Structure of Boc-D-Ser(Me)-OH
CAS No.: 86123-95-7
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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. : | 86123-95-7 |
Formula : | C9H17NO5 |
M.W : | 219.24 |
SMILES Code : | COC[C@@H](NC(=O)OC(C)(C)C)C(O)=O |
MDL No. : | MFCD08063987 |
InChI Key : | RFGMSGRWQUMJIR-ZCFIWIBFSA-N |
Pubchem ID : | 27281801 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 15 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.78 |
Num. rotatable bonds | 7 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 52.75 |
TPSA ? Topological Polar Surface Area: Calculated from |
84.86 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.88 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.41 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.61 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
0.01 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
-0.14 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.55 |
Log S (ESOL):? ESOL: Topological method implemented from |
-1.0 |
Solubility | 22.1 mg/ml ; 0.101 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.76 |
Solubility | 3.82 mg/ml ; 0.0174 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.79 |
Solubility | 35.2 mg/ml ; 0.161 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 |
-7.35 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 |
0.0 |
Bioavailability Score? Abbott Bioavailability Score: Probability of F > 10% in rat |
0.56 |
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) |
2.97 |
* 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 |
---|---|---|
90% | To a solution of acid (R)-9 (0.7 g, 3.2 mmol) in dry THF was added N-methylmorpholine (0.43 mL, 3.8 mmol) at -78 °C under an argon atmosphere. After 5 min, isobutyl chloroformate (0.5 mL, 3.8 mmol) was added and stirred for another 5 min. To this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added at -78 °C after which the reaction mixture was stirred at room temperature for 1 h. After completion of the reaction, the reaction mixture was filtered, and washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 85:15) to yield (R)-10 as a colorless solid (0.9 g, 90percent); mp 63-64 °C; (c 0.9, CHCl3); IR (CHCl3, cm-1): numax 3683, 3431, 3020, 2931, 2401, 1714, 1523, 1496, 1368, 1165, 1119, 928, 758, 669; 1H NMR (200 MHz, CDCl3): deltaH 1.43 (s, 9H), 3.37 (s, 3H), 3.47-3.54 (dd, J = 9.2, 6.1 Hz, 1H), 3.82 (dd, J = 9.3, 3.7 Hz, 1H), 4.27 (m, 1H), 4.47 (d, J = 5.1 Hz, 1H), 5.41 (br s, 1H), 6.77 (m, 1H), 7.22-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): deltaC 170.3 (CO), 155.5 (CO), 137.9 (C), 128.7 (CH, 2 carbons), 127.5 (CH, 3 carbons), 80.4 (C), 72.1 (CH2), 59.1 (CH3), 54.0 (CH), 43.5 (CH2), 28.3 (CH3, 3 carbons); MS: m/z 331 [M+Na]+. | |
90% | With 4-methyl-morpholine; isobutyl chloroformate; In tetrahydrofuran; at -78 - 30℃; for 1h;Inert atmosphere; | Example-5 Synthesis of (R)-tert-butyl 1-(benzylamino)-3-methoxy-1-oxopropan-2-ylcarbamate (R)-9 To a solution of acid (R)-8 (0.7 g, 3.2 mmol) in dry THF was added N-methylmorpholine (0.43 mL, 3.8 mmol) at -78° C. under argon atmosphere. After 5 min, isobutyl chloroformate (0.5 mL, 3.8 mmol) was added and stirred the content for another 5 min. To this reaction mixture benzylamine (0.4 mL, 3.8 mmol) was added at -78° C. and allowed the reaction mixture to stir at 30° C. for 1 h. After completion of the reaction, reaction mixture was filtered, washed with ethylacetate. The solvent was removed under reduced pressure and the crude product was subjected to column chromatography (silica gel, petroleum ether/acetone, 85:15) to yield (R)-9 as colorless solid (0.9 g, 90percent). m.p 63-64° C.; [alpha]25D=-20.5 (c 0.9, CHCl3); IR (CHCl3, cm-1): vmax 3683, 3431, 3020, 2931, 2401, 1714, 1523, 1496, 1368, 1165, 1119, 928, 758, 669; 1H NMR (200 MHz, CDCl3): deltaH 1.43 (s, 9H), 3.37 (s, 3H), 3.47-3.54 (dd, J=9.2, 6.1 Hz, 1H), 3.82 (dd, J=9.3, 3.7 Hz, 1H), 4.27 (m, 1H), 4.47 (d, J=5.1 Hz, 1H), 5.41 (bs, 1H), 6.77 (m, 1H), 7.22-7.37 (m, 5H); 13C NMR (50 MHz, CDCl3): deltaC 170.3 (CO), 155.5 (CO), 137.9 (C), 128.7 (CH, 2 carbons), 127.5 (CH, 3 carbons), 80.4 (C), 72.1 (CH2), 59.1 (CH3), 54.0 (CH), 43.5 (CH2), 28.3 (CH3, 3 carbons); MS: m/z 331 [M+Na]+. |
