* 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.
General procedure: 4-Methanesulfonylphenyl benzoic acid (209) (0340) In a 250-mL round-bottom flask were combined the product from the previous reaction (9 g, 29.57 mmol, 1.00 equiv), methanol (150 mL), NaOH (3 g, 75.00 mmol, 2.54 equiv). The resulting solution was stirred for 5 h at 25 C., then concentrated under vacuum and diluted with 200 mL of H2O. The pH value of the aqueous was adjusted to 2 with HCl (2 M). The solids that formed were collected by filtration and dried in an oven, affording 6 g (73%) of the product as a white solid.
REFERENCE EXAMPLE 17c By employing essentially the same procedure as used in reference example 17a, except using the product from reference example 18c, there is prepared 4-[Pyrimidin-5-yl]-Benzoic Acid. 1H NMR (DMSO) d 7.95 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 2H), 9.23 (s, 2H), 9.25 (s, 1H), MS (EI) m/z 200 (M)+.
Reference Example 11c By employing essentially the same procedure as used in reference example 11a, except using the product from reference example 12c, there is prepared 4-[Pyrimidin-5-yl]-Benzoic Acid. 1H NMR (DMSO) d 7.95 (d, J=8 Hz, 2H), 8.10 (d, J=8 Hz, 2H), 9.23 (s, 21H), 9.25 (s, 1H), MS (EI) m/z 200 (M)+.
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20.0℃;
[0168] Step 2: To a mixture of (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15- 3 (10.8 mg, 0.05 mmol), <strong>[216959-91-0]4-(pyrimidin-5-yl)benzoic acid</strong> 15-4 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added Nu,Nu-diisopropylethylamine (DIEA, 17 mu, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(3-fluoro-4-(2-methylpyridin-4- yl)benzyl)-4-(pyrimidin-5-yl)benzamide 15 as a white powder. [0168] Step 2: To a mixture of (3-fluoro-4-(2-methylpyridin-4-yl)phenyl)methanamine 15- 3 (10.8 mg, 0.05 mmol), <strong>[216959-91-0]4-(pyrimidin-5-yl)benzoic acid</strong> 15-4 (10.0 mg, 0.05 mmol), and HATU (23 mg, 0.06 mmol) were added Nu,Nu-diisopropylethylamine (DIEA, 17 mu, 0.1 mmol) and DMF (0.5 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-(3-fluoro-4-(2-methylpyridin-4- yl)benzyl)-4-(pyrimidin-5-yl)benzamide 15 as a white powder. MS m/z 399.2 (M + 1).
(S)-3-((R)-2-(3-(aminomethyl)-4-propoxybenzyl)-3-phenylpropanoyl)-4-benzyl-oxazolidin-2-one hydrochloride[ No CAS ]
[ 216959-91-0 ]
[ 1441811-05-7 ]
Yield
Reaction Conditions
Operation in experiment
With diethyl cyanophosphonate; triethylamine; In N,N-dimethyl-formamide;Inert atmosphere;
General procedure: This compound was prepared by means of a procedure similar to that used for 7g and 7a. Under an argon atmosphere, diethyl cyanophosphonate (DEPC) (0.09 mL, 0.61 mmol) and triethylamine (0.18 mL, 1.30 mmol) were added to a solution of compound 9 (246 mg, 0.47 mmol) and 4-(2-pyridyl)benzoic acid (94 mg, 0.47 mmol) in dehydrated N,N-dimethylformamide (10 mL) at 0 C. The reaction mixture was left to stand overnight, then poured into a saturated aqueous solution of sodium hydrocarbonate, and the whole was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluant; n-hexane/ethyl acetate = 1:2 v/v) to afford the intermediate compound.
