Structure of L-Prolinol
CAS No.: 23356-96-9
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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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Combinatorial design of nanoparticles for pulmonary mRNA delivery and genome editing
Li, Bowen ; Manan, Rajith Singh ; Liang, Shun-Qing ; Gordon, Akiva ; Jiang, Allen ; Varley, Andrew , et al.
Abstract: The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for mRNA and CRISPR-Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases.
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Purchased from AmBeed: 14916-80-4 ; 294-90-6 ; 13093-04-4 ; 65604-89-9 ; 22366-98-9 ; 143-28-2 ; 1484-84-0 ; 112-92-5 ; 3433-37-2 ; 34803-66-2 ; 622-26-4 ; 934-98-5 ; 3529-08-6 ; 123-70-6 ; 23356-96-9 ; 534-26-9 ; 20739-58-6 ; 4730-54-5 ; 108-00-9 ; 51388-00-2 ; 6711-48-4 ; 7209-38-3 ; 506-43-4 ; 2038-03-1 ; 142-25-6 ; 27578-60-5 ; 105-83-9 ; 67980-77-2 ; 877-96-3 ; 14712-23-3 ; 4572-03-6 ; 14156-95-7 ; 10563-26-5 ; 4097-88-5 ; 111-33-1 ; 123-12-6 ; 6261-22-9 ; 496808-04-9 ; 3644-18-6 ; 764-60-3 ; 1002-36-4 ; 51-45-6 ; 112086-54-1 ; 22104-79-6 ; 67529-83-3 ; 10563-29-8 ; 294-90-6 ; 506-43-4 ; 13901-38-7 ; 938459-02-0 ; 51721-39-2 ; 18128-28-4 ; 915922-79-1 ; 205059-32-1 ; 5298-72-6 ; 22763-69-5
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CAS No. : | 23356-96-9 |
Formula : | C5H11NO |
M.W : | 101.14 |
SMILES Code : | OC[C@H]1NCCC1 |
MDL No. : | MFCD00005255 |
InChI Key : | HVVNJUAVDAZWCB-YFKPBYRVSA-N |
Pubchem ID : | 640091 |
GHS Pictogram: |
![]() |
Signal Word: | Warning |
Hazard Statements: | H315-H319-H335 |
Precautionary Statements: | P261-P305+P351+P338 |
Num. heavy atoms | 7 |
Num. arom. heavy atoms | 0 |
Fraction Csp3 | 1.0 |
Num. rotatable bonds | 1 |
Num. H-bond acceptors | 2.0 |
Num. H-bond donors | 2.0 |
Molar Refractivity | 31.91 |
TPSA ? Topological Polar Surface Area: Calculated from |
32.26 Ų |
Log Po/w (iLOGP)? iLOGP: in-house physics-based method implemented from |
1.37 |
Log Po/w (XLOGP3)? XLOGP3: Atomistic and knowledge-based method calculated by |
-0.33 |
Log Po/w (WLOGP)? WLOGP: Atomistic method implemented from |
-0.65 |
Log Po/w (MLOGP)? MLOGP: Topological method implemented from |
-0.16 |
Log Po/w (SILICOS-IT)? SILICOS-IT: Hybrid fragmental/topological method calculated by |
0.7 |
Consensus Log Po/w? Consensus Log Po/w: Average of all five predictions |
0.18 |
Log S (ESOL):? ESOL: Topological method implemented from |
-0.19 |
Solubility | 64.8 mg/ml ; 0.641 mol/l |
Class? Solubility class: Log S scale |
Very soluble |
Log S (Ali)? Ali: Topological method implemented from |
0.11 |
Solubility | 131.0 mg/ml ; 1.3 mol/l |
Class? Solubility class: Log S scale |
Highly soluble |
Log S (SILICOS-IT)? SILICOS-IT: Fragmental method calculated by |
-0.56 |
Solubility | 27.7 mg/ml ; 0.274 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 |
-7.15 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 |
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) |
1.38 |
* 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 |
---|---|---|