90% | To a solution of acid 5 (0.985 g, 4.49 mmol) in dry THF (10ml) was added N-methylmorpholine (0.6 mL, 5.39 mmol) at -78 °C under an argon atmosphere.After 5 min, isobutyl chloroformate (0.7 mL, 5.39 mmol)was added and stirred for another 5 min. To this reaction mixture benzyl amine (0.6 mL, 5.39 mmol) was added at -78 °C andthe reaction mixture was allowed to come up to room temperature and stirred foranother 1 h. After completion of the reaction (TLC), the reaction mixture wasfiltered through a pad of celite, and washed with ethyl acetate (20 mL). Thesolvent was removed under reduced pressure and the crude reaction mixture wassubjected to flash chromatography (CombiFlash Rf 200i, Teledyne Isco) using RediSep silica gel column (12 g) eluting with petroleum ether?EtOAc (3:2,isocratic) to yield 6as a white solid (1.24 g, 90percent); Rf0.35 (40percent EtOAc inpetroleum ether); mp 63-64 °C [Lit.63-64 °C3]; [alpha]D26 -24.3 (c 1.04, CHCl3) [Lit. [alpha]D26-20.5 (c 0.9, CHCl3)3]; IR (CHCl3) umax:3428, 3345, 3017, 2933, 2405, 1708, 1671, 1493, 1365, 1220, 1167, 1116, 1075,1025, 922, 860, 762, 668 cm-1; 1H NMR (200 MHz, CDCl3) delta: 7.40-7.19 (m, 5H), 6.78 (brs, 1H),5.55-5.33 (m, 1H), 4.48 (d, J = 4.3 Hz, 2H), 4.27 (brs, 1H), 3.84 (dd, J= 3.9, 9.2 Hz, 1H), 3.50 (dd, J = 6.2, 9.1 Hz, 1H), 3.36 (s, 3H), 1.43(s, 9H); 13C NMR (50 MHz,CDCl3) delta: 170.3,155.5, 138.0, 128.7, 127.5, 80.4, 72.1, 59.1, 43.5, 28.3; HRMS (ESI): m/z calcdfor C16H24N2O4Na [M + Na]+331.1628; found: 331.1612. |
46.4% | With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; In dichloromethane; at 20℃; for 2h;Cooling with ice; | Synthesis of (R)-N-Benzyl-2-Boc-amino-3-methoxypropionamide[0157] (R)-2-N-Boc-amino-3-methoxypropanoic acid (15.0 g, 68.4 mmol), phenylmethanamine (7.33 g, 68.4 mmol), and DMAP (4.17 g, 34.2 mmol) were dissolved in DCM (150 mL). The solution was cooled in an ice-bath and EDC (21 .21 g, 137 mmol) was added dropwise to the solution. Once addition was complete, the reaction mixture stirred at warmed to room temperature and stirred for two hours. Then DCM (200 ml) was added to the mixture. The DCM organic phase was washed with H20 (200 mL x 1 ), 0.5 N HC1 (200 mL x 2), 5percent sodium bicarbonate (200 mL chi 2) and water (200 mL x 2). The organic phase was dried over sodium sulfate, filtered, and solvent removed under reduced pressure. The desired product was obtained as a colorless semi-solid with a purity >95percent (9.8 g, 46.4percent). NMR (500 MHz, CDC13) delta 1.46 (s, 9H), 3.38 (s, 3H), 3.51 (m, 1H), 3.86 (d, 1 H), 4.30 (br., 1H), 4.50 (s, 2H), 5.42 (br., 1H), 6.74 (br., 1H), 7.28 (m, 3H), 7.35 (m, 2H). LC-MS (m/z) , calculated. 308.2, found 309.1 [M + H]+, 331.1 [M + Naf. |
The C936 solution prepared as above in example 2 was cooled to <-10°C and isobutyl chloroformate (14.2ml, 0.107mol) at <-5°C. N-methylmorpholine (11.8ml, 0.17mol) was added at<-5°C and the mixture aged for 30 minutes at <-5O. A solution of benzylamine (12.2ml, 0.11mol) in methylene chloride was added at <-5°C and the mixture warmed to room temperature. After aging for 1 hour the mixture was washed with water (44ml), 1N HCI (44ml), 8percent sodium bicarbonate (44ml) and water (44ml) to yield a C937 solution in methylene chloride. | ||
Example-32: Preparation of (R)-2-tert-butyl l-(benzylamino)-3-methoxy-l- oxopropan-2-yl carbonate compound of formuIa-18:; Ethylchoroformate (49.3 g) followed by N-methylmorpholine (46 g) was added to a pre-cooled reaction mass of (R)-2-(tert-butoxycarbonylamino)-3-methoxy propionic acid (280 ml) obtained in example-31 at -10 to -15°C and stirred for 15 min at -15°C. Benzylamine (49 g) was added to the reaction mixture slowly at -10 to -15 °C and stirred for 1.5 hours. Reaction temperature was raised to 20-25°C and stirred for 1.5 hours. The reaction mixture was washed with dilute hydrochloric acid (100 ml), and further the organic layer was washed with sodium bicarbonate solution followed by washed with water. The reaction mixture containing title compound was directly used for next stage without any isolation and purification. | ||
Preparation of (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide(R)-2-((Tert-butoxy)carbonylamino)-3-methoxypropanoic acid (92.5 gm) as obtained in example 2 was dissolved in methylene chloride (925 ml) and then cooled to - 10°C. To the solution was added isobutyl chloroformate (57 ml) and then added 4- methylmorpholine (46.5 ml). The reaction mass was maintained for 30 minutes at -5°C and then added a solution of benzyl amine (46 ml) in methylene chloride (46 ml). The temperature of the reaction mass was raised to room temperature and then added water (140 ml). The separated organic layer was dried with sodium sulfate and the solvent was distilled off to obtain a residual mass. To the residual mass was added n-hexane (1200 ml) and stirred for 2 hours at room temperature. The solid obtained was collected by filtration and dried to obtain 116 gm of (R)-N-benzyl-2-((tert-butoxy)carbonylamino)-3- methoxypropionamide. |