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CAS No. : | 48068-25-3 |
Formula : | C10H19NO5 |
M.W : | 233.26 |
SMILES Code : | C(=O)(OC(C)(C)C)N[C@@H]([C@H](OC)C)C(=O)O |
MDL No. : | MFCD00076990 |
InChI Key : | VWSUOKFUIPMDDX-RQJHMYQMSA-N |
Pubchem ID : | 15460346 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
* 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 |
---|---|---|
In tetrahydrofuran; methanol; ethyl acetate; | [Process 1] Boc-Thr(Me)-OH In a THF solution containing 0.8 g of Boc-Thr-OH, 100 mg of sodium hydride (60% in oil) was added under ice cooling and the resultant mixture was stirred for 30 min at room temperature. Further, 2.8 ml of methyl iodide was added and the obtained reaction mixture was stirred overnight at room temperature. The reaction mixture was evaporated under reduced pressure and the resultant residue was redissolved in ethyl acetate, washed with 5% sodium hydrogensulfite aqueous solution, water and saturated sodium chloride aqueous solution, successively, and dried over anhydrous sodium sulfate. The dried solution was evaporated under reduced pressure, dissolved in methanol, mixed with DCHA and reevaporated. Ether-hexane was added to the residue to give 0.55 g of the title compound as its DCHA salt. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(1) Synthesis of (2S,4S)-2-(aminocarbonyl)-1-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxybutanoyl)-4-fluoropyrrolidine According to the manner similar to that of Example 1(3), the title compound (2.28 g) was obtained as a colorless amorphous substance from (2S,4S)-2-(aminocarbonyl)-4-fluoropyrrolidine hydrochloride (1.18 g) and <strong>[48068-25-3](2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxybutanoic acid</strong> (1.63 g). MS(ESI pos.)m/z: 370([M+Na]+), (ESI neg.)m/z: 346([M-H]-). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution containing Boc-L-Thr(Mc)- OH (105 mg, 0.45 mmol) in NMP (4 mL) at 0 0C was added HATU (169 mg, 0.44 mmol) followed by DIPEA (0.1 mL, 0.57 mmol). After 5 min, amine 59 (124 mg, 0.45 mmol) in NMP (5 mL) was added in a dropwise fashion. The reaction mixture was allowed to warm to ambient temperature. After 1 h, the solution was diluted with EtOAc, washed with IM HCl, saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 260 mg of amide 60 as an orange-colored oil that was used without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
48% | With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 6h; | To a solution containing crude 49 (0.3 g, 1.1 mmol) and <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (0.31 g, 1.3 mmol) in NMP (5 mL) at 0 0C was added DIPEA (0.25 mL, 1.44 mmol) followed by HATU (0.5 g, 1.3 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The reaction mixture was diluted with EtOAc and washed successively with dilute aqueous HCl, water, saturated aqueous NaHCO3, water, and brine. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The product was purified by reverse-phase HPLC (Cl 8; 50-100% ACN/watcr v/v 0.1% AcOH). The product-containing fractions were concentrated in vacuo to afford 0.28 g (48%) of 50 as a white solid. 1H NMR (CDCl3. 300 MHz): delta 8.2 (s, IH), 7.8-7.5 (m, IH), 7.05 (m, 2H), 6.92 (m, IH), 5.6 (d, J= 10.7 Hz, IH), 4.6 (m, IH), 4.1 (m, IH), 3.6 (m, 3H), 3.4 (s, 3H), 3.35 (m, IH), 2.6 (m, IH), 2.1 (m, 2H), 1.7 (m, I H), 1.48 (m, H) 1.45 (s, 9H), 1.21 (d, ./ = 6.45 Hz, 3 H, major rotamer), 1.14 (d, J = 6.45 Hz, minor rotamer), 0.90 (d, J = 7.03 Hz, minor rotamer), 0.76 (d, J= 6.45 Hz, 3H, major rotamer) ppm. Mass spectrum, m/z = [447.7] (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
38% | With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 2h; | To a solution containing amine 66 (225 mg, 0.72 mmol), <strong>[48068-25-3]Boc-Thr(Me)-OH</strong> (177 mg, 0.75 mmol), and HATU (289 mg, 0.76 mmol) in NMP (4 mL) at 0 C was added DIPEA (110 mg, 0.86 mmol). The reaction mixture was allowed to warm to ambient temperature. After 2 h, reaction mixture was diluted with diethyl ether and washed successively with dilute aqueous HCl, water (5X), aqueous NaHCO3, water (2X), then brine. The organic phase was dried with anhydrous Na2SO4, filtered, and concentrated to afford the crude product which was purified by flash silica gel chromatography (1 :1 hexanes/EtOAc) to afford 146 mg (38%) of 67 as a tan-colored foam. Mass spectrum, m/z = [526.0] (M)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With N-ethyl-N,N-diisopropylamine; HATU; In 1-methyl-pyrrolidin-2-one; at 0 - 20℃; for 12h; | To a