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CAS No. : | 6274-22-2 | MDL No. : | MFCD00665792 |
Formula : | C8H10N2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | XAGFYNSCWICYPA-UHFFFAOYSA-N |
M.W : | 150.18 | Pubchem ID : | 235516 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.12 |
Num. rotatable bonds : | 2 |
Num. H-bond acceptors : | 1.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 43.84 |
TPSA : | 55.12 Ų |
GI absorption : | High |
BBB permeant : | Yes |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -6.9 cm/s |
Log Po/w (iLOGP) : | 1.23 |
Log Po/w (XLOGP3) : | 0.44 |
Log Po/w (WLOGP) : | 0.64 |
Log Po/w (MLOGP) : | 0.91 |
Log Po/w (SILICOS-IT) : | 0.65 |
Consensus Log Po/w : | 0.77 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -1.32 |
Solubility : | 7.19 mg/ml ; 0.0479 mol/l |
Class : | Very soluble |
Log S (Ali) : | -1.17 |
Solubility : | 10.3 mg/ml ; 0.0683 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | -2.41 |
Solubility : | 0.588 mg/ml ; 0.00392 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.0 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* 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 |
---|---|---|
86% | With water; ammonium chloride; zinc In tetrahydrofuran; methanol | Synthesis of 4-Amino-N-methyl-benzamide Ammonium chloride (29.6 g, 55.4 mmol) in water (200 mL) and methanol (200 mL) was added to a solution of N-methyl-4-nitro-benzamide (10 g, 55.4 mmol) in THF (160 mL). Zinc powder (29 g, 44.4 mmol) was added portion wise and the mixture stirred for 15 minutes. The reaction mixture was filtered over celite, the filtrate was then concentrated and extracted with ethyl acetate. The organics were washed with brine solution, dried over Na2SO4 and concentrated to afford 7.2 g (86percent) of 4-amino-N-methyl-benzamide. 1H NMR: (DMSO-d6): δ 7.9 (s, 1H), 7.6 (d, 2H), 6.5 (d, 2H), 5.6 (s, 2H), 2.7 (s, 3H). |
84% | With hydrogen In ethanol at 20℃; for 12 h; | (b) Preparation of intermediary compound 4-amino-iV-methylbenzamide:To a solution of 7V-methyl-4-nitrobenzamide (23.0 g, 127.8 mmol) in ethanol (460 rnL) was added palladium on carbon (Pd/C, 10percent, 50percent moistened, 15.0 g). The mixture was hydrogenated under 2.0 atmospheric pressure at room temperature for 12 hours. After completion of the reaction, the reaction mixture was filtered through Celite and thoroughly washed with ethanol. The filtrate was evaporated and the residue washed with diisopropyl ether to give 16.0 g (84 percent yield) of 4-amino-N-methylbenzamide as an off-white solid. 1H-NMR (300 MHz, DMSOd6) δ 7.94 (bs, IH), 7.54 (d, J= 8.7 Hz, 2H), 6.52 (d, J= 8.7 Hz, 2H), 5.57 (s, 2H), 2.72 (d, J= 4.5 Hz, 3H). LC-MS 172.5 (M+Na). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium carbonate; In tetrahydrofuran; water; ethyl acetate; at 0 - 20℃; | General procedure: Into a stirringmixture of ethyl acetate (20 mL), tetrahydrofuran (4 mL), water(4 mL), sodium carbonate (0.8 g, 7.9 mmol, 0.6 equiv.), and 4-isopropoxyaniline (2.0 g, 13.2 mmol, 1 equiv.), phenyl chloroformate(2.3 g, 14.5 mmol, 1.1 equiv.) was added dropwise at 0 C.The reaction was stirred at room temperature overnight, then itwas evaporated under reduced pressure and the resultant wasadded into 20 mL water, the precipitate was filtered and washedwith water, then dried under vacuum to afford 3.2 g of 13a as whitesolid; yield: 90%. |
With sodium hydroxide; In 1,4-dioxane; methanol; chloroform; | (1) To a suspension of <strong>[6274-22-2]4-(methylcarbamoyl)aniline</strong> (1.0 g) in 1,4-dioxane (10 ml) were added 1N sodium hydroxide solution (13.4 ml) and phenyl chloroformate (1.26 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give phenyl 4-(methylcarbamoyl)phenylcarbamate (1.70 g) as pale yellow crystals. mp: 190-192 C., NMR (DMSO-d6, delta): 2.70 (1H, d, J=5 Hz), 2.77 (2H, d, J=5 Hz), 5.55 (0.6H, br s), 6.51 (0.9H, d, J=8 Hz), 6.71-6.80 (1.1H, m), 7.15 (0.8H, t, J=8 Hz), 7.20-7.31 (1.8H, m), 7.43 (1.2H, t, J=8 Hz), 7.50-7.60 (2H, m), 7.80 (1.2H, d, J=8 Hz), 7.92 (0.3H, br d, J=5 Hz), 8.31 (1H, br s), 9.30 (0.4H, s). | |
With sodium hydroxide; In 1,4-dioxane; water; at 20℃; for 2h; | To a suspension of <strong>[6274-22-2]4-(methylcarbamoyl)aniline</strong> (1.0 g) in 1,4-dioxane (10 ml) were added 1N sodium hydroxide solution (13.4 ml) and phenyl chloroformate (1.26 g) under ice-cooling, and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol. The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from ethyl acetate to give phenyl 4-(methylcarbamoyl)phenylcarbamate (1.70 g) as pale yellow crystals. mp: 190-192 C. NMR (DMSO-d6, delta): 2.70 (1H, d, J=5 Hz), 2.77 (2H, d, J=5 Hz), 5.55 (0.6H, br s), 6.51 (0.9H, d, J=8 Hz), 6.71-6.80 (1.1H, m), 7.15 (0.8H, t, J=8 Hz), 7.20-7.31 (1.8H, m), 7.43 (1.2H, t, J=8 Hz), 7.50-7.60 (2H, m), 7.80 (1.2H, d, J=8 Hz), 7.92 (0.3H, br d, J=5 Hz), 8.31 (1H, br s), 9.30 (0.4H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
30% | In butan-1-ol; at 20 - 35℃; for 96h;Heating / reflux; | Example 22Synthesis of N~Methyl-4-[4-(3-trifluoromethyl-pyrazol-l-yl)-quinolin-2-ylamino]- benzamide (E 22); E 22 EPO <DP n="143"/>4-Amino-N-methyl-benzamide (166 mg, 1.11 mmol) was added to a stirred solution of 2-chloro-4-(3-trifluoromethyl-pyrazol-l-yl)-quinoline (300 mg, 1.00 mmol) in 1-butanol (10 mL), under nitrogen, at room temperature. This reaction mixture was stirred under reflux for about 4 days and filtered while hot. The resulting pale brown solid was stirred in z-PrOH, filtered off, and dried to give the desired product (120 mg, 30%). Melting range: 250-252 0C1H NMR (400 MHz, DMSO) delta 10.02 (-NH, D2O exchangeable, IH), 8.28-8.27 (d, J=4.50 Hz, IH), 8.06 (d, J=8.59 Hz, 2H), 7.91-7.41 (m, 6H), 7.32 (s, IH), 7.19-7.18 (d, J=2.41 Hz, IH), 2.79 (s, 3H). IR (cm"1): 3203, 2690, 1667, 1608 MS (m/z): 412 (M+, 100%) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With triethylamine; In tetrahydrofuran; at 0℃; for 1h; | Thiophosgene (1.13 ml, 1.1 eq) is added dropwise to a solution cooled down to 0 C., of <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (2 g, 1 eq) and triethylamine (5.6 ml, 3 eq) in tetrahydofuran (260 ml). The mixture is stirred for 30 minutes at 0 C. then the cold bath is removed and stirring is continued for another 30 minutes. Water (100 ml) and diethyl ether (250 ml) are added to the mixture. After decantation and extractions, the organic phases are combined, washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40 C. The solid obtained is recrystallized from a dichloromethane/petroleum ether mixture (2.2 g; 86% yield). NMR (1H, 400 MHz, DMSO-d6): delta 2.77 (d, 3H), 7.51 (AB, 2H), 7.88 (AB, 2H), 8.52 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; ethyl acetate; | (1) To a suspension of <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (500 mg) in tetrahydrofuran (5 ml) was added di-tert-butyl dicarbonate (799 mg) and the mixture was stirred for 18 hours at 50 C. The mixture was concentrated and the residue was dissolved in ethyl acetate. The solution was stirred under ice-cooling, and the resulting precipitates were collected by filtration to give N-(tert-butoxycarbonyl)-4-methylcarbamoylaniline (500 mg). mp: 185.2 C. NMR (CDCl3, delta): 1.54 (9H, s), 3.00 (3H, d, J=6 Hz), 6.12 (1H, br s), 6.69 (1H, br s), 7.43 (2H, d, J=9 Hz), 7.70 (2H, d, J=9 Hz), |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(5) 8-[2,6-Dichloro-3-[4-[4-(methylcarbamoyl)phenylcarbamoylmethyl]-2,5-dioxopiperazin-1-yl]benzyloxy]-2-methylquinoline was obtained from 8-[2,6-dichloro-3-(4-carboxymethyl-2,5-dioxopiperazin-1-yl)benzyloxy]-2-methylquinoline and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> according to a similar manner to that of Example 7. NMR (CDCl3 -CD3 OD, delta): 2.62 (3H, s), 3.89 (3H, s), 4.07 (1H, d, J=16Hz), 4.18 (1H, d, J=16Hz), 4.27-4.41 (4H, m), 5.50 (2H, s), 7.19-7.30 (4H, m), 7.37-7.44 (3H, m), 7.56 (2H, d, J=8Hz), 7.70 (2H, d, J=8Hz), 8.02 (1H, d, J=8Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; In ethanol; | EXAMPLE 6 p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride A mixture of 0.1 mole of <strong>[6274-22-2]N-methyl-p-aminobenzamide</strong>, 0.1 mole of 4-chloro-7-trifluoromethylquinoline, 10 ml. of concentrated hydrochloric acid and 500 ml. of absolute ethanol is stirred at about 25 C. for 30 minutes. A precipitate begins to form, and the mixture is then heated at reflux for 4 hours. The mixture is cooled and filtered to obtain p-[(7-trifluoromethyl-4-quinolyl)amino]-N-methylbenzamide hydrochloride. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
TSOH; In methanol; sodium tetrahydroborate; water; N,N-dimethyl-formamide; toluene; | EXAMPLE XII 1,3,4,6,7,11b-Hexahydro-9,10-dimethoxy-2-(4-N-methylcarbamyl)anilino-2H-benzo[a]quinolizine (TR-3991) A mixture of 1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2-oxo-2H-benzo[a]quinolizine (8.7 g, 0.033 mole), 4-amino-N -methylbenzamide (6.5 g), a catalytic amount of TsOH, 250 ml of toluene and 30 ml of DMF was refluxed for 4 days with the water produced being collected in a Dean-Stark trap. The solvent was removed in vacuo whereupon the concentrate was dissolved in 150 ml of methanol, and cooled in an ice bath while 8 g of NaBH4 was added in portions. The mixture was stirred in the cold for 1 hour and refluxed for 1 hour. At this point the solvent was removed in vacuo and the concentrate dissolved in water, extracted with chloroform, dried over MgSO4 and concentrated. The concentrate was chromatographed over alumina using chloroform-acetone (9:1) as eluant to yield 9 g of product. The product was rechromatographed on silica gel using chloroform-methanol (9:1) as eluant. The 5.5 g of product was crystallized from 2-propanol/petroleum ether to yield 2.9 g of the desired product, m.p. 177-9. Anal. Calcd for C23 H29 N3 O3: C, 69.85; H, 7.39; N, 10.62; Found: C, 69.12; H, 7.36; N, 10.59. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With potassium carbonate;tris-(dibenzylideneacetone)dipalladium(0); XPhos; In tert-butyl alcohol; at 80℃;Product distribution / selectivity; | Intermediate 12; W-Methyl-4-({7-[(4-methylphenyl)sulfonyl]-4-[(2,2,2-trifluoroethyl)amino]-7H-py rrolo[2,3-d]pyrimidin-2-yl}amino)benzamide; A mixture of 2-chloro-7-[(4-methylphenyl)sulfonyl]-lambda/-(2,2,2-trifluoroethyl)-7/-/-pyrrolo[2,3-c/]pyrimi din-4-amine (404mg), 4-amino-lambda/-methylbenzamide (180mg), tris(dibenzylideneacetone)dipalladium (0) (91.6mg),2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (47.3mg) and potassium carbonate (193mg) in t-butanol (18ml) was degassed and then heated at 8O0C under nitrogen overnight. The cooled reaction was diluted with ethyl acetate, applied to a SCX-2 SPE (5Og), the column washed with ethyl acetate and methanol and the product eluted with methanol / 0.880 ammonia. The solvents were evaporated to give the title compound as a beige foam (385mg). LC/MS; Rt 3.52min, MH+ 519. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bis(dibenzylideneacetone)-palladium(0); DavePhos; In N,N-dimethyl-formamide; at 80℃; for 2h; | Example 27; 4-({4-[(1 ,1 -Dimethylethyl)amino]-1 W-pyrrolo[2,3-d]pyrimidin-2-yl}amino)-lambda/-met hylbenzamide trifluoroacetate; lambda/-(1 J-dimethylethyl)-2-iodo-7-[(4-methylphenyl)sulfonyl]-7/-/-pyrrolo[2,3-c(]pyrimidin- 4-amine (O.betammol) was dissolved in DMF (16ml). Bis(dibenzylideneacetone) palladium (10mol%, Aldrich), 2-dicyclohexylphosphino-2'-(lambda/,lambda/-dimethylamino) biphenyl (15mol%), cesium carbonate (0.3mmol) and 4-amino-lambda/-methylbenzamide (0.15mmol) were combined with an aliquot of this solution (2ml). The reaction was heated at 800C for 2h, allowed to cool, filtered through Celite and concentrated. The reaction was dissolved in methanol (1.5ml), treated with sodium methoxide in methanol (0.5M, 500mul), stirred at 700C for 2h and left to stand at room temperature overnight. The reaction was heated for a further 5h, concentrated and purified using MDAP. The fractions containing product were evaporated to dryness to give title compound (3mg). LC/MS; Rt 2.58min, MH+ 339. