51 (dd, 1H),7.59 (t, 1H), 7.95 (dt, 2H), 8.62 (s, 1H), 8.70 (s br, 2H), 10.64 (s, 1H), 11.24 (s br,1 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With N-ethyl-N,N-diisopropylamine; at 90℃;Sealed tube; | To a 4 mL vial was added 6-allyl-N-methyl-7-oxo-N-(4-piperidyl)-lH-pyrrolo[2,3-c]pyridine-4- carboxamide hydrochloride (40 mg, 0.1 1 mmol) followed by 2-chloro-6-pyrazol-l-yl-pyrazine (21mg, 0.1 1 mmol), diisopropylethylamine (0.08 mL, 0.46 mmol), and 0.16 mL. The reaction was capped and shaken at 90C overnight. The reaction was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic was concentrated under reduced pressure, and the residue was purified by HPLC (20-60%ACN/0.1%NH4OH in H20) yielding title compound (10 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ 12.15 (s, 1H), 8.59 (dd, J - 2.6, 0.7 Hz, 1H), 8.38 - 8.17 (m, 2H), 7.82 (dd, J = 1.7, 0.7 Hz, 1H), 7.42 - 7.21 (m, 2H), 6.57 (dd, J = 2.6, 1.7 Hz, 1H), 6.25 (dd, J = 2.8, 1.5 Hz, 1H), 6.07 - 5.89 (m, 1H), 5.24 - 5.13 (m, 1H), 5.13 - 5.02 (m, 1H), 4.67 - 4.61 (m, 2H), 4.57 (d, J - 13.2 Hz, 2H), 4.35 (s, 1H), 3.04 - 2.86 (m, 2H), 2.81 (s, 3H), 1.95 - 1.68 (m, 4H). LCMS M/Z (M+H) 459. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
60% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 1h; | l,4-Dioxa-8- azaspiro[4.5]decane (1.56 g, 10.9 mmol), 2-chloro-6-(lH-pyrazol-l-yl)pyrazine (1.80 g, 9.96 mmol), and potassium carbonate (2.75 g, 19.9 mmol) were combined in DMF (10 mL) and heated to 90 C for lh. The reaction was cooled to room temperature and diluted with ethyl acetate and brine. The organic layer was washed with brine 3 more times. The organic extracts were dried over Na2S04, filtered, and concentrated. This material was then dissolved in 20 mL of acetone and treated with 20 mL of IN HC1. The reaction mixture was heated to 50 C overnight. The organic solvent was removed under reduced pressure and the pH was adjusted to 12 with 6N NaOH solution. The product was extracted with DCM. The residue was taken up in DCM and the organic layer was washed with saturated NaHCO3, solution.The organic layer was then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 80g silica cartridge; 0-75% ethyl acetate in heptanes) to afford the title compound (1.45 g, 60%). LCMS: m/z =244.1 [M+l]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With potassium carbonate; In N,N-dimethyl acetamide; at 90℃; for 1h; | 4- phenylpiperidin-4-ol (42.1 mg, 238 mmol), 2-chloro-6-(lH-pyrazol-l-yl)pyrazine (36 mg, 199 pmol), and potassium carbonate (55.0 mg, 398 pmol) were combined in DMA (500 pL) and heated to 90 C for lh. The reaction was cooled to RT and directly purified by reverse phase chromatography (Biotage 30g C18 cartridge; 5-90% ACN in water + 0.1% TFA). The fractions containing product were concentrated. The residue was taken up in DCM and the organic layer was washed with saturated aqueous NaHCO3 solution. The organic layer was then dried over Na2S04, filtered and concentrated to afford the title compound (23.7 mg, 37%). LCMS: m/z = 322.2 [M+l] |
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