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CAS No. : | 134978-97-5 | MDL No. : | MFCD13185897 |
Formula : | C6H13NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | RUVRGYVESPRHSZ-UHFFFAOYSA-N |
M.W : | 163.17 | Pubchem ID : | 362706 |
Synonyms : |
|
Num. heavy atoms : | 11 |
Num. arom. heavy atoms : | 0 |
Fraction Csp3 : | 0.83 |
Num. rotatable bonds : | 7 |
Num. H-bond acceptors : | 5.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 37.61 |
TPSA : | 81.78 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | No |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | No |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -9.92 cm/s |
Log Po/w (iLOGP) : | 1.18 |
Log Po/w (XLOGP3) : | -3.7 |
Log Po/w (WLOGP) : | -0.94 |
Log Po/w (MLOGP) : | -1.29 |
Log Po/w (SILICOS-IT) : | -0.52 |
Consensus Log Po/w : | -1.05 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 2.0 |
Bioavailability Score : | 0.55 |
Log S (ESOL) : | 1.94 |
Solubility : | 14300.0 mg/ml ; 87.4 mol/l |
Class : | Highly soluble |
Log S (Ali) : | 2.57 |
Solubility : | 60800.0 mg/ml ; 372.0 mol/l |
Class : | Highly soluble |
Log S (SILICOS-IT) : | -0.39 |
Solubility : | 66.5 mg/ml ; 0.407 mol/l |
Class : | Soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 1.0 |
Synthetic accessibility : | 2.19 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | H302-H315-H319-H335 | Packing Group: | N/A |
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 |
---|---|---|
62.1% | With sodium carbonate In 1,4-dioxane; water at 20℃; for 12 h; | Step 3a: To a stirred solution of compound 1a (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)2O (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH=3) by 3N HCl solution and was extracted with DCM (2×200 mL). Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield: 62.1percent). LCMS: 263.0 (M+H)+ |
62.1% | With sodium carbonate In 1,4-dioxane; water at 20℃; for 12 h; | To a stirred solution of compound la (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)20 (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress ofreaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH = 3) by 3N HC1 solution and was extracted with DCM (2 x 200 mL). Organic layer was washed with water, brine, dried over Na2504 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield:62.1percent). LCMS: 263.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
200 g | With hydrogenchloride; In ethanol; water;pH 9.0; | In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product (Intermediate 3) was dissolved in 1000 ml of ethanol, and 350 g of 30% NaOH solution was added dropwise.After the completion of the dropwise addition, the mixture was heated to reflux, and monitored by TLC, the intermediate 3 was completely disappeared, and the temperature was lowered. The pH was adjusted to 9 with hydrochloric acid, and a solution of 337 g of Fmoc-Osu in 1000 ml of ethanol was added dropwise.If the pH has dropped, add sodium bicarbonate and keep it at around 8.TLC was monitored until Intermediate 4 disappeared. The pH was adjusted to 1-2 with hydrochloric acid, the ethanol was distilled off, 1000 ml of water was added, and the mixture was extracted three times with ethyl acetate 500*3, and washed twice with saturated brine.The ethyl acetate was concentrated to give 285 g of crude material.Recrystallization from 1000 ml of ethyl acetate gave 200 g of product[2-[1-(Fmoc-Amino)ethoxy]ethoxy]acetic acid, yield 51.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With PS-trisamine resin; In N,N-dimethyl-formamide; | The title compound was prepared by coupling of 4-[3-(2H-tetrazol-5-yl)carbazol-9- ylmethyl]benzoic acid 2,5-dioxopyrrolidin-1 -yl ester with [2-(2-aminoethoxy)ethoxy]acetic acid (prepared from [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid by treatment with PS-Trisamine resin in DMF). HPLC-MS (Method C): m/z: 515 (M+1 ); Rt = 3.10 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The title compound was prepared by coupling of 4-[3-(2H-tetrazol-5-yl)carbazol-9- ylmethyl]benzoic acid 2,5-dioxopyrrolidin-1 -yl ester with <strong>[134978-97-5][2-(2-aminoethoxy)ethoxy]acetic acid</strong> (prepared from [2-[2-(Fmoc-amino)ethoxy]ethoxy]acetic acid by treatment with PS-Trisamine resin in DMF). HPLC-MS (Method C): m/z: 515 (M+1 ); Rt = 3.10 min. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With hydrogenchloride; sodium hydroxide; In ethanol; water; ethyl acetate; | A2.2 8-Amino-3,6-dioxaoctanoic acid 63.5 g of sodium 8-acetylamino-3,6-dioxaoctanoate were dissolved in 200 ml of water. 11.2 g of NaOH were added at 20 C., and the reaction mixture was then heated at 100 C. for 8 h until precursor was no longer detectable. The pH was then adjusted to 6 with 53.7g of 37% by weight aqueous hydrochloric acid, and the solvent was distilled off under reduced pressure. The oily residue was dissolved in 200 ml of ethanol and filtered to remove undissolved sodium chloride, the mother liquor was slowly added dropwise to 1 l of ethyl acetate, and the oily phase which separated out was removed and dried under reduced pressure. This resulted in 40.6 g of 8-amino-3,6-dioxaoctanoic acid (corresponding to 89% of theory). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
