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CAS No. : | 6232-11-7 | MDL No. : | MFCD00182671 |
Formula : | C9H12ClNO2 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | GIZCKBSSWNIUMZ-UHFFFAOYSA-N |
M.W : | 201.65 | Pubchem ID : | 2729253 |
Synonyms : |
|
Num. heavy atoms : | 13 |
Num. arom. heavy atoms : | 6 |
Fraction Csp3 : | 0.22 |
Num. rotatable bonds : | 3 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 1.0 |
Molar Refractivity : | 52.36 |
TPSA : | 52.32 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) : | -6.12 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 1.99 |
Log Po/w (WLOGP) : | 1.58 |
Log Po/w (MLOGP) : | 1.67 |
Log Po/w (SILICOS-IT) : | 1.31 |
Consensus Log Po/w : | 1.31 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.49 |
Solubility : | 0.656 mg/ml ; 0.00325 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.71 |
Solubility : | 0.389 mg/ml ; 0.00193 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.51 |
Solubility : | 0.622 mg/ml ; 0.00308 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.2 |
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 |
---|---|---|
97% | With thionyl chloride In methanol at 20℃; for 16 h; | 4-(Aminomethyl)benzoic acid (302 mg, 2.00 mmol) was dissolved in MeOH (30 mL) and thionyl chloride (1.16 mL, 16.0 mmol) was carefully added dropwise at rt. The reaction mixture was stirred overnight at rt. Afterwards the solvent was removed under reduced pressure to yield 15d. Colorless solid, mp 234 °C, yield 390 mg (97 percent). C9H12ClNO2 (201.7). Rf = 0.22 (ethyl acetate/1percent diethylmethylamine, detection: 254 nm). 1H NMR (400 MHz, DMSO-D6): δ [ppm] = 3.86 (s, 3H, CO2CH3), 4.10 (s, 2H, H3NCH2), 7.63-7.67 (m, 2H, 3-HB, 5-HB), 7.96-8.01 (m, 2H, 2-HB, 6-HB), 8.61 (br s, 3H, NH3). 13C NMR (101 MHz, DMSO-D6): δ [ppm] = 41.7 (1C, H3NCH2), 52.2 (1C, CO2CH3), 129.2 (2C, C-3B, C-5B), 129.3 (2C, C-2B, C-6B), 129.5 (1C, C-1B), 139.4 (1C, C-4B), 165.9 (1C, CO2CH3). FT-IR: ν [cm-1] = 2963 (NH3+), 2878 (C-Haliph.), 2573 (NH3+), 1678 (C=O), 1597, 1578, 1477 (C=CAr), 864 (Ar-Hout of plane). HRMS (APCI): m/z = 166.0865 (calcd. 166.0863 for C9H12NO2 [M+H]+). HPLC: tR = 6.4 min, purity 99.9 percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | at 0℃; for 24 h; Reflux | Example 1: Preparation of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-l- oxoisoindolin-2-yl) methyl)benzamideStep 1 : Preparation of methyl 4-(aminomethyl)benzoate hydrochloride4-Aminomethylbenzoic acid (2.0 g, 13 mmol) was dissolved in MeOH(5.0 mL), thionylchloride (2.9 mL, 3 equiv.) was slowly added thereto at 0 °C and fluxed for 24 hrs. The mixture thus obtained was distilled under a reduced pressure to remove the solvent and thionyl chloride, and dried under vacuum to obtain the title compound (2.7 g, 99 percent).1H NMR (300 MHz, D2O): δ 7.93 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 4.12(s, 2H), 3.79 (s, 3H). |
93% | at 0 - 75℃; for 5 h; | Compound 5 (1.5 g, 10 mmol) was dissolved in 200 mL MeOH, thenacetyl chloride (2.4 g, 30 mmol) was added dropwise at 0 °C; themixed solution was refluxed at 75 °C for 5 h. The solvent wasevaporated under vacuum, the product was washed by diethylether to give compound 6, a white solid powder (1.7 g, 93percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With thionyl chloride at 0 - 20℃; for 24h; | |
99% | With thionyl chloride at 20℃; for 96h; | |
99% | With thionyl chloride at 0℃; for 24h; Reflux; | 1.1 Example 1: Preparation of N-(2-aminophenyl)-4-((4-bromo-5,6-dimethoxy-l- oxoisoindolin-2-yl) methyl)benzamideStep 1 : Preparation of methyl 4-(aminomethyl)benzoate hydrochloride4-Aminomethylbenzoic acid (2.0 g, 13 mmol) was dissolved in MeOH(5.0 mL), thionylchloride (2.9 mL, 3 equiv.) was slowly added thereto at 0 °C and fluxed for 24 hrs. The mixture thus obtained was distilled under a reduced pressure to remove the solvent and thionyl chloride, and dried under vacuum to obtain the title compound (2.7 g, 99 %).1H NMR (300 MHz, D2O): δ 7.93 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.4Hz), 4.12(s, 2H), 3.79 (s, 3H). |
99% | With thionyl chloride at 0 - 20℃; | |
98% | With hydrogenchloride for 5h; Heating; | |
98% | With thionyl chloride for 4h; Reflux; Inert atmosphere; | |
98% | With thionyl chloride for 12h; Reflux; | |
97% | With chloro-trimethyl-silane at 20℃; for 24h; | |
95% | With hydrogenchloride In water Reflux; | |
93% | With acetyl chloride at 0 - 75℃; for 5h; | 3.1.1.1. Methyl 4-(aminomethyl)benzoate hydrochloride (6). Compound 5 (1.5 g, 10 mmol) was dissolved in 200 mL MeOH, thenacetyl chloride (2.4 g, 30 mmol) was added dropwise at 0 °C; themixed solution was refluxed at 75 °C for 5 h. The solvent wasevaporated under vacuum, the product was washed by diethylether to give compound 6, a white solid powder (1.7 g, 93%). |
62% | for 0.166667h; Heating; | |
With thionyl chloride at 70℃; | ||
With thionyl chloride at 20℃; for 12h; Inert atmosphere; | ||
With hydrogenchloride In water Reflux; | ||
With thionyl chloride for 12h; Reflux; | 2.1 Synthesis Example of axle component 4- (aminomethyl) benzoic acid 9.06 g (60.0 mmol) was dissolved in methanol 400 mL, and then thionyl chloride 20 mL was added dropwise, and refluxed for 12 hours. Excess thionyl chloride and the solvent were distilled off under reduced pressure to obtain a white solid, which was then washed with ethyl acetate, & vacuum dried to give 8.16 g of 4- (methoxycarbonyl) benzyl ammonium hydrochloride. | |
With hydrogenchloride Reflux; | 2 Intermediate formation 6050 mg (40 mmol) of 4-(aminomethyl)benzoic acid was dissolved in 200 mL of methanol, to which was added 6 mLs of concentrated HC1 in one portion. The mixture was refluxed overnight and the volatiles condensed under vacuum. The resulting white solid was suspended in ethyl ether and separated via vacuum filtration to yield the benzoate HC1 salt. This compound was dissolved in a 1:2 mixture of ethyl acetate and water and chilled to 0°C to which 11040mg (80 mmol) was added followed by addition of 5623 mg benzoyl chloride (40 mmol). The vessel was warmed to room temperature and stirred for 2 additional hours. The mixture was separated via acid/base extraction, washing the water phase twice with ethyl acetate. All organic phases were combined and condensed under vacuum to yield a white solid. This was suspended in 200 mL of methanol and 10000 mg (200 mmol) of hydrazine water salt was added. The solution was refluxed for 48 hours, cooled to room temperature, and volatiles were removed under vacuum. This intermediate N-(4-(hydrazinecarbonyl)benzyl)benzamide (2sm) was used as the starting material for all further reactions for this family. | |
With thionyl chloride for 6h; Inert atmosphere; Reflux; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With dmap In dichloromethane at 20℃; for 16h; | 9 A solution of benzenesulfonyl chloride (1.76g, lOmmol), 4-aminomethyl-benzoic acid methyl ester HCl salt (2.02g, lOmmol) and Dimethyl-pyridin-4-yl-amine (DMAP, 3.66g, 30mmol) in CH2Cl2 (2OmL) was stirred at room temp for 16 hours. After dilution with CH2Cl2 (10OmL) and the resulting solution was washed with H2O (5OmL), HCl (IN, 5OmL), NaHCO3 (10%, 5OmL) and H2O (5OmL). The organic solvent was dried over anhydrous Na2SO4. The solvent was evaporated to provide 21 as a white solid (3.02g,1H NMR (300 MHz, DMSO-d6) δ 8.29 (t, J= 5.7 Hz, IH), 7.86 (d, J= 8.4 Hz, 2H), 7.80 (d, J= 7.2 Hz, 2H), 7.63 - 7.57 (overlapping, 3H), 7.39 (d, J= 7.5 Hz, 2H), 4.08 (d, J = 5.4 Hz, 2H), 3.83 (s, 3H). |
49% | With dmap In dichloromethane at 20℃; for 16h; Inert atmosphere; Schlenk technique; | |
49% | With dmap In dichloromethane at 20℃; for 16h; Inert atmosphere; Schlenk technique; | 28.a a. Preparation of methyl 4-(phenylsulfonamidomethyl)benzoate. A solution of benzenesulfonyl chloride (176.6 mg, 1 mmol, 128 pL, 1 eq.), methyl 4- (aminomethyl)benzoate hydrochloride (201.7 mg, 1 mmol, 1 eq.) and 4- dimethylaminopyridine (366.5 mg, 3 mmol, 3 eq.) in DCM (2 mL) was stirred for 16 h at room temperature. After dilution with DCM (10 mL) the solution was washed with water (10 mL), aqueous hydrochloric acid (1 M, 10 mL), aqueous sodium bicarbonate solution (10%, lO mL) and brine (10 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. The crude product was purified by preparative HPLC to provide the title compound (149 mg, 0.49 mmol, 49%).1H NMR (300 MHz; CD3CN): d = 3.85 (s, 3H, -OCH3), 4.13 (d, 2H, JHH = 6.2 Hz, -CH2-), 6.13 (t, 1H, 3JHH = 6.3 Hz, -NH-), 7.33 (d, 2H, JHH = %2 Hz, -CH2-C-CH-), 7.51-7.65 (m, 3H, -S02-C-CH-CH-CH-), 7.81-7.84 (m, 2H, -S02-C-CH-), 7.89 (d, 2H,3JHH = 8.2 HZ, -CO-C-CH-) ppm. 13C NMR (75.5 MHz; CDCl3): d = 47.0 (1C, -CH2-), 52.3 (1C, -OCH3), 127.2 (2C, -S02-C-CH-), 127.8 (2C, -CH2-C-CH-), 129.4 (2C, -S02-C-CH-CH-), 129.9 (1C, -CO-C-), 130.1 (2C, -CO-C-CH-), 133.01C, -S02-C-CH-CH-CH-), 139.9 (1C, -S02-C-), 141.5 (1C, -CH2-C-), 166.8 (1C, -CO-) ppm. HRMS (ESI+) calcd. for CI 5HI6N04S+: 306.0795; found: 306.0792. HRMS (ESI ) calcd. for C15H14NO4S-: 304.0649; found: 304.0653. |
