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CAS No. : | 25952-53-8 | MDL No. : | MFCD00012503 |
Formula : | C8H18ClN3 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FPQQSJJWHUJYPU-UHFFFAOYSA-N |
M.W : | 191.70 | Pubchem ID : | 2723939 |
Synonyms : |
|
Num. heavy atoms : | 12 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.88 |
Num. rotatable bonds : | 5 |
Num. H-bond acceptors : | 3.0 |
Num. H-bond donors : | 0.0 |
Molar Refractivity : | 55.49 |
TPSA : | 27.96 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) : | -5.57 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | 2.67 |
Log Po/w (WLOGP) : | 1.93 |
Log Po/w (MLOGP) : | 1.29 |
Log Po/w (SILICOS-IT) : | 1.72 |
Consensus Log Po/w : | 1.52 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 1.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -2.38 |
Solubility : | 0.798 mg/ml ; 0.00416 mol/l |
Class : | Soluble |
Log S (Ali) : | -2.91 |
Solubility : | 0.236 mg/ml ; 0.00123 mol/l |
Class : | Soluble |
Log S (SILICOS-IT) : | -2.12 |
Solubility : | 1.45 mg/ml ; 0.00759 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.22 |
Signal Word: | Danger | Class: | 6.1 |
Precautionary Statements: | P260-P264-P270-P272-P273-P280-P301+P312+P330-P302+P352+P312-P314-P333+P313-P391-P405-P501 | UN#: | 2811 |
Hazard Statements: | H302-H311-H315-H317-H373-H410 | Packing Group: | Ⅲ |
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 |
---|---|---|
71.2 g | at 30℃; | Weigh 24ml of carbon disulfide dissolved in 150ml methanol,43.8 g of N, N'-dimethylpropylenediamine was slowly added dropwise to control the temperature at 10-15 ° C,The dropwise addition process was carried out with a white solid which was added dropwise at 20 ° C for 2 hours, filtered and washed with methanol to give 75 g of a white solid (Intermediate 1) in 96percent yield.75 g of the product was weighed, 200 ml of dichloromethane was added, and the temperature was controlled at 10-15 ° C. 45.8 g of triethylamine was added, followed by slowly dropping 50.3 g of ethyl chloroformate, dropping for 2 hours,After the dropwise addition was carried out for 1 hour, the organic phase was washed, washed, filtered and dried to give the product (Intermediate 2).25.2 g of ethylamine (containing 70percent water) was weighed, 180 ml of dichloromethane was added,Cooling to 10-15 ° C, slowly dropping intermediate 2, dropping finish for 1 hour,The organic phase was washed with an alkali of pH 11-12, dried, under reduced pressure, and concentrated to give 90 g of an oil, (Intermediate 3)0.02 g of EDTA was added and oxidized at 30 ° C with 630 g of sodium hypochlorite at a mass concentration of 10percent. After completion of the oxidation,Extraction layer, the organic phase after drying and vacuum concentration 30 , the solvent evaporated, the vacuum distillation to get EDC,Purity 99.4percent;41.4 g of pyridine hydrochloride was weighed, 120 ml of dichloromethane was added, and the mixture was heated at 30 ° C,Slowly dropping the distillation of the EDC, first dissolved, and then precipitation of crystals, dripping finished, cooling to 5 ,Crystallization 1h, filtration, to be 71.2g EDC hydrochloride, purity 99.5percentYield 81percent (based on N, N'-dimethylpropylenediamine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54.7% | With triethylamine; In dichloromethane; at 0 - 25℃; for 20h;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. |
With triethylamine; In ethyl acetate; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. | |
With triethylamine; In N,N-dimethyl-formamide; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. |
With triethylamine; In chlorobenzene; at 20 - 25℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. | |
With triethylamine; In methoxybenzene; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. | |
With triethylamine; In acetonitrile; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. | |
With triethylamine; In 1,2-dichloro-ethane; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. | |
With triethylamine; In tetrahydrofuran; at 20℃;Product distribution / selectivity; | EXAMPLE 11 A mixture of 6-(2-propenyl)-ergoline-8beta-carboxylic acid 2 (180 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (163.8 g) and triethylamine (92 g) in dichloromethane (1.8 L) is stirred at room temperature for 20 h. The reaction mixture is evaporated under vacuum to about 360 mL and to it is added methyl t-butyl ether and water. The ethereal layer is separated and the aqueous layer is extracted with more methyl t-butyl ether. The combined extracts are washed with water and then evaporated under vacuum to remove the solvent. HPLC showed that the ratio of Cabergoline 1 and compound 4 is about 4:1. The residue was separated by silica gel column chromatography and eluding with acetone to give Cabergoline (150 g) having more than 99% purity in 54.7% yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
20% | With benzotriazol-1-ol; triethylamine; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | 1-(Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (115 mg, 0.6 mmol) was added to a solution of trans-4-[4(4-fluorophenyl)piperidin-1-yl]-1-phenylcyclohexylamine (Description 22, 50 mg, 0.14 mmol), lithium (RS)-alpha-(hydroxymethyl)-3,5-bis(trifluoromethyl) benzeneacetate (Description 8, 110 mg, 0.2 mmol), 1-hydroxybenzotriazole (81 mg, 0.6 mmol) and triethylamine (0.28 ML, 0.20 g, 2 mmol) in tetrahydrofuran (5 ML) and dimethylformamide (6 ML) and the mixture was stirred at room temperature for 48 hours.aqueous sodium hydrogen carbonate (saturated, 30 ML) and water (30 ML) were added and the mixture was extracted with ethyl acetate (2*30 ML) The combined organic fractions were washed with water (3*20 ML) and brine (20 ML), dried (MgSO4) and the solvent was evaporated under reduced pressure.The residue was purified by preparative thin layer chromatography on silica gel, eluding with CH2Cl/MeOH/NH3 (Aq.) (90:8:1), to give the title compound as a colorless solid (18 mg, 20%).m/z (ES+) 637 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 2-hydroxybenzotriazole; N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; at 20℃; for 0.166667h; | A solution of 2-amino-5-aminomethylpyridine in 1.60 mL tetrahydrofuran (0.13 M) was added to N,N-diisopropylethylamine (0.145 mL, 0.832 mmol). The resulting mixture was allowed to stir for 10 minutes at room temperature. The solution was then added to 3-(2-Phenylethylamino)-6-benzyl-5-chloro-1-methylenecarboxypyrazinone (81.6 mg, 0.2051 mmol), N-hydroxybenzotriazole (38.1 mg, 0.2819 mmol), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (49.6 mg, 3.511 mmol). The reaction mixture was then allowed to stir over night. The reaction mixture was diluted with ethyl acetate (50 mL). The organic solution was washed with 5% citric acid (125 mL), saturated NaHCO3 (125 mL), and brine (125 mL). The organic solution was dried (MgSO4), filtered and concentrated. The crude reaction mixture was purified by MPLC (ethyl acetate) to give pure product: 1H NMR (300 MHz, DMSO) ?8.50 (br s, 1 H), 7.83 (s, 1H), 7.68 (br s, 1H), 7.34-7.19 (m, 13H), 6.46-6.43 (m, 1H), 5.90 (br s, 1H), 4.42 (s, 2H), 4.09 (br s, 2H), 3.98 (br s, 2H), 3.56 (br s, 3H), 2.94 (br s, 3H); HRMS (EI) calcd for C27H28ClN6O2 503.1962, found 503.1968. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83% | With benzotriazol-1-ol; methylamine; In tetrahydrofuran; DMF (N,N-dimethyl-formamide); at 25℃; for 5h; | A mixture of Example 197 (4.7 mg, 0.0097 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.4 mg, 0.01 mmol), methylamine in tetrahydrofuran (2.0 M, 10 muL, 0.02 mmol) and 1-hydroxybenzotriazole (1.4 mg, 0.01 mmol) in N,N-dimethylformamide (0.2 ML) was stirred at 25 C. for 5 hours.The reaction mixture was diluted with ethyl acetate (40 ML), washed with saturated sodium bicarbonate, water and brine, and dried over anhydrous magnesium sulfate.The drying agent was removed by filtration and the solvent removed under reduced pressure to give the title compound as a pale yellow solid (4 mg, 83%).The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) delta ppm 0.96 (d, J=6.62 Hz, 6 H) 1.47 (m, 2 H) 1.64 (m, 1 H) 2.67 (d, J=4.78 Hz, 3 H) 4.30 (m, 2 H) 4.53 (s, 2 H) 7.18 (m, 4 H) 8.11 (m, 1 H) 8.36 (dd, J=7.54, 2.02 Hz, 1 H) 8.52 (dd, J=4.78, 1.84 Hz, 1 H) 15.90 (s, 1 H).(ESI-) m/z 498 (M-H)-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With dmap; ammonia; triethylamine; In 1,4-dioxane; for 24h; | A solution of [(1] [R* 2R* 5S*, 6R-8-BENZYL-2-[3,] 5- bis [(TRIFLUOROMETHYL) PHENYL] METHOXY} PHENYL-8-AZABICYCLOL3. 2.] 1] octan-6- carboxylic acid [TRIFLUOROACETATE] (Example 53; 2. [7MMOL)] was treated with ammonia solution in dioxane (0.5M, [10ML,] [5MMOL),] triethylamine (0. 6ml, 4. [3MMOL), 1- (3-] dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (960mg, 5. [02MOL),] and 4-N, N-dimethylaminopyridine (120mg, 1 mmol). The mixture was stirred for 24 hours, diluted with ethyl acetate (100ml), washed with 10% aqueous citric acid, saturated aqueous NaHCO3, dried [(NA2SO4)] and concentrated. The residue was purified by chromatography on silica gel (iso-hexane: ethyl acetate) to give the title compound (850mg, [56%).] AH (360 MHz, [CDCI3)] : 7.74 (1H, s), 7.70 (2H, s), 7.55 (2H, m), 7.42 (2H, m), 7.36- 7.27 (6H, m), 6.72 (1H, br), 4.93 (1H, br), 4.89 (1H, d, J13.0Hz), 4.60 (1H, d, J 12.6Hz), 4.22 [(1 H, BR S),] 4.07 (1 H, d, J 13. 7Hz), 3.83 (1 H, d, J 14. 0Hz), 3.51 [(1 H,] br s), 2.67 (1 H, dd, [J 3.] 9Hz, 9.5Hz), 2.41-2. 30 (1 H, m), 2. [35] [(1 H,] dd, [J 9.] 8Hz, 14. 0Hz), 2. 16 (1H, dd, J5. 6Hz, 15.8Hz), 2.03 (1H, dd, J4. 2Hz, 14. 0Hz), 1.96 [(1 H,] m), 1.27 [(1 H,] m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; dichloromethane; for 1h; | To a suspension of 3- [N- (TERT-BUTOXYCARBONYL)-N- methylamino] propanoic acid (3.33 g) in dichloromethane (33 ml) and tetrahydrofuran (33 ml) were added HOBT (3.33 g) and WSC HC1 (6.29 g), and the mixture was stirred for 1 hour. To the solution were added 1- METHYL-LH-PYRAZOLE-4, 5-diamine sulfate (3.45 g) and N, N- diisopropylethylamine (11.4 ml). The reaction mixture was stirred at room temperature overnight. To the resulting solution was added brine and extracted with tetrahydrofuran/ethyl acetate = 1/1. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl N- {3- [ (5-AMINO- 1-METHYL-LH-PYRAZOL-4-YL) AMINO]-3-OXOPROPYL}-N- methylcarbamate as an oil (2.4 g). This product was used in the next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With benzotriazol-1-ol; triethylamine; In dichloromethane; at 23℃; for 16h; | 0.73 ml (5.26 mmoles) of triethylamine, 0.71 g (5.26 mmoles) of hydroxybenzotriazole, 1.02 g (4.78 mmoles) of 2-tert-butoxycarbonylamino-pent-4-ynoic acid and 2.014 g (16.52 mmoles) of 1(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride are added to a suspension of 1 g (4.78 mmoles) of N,N dimethyl-1,4-phenylenediamine dihydrochloride in 25 ml of dichloromethane. The reaction mixture is agitated for 16 hours at 23 C. and finally diluted with 50 ml of water. The organic phase is decanted and washed with 350 ml of water followed by 50 ml of salt water. After drying over sodium sulphate, the organic solution is filtered and concentrated under vacuum. The evaporation residue is purified on a silica column (eluant: dichloromethane/ethanol: 30/0.5). A beige solid is obtained with a yield of 56% (0.88 g). NMR 1H (CDCl3, 100 MHz, ?): 1.40 (s, 9H, tBu); 2.10 (m, 1H, CH); 2.75 (m, 2H, CH2); 2.90 (s, 6H, 2CH3N); 4.40 (m, 1H, CHCO); 5.45 (broad d, 1H, NH); 6.70 (m, 2H, arom.); 7.30 (m, 2H, arom.); 8.10 (broad s, 1H, NH). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at 0℃; for 18h; | A mixture of 5- (4-METHOXYPHENYL)-4- (6-METHOXY-3-PYRIDINYL)-1, 3-oxa zole-2-carboxylic acid obtained by Example 74 (110MG, 0. 337MMOL), 1-hydroxybenzotriazole (61.5mg, 0. 455mmol) and 1- (3-DIMETHYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE hydrochloride (84mg, 0. 438MMOL) in N, N-dimethylformamide (6mL) was added ammonia solution (28%, 27mg, 0.438mmol) at 0C, and the mixture was stirred at the same temperature for 18HRS. The mixture was partitioned between water and ethyl acetate. The organic layer was separated, washed with lmol/L hydrochloric acid, water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give the title compound (LLOMG, 100. 3%) as an amorphous powder. 1H-NMR (300MHZ, CDCL3) : 8 3.85 (3H, s), 3.98 (3H, S), 5.69 (1H, br s), 6.79 (1H, d, J=8Hz), 6.89-7. 02 (3H, m), 7.59 (2H, d, J=8Hz), 7.82 (1H, dd, J=8,2Hz), 8.45 (1H, d, J=2Hz). MS (ES+) : 326.06. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43% | 1- (3-DIMETYLAMINOPROPYL)-3-ETHYLCARBODIIMIDE. hydrochloride (0.002 mol, 0.33g) was added portionwise to a solution of final compound 2 (prepared according to B l. b) (0.002 mol, LG), intermediate compound 19 (prepared according to A5. b) (0.002 mol, 0.56g), 1-hydroxybenzotriazole (0.002 mol, 0.29g) and triethylamine (0.003 mol, 0.37 ML) in CH2CI2 (10 ml) at room temperature. The mixture was stirred at room temperature during 18 hours, washed with K2CO3 10%, dried over MGS04 and concentrated. The crude product (1.65g) was purified by column chromatography over silica gel (eluent: CH2CL2/MEOH/NH4OH 96/4/0. 5) and the product fractions were concentrated. Yield: 0.62 g (43%) of final compound 356. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; triethylamine; In dichloromethane; at 20℃; for 16h; | 0.025 g of methylamine hydrochloride, 0.005 g of hydroxybenzotriazole hydrate, 0. 105 ml of triethylamine and 72 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are successively added to a solution of 0.055 g of 5,5-dimethyl-1-(2-hydroxycarbonylpyrid-4-ylmethyl)-3-(4-trifluoromethanesulfanylphenyl)imidazolidine-2,4-dione in 2 ml of dichloromethane, under an inert atmosphere of argon, at a temperature in the region of 20 C. Stirring is continued at this temperature for about 16 hours. The reaction mixture is washed with water and the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The crude product thus obtained is purified by flash chromatography using a cartridge 16 mm in diameter packed with 5 g of conditioned 20-40 mum silica, and then eluted with a mixture (dichloromethane/methanol) (95/05) (v/v) at a flow rate of 10 ml/minute. The fractions containing the expected product are concentrated under reduced pressure. 0.013 g of 5,5-dimethyl-1-[2-(methylamino)carbonylpyrid-4-ylmethyl]-3-(4-trifluoromethanesulfanylphenyl)imidazolidine-2,4-dione is thus obtained in the form of a white powder, the characteristics of which are as follows: Mass IE m/z = 452M+. m/z = 395(M - C2H3ON)+ base peak m/z = 219C8H4NOSF3+. m/z = 148C8H8N2O+ 1H NMR spectrum (300 MHz, (CD3)2SO d6, in ppm): 1.44 (s: 6H); 2.85 (d, J=5 Hz: 3H); 4.76 (broad s: 2H); 7.67 (dd, J=5 and 2 Hz: 1H); 7.70 (broad d, J=8.5 Hz: 2H); 7.89 (broad d, J=8.5 Hz: 2H); 8.10 (broad s: 1H); 8.60 (d, J=5 Hz: 1H); 8.75 (broad q, J=5 Hz: 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 19 Acetic acid 2-(4-[5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl ester 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-piperidin-4-yl-nicotinamide (100 mg, 0.251 mmol) and N,N-dimethylaminopyridine (5 mg) were dissolved in dichloromethane (3 ml) under nitrogen at room temperature and triethylamine (120 l, 0.753 mmol) was added followed by acetic acid chlorocarbonyl methyl ester (56 mg, 0.42 mmol). The reaction was allowed to stir at room temperature for 2 h and 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80 mg, 0.377 mmol) followed by triethylamine (120 ml, 0.753 mmol). The reaction was stirred at room temperature for 18 h, quenched with sat. ammonium chloride solution (0.5 ml), diluted with water (3 ml) and the organic layer was removed via a separation tube. The solvent was removed under reduced pressure and the residue was by flash column chromatography on a biotage system eluding with a solvent gradient of dichloromethane methanol:concentrated aqueous ammonia (99.5:0.5:0.05 changing to 95:5:0.5, by volume) to give Acetic acid 2-(4-([5-fluoro-2-(3-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-2-oxo-ethyl ester (81 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): delta=8.08-8.10 (1H, d), 7.97-8.00 (1H, dd), 7.28-7.32 (1H, t), 7.06-7.13 (1H, d), 7.03 (1H, s), 6.85-6.90 (1H, d), 4.75-4.84 (2H, quart, partially masked by solvent), 4.26-4.34 (1H, d), 4.12-4.18 (1H, m), 3.72-3.81 (1H, d), 3.18-3.29 (1H, m, partially masked by solvent), 2.90-3.00 (1H, d), 2.45 (3H, s), 2.10 (3H, s), 1.95-2.09 (2H, m), 1.46-1.63 (2H, m) ppm. LRMS (electrospray): m/z [M+Na]+ 484, [2M+Na]+ 945, [M-H]+ 460. Anal. Found C, 56.76; H, 65.26; N, 8.64. C22H24FN3O5S. 0.2 mol H2O requires C, 56.81; H, 5.29; N, 9.03%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
15% | With dmap; In dichloromethane; at 0 - 20℃; for 3h; | (S)-1- [N2- (L-CARBOXY-3-PHENYLPROPYL)-L-LYSYL (BOC)]-L- proline (5.70 g, 11.3 mmol), 3-BROMO-1-PROPANOL (8,80 mL, 97.3 mmol) and N, N-dimethylaminopyridine (295 mg, 2.41 mmol) were dissolved in CH2Cl2 (16 ML). The solution was cooled to 0 oC and 1- (3-DIMETHYLAMINOPROPYL-) 3- ethyl carbodiimide hydrochloride (6.96 g, 36.3 mmol) was added. The reaction was slowly warmed to room temperature and stirred for 3 hours. The mixture was partitioned between EtOAc (80 mL) and NAH2 PO4 (5 %, 75 ML) and the two phases were separated. The organic phase was washed with NAH2P04, NAHCO3 (5 %) and brine, dried over Na2SO4 and concentrated. The crude was purified by flash chromatography (EtOAC/Hexane 1: 1) affording N-[(1S)-1-(3- BROMOPROPOXYCARBONYL) -3-PHENYLPROPYL]-L-LYSYL (BOC)-L- proline 3-bromopropyl ester (1. 40 g, 15 %) as an oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
58.2% | Step D. (4-Isopropyl-piperazin-1-yl)-(2-piperidin-1-ylmethyl-oxazol-4-yl)-methanone. A solution of 2-piperidin-1-ylmethyl-oxazole-4-carboxylic acid, lithium salt (0.400 g, 1.85 mmol), 1-isopropyl-piperazine dihydrochloride (0.409 g., 2.03 mmol), 1-hydroxybenzotriazole (0.300 g., 2.22 mmol), and N-methylmorpholine (1.22 mL, 11.1 mmol) in anhydrous DCM (18 mL) was stirred for 1 h. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.426 g., 2.22 mmol) was added, and the reaction mixture was stirred at rt for 18 h. The reaction was quenched by the addition of 1 M NaOH (20 mL) was stirred for 1 h. The resulting mixture was extracted with DCM (3*30 mL). The combined organic extracts were washed with H2O, dried over Na2SO4, filtered, and concentrated to yield the crude product (0.700 g). The crude product was purified on silica gel column using 0-5% 2 M NH3 in MeOH/DCM to provide the title compound (0.345 g, 58.2%). MS (ESI): exact mass calcd. for C17H28N4O2, 320.22; m/z found, 321.5 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.10 (s, 1H), 4.09-4.00 (m, 2H), 3.77-3.70 (m, 2H), 3.68-3.65 (s, 2H), 2.75-2.67 (m, 1H), 2.58-2.52 (m, 4H), 2.47 (t, J=4.7, 4H), 1.63-1.57 (m, 4H), 1.45-1.39 (m, 2H), 1.04 (d, J=6.6, 6H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With propylamine; dmap; benzotriazol-1-ol; In DMF (N,N-dimethyl-formamide); at 0 - 20℃; for 18h; | 40 mg (0.11 mmol) of Example 2 are dissolved in dimethylformamide, 7. 4 mg (0. 12 mmol) n-propylamine, 17 mg (0.11 mmol) 1-hydroxy-lH-benzotriazole hydrate and 14 mg (0.11 mmol) 4-dimethylaminopyridine are added. The reaction mixture is stirred at 0C, then 24 mg (0.12 mmol) 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride are added. The mixture is stirred at room temperature for 18 hours, water is added and the resulting solid product is filtered. Yield: 27 mg (61%) IH-NMR (DMSO-d6,200 MHz): 8 = 0.9 (t, 3H), 1.2 (t, 3H), 1.6 (m, 2H), 1.7-1. 9 (m, 6H), 2.1 (m, 2H), 2.9 (q, 2H), 3.2 (m, 2H), 3.6 (m, 1H), 8.0 (m, 4H), 8.6 (br. t, 1H), 11. 9 (s, 1H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | b) 2-Methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid ethyl ester To a solution of 1.56 g (10.6 mmol) methyl-malonic acid monoethyl ester in 20 ml of tetrahydrofuran 1.58 g (10.6 mmol) of 2,2,3,3,3-pentafluoropropylamine, 2.05 g (10.6 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, 1.44 g (10.6 mmol) of 1-hydroxybenzotrizole hydrate and 2.75 g (21.2 mmol) of N,N-diisopropyl-ethylamine were added. The mixture was stirred at room temperature for 18 h. The mixture was poured onto 0.5 N HCl (50 ml) and afterwards extracted with dichloromethane (three times 50 ml). The combined organic layers were extracted with 0.5 N aqueous NaHCO3 solution, dried (MgSO4) and the solvent was removed by distillation. The residue was purified by column filtration (hexane/ethyl acetate=2:1) to yield 2.38 g (81%) of the title compound as white crystalline solid, MS m/e (%): 276.1 (M-H+, 100). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
74% | With benzotriazol-1-ol; triethylamine; In dichloromethane; at 20℃; for 3h; | t-Butyl (2S)-2-[(N-BOC-2-aminobenzimidazol-5-yl)carbonylamino]-3-(p-chlorophenyl)propanoate: p-Chloro-L-phenylalanine t-butyl ester hydrochloride (2.50 g, 8.56 mmol) is suspended in dichloromethane (100 mL). Triethylamine (2.4 mL, 17.22 mmol) is added to give a solution. 2d (2.37 g, 8.56 mmol), 1-(3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (1.64 g, 8.57 mmol), and 1-hydroxybenzotriazole (1.15 g, 8.55 mmol) are added to the reaction mixture to give a brown suspension. After stirring 3 hours at room temperature, tlc indicates that the reaction is complete. The reaction mixture is partitioned between 0.1N HCl and dichloromethane and resulting emulsion is filtered through a pad of Celite to help separate the layers. The organic layer is washed with dilute sodium bicarbonate solution and brine and dried over sodium sulfate. Concentration gave a foamy solid which was applied to a column of silica gel in 5% methanol/dichloromethane. Concentration of appropriate fractions gave 3.27 g (74%) and the desired product as a foamy solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