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bis(dibenzylideneacetone)-palladium(0); DavePhos; In N,N-dimethyl-formamide; at 80℃; for 3h;Product distribution / selectivity; | Method 5:; 2-lodo-7-[(4-methylphenyl)sulfonyl]-lambda/-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-c/]pyrimidi n-4-amine (992mg) was suspended in DMF (20ml). An aliquot (1ml) of this mixture was treated with a solution of the aniline (0.2mmol) in DMF (1ml), cesium carbonate (97.5mg), 2-dicyclohexylphosphino-2'-(lambda/,lambda/-dimethylamino)biphenyl (5.8mg) and bis(dibenzylideneacetone) palladium (5.8mg). The reaction was stirred at 80C EPO <DP n="52"/>under nitrogen for 3h. The reaction was filtered through Celite, concentrated (vacuum centrifuge) and the residue dissolved in methanol (1ml), treated with sodium methoxide in methanol (0.5M, 500mul) and stirred at 6O0C overnight. The reaction was concentrated and purified using MDAP. The appropriate fractions were reduced to dryness to give the title compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With caesium carbonate;bis(dibenzylideneacetone)-palladium(0); DavePhos; In N,N-dimethyl-formamide; at 80℃; for 3h; | Method 2:; Pyrrolo[2,3-cdpyrimidin-4-amine reagent, for example,Pyrrolo[2,3-c/]pyrimidin-4-amine (O.i mmol, 43mg), 4-amino-lambda/-methylbenzamide (29.8mg, Asinex), cesium carbonate (96mg), bis(dibenzylideneacetone)palladium (6mg, Acros) and 2-dicyclohexylphosphino-2'-(lambda/,lambda/-dimethylamino)biphenyl (6mg, Acros) were combined in DMF (2.0ml). The reaction mixture was heated at 800C for 3h. The reaction mixture was allowed to cool, filtered through Celite, the Celite washed with DMF and the combined filtrate and washings evaporated to dryness. The residue was heated with sodium methoxide solution (2N, 0.5ml) at 800C for 2h and allowed to cool to room temperature. The solution was evaporated to dryness, the residue dissolved in DMSO and purified by MDAP. The fractions containing product were evaporated to dryness to give the desired compound. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | Alternatively the compound of Example 20 can be made by the following three steps followed by steps 6-9 as described above. 1) 4-(4-methylaminocarbonyl-phenylamino)-piperidine-1-carboxylic acid benzyl ester hydrogen chloride; 4-arnino-N-methylbenzamide (7.51 g, 50.0 mmol), benzyl 4-oxo-1-piperidinecarboxylate (14.0 g, 60.0 mmol) and acetic acid (2.86 mL, 50.0 mmol) were added to dichloroethane (90 mL). Sodium triacetoxyborohydride (15.9 g, 75 mmol) was added in three portions over a period of 6 hours. The mixture was stirred at room temperature for 18 hours and then slowly added to water (20 mL). 3M aq. sodium hydroxide (50 mL) was added to adjust pH to 13. The organic layer was isolated and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with sat. aq. sodium bicarbonate and brine, and dried over magnesium sulfate. The filtrates were concentrated to dryness. Methanol (90 mL) was added. The solution was heated to 7O0C. 4.5M hydrogen chloride in isopropanol (12 mL, 54 mmol) was added. The slurry was stirred at 7O0C for 2 hours, 220C for 1 hour, and then filtered. The cake was washed with Methyl t-butyl ether and dried under vacuum to give 4-(4-methylaminocarbonyl- <n="68"/>phenylamino^piperidine-i-carboxylic acid benzyl ester hydrogen chloride (17.4 g) as a white powder in 86% yield. LC-MS APCI (m/z) 368 (M+H)+; 1H NMR (400 MHz, DMSO- dbeta): delta 8.21 (brs, 1 H), 7.69 (d, 2 H), 7.32 (m, 5 H), 6.92 (brs, 2 H), 5.03 (s, 2 H), 3.96 (d, 2 H), 3.53 (m, 1 H), 2.91 (brs, 2 H), 2.70 (s, 3 H), 1.86 (d, 2 H), 1.36 (m, 2 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | Preparation of 4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-ylamino)-N-methylbenzamide (B20) ; A solution of 2,4-dichloro-5-trifluoromethyl-pyrimidine (8.63 mmol) in 1:1 t-BuOH/DCE (10 mL) was cooled to 5 C., treated with solid ZnBr2 (22.5 mmol), and stirred at 5 C. for 30 minutes. The resultant solution was maintained at 5 C. and treated first with solid <strong>[6274-22-2]4-amino-N-methyl-benzamide</strong> (7.5 mmol) followed by TEA (16.5 mmol). The resultant white mixture was allowed to warm 25 C., and it was mixed at 25 C. for 20 hours. The mixture was adsorbed onto silica gel, and the fraction eluting 0-10% methanol/DCM was collected and concentrated. The resultant residue was triturated with water and filtered to provide B20. Yield: 3.0 mmol, 40%. LCMS 2.3 min, MZ+=331.1 1H NMR (500 MHz, d6-DMSO) delta ppm 10.89 (s, 1H), 8.87 (s, 1H), 8.34 (d, J=4.67 Hz, 1H), 7.73-7.89 (m, 3H), 2.78 (d, J=4.67 Hz, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40% | With diisopropyl-carbodiimide; In tetrahydrofuran; | Example 23 Synthesis of N-Methyl-4-{3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionylamino}-benzamide 4-Amino-N-methyl-benzamide (40 g, 0.3 mol) was added to a stirred solution of 3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionic acid (100 mg, 0.3 mmol) and DIC (50 mg, 0.4 mmol) in THF (2 mL) and the mixture was stirred overnight. The resulting precipitate was filtered and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The residue was purified by column chromatography using basic alumina (methanol in chloroform) to afford 56 mg (40%) of N-methyl-4-{3-oxo-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionylamino}-benzamide. LCMS: 477.17 (M+1)+, 94.5%, 1H NMR: (DMSO-d6): delta 7.8 (m, 2H), 7.6 (m, 4H), 7.4 (m, 1H), 4.0 (m, 2H), 3.8 (m, 4H), 3.6 (m, 3H), 3.2 (m, 2H), 3.0 (d, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | Example 5 Method H: 4-(4-(5,6,7,8-tetrahydro-7,7-dimethyl-4-oxo-4H-thiazolo[5,4-c]azepin-2-yl)pyridin-2-ylamino)-N-methylbenzamide (I-5) 2-(2-chloropyridin-4-yl)-5,6,7,8-tetrahydro-7,7-dimethylthiazolo[5,4-c]azepin-4-one (70 mg, 1.0 Eq.), <strong>[6274-22-2]4-amino-N-methyl-benzamide</strong> (41 mg, 1.2 Eq.), NaOtBu (61 mg, 2.8 Eq.), Pd(OAc)2 (5 mg, 0.1 Eq.) were suspended/dissolved in dry toluene and degassed (vacuum/N2 cycles*5). 2-Di-tert-butylphosphino)biphenyl (143 mg, 0.2 Eq.) was then added. The resultant mixture was then refluxed overnight. A further portion of NaOtBu (61 mg, 2.8 Eq.), Pd(OAc)2 (5 mg, 0.1 Eq.) and 2-(di-tert-butylphosphino)biphenyl (14 mg, 0.2 Eq.) were added, followed by dry dioxane (0.5 mL). The resultant mixture was refluxed for a further night. The reaction mixture was allowed to cool to RT, partitioned between EtOAc/MeOH (3:1)/NH4Cl, and then extracted into EtOAc/MeOH (3:1) (3*50 mL). The combined organic layers were washed with brine (1*20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. Purification was achieved using column chromatography (10% MeOH/90% DCM) to obtain the title compound as a bright yellow powder (18.6 mg, 19% yield); 1H NMR (DMSO D6) 1.0 (6H, s), 2.8 (3H, d), 3.0 (2H, s), 3.0 (2H, m), 7.3 (1H, m), 7.5 (1H, s), 7.8 (4H, s), 8.2 (1H, m), 8.3 (2H, m), 9.6 (1H, s); LC/MS M+1 (obs.) 422.20; LC/MS M-1 (obs.) 420.30. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
