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CAS No. : | 71810-97-4 | MDL No. : | MFCD00039093 |
Formula : | C3H9ClN2O | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | FIAINKIUSZGVGX-HSHFZTNMSA-N |
M.W : | 124.57 | Pubchem ID : | 2775814 |
Synonyms : |
|
Num. heavy atoms : | 7 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.67 |
Num. rotatable bonds : | 1 |
Num. H-bond acceptors : | 2.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 29.11 |
TPSA : | 69.11 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -7.46 cm/s |
Log Po/w (iLOGP) : | 0.0 |
Log Po/w (XLOGP3) : | -0.57 |
Log Po/w (WLOGP) : | -0.38 |
Log Po/w (MLOGP) : | -0.8 |
Log Po/w (SILICOS-IT) : | -1.28 |
Consensus Log Po/w : | -0.61 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | -0.19 |
Solubility : | 80.9 mg/ml ; 0.65 mol/l |
Class : | Very soluble |
Log S (Ali) : | -0.41 |
Solubility : | 48.3 mg/ml ; 0.388 mol/l |
Class : | Very soluble |
Log S (SILICOS-IT) : | 0.56 |
Solubility : | 447.0 mg/ml ; 3.59 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 1.08 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
GHS Pictogram: |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride; triethylamine In tetrahydrofuran; 1,4-dioxane; ethyl acetate | d.) (R)-alanine amide hydrochloride (45) Boc-D-Alanine (5.0 g) (26.43 mmol) was dissolved in dry THF (100 mL). Triethylamine (4 mL, 2.91 g, 28.76 mmol) was added, followed by ethyl chloroformate (2.5 mL, 2.951 g, 27.19 mmol). The solution was left stirring in a carbon tetrachloride/dry-ice cold bath for about 30 min. Concentrated ammonium hydroxide (5 mL, 74.0 mmol) was added and the solution was stored in the refrigerator overnight. The reaction was evaporated under vacuum and the residue taken up in ethyl acetate. The ethyl acetate was extracted with sodium carbonate and water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was treated with saturated hydrochloric acid/dioxane for 1 hour at room temperature. The dioxane was evaporated under vacuum, the residue taken up in a small amount of methanol and precipitated with diethyl ether to yield the title compound (45) (2.5 g, 76percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; for 0.416667h; | (S)-2-[(R)-5-(4-CYANO-BENZYL)-7-(3, 5-DICHLORO-PHENYL)-5-METHYL-6-OXO-6, 7-DIHYDRO-5H- imidazo [1, 2-a] imidazole-3-sulfonylamino]-propionic acid (see Example 14) (0.05 g, 0.091 mmol) was dissolved in anhydrous DMF (2 mL) and TBTU (0.044 g, 0. 137 mmol) was added to the reaction solution. The reaction mixture was stirred at room temperature for 10 min and <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (0.017 g, 0.137 mmol) was added to the mixture followed BY N, N-diisopropylethylamine (0.039 mL, 0.227 MMOL). The reaction mixture was stirred at room temperature for another 15 min. The mixture was then diluted with EtOAc (10 mL) and washed with water, 1 N HC1, saturated NAHCO3 and then water. The organic phase was dried over NA2S04 and concentrated. The crude product was purified by silica gel preparative thin layer chromatography to afford 0.035 g of the title compound as a white foam (M+1, 618.2). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In methanol; at 20℃; for 0.166667h; | Example 71; A [4-[(3-chloro-2-fluorophenyl) amino]-7-(2-methoxyethoxy) quinazolin-6-yl] methyl}-D- alaninamide; (Process (a)); DIPEA (0.032 g, 0.25 mmol) was added to a stirred suspension of 4- [ (3-chloro-2- fluorophenyl) amino]-7- (2-methoxyethoxy) quinazoline-6-carbaldehyde (0.10 g, 0.27 mmol) and <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (H-D-Ala-NH2. HCl) (0.031 g, 0.25 mmol) in methanol (1 ml). The resulting solution was stirred for 10 minutes and sodium triacetoxy borohydride (0. 053 g, 0.25 mmol) was added over a period of 10 minutes. The reaction mixture was stirred for an additional 10 minutes, concentrated and purified by preparative LCMS (standard basic system) to give the title product as a yellow solid, (0.10 g, 84percent) ; lH NMR Spectrum : (DMSO-d6) 1.24 (d, 3H), 3.29 (s, 3H), 3.61-3. 74 (m, 3H), 3.74 (t, 2H), 4.29 (t, 2H), 7.11 (s, 1H), 7,24 (s, 1H), 7.30 (t, 1H), 7.36 (brs, 1H), 7.47-7. 57 (m, 2H), 8.41 (s, 2H), 9.80 (s, 1H); Mass Spectrum: (M+H) + 448. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; sodium carbonate; | (a) [(1R)-2-amino-1-methyl-2-oxoethyl]carbamic acid, 9H-fluoren-9-ylmethyl ester A solution of D-Alaninamide hydrochloride (3 g) in 10percent sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24 g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0 g of the subtitle compound. MS (ESI) BP 311 (+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | In tetrahydrofuran; | A. Synthesis of (R)-1,2-Diaminopropane Dihydrochloride A solution of 1.0M lithium aluminum hydride in THF (480 ml, 0.480 mol) was added over a period of 30 minutes to a stirred solution of <strong>[71810-97-4]D-alanine amide hydrochloride</strong> (15.0 g, 0.120 mol) in anhydrous THF (100 ml) at room temperature under a dry argon atmosphere. The mixture was refluxed overnight. After cooling, the mixture was quenched with H2 O (120 ml). The precipitate (LiCl) was filtered and washed with THF (300 ml) and hot MeOH (2*600 ml). The filtrate and washes were combined and acidified with concentrated HCl. The solvent was removed in vacuo to give a yellow oil. The oil was crystallized from MeOH/ether to give 9.97 g (57percent yield) of a white crystalline solid: mp 240°-5° C.; [alpha]d20 =+7.60° (c=0.01, MeOH); 1 H NMR (DMSO-d6) delta 1.30 (d, J=6.9 Hz, 3 H), 3.09 (ABq of dd, deltanu=44.5 Hz, J=13.5, 6.2 Hz, 2 H) 3.52 (m, 1 H), 8.59 (br s, 6 H). |