65% | In pyridine; | (3) <strong>[29051-44-3]6-Phenylnicotinic acid</strong> (5.90 g) was dissolved in pyridine (150 ml), followed by addition of 4-methoxybutyric acid hydrazide hydrochloride salt (5.99 g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (8.51 g), and stirred at 60° C. for 10 hours. After the reaction solution was cooled to ambient temperature, the solvent was evaporated under reduced pressure. The resulting residue was washed with water, to afford <strong>[29051-44-3]6-phenylnicotinic acid</strong> N'-(4-methoxybutyryl) hydrazide as pale yellow solid (6.06 g, 65percent). The physico-chemical values are as follows. 1H-NMR (DMSO-d6) delta: 1.75-1.84 (2H, m), 2.26 (2H, t, J=7.4 Hz), 3.25 (3H, s), 3.37 (2H, t, J=6.4 Hz), 7.43-7.57 (3H, m), 8.11-8.19 (3H, m), 8.31 (1H, dd, J=2.7 Hz, 8.3 Hz), 9.10-9.12 (1H, m), 9.96 (1H, brs), 10.53 (1H, brs). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In pyridine; ethyl acetate; | (1) Carbazic acid tert-butyl ester (9.21 g) was dissolved in pyridine (120 ml), followed by addition of <strong>[29006-02-8]4-methoxybutyric acid</strong> (9.06 g) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride salt (20.0 g), and stirred at ambient temperature for 64 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, which was then washed with aqueous 1 mol/liter hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, N'-(4-methoxybutyryl) hydrazine carboxylic acid tert-butyl ester was obtained in yellow oil (9.30 g, 57%). The physico-chemical values are as follows. 1H-NMR (DMSO-d6) delta: 1.39 (9H, s), 1.65-1.78 (2H, m), 2.07-2.12 (2H, m), 3.21 (3H, s), 3.30-3.34 (2H, m), 8.64 (1H, s), 9.46 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With 2-(Dimethylamino)pyridine; In dichloromethane; | Step 3 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) was added to a solution of 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-propionic acid (609 mg, 1.84 mmol) p-toluidine (219 mg, 2.04 mmol) and dimethylaminopyridine (22 mg, 0.18 mmol) in methylene chloride (20 ml). After 4 h, the mixture was diluted with methylene chloride and washed with water. The organic layer was separated, dried with sodium sulfate and the solvent removed under reduced pressure to give an orange foam (839 mg). Column chromatography on silica gel with ethyl acetate as eluant yielded 2-[4-(3,4-dichlorobenzyl)piperazin-1-ylmethyl]-N-(4-methyl-phenyl)propionamide (636 g, 82%) as a white foam. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; In dichioromethane; | (1) 2-Amino-4-[1-(3,4-dibenzyloxybenzoyl)-4-piperidinyl]-6-(4-methoxyphenylmethyl) pyrimidine STR73 To a solution of 2-amino-4-(4-methoxyphenylmethyl)-6-(4-piperidinyl)pyrimidine (160 mg, 0.54 mmol), <strong>[1570-05-4]3,4-dibenzyloxybenzoic acid</strong> (179 mg, 0.54 mmol) and 1-hydroxybenzotriazole (72 mg, 0.54 mmol) in dichioromethane (150 ml) were added 1-ethyl-3-(N, N'-dimethylaminopropyl)carbodiimide hydrochloride (103 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. After stirring for about 30 minutes, the mixture was washed successively with saturated sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate and then evaporated. The residue was purified by column chromatography (chloroform:methanol=99:1) to give the titled compound (477 mg). 1 H-NMR (CDCl3): delta 1.77 (4H, m), 2.59 (1H, m), 2.84 (2H, m), 3.78 (3H, s), 3.82 (2H, s), 3.90 (1H, m), 4.70 (1H, m), 5.11 (2H, s), 5.17 (2H, s), 5.18 (2H,s), 6.24 (1H, s), 6.84-7.00 (5H, m), 7.14-7.44 (12H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In hydrogen chloride; water; at 4℃; for 24h;Aqueous phosphate buffer; | The above sponge-like collagen was dried under reduced pressure in a desiccator with silica gel and added with dilute hydrochloric acid (pH 3.0) previously cooled at 4 C. so as to be 0.50 (w/v)% using such a testing value, followed by being dissolved by gentle stirring. Subsequently, the collagen solution was filtered through membrane filters of 10 muM, 0.65 mum, and 0.45 mum in pore size, sequentially. Then filtrate was subdivided into fractions each having a volume of 20 mL into a polypropylene centrifugation tube (50 mL). (2) Preparation of Aqueous solution of Cross-Linking Agent Using a 30 mM sodium phosphate aqueous buffer solution(pH 6.8 ) containing 70 mM sodium chloride as a solvent, a 100 mM aqueous solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/hydrochloride was prepared. The resulting aqueous solution of a cross-linking agent was subdivided into fractions each having a volume of 20 mL into a polypropylene centrifugation tube (50 mL). (3) Preparation of Collagen Gel All of the steps described below were carried out at 4 C. A centrifugal tube containing the above 0.50% collagen aqueous solution (20 mL) was added with the above cross-linking agent solution (20 mL) and then covered with a lid. The centrifugal tube was shaken to mix the solution, and the solution was flown into a cell-culture polystyrene petridish of 35 mm inner diameter and a glass test tube of 15 mm inner diameter, followed by leaving at rest for 24 hours to obtain a collagen gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium chloride; In hydrogen chloride; water; at 4 - 37℃; for 24h;Aqueous phosphate buffer; | 30 ml of a 0.3% aqueous solution of atelocollagen originated from porcine skin (Cellmatrix Type I-P, pH 3 diluted hydrochloric acid solvent, manufactured by Nitta Gelatine) was placed in a centrifugal tube and kept at 4 C. Similarly, 6 ml of 90 mM sodium phosphate buffer aqueous solution (pH 6.8) containing 210 mM sodium chloride kept at 4 C. was added to the centrifugal tube containing the collagen aqueous solution, and the tube was covered with a lid. The centrifugal tube was shaken to mix the solution, and was the solution was flown into a cell-culture polystyrene petridish of 35 mm inner diameter and a glass test tube of 15 mm inner diameter. Then, it was left standing in a 37 C. incubator for 24 hours to obtain a collagen gel. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
83.0% | With hydrazine; In N,N-dimethyl-formamide; | Step f) 1'-Amino-2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]spiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrone To a solution of 1,2,3,4-tetrahydro-4-(methoxycarbonyl)-1,3-dioxo-2-[[5-(trifluoromethyl)-2-benzothiazolyl]methyl]-4-isoquinolineacetic acid (12.0 g, 24.39 mmol) in DMF (200 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrocholoride (DCC', 6.0 g, 31.7 mmol) and 1-hydroxybenzotriazole hydrate (HOBT, 4.94 g, 36.58 mmol). After stirring for 2 hours, anhydrous hydrazine (0.99 mL, 31.7 mmol) was added dropwise, followed by Et3 N (6.8 mL, 48.78 mmol) addition. The mixture was stirred for 30 minutes, poured into H2 O and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc 1:1) gave a white solid (9.6 g, 83.0%). 1 H NMR (DMSO-d6, 400 MHz): delta3.42 (d, J=18.2 Hz, 1H, --HCHCO--), 3.57 (d, J=18.2 Hz, 1H, --HCHCO--), 5.25 (s, 2H, --NH2 --), 5.57 (s, 2H, --NCH2), 7.6 (d, J=7.9 Hz, 1H, Ar--H), 7.67 (t, J=7.7 Hz, 1H, Ar--H), 7.77 (dd, J=8.5 Hz, 1.7 Hz, 1H, Ar--H), 7.82 (dt, J=7.5 Hz, 1.45 Hz, 1H, Ar--H), 8.22 (dd, J=7.7 Hz, 1.04 Hz, 1H, Ar--H), 8.3 (s, 1H, Ar--H), 8.35 (d, J=8.9 Hz, 1H, Ar--H); IR (KBr, cm-1): 3420 (NH2), 1715 (C=O), 1670 (C=O); MS (m/e): 475 (88, M+H)+. Anal. Calcd.: C, 53.17; H, 2.76; N, 11.81. Found: C, 53.05; H, 2.74; N, 12.13. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | With hydrogenchloride; dmap; In dichloromethane; | Step 2 1-(Isopropylsulfonylaminocarbonyl)-3-nitro-benzene To a mixture of isopropylsulfonamide (1.7 g, 13.8 mmol), 3-nitrobenzoic acid (2.31 g, 13.8 mmol)and 4-dimethylaminopyridine (1.69 g, 13.8 mmol) in anhydrous dichloromethane (100 ml) under an atmosphere of nitrogen was added 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide hydrochloride (2.65 g, 13.8 mmol). The mixture was stirred at ambient temperature for 20 hours, then extracted with 1M NaOH and the separated aqueous phase was acidified using 5M HCl. The solid which precipitated was collected by filtration, washed with water and dried under vacuum to afford the title compound (2.74 g, 75%) as a colorless solid, mp 175-177 C. 1 H NMR (360 MHz, D6 -DMSO) w1.34 (6H, d, J=6.9 Hz), 3.83 (1H, septet, J=6.9 Hz), 7.93 (1H, dd, J=8.0 and 8.0 Hz), 8.35 (1H, d, J= 8.0 Hz), 8.48 (1H, d, J=8.0 Hz, 8.78 (1H, s), 12.40 (1H, br s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | EXAMPLE 39 STR39 (+)-N-[(3R)-2,3-Dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzo-diazepin-3-yl]-2,3-dihydrobenzofuran-2-carboxamide Diisopropylethylamine (0.3 mL, 223 mg, 1.72 mmol) was added to a stirred, cooled (0 C.) solution of 3(R)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem. 1987, 52, 3232-3239)(400 mg, 1.5 mmol), <strong>[1914-60-9]2,3-dihydrobenzofuran-2-carboxylic acid</strong> (274 mg, 1.7 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodi-imide hydrochloride (583 mg, 3.0 mmol), and 1-hydroxybenzotriazole (479 mg, 3.1 mmol) in DMF (4.5 mL). The mixture was stirred at room temperature for 18 h., poured into aqueous hydrochloric acid (3M, 12 mL) and extracted with ethyl acetate (3*20 mL). The combined organic fractions were washed with saturated aqueous sodium hydrogen carbonate (20 mL) and brine (20 mL), dried (MgSO4) and evaporated under reduced pressure. The residue was crystallized from 2-chloro-2-methylpropane/hexane to give (+)-N-[(3R)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl]-2,3-dihydrobenzofuran-2-carboxamide as a colorless solid (156 mg, 25%), m.p. 141-180 C., [alpha]D +127.1 (c=0.425, CHCl3). deltaH (CDCl3)(3:1 Mixture of diastereoisomers) 8.44 (1H, m), 7.65-6.91 (13H, m), 5.52 (1H, m), 5.28 (1H, m), and 3.70-3.40 (5H, m). Anal. Calcd. for C25 H21 N3 O3.0.25 Hexane C, 73.50; H, 5.70; N, 9.71. Found: C, 74.12; H, 5.57; N, 9.71%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | In dichloromethane; | (3) A mixture of 1-(3-amino-2-pyridyl)-3-heptylurea (0.80 g), 3,5-di-t-butyl-4-hydroxybenzoic acid (0.80 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.67 g) was stirred in dichloromethane (35 ml) at room temperature for 3 hrs. After filtering off the insolubles and distilling off the solvent, the residue was purified by a silica gel column chromatography (chloroform:methanol=30:1) to give N-[2-(3-heptylureido)-3-pyridyl]-3,5-di-t-butyl-4-hydroxybenzamide (1.34 g, 87%) as a non-crystallizable solid. 1 H-NMR (delta ppm, CDCl3) 9.58(1H, br.s), 9.48(1H, br.s), 9.06(1H, br.s), 8.34(1H, dd, J=8 Hz, 1 Hz), 7.96(1H, dd, J=5 Hz, 1 Hz), 7.87(2H, s), 6.97(1H, dd, J=8 Hz, 5 Hz), 5.59(1H, s), 2.86(2H, q, J=6 Hz), 1.44 (18H, s), 1.40-1.10(10H, m), 0.85(3H, t, J=6 Hz) IR(cm-1) 3622, 3250, 2956, 2926, 1679, 1564, 1424, 1311, 1236, 1114 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
