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CAS No. : | 174148-03-9 | MDL No. : | MFCD00673782 |
Formula : | C25H28N2O6 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | UPXRTVAIJMUAQR-BTYIYWSLSA-N |
M.W : | 452.50 | Pubchem ID : | 2756134 |
Synonyms : |
|
Num. heavy atoms : | 33 |
Num. arom. heavy atoms : | 12 |
Fraction Csp3 : | 0.4 |
Num. rotatable bonds : | 9 |
Num. H-bond acceptors : | 6.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 125.23 |
TPSA : | 105.17 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | No |
CYP3A4 inhibitor : | Yes |
Log Kp (skin permeation) : | -6.38 cm/s |
Log Po/w (iLOGP) : | 2.48 |
Log Po/w (XLOGP3) : | 3.77 |
Log Po/w (WLOGP) : | 3.61 |
Log Po/w (MLOGP) : | 2.6 |
Log Po/w (SILICOS-IT) : | 2.36 |
Consensus Log Po/w : | 2.96 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -4.7 |
Solubility : | 0.00912 mg/ml ; 0.0000202 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.67 |
Solubility : | 0.000963 mg/ml ; 0.00000213 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -5.23 |
Solubility : | 0.00265 mg/ml ; 0.00000586 mol/l |
Class : | Moderately soluble |
PAINS : | 0.0 alert |
Brenk : | 1.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 4.54 |
Signal Word: | Warning | Class: | N/A |
Precautionary Statements: | P261-P305+P351+P338 | UN#: | N/A |
Hazard Statements: | 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 |
---|---|---|
With benzotriazol-1-ol; O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); at 20℃; | A 250 mL round-bottom flask is charged with compound 23 (3.0 g, 6.43 [MMOL)] (see Example 1), phenethylamine (0.86 g, 7 [MMOL),] and [DIEA] (30 mL). To this mixture, a 0.45 mM solution of HBTU/HOBt in DMF (15.5 mL, 7 [MMOL)] is added and the solution stirred at room temperature overnight. The reaction mixture is diluted with EtOAc and washed well with water (2X), 10% citric acid (2X), water, brine, and dried over anhydrous [MGS04.] The EtOAc solution is concentrated in vacuum and the product purified by flash chromatography to provide 2.1 g of the title compound. Retention Time: 8. 48 min (RP- HPLC, C18, 10-90%) acetonitrile/0. [1 %] TFA gradient, 10 min); MS: ESI 555.97 [(M+H) +.] |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
97% | In methoxybenzene; at 0℃; for 0.333333h; | [0343] (2S,4S)-4-(Fmoc-amino)-1-Boc-pyrrolidine-2-carboxylic acid (0.5 g, 1.1 mmol) was placed in a flask containing trifluoroacetic acid (20 mL) and anisole (2.0 mL), and stirred at 0 C. for 20 min. The reaction was concentrated in vacuo without heating, and diethyl ether (100 mL) was added. The resulting solid was filtered, washed with diethyl ether, and dried in vacuo to give (0.5 g, 97%) of the crude TFA salt of (2S,4S)-4-(Fmoc-amino)pyrrolidine-2-carboxylic acid. [0344] In a separate flask the compound from Example 7, Part A (0.14 g, 0.54 mmol) was suspended in CH2Cl2 (10 mL), and pyridine (0.044 mL, 0.54 mmol) was added. To the reaction mixture oxalyl chloride (0.47 mL, 0.54 mmol) was added, and the reaction mixture was stirred at room temperature for 5 min. The reaction solvent was removed in vacuo. The resulting oil was dissolved in CH2Cl2 (10 mL) and DMSO (10 mL) and added to a solution of the above TFA salt (0.25 g, 0.55 mmol), CH2Cl2 (5 mL), and pyridine (0.13 mL, 1.6 mmol). After the reaction mixture was stirred for 4 h, the reaction solvent was removed in vacuo. The resultant oil was dissolved in EtOAc (250 mL) and washed sequentially with 1.5 N citric acid, and water. The organic layer was dried (MgSO4) and evaporated in vacuo to an amorphous solid of the crude title compound (0.13 g, 39%). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With sodium carbonate; In 1,4-dioxane; at 20℃; for 5h; | To a solution of cz's-Boc-aminoprolinecarboxylic acid (« 40 g, 174 mmol) as a crude reaction mixture from previous step cooled to 0C was added sodium carbonate (32.76 g, 309 mmol). Dissolve FMOC-C1 (46g, 178 mmol) in 1,4-dioxane (500 mL). Combine the dioxane solution to the aqueous solution. Stirthe reaction mixture at room temperature for 5 h. Remove organics underreduced pressure. Extract the aqueous solution with ether to remove excessFMOC-C1 and discard organic layer. Adjust pH to 2-3 with con HC1. Extractaqueous with ethyl acetate 3 X 400 mL, combine fractions and dry overMgSCk, filter and remove solvent under reduced pressure. Coevaporate thematerial 3 X with chloroform to afford desired product (78.8 g, 100%) as awhite solid and use as is for the next step. 1H NMR (300 MHz, CDCls): 6 7.78(d, J= 9.1 Hz, 2H), 7.59 (d, J= 9.2 Hz, 2H), 7.45 (m, 4H), 5.11-4.92 (bs, 1H), 4.58-4.18 (bs, 6H), 3.81 (m, 1H), 3.42 (m, 1H), 2.50-2.15 (bs, 2H), 1.43 (s, 9H).LC/MS:453(M+ + 1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
76% | With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; triethylamine; In N,N-dimethyl-formamide; at 20℃; for 3.16667h; | To a solution of crude product from step 1 (12.0 g, 26.5 mmol) in DMF(100 mL) was added racemic vinylcyclopropylaminocarboxylicethyl ester(4.93g, 31.8 mmol), and TBTU (15g, 46.7 mmol). The reaction mixture wascooled to 0 C and Hunig's base (18.6 mL, 106 mmol) was added slowly over 5min. The reaction was allowed to warm to room temperature and stirred for3 h. Remove solvent under reduced pressure and dilute with ethyl acetate.Extract the organics with sat sodium bicarb, water and brine. Purification ofproduct on silica gel (10-100% ethyl acetate/hexane) to afford dipeptideintermediate (11.9g, 76%) as an off-white solid mixture of diastereomers. aHNMR (300 MHz, CDCls): 5 7.79 (d, J= 9.1 Hz, 2H), 7.61 (d, J= 9.0 Hz, 2H), 7.47(m, 4H), 5.83 (m, 1H), 5.37 (m, 1H), 5.14 (m, 1H), 4.83 (m, 1H), 4.58- 4.18 (bs,8H), 3.78 (m, 1H), 3.37 (m, 1H), 2.59 (m, 1H), 2.13-1.82 (bs, 4H) 1.41 (s, 9H),1.32 (m, 4H). LC/MS: 590 (M+ +1). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With diethylamine; In methanol; at 20℃; for 2.5h; | To a solution of the commercial available Boc-Fmoc-protected amino acid (1.05 g) in methanol (25 ml) was added diethyl amine (1.5 ml). After stirring for 2.5 h at room temperature the reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and Et2O (50 ml). The organic phase was extracted with water (3 x 50 ml) and the combined aqueous extracts were concentrated. The residue was used for the next step without any further purification. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride; N-ethyl-N,N-diisopropylamine; In acetonitrile; at 25℃; for 4h; | (2S,4S)-Fmoc-4-Amino-1-Boc-pyrrolidine-2-carboxylic acid (0.5 g) was dissolved under a nitrogen atmosphere in acetonitrile (5 ml). DIEA (280 mul), 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (248 mg) and BOP-Cl (422 mg) were added stepwise to the solution. The mixture was stirred for 4 d at 25 C. The precipitate was filtered off and the filtrate is evaporated to dryness. The crude product was dissolved in CH2Cl2 (50 ml), washed with 10% aqueous Na2CO3 solution (20 ml) and brine (20 ml). The organic phase was dried over Na2SO4, filtrated and evaporated to dryness. The crude product was purified twice by chromatography (silica gel; gradient: CH2Cl2->methanol and silica gel; gradient n-heptane->AcOEt) to yield (2S,4S)-4-(9H-Fluoren-9-ylmethoxycarbonylamino)-2-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless amorphous solid (178 mg). MH+=639.2 |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