62.1% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 12h; | Step 3a: To a stirred solution of compound 1a (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)2O (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress of reaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH=3) by 3N HCl solution and was extracted with DCM (2×200 mL). Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield: 62.1%). LCMS: 263.0 (M+H)+ |
62.1% | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 12h; | To a stirred solution of compound la (5.0 g, 30.6 mmol) in 1,4-Dioxane (50 mL), Sodium carbonate (8.12 g, 76.5 mmol, dissolved in 10 mL water) and (Boc)20 (9.98 mL, 45.7 mmol) were added and stirred at room temperature for 12 h. The progress ofreaction was monitored by TLC. The reaction mass was partitioned between diethyl ether and water. Then aqueous layer was made acidic (pH = 3) by 3N HC1 solution and was extracted with DCM (2 x 200 mL). Organic layer was washed with water, brine, dried over Na2504 and evaporated under reduced pressure to yield 50 g of pure 3a (Yield:62.1%). LCMS: 263.0 (M+H). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Xa is selected among the following amino acid residues: ... arginine; ornithine; tranexamic acid; N-methyl-tranexamic acid; 8-amino-3,6-dioxaoctanoic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)propionic acid; N-(4-aminobutyl)-glycine; ... | ||
...of the following groups: -(Gly)n-, n ranging from 1 to 10; -(Pro)n-, n ranging from 1 to 10; NH2-(CH2)n-COON, n ranging from 1 to 10; NH2-(CH2-CH2-O)m-CH2CH2COOH, m ranging from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... | ||
...ing amino acid residues: -(Gly)n-, n ranging from 1 to 10; -(Pro)n-, n ranging from 1 to 10; NH2-(CH2)n-COON, n ranging from 1 to 10; NH2-(CH2-CH2-O)m-CH2CH2COOH, m ranging from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... |
Xe is chosen from the following amino acid residues: NH2-(CH2)-COOH, n varying from 1 to 10; NH2-(CH2-CH2-O)m-CH2CH2COOH, m varying from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... | ||
Xg corresponding to the residue of one of the following groups: -NH2-(CH2)g-COOH, n varying from 1 to 10; -NH2-(CH2-CH2-O)m-CH2CH2COOH, m varying from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)-propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... | ||
Xg corresponding to the residue of one of the following groups: -NH2-(CH2)-COOH, n varying from 1 to 10; -NH2-(CH2-CH2-O)mCH2CH2COOH, m varying from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)-propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... | ||
Xf is chosen from the following amino acid residues: NH2-(CH2)-COOH, n varying from 1 to 10; NH2-(CH2-CH2-O)m-CH2CH2COOH, m varying from 3 to 6; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; 3(piperidin-4-yl)propionic acid; N-(4-aminobutyl)-glycine; 4-carboxymethyl-piperazine; 4-(4-aminophenyl)butanoic acid; ... | ||
Xc is chosen from the following amino acid residues: ... trans-4-aminocyclohexane acetic acid; 4-amino-1-carboxymethyl piperidine; 4-aminobenzoic acid; 4(2-aminoethoxy)benzoic acid; 8-amino-3,6-dioxaoctanoic acid; tranexamic acid; N-methyl-tranexamic acid; 4(piperidin-4-yl)butanoic acid; ... |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With pyridine; pivaloyl chloride; N-ethyl-N,N-diisopropylamine; trimethylsilylacetamide; In dichloromethane; N,N-dimethyl acetamide; at -5 - 20℃; | 8.9 g HOOCCH2OCH2C(O)-Phe-Glu(OtBu)-Phe-Lys(Boc)-Phe-Glu(OtBu)-Phe-Lys(Boc)-OEt (SEQ ID NO:101) (5.6 mmol), 1.15 ml diisopropylethylamine (5.68 mmol) and 0.47 ml pyridine (5.68 mmol) were dissolved in a mixture of 70 ml N,N-dimethylacetamide and 20 ml dichloromethane. The reaction mixture was cooled to -5C (solution n1). 1.02 g 8-amino-3,6-dioxaoctanoic acid (6.19 mmol) was dispersed in 2.30 ml dichloromethane containing 1.84 g trimethylsilylacetamide (12.4 mmol) (solution n2). Solution n2 was stirred at room temperature and then cooled to 10C. At -5C, 0.7 g pivaloyl chloride was added to solution n1. After about 5 min of further stirring, cooled solution n2 was added to solution n1. The reaction mixture was allowed to warm to room temperature. After controlling the completion of the reaction by HPLC, 2 ml water was added, the reaction mixture partially concentrated under vacuum and then poured into a solution of KHS04 (2.5 g) in 500 ml water. The resulting precipitate was filtered, washed with water (50 ml) twice and then dried under vacuum at 45C. After drying, 9.17 g (94 %) of an off-white product was obtained. The HPLC analysis of the product was carried out as follows : a sample was dissolved in 1 ml N,N-dimethylacetamide and analysed using method CH-GS-10 ; tR = 7.8 ± 0.5 min. Product purity : 89 % of surface area (HPLC). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61.1% | With sodium hydroxide; In water; at 20℃; for 3h; | Step la: Sodium hydroxide (12.2 g, 305 mmol) and Cbz-Cl (12.5 g, 73 mmol) were added to a solution of compound la (10.0 g, 61 mmol) in water (100 mL) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mass was partitioned between citric acid solution and ethyl acetate. Organic layer was washed with water, brine, dried over Na2504 and evaporated under reduced pressure to yield ii g of compound lb (Yield: 6 1.1%). LCMS: 298.0 (M+H). |