With TEA In tetrahydrofuran |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; methanesulfonyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 15h; Stage #2: With methanol; sodium hydroxide; water for 16h; Stage #3: With hydrogenchloride In water | 207.A 4-[(methylsulfonyl)amino]methyl}benzoic acid Step A 4-[(methylsulfonyl)amino]methyl}benzoic acid A suspension of methyl 4-(aminomethyl)benzoate hydrochloride salt (0.541 g, 2.7 mmol) in dry CH2Cl2 (7 mL) was cooled to 0° C., and methanesulfonyl chloride (0.48 mL, 6.2 mmol) and diisopropylethylamine (1.5 mL, 8.8 mmol) were added. The resulting mixture was allowed to warm to room temperature and stir for 15 h. The reaction was then diluted with CH2Cl2 (10 mL) and washed with H2O (10 mL), a saturated aqueous solution of NaHCO3 (10 mL), and brine (10 mL) successively. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (14 mL), and NaOH (1.29 g, 32 mmol) dissolved in H2O (7 mL) was added. The reaction was stirred for 16 h and was then concentrated in vacuo. The residue was dissolved in H2O (10 mL) and acidified to pH 1 with 3 N HCl. The aqueous phase was extracted with EtOAc (3*50 mL), and the combined organic phases were dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound as a slightly yellow powder (0.60 g, 98% over 2 steps), which was used in subsequent steps without further purification. 1H NMR (400 MHz, DMSO-D6) δ ppm 2.88 (s, 3H), 4.22 (d, J=6.2 Hz, 2H), 7.45 (d, J=8.6 Hz, 2H), 7.65 (t, J=6.3 Hz, 1H), 7.86-7.95 (m, 2H), 12.91 (s, 1H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; cyclopropanesulfonyl chloride With N-ethyl-N,N-diisopropylamine In dichloromethane at 0 - 20℃; for 89h; Stage #2: With methanol; sodium hydroxide; water for 20h; Stage #3: With hydrogenchloride In water | 236.A 4-[(cyclopropylsulfonyl)amino]methyl}benzoic acid Step A 4-[(cyclopropylsulfonyl)amino]methyl}benzoic acid A suspension of methyl 4-(aminomethyl)benzoate hydrochloride salt (0.395 g, 2.0 mmol) in dry CH2Cl2 (5 mL) was cooled to 0° C., and cyclopropanesulfonyl chloride (0.46 mL, 4.5 mmol) and diisopropylethylamine (1.1 mL, 6.3 mmol) were added. The resulting mixture was allowed to warm to room temperature and stir for 89 h. The reaction was then diluted with CH2Cl2 (10 mL) and washed with H2O (10 mL), a saturated aqueous solution of NaHCO3 (10 mL), and brine (10 mL) successively. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was dissolved in MeOH (10 mL), and NaOH (0.94 g, 24 mmol) dissolved in H2O (5 mL) was added. The reaction was stirred for 20 h and was then concentrated in vacuo. The residue was dissolved in H2O (7 mL) and acidified to pH 1 with 3 N HCl. The resulting precipitate was collected by filtration and washed with H2O to provide the title compound as a tan solid (0.46 g, 93% over 2 steps), which was used in subsequent steps without further purification. 1H NMR (400 MHz, METHANOL-D4) δ ppm 0.88-0.96 (m, 2H), 0.99-1.05 (m, 2H), 2.40-2.48 (m, 1H), 4.35 (s, 2H), 7.46-7.52 (m, 2H), 7.97-8.02 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With triethylamine In N,N-dimethyl-formamide at 80℃; for 4h; | 14 Example 14: Preparation of 4-[(3-Cyano-4-furan-3-yl-6-thiophen-2-yl-pyridin-2- ylamino)-methyl] -benzoic acid methyl ester (Step C); Trifluoro-methanesulfonic acid 3-cyano-4-furan-3-yl-6-thiophen-2-yl-pyridin-2-yl ester (80 mg, 0.20 mmol) was placed into reaction flask and dissolved with dry DMF (10 mL). Triethylamine (111 μL, 0.79 mmol) was added followed by methyl 4-(aminomethyl)-benzoate HCl (81 mg, 0.40 mmol). The reaction mixture was stirred at 80 0C. After 4 h of reaction time, the reaction was quenched by addition of water (10 mL). A light orange solid was formed which was collected by filtration and suction dried and obtained a dark cream solid (72.5 mg, 87%).ηPLCmethod2 91.7%/2.62 min.MS (ESI+) m/z 416 (M+l). 1HNMR (CDCl3, 300 MHz) 8.06(app t, H2 of furan), 7.92 (app d, /AA-BB- 8.7 Hz, 2xArH next to COOMe), 7.59 (app d, / 3.9 Hz, H5 of thiophene), 7.48 (t, / 1.8 Hz, H5 of furan), 7.43 (app d, /AA'BB- 8.4 Hz, 2xArH next to CH2NH), 7.37 (dd, / 5.1 Hz, 1.5 Hz, H4 of furan), 7.03 (dd, / 5.1 Hz, 3.6 Hz, H4 of thiophene), 6.99 (s, IH of pyridine), 6.80 (app d, /2.4 Hz, H2 of thiophene), 4.77 (s, CH2), 3.80 (s, CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91.3% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride With triethylamine; 1,1'-Thiocarbonyldiimidazole In chloroform at 20℃; for 3h; Stage #2: With ammonia In methanol; chloroform; water | 1.1 Example 1; 4-(N-(4-(4-(N-(4-cyclohexylbenzyl)-N-methylamino)phenyl)-2-thiazolyl)-N-methylaminomethyl)benzoic acid; (1) 1-(4-methoxycarbonylbenzyl)-2-thiourea Under an argon atmosphere, to a suspension of methyl 4-aminomethylbenzoate hydrochloride (170.0 g, 0.843 mol) in chloroform (850 ml, 5.0 v/w) were successively added 1,1'-thiocarbonyldiimidazole (purity 90%, 166.0 g, 0.843 mol) and triethylamine (123 ml, 0.885 mol). After stirring at room temperature for 3 hr, 28% aqueous ammonia (570 ml, 8.43 mol) and methanol (170 ml, 1.0 v/w) were added and the mixture was stirred overnight. n-Hexane (1700 ml, 10.0 v/w) and water (850 ml, 5.0 v/w) were successively added to the reaction mixture and the mixture was stirred at room temperature for 3 hrs. The precipitated crystals were collected by filtration, washed successively with n-hexane (500 ml) and water (500 ml) and dried in vacuo to give the title compound (172.5 g, yield 91.3%) as a colorless solid.1H-NMR(300MHz,DMSO-d6) δ 3.84(3H,s), 4.40(1H,brs), 4.72 (2H,brs) , 7.17(1H,brs), 7.41(2H,d,J=8.1Hz), 7.93(2H,d,J=8.4Hz), 8.07(1H,brs). |
Multi-step reaction with 2 steps 1: 83 percent / CaCO3 / H2O; CHCl3 / 16 h / 20 °C 2: 99 percent / NH3 / CH2Cl2 / 3.5 h / 0 °C |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.e To a solution of methyl 4- (aminomethyl) benzoate hydrochloride (0.22 g, [1.] [1] mmol) and triethylamine (0.22 g, 2.2 mmol) in dichloromethane (20 [ML)] was added the acid chloride (0.33 g, 1.01 mmol) prepared in (e). The reaction mixture was stirred at room temperature for 16 hour, then diluted with aqueous HCl [(1M,] 20 mL). The organic phase was separated, washed with brine, dried [(MGS04),] and concentrated in vacuo. The residue was recrystallized from hexane/ethyl acetate to give a white solid (0. [38] [G,] [83%). LHNMR] (DMSO-d6) [6] 9.4 (t, [1H),] 8.5 (s, 1H), 8. 2 (d, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7. [8] (t, [1H),] 7.5 (d, 2H), 7.4 (d, 2H), 6.9 (d, [2H),] 5.9 (s, 2H), 4.5 (d, [2H),] 3. [8] (s, [3H),] 3.7 (s, 3H) ppm. Mp [167-168 °C.] |
83% | With triethylamine In dichloromethane at 20℃; for 16h; | 1.e Step (e): 4-({3-[2-(4-Methoxy-benzyl)-2H-tetrazol-5-yl]-benzoylamino}-methyl)-benzoic acid methyl ester To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (0.22 g, 1.1 mmol) and triethylamine (0.22 g, 2.2 mmol) in dichloromethane (20 mL) was added the acid chloride (0.33 g, 1.01 mmol) prepared in Step (d). The reaction mixture was stirred at room temperature for 16 hour, then diluted with aqueous HCl (1M, 20 mL). The organic phase was separated, washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was recrystallized from hexane/ethyl acetate to give a white solid (0.38 g, 83%). 1H-NMR (DMSO-d6) δ9.4 (t, 1H), 8.5 (s, 1H), 8.2 (d, 1H), 8.1 (d, 1H), 7.9 (d, 2H), 7.8 (t, 1H),7.5 (d, 2H), 7.4 (d, 2H), 6.9 (d, 2H), 5.9 (s, 2H), 4.5 (d, 2H), 3.8 (s, 3H), 3.7 (s, 3H) ppm. Mp 167-168° C. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
70% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In DMF (N,N-dimethyl-formamide) at 20℃; | 2.1 To a stirred solution of 15 g (74.4 mmol) of methyl 4- (aminomethyl) benzoate hydrochloride, 300 ml of [DIMETHYLFORMAMIDE] and 10.3 ml (7.53g, 74.4 mmol) of triethylamine were added, at room temperature, followed by 10.06 g (74.4 mmol) of [1-] hydroxybenzotriazole hydrate, 19.6 g (74.4 mmol) of 2-amino-5-iodobenzoic acid and 14.3 g (74.4 mmol) of 1- (3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride. After stirring at room temperature overnight, the mixture was concentrated and the residue was dissolved in 300 ml of dichloromethane. The organic phase was washed with 150 ml water, 150 ml HCl [IN,] and 150 ml water, dried over sodium sulfate and concentrated. The residue was recrystallized from 170 [ML] acetonitrile to afford after filtration 19.6 g (70%) of the desired product. N. M. R: [DMSO 1H 6] (ppm): 3.8 (s, 3H), 4.45 (d, 2H), 6.5-6. 6 (m, 3H), 7.3-7. 45 (m, 3H), 7.8-7. 95 (m, 3H), [8.] 9 (t, lH); Purity (HPLC): 99.1 % |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With dmap; triethylamine In dichloromethane at 20℃; for 2.5h; | 5 To a solution of 4-Aminomethyl-benzoic acid methyl ester hydrochloride (0.425 g, 2.11 mmol), triethylamine (0.60 mL, 0.4. 31 mmol) and DMAP (0.020 g, 0.16 mmol) in CH2CI2 (10 mL) was added benzoyl isocyanate (Sigma-Aldrich, 90% pure, 0.413 g, 0.2. 53 mmol), The reaction mixture was stirred at room temperature for 2.5 h and was evaporated to dryness. The white residue was added water, filtered and the solid was washed with water (x4) and dried. 4- (3-Benzoyl-ureidomethyl)-benzoic acid methyl ester was obtained as white solid (0.586 g, 89%). HPLC purity at 254nm: 99.7% ; LC-MS (ESI, positive mode) m/z 313 ( [M+H] +) ; 'H NMR (DMSO-d6) 8 9. 12 (1H, t, J = 5.4 Hz), 8.68 (1H, s), 8.04 (2H, dt, J = 8.4, 1.8 Hz), 7.89 (2H, dt, J = 8. 2, 1.6 Hz), 7.62 (1 H, tt, J = 7.4, 1.8 Hz), 7.50 (2H, t, J = 8.0 Hz), 7.44 (2H, d, J = 8. 4 Hz), 4.64 (2H, d, J = 6. 0 Hz), 3.93 (3H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In ethanol for 3h; Heating / reflux; Stage #2: With sodium hydrogencarbonate In water for 1h; | 6; 29.2 To a solution of methyl 44aminomethyl) benzoate hydrochloride (5 g) in dry ethanol (25 mL) was added 1H-pyrazole-1-carboxamidine hydrochloride (4.4 g) followed by DIPEA (13.0 mL) and the mixture was refluxed for 3 h. Ethanol was removed under vacuum. To the remaining viscous oil saturated solution of NaHC03 (50 mL) was slowly added under vigorous stirring followed by addition of 300 ml water (resultant pH 9). A white solid is formed and stirring was continued for lh. This material was filtered off, washed with water (200 mL) and tert-butyl methyl ether (50 mL), and dried to give the title compound 24 as a white powder (4.7 g, 91%).'H NMR (400 MHz, DMSO-d6) 8 (ppm): 7.91 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 4.39 (s, 2H), 3.83 (s, 3H), 3.80-2. 80 [m, 4H + 2H20 (determined by elemental analysis]). |
77% | With N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide | |
77% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; 1H-pyrazole-1-carboximidamide hydrochloride With N-ethyl-N,N-diisopropylamine In DMF (N,N-dimethyl-formamide) at 20℃; for 4h; Stage #2: With sodium hydrogencarbonate In water | 7.2 Step 2: Methyl (4-GUANIDINOMETHYL) benzoate; (40) [0204] To a stirred suspension of methyl 4-aminomethyl-benzoate hydrochloride (39,15. 7 g, 77.8 MMOL) and DIISOPROPYLETHYLAMINE (29.5 ML, 171.2 MMOL) in DMF (85.6 ml) at room temperature under nitrogen was added PYRAZOLE-L-CARBOXAMIDINE HYDROCHLORIDE (12.55 g, 85.6 MMOL). After 4 h the reaction mixture as a clear solution was concentrated to dryness under vacuum and saturated aqueous solution of NAHC03 (35 ml) was added to give a suspension. The solid was separated by filtration and washed with cold water. The mother liquor was concentrated to produce additional amount of a solid material which was also collected by filtration. Both solids were combined, triturated with H20 (50 ml), filtered off, washed with cold H20 and diethyl ether, and dried to afford the title compound 40 (12.32 g, 77% yield) as a white crystalline solid. 1H NMR: (400 MHz, DMSO-d6) 5 (ppm): 9.20-8. 00 (m, 4H), AB system (8 A = 7.91, DB = 7. 39, JAB = 8. 2 Hz, 4H), 4.39 (bs, 2H), 3.83 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
67% | With 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate; triethylamine In dichloromethane at 0 - 20℃; for 6h; | 43.1 EXAMPLE 43 4-[( { [5-CHLORO-2-(4-FLUOROPHENOXY) PYRIDIN-3- YL] CARBONYL} AMINO) METHYL] BENZOIC ACID STEP 1. METHYL 4-R ( F5-CHLORO-2- (4-FLUOROPHENOXV) PYRIDIN-3- YLLCARBONYL} AMINO) METHYLLBENZOATE; To a stirred solution of 5-CHLORO-2- (4-FLUOROPHENOXY) nicotinic acid (150 mg, 0.56 mmol), methyl 4- (aminomethyl) benzoate hydrochloride (136 mg, 0.67 mmol), and triethylamine (0.31 mL, 2.24 mmol) in dichloromethane (8 mL) was added 2-bromo- 1-ethylpyridinium tetrafluoroborate (230 mg, 0.84 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane (50 ML) and washed with 1 N hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 ML), and brine (30 ML). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2: 1) to afford 155 mg (67%) of the title compounds as white solids : H-NMR (CDC13) B 8.59 (1H, dd, J = 2.6, 0.9 Hz), 8.26- 8.17 (1H, m), 8.13 (1H, dd, J = 2. 8,0. 9 HZ), 8.00 (2H, d, J = 8. 1 Hz), 7.41 (2H, d, J = 8.1 Hz), 7.15-7. 07 (4H, m), 4.76 (2H, d, J = 5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 415 (M + H) +, 413 (M-H)-. |
67% | With 2-bromo-1-ethylpyridin-1-ium tetrafluoroborate; triethylamine In dichloromethane at 0 - 20℃; for 16h; | 43.1 To a stirred solution of 5-chloro-2- (4-fluorophenoxy)nicotinic (EP 1229034, 150 mg, 0.56 mmol), methyl 4- (aminomethyl)benzoate hydrochloride(136 mg, 0.67 mmol), and triethylamine (0.31 mL, 2.24 mmol) in dichloromethane (8 mL) was added 2-bromo-1-ethylpyridinium tetrafluoroborate (230 mg, 0.84 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 16 h. The mixture was diluted with dichloromethane (50 mL) and washed with 1 M hydrochloric acid (30 mL), saturated aqueous sodium hydrogen carbonate solution (30 mL), and brine (30 mL). The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with hexane/ethyl acetate (2:1 ) to afford 155 mg (67%) of the title compounds as white solids: H- NMR (CDCI3) No. 8.59 (1 H, dd, J=2.6,0.9 Hz), 8.26-8.17 (1 H, m), 8.13 (1 H, dd, J=2.8,0.9 Hz), 8.00 (2H, d, J=8.1 Hz), 7.41 (2H, d, J=8.1 Hz), 7.15-7.07 (4H, m), 4.76 (2H, d, J=5.9 Hz), 3.90 (3H, s) ; MS (ESI) m/z 415 (M + H) +, 413 (M - H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Methyl 4-(aminomethyl)-benzoate hydrochloride (manufactured by Aldrich Corporation) (773 mg) was dissolved in THF (50 ml) and then gradually added with lithium aluminum hydride (300 mg) under ice-cooling. The solution was stirred at room temperature for 3 hours and then cooled with ice, followed by gradual addition of a concentrated sodium hydroxide aqueous solution until foam was not observed. Celite filtration was carried out on the solution using chloroform as a solvent and then the filtrate was concentrated and dried. The dried product was dissolved in purified water (10 ml) and THF (10 ml). After having been cooled with ice, the solution was added with N-carbethoxyphthalimide (1.26 g) and sodium carbonate (900 mg). After the mixture had been stirred at room temperature for 4 hours, THF was distilled off and chloroform was then added to the residue to carry out extraction. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. Subsequently, the residue was further dried under vacuum. Next, this compound was dissolved in chloroform (20 ml) and then added with manganese dioxide (5.0 g), followed by stirring at room temperature for 3 hours. After the solution had been subjected to Celite filtration, the filtrate was concentrated and then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (259 mg) as a white solid. MS(FAB,Pos.):m/z=266[M+H]+ 1H-NMR(500MHz,CDCl3):delta=4.92(2H,s),7.58(2H,d,J=8.3Hz),7.72-7.76(2H,m),7.83-7.89(4H,m)9.98(1H,s). | ||
Methyl 4-(aminomethyl)-benzoate hydrochloride (manufactured by Aldrich Corporation) (773 mg) was dissolved in THF (50 ml) and then gradually added with lithium aluminum hydride (300 mg) under ice-cooling. The solution was stirred at room temperature for 3 hours and then cooled with ice, followed by gradual addition of a concentrated sodium hydroxide aqueous solution until foam was not observed. Filtration through Celite was carried out using chloroform as a solvent and then the filtrate was concentrated and dried. The dried product was dissolved in purified water (10 ml) and THF (10 ml). After having been cooled with ice, the solution was added with N-carbethoxyphthalimide (1.26 g) and sodium carbonate (900 mg). After the mixture was stirred at room temperature for 4 hours, THF was distilled off and chloroform was then added to the residue to carry out extraction. The organic layer was dried with anhydrous sodium sulfate and the solvent was then distilled off. Subsequently, the residue was further dried under vacuum. Next, this compound was dissolved in chloroform (20 ml) and then added with manganese dioxide (chemically processed product) (5.0 g), followed by stirring at room temperature for 3 hours. After filtration through Celite, the filtrate was concentrated and then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (259 mg) as a white solid. MS(FAB,Pos.):m/z=266[M+H]+ 1H-NMR(500MHz,CDCl3):delta=4.92(2H,s),7.58(2H,d,J=8.3Hz),7.72-7.76(2H,m), 7.83-7.89(4H,m), 9.98(1H,s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
