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CAS No. : | 126727-04-6 | MDL No. : | MFCD00112977 |
Formula : | C24H21NO4 | Boiling Point : | - |
Linear Structure Formula : | - | InChI Key : | SJVFAHZPLIXNDH-UHFFFAOYSA-N |
M.W : | 387.43 | Pubchem ID : | 100105 |
Synonyms : |
|
Num. heavy atoms : | 29 |
Num. arom. heavy atoms : | 18 |
Fraction Csp3 : | 0.17 |
Num. rotatable bonds : | 8 |
Num. H-bond acceptors : | 4.0 |
Num. H-bond donors : | 2.0 |
Molar Refractivity : | 109.66 |
TPSA : | 75.63 Ų |
GI absorption : | High |
BBB permeant : | No |
P-gp substrate : | Yes |
CYP1A2 inhibitor : | No |
CYP2C19 inhibitor : | No |
CYP2C9 inhibitor : | Yes |
CYP2D6 inhibitor : | Yes |
CYP3A4 inhibitor : | No |
Log Kp (skin permeation) : | -5.37 cm/s |
Log Po/w (iLOGP) : | 2.58 |
Log Po/w (XLOGP3) : | 4.64 |
Log Po/w (WLOGP) : | 4.22 |
Log Po/w (MLOGP) : | 3.42 |
Log Po/w (SILICOS-IT) : | 4.04 |
Consensus Log Po/w : | 3.78 |
Lipinski : | 0.0 |
Ghose : | None |
Veber : | 0.0 |
Egan : | 0.0 |
Muegge : | 0.0 |
Bioavailability Score : | 0.56 |
Log S (ESOL) : | -5.1 |
Solubility : | 0.0031 mg/ml ; 0.00000801 mol/l |
Class : | Moderately soluble |
Log S (Ali) : | -5.95 |
Solubility : | 0.00043 mg/ml ; 0.00000111 mol/l |
Class : | Moderately soluble |
Log S (SILICOS-IT) : | -7.38 |
Solubility : | 0.0000162 mg/ml ; 0.0000000419 mol/l |
Class : | Poorly soluble |
PAINS : | 0.0 alert |
Brenk : | 0.0 alert |
Leadlikeness : | 3.0 |
Synthetic accessibility : | 3.94 |
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 |
---|---|---|
With O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate; N-ethyl-N,N-diisopropylamine; In DMF (N,N-dimethyl-formamide); dichloromethane; for 16h;Combinatorial reaction / High throughput screening (HTS); | EXAMPLE 10Synthesis of 27 Member Tripeptide PED Library 60 (FIG. 12) [00182] A suspension of the amino PBD scaffold resin 30 (example 9)(0.45 mmol), in 2:1 DCE:DMF (30 mL) was evenly distributed between 27 Alltech tubes (1.5 mL volume). The process was repeated twice, excess solvent was removed by suction and the resin was rinsed with CH2Cl2 (2×5 mL) and dried in vacuo. [00183] A solution of Fmoc-amino acid (0.05 mmol/tube) [Fmoc-alanine 15 mg/tube, Fmoc-glycine 14 mg/tube, Fmoc-phenylalanine 19 mg/tube], TBTU (15 mg, 0.05 mmol/tube) and DIPEA (8 mL, 0.05 mmol/tube) in DMF (500 mL) was added to resin 30 (0.017 mmol/tube) and allowed to shake for 16 hours. Resin 55 was filtered and rinsed with DMF (2×1 mL), CH2Cl2 (2×1 mL), MeOH (2×1 mL) and dried in vacuo. [00184] The procedure was repeated once. [00185] A solution of 20% piperidine in DMF (250 mL) was added to each tube and shaken for 2 hours. Resin 56 was filtered and rinsed with DMF (2×1 mL), CH2Cl2 (2×1 mL), MeOH (2×1 mL) and dried in vacuo. The procedure was repeated once. [00186] The above coupling and deprotection protocols were repeated twice until the library of 27 tripeptides 60 was generated. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
61% | With triethylamine; bromo-tris(1-pyrrolidinyl)phosphonium hexafluorophosphate; In dichloromethane; at 20℃; for 1h; | R2 H R = ISOBUTYL] R"= 9-fluorenylmethyl Sarcosine tert-butyl ester (350 mg, 2.7 mmol), triethylamine (0.25 ml), N-Fmoc phenylalanine (1.0 g, 2.6 mmol) and. PyBrop (1.1 g, 2.5 mmol) were added to dichloromethane (10 ml) in a 50 mL round bottomed flask with a magnetic stirring. The reaction mixture was left to stir at room temperature for 1 hour under an atmosphere of nitrogen. The reaction was monitored by tlc. The solution was washed with dilute citric acid solution, sodium bicarbonate solution, brine, dried [(MGSO4),] filtered and concentrated at reduced pressure. The crude residue was purified by column chromatography on silica eluting with 30% ethyl acetate-hexane to produce the dipeptide as a white solid (600 mg, [61%). 