61.1% | With sodium hydroxide; In water; at 20℃; for 3h; | Sodium hydroxide (12.2 g, 305 mmol) and Cbz-Cl (12.5 g, 73 mmol) were added to asolution of compound la (10.0 g, 61 mmol) in water (100 mL) and stirred at room temperature for 3 h. The completeness of the reaction was confirmed by TLC analysis.The reaction mass was partitioned between citric acid solution and ethyl acetate. Organic layer was washed with water, brine, dried over Na2SO4 and evaporated under reduced pressure to yield 11 g of compound lb (Yield: 61.1%). LCMS: 298.0(M+H). |
80 g | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 8h; | Sodium Carbonate (78 g, 736 mmol) and Cbz-CI (68.6 g, 405 mmol) were added to a solution of starting material la (60.0 g, 368 mmol) in water (250 mL) and 1,4- dioxane (250 mL) and stirred at room temperature for 8 h. The completeness of the reaction was confirmed by TLC analysis. The reaction mixture was diluted with water and washed with dichloromethane and the aqueous layer was acidified to pH 2-3 and extracted with dichloromethane. The organic layer was washed with water, brine, dried over Na2S04 and evaporated under reduced pressure to yield 80 g of compound lb. LCMS: 298.0 (M+H)+. |
79 g | With sodium carbonate; In 1,4-dioxane; water; at 20℃; for 9h; | Compound 1a (60.0 g, 368 mmol) was mixed with water (250 mL) and 1,4-dioxane (250 mL) to obtain a first mixture.a solution of sodium carbonate (78 g, 736 mmol) and Cbz-Cl (68.6 g, 405 mmol) in the first mixture at room temperatureStir under 9 hours. The reaction was confirmed to be complete by TLC analysis. The reaction mixture was diluted with water and washed with dichloromethane.The layer was acidified to pH 2-3 and extracted with dichloromethane. The organic layer was washed with water, brine, dried over anhydrous Na?79 g of compound 1b. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
The interaction of cyclic and linear RGD peptide ligands withalpha v beta 3 integrin receptor were studied using MolecularOperating Environment software (Details in SupplementaryMaterial). The peptide amphiphiles were synthesized by followingstandard solid phase peptide synthesis procedure. Thecyclic RGD amphiphile (C18-ADA5-cRGDfK) was synthesizedentirely on solid support. Several protocols for synthesisof the cyclic RGD (cRGDfV or cRGDfK) peptide have beenreported and modified for improved yields. The cyclic RGDpeptide was built on solid phase using the protocol reported byMcCusker et al. with some modifications [20]. The O-allylprotected aspartic acid, Fmoc-Asp-OAll (2.5 equivalents)was loaded on the 2-chloro trityl chloride resin in the presenceof 10 equivalents of N,N-diisopropylethylamine (DIPEA) for5 h. After washing the resin with DMF (3 times) and DCM (3times), the amino group was deprotected by treatment with20% piperidine in DMF for 30 min and the wash steps wererepeated. The Fmoc-Gly-OH was added in the presence of 2equivalents of HOBT (hydroxybenzotriazole), 2 equivalentsof HATU (2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) and 4 equivalents of DIPEA.The subsequent amino acids in the order of Fmoc-Arg(Pbf)OH, Fmoc-Lys-Dde and Fmoc-Phe-OH were conjugatedusing the same deprotection and conjugation protocol.Each conjugation step was performed for 2 h. Allyldeprotection was performed using chloroform and Nmethylmorpholinein the presence of palladium catalyst in aN2 atmosphere for 4 hours followed by amino groupdeprotection using 20% piperidine in DMF. Cyclization wascarried out overnight in the presence of PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate),DIPEA and DMF. This step was repeated for an additional6 h. Further, the 1-(4,4-Dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde) group was specifically cleaved by using 2% hydrazinehydrate in DMF. For synthesis of the amphiphiles, the 8-amino-3,6 dioxaoctanoic acid (ADA) groups were conjugatedto the lysine side chain using the same protocol as for theamino acids. Finally, stearic acid was conjugated in the presenceof PyBOP (4 equivalents) and DIPEA (8 equivalents).The amphiphile was cleaved from the resin by treating withTFA:TIS: H2O (95:2.5:2.5) for 3 hrs. After removal of TFA,the amphiphile was precipitated using ether:hexane (50:50)mixture. The amphiphile was then separated by centrifugationand freeze dried before further analysis. The synthesis oflinear RGD amphiphile (C18-ADA5-RGD) was carried outusing the same protocol as previously reported [18] (SpecificDetails are provided in Supplementary Materials). All amphiphilessynthesized were characterized for molecular weightand purity using Matrix Assisted Laser Desorption/Ionization- Time of Flight (MALDI-TOF) and reversed phaseHPLC (RP-HPLC) respectively. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