42.1% | With benzotriazol-1-ol; In N-methyl-acetamide; | Example 242 2-(Carbobenzyloxy-L-prolyl)aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one: 2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.00 g, 8.70 mmol) was dissolved in dimethylformamide (150 ml). To the obtained solution, carbobenzyloxy-L-proline (2.80 g, 11.3 mmol), WSC-HCl (2.00 g, 11.3 mmol) and HOBT (1.53 g, 11.3 mmol) were added, and the mixture was stirred at 50 C. for 48 hours. The reaction mixture was condensed under reduced pressure. The resultant residue was extracted using a solvent mixture (chloroform: methanol=4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=20:1). The crude crystals were subjected to a recrystallizing procedure using chloroform--methanol--ether. As a result, 1.69 g of the title compound was obtained as colorless powdery crystals (42.1%). mp. 131-132 C. IR(KBr): 3273, 1692, 1655, 1615, 1536, 1460, 1435, 1412, 1532, 830 cm-1. 1 H-NMR(CD3 OD) delta: 1.73-1.88 (4 H, complex m), 2.07-2.19 (2 H, m), 2.35 (3 H, s), 3.00 (1 H, m), 3.25 (1 H, m), 3.40-3.60 (2 H, complex m), 4.25 (1 H, m), 4.95-5.10 (3 H, complex m), 6.50 (1 H, d, J=9.8 Hz), 7.22 (1 H, s), 7.25-7.37 (5 H, m), 7.97 (1 H, m). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76.0% | With benzotriazol-1-ol; In N-methyl-acetamide; | Example 224 2-(Carbobenzyloxy-L-alanyl)aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one: 2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while cooled on ice. To the obtained mixture, carbobenzyloxy-L-alanine (2.3 g, 10.5 mmol), a hydrochloric acid salt of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (hereinafter referred to as WSC.HCl) (2.3 g, 11.0 mmol), and 1-hydroxybenzotriazol (hereinafter referred to as HOBT) (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was condensed under reduced pressure. The obtained residue was extracted with chloroform, washed with 1N-HCl and saturated aqueous NaCl solution, and dried. The solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform: methanol =20:1) to obtain 3.3 g of the title compound as colorless powdery crystals (76.0%) mp. 229-231 C. 1 H-NMR(CDCl3) delta: 1.15-1.32 (3 H, m), 2.31 (3 H, s), 2.93 (1 H, m), 3.28 (1 H, m), 3.50-3.80 (2 H, m), 3.93-4.05 (2 H, m), 4.18 (1 H, m), 5.00 (1 H, m), 6.50 (1 H, d, J=10 Hz), 7.12 (1 H, s), 7.29 (5 H, s), 7.91 (1 H, d, J=10 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85 - 95% | With acetic acid;1-hydroxy-pyrrolidine-2,5-dione; In water; at 20 - 45℃; for 0.0166667 - 1h;pH 6.3 - 7.1;Bis-Tris buffer; | EXAMPLE 1; Preparation of a Chitosan Guanidine using EDC; Chitosan was purified from residual proteins and inorganic impurities by dissolution in 0.1 M acetic acid, followed by precipitation in 0.1 M sodium hydroxide and extensive washing of the precipitate with deionized distilled water. The dissolution-precipitation-washing process was repeated twice.One gram of chitosan was dissolved in 0.1 M acetic acid (100 ml_). A cooled aqueous solution of Bis-Tris (10 ml_) was slowly added under continuous stirring. When the pH of the transparent homogeneous chitosan solution reached values ranging from about 6.3-7.1, without precipitation of the chitosan, an aqueous EDC solution (1g per ml_ of water) was slowly added. The final concentration of EDC in the reaction medium was controlled to provide for different guanidine:amine ratios. The reaction between the carbodiimide group of EDC and the primary amine group of the D-glucosamine residue of chitosan was allowed to proceed for 1h at room temperature, or, alternatively, for a period ranging from 1 to 30 minutes at temperatures ranging from 37-45 0C, while in the presence of a catalytic amount (1%) of NHS (1g per ml of water). The NHS can be added prior to, or following the addition of EDC. Transparent and strong hydrogels were obtained. The gels were washed extensively with deionized distilled water until complete removal of any unreacted EDC. The modified chitosan was then isolated by alcohol precipitation techniques. The substitution efficiency was found to be dependent on the degree of deacetylation of chitosan. Typical reaction yields were of the order of 85-95%. The FSC and CRC values for the resulting guanidinated product were measured to be of the order of 8 g/g and 3.17 g/g respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In dichloromethane; | EXAMPLE 2 Production of N-ethylcarbamoylmethoxy-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionamide (Compound No. 3) STR8 A mixture of 2-[4-(3,5-dichloropyridyl-2-oxy)-phenoxy]propionic acid (1 g), N-ethylaminoxyacetamide (0.43 g) and EDC-HCl (1.2 g) in dry dichloromethane (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was washed with water and concentrated. The residue was crystallized from a mixture of dichloromethane and n-hexane to give N-ethylcarbamoylmethoxy-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionamide (1.2 g). Yield, 90%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
56% | With ammonium chloride; diisopropylamine; In N-methyl-acetamide; | [Reference example 14] Preparation of (1S,5S,6R,7R)-3-(4-N,N-diisopropylcarbamoylbutyl)-6-[(E)-4-(m-tolyl)-1-butenyl]-7-(tetrahydropyran-2-yloxy)-bicyclo[3.3.0]-2-octene 40mg of (1S,5S,6R,7R)-3-(4-carboxybutyl)-6-[(E)-4-(m-tolyl)-1-butenyl]-7-(tetrahydropyran-2-yloxy)-bicyclo[3.3.0]-2-octene was dissolved in 4mL of dimethylformamide, and 27mg of 1-hydroxybenzotriazole monohydrate was added. While stirring on ice, 71muL of diisopropylamine was added and stirred at 0C for 20 minutes. 38mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride was added, and stirred for 13 hours. An aqueous solution of ammonium chloride was added and extracted with ethyl acetate. The organic layer was washed with a saline solution, and dried with anhydrous sodium sulfate. After filtration and concentration, it was subjected to a silicagel column chromatography, to obtain 29mg of the compound presented in the title (56% yield). 1H-NMR(270MHz, CDCl3):delta 1.22 (d, 6H, J=5.0Hz), 1.37 (d, 6H, J=5.0Hz), 1.1-1.8 (m, 13H), 2.34 (s, 3H), 1.8-2.7 (m, 11H), 2.9-3.1 (m, 1H), 3.5-4.0 (m, 5H), 4.1-4.3 (m, 1H), 5.15-5.3 (m, 2H), 5.45-5.9 (m, 1H), 6.9-7.05 (m, 3H), 7.1-7.25 (m, 1H). |
Yield | Reaction Conditions | Operation in experiment |
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With 4-methyl-morpholine; In dimethylformamide(DMF, 20ml); hexane; ethyl acetate; | Preparation 13 Synthesis of (S)-4-[2-(butyloxycarbonyl-amino)-3-(4-methylsulfonyl-piperazinyl)-3-oxo-propyl]-benzonitrile (S)-3-(4-cyanophenyl)-2-(butyloxycarbonylamino)propionic acid(0.5g, 1.7 mmole) was dissolved in dimethylformamide(DMF, 20ml) and then cooled to 0C. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC, 0.5g) and 1-hydroxybenzotriazole hydrate(HOBT,0.3g) were added to this solution and stirred until they are completely dissolved therein. To this reaction mixture were added 1-methanesulfonyl-piperazine(0.3g) and N-methylmorpholine(0.2ml), and then the temperature was slowly elevated to room temperature. The reaction solution was stirred for 3.5 hours. After the reaction is completed, the reaction solution was distilled under reduced pressure to remove the volatile substance and the remaining solution was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified with column chromatography using ethyl acetate/hexane(6/4, by volume) as an eluent to obtain the purified title compound(0.7g, Yield: 93%). |
Yield | Reaction Conditions | Operation in experiment |
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5.1 g (66.8%) | With oxalic acid;Pd-C; In methanol; ethyl acetate; acetone; toluene; | Reference Example 1 (S)-3-(3-tert-butoxycarbonylaminopropyl)-2-oxopiperazine-1-acetic acid tert-butyl ester oxalate (2,2-dimethoxyethyl)aminoacetic acid tert-butyl ester (6.0 g, 27.7 mmol) and N-Z-Orn(Boc)-OH (10.0 g, 27.7 mmol) were dissolved in 54.6 ml of acetone; under stirring at 15C, l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (5.6 g, 29.2 mmol) was added. After being stirred at room temperature for 1 hour, the reaction mixture was concentrated under reduced pressure; the residue was dissolved in ethyl acetate and washed with 5% aqueous potassium hydrogen sulfate and saturated aqueous sodium bicarbonate. The organic layer was concentrated under reduced pressure to yield a light-yellow oily substance. This oily substance and p-toluenesulfonic acid 1.0 hydrate (1.04 g, 5.46 mmol) were dissolved in 137 ml of toluene, followed by stirring at 70C for 2 hours. The reaction mixture was poured over saturated aqueous sodium bicarbonate and extracted with ethyl acetate for liquid phase separation. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (hexane/ethyl acetate = 3/2) to yield 8.3 g of a light-yellow oily substance. This oily substance (8.3 g, 16.5 mmol) was dissolved in 166 ml of ethyl acetate; 1.7 g of 10% Pd-C was added, followed by stirring in a hydrogen atmosphere for 2 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in 16.6 ml of methanol; oxalic acid 2.0 hydrate (2.1 g, 16.5 mmol) was added, followed by concentration under reduced pressure. The resulting crystal was washed with ethyl acetate to yield 5.1 g (66.8%) of the title compound as a white crystal. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium chloride; In chloroform; acetonitrile; | 1) Synthesis of N-[3-(1-tert-butoxycarbonyl-4-piperidyl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide In acetonitrile (120 ml) was suspended 6.55 g (30.0 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid as well as 6.91 g (60.0 mM) of N-hydroxysuccinimide, followed by additino of 11.50 g (60.0 mM) of N-ethyl-N'-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride, and the mixture was stirred at room temperature for 1 hour. The solvent was then distilled off under reduced pressure and the residue was extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4 and the solvent was distilled off under reduced pressure to provide the active ester. To a solution of this active ester in chloroform (100 ml) was added 8.4 ml (60.0 mM) m of triethylamine as well as 8.72 g (36.0 mM) of 3-(1-tert-butoxycarbonyl-4-piperidyl)propylamine and the mixture was stirred at room temperature for 30 minutes. This reaction mixture was washed with purified water and the organic layer was further washed with saturated m aqueous solution of sodium chloride. After the organic layer was dried over MgSO4, the solvent was distilled off under reduced pressure and the residue was purified by column chromatography (ethyl acetate/ethanol=10/1) to provide the title compound. Red solid. Yield 10.16 g (76%) 1H-NMR (200 MHz, CDCl3) delta: 0.95-1.41 (m, 4H), 1.45 (s, 9H), 1.48-1.72 (m, 5H), 2.61-2.73 (m, 2H), 3.28 (m, 2H), 4.05-4.14 (m, 2H), 5.79 (dd, J=2.2, 5.8 Hz, 1H), 6.02 (t, J=5.6 Hz, 1H), 6.63-6.70 (m, 3H), 7.02 (s, 1H). IR (KBr): 1684, 1624, 1278, 1161 cm-1. |