1H] NMR [(300MHZ,] CDCl3) [8 7.] 76- 7.20 (13H, m, ArH), 5.81-5. 78 [(1H,] m, NH), 5.02-5. 00 (1H, [M,] a-CH Phe), 4.37-4. 03 (7H, m, [CHCH2,] [NCH2,] 2 [XACH),] 3.11- 2. [93] (5H, m, NCH3, CHCH2), 1. [53-1. 45] (9H, m, tBu). 13C NMR (75MHz, CDC13) [6171.] 49,167. 41,155. 3,143. 58,140. 93, 136.01, 135.73, 129.28, 129.12, 128. [06,] 127. [32,] 126.71, 126.61, 124.88, 119. [59,] 81.63, 66.68, 50.06, 38.85, 35.89, 27.73, 27.65. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethyl-N,N-diisopropylamine; HATU; In DMF (N,N-dimethyl-formamide); at 55℃; for 4h; | [0166] 0.3 g of TentaGel HL12019 (bromoacetal linker, S=0.5 mmol/g, Rapp Polymere, Tuebingen) was washed with DMSO. 20 equivalents of 2M isopropylamine solution in DMSO were added, and the mixture was kept in a closed vessel at 60 C. for 15 hours. The polymer was washed 7 times with DMF. [0167] Fmoc-4-phenylalanine (3 equivalents) was coupled to the secondary amine on the polymer with HATU (3 equivalents) and DIEA (9 equivalents) in DMF. The final concentration was 0.2-0.3M. The reaction mixture was left at 55 C. for 4 hours. The polymer was washed 6 times with DMF. The Fmoc protective group was eliminated with 50% piperidine in DMF (5+15 minutes). [0168] Fmoc-beta-alanine (3 equivalents) was then coupled on with HOBt (3 equivalents) and DIC (3 equivalents) in DMF (final concentration: about 0.2M) over a period of at least 4 hours. The Fmoc protective group was eliminated with 50% piperidine in DMF (5+15 minutes). [0169] The polymer was washed 5 times with DMF and 4 times with DCM and mixed with a solution of 1.5 equivalents of 2-methoxy-4-chlorobenzenesulfonyl chloride and 3 equivalents of DIEA in acetonitrile (final concentration: 0.1-0.15M) and reacted at room temperature for 5 hours. It was then washed 5 times with DMF and 5 times with THF and dried in vacuo. [0170] For the cyclative cleavage off, the dry polymer was mixed with 10 ml of formic acid and shaken at room temperature for 16 hours. The polymer was filtered off and washed with DCM. The combined filtrates were evaporated in vacuo. The crude substance was dissolved in a mixture of acetonitrile and water and freeze dried. The pure title compound was removed after purification by HPLC. The system and processes described under ?General processes? were used in this case. MW=505.14 (calculated, monoisotopic); measured value (M+H)+: 506.3. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
1.2 g of Wang polystyrene resin (Rapp-Polymere, Tuebingen; loading 1.08 mmol/g) are swollen in dimethylformamide (DMF). The solvent is filtered off with suction and a solution of 1005 mg of Fmoc-phenylalanine (amino acid reagent) in 10 ml of dimethylformamide (DMF) is added. After shaking at room temperature for 15 min, the suspension is treated with 345 mul of pyridine and 543 mg of 2,6-dichlorobenzoyl chloride. It is shaken overnight at room temperature. The resin is then washed with dimethylformamide (DMF), methanol and dichloromethane. The resin is treated with 15 ml of a 20% strength piperidine solution dimethylformamide (DMF) and shaken at room temperature for 10 min. It is then washed 3 times with dimethylformamide (DMF) and a further 15 ml of a 20% strength piperidine solution in dimethylformamide (DMF) are added. After shaking for 20 min, it is washed with dimethylformamide (DMF) and tetrahydrofuran (THF). The resin is treated with a solution of 452 ml of diisopropylethylamine in 5 ml of tetrahydrofuran (THF) and a solution of 431 mg of 3-bromobenzenesulfonyl chloride in 5 ml of tetrahydrofuran (THF). It is shaken overnight at room temperature. The resin is then washed with dimethylformamide (DMF), methanol and tetrahydrofuran (THF). The resin is suspended in 7 ml of xylene, treated with 1.08 g of 3-nitrobenzeneboronic acid and a solution of 1.37 g of sodium carbonate in 6 ml of water and shaken for 5 min at room temperature. 