400 G of ice-water and 120 G (0.65 mol) of cyanuric chloride dissolved in 753 g of methyl ethyl ketone are introduced into a 2.5 litre flat-flanged flask equipped with a condenser, stirrer and pH meter. Then, in the course of 65 min, 977 ML of a 12 % solution of 4,4'- diaminostilbene-2, 2'-disulfonic acid in soda water are slowly added dropwise at pH 4.5-5. 0 so that no excess of disulfonic acid is formed. When the addition is complete, stirring is carried out at an intemal temperature OF 5-10C for a further 10 min. Then, in the course of 15 min, 97.6 G (0.65 mol) OF 4-AMINO-N-METHYLBENZAMIDE ARE intro- duced at 10-20C and pH 7.0-7. 5 into the resulting yellow suspension. The yellow suspension is then heated to 72C in the course of one hour and stirred at that temperature for a further 2 h. After the solvent has been distilled off, a further 200 mi of water are added and the mixture is stirred for a further 1.5 h at 85C. After cooling to 75C, the crude product is filtered through a suction filter, washed with 2.5 % NACI solution and dried in vacuo at 80C. Yield : 306.1 G Appearance: yellow crystals |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In toluene; at 100℃; for 3h; | (c) Preparation of intermediary compound 2-[(4-Methylcarbamoyl-phenylamino)- methylenejmalonic acid diethyl ester:To a solution of 4-amino-iV-methyl-benzamide (7.5 g, 50 mmol) in anhydrous toluene (15 mL) was added diethoxymethylene malonate (11.88 g, 55.0 mmol) at room temperature. The reaction mixture was stirred at 100 0C for 3 hours, cooled to 40 0C and petroleum ether (200 mL) was added and the reaction mixture was subsequently stirred for 30 minutes. The solid formed, was collected by filtration, washed with diisopropylether and dried in vacuo to afford 15.0 g (94 % yield) of 2-[(4-methylcarbamoylphenylamino)methylene]malonic acid diethyl ester as a white solid. 1H-NMR (300 MHz, CDCl3) delta 11.09 (d, J= 13.5 Hz, IH), 8.54 (d, J= 13.5 Hz, 2H), 7.81 (d, J= 8.4 Hz, 2H), 7.18 (d, J= 8.7 Hz, 2H), 6.20 (bs, IH), 4.36-4.24 (m, 4H), 3.03 (d, J= 4.8 Hz, 3H), 1.41-1.33 (m, 6H). LC-MS (m/z, 0A): 319.6 (M-I, 99.7). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 120℃; for 1h;Microwave irradiation; | Step 1To a solution of 2, 4-dichloropyridine (0.500 g, 3.39 mmoL) and 4-amino-N- methylbenzamide (0.510 g, 3.39 mmoL) in dimethylacetamide (1 mL) was added cesium carbonate (1.6 g, 5.08 mmoL) and the reaction mixture was degassed for 15 min. Pd2(dba)3 (0.154 g, 0.169 mmol) and BINAP (105 mg, 0.169 mmol) were added and the reaction mixture was irradiated in the microwave at 120 C for 1 h. Then reaction was quenched with water and extracted with EtOAc (2 x 50 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 3-((4-chloropyridin-2-yl)amino)-N-methylbenzamide (0.300 g, 38%) as a solid. Observed mass (M+l): 262.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 120℃; for 1h;Microwave irradiation; | Step 5To a solution of 2-chloro-4-(3-(2,4-dichlorophenoxy)azetidin-l-yl)pyrimidine (0.200 g, 609 mmoL) and 4-amino-N- methylbenzamide (0.109 g, 0.731 mmoL) in dimethyl acetamide (5 mL) was added cesium carbonate (300 mg, 9.14 mmol) and the reaction mixture was degassed for 15 min. Tris(dibenzylideneacetone)dipalladium (0) [Pd2(dba)3](0.030 g, 0.03 mmoL) and 2,2'-bis(diphenylphosphino)-l,r-binaphthyl [BINAP] (0.020 g, 0.03 mmoL) were added and the mixture was irradiated in the microwave at 120 C for lh . Then the reaction was quenched with water and extracted with EtOAc (2 x 25 mL). The organic extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided 4-(4-(3-(2,4- dichlorophenoxy)azetidin-l-yl)pyrimidin-2-ylamino)-N-methylbenzamide (0.077 g, 29%) as solid. Observed mass (M+l): 443.9. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 120℃;Microwave irradiation; | Step 2To a solution of 2-chloro-6-(3- (4-fluorophenoxy) azetidin-l-yl) pyridine (500 mg, 1.79 mmoL) and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (270 mg, 1.79 mmol) in dimethylacetamide (5 mL, 3 mL/mmol) was added cesium carbonate (873 mg, 2.68 mmol) and the reaction was degassed for 15 min. Pd2(dba) 3 (81 mg, 0.089 mmol) and BINAP (55 mg, 0.089 mmol) were added and the reaction was allowed to heat at 120 C in the microwave. The reaction was quenched with water and extracted with EtOAc (2 x 50 mL). The organic extracts were washed with brine, dried over sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography to afford 3-(6-(3-(4-fluorophenoxy) azetidin-l-yl) pyridin-2- ylamino)-N-methylbenzamide (61 mg, 13%) as a solid. Observed mass (M+l): 393.1 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
13% | With caesium carbonate;tris-(dibenzylideneacetone)dipalladium(0); 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl; In ISOPROPYLAMIDE; at 100℃; for 0.5h;Microwave irradiation; | Step 6To a solution of 2-chloro-N-(3-(4-trifluoromethoxy) phenoxy)propyl) pyrimidin-4- amine (400 mg, 1.15 mmol) and 4-amino-N- methyl benzamide (172 mg, 1.15 mmol) in DMA (4 mL, 3 mL/mmol) was added cesium carbonate (562 mg, 1.72 mmol) and the mixture was degassed for 15 min. Pd2(dba)3 (52 mg, 0.057 mmoL) and BINAP (35 mg, 0.057 mmol) were added and the reaction was allowed to heat at 100 C in the microwave for 0.5 h. The reaction was quenched with water and extracted with EtOAc (2 x 25 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure.Purification by silica gel column chromatography afforded N-methyl-3-(4-(3-(4- (trifluoromethoxy)phenoxy) propylamino) pyrimidin-2-ylamino) benzamide (260 mg, 13%) as a solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