31% | With dimethylsulfide borane complex; In tetrahydrofuran; at 20℃; for 1h;Heating / reflux; | Intermediate B-1: To a solution of N-Boc-cis-4-N-FMOC-amino-L-proline (2.03 g, 4.42 mmol) in THF (30 mL) was added 2 M borane-methyl sulfide complex in THF (8.84 mmol, 4.42 mL) dropwise at room temperature. The resulting mixture was heated to reflux for 1 hour and concentrated. The residue was partitioned between 20 mL of water and 60 mL of methylene chloride. The aqueous layer was back-extracted with methylene chloride (2×). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution, brine, dried with sodium sulfate, and concentrated. Flash chromatography of the residue over silica (45 g), using 20%, 30%, and 50% of ethyl acetate in hexane gave Intermediate B-1 as an off-white powder (593 mg, 31%). The product was analyzed by LC (LC Method 1: tR=3.8 min) and LCMS (LCMS Method 1: M+H=439). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
55% | (2S,4S)-1-N-Boc-4-(N'-Fmoc-amino)pyrrolidine-2-carboxylic acid (236. 8 mg, 337. 4 G/MOL, 0. 70 mmol, 1 EQ, Neosystem), DIC (110 mul, 126. 20 G/MOL, 0. 806 g/cm3, 0. 70 mmol, 1 EQ) and HOBt (95 mg, 135. 12 G/MOL, 0. 70 mmol, 1 EQ) were dissolved in dry DMF/DCM (1/1, 5 MI). After 5 minutes, ben- zylamine (78 mul, 107. 16 G/MOL, 0, 981 g/cm3 0. 70 mmol, 1 EQ) was added to the reaction mixture. The mixture was stirred overnight at RT and after that 4 hours at 55 C. Solvent was then evaporated and the residue dissolved in 20 ML ETOAC and washed three times with 10 ML water. Organic phase was dried with NA2S04 and evaporated. Flash chromatographic purification gave 209 mg of (2S, 4S)-N-benzyl-1-N'-Boc-4-(N''-Fmoc-amino)pyrrolidine-2-carbamide ; yield 55%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of N-Boc-cis-4-Fmoc-amino-L-proline (2.0 g, 4.42 mmol) in DMF cooled to 0 C. were sequentially added, DIPEA (3.86 mL, 22.10 mmol), HOBt (776 mg, 5.75 mmol) and HBTU (2.18 g, 5.75 mmol). After stirring for 10 minutes (S)-2-amino-2-phenylethanol (728 mg, 5.30 mmol) was added and the reaction mixture was stirred overnight at room temperature. Water and ethyl acetate were added, the organic layer was separated, washed with 10% citric acid, saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 7-a as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
To a solution of N-Boc-cis-4-amino-Fmoc-amino-L-proline (3-a) (2.0 g, 4.42 mmol) in DMF cooled to 0 C., were sequentially added DIPEA (7.72 mL, 44.2 mmol), HOBt (776 mg, 5.75 mmol) and HBTU (2.17 g, 5.75 mmol). After stirring for 10 minutes ammonium hydrogen carbonate (1.04 g, 13.2 mmol) was added and the reaction mixture was stirred overnight at room temperature. Water and ethyl acetate were added, the organic layer was separated, washed with 10% citric acid, aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography provided intermediate 5-b as a white solid |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PEG-1 peptidyl resin was synthesized manually by the solid-phase method using MBHA resin (500 mg, 0.63 mmol/g) as solid support following a combined Fmoc/Boc/Alloc strategy. Peptide synthesis was performed manually in a polypropylene syringe fitted with a polyethylene porous disc. Solvents and soluble reagents were removed by suction. Washings between deprotection, coupling, and subsequent deprotection steps were carried out with DMF (5×1 min) and DCM (5×1 min) using 10 mL solvent/g resin for each wash. Two units of Fmoc-8-amine-3,6-dioxaoctanoic acid were coupled consecutively to the resin using standard DIPCDI/HOBt coupling system (3 equiv). Then, alternate incorporations of Fmoc-Amp(Boc)-OH (3 equiv) and Fmoc-Amp(Alloc)-OH (3 equiv) were carried out with DIPCDI (3 equiv) and ethyl cyanoglyoxyl-2-oxime (3 equiv) in DMF for 2 h. The resin was washed with DMF (5×1 min) and DCM (5×1 min) after each coupling. Couplings were monitored by the Kaiser test.19 Once the alternate Boc/Alloc alpha-amino protected skeleton had been built, the Nalpha-Boc protecting group was removed, alkylation of the amino group was performed by on-resin reductive amination using phenylacetaldehyde (5 equiv for each amine) in 1% HOAc in DMF for 30min and then treating the resin with NaBH3CN (5 equiv for each amine) in MeOH for 2 h. After that, the resin was washed with DMF (5×1 min) and DCM (5×1 min). Alkylation was monitored by chloranil test.20 Then, Nalpha-Alloc protecting group was removed with Pd(PPh3)3/PhSiH (0.1:10) (2×10 min in DCM) and alkylation with isovaleraldehyde was performed as above. After removal of last Fmoc protecting group (which provided 1-MBHA) an aliquot of PEG-1-MBHA was cleaved to check the peptidyl resin quality by acidolytic cleavage with HF and PEG-1 was obtained, which was dissolved in H2O/CH3CN, lyophilized and analyzed by HPLC (88% purity). tR=6.28 min. MS (MALDI-TOF): m/z=MS (MALDI-TOF): m/z=1503.85 [M+H]+, 1525.85 [M+Na]+. ESI found: 752.8; 502.3. Finally, an additional unit of Fmoc-8-amine-3,6-dioxaoctanoic acid was ad added to the 1-MBHA resin as described above rendering PEG-1-MBHA-resin. Part of the PEG-1-MBHA resin (100 mg) was treated with acetic anhydride-pyridine-CH2Cl2 (1:1:1, 2×30 min) and then washed with CH2Cl2 (3×2 min), NMP (3×2 min), and CH2Cl2 (6×1 min). Acidolytic cleavage of the resulting resin afforded Ac-PEG-1. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
PEG-1 peptidyl resin was synthesized manually by the solid-phase method using MBHA resin (500 mg, 0.63 mmol/g) as solid support following a combined Fmoc/Boc/Alloc strategy. Peptide synthesis was performed manually in a polypropylene syringe fitted with a polyethylene porous disc. Solvents and soluble reagents were removed by suction. Washings between deprotection, coupling, and subsequent deprotection steps were carried out with DMF (5×1 min) and DCM (5×1 min) using 10 mL solvent/g resin for each wash. Two units of Fmoc-8-amine-3,6-dioxaoctanoic acid were coupled consecutively to the resin using standard DIPCDI/HOBt coupling system (3 equiv). Then, alternate incorporations of Fmoc-Amp(Boc)-OH (3 equiv) and Fmoc-Amp(Alloc)-OH (3 equiv) were carried out with DIPCDI (3 equiv) and ethyl cyanoglyoxyl-2-oxime (3 equiv) in DMF for 2 h. The resin was washed with DMF (5×1 min) and DCM (5×1 min) after each coupling. Couplings were monitored by the Kaiser test.19 Once the alternate Boc/Alloc alpha-amino protected skeleton had been built, the Nalpha-Boc protecting group was removed, alkylation of the amino group was performed by on-resin