(Assembly of Linear Peptide) 020c-020c-020c-020c- (SEQ ID NO: 62)Phenethylamine-AMEBA resin (Aldrich, 0.25 mmol) issubjected to solid phase peptide synthesis on the Liberty TM microwave peptide synthesizer. Coupling is performed as follows: Preparation of Intermediate lb(Cleavage from the Resin with Concomitant Protecting Group Removal then Purification)A solution made of 1.54 g of DTT and 0.75 mL of thioani-sole in 6 mL of TFATIPS/Water (95:2.5:2.5) is added to Intermediate la (0.25 mmol) and the suspension is shaken at it for 5 hr. The cleavage solution is filtered off and the resin is washed with 95% aq. TFA. The combined cleavage and wash-ing solutions are poured onto cold diethyl ether, giving a precipitate. The suspension is centrifuged andthe supernatant poured off. Diethyl ether is added to the residue, the suspension is vortexed for 3 mm, centrifuged, and the supematant is poured off. The washing process is repeated 3 times. The solidis dried in high vacuum. The crude is purified by preparative HPLC and lyophilized from ACN/H20 to afford Intermediatelb. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
51% | With N-ethyl-N,N-diisopropylamine; In methanol; at 0 - 20℃; | DIEA (850 muIota, 5.00 mmol) and solid 8-Amino-3,6-dioxaoctanoic acid (NH2-PEG2-OH) (392 mg, 2.40 mmol, 1 eq) were added slowly, over an hour, to a solution of NBD-CI (401 mg, 2.01 mmol) in methanol (20 mL) at 0C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the remaining material was purified by chromatography on silica with DCM/MeOH (8:2) as the eluent to give NBD-PEG2-OH (400 mg, 1.23 mmol, 51 %) as dark red oil. 1 H NMR (500 MHz, DMSO): delta 10.9 (s, 1 H; COOH), 8.49 (d, J = 8.5 Hz, 1 H; CH NBD), 7.1 (s, 1 H, NH), 6.23 (d, J = 8.5 Hz, 1 H; CH NBD), 4.25 (s, 2H), 3.93 (t, J = 5.3 Hz, 2H; CH2), 3.80 (s, 4H), 3.72 (t, J = 6.8 Hz, 2H; CH2) ppm; MS (ESI-): m/z calcd for Ci2Hi4N407 [M-H]: 325.1 ; found: 325.2. |
51% | With N-ethyl-N,N-diisopropylamine; at 0 - 20℃; | DIEA (850 p1, 5.00 mmol) and solid 8-Amino-3,6-dioxaoctanoic acid (NH2-PEG-OH) (392 mg, 2.40 mmol, 1 eq) were added slowly, over an hour, to a solution of NBD-Cl (401 mg, 2.01 mmol) in methanol (20 mL) at 000. The reaction mixture was stirred overnight at roomtemperature. The solvent was evaporated and the remaining material was purified by chromatography on silica with DCM/MeOH (8:2) as the eluent to give NBD-PEG2-OH (400 mg, 1.23 mmol, 51%) as dark red oil. 1H NMR (500 MHz, DMSO): O 10.9 (5, 1H; 000H), 8.49 (d, J= 8.5 Hz, 1H; OH NBD), 7.1 (5, 1H, NH), 6.23 (d, J= 8.5 Hz, 1H; OH NBD), 4.25 (5, 2H), 3.93 (t, J = 5.3 Hz, 2H; OH2), 3.80 (5, 4H), 3.72 (t, J = 6.8 Hz, 2H; OH2) ppm; MS (ESI-): m/zcalcd for O12H14N407 [M-H]: 325.1; found: 325.2. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With MP-CNBH3; In methanol; | [000521] To an ambient solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (22 mg) and Example 1.1.15 (100 mg) in methanol (1.3 mL) was added MP-CNBH3 (65 mg, 2.49 mmol/g loading). The reaction was gently shaken overnight and filtered through a 0.4 micron filter. The crude material was purified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 948.3 (M+H)+. | |
With methanol; at 20℃; | To an ambient solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (22 mg) and Example 1.1.15 (100 mg) in methanol (1.3 mL) was added MP-CNBH3 (65 mg, 2.49 mmol/g loading). The reaction was gently shaken overnight and filtered through a 0.4 micron filter. The crude material was purified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 948.3 (M+H)+. | |
With MP-CNBH3; In methanol; | To an ambient solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (22 mg) and Example1.1.15 (100 mg) in methanol (1.3 mL) was added MP-CNBH3 (65 mg, 2.49 mmol/g loading). Thereaction was gently shaken overnight and filtered through a 0.4 micron filter. The crude material waspurified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in water10 containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried toprovide the title compound. MS (ESI) m/e 948.3 (M+Ht. |
With methanol; | To an ambient solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (22 mg) and Example 1.1.15 (100 mg) in methanol (1.3 mL) was added MP-CNBH3 (65 mg, 2.49 mmol/g loading). The reaction was gently shaken overnight and filtered through a 0.4 micron filter. The crude material was purified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e 948.3 (M+H)+. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With triethylamine; In dimethyl sulfoxide; at 20℃; | Step 2. In a 40 ml vial was added (S)-5-(tert-butoxy)-4-(18-(tert-butoxy)-18-oxooctadecanamido)-5-oxopentanoic acid (305 mg, 0.55 mmol) and DMSO (1.5 ml). TSTU (182 mg, 0.60 mmol) and triethylamine (0.15 ml, 1.1 mmol) was added. The mixture was stirred at RT for 2 h. The resulted NHS ester product was added to a solution of 2-(2-(2-aminoe thoxy)ethoxy)acetic acid (90 mg, 0.55 mmol) and triethylamine (0.76 ml, 5.5 mmol) in DMSO (1 ml). The reaction was stirred at RT overnight, then diluted with water (50 mL), acidified with 1N HCl (15 ml), extracted with EtOAc (50 mL x 3), washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase C18 column (MeCN/water with 0.05% TFA as modifier, 0-100%). The appropriate fractions were combined and lyophilized to give (S)-13-(tert-butoxycarbonyl)-34,34-dimethyl-10,15, 32-trioxo-3,6,33-trioxa-9,14-diazapentatriacontanoic acid (195 mg, 51%) as a white solid. m/z 701.9[M+1]. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: PPS1-4P2H1 was synthesized on NovaSyn TGR resin utilizingstandard Fmoc-peptide synthesis protocol and microwave-assistedpeptoid synthesis [38,39], as described in Scheme 1. The peptideportion with methionine and lysines was completed prior to peptoidsynthesis. Internal linker(s) were developed using orthogonallyprotected Lysine (ivDde-Lys(Fmoc)-OH). Peptoid residueswere coupled by using microwave assisted two step peptoidcoupling procedure. First reacting with bromoacetic acid and N,Ndiisopropylcarbodiimide(DIC), followed by respective amine substitution to couple a peptoid residue. Briefly the steps from thebeginning, 200mg of beads were loaded in 5mL reaction vessel andswelled in DMF for 30 min. Fmoc-Met-OH (92.9 mg, 5.0 eq), HOBt(5.0 eq), HBTU (5.0 eq) and DiPEA (10.0 eq) in 2 mL of anhydrousDMF was added to the beads and the reaction vessel was shakenovernight (Scheme 1, A). The solution was drained and beads wererinsed with DMF (10 x 2 mL). Fmoc was deprotected by treatingbeads with 20% piperidine/DMF twice, each for 10 min. Afterrinsing the beads, subsequent amino acids Fmoc-D-Lys-(Boc)-OH,Fmoc-Lys-(Boc)-OH, ivDde-Lys(Fmoc)-OH, ivDde-Lys-(Fmoc)-OH,Fmoc-Lys-(Boc)-OH, Fmoc-D-Lys-(Fmoc)-OH and Boc-Gly-OH werecoupled under similar reaction conditions, however duration of thereaction was 2.0 h (Scheme 1, B-H). Next, two ivDde protectinggroups were removed by treating beads with 5% Hydrazine/DMFsolution three times, each for 10 min (Scheme 1, I). At this point,two hydrophobic regions with four peptoid units in each weresynthesized using the two step microwave assisted peptoid synthesisprotocol as follows. First, 1 mL of Bromoacetic acid (2.0 M inanhydrous DMF) and N,N-diisopropylcarbodiimide (3.2 M inanhydrous DMF) were added to beads, gently shaken for 30 s andplaced in the microwave oven for 15 s with power set at 10%. Thebeads were again shaken for 30 s and placed in the microwave ovenfor another 15 s. Solution was drained and the beads were washedwith DMF (10 x 2 mL). Next, the beads were treated with 2.0 Msolution of the first primary amine, 4-Methoxybenzylamine (Npmba)dissolved in anhydrous DMF (2 mL) and subjected to thesame microwave procedure described above. The next three peptoidresidues of the hydrophobic region was completed byrepeating these two peptoid coupling steps using primary amines,(R)-(alpha)-Methylbenzylamine (Nmba), Piperonylamine (Npip) and(R)-(alpha)-Methylbenzylamine (Nmba). The synthesized compoundwas finally cleaved off from beads with the concomitant removal ofprotecting groups by treating the beads with 2 mL solution of 95%TFA, 2.5% water, and 2.5% Triisopropylsilane (TIS) for 2.0 h. Thecompound was purified using HPLC. Synthesis was confirmed byMALDI-TOF analysis and purity was confirmed by analytical HPLC. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
130mg | With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 20℃; for 16h;Inert atmosphere; | [00295] To a solution of N-alpha-Fmoc-L-glutamic acid alpha-benzyl ester (250 mg, 0.544 mmol) in THF (Volume: 9 mL, Ratio: 9) was added N-hydroxy succinimide (75 mg, 0.653 mmol), EDC (0.144 mL, 0.816 mmol) and DMAP (6.65 mg, 0.054 mmol). The reaction was stirred at r.t. under N2 for 3 hours. LCMS analysis showed presence of starting material (1251) (Method C, SM Rt = 1.23 min, M+H 460.2; prod Rt = 1.30 min, M+H 557.2) and so a 0.25eq of N-hydroxysuccinimide was added and the reaction stirred at r.t. under N2 for 16 hours. LCMS analysis showed full conversion to NHS ester product (Method C, Rt = 1.30 min, M+H 557.2). <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (98 mg, 0.598 mmol) was dissolved in water (Volume: 1.000 mL, Ratio: 1.000) and added to the reaction mixture followed by DIPEA (0.442 mL, 2.72 mmol). The reaction mixture was stirred at r.t. under N2 for 16 hours. LCMS analysis showed formation of desired product with some hydrolyzed glutamic acid (Method C, Rt = 1.15 min, M+H 605.3). The reaction mixture (189 mg) was taken up in 5% MeOH/EtOAc and transferred to a separatory funnel, then washed 3x with 50 mL portions of 0.1N HC1. The combined aqueous layers were extracted once with 50 mL 5% MeOH/EtOAc and organic layers combined, dried over Na2S04, filtered and concentrated to a colorless film (130mg, 69%). LCMS analysis showed majority product in material (Method D, Rt = 2.43 min, M+H 605.3). Material was carried on to next step without further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In tetrahydrofuran; water; at 20℃; for 16h;Inert atmosphere; | [00301] 5 is dissolved in THF (0.02 molar) under N2 and N-hydroxysuccinimide (1.2 eq.), EDC (1.5 eq.) and DMAP (0.1 eq.) are added. The reaction is stirred under N2 at r.t. for 16 hours to give the NHS-ester intermediate. A solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1.1 eq.) in water (9: 1 THF/H20) and DIPEA (5 eq.) is added to the NHS-ester internediate. The reaction is