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Structure of 6-Azido-hexanoic acid
CAS No.: 79598-53-1
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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. : | 79598-53-1 |
Formula : | C6H11N3O2 |
M.W : | 157.17 |
SMILES Code : | O=C(O)CCCCCN=[N+]=[N-] |
MDL No. : | MFCD12406156 |
InChI Key : | JCORXJUUSVCJEP-UHFFFAOYSA-N |
Pubchem ID : | 11040949 |
GHS Pictogram: |
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Signal Word: | Danger |
Hazard Statements: | H228 |
Precautionary Statements: | P210-P240-P241-P280-P370+P378 |
Class: | 4.1 |
UN#: | 1325 |
Packing Group: | Ⅱ |
* 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 |
---|---|---|
General procedure: 4.1.1. Peptide synthesis; 4.1.2; Solid-phase peptide synthesis (SPPS) was performed with standardFmoc chemistry on rink amide resin using an automated peptidesynthesizer (Syro I, Multisyntech). The resin was loaded into a5 mL reactor with a frit at the bottom. Swelling was performed bydispensing 1 mL DMF and incubating for 15 min (2) with 10 sshaking every minute. Fmoc deprotection was achieved by treatmentwith 40percent piperidine DMF for 3 min and 20percent piperidine inDMF for 12 min (10 s/min shaking). Peptide couplings were carriedout by double couplings with Fmoc-protected amino acids(5 equiv), HBTU (5 equiv), HOBt (5 equiv) and DIPEA (10 equiv) inDMF for 40 min (10 s/min shaking). At the respective position,Fmoc-F2Pmp-OH (3 equiv) was coupled in DMF (1 mL) by manualaddition using TBTU (3 equiv), HOBt (3 equiv) and DIPEA (6 equiv)for 3 h, after 3 min preactivation. In case of the sequences for which side-chain labeling with biotinor carboxyfluorescein was planned, an additional 4-methyltrityl-(Mtt-) protected lysine was coupled to the N-terminus. Toselectively remove the Mtt group the resin was washed for 1 minwith DCM (3), deprotection was then achieved by treatment with1.8percent TFA in DCM for 3 min (10). During the deprotection the DCMsolution turned yellow.For fluorescein-labeling of the amine side-chain 5(6)-carboxyfluorescein(3 equiv), HATU (3 equiv), HOAt (3 equiv) andDIPEA (6 equiv) were dissolved in DMF and pre-activated for3 min. The solution was aspirated and coupling was allowed toproceed for 1 h. This step was repeated 4 times.For biotin-labeling of the amine side-chain the resin waswashed for 1 min in NMP (3). D-(+)-Biotin (3 equiv), HATU(3 equiv), HOAt (3 equiv) and DIPEA (6 equiv) were dissolved inNMP and pre-activated for 3 min. The solution was aspirated andcoupling was allowed to proceed for 2 h. This step was repeated2 times. N-terminal acetylation (where applicable) was achieved by dispensing800 lL of a mixture of acetic anhydride/pyridine (1:9) andreaction twice for 5 min (10 s/min shaking). After each deprotection,coupling or acetylation step, 5 washings (1 min each) withDMF were performed (10 s/min shaking).After synthesis the resin was transferred in a 5 mL syringeequipped with a frit, washed with DCM for 1 min (3) and driedin high vacuum for at least 30 min. For cleavage 1 mL of a mixtureof TFA and TIS (20:1) was added. The syringe with the mixture waskept on a shaker for 3 h. Then the liquid phase was filtered into20 mL of ice-cold Et2O. Formed precipitate was centrifuged,washed with ice-cold Et2O (2 20 mL) and purified by HPLC. 4.1.2. Azide functionalization of the N-terminus; To the peptides with the longer carbon linker, 6-azidohexanoicacid was coupled (with standard coupling conditions) to the Nterminalamine.The N-terminal amine of the peptides with the shorter linkerwas converted to an azide functionality directly on solid support.Using the compound imidazole-1-sulfonyl-azide*HCl (synthesissee beneath) and modified conditions, which were reported forsolution phase chemistry from Goddard?Borger and Stick:8 Theresin was washed for 1 min each with DCM (2), DCM/MeOH(2) and MeOH (3). Then (for 40 mg resin, loading= 0.62 mmole/g) 1.4 equiv of imidazole-1-sulfonyl-azide*HClin 1 mL MeOH and 100 ll of a saturated and centrifuged solutionof CuSO4*5H2O was added. After 1 min, DIPEA (1.8 equiv) wasadded and the coupling was allowed to proceed for 1 h andrepeated once more with an intermediate washing with MeOH(3 1 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: 4.1.1. Peptide synthesis; 4.1.2; Solid-phase peptide synthesis (SPPS) was performed with standardFmoc chemistry on rink amide resin using an automated peptidesynthesizer (Syro I, Multisyntech). The resin was loaded into a5 mL reactor with a frit at the bottom. Swelling was performed bydispensing 1 mL DMF and incubating for 15 min (2) with 10 sshaking every minute. Fmoc deprotection was achieved by treatmentwith 40percent piperidine DMF for 3 min and 20percent piperidine inDMF for 12 min (10 s/min shaking). Peptide couplings were carriedout by double couplings with Fmoc-protected amino acids(5 equiv), HBTU (5 equiv), HOBt (5 equiv) and DIPEA (10 equiv) inDMF for 40 min (10 s/min shaking). At the respective position,Fmoc-F2Pmp-OH (3 equiv) was coupled