Structure of H-Ala-NHMe·HCl
CAS No.: 61275-22-7
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The BI-3802 was designed by Boehringer Ingelheim and could be obtained free of charge through the Boehringer Ingelheim open innovation portal opnMe.com, associated with its negative control.
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CAS No. : | 61275-22-7 |
Formula : | C4H11ClN2O |
M.W : | 138.60 |
SMILES Code : | C[C@H](N)C(NC)=O.[H]Cl |
MDL No. : | MFCD00237739 |
InChI Key : | UHWFDFLWTAIHRE-DFWYDOINSA-N |
Pubchem ID : | 18595779 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H302-H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 8 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.75 |
Num. rotatable bonds | 2 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 34.02 |
TPSA ? Topological Polar Surface Area: Calculated from |
55.12 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
0.0 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.17 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.12 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.39 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.9 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
-0.32 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.46 |
Solubility | 48.0 mg/ml ; 0.347 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-0.53 |
Solubility | 40.7 mg/ml ; 0.294 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.27 |
Solubility | 74.6 mg/ml ; 0.538 mol/l |
Class? Solubility class: Log S scale |
Soluble |
GI absorption? Gatrointestinal absorption: according to the white of the BOILED-Egg |
High |
BBB permeant? BBB permeation: according to the yolk of the BOILED-Egg |
No |
P-gp substrate? P-glycoprotein substrate: SVM model built on 1033 molecules (training set) |
No |
CYP1A2 inhibitor? Cytochrome P450 1A2 inhibitor: SVM model built on 9145 molecules (training set) |
No |
CYP2C19 inhibitor? Cytochrome P450 2C19 inhibitor: SVM model built on 9272 molecules (training set) |
No |
CYP2C9 inhibitor? Cytochrome P450 2C9 inhibitor: SVM model built on 5940 molecules (training set) |
No |
CYP2D6 inhibitor? Cytochrome P450 2D6 inhibitor: SVM model built on 3664 molecules (training set) |
No |
CYP3A4 inhibitor? Cytochrome P450 3A4 inhibitor: SVM model built on 7518 molecules (training set) |
No |
Log Kp (skin permeation)? Skin permeation: QSPR model implemented from |
-7.27 cm/s |
Lipinski? Lipinski (Pfizer) filter: implemented from |
0.0 |
Ghose? Ghose filter: implemented from |
None |
Veber? Veber (GSK) filter: implemented from |
0.0 |
Egan? Egan (Pharmacia) filter: implemented from |
0.0 |
Muegge? Muegge (Bayer) filter: implemented from |
2.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.55 |
PAINS? Pan Assay Interference Structures: implemented from |
0.0 alert |
Brenk? Structural Alert: implemented from |
0.0 alert: heavy_metal |
Leadlikeness? Leadlikeness: implemented from |
No; 1 violation:MW<1.0 |
Synthetic accessibility? Synthetic accessibility score: from 1 (very easy) to 10 (very difficult) |
1.14 |
* 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 |
---|---|---|