solution containing crude 9 (0.33 g, 1.27 mmol) and Boc-L-Thr(Me)-OH (0.30 g, 1.27 mmol) in NMP ( 10 mL) at 0 0C was added DIPEA (0.22 mL, 1.27 mmol) followed by HATU (0.48 g, 1.27 mmol) and the reaction mixture was stirred to ambient temperature over 12 h at which point TLC analysis revealed the complete consumption of 9 [1 : 1 EtOAc/hexanes; Ri(9) = 0.01, Rf(IO) = 0.4]. The reaction mixture was diluted with diethyl ether and washed successively with dilute aqueous HCl, water, saturated aqueous NaHCO3, water (5X), brine, and dried over anhydrous Na2SO4, filtered, and concentrated to afford 0.5 g of <n="25"/>crude 10 which was purified by flash silica gel chromatography (20% EtOAc/hexancs) to provide 0.37 g (61%) of 10 as a white solid. 1H NMR (CDCl3, 300 MHz): delta 9.2 (s, IH), 8.4-8.2 ( m, 2H), 7.1 (s, IH), 5.6 (d, J= 10.7 Hz, IH), 5.3 (s, IH), 4.6-4.4 (m, 2H), 4.0 (m, 2h), 3.9 (m, IH), 3.6 (m, IH), 3.4 (s, 3H), 2.8 (dd, J = 16 Hz, 10 Hz). 2.1 (s, 3H), 1.4(s, 9H), 1.1 (d, J = 10.7 Hz, 3H) ppm. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Part A. ((lR,2R)-l-Hydroxymethyl-2-methoxy-propyl)-carbamic acid tert-butyl ester To a cold solution (-15C) of BocThr(Me)OH (5.14 g, 22 mmol) in dichloroethane (22 mL) were successively added N-methyl morpholine (2.44 mL, 22 mmol) and isobutyl chloroformate (2.99 mL, 22 mmol). After one min, the precipitate was filtered and washed with dichloroethane (5 x 4mL). The filtrate and washings were combined in a large three neck flask in an ice-salt bath. A solution of NaBH4 (1.26 g, 33 mmol) in H2O (11 mL) was added at once, proceeding a strong evolution of gas, followed by H20 (500 mL). The mixture was then extracted with EtOAc (5 x 150 mL). The combined EtOAc was dried ( a2S04) and concentrated to give the titled compound (5 g). MS (MH+ 220). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
78% | With O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Preparation of Compound 57Step 1: Tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2-yl)carbamate. A solution of <strong>[48068-25-3](2S,3R)-2-(tert-butoxycarbonylamino)-3-methoxy-butanoic acid</strong> (400 mg, 1.7 mmol) in DMF (3 mL) was added DIEA (665 mg, 0.9 mL, 5.1 mmol) , HBTU (976mg, 2.6 mmol) and N-methylmethanamine (580 mg, 0.62 mL of 40 %w/w, 5.1 mmol) and stirred overnight at RT. The mixture was diluted with EtOAc (20 mL), washed with H20 (15 mL), brine (15 mL), dried over Na2S04 and concentrated. The residue was purified by silica gel chromatography, eluting with 0-60% EtOAc in hexane to afford tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2-yl)carbamate (350 mg, 1.3 mmol, 78%). To resulting tert-butyl ((2S,3R)-l-(dimethylamino)-3-methoxy-l-oxobutan-2- yl)carbamate (350 mg, 1.3 mmol) was added HC1 (5 mL of 4.0 M, 20 mmol) in dioxane and stirred for 2 h at RT. The solution was concentrated and used directly in next step. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
95% | Compound Gl: Tert-butyl (2S,3R)-3-methoxy-l-oxo-l-(pyrrolidin-l-yl)butan-2- ylcarbamate; (2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid (643 mg, 2.76 mmol), which is commercially available, and DIPEA (1.440 mL, 8.27mmol) was mixed in DCM (10 mL). The mixture was cooled to 0 C. TBTU (974 mg, 3.03 mmol) was added and the mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol) was added and the resultant mixture was stirred at rt for 16 h. The mixture was diluted with DCM (10 mL). The organic phase was washed with NaHCC^ (8% in aq. solution) and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM / iso-propanol, 99:1 to 95:5, KP-SIL 340g column). The solvent was removed under reduced pressure to give the title compound (0.704 g, 95%). .H NMR (400 MHZ, CD3OD) delta 1.15, 1.44, 1.82 - 2.05, 3.33, 3.35 - 3.52, 3.54 - 3.65, 3.66 - 3.79, 4.36. Total no of protons: 25. LCMS (M+H)+: 287. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
2.02 g | With N-ethyl-N,N-diisopropylamine; HATU; In water; N,N-dimethyl-formamide; at 20℃; | To a solution of N- (tert-butoxycarbonyl) -O-methyl-L- threonine (2.33 g) , 50% aqueous dimethylamine solution (1.08 g) and N-ethyl-N- (1-methylethyl) propan-2-amine (2.58 g) in D F (30 mL) was added 0- (7-azabenzotriazol-l-yl) -Nu,Nu,Nu' ,Nu'- tetramethyluronium hexafluorophosphate (4.18 g) under ice- cooling. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.02 g) .XH NMR (300 MHz, DMSO-d6) delta 1.01 (3H, d, J = 6.1 Hz), 1.37 (9H, s), 2.83 (3H, s), 3.06 (3H, s) , 3.23 (3H, s) , 3.49 (1H, qd, J = 6.1, 6.1 Hz), 4.42 (1H, dd, J = 8.4, 6.1 Hz), 6.56 (1H, d, J = 8.4 Hz) . |