50% | With caesium carbonate In toluene at 100℃; for 16h; | 5; 25.4 To a solution of 19 (2.7 g, 8.4 mmol) and methyl 44aminomethyl) benzoate hydrochloride (2.7 g, 13.5 mmol) in dry toluene (33 mL) was added cesium carbonate (8.2 g, 25.3 mmol) followed by Pd2 (dba) 3 (464 mg, 0.51 mmol) and rac-BINAP (473 mg, 0.76 mmol). The solution was degassed and heated at 100°C for 16 h. The reaction mixture was partitioned between water and EtOAc and the phases were separated. The organic layer was successively washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to form a residue which was purified by flash chromatography on silica gel (MeOH/CH2CI2 : 2/98) to afford the title compound 20 (1.9 g, 4.2 mmol, 50% yield). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | Stage #1: 4,6-Dichloro-2-(methylthio)pyrimidine; methyl 4-(aminomethyl)benzoate hydrochloride With N-ethyl-N,N-diisopropylamine In tetrahydrofuran; DMF (N,N-dimethyl-formamide) at 70 - 80℃; for 24h; Stage #2: With sodium hydrogencarbonate In tetrahydrofuran; DMF (N,N-dimethyl-formamide); water | 16; 48.1 A stirred suspension of 4, 6-dichloro-2- (methylthio) pyrimidine (657 mg, 3.37 mmol) or 4, 6-dichloro-2-(R)-pyrimidine, methyl 4-(aminomethyl) benzoate. HCI (744 mg, 3.69 mmol) and F Pr2NEt (2.34 mL, 13.43 mmol) in a mixture of anhydrous THF/DMF (10 mL/2 mL) under nitrogen was heated at 70-80ex for 24 h. The mixture was allowed to cool down to room temperature, poured into a saturated NaHC03 and extracted with AcOEt. The organic layer was washed with water, saturated NH4CI, H20 and brine, dried over anhydrous MgS04, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent AcOEt/CH2Cl2, 30/70, then 40/60) to afford the title compound 59a (929 mg, 2.87 mmol, 85% yield) as a beige powder. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | With triethanolamine; In dichloromethane; | Step 1 Synthesis of methyl 4-N-(1,1-dimethylethoxycarbonyl)aminomethylbenzoate(32) To a solution of 500 mg (2.48 mmol) of methyl 4-aminomethylbenzoate HCl salt (31) in CH2Cl2 (10 mL) were added 753 mg (7.45 mmol) of TEA and 568 mg (2.60 mmol) of Boc2O in CH2Cl2 (1 mL) at 0 C. After 30 minutes, the reaction mixture was warmed to room temperature. After additional stirring for 4 hours, CH2Cl2 was added to the reaction solution. The organic layer was washed with 0.1 N HCl solution, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc =1:1) to give 620 mg of compound 32 in 94% yield. H NMR (CDCl3): 7.58 (d, J8.2 Hz, 2H), 7.34 (d, J=8.2 Hz, 2H), 4.90 (br s, 1H), 4.37 (d, 2H), 3.91 (s, 3 H), 1.46 (s, 9H); 13C NMR (CDCl3): 167.02, 156015, 144042, 130.03, |
With triethylamine; In methanol; for 0.5h; | Triethylamine (1 ml) and di-tert-butyl dicarbonate (1.2 g, 5.5 mmol) were added to a solution of methyl 4-(aminomethyl)-benzoate hydrochloride (1.0 g, 5.0 mmol) in methanol (10 ml). After 30 minutes of stirring, water was added thereto, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution and then concentrated under reduced pressure. To the resulting residue were added methanol (15 ml) and a 1N aqueous sodium hydroxide solution (5 ml), and the resulting mixture was heated to 60C. After 1 hour of stirring, water was added thereto and the aqueous layer was washed with diethyl ether, followed by adding thereto a 2N-aqueous hydrochloric acid solution. The crystals were collected by filtration using a Kiriyama funnel, and dried under reduced pressure to obtain the desired compound (0.88 g, 70%). 1H-NMR (CDCl3) delta 1.47(s, 9H), 4.39(br.s, 2H), 4.96(br.s., 1H), 7.38(d, J=8.3Hz, 2H), 8.07(d, J=8.3Hz, 2H). | |
1.93 g | Et3N (1.882 g, 2.592 mL, 18.60 mmol) was added to a stirred suspension of methyl 4-(aminomethyl)benzoate (Hydrochloric Acid (1)) (1.5 g, 7.439 mmol) in THF (20 mL) at 0 C. The reaction was allowed to stir at this te,perature for 30 minutes then B0C2O (1.705 g, 1.795 mL, 7.81 1 mmol) was added in portions. The reaction was allowed to warm to ambient temperature and stirred for 18 hours. The mixture was diluted with EtOAc. The organic layer was washed with 1M aqueous HCl (x 2), saturated aqueous aHC03 (x 2) and brine (x 1). The organic layer was dried (MgS04), filtered and concentrated in vacuo to give the sub-title compound as a white solid that was used without further purification (1.93 g, 98% Yield); 1H NMR (400 MHz, DMSO) ? 1.40 (s, 9H), 3.85 (s, 3H), 4.20 (d, J = 6.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.49 (t, J = 6.1 Hz, 1H) and 7.92 (d, J = 8.2 Hz, 2H) ppm; MS (ES+) 251.1 (M-Me). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium tris(acetoxy)borohydride In water; acetic acid; 1,2-dichloro-ethane | 4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-ylureidomethyl]-N-(2H-tetrazol-5-yl)-benzamide 4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-ylureidomethyl]-N-(2H-tetrazol-5-yl)-benzamide 4-Aminomethylbenzoic acid methyl ester hydrochloride (1.45 g, 7.2 mmol) was suspended in 1,2-dichloroethane (50 mL) and added saturated aqueous potassium carbonate. The phases were separated and the aqueous layer was extracted with another portion of 1,2-dichloro-ethane (50 mL). The combined organic phases were added glacial acetic acid (435 μL, 7.6 mmol) followed by spiro[5.5]undecan-3-one (1.2 g, 7.2 mmol). The suspension was stirred for 30 min at 25° C. and sodium triacetoxyborohydride (2.27 g, 10.7 μmol) was added. After stirring for 2 days at 25° C., water (100 mL) and saturated aqueous potassium carbonate (15 mL) were added. The phases were separated and the aqueous layer was extracted with 1,2-di-chloroethane (2*100 mL). The combined organic phases were washed with water (100 mL) and brine (100 mL), dried over MgSO4 and evaporated to afford 4-(spiro[5.5]undec-3-ylaminomethyl)benzoic acid methyl ester which was used in the subsequent steps without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.3% | With methanol; thionyl chloride Reflux; | |
97% | With thionyl chloride In methanol at 20℃; for 16h; | Methyl 4-(aminomethyl)benzoate hydrochloride (15d) 4-(Aminomethyl)benzoic acid (302 mg, 2.00 mmol) was dissolved in MeOH (30 mL) and thionyl chloride (1.16 mL, 16.0 mmol) was carefully added dropwise at rt. The reaction mixture was stirred overnight at rt. Afterwards the solvent was removed under reduced pressure to yield 15d. Colorless solid, mp 234 °C, yield 390 mg (97 %). C9H12ClNO2 (201.7). Rf = 0.22 (ethyl acetate/1% diethylmethylamine, detection: 254 nm). 1H NMR (400 MHz, DMSO-D6): δ [ppm] = 3.86 (s, 3H, CO2CH3), 4.10 (s, 2H, H3NCH2), 7.63-7.67 (m, 2H, 3-HB, 5-HB), 7.96-8.01 (m, 2H, 2-HB, 6-HB), 8.61 (br s, 3H, NH3). 13C NMR (101 MHz, DMSO-D6): δ [ppm] = 41.7 (1C, H3NCH2), 52.2 (1C, CO2CH3), 129.2 (2C, C-3B, C-5B), 129.3 (2C, C-2B, C-6B), 129.5 (1C, C-1B), 139.4 (1C, C-4B), 165.9 (1C, CO2CH3). FT-IR: ν [cm-1] = 2963 (NH3+), 2878 (C-Haliph.), 2573 (NH3+), 1678 (C=O), 1597, 1578, 1477 (C=CAr), 864 (Ar-Hout of plane). HRMS (APCI): m/z = 166.0865 (calcd. 166.0863 for C9H12NO2 [M+H]+). HPLC: tR = 6.4 min, purity 99.9 %. |
With hydrogenchloride In methanol | Preparation of methyl 4-[[(6-chloro-5-amino) pyrimidin-4-yl]aminomethyl]benzoate (3-1): Preparation of methyl 4-[[(6-chloro-5-amino) pyrimidin-4-yl]aminomethyl]benzoate (3-1): Step (a) Hydrogen chloride gas was blown into methanol (250 ml) on ice with stirring to prepare a methanol solution of hydrogen chloride (44.4 g). To the solution, 4-aminomethylbenzoic acid (25.70 g) was added at room temperature and the mixture was heated under reflux with stirring for 28 hours to obtain an almost homogeneous solution. The solvent was evaporated under reduced pressure from the solution to obtain methyl 4-aminomethylbenzoate hydrochloride (33.11 g) as a colorless solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