83% | With potassium carbonate; In acetonitrile; at -10 - 0℃; for 2h;Inert atmosphere; | A solution of benzyl chloroformate (3.81 g, 22.44 mmol) in acetonitrile (5 mL) was added slowly to a stirred solution of (S)-prolinol (2.07 g, 20.4 mmol) and finely powdered K2CO3 (6.20 g, 44.88 mmol) in dry acetonitrile (20 mL) at -10 oC under N2 atmosphere. Further, solution was stirred at -10 to 0 oC for 2 h. H2O (50 mL) was added to the reaction mixture and the aqueous layer was extracted with CHCl3 (3 × 20 mL). The combined organic extract was washed successively with H2O (20 mL), 5percent HCl (20 mL), H2O (3 × 20 mL) and then dried over anhyd Na2SO4. The solvent was removed under reduced pressure, the crude product was subjected to column chromatography (SiO2, hexanes/ EtOAc, 6:4) to give (S)-N benzyloxycarbonyl prolinol 14 (3.97 g, 83percent). [alpha]D27 -41.5 (c 0.448, CHCl3), [lit.2[alpha]D27 -40.0 (c 1.05, CH2Cl2)]; 1H NMR (CDCl3, 300 MHz): delta 1.45-2.05 (m, 4H, CH2CH2), 3.36-3.69 (m, 4H, CH2N & CH2OH), 4.01 (m, 1H, CHN), 5.15 (s, 2H, OCH2Ph), 7.26-7.37 (m, 5H, Ar-H); 13C NMR (CDCl3, 75 MHz): delta 24.0 (CH2), 28.4 (CH2), 47.3 (CH2N), 58.7 (CHN), 66.2 (CH2OH), 67.2 (OCH2), 127.9-128.3 (Ar-H), 136.0 (Ar-C), 156.9 (CO). |
With sodium hydroxide; In diethyl ether; | EXAMPLE 50 (S)-2-[[[(1,1-Dimethylethyl)dimethylsilyl]oxy]methyl]-1-pyrrolidinecarboxylic acid phenylmethyl ester To a 0° C. solution of 25 g of (S)-2-pyrrolidinemethanol in 150 ml of diethyl ether is added 54.8 g of benzyl chloroformate. At mid point of addition, 49.4 ml of 5N sodium hydroxide is added, simultaneously, and the reaction stirred at 0° C. for 2 hours. Diethyl ether is added, the layers are separated and the aqueous layer reextracted with diethyl ether. The combined organic layers are dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 0-10percent methyl alcohol/methylene chloride) to give 59.1 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester. | |
With potassium carbonate; In hexane; acetone; | (A) S-N-(Benzyloxycarbonyl)-2-pyrrolidinemethanol Powdered anhydrous potassium carbonate (41 g, 297 mmol) was added with stirring to a solution of S-2-pyrrolidinemethanol (6 g, 59.32 mmol) in acetone (120 ml). The mixture was cooled to 0° C. and benzyl chloroformate (16.94 ml, 118.6 mmol) was added dropwise. After 40 minutes, the reaction mixture was diluted with ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The organic extracts were combined, dried (magnesium sulfate) and concentrated. The crude oil was chromatographed on a silica gel column and eluted with 25percent ethyl acetate in hexane to obtain the title compound 2 (12.22 g) as a pale yellow oil. |
With sodium bicarbonate; In dichloromethane; water; | (1) A solution of carbobenzoxychloride 7.87 g in methylene chloride 50 ml is dropped to a mixture of L-prolinol 4.9 g in methylene chloride 50 ml and sodium hydrogen carbonate 11.6 g in water 50 ml at 0° C. under vigorously agitation. The mixture is stirred for 1 hour at room temperature. The organic layer is separated, washed, dried and concentrated in vacuo to give N-carbobenzoxy-L-prolinol 10.25 g. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In tetrahydrofuran; at -78 - 20℃; for 6h; | 4-(5-Methyl-3-phenylisoxazol-4-yl) benzenesulfonyl chloride (200 mg, 0.60 mmol) was dissolved in THF (3 ml) and the solution was cooled to-78C. After S- (-)-prolinol (182 mg, 1.80 mmol) was added to the solution, the mixture was gradually warmed to room temperature and stirred at room temperature for 6 hours. Ethyl acetate (8 ml) was added thereto, and the mixture was washed with water (3 ml) and subsequently with brine (2 ml), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-> 1: 1) to give ((2S)-1-[4- (5-methyl-3-phenylisoxazol-4-yl)- phenyl] sulfonyl} pyrrolidin-2-yl) methanol (232 mg, 97%) as a liquid. MS: 399 [M+H] +, APCI (MeOH) |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In 1,4-dioxane; at 70 - 80℃; for 12 - 48h;Combinatorial reaction / High throughput screening (HTS); | Example 1. Preparation of a combinatorial library of substituted 2-aminomethyl-5-hydroxy-1H-indole-3-carboxylic acids esters of general formula 1.1. A mixture of 0.357 mmol of ester 2, 0.43 mmol of a secondary amine 3, and 0.43 mmol of formaldehyde in the form of formalin in 3 ml of dioxane is heated at 70-80°C at stirring for 12 to 48 hours. Progress of the reaction is monitored by chromato-mass-spectrometry. Upon completion of the reaction, the reaction mass is diluted with water, the residue is filtered and recrystallized from a suitable solvent, or purified by chromatography. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
64% | A solution of 2,4-dichloro-5-pyrimidinecarbonyl chloride (0.6 g, 2.8 mmol) in dichloromethane (8 ml) was added to a 50 ml three-necked flask and cooled in an ice bath. The 2-aminomethylpyrimidine acetate (0.48 g, 2.8 mmol) and triethylamine (2.8 mmol) were first dissolved in dichloromethane,And then dropwise dropwise into the reaction solution. Plus finished, the reaction 1 hour,A mixture of 3-chloro-4-methoxybenzylamine hydrochloride (0.59 g, 2.8 mmol) and triethylamine (0.29 g, 2.8 mmol) was added dropwise to the above reaction solution, 2 hours,To the reaction solution was added L-proline alcohol (0.43 g, 4.3 mmol), and the reaction was carried out overnight at room temperature.The reaction solution was poured into ice water, quenched and extracted twice with methylene chloride. The organic phase was combined and washed twice with water,Dried over anhydrous sodium sulfate and concentrated to give the crude product which was purified by column chromatography to give 0.9 g of white solid, and the yield was 64%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
93% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 50℃; for 5h; | General procedure: To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 % yield) as a white solid; NMR (300 MHz, DMSO-i/e): delta 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
85% | With N-ethyl-N,N-diisopropylamine; In isopropyl alcohol; at 20℃; for 2h; | General procedure: To a solution of 2,4-dichloropyrrolo[1,2-f][1,2,4]triazine (4a) (0.5 g, 2.7 mmol) in 2-Propanol (6 mL) was added (S)-pyrrolidin-2-ylmethanol (0.39 mL, 4.0 mmol), DIPEA (1.39 mL, 8.0 mmol) and heated at 90 °C for 1 hr. The reaction was cooled to room temperature and solid obtained was collected by filtration to afford (S)-(l-(2-chloropyrrolo[2,l-f][l,2,4]triazin-4- yl)pyrrolidin-2-yl)methanol (96a) (0.49 g, 73 percent yield) as a white solid; NMR (300 MHz, DMSO-i/e): delta 7.70 (dd, J= 2.6, 1.4 Hz, 1H), 6.97 (dd, J= 4.7, 1.6 Hz, 1H), 6.80 - 6.57 (m, 1H), 5.15 (t, J = 5.7 Hz, 1H, D2O exchangeable), 4.87 (t, J= 5.7 Hz, 1H), 4.44 (d, J= 17.8 Hz, 1H), 4.05 - 3.82 (m, 1H), 3.72 - 3.39 (m, 2H), 2.22 - 1.84 (m, 4H). MS (ES+): 253.3, 255.3 (M+2); MS (ES-): 287.2, 289.2 (M+Cl). |