227 mg of bis-(triphenylphosphane)-palladium(II) chloride and 170 mg of triphenylphosphane are then added and the mixture is stirred overnight at 85C. The resin is then washed with tetrahydrofuran (THF)/water 1:1, 0.25 M aqueous hydrochloric acid, water, dimethylformamide (DMF), methanol, tetrahydrofuran (THF) and dichloromethane. The resin is treated with a solution of 5.4 g of tin(II) chloride dihydrate in 12 ml of N-methylpyrrolidone (NMP) and shaken overnight at room temperature. The resin is then washed with N-methylpyrrolidone (NMP), methanol, tetrahydrofuran (THF) and dichloromethane. The resin is treated with a solution of 1.45 g 2-furanyl-carboxylic acid (acid reagent) in 20 ml dimethylformamide (DMF). After shaking for 1 minute a solution of 2.64 ml diisopropylcarbodiimide in 5 ml dimethylformamide (DMF) is added and the mixture is shaken for 3 hours at room temperature. The resin is then washed with dimethylformamide (DMF) and is treated with 1.45 g 2-furanyl-carboxylic acid in 20 ml dimethylformamide (DMF) and 2.64 ml diisopropylcarbodiimide in 5 ml dimethylformamide (DMF) again. After shaking for 3 hours the resin is washed with dimethylformamide (DMF), methanol, tetrahydrofurane (THF) and dichloromethane. For removal of the product, the resin is shaken with 10 ml of trifluoroacetic acid (TFA)/dichloromethane 1:1 for 1 hour, filtered off. The filtrate is concentrated in vacuo and purified on silica gel. 201 mg of the title compound are obtained. Mass spectrometry (ESI): 491. Retention time (HPLC): Rt = 9,6.1H-NMR (400 MHz, methanol) delta = 7,99 (s, 1H), 7,91 (s, 1H), 7,81 (d, 1H), 7,75 (m, 2H), 7,66 (m, 1H), 7,52 - 7,43 (m, 2H), 7,41 (d, 1H), 7,29 (d, 1H), 7,11 (s, 5H), 7,68 (m, 1H), 4,10 (dd, 1H, J =5,6 Hz, J = 10,8 Hz, H-2), 3,06 (dd, 1H, J = 5,6 Hz, J = 13,8 Hz, H-3a), 2,85 (dd, 1H, J = 10,8 Hz, J = 13,8 Hz, H-3b). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; EXAMPLE 4 N-f 1-f 1-Butvl-5- (methoxvcarbonvlmethvl-carbamoyl)-1 H-benzoimidazol-2-vll-2-phenyl- ethvlT-succinamic acid The title compound was prepared according to Method A using butyl amine in step 2, phenylalanine in step 4 and succinic acid anhydride in step 6.; EXAMPLE 47 ({1-Butyl-2-[1-(3-hydroxycarbamoyl-propionylamino)-2-phenyl-ethyl]-1 H- benzoimidazole-5-carbonvlT-amino)-acetic acid methyl ester The title compound was prepared according to Method A using benzyl amine in step 2, 1-naphthyl alanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; EXAMPLE 6 N-{1-[1-(4-Chloro-benzyl)-5-(methoxycarbonylmethyl-carbamoyl)-1H-benzoimidazol-2- vll-2-phenyl-ethvl-succinamic acid The title compound was prepared according to Method A using 4-chlorobenzyl amine in step 2, phenylalanine in step 4 and succinic acid anhydride in step 6. ;EXAMPLE 39 (f1-Furan-2-vlmethyl-2-f1- (3-hvdroxvcarbamovl-propionylamino)-2-phenvl-ethyll-1 H- benzoimidazole-5-carbonylT-amino)-acetic acid methyl ester The title compound was prepared according to Method A using furylmethyl amine in step 2, phenylalanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; The