Yield | Reaction Conditions | Operation in experiment |
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55% | With potassium hydroxide; sodium hydrogencarbonate; benzotriazol-1-ol; In water; N,N-dimethyl-formamide; | Example 2 Production of 3-(benzoxazol-2-ylthio)-N-(2,6-diisopropylphenyl)propanamide: Ethanol (EtOH) (35 ml), 3-bromopropanoic acid (1.53 g, 10 mmols) and 2-mercaptobenzoxazole (1.51 g, 10 mmols) were added in that order to an aqueous (15 ml) solution of potassium hydroxide (KOH) (1.0 g, 17.8 mmols), and heated under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the resulting residue, and this was made acidic (pH=1) with 1N HCl added thereto. The precipitate formed was taken out through filtration, and crystallized in acetone-ether-hexane to obtain 1.3 g (58% of 3-benzoxazol-2-ylthio)propanoic acid as colorless crystals. WSC (211 mg, 1.1 mmols) and HOBt (148 mg, 1.1 mmols) were added in that order to an DMF (5 ml) solution of the carboxylic acid (223 mg, 1 mmol) prepared above and 2,6-diisopropylaniline (178 mg, 1 mmol), and stirred at room temperature for 12 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from acetone-ether-hexane. 211 mg (yield: 55%) of the intended product was obtained as colorless needle-like crystals. m.p.: 174-176 C. IR (KBr) cm-1: 3432, 3244, 1652, 1501, 1454 1H-NMR (d6-DMSO) delta: 1.14 (12H, d, J=6.8 Hz), 2.97 (2H, t, J=6.6 Hz), 3.13 (2H, sept, J=6.8 Hz), 3.64 (2H, t, J=6.6 Hz), 7.10-7.16 (2H, m), 7.23 (1H, dd, J=8.5, 6.8 Hz), 7.27-7.37 (2H, m), 7.56-7.64 (2H, m), 8.96 (1H, br s) EIMS m/z (relative intensity): 382 (M+), 232 (100) |
Yield | Reaction Conditions | Operation in experiment |
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With potassium carbonate; In trifluoromethylbenzene (BTF); water; | Example 1 Synthesis of Cabergoline N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (EDAC.HCl) is added to a stirred mixture of trifluoromethylbenzene (BTF) and 25% w/w aqueous potassium carbonate. The mixture is stirred until a clear two-phase solution is obtained. The layers are allowed to separate and the lower aqueous layer is discarded. The upper organic layer is stirred with anhydrous potassium carbonate and filtered to provide a solution of EDAC in BTF. A suspension of a compound of formula (II) in BTF is stirred at IS to 24 C. and the required quantity of EDAC in BTF solution is charged. The resulting suspension is then heated to a temperature of 35 to 38 C. and maintained at this temperature until the reaction is complete. The solution is filtered and purified water added. Glacial acetic acid is then added to bring the pH to 5.0 to 5.5. The upper aqueous phase is separated. t-Butyl methyl ether is added to the upper aqueous phase and a 20% w/w potassium hydroxide solution is added to adjust the mixture to pH 9.5 to 10.0. The layers are separated and the lower aqueous layer is extracted with t-butyl methyl ether. The two upper organic layers are combined and washed with 13% aqueous sodium chloride. The upper organic layer is then separated and stirred with charcoal. The mixture is then filtered and concentrated under vacuum at 35 to 38 C. to about 2 to 3 volumes. Acetonitrile is added and the solvent exchanged via distillation under vacuum at 35 to 38 C. to about 2 to 3 volumes. The resulting acetonitrile solution may then be used as starting material for producing desired polymorphs for incorporation into pharmaceutical preparations, e.g. by the procedures of the above-mentioned international Patent Application No. WO 05/105796 and UK Patent Application Nos. 0505965.4 and 0515430.7. |
Yield | Reaction Conditions | Operation in experiment |
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17 g of (9R)-7-allyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-fg]quinoline-9-carboxylic acid were suspended in 300 ml of dimethylformamide. 20,6 g of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride were added and 18,2 ml of ethyldiisopropylamine were slowly added drop wise in the reactor vessel. The mixture was stirred for 30 hours at room temperature. The solvent was evaporated when the reaction was finished. Further 60 ml of dichloromethane was added and the obtained solution was washed with 2 portions of 40 ml of 2 % water solution of ammonia, 2 portions of 40 ml of water and 40 ml of 10 % water solution of NaCl. First two alkaline solutions are extracted again with another 30 ml of dichloromethane and evaporated. The obtained crude cabergoline was purified on the RP-18 column with mobile phase of acetonitrile/water. The obtained solution was extracted with dichloromethane at pH=7. Organic phase was evaporated to the oily, foamy or semi-solid material of amorphous cabergoline with 0,2 % (wlw) of total impurities. |
Yield | Reaction Conditions | Operation in experiment |
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96.7% | With sodium cyanamide; In ethanol; N,N-dimethyl-formamide; at 20℃; for 6h;Heating / reflux; | Sodium cyanamide (1.0 eq.) and the corresponding isothiocyanate (1.0 eq.) were dissolved in 10 mL of dry ethanol. The mixture was stirred under reflux for 3 h. After cooling down to room temperature 5 or 9 (1.0 eq.), and N1-((ethylimino)methylen)-N3,N3-dimethylpropan-1,3-diamine hydrochloride (1.2 eq.) and 5 mL of dimethylformamide were added and the mixture was stirred at room temperature for 3 h. The solvent was removed and the remaining residue was taken up in 30 mL of chloroform. The organic layer was washed one times by means of water, dried over Na2SO4, filtered and than the solvent was removed. Purification of the products was done by means of flash-chromatography utilizing basic aluminum oxide and a gradient consisting of chloroform and methanol or was purified by means of semi-preparative HPLC.Yield: 0.45 g (96.7%). 1H NMR: (CDCl3) delta 1.16-1.20 (m, 3H); 2.08-2.13 (br m, 2H); 2.27 (s, 3H); 2.55-2.60 (m, 2H); 3.39-3.44 (m, 2H); 4.18-4.22 (m, 2H); 6.54-6.57 (m, H); 6.93 (s, H); 7.11-7.16 (br m, 4H); 8.06 (s, H); 9.13 (s, H); MS m/z 311.2 (M+H)+; HPLC (A=214 nm, [C]): rt 9.07 min (99.6%). |
Yield | Reaction Conditions | Operation in experiment |
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d. Synthesis of 1-O-Dodecyl-2,3-O-isopropylidene-4-O-methyl-6-deoxy-6-[(4-fluorophenyl)acetyl]amino}-alpha-L-sorbofuranoside (Compound No. 108) 4-Fluorophenylaceticacid (21 mg), 1-hydroxybezotriazole (20 mg) and N-methylmorpholine (0.1 ml) was added to a solution of 1-O-Dodecyl-2,3-O-isopropylidene-4-O-methyl-6-deoxy-6-amino-alpha-L-sorbofuranoside (55 mg) obtained from step c above in dimethylformamide (5 mL) at 0 C. and after 20 minutes at the same temperature was added EDCI.HCl (28 mg). The reaction mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure the residue was taken in distilled water and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified over preparative TLC (thickness 2 mm) using 40% ethylacetate-hexane as eluant to yield the title compound (35 mg). 1H NMR (400 MHz, CDCl3): delta 7.21-7.26 (m, 2H), 7.00-7.05 (m, 2H), 5.84 (bs, 1H, NH), 4.49 (s, 1H), 4.31-4.33 (m, 1H) 3.63-3.65 (m, 1H), 3.43-3.59 (m, 8H), 3.44 (s, 3H), 1.55-1.58 (m, 2H), 1.26-1.48 (m, 24H), 0.86-0.89 (m, 3H). LCMS; (m/z), 538 (M+1), 560 (M+Na) |
Yield | Reaction Conditions | Operation in experiment |
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63% | 1- [3- (DIMETHYLAMINO) PROPYL]-3-ETHYL-CARBODIIMIDE HYDROCHLORIDE (EDC, 126 mg, 0.67 MMOL) and 1-hydroxybenzotriazole (HOBT, 56 mg, 0. 56MMOL) was added to a the stirred solution of 1-(2,4-difluorobenzyl)-1H-pyrrolo[2, 3-c] pyridine-5-carboxylic acid (70 mg, 0.24 MMOL) in DMF (8 mL). The mixture was stirred for 1 h, and then triethylamine (0.33 ML, 2.37 MMOL) and O-benzylhydroxylamine (231 mg, 1.80 MMOL) were added. The resulting mixture was stirred for 24 h at ambient temperature, and then water (50 mL) was added. The precipitates were collected, and dried to give the title compound (60 mg, 63%). 1H NMR (DMSO-D6) o ; 11. 71 (s, 1H), 8.81 (s, 1H), 8.20 (s, 1H), 7.74 (s, 1H), 7.15-7. 45 (m, 7H), 7.02 (m, 1 H), 6.68 (s, 1 H), 5.60 (s, 2H), 4.88 (s, 2H). HRMS calcd for C22H18F2N3O2 (M+H) 394. 1367, FOUND 394. 1388. |
Yield | Reaction Conditions | Operation in experiment |
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With sodium hydrogencarbonate; benzotriazol-1-ol; triethylamine; In dichloromethane; ethyl acetate; | [Example 3] Synthesis of gamma-Glu-Val-Gly Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl·HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml) and the solution was kept at 0C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC·HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), a 5% citric acid aqueous solution (50 ml * twice), saturated brine (50 ml), a 5% sodium bicarbonate aqueous solution (50 ml * twice), and saturated brine again (50 ml). The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol) as a white crystal. | |
With sodium hydrogencarbonate; benzotriazol-1-ol; triethylamine; In dichloromethane; ethyl acetate; | Reference Example 3 Synthesis of gamma-Glu-Val-Gly Boc-Val-OH (8.69 g, 40.0 mmol) and Gly-OBzl·HCl (8.07 g, 40.0 mmol) were dissolved in methylene chloride (100 ml) and the solution was kept at 0 C. Triethylamine (6.13 ml, 44.0 mmol), HOBt (1-hydroxybenzotriazole, 6.74 g, 44.0 mmol), and WSC·HCl (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 8.44 g, 44.0 mmol) were added to the solution, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (200 ml). The solution was washed with water (50 ml), 5% citric acid aqueous solution (50 ml* twice), saturated brine (50 ml), 5% sodium bicarbonate aqueous solution (50 ml* twice), and saturated brine (50 ml). The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to obtain Boc-Val-Gly-OBzl (13.2 g, 36.2 mmol) as a white crystal. |
Yield | Reaction Conditions | Operation in experiment |