44% | With triethylamine; In tetrahydrofuran; N,N-dimethyl-formamide; at 20℃; for 2h; | The title compound from Step C above (256 mg), commercially available 4-aminomethyl-benzoic acid methyl ester hydrochloride (160 mg), PyBOP (800 mg) and NEt3 (202 muL) were dissolved in THF/DMF (2:1, 15 mL). The mixture was stirred at room temperature for 2 h, concentrated, diluted with EtOAc, washed with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, CH2Cl2/acetone) to afford the title compound (196 mg, 44%). [MH]+ = 570. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Intermediate 44: methyl 4-[({2-chloro-5-[(2,2- dimethylpropanoyl)oxy] phenyl}carbonyl)amino] methyl}benzoate; <n="39"/>A solution of <strong>[56961-30-9]2-chloro-5-hydroxybenzoic acid</strong> (1.Og, 5.8 mmol) in DCM (10 ml) was treated with triethylamine (2.5 eq, 2.0 ml, 14.5 mmol) and 2,2-dimethylpropanoyl chloride (2.0 eq, 1.43 ml, 11.6 mmol). Mixture stirred at room temperature for 2hours. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (1.5 eq, 1.75g, 8.7 mmol) and triethylamine (2.0 eq, 1.6 ml, 11.6 mmol) in DCM (10ml) was then added and the mixture stirred at room temperature for another 2 hours. The mixture was diluted with DCM (300ml) and aqueous sodium bicarbonate (100ml), layers separated and aqueous layer extracted again with DCM (200ml). Organic layers combined, washed with brine, dried over magnesium sulphate and evaporated. Residue purified by column chromatography (Biotage SP4) eluting with 0-30percent EtOAc in Hex to give the title compound as a white solid. MS (ES+) m/z 404 [M+H]+ (C2IH2235ClNO5). 1H-NMR (400MHz, d-OMSO) delta 1.30 (9H, s), 3.85 (3H, s), 4.51 (2H, d, J 6), 7.24 (IH, dd, J 8.8, J 2.8), 7.29 (IH, d, J 2.8), 7.51 (2H, d, J 8.8), 7.56 (2H, d, J 8.4), 7.95 (2H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With triethylamine; In tetrahydrofuran; water; at 20.0℃; | Step 2: Preparation of methyl 4-((4-bromo-5,6-dimethoxy-l-oxoisoindolin-2- vDmethvO-benzoate Methyl 3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate (1.5 g, 4.1 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (1.6 g, 2 equiv.) in the step 1 were dissolved in a mixture of THF and distilled water (mixture ratio=4: l(v/v), 10 mL). Triethyl amine (1.7 mL, 3 equiv.) was added thereto and stirred at room temperature for 1 night. The reaction proceeded until no methyl3-bromo-2-(bromomethyl)-4,5-dimethoxybenzoate was detectable by thin-layer chromatography (TLC). The resulting mixture thus obtained was distilled under a reduced pressure to remove THF. The resulting material was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and the distilled water. The isolated organic layer was collected, dried over anhydrousMgSO4, and distilled under a reduced pressure to remove solvent. The resulting residue was subjected to a silica gel column chromatography (EtOAc/hexane=l :l) to obtain the title compound (1.6 g, 93 %).1H NMR (300 MHz, CDCl3): delta 8.02 (d, 2H, J = 8.1 Hz), 7.39 (s, IH), 7.36 (d, 2H, J= 8.1 Hz), 4.85 (s, 2H), 4.13 (s, 2H), 3.95 (s, 3H), 3.91 (s, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | Stage #1: naphthalene-2-carboxylate With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane for 0.5h; Cooling with ice; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In dichloromethane at 20℃; | 1.a Synthesis of compound 1 [methyl 4-((2-naphthylamide)methyl)benzoate] At room temperature, 2-naphthoic acid (345mg, 2mmol) was placed in a 100mL eggplant-shaped bottle,Add 30 mL of dichloromethane to dissolve. Add 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl) (460mg, 2.4mmol), 1-hydroxybenzotriazole (HOBt) under ice bath (325 mg, 2.4 mmol) and triethylamine (506 mg, 5 mmol), reacted for 0.5 hours. Methyl 4-aminomethylbenzoate hydrochloride (483 mg, 2.4 mmol) was added and reacted at room temperature overnight. TLC detected that the reaction of the raw materials was complete, then the reactant was washed with water (20 mL×3), and the organic phase was dried with anhydrous Na 2 SO 4 . After separation by column chromatography, compound 1 (415 mg, yield 65%) was obtained as a white solid, which was directly used in the next synthesis. |
With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98.1% | With triethylamine In tetrahydrofuran at 0 - 25℃; for 12h; | |
98.1% | With triethylamine In tetrahydrofuran at 0 - 20℃; | 2.2 4- (methoxycarbonyl) benzyl ammonium hydrochloride 4.02 g (20.0 mmol) was dissolved in dehydrated tetrahydrofuran 60 mL, and then was added triethylamine 10 mL. Herein, solution of pivalic acid chloride 2.40g (20.0mmol) and dehydrated tetrahydrofuran 30mL was added at 0 , and the mixture was stirred overnight at room temperature. 1M hydrochloric acid was added to the reaction solution until it becomes acidic, and extracted with ethyl acetate 200 mL. The solvent was evaporated under reduced pressure, and the residue was dried under vacuum to give white solid of N- (4- (methoxycarbonyl) benzyl) pivalamide 4.87g (98.1% yield). |
87% | With triethylamine In dichloromethane at 0 - 20℃; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
72% | With triethylamine In N,N-dimethyl-formamide at 20℃; for 16h; | |
72% | With triethylamine In N,N-dimethyl-formamide at 20℃; | 3 In 5 mL of anhydrous DMF was dissolved methyl 4-(aminomethyl)benzoate hydrochloride (65 mg, 0.32 mmol), B2a (100 mg, 0.25 mmol), and Et3N (105 μL, 0.75 mmol). The reaction was allowed to stir overnight at room temperature. The solvent was removed by rotary evaporation and the residue was redissolved in EtOAc and washed three times with water and once with brine. The organic layer was dried over MgSO4, filtered, and concentrated. Product was ran on a silica gel column and eluted with 10% EtOAc in hexanes yielding B8 in 72% yield (77 mg, 0.18 mmol). 1H NMR (400 MHz, CDCl3) δ=8.01 (d, J=7.3 Hz, 2H), 7.80 (d, J=7.5 Hz, 1H), 7.36-7.33 (m, 4H), 5.15 (s, 2H), 4.44 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 1.34 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=167.1, 156.6, 143.8, 139.5, 135.2, 130.2, 129.6, 127.2, 126.4, 84.1, 67.1, 52.4, 45.0, 25.1. ESI-MS(+): m/z 426.1 [M+H]+, 443.08 [M+NH4]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | Stage #1: monensin A With benzotriazol-1-ol In tetrahydrofuran at 5℃; for 0.5h; Stage #2: With dicyclohexyl-carbodiimide In tetrahydrofuran for 1h; Stage #3: methyl 4-(aminomethyl)benzoate hydrochloride With 4-methyl-morpholine In tetrahydrofuran at 20℃; for 96h; | 2 Compound (3b)-1-(4-methylbenzoate)methylene Amidomonensine; NMR 1H (300 MHz, CDCl3) ppm: 7.97 (2H, d, J=8.46 Hz), 7.36 (2H, d, J=8.46 Hz), 4.47 (2H, d, J=5.85 Hz), 4.30 (1H, m), 4.17 (1H, dd, J1=2.07 Hz, J2=7.71 Hz), 3.91 (5H, m), 3.74 (1H, d, J=2.82 Hz), 3.40 (1H, q), 3.39 (6H, m), 2.56 (1H, m), 2.23 (2H, m), 2.04-1.35 (24H, m), 1.26 (5H, m), 1.15 (1H, m), 1.02 (3H, d, J=6.96 Hz), 0.91 (6H, m), 0.83-0.75 (8H, m).NMR 1H (400 MHz, CDCl3) ppm: 7.95 (2H, d, J=8.32 Hz), 7.52 (1H, t, J=5.76 Hz), 7.35 (2H, d, J=8.32 Hz), 4.67 (1H, m), 4.47 (2H, qd, J1=6.32 Hz, J2=15.60 Hz), 4.30 (1H, m), 4.13 (1H, m), 3.96 (1H, d, J=4.28 Hz), 3.90 (5H, m), 3.72 (1H, s), 3.50 (1H, q), 3.39 (6H, m), 2.99 (1H, s), 2.53 (1H, m), 2.25-2.16 (2H, m), 2.13-2.05 (1H, m), 2.04-1.87 (3H, m), 1.86-1.83 (1H, d, J=10.32 Hz), 1.74-1.24 (20H, m), 1.01 (3H, d, J=7.08 Hz), 0.92 (6H, m), 0.83-0.72 (9H, m).NMR 13C (400 MHz, CDCl3) ppm: 176.66, 167.18, 144.87, 129.88, 128.83, 127.42, 107.94, 97.85, 86.35, 86.06, 85.39, 83.16, 82.16, 74.53, 71.14, 67.65, 67.37, 59.01, 52.13, 42.90, 42.31, 38.96, 37.57, 36.98, 36.63, 35.08, 34.59, 34.48, 34.07, 33.33, 33.29, 32.73, 31.18, 30.50, 27.63, 26.95, 17.32, 16.41, 15.47, 14.35, 12.92, 10.93, 8.43.Exact mass: HR ESIMS: Calculated for C45H71O12NNa+=840.4874, found=840.4873.; A mixture of monensin acid (500 mg, 0.75 mmol, 1 eq) and HOBt (127 mg, 0.90 mmol, 1.2 eq) in THF (4 mL) was stirred at 5° C. for 30 min and then DCC (187.5 mg, 0.90 mmol, 1.2 eq) was added. After being stirred for 1 h, the reaction mixture was treated with a solution of methyl 4-(aminomethyl)benzoate hydrochloride (198.6 mg, 0.98 mmol, 1.3 eq) and N-methylmorpholine (110 μL, 0.98 mmol, 1.3 eq) in THF (1 mL), and stirring was maintained at room temperature during 4 days. The mixture was evaporated to dryness to give a powder, which was suspended in EtOAc (6 mL) and filtered off. The organic phase was washed with 10% citric acid solution (3 mL), saturated NaHCO3 (3 mL) and distilled water (3 mL), successively, dried over MgSO4 and evaporated to dryness to afford 585.9 mg (93%) of the desired amide. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
49% | With potassium carbonate; In ethanol; water; for 0.166667h; | methyl 4-(((l,4-dioxo-l,4- dihydronaphthalen-2-yl)amino)methyl)benzoate (2u). To a solution of 2-bromo-l,4- napthoquinone (283 mg, 1.2 mmol) in abs EtOH (40 mL) was added an excess of Methyl 4- (aminomethyl)benzoate hydrochloride (569 mg, 2.4 mmol) and K2CO3 dissolved in water. Reaction was stirred for 10 min after which the precipitated solid was filtered to yield 189 mg (49% yield) yellow powder. MS m/z calcd (M+) 322.1, found 322.1. 1H NMR (400 MHz, DMSO-d6) Shift 8.27 (t, J = 6.40 Hz, 1H), 8.01 (d, J = 7.53 Hz, 1H), 7.87 - 7.98 (m, 3H), 7.82 (dt, J = 1.00, 7.53 Hz, 1H), 7.70 - 7.78 (m, 1H), 7.49 (d, J = 8.03 Hz, 2H), 5.53 (s, 1H), 4.54 (d, J = 6.53 Hz, 2H), 3.84 (s, 3H). C13-HSQC (400 MHz, DMSO-d6) Shift (ppm) 40.03, 45.25, 52.64, 100.97, 125.56, 126.49, 127.84, 129.87, 132.61, 135.33, 146.82, 152.19. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
96% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; | Methyl 4-(methylsulfonamidomethyl)benzoate (15e) 15d (252 mg, 1.25 mmol) was dissolved in a mixture of CH2Cl2 (10 mL) and DIPEA (0.5 mL, 2.87 mmol). After addition of mesyl chloride (110 µL, 1.42 mmol), the reaction mixture was stirred overnight at rt. For purification 1 M HCl (15 mL) was added and the aqueous layer was extracted with CH2Cl2 twice. The combined organic layer was washed with brine and dried (Na2SO4). Removal of the solvent under reduced pressure gave 15e. Colorless solid, mp 132 °C, yield 292 mg (96 %). C10H13NO4S (243.3). Rf = 0.78 (ethyl acetate, detection: 254 nm). 1H NMR (400 MHz, DMSO-D6): δ [ppm] = 2.89 (s, 3H, H3CSO2), 3.85 (s, 3H, CO2CH3), 4.24 (d, J = 6.4 Hz, 2H, NHCH2), 7.47-7.52 (m, 2H, 3-HB, 5-HB), 7.66 (t, J = 6.4 Hz, 1H, SO2NHCH2), 7.93-7.97 (m, 2H, 2-HB, 6-HB). 13C NMR (101 MHz, DMSO-D6): δ [ppm] = 39.9 (1C, H3CSO2), 45.6 (1C, NHCH2), 52.1 (1C, CO2CH3), 127.7 (2C, C-3B, C-5B), 128.5 (1C, C-1B), 129.2 (2C, C-2B, C-6B), 144.1 (1C, C-4B), 166.0 (1C, CO2CH3). FT-IR: ν [cm-1] = 3237 (N-H), 3013 (C-HAr), 2955, 2932 (C-Haliph.), 1713 (C=O), 1612, 1578 (C=CAr), 1312, 1134 (SO2), 856 (Ar-Hout of plane). HRMS (APCI): m/z = 244.0633 (calcd. 244.0638 for C10H14NO4S [M+H]+). HPLC: tR = 15.3 min, purity 99.6 %. |
With pyridine at 20℃; for 3h; | 18.1 Step 1: Step 1: Synthesis of methyl 4-(methylsulfonamidomethyl)benzoate (156) To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (2 g, 9.92 mmol) in pyridine (90 ml), methanesulfonyl chloride (1.183 ml, 14.88 mmol) was added, and the mixture was stirred at RT for 3 hours. The solvent was evaporated, the residue was partitioned between ethyl acetate (100 ml) and 1N HCl (100 ml) and the aqueous layer was extracted with ethyl acetate (3*100 ml). The combined organic layers were dried over Na2SO4 and the solvent was removed affording crude methyl 4-(methylsulfonamidomethyl)benzoate as a pale yellow solid (2.8 g) that was used for the next step without any additional purification. MS/ESI+ 244.1 [MH]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | Stage #1: methyl 4-(aminomethyl)benzoate hydrochloride; 1,1'-Thiocarbonyldiimidazole With hydrogenchloride; triethylamine In water at 20℃; for 3h; Stage #2: With ammonium hydroxide In methanol; water at 20℃; for 2h; | 39 (Formula 11-3: methyl 4-(thioureidomethyl)benzoate) (Formula 11-3: methyl 4-(thioureidomethyl)benzoate)[618][619]Compound ofFormula 11-2(1,1’- thiocarbonyldiimidazole; 8.26 g, 46.4 mmol) was dissolved in hydrogen chloride (40 mL), and then triethylamine (6.34 mL, 46.4 mmol) and compound ofFormula 11-1(4-(aminomethyl)benzoate hydrochloride; 8.50 g, 42.2 mmol) were slowly added sequentially and then stirred at room temperature for 3 hours. Then, ammonia (28.0 wt% aqueous solution; 30 mL) and methanol (10 mL) were added to the mixture and stirred at room temperature for 2 hours, and then hexane (85 mL) and water (45 mL) were further added and stirred at the same temperature for 1 hour. The solid product was filtered, washed with hexane and then with water, and then vacuum dried to give the desired compound ofFormula 11-3(9.40 g, 99%) in the form of a light brown solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | With copper(l) iodide; potassium carbonate; In dimethyl sulfoxide; at 20℃;Inert atmosphere; | To a solution of methyl 4-(aminomethyl)benzoate hydrochloride (1 .47g, 7.3mmol) in DMSO (14ml_) was added <strong>[32111-21-0]2-<strong>[32111-21-0]iodopyrazine</strong></strong> (1 g, 4.9mmol) followed by K2C03 (1 .7g, 12.1 mmol) under Ar(g). After 2 min vigorous stirring, Cul (46mg, 0.2mmol) was added and the mixture was left to stir at rt overnight. It was partitioned between EtOAc (150ml_) and 50% brine (50ml_) and the organic layer separated, the aqueous extracted with EtOAc (2 x 15ml_), before the combined organic phase was washed with 50% brine (15ml_), dried (MgS04), and concentrated in vacuo. The residue was purified by flash column chromatography with Hexane/EtOAc (7:3-0: 1 ) to yield (3) (670mg, 57%) as a white solid. 1 H NMR (300MHz, CHLOROFORM-d) deltaEta ppm: 7.76-8.1 1 (m, 5H), 7.43 (d, J=8.5 Hz, 2H), 5.01 -5.16 (m, 1 H), 4.66 (d, J=5.8 Hz, 2H), 3.92 (s, 3H). LCMS (ES): Found 352.0 [M+H]+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
99% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 40℃; for 18h; | 3.2 Step 2. Methyl 4-((2-(3,5-dimethoxybenzyl)cyclopent-l-enecarboxamido) methyl)benzoate Step 2. Methyl 4-((2-(3,5-dimethoxybenzyl)cyclopent-l-enecarboxamido) methyl)benzoate [0062] TBTU (O-Benzotriazol-l -tetramethyluronium hexafiuorborate (28.0 mg, 0.0863 mmol), methyl 4-(aminomethyl)benzoate hydrochloride (18.1 mg, 0.0870 mmol) and diisopropylethylamine (45 μL,, 0.26 mmol), were added to a solution of 2-(3,5- dimethoxybenzyl)cyclopent-l-enecarboxylic acid (22.5 mg, 0.858 mmol) in DMF (0.43 mmol). After stirring at 40 °C for 18 h, the reaction mixture was diluted with EtOAc and washed with 1 N HCl (2x), 1 N NaOH (2x) and brine. The organic phase was dried (MgS04), filtered and concentrated in vacuo to afford 35 mg (99%) of methyl 4-((2-(3,5-dimethoxybenzyl)cyclopent-l- enecarboxamido)methyl)benzoate as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 8.4 (4) To a solution of the foregoing compound (f-4) (136 mg, 0.438 mmol) in DMF (4.4 mL), methyl 4-aminomethylbenzoate hydrochloride (f-5) (106 mg, 0.526 mmol), DIPEA (0.191 mL, 1.10 mmol) and HATU (183 mg, 0.482 mmol) were added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and after extraction with ethyl acetate, the organic layer was successively washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvents were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give methyl 4-({2-cyclopropyl-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}methyl)benzoate (f-6) (amount, 178 mg; yield, 89%). |
89% | 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℃; | 8.4 To a solution of the foregoing compound (f-4) (136 mg, 0.438 mmol) in DMF (4.4 mL), methyl 4-aminomethylbenzoate hydrochloride (f-5) (106 mg, 0.526 mmol), DIPEA (0.191 mL, 1.10 mmol) and HATU (183 mg, 0.482 mmol) were added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and after extraction with ethyl acetate, the organic layer was successively washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvents were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give methyl 4-({2-cyclopropyl-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}methyl)benzoate (f-6) (amount, 178 mg; yield, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 9.3 (3) To a solution of the foregoing compound (g-3) (314 mg, 0.909 mmol) in DMF (9.1 mL), methyl 4-aminomethylbenzoate hydrochloride (f-5) (220 mg, 1.09 mmol), DIPEA (0.397 mL, 2.27 mmol) and HATU (380 mg, 1.00 mmol) were added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and extraction was conducted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvents were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give methyl 4-({2-bromo-1-[2-(4-chlorophenoxy)ethyl]-1H-imidazole-5-carboxamido}methyl)benzoate (g-4) (amount, 398 mg; yield, 89%). |
89% | 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℃; | 9.3 To a solution of the foregoing compound (g-3) (314 mg, 0.909 mmol) in DMF (9.1 mL), methyl 4-aminomethylbenzoate hydrochloride (f-5) (220 mg, 1.09 mmol), DIPEA (0.397 mL, 2.27 mmol) and HATU (380 mg, 1.00 mmol) were added and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, water was added and extraction was conducted with ethyl acetate. The organic layer was successively washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvents were distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to give methyl 4-({2-bromo-1-[2-(4-chlorophenoxy)ethyl]-1H-imidazole-5-carboxamido}methyl)benzoate (g-4) (amount, 398 mg; yield, 89%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; HATU In N,N-dimethyl-formamide at 20℃; | 2.1 (1) To a solution in DMF (87 mL) of compound (a-5) (8.7 g, 29 mmol) as obtained in Example 1, methyl p-(aminomethyl)benzoate hydrochloride (a-11) (6.9 g, 34 mmol), DIPEA (12 mL, 71 mmol) and HATU (12 g, 31 mmol) were added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture and after extraction with ethyl acetate, the organic layer was successively washed with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvents were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:500:100) to give methyl 4-({2-chloro-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}methyl)benzoate (a-12) (amount, 11 g; yield, 85%). |