title compound was prepared according to Method A using 2-chlorobenzyl amine in step 2, phenylalanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; TEXAMPLE 22 (81-(2-Hydroxy-ethyl)-2-r1-(3-mercapto-propionylamino)-2-phenvl-ethvl1-1 H- benzoimidazole-5-carbonyl}-amino)-acetic acid methyl ester The title compound was prepared according to Method A using aminoethanol in step 2, phenyl alanine in step 4 and S-trityl protected mercaptopropionic acid in step 6.; EXAMPLE 27 N-{1-[1-(2-Hydroxy-ethyl)-5-(methoxycarbonylmethyl-carbamoyl)-1H-benzoimidazol-2- yl]-2-phenyl-ethyl}-succinamic acid The title compound was prepared according to Method A using aminoethanol in step 2, phenylalanine in step 4 and succinicacid anhydride in step 6.; EXAMPLE 59 [2-[1-(3-Hydroxycarbamoyl-propionylamino)-2-phenyl-ethyl]-1-(2-hydroxy-ethyl)-1 H- benzoimidazole-5-carbonvI1-aminoT-acetic acid methyl ester The title compound was prepared according to Method A using aminoethanol in step 2, phenylalanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; EXAMPLE 50 ({1-(2-Amino-ethyl)-2-[1-(3-mercapto-propionylamino)-2-phenyl-ethyl]-1 H- benzoimidazole-5-carbonvlT-amino)-acetic acid methyl ester The title compound was prepared according to Method A using ethylenediamine in step 2, phenylalanine in step 4 and S-trityl propionic acid in step 6.; EXAMPLE 52 N-1-r1- (2-Amino-ethvl)-5- (methoxvcarbonvlmethvl-carbamovi)-1 H-benzoimidazol-2-yll- 2-phenyl-ethyl}-succinamic acid The title compound was prepared according to Method A using ethylenediamine in step 2, phenylalanine in step 4 and succinic acid anhydride in step 6.; EXAMPLE 56 ({1-(2-Amino-ethyl)-2-[1-(3-hydroxycarbamoyl-propionylamino)-2-phenyl-ethyl]-1 H- benzoimidazole-5-carbonvlT-amino)-acetic acid methyl ester The title compound was prepared according to Method A using ethylenediamine in step 2, phenylalanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With N-ethylmorpholine;; 1-hydroxy-7-aza-benzotriazole; HATU; In DMF (N,N-dimethyl-formamide); at 20℃; for 48h; | A solution of HATU (0.95 mmol, 361 mg), HOAt (0.35 mmol, 50 mg), NEM (1.0 mmol, 126/il) and the appropriate Fmoc-protected aminoacid in DMF was added to the resin and allowed to react for 48h at room temperature. The resin was washed with DMF (10 times) and used directly in step 5.; EXAMPLE 2 ({1-(4-Chloro-benzyl)-2-[1-(3-mercapto-propionylamino)-2-phenyl-ethyl]-1 H- benzoimidazole-5-carbonylT-amino)-acetic acid methyl ester The title compound was prepared according to Method A using 4-chlorobenzyl amine in step 2, phenylalanine acid in step 4 and S-trityl protected mercaptopropionic acid in step 6.; EXAMPLE 6 N-{1-[1-(4-Chloro-benzyl)-5-(methoxycarbonylmethyl-carbamoyl)-1H-benzoimidazol-2- vll-2-phenyl-ethvl-succinamic acid The title compound was prepared according to Method A using 4-chlorobenzyl amine in step 2, phenylalanine in step 4 and succinic acid anhydride in step 6.; EXAMPLE 40 ({1-(4-Chlroo-benzyl)-2-[1-(3-hydroxycarbamoyl-propionylamino)-2-phenyl-ethyl]-1 H- benzoimidazole-5-carbonvl}-amino)-acetic acid methyl ester The title compound was prepared according to Method A using 4-chlorobenzyl amine in step 2, phenylalanine in step 4 and 0-trityl succinicacid hydroxamide in step 6. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With dicyclohexyl-carbodiimide; In DMF (N,N-dimethyl-formamide); at 20℃; for 15h; | Example 6; Solid Phase Preparative Scale Procedure; To explore the effectiveness of cyanide in the assistance of hydroxylamine mediated cleavage for solid phase library synthesis, hydroxymethylbenzamide (HMBA-AM) resin was chosen for the well-established compatibility between the ester linkage and Fmoc- and Boc-chemistry, and its stability towards Mitsunobu and reductive amination conditions. A solid phase library of DL-phenylalanine and several constrained analogs (AAa-c, Scheme 3) was prepared on the HMBA resin by the esterification of the Fmoc protected DL-aminoacids using standard DCC coupling conditions at room temperature overnight. The resin-bound Fmoc aminoacids BBa-c were deprotected with piperidine-DMF (1:4) and sulfonated with 4-methoxybenzenesulfonyl chloride to give Compounds IIIa-c. In this instance, the optimal reaction conditions for cleavage from the resin of the sulfonamide esters to yield the free hydroxamic acids (IVa-c, Table 2) were 5: 5:2 THF: MeOH: 50% aqueous NH2OH and 5 mg (0.08 mmol, 40 to 80 mol %) of KCN for 100 to 200 mg of loaded resin. The importance of KCN additive using these conditions was assessed with this series of analogs by following the time-dependant cleavage of the substrates from the solid support by hydroxylamine in parallel experiments with and without KCN (Table 2). In the case of entries 1 and 2, KCN assisted cleavage to the hydroxamic acid is complete after 2 hours, while in the unassisted parallel experiments, up to 20 h or more for entries 1 and 2 are required. For entry 3, the KCN assisted experiment is complete after 2 hours while the unassisted cleavage from the resin to the hydroxamic acid is complete in 4 hours. It was important to follow these reactions carefully and work up them upon completion. Extended exposure to the hydroxylamine solution appeared to result in decomposition of the product. Scheme 3. Preparation of the Solid Phase Library. To demonstrate the utility of this procedure on a synthetic scale, 200 mg of the resin IIIa (0.2 mmol of compound based on a loading capacity of 1 mmol of compound per 1 g of HMBA-AM resin) was treated with a mixture of THF: MeOH: 50% aqueous NH2OH (1:1:0.4, 2.4 mL) and KCN (5 mg, 40 mol %) to give a 57% yield of hydroxamic acid IVa, based upon the presumed resin loading. |
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 N,N-dimethyl-formamide; for 2h;Product distribution / selectivity; | Fmoc-Lys(Boc)-Wang resin (100 mg, 0.43 mM) was allowed to swell with CH2Cl2 (3 mL) followed by DMF (3 mL). A solution of 20 % piperidine in DMF (3 x 3 mL) was added to the resin that was then shaken gently on a mechanical shaker for 30 min at ambient temperature. The resin was washed with DMF (3 x 3 mL) and CH2Cl2 (3 x 3 mL). Formation of free amine was assessed by the Kaiser test (Kaiser et al., Anal Biochem, vol. 34, pp. 595-598, 1970). After swelling the resin in DMF, a solution of Fmoc-Phe-OH (3eq), HBTU (3eq), HOBt (3eq), and DIPEA (4.0eq) in DMF was added and gently shaken for 2 h. The resin was then washed with DMF (3 x 3 mL) and CH2Cl2 (3 x 3 mL). The coupling efficiency was assessed by the Kaiser Test. That aforementioned sequence was repeated for two more coupling steps with Fmoc-Phe- OH and DOTA-(t-butyl ester)3-CO2H. The resulting compound was cleaved from the resin using TFA: CH2Cl2 (1 :1) and concentrated under vacuum to produce the free amine. The concentrated product was purified by using a Cj8 SepPak Vac 2g column. The product was eluted with a solution 70/30 water/acetonitrile (0.1% TFA in each). ESIMS:827 [M+l]+. Lyophilized amine (10 mg, 12 mumol in 2 mL DMF) was added to 1 (prepared separately) (20 mg, 21.4 mumol in 1 niL DMF) followed by TEA (214 mumol, 30 muL) and then stirred at 250C for 16 h. After solvent removal, solid residue was treated with 3 mL TFA: CH2Cl2 to remove the PMB group. The residue was washed 2 x 5 mL CH2Cl2 to remove impurities. The colorless solid residue thus obtained was purified by a Cl 8 SepPak Vac 2g column using an eluent of 70/30 water/acetonitrile (0.1% TFA in each) to produce SRVlOO (SR-V-100). The product was further purified using preparative RP-HPLC by Method 1, retention time 17 min. Yield: ~ 30%. ESMS m/Z: 1284[M+H]+, HRESI+-MS: Calcd. for C68H90N11O20, 1284.6365 [M+H], found: 1284.6358. 