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79% | A solution of EDCI·HCl (9.0 g, 58.1 mmol) in CH2Cl2 (20 mL) was washed with a solution of 40% aq K2CO3. Addition of pyridinium·HBr (7.5 g, 46.5 mmol) to the organic portion followed by addition of Et2O produced a precipitate. The precipitate was filtered off and the solid was washed with Et2O to give EDCI·HBr (8.63 g, 79%) as a white powder. |
Yield | Reaction Conditions | Operation in experiment |
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91% | With benzotriazol-1-ol; In chloroform; water; ethyl acetate; N,N-dimethyl-formamide; | Preparation 79 [(S)-2-tert-Butoxycarbonylamino-3-(2-nitro-benzenesulfonylamino)-propionyl]-methyl-amino}-acetic acid ethyl ester (B) Free basing procedure of Sarcosine ethyl ester: Sarcosine ethyl ester hydrochloride (39.3 g, 256.8 mmol) was dissolved in water (300 mL), washed with Et2O (2*100 mL), pH adjusted to ~pH 8, extracted with CHCl3 (3*100 mL) and dried over Na2SO4 and finally filtered. To a solution of compound A (10.0 g, 25.7 mmol) in DMF (100 mL) was added HOBt (5.2 g, 38.5 mmol) and the reaction mixture was cooled to -10 C. To this reaction mixture, EDC-HCl (5.4 g, 28.2 mmol) was added in portions over 10 min and stirred at -10 C. for 20 min. To the reaction mixture, Sarcosine ethyl ester (256.8 mmol) in CHCl3 (300 mL) was added drop wise over 30 min. The reaction mixture was stirred at this temperature for 30 min followed by stirring at ambient temperature overnight. Solvents were then removed in vacuo, and the residue was dissolved in EtOAc (500 mL), washed with water (3*300 mL), saturated aqueous NaHCO3 (2*300 mL) and brine (100 mL). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo to afford compound B (11.5 g, 91%) as a cream solid. LC-MS [M+H] 489.5 (C19H28N4O9S+H, calc: 489.3). Purity>95% (UV/254 nm). |
Yield | Reaction Conditions | Operation in experiment |
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77% | With benzotriazol-1-ol; triethylamine; In N,N-dimethyl-formamide; | Example 8 Preparation of 4-(aminomethyl)-N-(2-aminophenyl)benzamide 4-Cyanobenzoic acid (294 mg, 2 mmol) was dissolved in 8 ml of DMF, then 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (768 mg, 4 mmol), 1-hydroxybenzotriazole (324 mg, 2.4 mmol), triethylamine (808 mg, 8 mmol) and o-phenylenediamine (432 mg, 4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give N-(2-aminophenyl)-4-cyanobenzamide (364 mg, 77%) as a grey solid. LC-MS (m/z) 238 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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84% | With benzotriazol-1-ol; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 20h; | Example 16 Preparation of N-(2-aminophenyl)-6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthamide 6-(6,7-Dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) was dissolved in 4 ml of DMF, then 1-ethyl-3-(3-dimethyllaminopropyl)carbodi-imide hydrochloride (38.4 mg, 0.2 mmol), 1-hydroxybenzotriazole (16.2 mg, 0.12 mmol), triethylamine (40.4 mg, 0.4 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 200 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (39.1 mg, 84%) as a brown solid. 1H NMR (DMSO-d6) delta 4.01 (s, 6H, 2 * OCH3), 4.97 (s, 2H, benzene-NH2), 6.65 (t, J= 7.2 Hz, 1H, Ar-H), 6.82 (d, J= 7.0 Hz, 1H, Ar-H), 7.00 (t, J= 7.1 Hz, 1H, Ar-H), 7.38 (d, J= 7.1 Hz, 1H, Ar-H), 7.42 (s, 1H, Ar-H), 7.60 (dd, J= 2.4 and 9.2 Hz, 1H, Ar-H), 7.64-7.68 (m, 2H, Ar-H), 7.87 (d, J= 6.7 Hz, 1H, Ar-H), 7.97 (d, J= 2.3 Hz, 1H, Ar-H), 8.09 (d, J= 8.2 Hz, 1H, Ar-H), 8.38 (d, J= 9.2 Hz, 1H, Ar-H), 8.54 (s, 1H, Ar-H), 9.85 (s, 1H, benzene-NH). LC-MS (m/z) 467 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
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57.2% | In dimethyl sulfoxide; at 20℃; for 24h; | General procedure: The conjugate Pt-AD,2,was synthesized by adding 1-adamatanemethylamine (18.2 mg, 110 lmol), 1 (43.4 mg, 100 lmol) [5], N-hydroxysuccinimide (12.7mg, 110 lmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 23.0mg, 120 lmol) to anhydrous DMSO (0.6 ml) and stirring the resulting solution at room temperature for 24 h.The volume of th esolution was reduced in vacuo to produce bright yellow oil which was washed with 10 ml diethylether. After removal of the diethyl ether, 5ml of water was added which produced a light yellow precipitate. The product was collected by filtration, washed with ice cold diethyl ether and dried in vacuo. |
Yield | Reaction Conditions | Operation in experiment |
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71% | In dichloromethane; ethyl acetate; toluene; | 9.1 Preparation of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]-ethyl}phenyl)prop-2-enoate 2.50 g (11.8 mmol) of <strong>[4836-69-5]2-(2,4-dinitrophenyl)ethanol</strong>, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-di-methylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0 C. The solution is stirred for 1 h at 0 C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloro-methane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yields 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenoxy]methyl}phenyl)prop-2-enoate as yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
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71% | With dmap; In dichloromethane; ethyl acetate; toluene; | 2.2 Preparation of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}-phenyl)prop-2-enoate 2.50 g (11.8 mmol) of <strong>[4836-69-5]2-(2,4-dinitrophenyl)ethanol</strong>, 4.91 g (11.8 mmol) of (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoic acid, 144 mg (1.2 mmol) of 4-dimethylaminopyridine are dissolved in 30 mL of dichloromethane. 2.48 g (13.0 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC hydrochloride) are added at 0 C. The solution is stirred for 1 h at 0 C. and allowed to stir at room temperature overnight. After 22 hours at room temperature, the reaction mixture is partitioned between dichloromethane and water. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Chromatography of the residue on 200 g silica gel using toluene: ethyl acetate 95:5 as eluent and crystallization from ethyl acetate:hexane mixture yielded 5.11 g (71%) of 2-(2,4-dinitrophenyl)ethyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]methoxy}phenyl)prop-2-enoate as yellow crystals. |
Yield | Reaction Conditions | Operation in experiment |
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In ethanol; at 20℃; | General procedure: Chitosan solution (1.2% w/v) was prepared by agitating chitosan flakes in an aqueous acetic acid solution (1% v/v) at ambient temperature overnight. A solution of ferulic acid, EDAC (1 mol equivalent to ferulic acid) and ethanol (10 mL) was then added dropwise into the chitosan solution (50 mL) while stirring and keeping at a constant temperature. Different mole ratios of chitosan to ferulic acid (i.e. 1.0:0.0, 1.0:0.5, 1.0:1.0, 1.0:1.5, 1.0:2.0 and 1.0:2.5) and various reaction temperatures (i.e. 40, 60 and 80C) were used. The reaction was performed at different times (i.e. 1.5, 3.0, 4.5 and 6.0h). The mixture was subsequently dialyzed against water for a few days to eliminate free acetic acid and isourea by-products (Scheme 1), followed by centrifuging at 10,000rpm for 30min to remove residual ferulic acid. The supernatant was lyophilized to provide ferulic acid grafted chitosan. |
Yield | Reaction Conditions | Operation in experiment |
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70% | With benzotriazol-1-ol; In N,N-dimethyl-formamide; | Step-1: Preparation of trans-2-(N"-acetylhydrazinocarbonyl)-5-benzyloxyamino-piperidine-1-carboxylic acid-tert-butyl ester To a solution of trans-5-benzyloxyamino-piperidine-1,2-dicarboxylic acid-1-tert-butyl ester (12 gm, 0.034 mol) in N,N-dimethyl formamide (60 ml), EDC-HCl (9.82 gm, 0.051 mol) and N-methyl morpholine (11.4 ml) were added successively at 10 C. to 15 C. under stirring. To the reaction mixture, were added acetyl hydrazide (2.79 gm, 0.0377 mol) and HOBt (4.62 gm, 0.034 mol). The resulting mixture was allowed to warm at 25 C. to 35 C. and stirred for 16 hours. The reaction mixture was poured into water (600 ml) and stirred for 30 min. The separated solid was filtered and the filtrate was extracted with ethyl acetate (3*400 ml). The combined organic extract was dried over sodium sulphate and the solvent was evaporated under vacuum to provide a residue. The residue was purified by column chromatography to obtain the Step-1 product, as a pale yellow thick oil in 9.8 gm quantity (yield 70%). Analysis: MS: 407 (M+H); MF: C20H30N4O5; MW: 406.49. |
Yield | Reaction Conditions | Operation in experiment |
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With triethanolamine; In n-heptane; dichloromethane; | Step 1: 5-Chloro-3-fluoro-N-methoxy-N-methylpicolinamide To a stirred mixture of <strong>[207994-08-9]5-chloro-3-fluoropicolinic acid</strong> (3.62 g, 20.62 mmol) in dichloromethane (50 mL) were added 1H-benzo[d][1,2,3]triazol-1-ol (0.42 g, 3.09 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine HCl (5.93 g, 30.9 mmol), N,O-dimethylhydroxylamine HCl (3.02 g, 30.9 mmol), and TEA (7.19 mL, 51.6 mmol). The reaction mixture was stirred at RT for 2 hours, and then partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography, eluting with 0-100% EtOAc in heptane, to provide the title intermediate (3.71 g) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