29.7% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | Example 33-(7-(3,4-Dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide Procedure:A solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-d]pyrimidin-5-yl]-benzoic acid (170 mg, 0.41 mmol) in 10 mL of DMF were added <strong>[6274-22-2]4-amino-N-methyl-benzamide</strong> (81 mg, 0.54 mmol), HATU (205 mg, 0.54 mmol) and DIEA (79 mg, 0.61 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to give a solid as a crude product. It was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1% TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4-dimethoxyphenylamino)thiazolo[5,4-d]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (66 mg, 29.7%) as a yellow solid. 1H NMR (300 MHz, DMSO): delta 10.66 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.59 (d, 1H, J=7.2 Hz), 8.38-8.37 (m, 1H), 8.05 (d, 1H, J=8.7 Hz), 7.89-7.82 (m, 6H), 7.71-7.68 (m, 12H), 7.54-7.50 (m, 1H), 6.97 (d, 1H, J=8.7 Hz), 3.78 (s, 3H), 3.72 (s, 3H), 2.78 (d, 1H, J=3.9 Hz). LC-MS: 541.1 [M+H]+, tR=1.72 min. HPLC: 96.60% at 214 nm, 97.75% at 254 nm, tR=6.68 min. |
29.7% | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 16h; | A solution of 3-[7-(3,4-dimethoxy-phenylamino)-thiazolo[5,4-<i]pyrimidin-5-yl]-benzoic acid (170 mg, 0.41 mmol) in 10 mL of DMF were added <strong>[6274-22-2]4-amino-N-methyl-benzamide</strong> (81 mg, 0.54 mmol), HATU (205 mg, 0.54 mmol) and DIEA (79 mg, 0.61 mmol) at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated to give a solid as a crude product. It was purified by preparative HPLC (Gemini 5u C 18 150 x 21.2 mm; inject volume: 3ml/inj, flow rate: 20ml/min; wavelength: 214nm and 254 nm; the gradient conditions are: 40% acetonitrile/60% water (0.1%TFA V/V) initially, and then proceed to 70% acetonitrile/30% water (0.1%TFA V/V) in a linear fashion after just 9 min.) to give 3-(7-(3,4- dimethoxyphenylamino)thiazolo[5,4-<i]pyrimidin-5-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (66 mg, 29.7 %) as a yellow solid. 1H NMR (300 MHz, DMSO): delta 10.66 (s, 1H), 10.21 (s, 1H), 9.39 (s, 1H), 8.93 (s, 1H), 8.59 (d, 1H, J = 7.2 Hz), 8.38 - 8.37 (m, 1H), 8.05 (d, 1H, = 8.7 Hz), 7.89 - 7.82 (m, 6H), 7.71 - 7.68 (m, 12H), 7.54 - 7.50 (m, 1H), 6.97 (d, 1H, = 8.7 Hz), 3.78 (s, 3H), 3.72 (s, 3H), 2.78 (d, 1H, = 3.9 Hz). LC-MS: 541.1 [M+H]+, tR = 1.72 min. HPLC: 96.60 % at 214 nm, 97.75 % at 254 nm, tR = 6.68 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 24h; | A mixture of 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzoic acid (0.8 g, 3.22 mmol), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (0.58 g, 3.86 mmol), HATU (1.47 g, 3.8 mmol) and DIEA (1 g, 7.7 mmol) in DMF (10 mL) was stirred at room temperature for 24 h. The solvent was evaporated at 70C under reduced pressure to give a crude product. It was filtered through a plug of silica gel and the filter cake washed with ethyl acetate / petroleum ether (1: 1, v/v). The combined filtrates were concentrated to give crude N-(4- (methylcarbamoyl)phenyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzamide (0.56 g, 45.9 %) as a white solid that was used directly without further purification.LC/MS: 381.1 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
28% | 3-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (58 mg, 148 mumol), HOBt (34.0 mg, 222 mumol) and EDCI (42.6 mg, 222 mumol) were combined with DMF (10 mL) to give a light yellow suspension. After 1 h, a clear yellow solution had been generated. DIPEA (47.9 mg, 64.7 muL, 370 mumol) and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (31.2 mg, 207 mumol) were added. After 15 h the mixture was concentrated in vacuo then diluted with water (10 mL) and filtered. The collected solid was washed with water (3×3 mL) and dried in vacuo. Purification by chromatography (silica, 50 g, Supelco VersaFlash, 0-5% methanol in dichloromethane, gradient over 15 min) gave a residue that was recrystallized from methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)-N-(4-(methylcarbamoyl)phenyl)benzamide (22 mg, 42.0 mumol, 28%) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) delta ppm 10.60 (s, 1H) 9.98 (s, 1H) 8.62 (s, 1H) 8.53 (s, 1H) 8.36 (d, J=4.91 Hz, 1H) 8.16-8.27 (m, 2H) 8.10 (d, J=7.93 Hz, 1H) 7.87 (d, J=1.51 Hz, 4H) 7.61-7.76 (m, 2H) 7.42 (d, J=8.31 Hz, 1H) 7.13 (d, J=8.31 Hz, 1H) 4.03 (s, 3H) 3.77 (s, 3H) 2.79 (d, J=4.53 Hz, 3H); LC/MS: 524.1 [MH]+. | |
28% | 3-(8-(5,6-Dimethoxypyridin-2-ylamino)imidazo[l,2-b]pyridazin-6-yl)ben^ acid (58 mg, 148 muetaiotaomicron?), HOBt (34.0 mg, 222 muiotaetaomicron?) and EDCI (42.6 mg, 222 muiotaetaomicron?) were combined with DMF (10 mL) to give a light yellow suspension. After 1 h, a clear yellow solution had been generated. DIPEA (47.9 mg, 64.7 mu?^, 370 muiotaetaomicron?) and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (31.2 mg, 207 muiotaetaomicron?) were added. After 15 h the mixture was concentrated in vacuo then diluted with water (10 mL) and filtered. The collected solid was washed with water (3 x 3 mL) and dried in vacuo. Purification by chromatography (silica, 50 g, Supelco VersaFlash, 0 - 5 % methanol in dichloromethane, gradient over 15 min) gave a residue that was recrystallized from methanol to give 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[l,2-b]pyridazin-6-yl) -N-(4- (methylcarbamoyl)phenyl)benzamide (22 mg, 42.0 muiotaetaomicron?, 28 %) as an off-white powder. 1H NMR (300 MHz, DMSO-d6) delta ppm 10.60 (s, 1 H) 9.98 (s, 1 H) 8.62 (s, 1 H) 8.53 (s, 1 H) 8.36 (d, J=4.91 Hz, 1 H) 8.16 - 8.27 (m, 2 H) 8.10 (d, J=7.93 Hz, 1 H) 7.87 (d, J=1.51 Hz, 4 H) 7.61 - 7.76 (m, 2 H) 7.42 (d, J=8.31 Hz, 1 H) 7.13 (d, J=8.31 Hz, 1 H) 4.03 (s, 3 H) 3.77 (s, 3 H) 2.79 (d, J=4.53 Hz, 3 H); LC/MS: 524.1 [MH]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In acetone; at 20℃; | General procedure: CS2 (50 mL) was added to a stirring mixture of DABCO (30 mmol) and amine (10 mmol) in acetone (10 mL). The resulting mixture was further stirred at room temperature to achieve dithiocarbamate, and the process of the reaction was monitored by TLC. After completion of the reaction, the solution was filtered and the solid was washed with acetone. After it was dried in an infrared-ray oven, the salt was dissolved in dried CHCl3 (10 mL) and the mixture was chilled to 0-5 C in an ice bath. BTC (1010 mg, 3.4 mmol), dissolved in CHCl3 (5 mL), was added dropwise for 30 min with constant stirring. The reaction mixture was then allowed to reach room temperature and stirred for a further 4 h. Triethylenediammmonium hydrochloride was filtered off, and the filtrate was evaporated in vacuo to afford the desired isothiocyanate in good purity. All products were identified by comparison with authentic samples. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | With toluene-4-sulfonic acid; In butan-1-ol; at 130℃; for 12h; | General procedure: 3 (244 mg, 1 mmol), methyl 4-aminobenzoate 4a (181 mg, 1.2 mmol), and p-toluenesulfonic acid monohydrate (152 mg, 0.8 mmol) were dissolved in n-butanol (10 mL), then refluxed at 130 C for 12 h. The resulting solution was neutralized with saturated NaHCO3 (2.5 mL). The mixture was extracted with ethyl acetate (50 mL×3). The organic layer was combined, dried over anhydrous Na2SO4, concentrated. The crude product was purified by silica gel chromatography to afford 5a (233 mg, 65% yield) as white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With tris[2-phenylpyridinato-C2,N]iridium(III); In N,N-dimethyl-formamide; at 20℃;Inert atmosphere; Irradiation; | Under nitrogen or argon, 0.4 mmol, 0.2mmol, Ir(ppy) 3(2mg) and DMF1 ml was added to the reaction flask, followed by blue LED lights(7W) at room temperature irradiation straight trivalent iodine reagent completeconversion of the reaction. Add 10 ml of saturated Na 2CO 3Aqueous solution, andextracted three times with ethyl acetate, the organic layer was washed with water andonce with saturated brine, dried over anhydrous Na 2SO 4The organic layer was dried.Column chromatography (eluent: petroleum ether 60-90: ethyl acetate = 10: 1-3: 1) to give the product in 85% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of acetaldehyde (0.292 mL, 5.23 mmol) in anhydrous DCM (10 mL) was added 4- amino-N-methylbenzamide (0.785 g, 5.23 mmol) and the reaction stirred at rt for I h. Diphenyl hydrogen phosphate (0.131 g, 0.523 mmol) in anhydrous DCM (5 mL) was added followed by (E)benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 1 g, 5.23 mmol) in anhydrous DCM (5 mL). The mixture was then left to stir for 1 .5 h. The mixture was partitioned between 100 mLDCM and 25 mL sat. NaHCO3. The organic and aqueous layers were combined and evaporated to dryness under reduced pressure. The residue was treated with 30 mL MeOH and filtered. The filtrate was applied to a 100 g silica gel column which was then dried in a vacuum oven at 40 C. The dry column was then eluted with 0-8% MeOH in DCM to afford the crude desired product, as a white solid (1.15 g), which was used in the next step without further purification.LCMS (2 mm Formic): Rt = 0.92 mi [MH] = 368. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
403 mg | To a solution of propionaldehyde (0.105 mL, 1.464 mmol) in anhydrous DCM (10 mL), was added <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (220 mg, 1.464 mmol) and the reaction mixture stirred at rt for I h.Diphenyl hydrogen phosphate (36.6 mg, 0.146 mmol) in anhydrous DCM (5 mL) was then added followed by (E)-benzyl prop-1-en-1-ylcarbamate (for a preparation see Intermediate 1, 280mg, 1.464 mmol) in anhydrous DCM (5 mL). The reaction mixture was then left to stir for 2 h.The reaction mixture was diluted with DCM (10 mL) and washed with NaHCC3 (40 mL) and then water (40 mL)and the organic and aqueous layers separated. The organic layer was passed through a hydrophobic frit and then concentrated in vacuo to give a yellow oil which was purified by chromatography on silica gel (25 g column, eluting with 0-10% MeCH in DCM) to afford the desired product as a pale yellow solid (403 mg). LCMS (2 mm Formic): Rt = I .00mm, [MH] = 382. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31 mg | With acetic acid; In isopropyl alcohol; at 150℃; for 1h;Microwave irradiation; | B) 4-((4-((3R)-3-cyano-3-ethyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-N-methylbenzamide A solution of (3R)-1-(2-chloropyrimidin-4-yl)-3-ethyl-2-oxopyrrolidine-3-carbonitrile (51 mg), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (32 mg) and acetic acid (12 muL) in 2-propanol (1 mL) was stirred in a microwave reactor at 150C for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (31 mg). 1H NMR(300 MHz, CDCl3) delta 1.15-1.26 (3H, m), 1.77-1.95 (1H, m), 2.10-2.34 (2H, m), 2.59-2.72 (1H, m), 2.96-3.08 (3H, m), 4.15 (2H, t, J = 6.6 Hz), 6.11 (1H, brs), 7.29 (1H, brs), 7.61-7.69 (2H, m), 7.73-7.85 (3H, m), 8.35-8.45 (1H, m). MS (ESI+) : [M+H]+365.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65 mg | B) 4-((4-((3S)-3-cyano-3-isopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-N-methylbenzamide hydrochloride A solution of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (55 mg) obtained in Step A, <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (37 mg) and acetic acid (13 muL) in ethanol (2 mL) was stirred in a microwave reactor at 150C for 1 hr, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate). To a solution of the residue (87 mg) in ethanol (3 mL) was added lM hydrochloric acid (230 muL), and the solvent was evaporated under reduced pressure. The residue was recrystallized (diisopropyl ether/ethanol) to give the title compound (65 mg). 1H NMR(300 MHz, DMSO-d6) delta 1.02 (3H, d, J = 6.8 Hz), 1.12 (3H, d, J = 6.8 Hz), 2.33 (1H, dt, J = 13.6, 6.8 Hz), 2.40-2.48 (1H, m), 2.53-2.63 (1H, m), 2.77 (3H, d, J = 4.2 Hz), 3.95-4.21 (2H, m), 7.68 (1H, d, J = 5.7 Hz), 7.80 (4H, s), 8.28 (1H, d, J = 4.2 Hz), 8.49 (1H, d, J = 5.7 Hz), 9.98 (1H, s). MS(ESI+): [M+H]+379.