reductive amination using phenylacetaldehyde (5 equiv for each amine) in 1% HOAc in DMF for 30min and then treating the resin with NaBH3CN (5 equiv for each amine) in MeOH for 2 h. After that, the resin was washed with DMF (5×1 min) and DCM (5×1 min). Alkylation was monitored by chloranil test.20 Then, Nalpha-Alloc protecting group was removed with Pd(PPh3)3/PhSiH (0.1:10) (2×10 min in DCM) and alkylation with isovaleraldehyde was performed as above. After removal of last Fmoc protecting group (which provided 1-MBHA) an aliquot of PEG-1-MBHA was cleaved to check the peptidyl resin quality by acidolytic cleavage with HF and PEG-1 was obtained, which was dissolved in H2O/CH3CN, lyophilized and analyzed by HPLC (88% purity). tR=6.28 min. MS (MALDI-TOF): m/z=MS (MALDI-TOF): m/z=1503.85 [M+H]+, 1525.85 [M+Na]+. ESI found: 752.8; 502.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
87% | To a solution of (2S,45)-Boc-gamma-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0 C were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)- 1,2,3, 4- tetrahydronaphthalen- 1 -amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in (( (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgS04, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2CI2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2CI2) provided the title compound (6.70 g, 87%) as a light tan solid. *H NMR (400 MHz, CDCI3) delta 7.79 (d, J= 7.5 Hz, 2H), 7.67 (d, J= 7.3 Hz, 2H), 7.42 (td, J= 7.2, 4.0 Hz, 2H), 7.37 - 7.03 (m, 6H), 5.22 (br. s., 1H), 4.57 - 4.23 (m, 5H), 3.68 - 3.49 (m, 2H), 2.91 - 2.74 (m, 2H), 2.52 (d, J= 13.4 Hz, 1H), 2.35 - 2.21 (m, 1H), 2.14 (d, J= 5.1 Hz, 1H), 1.97 - 1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+H)+ | |
87% | To a solution of (2S,4S)-Boc-4-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0 C were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)- 1 ,2, 3,4- tetrahydronaphthalen-1 -amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2CI2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgS04, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2C12 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2C12)provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCls) delta 7.79 (d, J= 7.5 Hz, 2H), 7.67 (d, J= 7.3 Hz, 2H), 7.42 (td, J= 7.2, 4.0 Hz, 2H), 7.37 - 7.03 (m, 6H), 5.22 (br. s., 1H), 4.57 - 4.23 (m, 5H), 3.68 - 3.49 (m, 2H), 2.91 - 2.74 (m, 2H), 2.52 (d, J= 13.4 Hz, 1H), 2.35 - 2.21 (m, 1H), 2.14 (d, J= 5.1 Hz, 1H), 1.97 - 1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+ | |
87% | A) (2S,4S)-tert-Butyl 4-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-(((R)- 1 ,2,3 ,4-tetrahydronaphthalen- 1 -yl)carbamoyl)pyrrolidine- 1 -carboxylate [00147] To a solution of (2S,4S)-Boc-gamma-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0 C were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and 4-methylmorpholine (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)- 1,2,3,4-tetrahydronaphthalen-l -amine (ALFA AESAR, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2CI2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgS04, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2CI2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2CI2) provided the title compound (6.7 g, 87%) as a light tan solid. XH NMR (400 MHz, CDCI3) delta 7.79 (d, J= 7.5 Hz, 2H), 7.67 (d, J= 7.3 Hz, 2H), 7.42 (td, J= 7.2, 4.0 Hz, 2H), 7.37 - 7.03 (m, 6H), 5.22 (br. s., 1H), 4.57 - 4.23 (m, 5H), 3.68 - 3.49 (m, 2H), 2.91 - 2.74 (m, 2H), 2.52 (d, J= 13.4 Hz, 1H), 2.35 - 2.21 (m, 1H), 2.14 (d, J= 5.1 Hz, 1H), 1.97 - 1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+H)+. |