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With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | A) tert-butyl (cyclopropylmethyl)(trans-2-{4-[(1H-pyrazol-4-ylcarbonyl)amino]phenyl}cyclopropyl)carbamate A solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75 mg) in DMF (3 mL) was ice-cooled, and <strong>[37718-11-9]1H-<strong>[37718-11-9]pyrazole-4-carboxylic acid</strong></strong> (33.4 mg), N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (143 mg), 1-hydroxybenzotriazole (49.4 mg) and diisopropylethylamine (80 mg) were added. The mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution was added under ice-cooling. The mixture was extracted with ethyl acetate, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (72 mg). MS (API+): [M-tBu+2H]+ 341.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; In N,N-dimethyl-formamide; | A) tert-butyl [trans-2-(4-[4-(benzoylamino)benzoyl]amino}-phenyl)cyclopropyl](cyclopropylmethyl)carbamate To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (90.9 mg), <strong>[582-80-9]4-benzamidobenzoic acid</strong> (87 mg) and 1-hydroxybenzotriazole (60.9 mg) in DMF (1.5 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (86 mg). The reaction mixture was stirred at room temperature for 2 hr, and poured into 0.5N hydrochloric acid. The mixture was extracted with ethyl acetate, and the extract was washed successively with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was washed with ethyl acetate/diisopropyl ether to give the title compound (98.0 mg). 1H NMR (300 MHz, DMSO-d6) delta 0.07-0.17 (1H, m), 0.18-0.29 (1H, m), 0.34-0.52 (2H, m), 0.91-1.02 (1H, m), 1.15-1.28 (2H, m), 1.37 (9H, s), 2.01-2.12 (1H, m), 2.67-2.76 (1H, m), 3.00 (1H, dd, J = 14.5, 7.0 Hz), 3.20 (1H, dd, J = 14.5, 6.9 Hz), 7.12 (2H, d, J = 8.7 Hz), 7.50-7.63 (3H, m), 7.67 (2H, d, J = 8.7 Hz), 7.91-8.01 (6H, m), 10.09 (1H, s), 10.51 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In N,N-dimethyl-formamide; | A) tert-butyl (cyclopropylmethyl)[trans-2-(4-[(1-methyl-1H-pyrazol-4-yl)carbonyl]amino}phenyl)cyclopropyl]carbamate To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (85.8 mg) and <strong>[5952-92-1]1-methyl-1H-pyrazole-4-carboxylic acid</strong> (42.9 mg) in DMF (1.42 mL) was added N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide hydrochloride (82 mg). The mixture was stirred at room temperature overnight, and poured into water. The mixture was extracted with ethyl acetate, and the extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (114.8 mg). 1H NMR (300 MHz, DMSO-d6) 5 0.05-0.16 (1H, m), 0.16-0.28 (1H, m), 0.32-0.52 (2H, m), 0.89-1.05 (1H, m), 1.09-1.26 (2H, m), 1.36 (9H, s), 2.00-2.10 (1H, m), 2.65-2.72 (1H, m), 2.98 (1H, dd, J = 14.2, 6.9 Hz), 3.19 (1H, dd, J = 14.2, 6.9 Hz), 3.88 (3H, s), 7.10 (2H, d, J = 8.5 Hz), 7.59 (2H, d, J = 8.7 Hz), 7.99 (1H, s), 8.28 (1H, s), 9.74 (1H, s). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With hydrogenchloride; triethylamine; In tetrahydrofuran; 1,4-dioxane; methanol; ethyl acetate; | Step 8: N-((4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide To a solution of (R)-N-((2S,4S)-2-(2-chloro-3-fluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.75 g, 4.49 mmol) in DCM (10 mL) and methanol (5.00 mL) was added hydrogen chloride, 4M in 1,4-dioxane (11.22 mL, 44.9 mmol). After 30 min, the mixture was concentrated, diluted with DCM and saturated NaHCO3. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. This material was dissolved in THF (25 mL) and then treated with benzoyl isothiocyanate (0.695 mL, 5.16 mmol). After 30 min, triethylamine (0.751 mL, 5.39 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.947 g, 4.94 mmol) were added, and the resulted reaction mixture was brought up to 70 C. for 40 min. The reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo and the crude was purified by silica gel column (40 g, 0-40% EtOAc/hexane in 25 min) to afford N-((4S,6S)-4-(2-chloro-3-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide as an off-white solid (1.73 g, 93% yield). MS m/z=415 [M+H]+. Calculated for C19H15ClF4N2O2: 414.8. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
59.4% | With triethylamine; In hexane; ethyl acetate; | Then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.889 g, 4.64 mmol) and triethylamine (0.703 ml, 5.06 mmol) were added and the reaction mixture was heated at 70 C. for 1.5 h. The reaction mixture was diluted with EtOAc, washed with water and dried over sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using 0-20% EtOAc/hexane to give N-((4S,6S)-4-(3-bromophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.15 g, 2.504 mmol, 59.4% yield). MS m/z=460.9 [M+H]+. Calculated for C19H15BrF4N2O2: 459.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
82% | With sodium hydrogencarbonate; N-ethyl-N,N-diisopropylamine; In ethyl acetate; | Step 8: N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (11i) To a 150 mL round-bottomed flask was added (2S,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5-tetrafluoropentan-2-ol (1.54 g, 4.41 mmol), MeCN (30 mL) and benzoyl isothiocyanate (Aldrich; 0.712 mL, 5.29 mmol). The reaction mixture was stirred at rt for 45 min and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (Oakwook Products, Inc.; 1.015 g, 5.29 mmol) and N,N-diisopropylethylamine (Aldrich; 1.54 mL, 8.82 mmol) were added. The solution was stirred at rt for 2 h and then treated with sat NaHCO3 and extracted with EtOAc (2*100 mL). The combined extracts were washed with water (1*100 mL) and brine and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane) afforded N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.74 g, 3.64 mmol, 82% yield) as an off-white foam. MS m/z=480.0 [M+H]+. Calculated for C18H13BrF5N3O2: 479.0. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With 4-methyl-morpholine; In dichloromethane; | (S)-3-(tert-Butoxycarbonyl)-N-methoxy-2,2,N-trimethyloxazolidine-4-carboxamide (3) To a solution of L-Boc-serine 2 (12.33 g, 60.1 mmol) in CH2Cl2 (240 mL) were added N,O-dimethylhydroxylamine hydrochloride (6.04 g, 61.9 mmol) and N-methylmorpholine (6.8 mL, 61.9 mmol) at 0 C. To this solution was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (11.86 g, 61.9 mmol) portionwise over a period of 20 min. and the solution was stirred for another 1 h. Then, aq. HCl solution (1.0 M, 30 mL) was added and the aqueous layer was extracted with CH2Cl2 (2 x 100 mL). The combined organic layers were washed with sat. aq. NaHCO3 solution (30 mL) and the aqueous layer was again extracted with CH2Cl2 (100 mL). The combined organic layers were dried over MgSO4 and the solvent was removed in vacuo to obtain the corresponding Weinreb amide (14.07 g, 94%) as white solid. Rf = 0.3 (EtOAc); 1H NMR (250 MHz, CDCl3) delta 5.60 (d, J = 6.0 Hz, 1 H), 4.77 (br s, 1 H), 1.42 (s, 9 H), 3.80 (d, J = 3.3 Hz, 2 H), 3.76 (s, 3 H), 3.21 (s, 3 H), 2.66 (br s, 1 H). The crude product was dissolved in acetone (180 mL) to which 2,2-dimethoxypropane (57 mL) and BF3·Et2O (0.5 mL) were added. The orange solution was stirred for 90 min. at r.t. and then quenched with Et3N (1.2 mL) and solvents removed in vacuo. The crude product was purified by flash column chromatography on silica gel (gradient EtOAc/cyclohexane = 1:2 ? 1:1) to yield isopropylidene-protected Weinreb amide 3 (15.32 g, 89% over two steps) as a white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; | 1-3. Synthesis of Low-Molecular-Weight Compound ID-52 (8a) Among the above-described low-molecular-weight compounds, ID-52 (3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid methyl ester (8a)) was prepared in the following manner. Trans-3-indoleacrylic acid (7a, 150 mg, 0.8 mmol) and 3-amino-benzoic acid methyl ester (6a, 218 mg, 1.44 mmol) were dissolved in DMF, and 1-[3-(dimethyamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC, 230 mg, 1.2 mmol), hydroxy-7-azabenotriazole (HOAT, 163 mg, 1.2 mmol) and N,N-diisopropylethylamine (DIPEA, 0.21 mL, 1.2 mmol) were added to the solution to cause a coupling reaction. The reaction solution was stirred overnight at room temperature. Then, the resulting material was separated and purified to obtain 3-(3-1H-indol-3-yl-acryloylamino)-benzoic acid methyl ester (ID-52) as a yellow solid. 1H NMR (CDCl3, 300 MHz) d=8.90 (s, 1H), 8.21 (s, 1H), 7.86-8.03 (m, 4H), 7.76 (d, J=8.1 Hz, 1H), 7.36-7.41 (m, 3H), 7.20 (m, 2H), 6.60 (d, J=15.3 Hz, 2H), 3.88 (s, 3H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dmap; trimethylsilyl trifluoromethanesulfonate; In dichloromethane; acetonitrile; | Example 24 To a solution of (R)-1-(7-bromo-quinolin-2-yl)-ethanol (295 mg, 1.17 mmol) in anhydrous acetonitrile (12 mL) were added but-3-enoic acid tert-butyl ester (0.44 mL, 2.75 mmol), bis(tri-tert-butylphosphine)palladium(0) (25 mg, 0.049 mmol) and N,N-dicyclohexylmethylamine (0.39 mL, 1.83 mmol) then the mixture was heated at reflux for 2 h. The reaction mixture was concentrated in vacuo to give a crude residue. This was purified by silica gel chromatography using iso-hexanes/ethyl acetate 95:5 to yield the title compound (348 mg, 95%) as a white solid. To 24a (363 mg, 1.16 mmol) and (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (505 mg, 1.26 mmol) in dichloromethane (20 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (311 mg, 1.62 mmol) and 4-dimethylaminopyridine (142 mg, 1.16 mmol). The reaction mixture was then stirred at RT for 16 h. To the mixture was added saturated aqueous ammonium chloride solution (100 mL) and the aqueous layer extracted with dichloromethane (2*50 mL). The aqueous phase was further washed with dichloromethane (20 mL) and the combined organics washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude residue. This was purified by silica gel chromatography using iso-hexanes/ethyl acetate 4:1 (120 mL) then iso-hexanes/ethyl acetate 7:3 (855 mL) then iso-hexanes/ethyl acetate 3:2 (540 mL) to yield the title compound (357 mg, 44%) as a white solid. To a solution of 24b (342 mg, 0.492 mmol) in dichloromethane (2.5 mL) at 0 C. was added trimethylsilyl trifluoromethanesulfonate (0.18 mL, 0.96 mmol) and the pale yellow solution stirred at 0 C. for 2.75 h. Additional trimethylsilyl trifluoromethanesulfonate (0.073 mL, 0.45 mmol) was added and stirring continued for 1.33 h. N,N-Diisopropylethylamine (0.6 mL, 3.44 mmol) was added and the mixture stirred for 10 min then concentrated in vacuo to give intermediate (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid (R)-1-[7-((E)-3-carboxy-propenyl)-quinolin-2-yl]-ethyl ester (266 mg, 0.45 mmol). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.5% | With benzoic acid; In N,N-dimethyl-formamide; | Methyl 6-benzamidohexanoate (Intermediate 8) To a solution of methyl 6-aminohexanoate (intermediate 7, 17.8 g, 0.098 mol) in DMF (150 mL), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (19.05 g, 0.122 mol), hydroxybenzotriazole (16.47 g, 0.122 mol) and diisopropyl ethyl amine (31.72 g, 0.245 mol) were added. The reaction mixture was stirred for 10 min and benzoic acid (10 g, 0.08 mol) was added. The reaction mixture was stirred overnight at room temperature, then diluted with water and extracted with ethyl acetate. The combined organic layers were combined, dried over anhydrous sodium sulfate and evaporated under reduced pressure to afford the desired intermediate 8. (12.76 g, 62.5%). TLC: 10% MeOH/DCM (Rf: 0.5) 1H NMR (400 MHz, DMSO-d6) delta8.42 (d, J=6.0 Hz, 1H), 7.83 (d, J=7.3 Hz, 2H), 7.47 (m, 3H), 3.57 (s, 3H), 3.24 (m, 2H), 2.30 (t, J=7.4 Hz, 2H), 1.54 (m, 4H), 1.30 (m, 2H). LC-MS (ESI+): m/z 250 [M+H]+ (66% purity). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