50% | With sodium cyanoborohydride; In methanol; at 20℃; for 12h;Molecular sieve; | EXAMPLE 2 2-[(3-Benzyl-2,3-dihydro-benzofuran-5-ylmethyl)-amino]-N-methylpropanamide To a solution of (S)-N-methyl-alaninamide hydrochloride (0.50 g, 3.6 mmol) in methanol (10 ml), in the presence of molecular sieves (1.00 g), sodium cyanoborohydride (0.44 g, 6.9 mmol) and a solution of 3-benzyl-2,3-dihydro-l-benzofuran-5-carbaldehyde (0.75 g, 3.6 mmol) in methanol (10 ml) were added at room temperature. The reaction mixture was kept under stirring and an argon atmosphere for 12 h. Then, the solvent was evaporated under vacuum and the residue was purified by flash chromatography on silica gel (ethyl acetate) affording 0.58 g of title compound (50% yield). 1H-NMR (400 MHz, CDCl3); delta: 1.32 (d, 3H, J = 6.9 Hz); 2.83-2.91 (m, 4H); 3.05 (dd, J = 2.4. 6.5 Hz, 1H); 3.26 (q, 1H, J = 7.0 Hz); 3.62 (s, 2H); 3.73-3.76 (m, 1H); 4.32 (dd, 1H, J = 5.7, 8.9 Hz); 4.55 (t, 1H, J = 9.0 Hz); 6.76 (d, 1H, J = 8.1 Hz); 6.86 (bs, 1H), 7.07 (d, 1H, J = 8.1 Hz); 7.27-7.36 (m, 5H). 13C-NMR (400 MHz, CDCl3); delta: 19.72; 25.84; 41.04; 43.39; 52.29; 57.55; 109.42; 124.49; 126.51; 128.35; 128.53; 129.05; 130.68; 131.16; 139.06; 159.36; 175.37. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In tetrahydrofuran; | EXAMPLE XXI (S)-2-amino-1-methylamino-propane-dihydrochloride Prepared by refluxing (S)-alanine-methylamide-hydrochloride with lithium aluminium hydride in tetrahydrofuran and precipitating the product obtained after working up in the form of the dihydrochloride Rf value: 0.08 (silica gel, methylene chloride/methanol/conc. aqueous ammonia=90:10:1) Mass spectrum (ESI-): m/z=159,161, 163 [M+HCl+Cl]- |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
EXAMPLE 9 Synthesis of N-{D,L-2-(hydroxyaminocarbonyl)methyl-4-methylpentanoyl}-L-3-(2'-naphthyl)alanyl-L-alanine Methylamide (Compound 11) STR13 Referring to Scheme 9, Compound (11a) was prepared from N-BOC-L-3-(2'-naphthyl)alanine and L-alanine methylamide hydrochloride, in 89% yield using the method previously described to prepare Compound (1i). TLC: Rf 0.58 (chloroform-isopropanol 9:1); 1 H NMR (d6 -DMSO) delta 1.21 (d, 3H), 1.25(s, 9H), 2.54(d, 3H), 2.91(m, 1H), 3.18(m, 1H), 4.28(m, 2H), 7.04(d, 1H), 7.46(m, 3H), 7.75(s, 1H), 7.83(m, 4H), 8.07(d, 1H); 13 C NMR (d6 -DMSO) delta 18.5, 25.5, 28.0, 37.5, 48.1, 55.7, 78.1, 125.4, 125.9, 127.3, 127.4, 127.5, 127.9, 131.8, 132.9, 135.9, 155.3, 171.1, 172.3. Compound (11b) was prepared from Compounds (11a) and (1d), in 86% yield using the method previously described to prepare Compound (A2). TLC: Rf 0.57 and 0.62 (chloroform-isopropanol 9:1); 1 H NMR (d6 -DMSO; mixture of diastereomers) delta 0.23 & 0.40(d, 3H), 0.70 & 0.79(d, 3H), 1.01(m, 2H), 1.18 & 1.26(d, 3H), 1.32(m, 2H), 2.22(m, 2H), 2.53(d, 3H), 2.92(m, 1H), 3.22(m, 1H), 3.38 & 3.39(s, 3H), 4.22(m, 1H), 4.63(m, 1H), 7.44(m, 4H), 7.73(s, 1H), 7.81(m, 4H), 8.22 & 8.46(d, 1H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In tetrahydrofuran; at -20 - 20℃; | EXAMPLE 9; 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((S)-1-methylcarbamoylethyl)benzamide (Compound No. 9); Pathway A; 0.113 cm3 of isobutyl chloroformate is added to a solution of 0.4 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)benzoic acid and 0.256 cm3 of triethylamine in 4 cm3 of tetrahydrofuran, stirred under an inert atmosphere at a temperature of between -10 and -20 C. A precipitate appears. The reaction medium is stirred at a temperature of less than 0 C. for 1 hour, before adding 0.143 g of L-alanine methylamide hydrochloride with 2 cm3 of tetrahydrofuran while at the same time maintaining the temperature of the reaction medium between -10 and -20 C. The white suspension obtained is stirred at a temperature in the region of 20 C. for 18 hours. The reaction