85% | 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℃; | 2.1 To a solution in DMF (87 mL) of compound (a-5) (8.7 g, 29 mmol) as obtained in Example 1, methyl p-(aminomethyl)benzoate hydrochloride (a-11) (6.9 g, 34 mmol), DIPEA (12 mL, 71 mmol) and HATU (12 g, 31 mmol) were added and the resulting mixture was stirred overnight at room temperature. Water was added to the reaction mixture and after extraction with ethyl acetate, the organic layer was successively washed with water and saturated brine. After drying the organic layer over anhydrous sodium sulfate, the solvents were distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:500:100) to give methyl 4-({2-chloro-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-5-carboxamido}methyl)benzoate (a-12) (amount, 11 g; yield, 85%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | Indole butyric acid (1.0 g, 5 mmol) was dissolved in 25 mL of tetrahydrofuran,Triethylamine (0.55 g, 5.5 mmol) was added and addedO-benzotriazole-N, N, N ', N'-tetramethyluronium tetrafluoroboric acid (TBTU) (1.8 g, 5.5 mmol).After reaction at room temperature for 20 minutes,Methyl 4- (aminomethyl) benzoate hydrochloride (1.0 g, 5 mmol) was added followed by triethylamine (0.5 g, 5 mmol).After 6 hours of reaction at room temperature,The tetrahydrofuran in the reaction solution was distilled off,The product was dissolved with ethyl acetate,Respectively, with 1mol / L citric acid solution,Saturated sodium bicarbonate solution,Saturated salt water washed 3 times,Dried over anhydrous magnesium sulfate,Evaporated crude solvent,The crude product was recrystallized from ethyl acetate to give 1.3 g of a pale white solid.Yield: 57% |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; Inert atmosphere; Schlenk technique; | |
90% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 16h; Inert atmosphere; Schlenk technique; | 29.a a. Preparation of 4-(((4-methoxyphenyl)sulfonamido)methyl)benzoate. A solution of 4-methoxybenzenesulfonyl chloride (206.6 mg, 1 mmol, 1 eq.), methyl 4-(aminomethyl)benzoate hydrochloride (201.7 mg, 1 mmol, 1 eq.) and A, V- d i i s o p r o p y 1 c t h y 1 a m i n c (284.4 mg, 383.2 pL, 2.2 mmol, 2.2 eq.) in DCM (4 mL) was stirred for 16 h at room temperature. After dilution with ethyl acetate (20 mL) the solution was washed with water (10 mL), aqueous hydrochloric acid (1 M, 10 mL) and brine (10 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure. The crude product was purified by recrystallization from ethyl acetate which provided the title compound as a white powder (302 mg, 0.9 mmol, 90%)1H NMR (300 MHz; CDCl3): 5 = 3.86 (s, 3H, -C(OCH3)), 3.89 (s, 3H, -COOCH3), 4.17 (d, 2H, 3JHH = 6.4 Hz, -CH2-), 4.97 (t, 1H, JHH = 6.4 Hz, -NH-), 6.95 (d, 2H,3JHH = 8.9 Hz, -C(OMe)-CH-), 7.27 (d, 2H, 3T^ = 8.4 Hz, -CH2-C-CH-), 7.78 (d, 2H, 3JHH = 8.9 Hz, -C(OMe)-CH-CH-), 7.92 (d, 2H, JHH = 8.4 Hz, -CH2-C-CH-CH-) ppm. 13C NMR (75.5 MHZ; CDCl3): 5 = 46.8 (1C, -CH2-), 52.1 (1C, -COOCH3), 55.6 (1C, -C(OCH3)), 114.3 (2C, -C(OMe)-CH-), 127.6 (2C, -CH2-C-CH-), 129.2 (2C, -C(OMe)-CH-CH-), 129.6 (1C, -C(COOMe)), 129.9 (2C, -CH2-C-CH-CH-), 131.3 (1C, -C-SO2-), 141.5 (1C, -CH2-C-), 163.0 (1C, -C(OMe)), 166.6 (1C, -C(O)-OMe) ppm. HRMS (ESI ) calcd. for CI6HI 8N05S+: 336.0900; found: 336.0895. HRMS (ESI) calcd. for CieHieNOsS-: 334.0755; found: 334.0755. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; Schlenk technique; | |
84% | With N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 1h; Inert atmosphere; Schlenk technique; | 1.a a. Synthesis of the precursor methyl 4-(((4-methylphenyl)sulfonamido)methyl)benzoate according to general formula II A solution of 4-methylbenzenesulfonyl chloride (190.6 mg, 1 mmol, 1 eq.), methyl 4- (aminomethyl)benzoate hydrochloride (201.7 mg, 1 mmol, 1 eq.) and A, A- d i i s o p r o p y 1 c t h y 1 a m i n c (284.4 mg, 383.2 pL, 2.2 mmol, 2.2 eq.) in DCM (4 mL) was stirred for 1 h at room temperature. After dilution with ethyl acetate (20 mL) the solution was washed with water (20 mL), aqueous hydrochloric acid (1 M, 20 mL) and brine (20 mL). The organic layer was dried with sodium sulfate, filtered and the solvent was evaporated. The crude product was recrystallized from ethanol/water (v/v = 1/1) to afford the pure title compound (268.2 mg, 0.84 mmol, 84%) as white crystals.1H NMR (300 MHz; CDCl3): 5 = 2.42 (s, 3H, CH3-C), 3.89 (s, 3H, CH3-0), 4.17 (d, 2H, 3JHH = 6.3 Hz, CH2), 5.01 (t, 1H, ^ = 6.3 Hz, NH), 7.25 - 7.30 (m, 4H,CH2-C-(CH)2 + CH3-C-(CH)2), 7.74 (d, 2H, ^ = 8.3 Hz, S02-C-(CH)2), 7.92 (d, 2H, 3JHH = 8.3 Hz, CO-C-(CH)2) ppm. 13C NMR (75.5 MHz; CDCl3): 5 = 21.7 (1C, CH3-C), 47.0 (1C, CH2), 52.3 (1C, CH3-0), 127.3 (2C, S02-C-(CH)2), 127.8 (2C, CH2-C-(CH)2), 129.8 (1C, CO-C), 129.9 (2C, CH3-C-(CH)2), 130.0 (2C, CO-C-(CH)2), 136.7 (1C, S02-C), 141.7 (1C, C-CH2), 143.8 (1C, C-CH3), 166.8 (1C, O-CO-C) ppm. HRMS (ESI+) calcd. for CI6HI 8N04S+: 320.0951; found: 320.0952. HRMS (ESI) calcd. for C^H^ ^S-: 318.0806; found: 318.0809. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; trifluoroacetic acid; | The Boc-protected glycine, 1925 mg TBTU and 1 mL TEA were dissolved in 50 mL DCM. 30 mins later, (4-(methoxycarbonyl)phenyl)methanaminium chloride (1206 mg, 6 mM) was added and the mixture was allowed to stir at room temperature overnight. Volatiles were removed under vacuum, the residue was recrystallized by ethyl estate and hexane to yield a white solid. This intermediate was refluxed with Hydrazinehydrate (500 mg, 10 mM) in methanol for 48 h. After removing volatiles, residue was dissolved in 50 mL ethanol with 348 mg propionaldehyde. 2 hours later, vacuum evaporation afforded the desired intermediate which was dissolved in 50 mL methanol, to this solution was added 5 mg methyl orange and 1256 mg sodium cyanoborohydride. Mixture of methanol and concentrated hydrochloric acid (1:1) was added dropwise until the solution turned and stayed red. After 6 hours, methanol were removed under vacuum and purified on reverse phase columns eluted with acetonitrile and water to yield pure product. This intermediate was dissolved in 10 mL mixed solution of DCM and TFA (1:1), the solution was stirred at room temperature for 1 hour. The volatiles were evaporated under vacuum to afford a color less oil. 100 mg oil was dissolved in 5 mL DMF then 193 mg N,N-Diisopropylethylamine and 114 mg <strong>[13558-31-1]Rhodamine 110 chloride</strong> was added. After the reaction finished, 30 mL water was added and the mixed solution was extracted by ethyl estate. The organic phase was dried by MgSO4 and evaporated under vacuum. The crude residue was purified on C18 reverse phase columns eluted with acetonitrile and water (containing 0.2% TFA) to yield the end product. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | Stage #1: 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride With N-ethyl-N,N-diisopropylamine In dimethyl sulfoxide; N,N-dimethyl-formamide at 20℃; for 20h; | Methyl 4-((5-amino-1-phenyl-1H-pyrazole-4-carboxamido)methyl)benzoate (69). Prepared as previously published by Röhm etal.[4]5-Amino-1-phenyl-1H-pyrazole-4-carboxylic acid (68, 2.00g, 9.84mmol), HOBt (1.56g, 11.81mmol) and EDC-HCl (2.26g, 11.81mmol) were dissolved in DMF (dry, 20mL) and DIPEA (1.91g, 14.77mmol) was added. The mixture was stirred for 30minat rt, and a solution of methyl 4-(aminomethyl)benzoate hydrochloride (1.95g, 11.81mmol) in DMF/DMSO (dry, 20mL, 1:1) and DIPEA (1.91g, 14.77mmol) was added. The reaction mixture was stirred for 20hat rt. CH2Cl2 (100mL) was added, and the mixture was washed with H2O (5×50 mL). The organic phase was dried over MgSO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica (CH2Cl2/MeOH, 98:2) to afford 3.10g (8.85mmol, 90%) of 69 as a colorless solid. TLC: RF=0.33 (SiO2, CH2Cl2/MeOH 10:1); 1H NMR (400MHz, DMSO-d6, 300K): δ=8.54 (t, 3J=6.1Hz, 1H), 7.99 (s, 1H), 7.94 (d, 3J=8.2Hz, 2H), 7.60-7.49 (m, 4H), 7.45 (d, 3J=8.2Hz, 2H), 7.42-7.36 (m, 1H), 6.38 (s, 2H), 4.50 (d, 3J=6.1Hz, 2H), 3.85 (s, 3H) ppm; 13C NMR (101MHz, DMSO-d6, 300K): δ=166.1, 164.2, 149.2, 145.9, 138.4, 138.2, 129.3, 129.2, 128.0, 127.3, 127.1, 123.1, 97.3, 52.0, 41.3ppm; MS (ESI pos.): m/z (%)=351.13 (100) ([M+H]+, calcd. 351.15). |