71.2 g | In dichloromethane; at 30℃; | Weigh 24ml of carbon disulfide dissolved in 150ml methanol,43.8 g of N, N'-dimethylpropylenediamine was slowly added dropwise to control the temperature at 10-15 C,The dropwise addition process was carried out with a white solid which was added dropwise at 20 C for 2 hours, filtered and washed with methanol to give 75 g of a white solid (Intermediate 1) in 96% yield.75 g of the product was weighed, 200 ml of dichloromethane was added, and the temperature was controlled at 10-15 C. 45.8 g of triethylamine was added, followed by slowly dropping 50.3 g of ethyl chloroformate, dropping for 2 hours,After the dropwise addition was carried out for 1 hour, the organic phase was washed, washed, filtered and dried to give the product (Intermediate 2).25.2 g of ethylamine (containing 70% water) was weighed, 180 ml of dichloromethane was added,Cooling to 10-15 C, slowly dropping intermediate 2, dropping finish for 1 hour,The organic phase was washed with an alkali of pH 11-12, dried, under reduced pressure, and concentrated to give 90 g of an oil, (Intermediate 3)0.02 g of EDTA was added and oxidized at 30 C with 630 g of sodium hypochlorite at a mass concentration of 10%. After completion of the oxidation,Extraction layer, the organic phase after drying and vacuum concentration 30 , the solvent evaporated, the vacuum distillation to get EDC,Purity 99.4%;41.4 g of pyridine hydrochloride was weighed, 120 ml of dichloromethane was added, and the mixture was heated at 30 C,Slowly dropping the distillation of the EDC, first dissolved, and then precipitation of crystals, dripping finished, cooling to 5 ,Crystallization 1h, filtration, to be 71.2g EDC hydrochloride, purity 99.5%Yield 81% (based on N, N'-dimethylpropylenediamine). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
98% | With sodium hydrogencarbonate; benzotriazol-1-ol; benzoic acid; | Example 1. Preparation of Compound 8 Methyl 2-benzamidoacetate To a solution of benzoic acid (4.35 g, 35.31 mmol) and glycine methyl ester hydrochloride (4.03 g, 32.10 mmol) in DMF (50 ml) was added EDC hydrochloride (6.77 g, 35.31 mmol), HOBt (4.77 g, 35.31 mmol) and DIPEA (12.30 ml, 70.62 mmol) at room temperature. The mixture was stirred overnight, prior to be quenched with sat. NaHCO3 (150 ml). The aqueous layer was extracted with AcOEt (3*30 ml), and the combined organic layers washed with sat. NaHCO3 (1*20 ml), brine (2*30 ml), dried over MgSO4, filtered and concentrated to furnish methyl 2-benzamidoacetate (6.07 g, 98% yield) in good purity. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dmap; In dichloromethane; at 20℃; | Take 25mL eggplant bottle, at room temperature will be2- (3-carbonyl-oleanolic-12-ene-2,8-benzyl ester-23-oxy) -carbonyl-benzoic acid(20 mg, 0.030 mmol)Dissolved in anhydrous dichloromethane,EDCI (10 mg, 0.05 mmol) was added followed by stirring, DMAP(8 mg, 0.06 mmol) at room temperature for 5-8 hours, washed sequentially with 5% hydrochloric acid, deionized water, saturated brine, anhydrous sulfuric acidSodium was dried and concentrated, and silica gel column chromatography (V: chloroform: 80 M, 80: 1 to 50: 1) gave a white solid (17 mg, 61%). M.p 100 to 103. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With dmap; In dichloromethane; at 20℃; for 5h; | To a solution of EDCI (0.01g, 0.05mmol) and DMAP (0.01g, 0.06mmol) in dry dichloromethane (5mL), compound 11 (0.02g, 0.03mmol) was added. The mixture was stirred for 5hat room temperature, then washed with 5% HCl, water, and brine successively, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (50:1 chloroform:methanol) to provide the compound 15. White solid (0.02g, 61% yield) mp 100-103C. Rf=0.48 (chloroform/methanol 15:1 v/v); [alpha]20D=16.14 (c=0.14, CH3OH/CHCl3 3:2 v/v); 1H NMR (400MHz, CDCl3) delta 0.66 (3H, s, -CH3), 0.89 (3H, s, -CH3), 0.92 (3H, s, -CH3), 1.06 (3H, s, -CH3), 1.09 (3H, s, -CH3), 1.25 (3H, s, -CH3), 2.50-2.53 (2H, m), 2.92 (1H, dd, J=3.9, 13.6Hz, H-18), 4.30 (1H, d, J=10.72Hz, H-23A), 4.32 (1H, d, J=11.30Hz, H-23B), 5.06 (1H, d, J=12.76Hz, CH2Ar), 5.10 (1H, d, J= 12.76Hz, CH2Ar), 5.30 (1H, t, H-12), 7.31-7.36 (5H, m, H-Ar), 7.48(1H, t, J=7.32Hz, H-Ar), 7.61-7.63 (2H, m, H-Ar), 7.89-7.91 (1H, m, H-Ar), 9.12 (1H, m, -NH-); 13C NMR (100MHz, CDCl3) delta 14.10, 14.60, 14.92, 16.88, 17.49, 19.54, 22.99, 29.54, 23.46, 23.57, 25.61, 27.56, 29.67, 30.66, 31.97, 32.11, 32.25, 32.28, 32.56, 33.04, 33.05, 34.75, 35.42, 36.39, 37.94, 39.19, 41.49, 41.83, 44.57, 45.80, 46.69, 46.73, 48.66, 50.41, 65.93, 68.48, 71.13, 76.54, 76.86, 77.21, 122.07, 126.21, 127.92, 128.00, 128.40, 129.27, 130.09, 131.02, 133.16, 136.36, 143.83, 167.60, 177.39. ESI-HRMS m/z calcd. for C53H73N3O7 [M+H]+: 864.5435, found: 864.5501. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | A solution of Boc-Alanine (1 g, 5.3 mmol) was formed in DCM (40 mL). EDC hydrochloride (1.02 g, 5.3 mmol) was added followed by 1-hydroxybenzotriazole hydrate (716 mg, 5.3 mmol) and the mixture stirred for 5 mins. N,N-diisopropylethylamine (1.85 mL, 10.6 mmol) was added giving a yellow solution. Girard's Reagent D (1.1 g, 5.8 mmol) was added and the mixture stirred for 24 h. The mixture was partitioned between DCM and sat. aqueous sodium bicarbonate The organic phase was isolated using a phase separation cartridge and evaporated. Purification by flash column chromatography (40 g Si cartridge) eluting with a gradient of 0-10% (2N NH3 in MeOH) in DCM gave Intermediate C1 as a colourless gum (870 mg, 57%).1H NMR (400 MHz, CDCl3): delta 8.63 (1H, br s), 5.00-4.89 (1H, m), 4.34-4.22 (1H, m), 3.08 (2H, s), 2.34 (6H, s), 1.46 (9H, s), 1.41 (3H, d, J=7.1 Hz). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; N-ethyl-N,N-diisopropylamine; | Trifluoroacetic Acid/tert-butyl {(2S)-4-[{(1R)-1-[1-benzyl-4-(2,5-difluorophenyl)-1H-imidazol-2-yl]-2,2-dimethylpropyl}(glycoloyl)amino]-1-hydrazino-1-oxobutan-2-yl}carbamate (1:1) 150 mg (0.16 mmol) of Intermediate C3 were dissolved in 21 ml of DMF, and then 37.2 mg (0.19 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC), 37 mg (0.243 mmol) of 1-hydroxybenzotriazole, 85 mul of N,N-diisopropylethylamine and finally 45 mg (0.18 mmol) of commercially available 9H-fluoren-9-ylmethyl hydrazinecarboxylate were added. The mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was purified by preparative HPLC. The appropriate fractions were concentrated and the residue was lyophilized from acetonitrile/water. This gave 60 mg (41percent of theory) of the protected intermediate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With triethylamine hydrochloride; In acetonitrile; at 15℃; for 1h; | Add 1100 g of triethylamine hydrochloride to a 3000 ml reaction flask.1000g of acetonitrile, wherein the mass ratio of triethylamine to HCL is 5:1,EDC213.6g was slowly added dropwise, and the temperature was controlled at 15 C.The dropping time is controlled at 60 min, filtered,EDC hydrochloride was obtained with a purity of 99.5% and a yield of 92%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
25% | To a stirred solution of (tert-butoxycarbonyl)-L-alanine (5 g, 26.4 mmol, 1 eq.), 4- (dimethylamino)pyridine 29 (323 mg, 2.64 mmol, 10 mol%) and Et3N (14.7 mL, 106 mmol, 4 eq.) in CH2CI2 (50 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10.1 g, 52.9 mmol, 2 eq.). The reaction mixture was stirred at 0 C for 1 h. Cyclohexanol (3.35 mL, 31.7 mmol, 1.2 eq.) was added, and the reaction mixture stirred for 48 h at ambient temperature. The reaction mixture was concentrated in vacuo to give an oily solid which was partitioned with Et20 and water . The phases were separated and the organic phase washed with water (50 mL), brine (50 mL), dried over MgS04, filtered and concentrated in vacuo to give a colorless oil. Purificationby flash chromatography (S1O2, eluting 11-14% EtO Ac/heptane) gave cyclohexyl (tert-butoxycarbonyl)-L-alaninate, 30, (1.76 g, 25% yield). MR (CDC13, 300 MHz) deltaEta 5.04 (br s, 1H), 4.83-4.76 (m, 1H), 4.27 (br quint, 1H), 1.84 (br s, 2H), 1.72 (br s, 2H), 155-1.23 (m, 6H), 1.37 (d, 3H) . |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
52% | tett-Butyl (E)-4-(3-(3-amino-2-((4-((2-amino-4-carbamoyl-6- methoxyphenyl)amino)but-2-en-1-yl)amino)-5-carbamoylphenoxy)propyl)piperidine-1- carboxylate (77 mg, 0.123 mmcl) was dissolved in DMF (3 mL) at 0 C, and then 1-ethyl-3-methyl-1H-pyrazole-5-carbonyl isothiocyanate (0.308 ml, 0.123 mmol) was added. The reaction mixture was then maintained at 0 C for 15 mm. then EDC (28.3 mg, 0.148 mmol) and TEA (0.043 ml, 0.308 mmol) were then added to the reaction mixture. The reaction mixture was then maintained at RT for 16 hrs. The reaction mixture was concentrated and the yellow residue was purified on silica gel (20 %-50 % MeOH/CH2CI2, 10% TEA in MeOH; 40 gRediSep column). Collected fractions containing the product were combined and concentrated to afford the title compound as a white solid (87 mg, 52 % yield). LCMS (LCMS Method K): Rt = 1.11 mi [M+H] = 948.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. IR (KBr)tmax: 3403, 3053, 2966, 2869, 2721, 2659, 1916, 1873, 1760, 1640, 1599,1584, 1512, 1462, 1348, 1253, 1141, 1121, 1020, 917, 843, 746, 678, 579 cm1. Melting Range: 138-141 C, 1H NMR (400 MHz, DMSO-d6) d10.60 (br s,1H), 7.12-7.08 (m, 2H), 6.91-6.82 (m, 2H), 6.48 (br s, 1H), 3.33-3.27 (m, 2H), 1.17 (t, J7.1 Hz, 3H), 13C NMR (DMSO-d6, 100 MHz): d 155.4, 138.7, 118.8, 111.4, 40.1, 39.9, 39.7, 39.5, 39.2, 39.0, 38.8, 36.9, 15.1; HRMS (ESI) m/z calcd. for C9H11N3 ([MH]) 162.0953; found: 162.0108 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
94% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 °C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5percent MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90percent yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
79% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
75% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5% MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90% yield) as an off white solid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | In isopropyl alcohol; at 80℃; for 0.25h;Microwave irradiation; | General procedure: A mixture of o-phenylenediamine (1.0 mmol) and EDC.HCl (1.1 mmol) in 2-propanol (10 mL) was irradiated in microwave apparatus at 200 W (80 °C) for 15 min. The reaction was monitored by TLC (eluent CH2Cl2 / MeOH 95:5). After completion, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure and the obtained crude product was purified by flash column chromatography using silica gel (100-200 mesh) with 1-5percent MeOH/CH2Cl2 as eluent. The fractions containing product were collected and concentrated under reduced pressure to afford N-ethyl-1Hbenzo[d]imidazol-2-amine (1a, 90percent yield) as an off white solid. |
Tags: 25952-53-8 synthesis path| 25952-53-8 SDS| 25952-53-8 COA| 25952-53-8 purity| 25952-53-8 application| 25952-53-8 NMR| 25952-53-8 COA| 25952-53-8 structure
A848717[ 7084-11-9 ]
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine xhydrochloride
Reason:
[ 7084-11-9 ]
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine xhydrochloride
Similarity: 1.00
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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