medium is again cooled and maintained at a temperature of between -10 C. and -20 C., before adding: 22 mul of triethylamine, 20.6 mul of isobutyl chloroformate and 22 mg of L-alanine methylamide hydrochloride in 2 cm3 of tetrahydrofuran. After stirring for 24 hours at a temperature in the region of 20 C., the reaction medium is filtered through sintered glass and rinsed with dichloromethane. The filtrate is concentrated to dryness under reduced pressure, to give 0.684 g of a white foam which is purified by flash chromatography on a Merck 70 g silica cartridge (particle size: 15-40 mum; eluent: 98/2 ethyl acetate/methanol). After concentration of the fractions under reduced pressure, a white residue is obtained which is recrystallized from an absolute ethanol/water mixture. The solid obtained is filtered through sintered glass and dried under vacuum at a temperature in the region of 40 C. 0.128 g of 3-({1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}methanesulphonylamino)-N-((S)-1-methylcarbamoylethyl)benzamide is thus obtained in the form of a white solid.Mp.: 171-173 C.1H NMR spectrum (400 MHz; (delta in ppm); (DMSO-d6); referenced at 2.50 ppm): 1.32 (d, J=7.0 Hz, 3H); 2.59 (d, J=4.9 Hz, 3H); 2.71 (t, J=7.6 Hz, 2H); 2.97 (s, 3H); 3.33 (t, J=7.6 Hz partially masked, 2H); 4.38 (s, 1H); 4.44 (m, 1H); 4.74 (m, 1H); 7.31 (d, J=8.5 Hz, 4H); 7.35 (d, J=8.5 Hz, 4H); 7.44-7.52 (m, 2H); 7.80 (s, 1H); 7.83-7.91 (m, 2H); 8.59 (d, J=7.8 Hz, 1H)Mass spectrum: ES m/z=589 (MH+, base peak)Elemental Analysis:Calculated: C, 57.05%; H, 5.13%; N, 9.50%; S, 5.44%.Measured: C, 55.49%; H, 5.50%; N, 9.14%; S, 5.10%; H2O=2.57%.Optical rotation: alphaD=+25.4+/-0.7 (c=0.427, DMSO) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.2 g | l-Alanine ethyl ester hydrochloride (8.1 g, 52.4 mmol) was stirred in an ethanolic methylamine solution (36 mL, 289 mmol) for 97 h then evaporated. The residue was taken up in potassium carbonate (4 M, 30 mL) and sodium bicarbonate (saturated, 20 mL) then extracted with chloroform (5×25 mL), which was dried over sodium carbonate and evaporated to yield crude l-Alanine N-methylamide, a red oil (3.62 g, 35.5 mmol, 68%). A solution of the free amine (1.9 g, 18.5 mmol) in diethyl ether (200 mL) was treated with hydrogen chloride gas for 10 min before the product was removed by filtration and washed with diethyl ether to yield the hydrochloride salt, a clear crystalline solid (2.2 g, 16.0 mmol, 86%). This was further purified by recrystallisation from ethanol and hexane; mp 213-215 C; [alpha]D25 19.6 (c 0.1, CH3OH); numax (NaCl disk)/cm-1 3408, 1674, 1514, 1417, 1275, 1169; deltaH (400 MHz, D2O) 3.85 (1H, q, J 7.1, CH), 2.60 (3H, s, NCH3), 1.32 (3H, d, J 7.1, CCH3); deltaC (100 MHz, D2O) 174.1 (C), 51.2 (CH), 28.5 (CH3), 19.2 (CH3). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium carbonate; In ethanol; at 60℃; for 0.0166667h; | l-Alanine N-methylamide hydrochloride (0.58 g, 4.17 mmol) and sodium carbonate (0.56 g, 5.30 mmol) were stirred in ethanol (40 mL) at 60 C for 1 min, then cooled to room temperature, filtered and evaporated to yield the desired product; [alpha]D34 +2.0 (c 0.1, CH2Cl2); numax (NaCl disk)/cm-1 3364, 1646, 1575, 1456, 1413, 1375, 1318, 1272, 1160; deltaH (500 MHz, CDCl3) 7.29 (1H, br s, NH), 3.34 (1H, q, J 7.0, CH), 2.66 (3H, d, J 5.0, NCH3), 1.39 (2H, br s, NH2), 1.17 (3H, d, J 7.0, CHCH3); deltaC (125 MHz, CDCl3) 176.5 (C), 50.7 (CH), 25.7 (CH3), 21.6 (CH3); m/z (EI+): 102.1 (M+); HRMS (EI+): found M+, 102.0788. C4H10N2O1 requires, 102.0793. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