stirred at r.t. under N2 for 16 hours. The solvent is removed and crude material taken up in a minimal amount of ACN and then loaded onto a 20g C18 15uM column for reverse phase chromatography. The crude material is purified over 0-100% ACN/H20 (0.1%TFA) 24min gradient. Fractions with desired product are pooled, concentrated, frozen and lyophilized |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2 atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1.15 equiv.). After stirring for 15 minutes, Et3N was added dropwise (1.42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1.0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2chi100 mL), the organic layers were combined and dried (Na2S04), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2Cl2 to 20% MeOH in CH2CI2. Yield 0.42 g (1.0 mmole, 39%) of 126 as a colourless sticky wax. | |
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1 .15 equiv.). After stirring for 15 minutes, Et3N was added dropwise (1.42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (1.0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2 100 mL), the organic layers were combined and dried (Na2S04), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2CI2to 20% MeOH in CH2CI2Yield 0.42 g (1.0 mmole, 39%) of 3 as a colorless sticky wax. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | EXAMPLE 4 (0723) Synthesis of Linker 2-(2-(2-(Pent-4-ynamido)ethoxy)ethoxy)acetic acid (0724) (Propargyl-C5-PEG2-acid) may be as follows. (0725) To a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1.0 g, 6.13 mmol) and 2,5-dioxopyrrolidin-1-yl pent-4-ynoate (1.2 g, 6.13 mmol) in dimethylformamide (DMF) (10 mL) is added N,N-diisopropylethylamine (DIPEA) (1.28 ml, 7.35 mmol) at RT. The mixture is stirred at RT overnight. The reaction is quenched with water and lyophilized to dryness. The residue is purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 2-(2-(2-(pent-4-ynamido)ethoxy)ethoxy)acetic acid. MS: 266 (M+23). | |
With N-ethyl-N,N-diisopropylamine; In N,N-dimethyl-formamide; at 20℃; | Synthesis of Linker 2-(2-(2-(Pent-4-ynamido)ethoxy)ethoxy)acetic acid (1212) (Propargyl-C5-PEG2-acid) may be as follows. (1213) To a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1.0 g, 6.13 mmol) and (1214) 2,5-dioxopyrrolidin-l-yl pent-4-ynoate (1.2 g, 6.13 mmol) in dimethylformamide (DMF) (10 mL) is added Nu,Nu-diisopropylethylamine (DIPEA) (1.28 ml, 7.35 mmol) at RT. The mixture is stirred at RT overnight. The reaction is quenched with water and lyophilized to dryness. The residue is purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 2-(2-(2-(pent-4-ynamido)ethoxy)ethoxy)acetic acid. MS: 266 (M+23). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 1: In a 20 mL vial is added 2-(2-(2-(pent-4- ynamido)ethoxy)ethoxy)acetic acid (500 mg, 2.055 mmol) and DMSO (2 mL). TSTU (dimethylamino-(2,5-dioxopyrrolidin-1-yl)oxymethylidene]- dimethylazanium;tetrafluoroborate; 681 mg, 2.261 mmol) and triethylamine (573 mul, 4.11 mmol) are added. The mixture is stirred at RT for two hours. The freshly prepared N- Hydroxysuccinimide (NHS) ester is then added to a solution of 2-(2- aminoethoxy)ethoxy)acetic acid (419 mg, 2.57 mmol) and triethylamine (2.86 ml, 20.55 mmol) in DMSO (1 mL). The reaction is stirred at RT for 48 hours and triethylamine is removed under reduced pressure. Two drops of trifluoroacetate (TFA) are added to neutralize the reaction. The mixture is filtered through a syringe filter. The residue is purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 10,19- dioxo-3,6,12,15-tetraoxa-9,18-diazatricos-22-ynoic acid. | ||
With triethylamine; In dimethyl sulfoxide; at 20℃; for 48h; | Step 1 : In a 20 mL vial is added 2-(2-(2-(pent-4-ynamido)ethoxy)ethoxy)acetic acid (500 mg, 2.055 mmol) and DMSO (2 mL). TSTU (dimethylamino-(2,5-dioxopyrrolidin-l- yl)oxymethylidene]-dimethylazanium;tetrafluoroborate; 681 mg, 2.261 mmol) and triethylamine (573 mu, 4.11 mmol) are added. The mixture is stirred at RT for two hours. The freshly prepared N-Hydroxysuccinimide (NHS) ester is then added to a solution of 2-(2- aminoethoxy)ethoxy)acetic acid (419 mg, 2.57 mmol) and triethylamine (2.86 ml, 20.55 mmol) in DMSO (1 mL). The reaction is stirred at RT for 48 hours and triethylamine is removed under reduced pressure. Two drops of trifluoroacetate (TF A) are added to neutralize the reaction. The mixture is filtered through a syringe filter. The residue is purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 10,19-dioxo-3,6,12, 15-tetraoxa-9,18- diazatricos-22-ynoic acid. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Step 2: In a 20 ml vial is added 10,19-dioxo-3,6,12,15-tetraoxa-9,18- diazatricos-22-ynoic acid (132 mg, 0.340 mmol) and DMSO (1 mL). TSTU (113 mg, 0.374 mmol) and triethylamine (95 mul, 0.680 mmol) are added. The mixture is stirred at RT for two hours. The freshly prepared NHS ester is then added to a solution of 2-(2-(2- aminoethoxy)ethoxy)acetic acid (111 mg, 0.680 mmol) and triethylamine (474 mul, 3.40 mmol) in DMSO (1 mL). The reaction is quenched with TFA aqueous solution to slightly acidic. Water is added and the mixture is lyophilized to dryness. The residue purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 10,19,28-trioxo- 3,6,12,15,21,24-hexaoxa-9,18,27-triazadotriacont-31-ynoic acid. MS: 534 (M+1). | ||