57% | In tetrahydrofuran; | A. Synthesis of (R)-1,2-Diaminopropane Dihydrochloride A solution of 1.0M lithium aluminum hydride in THF (480 ml, 0.480 mol) was added over a period of 30 minutes to a stirred solution of <strong>[71810-97-4]D-alanine amide hydrochloride</strong> (15.0 g, 0.120 mol) in anhydrous THF (100 ml) at room temperature under a dry argon atmosphere. The mixture was refluxed overnight. After cooling, the mixture was quenched with H2 O (120 ml). The precipitate (LiCl) was filtered and washed with THF (300 ml) and hot MeOH (2*600 ml). The filtrate and washes were combined and acidified with concentrated HCl. The solvent was removed in vacuo to give a yellow oil. The oil was crystallized from MeOH/ether to give 9.97 g (57percent yield) of a white crystalline solid: mp 240°-5° C.; [alpha]d20 =+7.60° (c=0.01, MeOH); 1 H NMR (DMSO-d6) delta1.30 (d, J=6.9 Hz, 3 H), 3.09 (ABq of dd, deltanu=44.5 Hz, J=13.5, 6.2 Hz, 2 H) 3.52 (m, 1 H), 8.59 (br s, 6 H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With hydrogenchloride; triethylamine; In tetrahydrofuran; 1,4-dioxane; ethyl acetate; | d.) (R)-alanine amide hydrochloride (45) Boc-D-Alanine (5.0 g) (26.43 mmol) was dissolved in dry THF (100 mL). Triethylamine (4 mL, 2.91 g, 28.76 mmol) was added, followed by ethyl chloroformate (2.5 mL, 2.951 g, 27.19 mmol). The solution was left stirring in a carbon tetrachloride/dry-ice cold bath for about 30 min. Concentrated ammonium hydroxide (5 mL, 74.0 mmol) was added and the solution was stored in the refrigerator overnight. The reaction was evaporated under vacuum and the residue taken up in ethyl acetate. The ethyl acetate was extracted with sodium carbonate and water, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was treated with saturated hydrochloric acid/dioxane for 1 hour at room temperature. The dioxane was evaporated under vacuum, the residue taken up in a small amount of methanol and precipitated with diethyl ether to yield the title compound (45) (2.5 g, 76percent). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium cyanoborohydride; triethylamine; In methanol; chloroform; | e) N-benzyloxycarbonyl,N-(2-[(1R)-1-aminocarbonyl-ethyl]amino-ethyl)-(S)-alanine t-butyl ester (46) The <strong>[71810-97-4]D-alanine amide hydrochloride</strong>, (45) (2.5 g) (20.18 mmol) was dissolved in methanol, followed by the aldehyde (44) (3.30 g, 10.27 mmol) and triethylamine (1.40 mL, 1.0 g, 10.07 mmol). Sodium cyanoborohydride (0.86 g, 13.7 mmol) was added and the solution was kept stirring at room temperature overnight. The solution was evaporated under vacuum. The residue was taken up in chloroform:methanol (98:2) and flash chromatographed silica gel to yield the titled product (46): (2.48 g, 61percent). 1H-NMR CDCl3) delta7.33 (s, 5H), 6.00 (br s, 1H), 5.20 (d, 2H), 4.67-3.00 (m, 4H), 2.77 (t, 2H), 1.83-1.23 (s/m, 13H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46% | With potassium carbonate; potassium iodide; In acetonitrile; at 80℃; for 18h; | To a mixture of (f?)-2-aminopropanamide hydrochloride (685 mg, 5.50 mmol), K2C03 (760 mg, 5.50 mmol), and Kl (2.74 mg, 0.016 mmol) in acetonitrile (17 ml_) was added 1 ,4-dibromobutane (0.657 ml_, 5.50 mmol). After heating to 80 °C for 18 h, the reaction was cooled to RT and 2N HCI (15 ml_) and DCM (20 ml_) were added. The aqueous layer was basified with aq NaOH, and extracted sequentially with DCM, EtOAc and CHCI3-IPA (4: 1). The combined organic extracts were dried (Na2S04) and concentrated in vacuo to give the title compound (362 mg, 46percent) as a white solid. 1H NMR (400 MHz, CDCI3): delta 6.85 (br s, 1 H), 5.25 (br s, 1 H), 2.90 (br m, 1 H), 2.50-2.70 (br m, 4H), 1.40-1.60 (br m, 4H), 1.35 (d, 3H). |
With potassium carbonate; potassium iodide; In acetonitrile; for 14h;Heating / reflux; | Method 5; (R)-2-pyrrolidin- 1 -yl-propylaminea) (R)-2-pyrrolidin- 1 -yl-propionamide2 g (16.06 mmol) R-alaninamine hydrochloride, 6.67 g (16.08 mmol) potassium carbonate and 8 mg (0.05 mmol) potassium iodide are suspended in 50 mL acetonitrile and then the mixture is combined with 1.92 mL (16.08 mmol) 1,4-dibromobutane. This reaction mixture is stirred for 14 h under reflux conditions. 100 mL of 1 N hydrochloric acid and <n="25"/>100 mL dichloromethane are added to the reaction mixture. The organic phase is separated off and discarded. The aqueous phase is made basic with sodium hydroxide solution and extracted 3 times with dichloromethane. The organic phases are combined, dried and freed from the solvent in vacuo. Yield: 1.31 gMS (ESI): 143 (M+H)+ |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.0% | To 50 ml of dry methanol with bubbling in (R) alaninamide hydrochloride (1.37 g, 11 mmol) , 4-(2- fluorobenzyloxy)benzaldehyde (2.3 g 10 mmol), triethylamine (1,12 g, 11 mmol) and Ig of 3-A molecular sieves were added and the mixture was stirred for 4 h at 40 0C. The temperature was then lowered to 10 0C and sodium borohydryde (0.19 g, 5 mmol) was added in 15'. The reaction mixture was stirred for betah at room temperature, then it was filtered and evaporated to dryness under vacuo. The residue was taken up with water and toluene at 60 0C, and the organic phase was washed twice with warm water and dried at the same temperature with anhydrous sodium sulphate. The solution was filtered, and gradually cooled at 10 0C. The precipitate was filtered, washed with a small amount of cooled toluene and dried under vacuum to give 2,69 g (89.0percent yield) of white crystals. | |
30.3 - 32% | In a 250 mL glass reactor, dry methanol 109 mL), containing 0.01percent water, (pH of the mixture = 7.30 ) D-alanimamide hydrochloride ( 3 g; 24 mmol ) (Nova Biochem A36136821) (pH of the mixture = 3.98), , triethylamine (2.43 g; 24 mmol), 4-(2-fluorobenzyloxy)benzaldehyde (5.06 g, 22 mmol) (pH of the mixture = 8.60), prepared as described in Example (23.1a) with GC purity 94.21 (area percent, see example 24A) and a content of 3- (2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.39percent by weigth determined by G. C; see Example 24B, and 3A° molecular sieves (2.19 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40°C and stirred at this temperature for 4 h. The reaction temperature is then lowered to 10°C (pH of the mixture 8.24) and sodium borohydride (0.42g, 11 mmol) is added portion wise in 15 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at room temperature. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (80 mL) and toluene (70 mL) at 60°C, the organic phase is separated and added with water (80 mL). The two phases mixture is warmed up to 60°C under stirring. The organic phase is separated and added with water (80 mL). The two phases mixture is warmed up to 60°C under stirring. The organic phase is dried at 60°C over anhydrous sodium sulphate. The aqueous phases are combined together (solution A, about 240 mL). The toluenic mixture is filtered, and the solution is gradually cooled to 10°C. The mixture is kept under stirring and under nitrogen at 10°C for 3 hours. The mixture is filtered and the solid is washed with cold (10°C) toluene (10 mL), dried under vacuum at room temperature to provide 2.13 g (7.1 mmol; 32percent <n="87"/>yield) of (R)-2-[4-(2-fluorobenzyloxy)benzylamino] propanamide (I'b) as white crystals.The product has 98.00 (area percent, see Example 25A) HPLC purity and a content of (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)- benzylamino]propanamide (Il'b) of 0.15percent by weight determined by HPLC(see Example 25B).Enantiomeric ratio R: S = 99.6: 0.4 as determined with a chiral HPLC column (area percent, see Example 26B).The toluenic mother liquor and the toluenic washing are combined together and the solution is concentrated, under vacuum, in a rotary evaporator to provide a yellow residue (1.97 g).The residue is dissolved in methanol (30 mL) and the known species present in solution are determined quantitatively vs. external standard byHPLC (see Example 25A): (i?)