87% | With 1-hydroxy-7-aza-benzotriazole; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 0 - 20℃; for 20h; |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With N-ethyl-N,N-diisopropylamine In isopropyl alcohol at 160℃; for 1h; Microwave irradiation; Sealed tube; | 6.1 1. Synthesis of Intermediate 6-2: [0216] To a mixture of methyl 4-(aminomethyl)benzoate hydrochloride (0.92 g, 4.6 mmol, 1.0 equiv) and IPA (15 mL) in a microwave vial were added 4,6-dichloropyrimidine (1.4 g, 9.1 mmol, 2.0 equiv) and DIPEA (1.4 g, 11.0 mmol, 2.4 equiv). The vial was sealed and heated at 160 °C in a microwave reactor for 1 h. The mixture was concentrated and purified by silica gel chromatography (40 g column, 0-10% MeOH in DCM with 1% TEA) to provide 1.1 g (87%) of methyl 4-(((6-chloropyrimidin-4-yl)amino)methyl)benzoate. LRMS (ES) m/z 278.1 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine In N,N-dimethyl-formamide at 20℃; for 12h; | 4.1.1. Methyl 4-((4-nitro-1H-pyrazole-3-carboxamido)methyl)benzoate (4) 4-nitro-1H-pyrazole-3-carboxylic acid (3.18 mmol, 1.1equiv),methyl 4-(aminomethyl)benzoate hydrochloride (2.89 mmol,1equiv), EDCI (3.47 mmol, 1.2equiv), HOBt (3.47 mmol, 1.2equiv),DIEA (6.94 mmol, 2.4equiv) were mixed in DMF (20 mL). The reactionwasstirred for 12 h at room temperature. TLC analysis, usingpetroleum ether: ethyl acetate (1:2) as the eluent, indicated thecomplete reaction. The mixture was diluted with a large amount ofwater and then extracted with ethyl acetate. The organic layer wascollected and dried by anhydrous sodium sulfate. The solvent wasconcentrated to obtain 4 as a light purple solid. 1H NMR (400 MHz DMSO-d6): d 7.91(3H, m), 7.50(2H, m), 4.50(2H, s), 3.84(3H, s);HRMS (ESI) (M H) Calc’d for C13H12N4O5: 305.0887Found:305.0884. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With N-ethyl-N,N-diisopropylamine In tetrahydrofuran at 20℃; for 12h; regioselective reaction; | 4.1.1 Procedure for the preparation of methyl 4-(((2-chloroquinazolin-4-yl)amino)methyl)benzoate (4) To a solution of intermediate 3 (8.47g, 43mmol) and methyl 4-(aminomethyl)-benzoate hydrochloride (8.67g, 43mmol) in THF (100mL) was slowly added DIPEA (11.67g, 90.3mmol). The solution was stirred at room temperature for 12h. After this time, TLC analysis indicated the reaction was completed. The mixture was filtered off, and then the filtrate was concentrated under reduced pressure. The residue was recrystallized from H2O/MeOH to give intermediate 4 as a white solid (yield:92%). 1H NMR (400MHz, DMSO-d6) δ 9.40 (t, J=5.9Hz, 1H), 8.35 (dd, J=8.3, 1.3Hz, 1H), 7.99-7.92 (m, 2H), 7.84 (ddd, J=8.4, 6.9, 1.3Hz, 1H), 7.71-7.64 (m, 1H), 7.59 (ddd, J=8.2, 6.9, 1.2Hz, 1H), 7.53 (d, J=8.1Hz, 2H), 4.86 (d, J=5.8Hz, 2H), 3.85 (s, 3H). LC-MS (ESI+): m/z: 328.22 [M+H]+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-(2-chloro-6-methylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. 4.1.10.1. Methyl 4-(4-(2-chloro-6-methylamino-9H-purin-9-yl) butanamido)methyl) benzoate (11a). White solid, yield: 78%, mp: 189-190 C.1H NMR (600 MHz, DMSO-d6) δ 8.44 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 4.4Hz, 1H), 8.13 (s, 1H), 7.91 (dd, J = 10.6, 4.0 Hz, 2H), 7.37 (d, J = 8.2 Hz,2H), 4.32 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 2.92(d, J = 4.5 Hz, 3H), 2.17 (t, J = 7.4 Hz, 2H), 2.09-2.02 (m, 2H). |
78% | Stage #1: 4-(2-chloro-6-methylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. 4.1.10.1. Methyl 4-(4-(2-chloro-6-methylamino-9H-purin-9-yl) butanamido)methyl) benzoate (11a). White solid, yield: 78%, mp: 189-190 C.1H NMR (600 MHz, DMSO-d6) δ 8.44 (t, J = 5.9 Hz, 1H), 8.19 (d, J = 4.4Hz, 1H), 8.13 (s, 1H), 7.91 (dd, J = 10.6, 4.0 Hz, 2H), 7.37 (d, J = 8.2 Hz,2H), 4.32 (d, J = 5.9 Hz, 2H), 4.13 (t, J = 6.9 Hz, 2H), 3.84 (s, 3H), 2.92(d, J = 4.5 Hz, 3H), 2.17 (t, J = 7.4 Hz, 2H), 2.09-2.02 (m, 2H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | Stage #1: 4-(2-chloro-6-ethylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | Stage #1: 4-(2-chloro-6-propylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
73% | Stage #1: 4-(2-chloro-6-butylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | Stage #1: 4-(2-chloro-6-diethylamino-9H-purin-9-yl)butanoic acid With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In tetrahydrofuran at 0 - 20℃; for 0.5h; Stage #2: methyl 4-(aminomethyl)benzoate hydrochloride In tetrahydrofuran at 20℃; Inert atmosphere; | 4.1.10. General procedure for the synthesis of 11a-f General procedure: The 10a-f (1.0 g) were dissolved in 40 mL of anhydrous tetrahydrofuran, EDCI (1.5 eq) and triethylamine (3 eq) were added in 0 C, the mixture was stirred at room temperature for 30 min. Methyl 4-(aminomethyl)benzoate hydrochloride (1 eq) was dissolved in 30 mL of anhydrous tetrahydrofuran, and then was added dropwise to above 10a-f mixture. The solution was stirred under nitrogen atmosphere at room temperature overnight. Filtration and drying, the residue was purified by silica gel chromatography to yield the desired products 11a-f. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 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 dichloromethane at 0 - 20℃; for 16h; | General procedure for the preparation of compounds (34-50): General procedure: To a solution of 25a-25f, 28, or 30a-30e (0.37 mmol) in DCM (5 mL) were added HATU (0.17 g, 0.44 mmol) and DI- PEA (0.24 mL, 1.48 mmol) at 0 °C followed by the addition of methyl 4-(aminomethyl)benzoate hydrochloride (31) , methyl 4- (1-aminoethyl)benzoate hydrochloride (32) or methyl ( S ) -4-(1- aminoethyl)benzoate hydrochloride [38] (33)(0.45mmol) andthe reaction mixture was stirred at RT for 16 h. Sat. NH 4 Cl solu- tion was added to the reaction mixture and extracted with DCM (3 ×50 mL). Organic layer was dried over anhyd Na 2 SO 4 and con- centrated in vacuo to give a crude which was purified by Combi- flash column chromatography (silica; 0-50% ethyl acetate/hexanes) to give compounds 34-50. Methyl 4-((5-chloro-2-((3-fluorophenyl)amino)nicotinamido) methyl)benzoate (34): 5-Chloro-2-((3-fluorophenyl)amino) nicotinic acid (25a) was treated with methyl 4- (aminomethyl)benzoate hydrochloride (31) to give 4-((5-chloro-2- ((3-fluorophenyl)amino)nicotinamido)methyl)benzoate (34) as an off-white solid; Yield: 90%. 1 H NMR (400 MHz, DMSO): δ11.02 (s, 1H), 9.54 (s, 1H), 8.43-8.36 (m, 2H), 7.95 (d, 2H, J = 8.2 Hz), 7.83 (d, 1H, J = 11.7 Hz), 7.51 (d, 2H, J = 7.9 Hz), 7.32-7.23 (m, 2H), 6.80 (s, 1H), 4.58 (s, 2H), 3.84 (s, 3H), 2.28 (s, 3H); LCMS-ESI (Method-A): m/z calculated for C21H17ClFN3O3 [ M + H ] + 414.1 found 414.2, R t = 3.82 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 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 dichloromethane at 0 - 20℃; for 16h; | General procedure for the preparation of compounds (34-50): General procedure: To a solution of 25a-25f, 28, or 30a-30e (0.37 mmol) in DCM (5 mL) were added HATU (0.17 g, 0.44 mmol) and DI- PEA (0.24 mL, 1.48 mmol) at 0 °C followed by the addition of methyl 4-(aminomethyl)benzoate hydrochloride (31) , methyl 4- (1-aminoethyl)benzoate hydrochloride (32) or methyl ( S ) -4-(1- aminoethyl)benzoate hydrochloride [38] (33)(0.45mmol) andthe reaction mixture was stirred at RT for 16 h. Sat. NH 4 Cl solu- tion was added to the reaction mixture and extracted with DCM (3 ×50 mL). Organic layer was dried over anhyd Na 2 SO 4 and con- centrated in vacuo to give a crude which was purified by Combi- flash column chromatography (silica; 0-50% ethyl acetate/hexanes) to give compounds 34-50. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | 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 dichloromethane at 0 - 20℃; for 16h; | General procedure for the preparation of compounds (34-50): General procedure: To a solution of 25a-25f, 28, or 30a-30e (0.37 mmol) in DCM (5 mL) were added HATU (0.17 g, 0.44 mmol) and DI- PEA (0.24 mL, 1.48 mmol) at 0 °C followed by the addition of methyl 4-(aminomethyl)benzoate hydrochloride (31) , methyl 4- (1-aminoethyl)benzoate hydrochloride (32) or methyl ( S ) -4-(1- aminoethyl)benzoate hydrochloride [38] (33)(0.45mmol) andthe reaction mixture was stirred at RT for 16 h. Sat. NH 4 Cl solu- tion was added to the reaction mixture and extracted with DCM (3 ×50 mL). Organic layer was dried over anhyd Na 2 SO 4 and con- centrated in vacuo to give a crude which was purified by Combi- flash column chromatography (silica; 0-50% ethyl acetate/hexanes) to give compounds 34-50. |
Tags: 6232-11-7 synthesis path| 6232-11-7 SDS| 6232-11-7 COA| 6232-11-7 purity| 6232-11-7 application| 6232-11-7 NMR| 6232-11-7 COA| 6232-11-7 structure
[ 922163-35-7 ]
Methyl 3-((methylamino)methyl)benzoate
Similarity: 0.92
[ 1236353-78-8 ]
(R)-Methyl 3-(1-aminoethyl)benzoate hydrochloride
Similarity: 0.90
[ 847728-91-0 ]
(S)-Methyl 4-(1-aminoethyl)benzoate hydrochloride
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[ 1391439-19-2 ]
(S)-Methyl 3-(1-aminoethyl)benzoate hydrochloride
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[ 922163-35-7 ]
Methyl 3-((methylamino)methyl)benzoate
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[ 1236353-78-8 ]
(R)-Methyl 3-(1-aminoethyl)benzoate hydrochloride
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[ 847728-91-0 ]
(S)-Methyl 4-(1-aminoethyl)benzoate hydrochloride
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[ 1391439-19-2 ]
(S)-Methyl 3-(1-aminoethyl)benzoate hydrochloride
Similarity: 0.90
[ 922163-35-7 ]
Methyl 3-((methylamino)methyl)benzoate
Similarity: 0.92
[ 1236353-78-8 ]
(R)-Methyl 3-(1-aminoethyl)benzoate hydrochloride
Similarity: 0.90
[ 847728-91-0 ]
(S)-Methyl 4-(1-aminoethyl)benzoate hydrochloride
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[ 1391439-19-2 ]
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P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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