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With silver hexafluoroantimonate; carbonyl(pentamethylcyclopentadienyl)cobalt diiodide; silver(I) acetate; In 1,2-dichloro-ethane; at 60℃; for 13h;Inert atmosphere; | General procedure: To a dried screw-capped vial were added benzamide 2 (0.10mmol), ethyl acrylate 3 (0.15mmol), 1b (4.8mg, 0.01mmol), AgSbF6 (6.8mg, 0.02mmol), AgOAc (41.7mg, 0.25mmol), and 1,2-dichloroethane (1.0mL) under Ar atmosphere. The vial was capped and the mixture was heated at 60C for 13h with stirring. After the mixture was cooled to room temperature, saturated EDTA·2Na aqwas added following dilution with CH2Cl2. Organic layer was separated and aqueous layer was extracted with CH2Cl2 (×2). Combined organic layers were dried over Na2SO4. After filtration and evaporation, obtained crude mixture was purified by silica gel column chromatography (CH2Cl2/EtOAc) to give product 3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In N,N-dimethyl-formamide; at 100℃; for 10h; | General procedure: To a 0.5 M solution of carboxylic acid (1.0 eq.) in DMF, aniline (1.0 or 1.2 eq.), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.2 eq.), and HOBt.H2O (1.2 eq.) were added. The mixture was stirred at 100C for 10 hours. After cooling, the mixture was poured into water (10 x DMF volume). The resulting precipitate was collected by filtration. The collected powder was washed with water, and dried in vacuoto afford the product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In acetonitrile; at 120℃; for 2h;Microwave irradiation; | A suspension of 5-(4-chloro-1,3,5-triazin-2-yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)benzonitrile (53 mg, 0.17 mmol) and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (30 mg, 0.20 mmol) in acetonitrile (2.5 mL) was treated with N,N-diisopropylethylamine (0.12 mL, 0.67 mmol). The mixture was heated in a microwave reactor for 120 minutes at 120 C. After cooling to room temperature, the solid was collected by filtration, washed with acetonitrile, and dried under house vacuum and then in a vacuum oven (60 C.) over P2O5 to provide 4-((4-(3-cyano-4-((tetrahydro-2H-pyran-4-yl)oxy)phenyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide. LCMS-ESI+ (m/z): [M+H]+ calcd for C23H23N6O3: 431.2. found: 431.0 1H NMR (400 MHz, DMSO-d6) delta 10.61 (s, 1H), 8.91 (s, 1H), 8.64 (m, 2H), 8.40 (m, 1H), 7.90 (m, 4H), 7.61 (d, J=9.5 Hz, 1H), 4.99 (m, 1H), 3.91 (m, 2H), 3.59 (m, 2H), 2.83 (d, J=4.4 Hz, 3H), 2.10 (m, 2H), 1.74 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
17% | With triethylamine; In dimethyl sulfoxide; at 20℃; for 72h;Inert atmosphere; | [00252] Compound 37 [00253] [00255] [00256] To a mixture of 4-chloro-6-((4,7-difluoro-2-methyl-lH-indol-5- yl)oxy)pyrimidine-5-carbonitrile (80 mg, 0.25 mmol) and <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (45 mg, 0.30 mmol) in anhydrous DMSO (1.5 mL) was added TEA (0.122 mL; 0.875 mmol), and the resulting biphasic mixture was efficiently stirred at room temperature for ca. 3 days. The resulting mixture was diluted with EtOAc (100 mL) and washed with aq. NaHC03 (ca. 100 mL each; 50% NaHC03 saturation). The organic layer was separated and dried over anhydrous Na2S04 and concentrated. The resulting residue was purified by flash column chromatography on silica gel using 0.5-15%) MeOH in DCM (v/v) to afford the desired product as a white solid (18 mg, 17% yield). 1H NMR (DMSO-d6, 400 MHz) delta 11.85 (br s, 1H), 10.23 (br s, 1H), 8.37-8.34 (m, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.64-7.62 (m, 2H), 7.04- 7.00 (m, 1H), 6.35 (s, 1H), 2.78 (d, J = 4.0 Hz, 3H), 2.42 (s, 3H); MS (ESI): calcd for C22H16F2N602: 434, found: 435 (MH+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dichloromethane; at 0 - 20℃; for 4h; | General procedure: To a solution of alpha-ketoacids (1.0 eq., 0.5 M) in DCM was added a drop of DMF at room temperature followed by the addition of oxalyl chloride (1.2 eq.). The resulting mixture was stirred at this temperature until no gas was released. The reaction mixture was subsequently cooled to 0oC followed by the addition of amine (1.2 eq.) and Et3N (2.0 eq.). The resulting reaction mixture was warmed to room temperature and stirred for 4 h. After addition of water (5 mL), the mixture was washed with 1N HCl and water respectively and dried over Na2SO4. Purification by flash column chromatography afforded the desired alpha-ketoamides. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With pyridine; 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide; In ethyl acetate; at 60℃; for 0.5h; | 50 mg (0.137 mmol, 95% purity) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 31 mg (0.205 mmol, 1.5 eq.) of <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> were initially charged in 1.2 ml of pyridine, the mixture was heated to 60 C., 130 mul (0.548 mmol, 50% in ethyl acetate, 4.0 eq.) of T3P were added and the mixture was stirred at 60 C. for 30 min. The reaction mixture was admixed with water and ethyl acetate. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were washed once with aqueous buffer solution (pH=5) and once with saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated. The residue was purified by means of preparative HPLC (RP18 column, eluent: acetonitrile/water gradient with addition of 0.1% formic acid). Yield: 65 mg (96% of theory). (1063) LC/MS [Method 8]: Rt=1.12 min; MS (ESIneg): m/z=477 (M-H)-, (1064) 1H-NMR (400 MHz, DMSO-d6): delta [ppm]=10.69 (s, 1H), 8.37-8.29 (m, 1H), 8.03-7.96 (m, 1H), 7.84-7.78 (m, 2H), 7.77-7.67 (m, 4H), 7.50 (s, 1H), 6.54 (s, 1H), 5.64 (dd, 1H), 3.69 (s, 3H), 2.76 (d, 3H), 2.27-2.08 (m, 2H), 0.91 (t, 3H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
19% | With pyridine; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 0.833333h; | 4-Amino-N-methylbenzamide (14.70 mg, 0.098 mmol) was dissolved in DCM (1.0 mL) along with pyridine (0.021 mL, 0.261 mmol) and DIEA (0.017 mL, 0.098 mmol). Intermediate 14SF (15 mg, 0.033 mmol) in 2 mL of DCM was added dropwise, and the reaction mixture was stirred at room temperature for 50 minutes. The reactionwas quenched with 1.0 N HC1 (0.5 mL). All solvent was removed under vacuum. The crude was dissolved in DMSO/THF (2:1, 6 mL) and purified via preparative LC/MS (method C, 5 5-100% B over 20 mm, then a 5-mm hold at 100% B). Fractions containing the desired product were combined and dried via centrifugal evaporation to yield Example 208 (3.7 mg, 19% yield). ?H NMR (500MHz, DMSO-d6) 8.75 (s, 1H), 8.59 (d,J=1.2 Hz, 1H), 8.26 (d, J=4.3 Hz, 1H), 7.89 (d, J11.3 Hz, 1H), 7.84 (s, 1H), 7.75 (d,J=8.5 Hz, 2H), 7.52 (d, J=8.2 Hz, 2H), 5.47-5.39 (m, 1H), 4.54 (dd, J=12.5, 2.7 Hz, 1H),4.41 (dd, J12.2, 7.0 Hz, 1H), 4.09 (s, 3H), 3.67 (dd, J15.9, 9.8 Hz, 1H), 2.76 (d, J=4.3Hz, 3H), 2.64 (s, 3H); LC-MS: method C, 2 to 98% B. RT = 2.28 mm, MS (ESI) m/z:574.30 (M+H) Analytical HPLC purity (method B): 96%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