87% | To a solution of (2S,4S)-Boc-4-(Fmoc-amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mL) at 0 C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mL, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 min then treated with a solution of (R)-1,2,3,4-tetrahydronaphthalen-1-amine (ALFA AESAR, 2.15 g, 14.6 mmol) in DMF (2 mL). The reaction mixture was stirred at rt for 1 h and cold water (100 mL) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mL). The solid was dissolved in CH2Cl2 (200 mL) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2Cl2 and purified by flash column chromatography (gradient elution from 10 to 30% EtOAc in CH2Cl2) provided the title compound (6.70 g, 87%) as a light tan solid. 1H NMR (400 MHz, CDCl3) delta 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J=7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (br. s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.1 Hz, 1H), 1.97-1.80 (m, 3H), 1.44 (s, 9H); MS(ESI+) m/z 582.2 (M+H)+. | |
87% | To a solution of (2S,4S)-l3oc-gamma-(Fmoc- amino)-proline (Chem-Impex, 6.00 g, 13.3 mmol) in DMF (20 mE) at 00 C. were added EDC (3.05 g, 15.9 mmol), HOAt (2.17 g, 15.9 mmol) and NMM (4.38 mE, 39.8 mmol). The reaction mixture was stirred at ice bath temperature for 20 mm then treated with a solution of (R)-1 ,2, 3,4-tetrahydronaphthalen- i-amine (Alfa Aesar, 2.15 g, 14.6 mmol) in DMF (2 mE). The reaction mixture was stirred at it for 1 hand cold water (100 mE) was added to the reaction mixture. The solid that formed was collected by filtration and washed with cold water (100 mE). The solid was dissolved in CH2C12 (200 mE) and the organic solution was washed with 5% aq. citric acid solution and brine, dried over MgSO4, and filtered. The filtrate was concentrated in vacuo. The residue was dissolved in CH2C12 and purified by flash colunm chromatography (gradient elution from 10 to 30% EtOAc in CH2C12) provided the title compound (6.70 g, 87%) as a light tan solid. ?H NMR (400 MHz, CDC13) oe 7.79 (d, J=7.5 Hz, 2H), 7.67 (d, J7.3 Hz, 2H), 7.42 (td, J=7.2, 4.0 Hz, 2H), 7.37-7.03 (m, 6H), 5.22 (bt s., 1H), 4.57-4.23 (m, 5H), 3.68-3.49 (m, 2H), 2.91-2.74 (m, 2H), 2.52 (d, J=13.4 Hz, 1H), 2.35-2.21 (m, 1H), 2.14 (d, J=5.i Hz, 1H), 1.97- 1.80 (m, 3H), 1.44 (s, 9H); MS(ESI) mlz 582.2 (M+H). | |
9.6 g | With N-ethyl-N,N-diisopropylamine; HATU; In N,N-dimethyl-formamide; at 0℃; for 4h; | To a solution of (2S,4S )-4-(9H-fluoren-9 -ylmethoxycarbonylamino)-pyrrolidine- 1,2-dicarboxylic acid 1-tert-butyl ester (Aldrich) (7.5 g, 16.593 mmol) in DMF (100 mL) were addedHATU (6.93 g, 18.252 mmol) and DIPEA (14.36 mL, 82.965 mmol) and the mixture was cooled to 0 C. (R)-(1,2,3,4-tetrahydro-naphthalen-1-yl)amine (2.44 g, 16.593 mmol) was added dropwise and the cooling bath removed. After 4 h the mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated to afford the title compound as an off white solid (9.6 g) which was used without purification. LC-MS: 582 (M+H). |
Tags: 174148-03-9 synthesis path| 174148-03-9 SDS| 174148-03-9 COA| 174148-03-9 purity| 174148-03-9 application| 174148-03-9 NMR| 174148-03-9 COA| 174148-03-9 structure
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H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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