With triethylamine; In dimethyl sulfoxide; | Step 2: In a 20 ml vial is added 10, 19-dioxo-3,6, 12,15-tetraoxa-9, 18-diazatricos- 22-ynoic acid (132 mg, 0.340 mmol) and DMSO (1 mL). TSTU (113 mg, 0.374 mmol) and triethylamine (95 mu, 0.680 mmol) are added. The mixture is stirred at RT for two hours. The freshly prepared NHS ester is then added to a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (111 mg, 0.680 mmol) and triethylamine (474 mu, 3.40 mmol) in DMSO (1 mL). The reaction is quenched with TFA aqueous solution to slightly acidic. Water is added and the mixture is lyophilized to dryness. The residue purified by mass-directed RP-HPLC (ACN/water with 0.1% TFA as modifier) to give 10,19,28-trioxo-3,6,12, 15,21,24-hexaoxa-9,18,27-triazadotriacont-31- ynoic acid. MS: 534 (M+l). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
39% | A solution of BCN alcohol (0.384 g, 2.55 mmole) in MeCN (25 mL) under a N2 atmosphere was cooled to 0 C, and chlorosulfonyl isocyanate was added (CSI) was added dropwise (0.255 mL, 415 mg, 2.93 mmole, 1.15 equiv.). After stirring for 15 minutes, EtsN was added dropwise (1 .42 mL, 1.03 g, 10.2 mmole, 4 equiv.) and stirring was continued for another 10 minutes. Next, a solution of <strong>[134978-97-5]2-<strong>[134978-97-5](2-(2-aminoethoxy)ethoxy)acetic acid</strong></strong> (1 .0 g, 6.1 mmole, 2.4 equiv.) in H2O (5 mL) was added and the reaction mixture was stirred to room temperature for 2 h. After this time, CHCI3 (50 mL) and H2O (100 mL) were added, and the layers were separated. To the aqueous layer in a separatory funnel was added CH2CI2 (100 mL) and the pH was adjusted to 4 with 1 N HCI, before separation of layers. The water layer was extracted twice with CH2CI2 (2 chi 100 mL), the organic layers were combined and dried (Na2SC>4), filtered and concentrated. The residue was purified by flask column chromatography on silica, elution with CH2CI2 to 20% MeOH in CH2CI2. Yield 0.42 g (1 .0 mmole, 39%) of 3 as a colorless sticky wax. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | With sodium hydrogencarbonate; In tetrahydrofuran; water; for 4h; | H-AEEA-OH (1.96 g, 12 mmol) and NaHCO3 (1.68 g, 20 mmol) were dissolved in 100 ml deionized water, a solution of Boc-Glu(OBt)-OtBu (4.39 g, 10 mmol) dissolved in THF (20 ml) was added while stirring, and after the addition was completed, reaction was continued for 4 h. TLC showed that the reaction of the raw materials had almost completed. Then vacuum concentration was performed to remove the organic solvent, the aqueous phase was washed with EA (20 ml*3), the pH of the aqueous phase was adjusted to 3 with 1N HCl, and extraction was performed with EA (20 ml*2). After that, the organic phases were combined, washing was performed with saturated salt water (20 ml*3), and drying was performed with anhydrous sodium sulfate, and the residue was crystallized with EtOH to obtain 3.41 g of Boc-Glu(AEEA)-OtBu with yield: 87%, purity: 97.8%, MS: 393.4 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
86% | With sodium hydrogencarbonate; In tetrahydrofuran; water; for 4h; | H-AEEA-OH (9.8 g, 60 mmol) and NaHCO3 (8.4 g, 100 mmol) were dissolved in 100 ml deionized water, a solution of Boc-AEEA-OSu (18.0 g, 50 mmol) dissolved in THF (100 ml) was added while stirring, and after the dropwise addition was completed, the reaction was continued for 4 h. TLC showed that the reaction of Boc-AEEA-OSu had almost completed. Vacuum concentration was performed to remove the organic solvent, the aqueous phase was washed with EA (100 ml*3), the pH of the aqueous phase was adjusted to 3 with 1N HCl, and extraction was performed with EA (100 ml*2). After that, the organic phases were combined, washing was performed with saturated salt water (100 ml*3), drying was performed with anhydrous sodium sulfate, and vacuum concentration was performed to obtain 17.6 g of Boc-AEEA-AEEA-OH with yield: 86%, purity: 95.8%, MS: 409.4 (M+1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
203 g | With hydrogenchloride; In ethanol; water;pH 9.0; | In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product was dissolved in 1000 ml of ethanol, and 400 g of 30% NaOH solution was added dropwise.After the addition is completed, the mixture is heated to reflux, and the TLC is monitored. The etherification intermediate disappears completely and the temperature is lowered.The pH was adjusted to 9 with hydrochloric acid, and 259 g of Fmoc-Cl was added dropwise to dissolve in 1000 ml of ethanol solution.If the pH has dropped, add sodium bicarbonate and keep it at around 8.TLC was monitored until the free amino intermediate disappeared. Adjust the pH to 1-2 with hydrochloric acid,Distill the ethanol, add 1000 ml of water, and extract three times with ethyl acetate 500*3.Wash twice with saturated brine and concentrate ethyl acetate to give 288 g of crude material.Recrystallization from 1000 ml of ethyl acetate gave 203 g of product[2-[1-(Fmoc-Amino)ethoxy]ethoxy]acetic