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) (0.81 g; 2.7 mmol) ;4-(2-fluorobenzyloxy)benzaldehyde (0.16 g; 0.7 mmol);4-(2-fluorobenzyloxy)benzyl alcohol (0.53 g: 2.2 mmol) and others non quantified impurities. (I'b) HPLC purity is 28.65percent (area percent, see Example 25A)Aqueous solution A is evaporated in a rotary evaporator, under vacuum, to residue. The residue is suspended in methanol (30 mL), filtered, the solvent evaporated under vacuum to residue (4.5 g). The residue is dissolved in methanol (30 mL) and the known species present in solution are determined quantively vs. external standard by HPLC (see Example 25A):(i?)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) (0.69 g; 2.3 mmol) ;4-(2-fluorobenzyloxy)benzaldehyde (0.07 g; 0.3 mmol);4-(2-fluorobenzyloxy)benzylalcohol (0.06 g: 0.2 mmol) and others non quantified impurities.(I'b) HPLC purity is 53.87percent (area percent, see Example 25A).As per above, the overall quantity of (I'b) produced is 3.63 g; 12.1 mmol;55percent yield. The mass balance accounts for about 90 percent of the charged 4-(2- fluorobenzyloxy)benzaldehyde .; The preparation described above has been repeated on a larger scale as follows: al) In a 50 L glass reactor, dry methanol 21.43 L, containing 0.01percent water, <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (589.9 g; 4.72 mol), triethylamine (477.8 g; 4.72 mol) 4-(2-fluorobenzyloxy)benzaldheyde (1000 g, 4.33 mol) prepared as described in Example 23.1a) with GC purity 93.20 (area percent, see Example 24A) and a content of 3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)benzaldehyde of 0.43percent by weigth determined by GC (see Example 24B), and 3A° molecular sieves (430.62 g) are loaded under stirring and under nitrogen at room temperature. The mixture is heated up to 40°C and stirred at this temperature for 4 hours. The reaction temperature is then lowered to 10°C and sodium borohydride (82.58g, 2.16 mol) is added portion wise in 30 min. The reaction mixture is warmed up to room temperature while stirring for additional 6 hours at 20+/-2 °C. The reaction mixture is filtered and evaporated to dryness under vacuum. The residue is taken up with water (16 L) and toluene (14 L) at 60°C, the organic phase is separated and added with water (16 L). The two phases mixture is warmed up to 60°C +/- 2 under stirring. The organic phase is separated and added with water (16 L). The two phases mixtu... | |
R)-2-[4-(2-Fluorobenzyloxy)benzylamino]propanamide (I'b) A reactor is loaded under stirring with methanol (28 L) and <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (2.1 kg) and the mixture is stirred at 23°C for 15 min; then, triethylamine (1.65 kg) and 4-(2-fluorobenzyloxy)benzaldehyde (3.30 kg), prepared according to Example 1.1, are added to the previously prepared solution. The mixture is stirred at 25°C for 3 hours and cooled under stirring to 8 °C. Sodium borohydride (0.50 kg) is added in small portion in 3 hours under stirring and the mixture is stirred for additional 30 min. The reaction mixture is concentrated under vacuum at 40°C until a residue (5.0 L) and then toluene (14 kg) and water (25.0 L) are added to the reaction mixture under stirring under nitrogen. The mixture is heated up to 60 °C and kept at this temperature under stirring for 30 min. After separation of the phases, the organic phase is washed with water (7.0 L) at 60°C and the water is discharged. The organic phase is cooled to 18°C in two hours and kept under these conditions for 1 hour. The heterogeneous mixture is filtered and the solid is washed with toluene ( 3 x 1.2 L ) and dried at about 40°C under vacuum to provide 3.90 Kg of (R)-2-[4-(2-fluorobenzyloxy)benzylamino]propanamide (I'b) with a HPLC purity of 99.9 (areapercent) determined according to the method of Example 25A and a C,O-dialkylated (R)-2-[3-(2-fluorobenzyl)-4-(2-fluorobenzyloxy)- benzylamino]propanamide content less than 0.005percent by weight determined by HPLC, according to the method of Example 25B. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In 1,4-dioxane; water; | A solution of D-Alaninamide hydrochloride (3g) in 10percent sodium carbonate solution (50 ml) and dioxan (50 ml) was treated with FMOC chloride (6.24g) in dioxane (40 ml) and allowed to stir overnight. The mixture was diluted with water (500 ml) and the product collected by filtration and dried in vacuo to give 9.0g of the subtitle compound. MS (ESI) BP 311 (+H) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; for 96h; | lambda/,lambda/-Diisopropylethylamine (0.0738mL, 0.425mmol) was added to a solution of 3-(4- [4-[5-fluoro-2-(methyloxy)phenyl]-2-hydroxy-4-methyl-2-(trifluoromethyl)pentyl]amino}-6-methyl-1 H-pyrazolo[3,4-c/]pyrimidin-1-yl)benzoic acid (47.6mg, 0.085mmol) in anhydrous DMF (0.66mL) under nitrogen. HATU (33.8mg, 0.0889mmol) was then added followed after 10min by <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (26.4mg, 0.212mmol). The mixture was stirred at room temperature for 5 hours and then allowed to stand at room temperature for 4 days. The resulting yellow solution <n="47"/>was diluted with methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and aqueous sodium bicarbonate. The aqueous phase was back-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried by passage through a hydrophobic frit and evaporated to give the title compound as an off-white gum (32.4mg). LCMS: tRET = 3.46 min; MH+ = 632 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | In a 500 ml round bottom flask equipped with a magnetic stirrer and an inert gas supply H-D-alanine-NH2 HCl (4.49 g, 36.1 mmol), was dissolved under argon in 175 mL methanol and then 12 g of molecular sieves (0.4 nM), was added followed by sodium cyanoborohydride (1.65 g, 26.25 mmol). The colorless mixture was stirred for 20 minutes and a solution of [5-(4-fluoro-benzyloxy)-2-iodo-phenyl]-acetaldehyde (12.1 g, 32.8 mmol) was added in 175 mL methanol. The light yellow reaction was stirred overnight at room temperature. Filtration and concentration in a rotatory evaporator left a solid that was purified through a Silica-gel column using hexane/ethyl acetate 1/1 and MeCl2/MeOH 9/1 as eluents gave two fractions of (7.25 g, 50percent) of a white solid pure and 1 g of other more impure compound that was crystallized using ethyl acetate to obtain 550 mg of a white solid (in total 7.8 g, 55percent yield). MS: m/e=443.2 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
