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Folate-conjugated organic CO prodrugs: Synthesis and CO release kinetic studies
Shameer M. Kondengadan ; Shubham Bansal ; Xiaoxiao Yang , et al. Research Square,2024. DOI: 10.21203/rs.3.rs-4213303/v1
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Abstract: Carbon monoxide (CO) is an endogenous produced molecule and has shown efficacy in animal models of inflammation, organ injury, colitis and cancer metastasis. Because of its gaseous nature, there is a need for developing efficient CO delivery approaches, especially those capable of targeted delivery. In this study, we aim to take advantage of a previously reported approach of enrichment-triggered prodrug activation to achieve targeted delivery by targeting the folate receptor. The general idea is to exploit folate receptor-mediated enrichment as a way to accelerate a biomolecular Diels-Alder reaction for prodrug activation. In doing so, we first need to find ways to tune the reaction kinetics in order to ensure minimal rection without enrichment and optimal activation upon enrichment. In this feasibility study, we synthesized two diene-dienophile pairs and studied their reaction kinetics and ability to target the folate receptor. We found that folate conjugation significantly affects the reaction kinetics of the original diene-dienophile pairs. Such information will be very useful in future designs of similar targeted approaches of CO delivery.
Keywords: Enrichment triggered delivery ; Carbon Monoxide ; Folate conjugate ; Reaction kinetics ; Diels-Alder reaction
Purchased from AmBeed: 7693-46-1 ; 59-30-3 ; 57260-73-8 ; 74426-51-0
CAS No. : | 57260-73-8 | MDL No. : | MFCD00191871 |
Formula : | C7H16N2O2 | Boiling Point : | - |
Linear Structure Formula : | (CH3)3COC(O)NHCH2CH2NH2 | InChI Key : | AOCSUUGBCMTKJH-UHFFFAOYSA-N |
M.W : | 160.21 | Pubchem ID : | 187201 |
Synonyms : |
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Chemical Name : | tert-Butyl (2-aminoethyl)carbamate |
Signal Word: | Danger | Class: | 8 |
Precautionary Statements: | P280-P305+P351+P338-P310 | UN#: | 2735 |
Hazard Statements: | H314 | Packing Group: | Ⅲ |
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 |
---|---|---|
92% | Stage #1: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16 h; |
Preparation 63 Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A) To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3 Å. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10° C. (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3*100 mL). The combined aqueous solution was cooled to 0° C., basified with sat. NaHCO3 and extracted with CHCl3 (3*100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgSO4 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2+H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. |
92% | Stage #1: at 20℃; molecular sieve 3Å Stage #2: at -10 - 20℃; for 16.5 h; |
Example 34: Synthesis of N-((S)-l-{2-[(Dihydrocodein-6-enyloxycarbonyl)-methylamino]- ethylcarbamoyl-4-guanidino}-butyl)-malonamic acid (Compound KC-4)Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification. |
92% | Stage #1: at 20℃; Molecular sieve 3 Å Stage #2: With sodium tetrahydroborate In methanol at -10 - 20℃; for 16.5 h; Cooling with ice |
Preparation 63: Synthesis of tert-butyl 2-(benzylamino)ethylcarbamate (A)To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL) was added benzaldehyde (4.7 g, 44.0 mmol) and molecular sieve 3A. After stirring at ambient temperature overnight, the mixture was cooled down to ca. -10 °C (ice/salt bath) and treated portion wise with NaBH4 (9.1 g, 240.0 mmol) over 30 min. After complete addition, the bath was removed and the reaction mixture stirred at ambient temperature for 16 h. The solvent was evaporated and the residue taken into EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HC1 (3 x 100 mL). The combined aqueous solution was cooled to 0 °C, basified with sat. NaHC03 and extracted with CHC13 (3 x 100 mL). The combined organic layers were washed with brine (200 mL). After drying over MgS04 and filtering, the solvent was evaporated in vacuo to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. LC-MS [M+H] 251.2 (C14H22N2O2 +H, calc: 251.3). TLC Rf (DCM/MeOH 9:1): 0.30. Compound A was used without further purification. |
92% | Stage #1: at 20℃; Molecular sieve Stage #2: at -10 - 20℃; for 16.5 h; |
To a solution of tert-butyl 2-aminoethylcarbamate (6.4 g, 40.0 mmol) in methanol (60 mL), Benzaldehyde (4.7 g, 44.0 mmol)And molecular sieves 3 Å were added.After stirring overnight at ambient temperature, the mixture was cooled to about -10 ° C. (ice / salt bath) and treated in portions with NaBH 4 (9.1 g, 240.0 mmol) for 30 minutes. After all addition, the bathtub was removed and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated and the residue was taken up in EtOAc (150 mL) and poured into water (100 mL). The organic layer was extracted with 0.5 N HCl (3 × 100 mL). The combined aqueous solution was cooled to 0 ° C., basified with saturated NaHCO 3 and extracted with CHCl 3 (3 × 100 mL). The combined organic layers were washed with brine (200 mL). After drying and filtering over MgSO 4, the solvent was evaporated under reduced pressure to give compound A (9.2 g, 36.8 mmol, 92percent) as a colorless oil. |
51% | Stage #1: at 20℃; for 2 h; Stage #2: at 0 - 20℃; |
Example 3Atert-butyl [2-(benzylamino)ethyl]carbamate; 2.0 g (18.4 mmol) benzaldehyde and 3.32 g (20.7 mmol) N-Boc-ethylendiamine are dissolved in 25 ml methanol. The mixture is stirred 2 h at rt before cooled to 00C and 3.57 g (94.2 mmol) sodium borohydride and water are added to generate a solution, which is stirred over night at rt. Solvents are removed in vacuo and the residue is dissolved in dichloromethane and washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude product is purified by reverse phase HPLC (water / acetonitrile) to afford 2.4 g (51percent of th.) of the title compound.HPLC (method 1): R, = 3.70 min; MS (ESIpos): m/z = 251 (M+H)+1H-NMR (400 MHz, DMSOd6): δ = 7.30 (m, 4H), 7.21 (m, IH), 6.72 (m, IH), 3.68 (s, 2H), 3.02 (m, 2H), 2.53 (m, 2H), 2.08 (bs, IH), 1.37 (s, 9H). |
23% | Stage #1: With sodium tris(acetoxy)borohydride; magnesium sulfate; triethylamine In 1,2-dichloro-ethane at 20℃; for 16 h; Stage #2: With water; sodium hydrogencarbonate In 1,2-dichloro-ethane |
To a solution of tert-butyl 2-aminoethylcarbamate (3.7 g, 22.3 mmol), benzaldehyde (2.36 g, 22.3 mmol) and MgSO4 (1.33 g) in 1,2-dicholoroethane (300 mL) and Et3N (3.1 mL, 22.3 mmol) at RT was added NaHB(AcO)3. The mixture was stirred (RT, 16 h) and filtered. The solution was washed with saturated NaHCO3 (200 ml), dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, eluting with MeOH-DCM (0-10percent) to afford tert-butyl 2-(benzylamino)ethylcarbamate (1.4 g, 23percent). Mass calculated for C14H22N2O2=250.34; found: [M+H]+=251.3. |