[Co(4-(5-pyrimidyl)benzoic acid(-1H))2(H2O)2][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
With sodium hydroxide; at 160.0℃; for 60h;pH 8.0;
A mixture of Co(NO3)2·6H2O (0.2 mmol, 0.058 g), HL(0.020 g, 0.1 mmol), and H2O 10 mL was placed in a ParrTeflon-lined stainless steel vessel (23 mL). Then the pH valuewas tuned into 8 using NaOH solution (0.5 M). After that themixturewas heated to 160C and held for 60 h. Then the reactantmixture was cooled at a rate of 0.5C/min to lead to the formationof red block crystal 1. Yield: 37% based on HL. ElementalAnal. Calcd. for C22H18CoN4O6 (493.33): C, 53.51; H, 3.65;N, 11.35%. Found: C, 53.50; H, 3.58; N, 11.45%. IR (KBr,cm-1): 3395(w), 1648(s), 1573(s), 1433(m), 1385(s), 1082(s),778(s).
[Co(4-(5-pyrimidyl)benzoic acid)2(H2O)4][ No CAS ]
Yield
Reaction Conditions
Operation in experiment
34%
With nitric acid; at 160.0℃; for 60h;pH 4.0;
A mixture of Co(NO3)2·6H2O (0.2 mmol, 0.058 g), HL(0.020 g, 0.1 mmol), and H2O 10 mL was placed in a ParrTeflon-lined stainless steel vessel (23 mL). Then the pH valuewas tuned into 8 using NaOH solution (0.5 M). After that themixturewas heated to 160C and held for 60 h. Then the reactantmixture was cooled at a rate of 0.5C/min to lead to the formationof red block crystal 1. Yield: 37% based on HL.
N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl](prop-2-en-1-yl)amino]-1-(4-methylpiperazin-1-yl)-1-oxopentan-2-yl]-4-(pyrimidin-5-yl)benzamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
70%
General procedure: 4-Cyano-N-[(2S)-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl](prop-2-en-1-yl)amino]-1-(4-hydroxypiperidin-1-yl)-1-oxopentan-2-yl]benzamide (211) (0366) In a 100-mL round-bottom flask were combined a solution of 4-cyanobenzoic acid (136.7 mg, 0.93 mmol, 1.20 equiv) CH2Cl2 (20 mL), i-Pr2NEt (298 mg, 2.31 mmol, 3.00 equiv), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (?HATU?) (439 mg, 1.15 mmol, 1.50 equiv), The mixture was stirred for 1 h, then a solution of (2S)-2-amino-5-[[(1R,2S)-2-(4-fluorophenyl)cyclopropyl](prop-2-en-1-yl)-amino]-1-(4-hydroxypiperidin-1-yl)pentan-1-one (300 mg, 0.77 mmol, 1.00 equiv) in CH2Cl2 (5 mL) was added. The resulting solution was stirred for 60 min at 25 C., then concentrated under vacuum and applied onto a silica gel column with CH2Cl2/methanol (10:1), affording 480 mg (120%) of the product as a light yellow liquid.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;
2.1.2. general procedure for amide synthesis (GP1)
General procedure: Method B: The primary free amine (1 mmol, 1 equiv.) was added to asolution of the carboxylic acid (1.3 mmol, 1.3 equiv., see SupportingInformation for the synthesis and characterization of the carboxylicacids 11a and 11b and its precursor, the rest of the carboxylic acids werepurchased), HATU (1.3 mmol, 1 equiv., 0.49 g) and DIPEA (2.60 mmol,2 equiv., 0.45 mL) in dry DMF (5 mL), under argon atmosphere. Theresulting solution was stirred at room temperature for 20 h. The reactionmixture was diluted with ethyl acetate (25 mL) and washed with asaturated NaHCO3 solution (3 × 20 mL) and brine (3 × 20 mL). Theorganic phase was dried over Na2SO4 and evaporated to give a cruderesidue that was purified by flash column chromatography.