40.2% | With 4-methyl-morpholine; HATU; In N,N-dimethyl-formamide; | (R/5)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)- l,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.031 mL, 0.278 mmol), (S)-2-amino-N-methylpropanamide-HCl (6.43 mg, 0.046 mmol), and HATU (31.7 mg, 0.083 mmol). The reaction mixture was stirred overnight and was then purified via preparative LCMS with the following conditions: Column: Waters XBridge CI 8, 19 x 250 mm, 5-muiotaeta particles; Guard Column: Waters XBridge C18, 19 x 10 mm, 5- muiotaeta particles; Mobile Phase A: 5:95 methanol: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanohwater with 10-mM ammonium acetate; Gradient: 50- 100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate = 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-(2-hydroxy-2-(4-(5-(3-phenyl-4- (trifluoromethyl)isoxazol-5-yl)-l,2,4-oxadiazol-3-yl)phenyl)acetamido)-N- methyl(S)propanamide (9.6 mg, 0.019 mmol, 40.2 % yield): LCMS = 516.1 [M+H]+; XH NMR (Mixture of Diastereomers, 400 MHz, methanol^) delta ppm 8.1 1-8.25 (4 H, m), 7.50-7.78 (14 H, m), 5.16 (2 H, d, J=3.08 Hz), 4.37 (2 H, qd, J=7.08, 1.43 Hz), 2.75 (3 H, s), 2.72 (3 H, s), 1.39 (3 H, d, J=7.26 Hz), 1.35 (3 H, d, J=7.04 Hz);Analytical LCMS: column: Mac-mod Halo CI 8, 4.6 x 50 mm, 2.7-muiotaeta particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 90: 10 acetonitrile:water with 10 mM ammonium acetate; Temperature: 45 C; Gradient: 0-100% B over 4 minutes, flow rate = 4 mL/min, product retention = 2.3 min +2.4 min (mixture of diastereomers). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
57% | General procedure: 1?-Acetylferrocene-1-carboxylic acid (150 mg, 0.526 mmol) was activated using EDC/HOBt as described in the previous paragraph. The solution was cooled to 0 C and AA-NHMe (obtained from AA-NHMe·HCl by treatment with NEt3 in CH2Cl2, pH ?8) was added. After stirring for 1 h at room temperature the reaction mixture was washed with saturated aqueous NaHCO3, 10% aqueous solution of citric acid and water. The organic layer was dried over Na2SO4 and evaporated in vacuo. The products were purified by TLC using (CH2Cl2/EtOAc=10:1) as eluent. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; | General procedure: To a cooled solution of compound 4 (1 equiv.), any of compounds IB1-3, IB5-7 or IB31-38 (1.2-1.5 equiv.), and PyBop (1.2 equiv.) in anhydrous DCM was added diisopropylethylamine (4 equiv.) gradually. The reaction mixture was stirred at r.t. for 6 h to overnight. The reaction mixture was then diluted with DCM up to 25 mL; extracted with 5% citric acid (2 12 mL), saturated sodium bicarbonate (2 x 12 mL), and brine (2 x 10 mL); and dried over anhydrous sodium sulfate. The solvent was then evaporated under reduced pressure and the residue was purified by semi-preparative HPLC to give the intermediate that corresponds to the starting material among IC1-3, IC5-7 or IC31-38. This intermediate was then hydrolyzed in the following manner: 0.2 mmol of this intermediate was vigorously shaken at room temperature with 1-2 mL 0.4 M LiOH aqueous solution until all the solid dissolves (acetonitrile was used as a co-solvent whenever needed). The solution was then stirred for 2-24 h and concentrated under vacuum. The final compound was then separated as a pure lithium or di-lithium salt using semi-preparative reverse phase HPLC. |