37% | With toluene-4-sulfonic acid; In butan-1-ol; at 50℃; for 4h; | A mixture of the compound 4b (205mg, 0.S3mmol), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (80mg,0.S3mmol), p-toluenesulfonic acid (152mg, 0.8Ommol) and n-butyl alcohol (lOmL) was heated to50C for 4 hours. The mixture was cooled and concentrated under reduced pressure, the residue was suspended in EtOAc (3OmL), then filtered, the crude solid was dissolved in DCM (5OmL), washed with aqueous solution of potassium carbonate (3OmL) and brine (5OmL), dried overanhydrous Na2SO4 and concentrated under reduced pressure, the residue was triturated with EtOAc:n-hexane=1:5(3OmL) to afford the compound 4 (97mg, 37%). MS: 501(M+H)tH-NMR (DMSO-d6, 400MHz): oe 9.83 (s, 1H), 8.31 (s, 1H), 8.12 (m, 1H), 7.80-7.82 (d, 1H),7.68-7.72 (t, 1H), 7.43-7.57 (m, 6H), 5.06 (s, 2H), 3.06 (s, 3H), 2.92 (s, 3H), 2.75-2.76 (d,3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | With potassium carbonate; In N,N-dimethyl-formamide; at 90℃; for 4h; | General procedure: To a flask was added Q08 (0.4g, 1.07mmol), DMF (5mL), anhydrous K2CO3 (0.3g, 2.14mmol), and intermediate Q10 (0.5g, 2.14mmol). The mixture was stirred at 90C for 4h, cooled to rt, and poured into ice-water. The solid was filtered, washed with water, and dried, recrystallized from methanol to give product 12 (0.35g, yield 56%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; sodium cyanoborohydride; acetic acid; at 45℃; for 12h; | To a solution of intermediate 4 (200 mg, 0.586 mmol), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (132 mg, 0.879 mmol), sodium cyanoborohydride (73.6 mg, 1.17 mmol), and MeOH (20 mL) was added a solution of CH;3COOH(70.4 mg, 1.17 mmol) in MeOH (6 mL). After stirring at 45 C for 12 hours, the reaction mixture was concentrated to dryness under reduced pressure to afford the crude product, which was purified by prep-HPLC (Gilson 281, Xtimate C18 150 x 25 mm x 5 um column (eluent: 30% to 60% (v/v) water(0.225%FA)-ACN)). The pure fractions were collected and evaporated under reduced pressure to obtain a residue, which was lyophilized to dryness to give Compound 96 (150 mg) (white solid). Compound 96 wasfurther separated by SFC (Amylose-C, 3*25cm, 10um, mobile phase:CO2/ EtOH(0.1% NH3H20)=45/55, 80 ml/min). The pure fractions were collected and the volatiles were removed under reduced pressure to obtain residues which were then lyophilized to dryness to give Compound 97 (38.8 mg, 14% yield) as a white solid and Compound 98 (41.2 mg, 15% yield) as a white solid.Compound 96: 'H NMR (400MHz,Methol-d4) 6 8.26 (s, 1H), 7.65 - 7.59 (m, 2H), 7.37 (s, 1H), 6.65 - 6.60 (m, 2H), 4.52 - 4.15 (m, 4H), 4.00 - 3.90 (m, 1H), 3.90 - 3.81 (m, 2H), 2.87 (s, 3H), 2.47 - 2.37 (m, 1H), 2.28 - 2.12 (m, 2H), 2.08 - 1.90 (m, 2H), 1.73 1.61 (m, 1H). Compound 97: 'H NMR DMSO-ds (400 MHz): 6 8.26 (s, 1H), 7.65 - 7.58 (m, 2H), 7.37 (s, 1H), 6.68 - 6.55 (m, 2H), 4.53 - 4.06 (m, 4H), 4.01 - 3.90 (m, 1H), 3.90 - 3.78 (m, 2H), 2.87 (s, 3H), 2.48 - 2.36 (m, 1H), 2.28 - 2.10 (m, 2H), 2.08 - 1.90 (m, 2H), 1.73 - 1.59 (m, 1H). Compound 98: 'H NMR DMSO-ds (400 MHz): 6 8.26 (s, 1H), 7.66 - 7.56 (m, 2H), 7.37 (s, 1H), 6.66 - 6.57 (m, 2H), 4.58 - 4.03 (m, 4H), 3.99 - 3.90 (m, 1H), 3.90 - 3.81 (m, 2H), 2.87 (s, 3H), 2.49 - 2.35 (m, 1H), 2.30 - 2.11 (m, 2H), 2.09 - 1.89 (m, 2H), 1.76 - 1.51 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With methanol; sodium cyanoborohydride; acetic acid; at 45℃; for 12h; | To a solution of intermediate 5 (6-(6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)6-azaspiro[3.4]octan-2-one) (200 mg, 0.586 mmol), <strong>[6274-22-2]4-amino-N-methylbenzamide</strong> (132 mg, 0.879 mmol), sodium cyanoborohydride (73.6 mg, 1.17 mmol), and MeOH (20 mL) was added a solution of AcOH (70.4 mg, 1.17 mmol) in MeOH (5 mL). After stirring at 45 C for 12 h, the reaction mixture was concentrated to dryness under reduced pressure to afford the crude product, which was purified by prep-HPLC (Gilson 281, Column: Agela ASB 150 x 25 mm x 5 um column, Mobile Phase A:water(0.05%HCI), B: ACN)). The pure fractions were collected and evaporated under vacuum to give a residue, which was lyophilized to dryness to give Compound 93 as a mixture of cis and trans isomers (173.9 mg, 61 % yield). The mixture was separated by SFC (AS-H, 3*25cm, Sum, mobile phase:CO,/ EtOH(0.1%NH3H20)=55/45, 40 ml/min). The pure fractions were collected and evaporated under vacuum to obtain residues, which were lyophilized to dryness to give the Compound 94 (36.83 mg, 23 % yield; trans or cis) as a white solid and Compound 95 (48.21 mg, 30% yield; cis or trans) as a white solid. Compound 93: 'H NMR (400MHz, Methol-a4) 6 8.65 - 8.55 (m, 1H), 8.04 - 7.86 (m, 3H), 7.55 - 7.33 (m, 2H), 4.46 - 4.13 (m, 3H), 4.12 - 3.82 (m, 4H), 2.93 (s, 3H), 2.71 2.42 (m, 4H), 2.39 - 2.31 (m, 1H), 2.28 - 2.19 (m, 1H). Compound 94: 'HNMRDMSO-d; (400 MHz): 68.32 (s, 1H), 7.99 - 7.96 (m, 1H), 7.70 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 8.8 Hz, 2H), 6.45 (d, J = 6.4 Hz, 1H), 4.36 - 3.75 (m, 7H), 2.72 (d, J= 4.4 Hz, 3H), 2.47 - 2.44 (m, 2H), 2.12 (br s, 2H), 1.99 - 1.95 (m, 2H). Compound 95: 'H NMR DMSO-d, (400 MHz): 6 8.33 (d, J= 5.6 Hz, 1H), 7.99 - 7.97 (m, 1H), 7.74 (s, 1H), 7.60 (d, J= 8.8 Hz, 2H), 6.53 - 6.47 (m, 2H), 4.11 - 3.76 (m, 7H), 2.72 (d, J= 4.4 Hz, 3H), 2.58 - 2.51 (m, 2H), 2.02 (br s, 2H), 1.95 - 1.90 (m, 2H). |
Tags: 6274-22-2 synthesis path| 6274-22-2 SDS| 6274-22-2 COA| 6274-22-2 purity| 6274-22-2 application| 6274-22-2 NMR| 6274-22-2 COA| 6274-22-2 structure
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