acid, yield 52.68%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol;Reflux; | In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product (Intermediate 3) was dissolved in 1000 ml of ethanol, and 350 g of 30% NaOH solution was added dropwise.After the completion of the dropwise addition, the mixture was heated to reflux, and monitored by TLC, the intermediate 3 was completely disappeared, and the temperature was lowered. The pH was adjusted to 9 with hydrochloric acid, and a solution of 337 g of Fmoc-Osu in 1000 ml of ethanol was added dropwise.If the pH has dropped, add sodium bicarbonate and keep it at around 8.TLC was monitored until Intermediate 4 disappeared. The pH was adjusted to 1-2 with hydrochloric acid, the ethanol was distilled off, 1000 ml of water was added, and the mixture was extracted three times with ethyl acetate 500*3, and washed twice with saturated brine.The ethyl acetate was concentrated to give 285 g of crude material.Recrystallization from 1000 ml of ethyl acetate gave 200 g of product[2-[1-(Fmoc-Amino)ethoxy]ethoxy]acetic acid, yield 51.9%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With sodium hydroxide; In ethanol;Reflux; | In a 3000L three-necked flask equipped with mechanical stirring, condenser and constant pressure dropping funnel,330 g of crude product was dissolved in 1000 ml of ethanol, and 350 g of 30% NaOH solution was added dropwise.After the completion of the dropwise addition, the mixture was heated to reflux, and monitored by TLC until the etherification intermediate completely disappeared and the temperature was lowered.The pH was adjusted to 9 with hydrochloric acid, and a solution of 337 g of Fmoc-Osu in 1000 ml of ethanol was added dropwise, and if the pH was decreased,Add sodium bicarbonate and keep at around 8.TLC was monitored until the free amino intermediate disappeared. Adjust the pH to 1-2 with hydrochloric acid,The ethanol was distilled off, 1000 ml of water was added, and the mixture was extracted three times with ethyl acetate 500*3, and washed twice with saturated brine.Concentrate ethyl acetate to give 280 g of crude product.Recrystallization from 1000 ml of ethyl acetate gave 198 g of the product [2-[1-(Fmoc-amino)ethoxy]ethoxy]acetic acid in a yield of 51.38%. |
[ 134979-01-4 ]
2-(2-(2-Aminoethoxy)ethoxy)acetic acid hydrochloride
Similarity: 0.95
[ 52605-49-9 ]
Ethyl 2-(methylamino)acetate hydrochloride
Similarity: 0.55
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P402 | Store in a dry place. |
P403 | Store in a well-ventilated place. |
P404 | Store in a closed container. |
P405 | Store locked up. |
P406 | Store in corrosive resistant/ container with a resistant inner liner. |
P407 | Maintain air gap between stacks/pallets. |
P410 | Protect from sunlight. |
P411 | |
P412 | Do not expose to temperatures exceeding 50 oC/ 122 oF. |
P413 | |
P420 | Store away from other materials. |
P422 | |
P402 + P404 | Store in a dry place. Store in a closed container. |
P403 + P233 | Store in a well-ventilated place. Keep container tightly closed. |
P403 + P235 | Store in a well-ventilated place. Keep cool. |
P410 + P403 | Protect from sunlight. Store in a well-ventilated place. |
P410 + P412 | Protect from sunlight. Do not expose to temperatures exceeding 50 oC/122oF. |
P411 + P235 | Keep cool. |
Disposal | |
Code | Phrase |
P501 | Dispose of contents/container to ... |
P502 | Refer to manufacturer/supplier for information on recovery/recycling |
Physical hazards | |
Code | Phrase |
H200 | Unstable explosive |
H201 | Explosive; mass explosion hazard |
H202 | Explosive; severe projection hazard |
H203 | Explosive; fire, blast or projection hazard |
H204 | Fire or projection hazard |
H205 | May mass explode in fire |
H220 | Extremely flammable gas |
H221 | Flammable gas |
H222 | Extremely flammable aerosol |
H223 | Flammable aerosol |
H224 | Extremely flammable liquid and vapour |
H225 | Highly flammable liquid and vapour |
H226 | Flammable liquid and vapour |
H227 | Combustible liquid |
H228 | Flammable solid |
H229 | Pressurized container: may burst if heated |
H230 | May react explosively even in the absence of air |
H231 | May react explosively even in the absence of air at elevated pressure and/or temperature |
H240 | Heating may cause an explosion |
H241 | Heating may cause a fire or explosion |
H242 | Heating may cause a fire |
H250 | Catches fire spontaneously if exposed to air |
H251 | Self-heating; may catch fire |
H252 | Self-heating in large quantities; may catch fire |
H260 | In contact with water releases flammable gases which may ignite spontaneously |
H261 | In contact with water releases flammable gas |
H270 | May cause or intensify fire; oxidizer |
H271 | May cause fire or explosion; strong oxidizer |
H272 | May intensify fire; oxidizer |
H280 | Contains gas under pressure; may explode if heated |
H281 | Contains refrigerated gas; may cause cryogenic burns or injury |
H290 | May be corrosive to metals |
Health hazards | |
Code | Phrase |
H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
Sorry,this product has been discontinued.
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