With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate In N,N-dimethyl-formamide at 20℃; for 20h; Inert atmosphere;
2.1.2. general procedure for amide synthesis (GP1)
General procedure: Method B: The primary free amine (1 mmol, 1 equiv.) was added to asolution of the carboxylic acid (1.3 mmol, 1.3 equiv., see SupportingInformation for the synthesis and characterization of the carboxylicacids 11a and 11b and its precursor, the rest of the carboxylic acids werepurchased), HATU (1.3 mmol, 1 equiv., 0.49 g) and DIPEA (2.60 mmol,2 equiv., 0.45 mL) in dry DMF (5 mL), under argon atmosphere. Theresulting solution was stirred at room temperature for 20 h. The reactionmixture was diluted with ethyl acetate (25 mL) and washed with asaturated NaHCO3 solution (3 × 20 mL) and brine (3 × 20 mL). Theorganic phase was dried over Na2SO4 and evaporated to give a cruderesidue that was purified by flash column chromatography.
Stage #1: 4-methoxycarbonylphenyl bromide; pyrimidine 5-boronic acid With (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; sodium carbonate In N,N-dimethyl-formamide at 80℃; for 3h; Inert atmosphere;
Stage #2: With lithium hydroxide In tetrahydrofuran; water at 20℃; for 2h; Inert atmosphere;
1.2. general procedure for the synthesis of 11a and 11b (GP6)
General procedure: Compound 10 was synthesized according to the procedure reported in literature1 using room temperature conditions overnight. A stream of argon was passed through a suspension of aryl bromide 10 (0.43 mmol, 1 equiv.) the proper aryl/heteroaryl boronic acid (0.56 mmol, 1.3 equiv.), 2 M Na2CO3 (1.52 mL) and DMF (5 mL) for 10 min. PdCl2dppf (5 mol%) was then added and the reaction was warmed to 80 C and stirred under argon atmosphere. After 3h, 15 mL of water was added and the aqueous phase was extracted with ethyl acetate (3×15 mL). The crude product was used without purification in the next step that was performed according to the procedure from literature, 2 except for the reaction time, which was set at 2 hours.
Stage #1: 4-[Pyrimidin-5-yl]-Benzoic Acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: (l)-serine methyl ester hydrochloride In N,N-dimethyl-formamide
4.2. General procedure for the synthesis of intermediates 10a-k
General procedure: To a solution of different acids (2.45 mmol, 0.50 g) in DMF, HOBt(2.70 mmol, 0.36 g) and EDCI (2.70 mmol, 0.52 g) were added andthe mixture was stirred for 30 min at room temperature. Then, LSerineMethyl Ester Hydrochloride (2.70 mmol, 0.42 g) and DIEA(4.90 mmol, 0.64 g) were added. The reaction was stirred andmonitored with TLC. The mixture was poured into water andextracted with ethyl acetate three times. The combined organiclayers were dried over Na2SO4 and filtered. The filtrate was evaporatedunder reduced pressure to afford intermediates 10a-k, yield73.71% [17].
Stage #1: 4-[Pyrimidin-5-yl]-Benzoic Acid With benzotriazol-1-ol; N-[3-(N,N-dimethylamino)-propyl]-N'-ethyl-carbodiimide hydrochloride In N,N-dimethyl-formamide at 20℃; for 0.5h;
Stage #2: (l)-serine methyl ester hydrochloride In N,N-dimethyl-formamide
4.2. General procedure for the synthesis of intermediates 10a-k
General procedure: To a solution of different acids (2.45 mmol, 0.50 g) in DMF, HOBt(2.70 mmol, 0.36 g) and EDCI (2.70 mmol, 0.52 g) were added andthe mixture was stirred for 30 min at room temperature. Then, LSerineMethyl Ester Hydrochloride (2.70 mmol, 0.42 g) and DIEA(4.90 mmol, 0.64 g) were added. The reaction was stirred andmonitored with TLC. The mixture was poured into water andextracted with ethyl acetate three times. The combined organiclayers were dried over Na2SO4 and filtered. The filtrate was evaporatedunder reduced pressure to afford intermediates 10a-k, yield73.71% [17].
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