89.5% | A mixture of [5-(4-fluoro-benzyloxy)-2-iodo-phenyl]-acetic acid (300 mg, 0.777 mmol) and 1,1'-carbonyl-diimidazole (138 mg, 0.855 mmol) in N,N'-dimethyl-formamide (2 mL) was stirred at 50° C. for 0.5 h. H-D-alanine-NH2.HCl (145 mg, 1.16 mmol) was added and the mixture was stirred at 50° C. for 2 h. Water was added and the product precipitated. The solid was filtrated (317 mg, 89.5percent). MS: m/e=457.3(M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | Example 9; (R)-N-(1-carbamoyl-ethyl)-2-fluoro-4-(3-fluoro-benzyloxy)-benzamide; A mixture of 2-fluoro-4-(3-fluoro-benzyloxy)-benzoic acid (1.0 g, 3.8 mmol) and carbonyldiimidazole (675 mg, 4.2 mmol) in dry DMF (10 mL) under Argon was heated under reflux for 30 min. After cooling to room temperature a suspension of H-D-alanine-NH2 HCl (707 mg, 5.7 mmol) containing pyridine (0.49 mL, 6.1 mmol) in dry DMF (5 mL) was added. After 48 h, water (15 mL) was added and the resulting precipitate was filtered off and washed with water to afford the title compound (1.27 g, 100percent) as a white solid. MS: m/e = 335.3 (M+H+). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Example 6: lambda/-fpiffl-2-Amino-1-methyl-2-oxoethyll-3-(4-ff2-(3.4-dihvdro-1 (2H)- quinolinylmethyl)-3,3.3-trifluoro-2-hvdroxypropynamino'y-6-methyl-1/-/-indazol-1- vDbenzamide; lambda/,lambda/-Dsopropylethylamine (0.079mL, 0.451 mmol) and HATU (36mg, 0.095mmol) were added to a solution of 3-(4-[2-(3,4-dihydro-1 (2H)-quinolinylmethyl)-3,3,3- trifluoro-2-hydroxypropyl]amino}-6-methyl-1 /-/-indazol-1-yl)benzoic acid (47.3mg, 0.09mmol) in anhydrous DMF (1.7mL) and the mixture stirred at room temperature under nitrogen for 10 min. D-Alaninamide hydrochloride (28.1 mg, 0.225mmol) was then added and stirring continued at room temperature for 7 hours when the mixture was partitioned between water and ethyl acetate. The organic phase was separated, combined with a second ethyl acetate extract, washed successively with aqueous sodium bicarbonate and water, dried through a hydrophobic frit and evaporated. The residue was dissolved in a mixture of DMSO and methanol and purified by mass directed autopreparation. Product containing fractions were combined and partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous phase was re-extracted with dichloromethane and the combined organic extracts were washed successively with water and brine, dried through a hydrophobic frit and evaporated to give the title compound (24.6mg). LCMS: tRET = 3.51 min; MH+ = 59521 mg of this mixture of diastereomers was resolved by chiral HPLC on a 2 x 25cm Chiralpak 1A column eluted with heptane : EtOH 6 : 4 + 0.1 percent TFA with a flow rate of 15 mL/min to provide Example 6-A (diastereomer A, 4.14mg) and Example 6-B (diastereomer B, 5.64mg).Example 6-A (diastereomer A): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : EtOH 6 : 4 + 0.1 percent TFA eluting at 1 mL/min): tREtau = 11.4 min LCMS (System A): tRET = 3.52 min; MH+ = 595 <n="67"/>Example 6-B (diastereomer B): Analytical chiral HPLC (25 x 0.46 cm Chiralpak 1A column, heptane : EtOH 6 : 4 + 0.1 percent TFA eluting at 1 mL/min): tREtau = 16.4 min LCMS (System A): tRET = 3.51 min; MH+ = 595 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | (R)-2-[4-(3-Fluorobenzyloxy)benzylamino]propanamide (I 'a) The compound is prepared according to Example 12 al) by substituting L- alaninamide hydrochloride with <strong>[71810-97-4]D-alaninamide hydrochloride</strong> to give (R) -2- [4-(3-fluorobenzyloxy)benzylamino] propanamide in 91percent yield with a HPLC purity of 99.8 (area percent, see Example 25A) and a content of (R)-2-[3-(3- fluorobenzyl)-4-(3-fluorobenzyloxy)benzylamino]propanamide is 0.005percent by weight determined by HPLC (see Example 25B). | |
86.1% | In a round bottom flask 12.2 g of D-alaninammide hydrochloride is dissolved in 166.8 mL of methanol and added in sequence with 9.9 g of triethylamine while keeping temperature lower than 30°C and then with 20 g of 4-(3-fluorobenzyloxy)benzaldehyde. The mixture was stirred at room temperature for 3 hours and then cooled at 8 +/- 2°C and added with 3.3 g of solid NaBH4 keeping the temperature around 8 °C.The reaction was stirred for at least 1 hour , concentrated to a minimum volume and then added with toluene (110 mL) and water (152 mL) .The biphasic mixture is stirred at 70°C and the organic layer is separated and washed with water (30 mL) at 70°C.The resulting solution is cooled to room temperature, filtered and washed with toluene. The solid is dried at 40°C under vacuum, yielding 22.6 g of the title product as white powder (86.1percent yield)[Ot]25D (c 2percent in methanol ) : +10.63°300 MHz 1H-NMR (DMSO-d6): 7.55 - 7.48 (lH,m), 7.37-7.30 (5H,m) 7.26- 7.19 (lH,m) 7.02-7.01(3H,m) 5.19 (2H,s), 3.70(lH,d), 3.57-5.53(lH,d), 3.10- 3.04(lH,q), 1.21- 1.19(3H,d). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
46.4% | With triethylamine; In methanol; at 5 - 30℃; for 6.66667h; | (R)-2-[4-(3-Fluorobenzyloxy)benzylideneamino]propanamide (III 'a) In a 250 mL, 4 necked round bottom flask, equipped with mechanical stirrer, thermometer, reflux condenser and under a flow of nitrogen, D- alaninamide hydrochloride (6.1 g) and methanol (80 mL) are charged and stirred for 15 min at 20 °C. Triethylamine (5 g) is added at such a rate that the temperature remains below 30 °C. The mixture is stirred for 10 min, whereupon solid 4-(3-fluorobenzyloxy)benzaldehyde (1O g, Example 10 b) is added portion wise in about 30 min. After stirring for 3 hours at 20 °C, the mixture is cooled to 5°C. After stirring for 3 hours at this temperature, the solid is filtered and washed with small amount of pre-cooled methanol. The wet solid is dried under vacuum for 12 hours a 25 °C, yielding 6.4 g of title compound as white solid, with 46.4percent yield; m.p 1 1 1.9. [CC]D = -67.9° (c = 1 in chloroform);1H-NMR (DMSO-de) (Bruker AV300) delta (ppm, with respect to TMS at 2.55 ppm; DMSO solvent at 3.35 ppm): 1.31 (3H, d, J = 7 Hz, CH3 ); 3.86 (IH, q, <n="72"/>J = 7 Hz, H-2); 5.18 (2H, s, CH2OR); 7.08 and 7.79 (4H, AA'XX' p- disubstituted aromatic system ); 7.10-7.50 (4H, m, aromatic H ); 8.27 (IH, s, CH=NR).13C-NMR (DMSO-de) (Bruken AV300) delta (ppm): 20.5 (CH3); 67.6 (CH); 68.4 (OCH2); 1 14.1 e 1 14.4 (d, Jc F = 21 Hz, aromatic)CH; 1 14.5 e 1 14.8 (d, Jc F = 21 Hz; aromatic CH; 1 14.8 (aromatic CH); 123.5 (d, Jc F = 2 Hz, aromatic CH); 129.0 and 129.9 (aromatic CH ); 130.4 and 130.5 (d, JCF = 7 Hz, aromatic CH ); 139.6 and 139.7 (d, Jc F = 6 Hz aromatic quaternary C ); 160.2; 160.5 and 163.8 (d, Jc F = 245 Hz C-F); 160.6 (CH=N); 174.8 (CO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With triethylamine; In methanol; at 20℃; for 1h; | (R)-2-[4-(2-Fluorobenzyloxy)benzylideneamino]propanamide (Ill'b) To a suspension of 4-(2-fluorobenzyloxy)benzaldehyde (60.0 g, 0.26 mol), prepared as in the Example 1.1 and <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (35.7 g, 0.29 mol) in methanol (280 mL), triethylamine (29.1 g, 0.29 mol) is added at room temperature with stirring under nitrogen atmosphere. Stirring is maintained for one additional hour.The solution is then seeded with a few mg of (R) -2- [4- (2- fluorobenzyloxy)benzylideneamino]propanamide, the temperature is lowered to 5- 10 °C and the stirring continued for 2 hours. The solid is collected by filtration and washed with methanol at 0 °C.After drying it at reduced pressure, the title compound is obtained in 91percent yield with m. p. 121 °C (capillary).1H-NMR: (CDCl3, 300 MHz, 298K) delta (ppm, with respect to TMS): 1.46 (3H, d, J= 7.0 Hz, CH3); 3.91 (IH, q, J= 7.0 Hz, CH-CO); 5, 17 (2H, s, O-CH2);7,02 (2H, d, J=8,9 Hz aromatic H ortho to O-CH2 ); 7.09 (IH, ddd, JH F=9,78 Hz Jorto= 8,55 Hz Jmeta= 1 ,23 Hz aromatic H ortho to F); 7, 15 (IH, dt,Jorto= 7,35 Hz Jmeta= 1 ,23 Hz aromatic H para to F); 7,27-7,40 (IH, m, aromatic H para to CH2); 7,48 (IH, dt, JOrto= JH F= 7,35 Hz Jmeta= 1 ,53 Hz aromatic H ortho to CH2); 7,71 (2H, d, J=8,9 Hz aromatic H ortho to CH=N);8, 17 (IH, s, C=N)13C-NMR: (CDCl3, 75.4 MHz, 298K) delta (ppm): 21.4 (CH3); 63.8 (OCH2); 68.4 (H2NCOCH); 1 15.0 (d, Jc F= 22.4 Hz, aromatic CH), 1 15.5 (d, Jc F= 20.7 Hz, <n="49"/>aromatic CH); 123.7 (d, Jc F= 14.4 Hz, quaternary aromatic C); 124.5 (bd, aromatic CH ); 129.0 (quaternary aromatic C); 129.8 (bd, aromatic CH); 130.1 (bd, 2 aromatic CH); 160.5 (d, Jc F= 246.4 Hz, quaternary aromatic C); 161.1 (aromatic C-O); 161.1 (C=N); 176.9 (CONH2) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In tetrahydrofuran; at 20℃; | EXAMPLE 5; 3-({1-[Bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((R)-1-carbamoylethyl)benzamide (Compound No. 5); 67 mg of 1-hydroxybenzotriazole, 0.4 cm3 of triethylamine and 228 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added successively to a solution of 500 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylaminobenzoic acid and 150 mg of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> in 20 cm3 of tetrahydrofuran. The reaction mixture is left stirring overnight at a temperature in the region of 20° C. After concentration of the reaction medium to dryness under reduced pressure, the yellowish-white powder obtained is dissolved with dichloromethane. The organic phase is washed with water. After separation by settling out, the aqueous phase is again extracted with dichloromethane. The reaction crude obtained after concentration of the organic phases to dryness under reduced pressure is purified by flash chromatography on a Merck 30 g silica cartridge (elution gradient: 100/0 to 95/5 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a product is obtained which is washed with diethyl ether and oven-dried under vacuum. 220 mg of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((R)-1-carbamoylethyl)benzamide are thus obtained in the form of white crystals.Mp.: 235° C.1H NMR spectrum (300 MHz; (delta in ppm); (DMSO-d6); referenced at 2.50 ppm): 1.34 (d, J=7.3 Hz, 3H); 2.71 (t, J=6.8 Hz, 2H); 2.97 (s, 3H); 3.32 (broad m, 2H); 4.38 (s, 1H); 4.42 (m, 1H); 4.74 (quin, J=6.8 Hz, 1H); 6.98 (broad s, 1H); 7.31 (d, J=8.8 Hz, 4H); 7.36 (d, J=8.8 Hz, 4H); 7.39 (broad s, 1H); 7.45-7.54 (m, 2H); 7.80 (broad s, 1H); 7.88 (m, 1H); 8.50 (d, J=7.6 Hz, 1H)Mass spectrum: ES m/z=575 (MH+, base peak), m/z=235 (C13H9Cl2+.)Elemental Analysis:Calculated: C, 56.35percent; H, 4.90percent; N, 9.73percent; S, 5.57percent.Measured: C, 56.84percent; H, 5.17percent; N, 9.56percent; S, 5.51percent.Optical rotation: alphaD=-6.6+/-0.5 (c=0.493, DMSO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at 20℃; for 24h; | EXAMPLE 4; 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((R)-1-carbamoylethyl)-5-fluorobenzamide (Compound No. 4); 0.1 cm3 of isobutyl chloroformate is added to a solution of 0.35 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-5-fluorobenzoic acid and 0.216 cm3 of triethylamine in 7 cm3 of tetrahydrofuran. A precipitate appears. The reaction medium is stirred at a temperature in the region of 20° C. for 1 hour 25 minutes, before adding, in a single step, 0.108 g of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> with 2 cm3 of tetrahydrofuran. The white suspension obtained is stirred at a temperature in the region of 20° C. for 24 hours. The reaction medium is filtered through sintered glass, rinsing with tetrahydrofuran. The filtrate is concentrated to dryness under vacuum, to give 0.5 g of a white foam which is purified by flash chromatography on a Merck 70 g silica cartridge (particle size: 15-40 mum; eluent: 97/3 dichloromethane/methanol). After concentration of the fractions under reduced pressure, a foam is obtained which is taken up with diethyl ether, filtered, and then dried under vacuum at a temperature in the region of 50° C., to give a solid. This solid is recrystallized under hot conditions from an ethanol/water mixture and dried under vacuum at a temperature in the region of 45° C. 0.095 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((R)-1-carbamoylethyl)-5-fluorobenzamide is thus obtained in the form of a white solid.Mp.: 219-221° C.1H NMR spectrum (400 MHz; (delta in ppm); (DMSO-d6); referenced at 2.50 ppm): 1.33 (d, J=6.8 Hz, 3H); 2.73 (t, J=7.1 Hz, 2H); 3.00 (s, 3H); 3.35 (m, 2H); 4.35-4.45 (m, 2H); 4.73 (quin, J=6.8 Hz, 1H); 6.99 (broad s, 1H); 7.31 (d, J=8.8 Hz, 4H); 7.37 (d, J=8.8 Hz, 4H); 7.39-7.45 (m, 2H); 7.68 (t, J=1.7 Hz, 