Structure of Alloc-OSu
CAS No.: 135544-68-2
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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. : | 135544-68-2 |
Formula : | C8H9NO5 |
M.W : | 199.16 |
SMILES Code : | O=C(OCC=C)ON1C(CCC1=O)=O |
MDL No. : | MFCD02684388 |
InChI Key : | OIXALTPBNZNFLJ-UHFFFAOYSA-N |
Pubchem ID : | 11788855 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319 |
Precautionary Statements: | P264-P280-P302+P352-P337+P313-P362+P364-P332+P313 |
Num. heavy atoms | 14 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 0.38 |
Num. rotatable bonds | 5 |
Num. H-bond acceptors | 5.0 |
Num. H-bond donors | 0.0 |
Molar Refractivity | 47.95 |
TPSA ? Topological Polar Surface Area: Calculated from |
72.91 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.8 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
0.28 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
0.01 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.07 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.12 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.43 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.92 |
Solubility | 23.9 mg/ml ; 0.12 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
-1.37 |
Solubility | 8.44 mg/ml ; 0.0424 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.39 |
Solubility | 81.3 mg/ml ; 0.408 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) |
Yes |
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 |
-7.32 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 |
1.0 |
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 |
2.0 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) |
2.32 |
* 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 |
---|---|---|
100% | With pyridine; In methanol; N,N-dimethyl-formamide; at 23℃; for 16h;Inert atmosphere; | To a stirred suspension of AmB (4.0 g, 4.3 mmol, 1.0 equiv.) in DMF:MeOH (75 mL: 75 mL) in a 300 mL round bottom at 23 C, was added sequentially, pyridine (5.0 mL, 50.0 mmol, 11.5 equiv.), and alloc-succinimide (2.4 g, 12.05 mmol, 2.8 equiv.). After stirring for 16 h at 23 C, the dark orange, homogeneous solution was slowly poured into rapidly stirring Et20 (3.5 L). The yellow suspension was filtered through Whatman 42 filter paper and washed with Et20 (3 x 100 mL) before the cake was allowed to fully dry. The fully dried alloc-AmB yellow powder (4.3 mmol, quantitative) was taken on to the subsequent reaction without further purification. |
100% | In methanol; N,N-dimethyl-formamide; at 23℃; for 16h; | To a stirred suspension of AmB (4.0 g, 4.3 mmol,1.0 equiv.) in DMF:MeOH (75 mE: 75 mE) in a 300 mE round bottom flask at 23 C. was added pyridine (5.0 mE, 50.0 mmol, 11.5 equiv.) and alloc-succinimide (2.4 g, 12.05 mmol, 2.8 equiv.). After stirring for 16 hat 23 C., the dark orange, homogeneous solution was slowly poured into rapidly stirring Et20 (3.5 E). The yellow suspension was filtered through Whatman 42 filter paper (110 mm diameter) and washed with Et20 (3x100 mE) before the cake was allowed to fully dry. The fully dried alloc-AmB yellow powder (4.3 mmol, quantitative) was taken on to the subsequent reaction without thrther purification. |
With pyridine; In methanol; N,N-dimethyl-formamide; at 23℃; for 16h; | To a stirred suspension of AmB (4.0 g, 4.3 mmol, 1.0 equiv.) in DMF:MeOH (75 mL: 75 mL) in a 300 mL round bottom flask at 23 C was added pyridine (5.0 mL, 50.0mmol, 11.5 equiv.) and alloc-succinimide (2.4 g, 12.05 mmol, 2.8 equiv.). After stirring for16 h at 23 C, the dark orange, homogeneous solution was slowly poured into rapidlystirring Et20 (3.5 L). The yellow suspension was filtered through Whatman 42 filter paper(110 mm diameter) and washed with Et20 (3 x 100 mL) before the cake was allowed tofully dry. The fully dried alloc-AmB yellow powder (4.3 mmol, quantitative) was taken onto the subsequent reaction without further purification. |