in DMF (1 mL) by manualaddition using TBTU (3 equiv), HOBt (3 equiv) and DIPEA (6 equiv)for 3 h, after 3 min preactivation. In case of the sequences for which side-chain labeling with biotinor carboxyfluorescein was planned, an additional 4-methyltrityl-(Mtt-) protected lysine was coupled to the N-terminus. Toselectively remove the Mtt group the resin was washed for 1 minwith DCM (3), deprotection was then achieved by treatment with1.8percent TFA in DCM for 3 min (10). During the deprotection the DCMsolution turned yellow.For fluorescein-labeling of the amine side-chain 5(6)-carboxyfluorescein(3 equiv), HATU (3 equiv), HOAt (3 equiv) andDIPEA (6 equiv) were dissolved in DMF and pre-activated for3 min. The solution was aspirated and coupling was allowed toproceed for 1 h. This step was repeated 4 times.For biotin-labeling of the amine side-chain the resin waswashed for 1 min in NMP (3). D-(+)-Biotin (3 equiv), HATU(3 equiv), HOAt (3 equiv) and DIPEA (6 equiv) were dissolved inNMP and pre-activated for 3 min. The solution was aspirated andcoupling was allowed to proceed for 2 h. This step was repeated2 times. N-terminal acetylation (where applicable) was achieved by dispensing800 lL of a mixture of acetic anhydride/pyridine (1:9) andreaction twice for 5 min (10 s/min shaking). After each deprotection,coupling or acetylation step, 5 washings (1 min each) withDMF were performed (10 s/min shaking).After synthesis the resin was transferred in a 5 mL syringeequipped with a frit, washed with DCM for 1 min (3) and driedin high vacuum for at least 30 min. For cleavage 1 mL of a mixtureof TFA and TIS (20:1) was added. The syringe with the mixture waskept on a shaker for 3 h. Then the liquid phase was filtered into20 mL of ice-cold Et2O. Formed precipitate was centrifuged,washed with ice-cold Et2O (2 20 mL) and purified by HPLC. 4.1.2. Azide functionalization of the N-terminus; To the peptides with the longer carbon linker, 6-azidohexanoicacid was coupled (with standard coupling conditions) to the Nterminalamine.The N-terminal amine of the peptides with the shorter linkerwas converted to an azide functionality directly on solid support.Using the compound imidazole-1-sulfonyl-azide*HCl (synthesissee beneath) and modified conditions, which were reported forsolution phase chemistry from Goddard?Borger and Stick:8 Theresin was washed for 1 min each with DCM (2), DCM/MeOH(2) and MeOH (3). Then (for 40 mg resin, loading= 0.62 mmole/g) 1.4 equiv of imidazole-1-sulfonyl-azide*HClin 1 mL MeOH and 100 ll of a saturated and centrifuged solutionof CuSO4*5H2O was added. After 1 min, DIPEA (1.8 equiv) wasadded and the coupling was allowed to proceed for 1 h andrepeated once more with an intermediate washing with MeOH(3 1 min). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
81% | With sodium azide; In water; N,N-dimethyl-formamide; | Example 1 Synthesis of 4-Azidobutyl Acetate (4.22) To a 500 mL flask was added 5.0 g (33 mmol, 1.0 eq) of 4-chlorobutylacetate and dissolved in 100 mL of DMF. Next 2.6 g (40 mmol, 1.2 eq) of sodium azide was added by a glass pipette. A water condenser was placed onto the flask and the reaction heated to 80° C. for 16 hr with stirring. The reaction was then cooled to room temperature and quenched with 300 mL of water to dissolve the sodium salts. The aqueous solution was extracted with diethyl ether 3*100 mL. The organic layers were combined and dried with MgSO4. The solution was filtered and concentrated under vacuum with no external heat, resulting in 4-azido-1-butylacetate (4.22), which was carried onto the next step without further purification; 1H NMR (CDCl3, 300 MHz): delta: 4.04 (t, J=6.0 Hz, 2H), 3.27 (t, J=6.2 Hz, 2H), 2.00 (s, 3H), 1.76-1.52 (m, 4H). 13C NMR (75 MHz, CDCl3) delta: 170.82, 63.55, 50.84, 25.73, 25.39, 20.73. 81percent yield, clear oil. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
91% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine; In dichloromethane; at 0 - 20℃; | To a solution of <strong>[121148-00-3](2S,4R)-1-tert-butyl 2-methyl 4-aminopyrrolidine-1,2-dicarboxylate</strong>6[1] (1.22 g, 5.0 mmol), whichwas prepared from (2S,4R)-1-tert-butyl2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate 3,[2] and 6-azidohexanoic acid (0.86 g, 5.5 mmol, 1.1equiv.) in CH2Cl2 (15 mL) were added EDC?HCl (1.05 g, 5.5mmol, 1.1 equiv.) and HOBt?H2O (0.84 g, 5.5 mmol, 1.1 equiv.) at 0°C, followed by the slow addition of Et3N (0.77 mL, 5.5 mmol, 1.1equiv.). After 1 h at 0 °C, the reaction mixture was stirred overnight at roomtemperature. The reaction mixture was then concentrated on a rotary evaporatorand the residue was diluted with water. The aqueous layer was extracted withAcOEt (three times) and the combined organic layer was successively washed with5percent NaHCO3 aq. (three times), 5percent citric acid aq. (three times), andbrine, and dried over anhydrous MgSO4. The solvents were evaporatedunder reduced pressure, and purification by silica gel chromatography(hexane/AcOEt = 1/3 to 0/100) to give 7(1.47 g, 91percent) |