1H); 7.74 (dt, J=9.0; 1.7 Hz, 1H); 8.62 (d, J=7.8 Hz, 1H)Mass spectrum: ES m/z=593 (MH+, base peak), m/z=235 (C13H9Cl2+.)Elemental Analysis:Calculated: C, 54.64percent; H, 4.59percent; N, 9.44percent; S, 5.40percent.Measured: C, 54.44percent; H, 4.54percent; N, 9.48percent; S, 5.36percent; H2O<0.1percent.Optical rotation: alphaD=-23.3+/-0.7 (c=0.476, DMSO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 20℃; | 183-C. N-((R)-1-Carbamoyl-ethyl)-3-[5-(4-hydroxymethyl-phenyl)-isoxazol-3-yl]-benzamide.To a mixture of compound 183-B (4.04 g, 13.7 mmol), (R)-2-amino-propionamide hydrochloride (3.35 g, 26.9 mmol), and O-^-AzabenzotriazoM-yO-N.N.N'.N'- tetramethyluronium hexafluorophosphate (7.72 g, 20.3 mmol) in N,N-dimethylformamide (25 mL) is added DIPEA (7.0 mL, 40.3 mmol). The reaction is stirred at ambient temperature until conversion is judged to be complete. The mixture is diluted with water (100 mL) and 1N aqueous HCI solution (80 mL). The resulting precipitate is collected by centrifugation, and the supernatant is discarded. The pelleted solid is washed with water, 0.25 N aqueous NaOH solution, and water. The solid is dried under reduced pressure to provide product. MS(ESI) m/z = 366.3 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of <strong>[71810-97-4]D-alanamide hydrochloride</strong> (18.5 g, 149 mmol) in methanol (230 mL) and water (23 mL) was added 50percent aqueous sodium hydroxide (13.5 g, 338 mmol) at - 10 °C, and then 1,2-cyclohexanedione (15.1 g, 135 mmol) was added subsequently at same temperature. After being stirred overnight, the reaction mixture was neutralized with 2N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The resulting precipitate was collected and washed with water and diisopropyl ether to give 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxaline. MS (APCI): m/z 165 (Mu+Eta). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In dimethyl sulfoxide; at 100℃; for 18h; | A solution of 2-bromo-4-fluorobenzonitrile (200 mg, 1.OOmmol), <strong>[71810-97-4]D-alanine amide hydrochloride</strong> (148 mg, 1.19 mmol) and DIEA (0.620 mL, 3.56 mmol) in DMSO (3 mL) was stirred at 100 C for 18 h. EtOAc and water were added. The organic phase was separated, dried over Na2S04, concentrated in vacuo. The residue was purified by a silicsa gel column, eluted first with 30percent EtOAc in hexane, then with 100percent EtOAc to give (R)-2-(3-bromo-4- cyanophenylamino)propanamide (185 mg). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
35% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide;Inert atmosphere; | General procedure: To a stirring solution of 15, (S)-16 or (R)-16(0.10 g, 0.23 mmol), amino acid amide hydrochloride salt (0.24 mmol)and HBTU (0.091 g, 0.24 mmol) in dimethylformamide (5 mL) was added DIPEA(0.056 g, 0.44 mmol) and stirred under nitrogen until reaction was completed asmonitored by LCMS. Water was added and the precipitate was collected and thenwashed with water and methanol and dried under vacuum. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In methanol; at 20℃; | General procedure: Triethylamine (1.0 equiv) was added to a mixture of amino acid derivative hydrochloride (1.0 equiv) and aldehyde (1.0 equiv) in methanol. The mixture was stirred for 1?5 h at room temperature. Sodium borohydride (5.0 equiv) was added carefully to the mixture cooled with ice. The mixture was stirred for 1 h at 0 °C and then partitioned between water and EtOAc. The organic layer was washed with brine, and dried over anhydrous MgSO4. Thes olution was concentrated in vacuo, and the residue was purified using either silica gel column chromatography or crystallization. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
41% | A 250 mL eggplant-shaped flask was weighed and 0.34 g of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (2.7 mmol; 1.0 equiv) was weighed out,0.13 g of sodium cyanoborohydride (2.2 mmol; 0.8 equiv), molecular sieve,0.5ml triethylamine and 50ml methanol was added to the flask, the reaction was stirred at room temperature for 20min,Subsequently, 0.68 g of intermediate IV-1 (5.4 mmol; 1.0 equiv) was added rapidly and the reaction was continued for 12 h with heating to 40°C. TLC plate, UV analyzer (254nm) to monitor the progress of the reaction. After the reaction was over the solution was filtered,The reaction mixture was then swirled to dryness. The resulting residue was re-dissolved in water and ethyl acetate and added to a separatory funnel.The aqueous phase is extracted with an equal volume of ethyl acetate 2 to 3 times, the combined ethyl acetate layers are washed with saturated aqueous sodium chloride solution.Subsequently, the organic phase is dried overnight over anhydrous sodium sulfate or anhydrous magnesium sulfate. Filter out the desiccant,Weigh about 60-100 mesh silica gel powder about 4g added to the filtrate, spin to dry sand, silica gel column chromatography,The elution system chosen was dichloromethane: methanol (using gradient elution,The volume ratio of methanol to dichloromethane gradually increases from 0percent to 5percent within 50 min)The final product Ia-2 was obtained as a brown solid in a total amount of 0.36 g with a yield of 41.0percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39.2% | A 250 mL eggplant flask was weighed and 0.34 g of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (2.7 mmol; 1.0 equiv) was weighed out,0.13 g of sodium cyanoborohydride (2.2 mmol; 0.8 equiv), molecular sieve,0.5ml triethylamine and 50ml methanol was added to the flask, the reaction was stirred at room temperature for 20min,Then 0.68 g of intermediate IV-2 (5.4 mmol; 1.0 equiv) was added rapidly,Heated to 40 to continue the reaction 12h TLC TLC plate, UV analyzer (254nm) to monitor the progress of the reaction.After the reaction was over the solution was filtered, and then the reaction mixture was swirled to dryness, the resulting residue with water,The ethyl acetate is re-dissolved and added to a separatory funnel. The aqueous phase is extracted with an equal volume of ethyl acetate 2 to 3 times,The combined ethyl acetate layers were washed with saturated aqueous sodium chloride solution. Then,The organic phase is dried over anhydrous sodium sulphate or anhydrous magnesium sulphate overnight. Filter out the desiccant,Weigh about 60-100 mesh silica gel powder about 4g added to the filtrate, spin to dry sand, silica gel column chromatography,The elution system chosen was dichloromethane: methanol (using gradient elution,The volume ratio of methanol to dichloromethane gradually increases from 0percent to 5percent within 50 min)The final product Ib-2 was obtained as a gray solid in a total amount of 0.34 g with a yield of 39.2percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