With pyridine; In methanol; N,N-dimethyl-formamide; at 20℃; for 16h; | To a stirred solution of Amphotericin B (25.0 g, 27.05 mmol) in DMF:MeOH (2:1, 750 ml) and pyridine (25 ml. 308.4 mmoi) was added allocsuccinimide (15.08 g, 75.75 mmoi) at room temperature. After 1 6h, the reaction mixture was poured into cold Et20. The resulting solid was filtered and dried under reduced pressure to provide a yellow solid. The solid compound was washed with diethyl ether (5 x 100 mL) to afford compound 2 I as a yellow solid. Compound 24 analysis: LC/MS (ESI) m/z 1006.4 [MH]. | |
15.08 g | With pyridine; In methanol; N,N-dimethyl-formamide; at 20℃; for 16h; | EXAMPLE 1 [0094] Compound 1 (FIGURE 1 A) was prepared as follows (Figure IB): Step 1 : To a stirred solution of Amphotericin B (25.0 g, 27.05 mmol) in DMF: MeOH (2:1, 750 ml) and pyridine (25 ml, 308.4 mmol) was added alloc-succinimide (15.08 g, 75.75 mmol) at room temperature. After 16 h, the reaction mixture was poured into cold Et20. The resulting solid was filtered and dried under reduced pressure to provide a yellow solid. The solid compound was washed with diethyl ether (5 x 100 mL) to afford Compound 1-1 as a yellow solid. Compound 1-1 analysis: LC/MS (ESI) m/z 1006.4 [M-H]-. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
54% | A suitable fully protected intermediate was quickly generated from AmB (Scheme 3, FIG. 16). This sequence involved Alloc protection of the amine, C3/C5 and C9/C11 rho-methoxyphenyl acetal formation, TES silylation of the remaining alcohols, and lastly TMSE formation of the C16 carboxylate to form fully protected intermediate 5. Exposure of 5 to NaHMDS at low temperatures smoothly eliminated the C3 alcohol, generating an alpha-beta unsaturated lactone. Stryker reduction of this intermediate efficiently reduced the unsaturation yielding 6, leaving only a deprotection sequence to generate C3deOAmB. Exposure of 6 to HF cleanly removed the TES groups, followed by TBAF-promoted TMSE removal. Methyl ketal and PMP ketal hydrolysis was achieved concomitantly under acidic conditions with HCl. Efforts are currently underway to achieve the final Alloc deprotection of 7 and synthesize C3deOAmB. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With sodium hydrogencarbonate; In water; acetone; at 20℃; for 16h; | <strong>[1115-74-8](S)-2-((S)-2-amino-3-methylbutanamido)propanoic acid</strong> (1.74 g, 9.24 mmol), allyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.84 g, 1 eq), NaHCO3 (776 mg, 1 eq), water (37 mL) and acetone (37 mL) was stirred at room temperature for 16 h. The acetone was removed by rotary evaporation, the residue was diluted with water (250 mL) and the pH adjusted to 3 using concentrated HCl (17 mL), followed by extraction with EtOAc (3×400 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give ((allyloxy)carbonyl)-<strong>[1115-74-8]L-valyl-L-alanine</strong> (89) as a white solid (2.28 g, 91% yield). 1H NMR (DMSO-d6) delta 12.49 (s, 1H), 8.12 (d, 1H), 7.14 (d, 1H), 5.97 (m, 1H), 5.14 (d, 1H), 5.09 (d, 1H), 4.23 (s, 2H), 1.98 (m, 1H), 1.13 (d, 3H), 0.80 (m, 6H) |
44% | With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; for 3h; | To a solution of NH2-<strong>[1115-74-8]Val-Ala</strong>-OH (941 mg, 5 mmol) in DMF ( 10 mL), added DIEA (1.73 mL, 10 mmol) and N-(Allyloxycarbonyloxy)succinimide (1.15 rnL, 7.5 mmol). Reaction mixture was stirred for 3 hr, quenched with water (3 mL) and stirred overnight. Solvent was removed in vacuo and the residue was diluted with HCl in water (40 mL, 0.25 M). After sonication, the precipitate was filtered off and dried thoroughly to afford 2 (600 mg, 44% yield). 1H NMR (500 MHz, DMSO-d6) delta: 12.48 (bs, 1H), 8.18 id. J= 7,0 Hz, 1H), 7, 16 id. ./ 9.4 Hz, 1H), 5.95-5.83 (m, IH), 5.28 (d, J= 15.8 Hz, 1H), 5.17 (d. J = 10.5 Hz, 1H), 4 ,47 (m, 2H), 4.18 (m, 1H). 3,87 (m, 1H). 1.94 (m, 1H), 1.26 (d, J= 7.6 Hz, 3H), 0.86 (dd, J = 14.6, 6.7 Hz, 6H). LC/MS: retention time 0.25 min. (ESI) C12H21N2O5: [M+H]+ 273; found 273. |