43.5% | A 250 mL eggplant flask was weighed and 0.34 g of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (2.7 mmol; 1.0 equiv)0.13 g of sodium cyanoborohydride (2.2 mmol; 0.8 equiv), molecular sieve,0.5ml triethylamine and 50ml methanol was added to the flask, the reaction was stirred at room temperature for 20min,Subsequently, 0.68 g of intermediate IV-5 (5.4 mmol; 1.0 equiv) was added rapidly and the reaction was continued for 12 h with heating to 40°C TLC TLC plate, UV analyzer (254nm) to monitor the progress of the reaction. After the reaction was over the solution was filtered,The reaction mixture was then swirled to dryness. The resulting residue was re-dissolved in water and ethyl acetate and added to a separatory funnel.The aqueous phase is extracted with an equal volume of ethyl acetate 2 to 3 times, the combined ethyl acetate layers are washed with saturated aqueous sodium chloride solution.Subsequently, the organic phase is dried overnight over anhydrous sodium sulfate or anhydrous magnesium sulfate. Filter out the desiccant,Weigh about 60-100 mesh silica gel powder about 4g added to the filtrate, spin to dry sand, silica gel column chromatography,The elution system chosen was dichloromethane: methanol (using gradient elution,The volume ratio of methanol to dichloromethane gradually increases from 0percent to 5percent within 50 min)The final product Ie-2 was obtained as a brown solid in a total amount of 0.38 g with a yield of 43.5percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.1% | A 250 mL eggplant flask was weighed and 0.34 g of <strong>[71810-97-4]D-alaninamide hydrochloride</strong> (2.7 mmol; 1.0 equiv)0.13 g of sodium cyanoborohydride (2.2 mmol; 0.8 equiv), molecular sieve,0.5ml triethylamine and 50ml methanol was added to the flask, the reaction was stirred at room temperature for 20min,Subsequently, 0.68 g of intermediate IV-6 (5.4 mmol; 1.0 equiv) was added rapidly and the reaction was continued for 12 h with heating to 40°C TLC TLC plate, UV analyzer (254nm) to monitor the progress of the reaction. After the reaction was over the solution was filtered,The reaction mixture was then swirled to dryness. The resulting residue was re-dissolved in water and ethyl acetate and added to a separatory funnel.The aqueous phase is extracted with an equal volume of ethyl acetate 2 to 3 times, the combined ethyl acetate layers are washed with saturated aqueous sodium chloride solution.Subsequently, the organic phase is dried overnight over anhydrous sodium sulfate or anhydrous magnesium sulfate. Filter out the desiccant,Weigh about 60-100 mesh silica gel powder about 4g added to the filtrate, spin to dry sand, silica gel column chromatography,The elution system was selected to be dichloromethane: methanol (gradient elution with a gradual increase of methanol to dichloromethane from 0percent to 5percent in 50 min), the final product If-2 was obtained as a gray solid ,total0.35 g, yield 40.1percent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With titanium(IV) isopropylate; In isopropyl alcohol; for 24h;Reflux; | To a flask containing 1 (200 mg, 0.65 mmol), iso-propanol (5 mL) and (R)-2- aminopropanamide hydrochloride (161 mg, 1.29 mmol) was added titanium(IV) isopropoxide (383 pL, 1.29 mmol). The mixture was heated to reflux for 24 hours and cooled to ambient to afford a solution of 2/3 in Ao-propanol. UPLC-MS : Method 1 , UV - 220 nm. Selectivity (2/3) unknown - isomers did not separate on this method. Combined purity (area% by UPLC): 11.8% MS [M+H]+: 379.102 (79Br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 65℃; for 2.5h;Molecular sieve; | To a flask containing 4 (250 mg, 0.73 mmol), /.so propanol (7.5 mL), NN- diisopropylethylamine (379 pL, 2.17 mmol) and <strong>[71810-97-4](R)-2-aminopropanamide hydrochloride</strong> (181 mg, 1.45 mmol) was added 4 molecular sieves. The mixture was heated to 65 C for 2.5 hours and cooled to ambient. The mixture was fdtered and the filtrate was concentrated to dryness to afford a solid. The solid was diluted with dichloromethane (20 mL) and washed with water (20 mL). The organic layer was dried (MgSCL) and concentrated to afford a pale yellow solid. The crude reaction mixture was purified by chromatography (silica gel, 3 cm x 9cm, eluting with 60% hexane / 35% ethyl acetate / 5% methanol) to afford 2/3 as a colourless oil (263 mg, 96%). Selectivity (by 1H- NMR): 9: 1 mixture of isomers 2 and 3. -NMR of 2 (500 MHz, CDCb): d 1.4-1.2 (m, 3H) 1.5-1.4 (m, 4H) 1.6-1.5 (m, 2H) 1.8 (dt, J= 13.7, 3.2 Hz, 1H) 2.1-2.0 (m, 2H) 2.8-2.7 (m, 1H) 2.8-2.8 (m, 1H) 2.9-2.8 (m, 1H) 3.2-3.1 (m, 1H) 3.4-3.3 (m, 3H) 4.6 (q, J = 6.9 Hz, 1H) 6.4 (br s, 1H) 7.3-7.1 (m, 1H) 7.4 (br d, J = 3.7 Hz, 1H) 7.5- 7.4 (m, 1H) 7.8- 7.7 (m, 1H). 13C-NMR of 2 (125 MHz, CDCb): 5177.7, 174.8, 147.8, 135.0, 134.3, 129.6, 128.2, 120.7, 78.6, 58.4, 55.6, 48.8, 39.3, 34.4, 33.6, 28.4, 28.4, 19.0. UPLC-MS: Method 1, UV - 220 nm. Purity (area% by UPLC): Isomer 2 - 76.76%, Isomer 3 - 8.88%. Selectivity (area% by UPLC): 9: 1 mixture of isomers 2 and 3. (0545) MS [M+H]+: Isomer 2 - 379.094 (79Br), Isomer 3 - 379.151 (79Br) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine In 1-methyl-pyrrolidin-2-one at 150℃; | 72 (R)-2-((2-chloro-5-iodopyridin-4-yl)amino)propenamide: To a solution of 2-chloro-4- fluoro-5-iodo-pyridine (3.50 g, 13.6 mmol) and D-alaninamide hydrochloride (4.23 g, 68.0 mmol) in NMP (30.0 mL) was added N,N-diisopropylethylamine (11.8 mL, 68.0 mmol). The reaction mixture was heated to 150 °C overnight, then cooled and diluted with water (125 mL). The solution was stirred at RT for 2 hours, then the resulting solid was isolated by vacuum filtration, washed with water, and dried by high vacuum. The crude solids were used without additional purification. (0875) ES/MS: 326.24 (M+H+) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
92% | With laccase; ammonia In water at 38 - 40℃; Enzymatic reaction; | 1-3 Example 2 Add 10 grams of DL-alanine and 50 grams of 25% ammonia in a 250 ml single-neck flask, add 60 grams of water for dilution, and stir under the condition of stirring. The temperature of the system rises to 38-40°C, and 0.1 grams of laccase is added. After the reaction is completed for 16-18 hours, the laccase is filtered out and stored in the refrigerator, ready for the next application.The filtrate was directly fed with hydrogen chloride until the pH value of the system reached between 4.3-4.5 to precipitate solids, filtered and dried to obtain 9.2 grams of L-propionamide hydrochloride.The yield is 92% based on the mass of D,L-alanine. |
Tags: 71810-97-4 synthesis path| 71810-97-4 SDS| 71810-97-4 COA| 71810-97-4 purity| 71810-97-4 application| 71810-97-4 NMR| 71810-97-4 COA| 71810-97-4 structure
[ 51127-08-3 ]
(S)-2,6-Diaminohexanamide dihydrochloride
Similarity: 0.81
[ 94787-97-0 ]
(S)-2-Aminohexanamide hydrochloride
Similarity: 0.81
[ 65414-74-6 ]
(S)-2-Amino-3-hydroxypropanamide hydrochloride
Similarity: 0.78
[ 61275-22-7 ]
(S)-2-Amino-N-methylpropanamide hydrochloride
Similarity: 0.78
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P251 | Pressurized container: Do not pierce or burn, even after use. |
P260 | Do not breathe dust/fume/gas/mist/vapours/spray. |
P261 | Avoid breathing dust/fume/gas/mist/vapours/spray. |
P262 | Do not get in eyes, on skin, or on clothing. |
P263 | Avoid contact during pregnancy/while nursing. |
P264 | Wash hands thoroughly after handling. |
P265 | Wash skin thouroughly after handling. |
P270 | Do not eat, drink or smoke when using this product. |
P271 | Use only outdoors or in a well-ventilated area. |
P272 | Contaminated work clothing should not be allowed out of the workplace. |
P273 | Avoid release to the environment. |
P280 | Wear protective gloves/protective clothing/eye protection/face protection. |
P281 | Use personal protective equipment as required. |
P282 | Wear cold insulating gloves/face shield/eye protection. |
P283 | Wear fire/flame resistant/retardant clothing. |
P284 | Wear respiratory protection. |
P285 | In case of inadequate ventilation wear respiratory protection. |
P231 + P232 | Handle under inert gas. Protect from moisture. |
P235 + P410 | Keep cool. Protect from sunlight. |
Response | |
Code | Phrase |
P301 | IF SWALLOWED: |
P304 | IF INHALED: |
P305 | IF IN EYES: |
P306 | IF ON CLOTHING: |
P307 | IF exposed: |
P308 | IF exposed or concerned: |
P309 | IF exposed or if you feel unwell: |
P310 | Immediately call a POISON CENTER or doctor/physician. |
P311 | Call a POISON CENTER or doctor/physician. |
P312 | Call a POISON CENTER or doctor/physician if you feel unwell. |
P313 | Get medical advice/attention. |
P314 | Get medical advice/attention if you feel unwell. |
P315 | Get immediate medical advice/attention. |
P320 | |
P302 + P352 | IF ON SKIN: wash with plenty of soap and water. |
P321 | |
P322 | |
P330 | Rinse mouth. |
P331 | Do NOT induce vomiting. |
P332 | IF SKIN irritation occurs: |
P333 | If skin irritation or rash occurs: |
P334 | Immerse in cool water/wrap n wet bandages. |
P335 | Brush off loose particles from skin. |
P336 | Thaw frosted parts with lukewarm water. Do not rub affected area. |
P337 | If eye irritation persists: |
P338 | Remove contact lenses, if present and easy to do. Continue rinsing. |
P340 | Remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P341 | If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P342 | If experiencing respiratory symptoms: |
P350 | Gently wash with plenty of soap and water. |
P351 | Rinse cautiously with water for several minutes. |
P352 | Wash with plenty of soap and water. |
P353 | Rinse skin with water/shower. |
P360 | Rinse immediately contaminated clothing and skin with plenty of water before removing clothes. |
P361 | Remove/Take off immediately all contaminated clothing. |
P362 | Take off contaminated clothing and wash before reuse. |
P363 | Wash contaminated clothing before reuse. |
P370 | In case of fire: |
P371 | In case of major fire and large quantities: |
P372 | Explosion risk in case of fire. |
P373 | DO NOT fight fire when fire reaches explosives. |
P374 | Fight fire with normal precautions from a reasonable distance. |
P376 | Stop leak if safe to do so. Oxidising gases (section 2.4) 1 |
P377 | Leaking gas fire: Do not extinguish, unless leak can be stopped safely. |
P378 | |
P380 | Evacuate area. |
P381 | Eliminate all ignition sources if safe to do so. |
P390 | Absorb spillage to prevent material damage. |
P391 | Collect spillage. Hazardous to the aquatic environment |
P301 + P310 | IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
P301 + P312 | IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell. |
P301 + P330 + P331 | IF SWALLOWED: Rinse mouth. Do NOT induce vomiting. |
P302 + P334 | IF ON SKIN: Immerse in cool water/wrap in wet bandages. |
P302 + P350 | IF ON SKIN: Gently wash with plenty of soap and water. |
P303 + P361 + P353 | IF ON SKIN (or hair): Remove/Take off Immediately all contaminated clothing. Rinse SKIN with water/shower. |
P304 + P312 | IF INHALED: Call a POISON CENTER or doctor/physician if you feel unwell. |
P304 + P340 | IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing. |
P304 + P341 | IF INHALED: If breathing is difficult, remove victim to fresh air and keep at rest in a position comfortable for breathing. |
P305 + P351 + P338 | IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continue rinsing. |
P306 + P360 | IF ON CLOTHING: Rinse Immediately contaminated CLOTHING and SKIN with plenty of water before removing clothes. |
P307 + P311 | IF exposed: call a POISON CENTER or doctor/physician. |
P308 + P313 | IF exposed or concerned: Get medical advice/attention. |
P309 + P311 | IF exposed or if you feel unwell: call a POISON CENTER or doctor/physician. |
P332 + P313 | IF SKIN irritation occurs: Get medical advice/attention. |
P333 + P313 | IF SKIN irritation or rash occurs: Get medical advice/attention. |
P335 + P334 | Brush off loose particles from skin. Immerse in cool water/wrap in wet bandages. |
P337 + P313 | IF eye irritation persists: Get medical advice/attention. |
P342 + P311 | IF experiencing respiratory symptoms: call a POISON CENTER or doctor/physician. |
P370 + P376 | In case of fire: Stop leak if safe to Do so. |
P370 + P378 | In case of fire: |
P370 + P380 | In case of fire: Evacuate area. |
P370 + P380 + P375 | In case of fire: Evacuate area. Fight fire remotely due to the risk of explosion. |
P371 + P380 + P375 | In case of major fire and large quantities: Evacuate area. Fight fire remotely due to the risk of explosion. |
Storage | |
Code | Phrase |
P401 | |
P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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