1H NMR (CD3CO2D) delta: 7.35-7.20(m, 10H), 4.86 (bm, 2H), 4.57-4.46 (4H), 4.4-2.8 (m, 14 H), 2.51 (t, 2h), 2.4-1.2 (m, 28H). 13C (CD3CO2D) delta: 176.5, 177, 177.06, 177.6, 173.6, 173.24, 161.3, 160.92, 160.53, 160.14, 159.77, 137.95, 137.06, 130.5, 129.5, 127.9, 127.71,, 120.8, 118.0, 115.1, 112.3, 56.1, 55.5, 53.5, 53.3, 40.1, 38.8, 36.832.6, 31.8, 30.7, 29.42, 27.9, 26.53. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
100% | With benzotriazol-1-ol; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; N-ethyl-N,N-diisopropylamine; In dichloromethane; at 20℃; for 6h;Cooling with ice; | Example 1: Synthesis of Cyclic dipeptide: Cyclic Phenylalanylphenylalanine [(3,6- dibenzylpiperazine-2-5-dione) or cyclic (Phe-Phe)]. The synthesis of Cyclic dipeptide involves the following 2 steps.Step I: Synthesis of protected Dipeptide9-fluorenylmethoxycarbonyl (Fmoc)-phenylalanine (Fmoc-Phe-OH) and phenylalanine methyl ester (H-Phe-OMe) are prepared using standard protection methods. Fmoc protected L/D-phenylalanylphenylalanine methylester (Fmoc-Phe-Phe-OMe) is prepared by standard peptide coupling procedure. Fmoc-Phe-OH (2 g, 5.16 mmol) is dissolved in dichloromethane, H-Phe-OMe (1.23 g, 5.67 mmol), l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC.HC1, 1.19 g, 6.19 mmol), 1- hydroxybenzotriazole and (HOBt, 1.2 g, 6.19) are added. The solution is cooled to ice temperature. Diisopropylethylamine (DIPEA, 2.14, 16.51 mmol) is added and the reaction mixture is stirred at ice temperature for 1 h and then at room temperature for 5 h. The reaction progress is monitored by thin layer chromatography (TLC). Reaction mixture is evaporated to dryness and extracted from dichloromethane, washed with water, dried over anhydrous sodium sulfate. The solvent is evaporated to obtain Fmoc- Phe-Phe-OMe in quantitative yield. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: The N-FMOC derivatizedracemic and L-amino acids and methyl esters were preparedaccording to conventional methods.22 Racemic or L-alpha-amino acid (5 mmol) was dissolved in 10% aqueoussodium carbonate solution (12.5 mmol). Dioxane (7.5 mL)was then added and the mixture was stirred in an ice-bath.After that, 9-FMOC chloride (5 mmol) was added slowlyand stirred at room temperature for 5 h. Now, the reactionmixture was poured into water and extracted with ether.The aqueous solution obtained was acidified with c-HCl inan ice-bath. Finally, the resulting N-FMOC alpha-amino acidwas filtered and dried under vacuum. In order to prepareracemic or L-FMOC alpha-amino acid methyl ester, the correspondingFMOC alpha-amino acid (1 mmol) synthesized in theprevious step was dissolved in 5 mL of anhydrous methanolwith N,N0-dicyclohexylcarbodiimide (1.1 mmol). Themixture was stirred at room temperature for 12 h, filteredand dried under vacuum to get N-FMOC alpha-amino acidmethyl ester. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
69% | General procedure: Ethyl 2-(tertbutoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma, I) (1 mmol) wasadded to a stirred solution of carboxylic acid (1 mmol), DIPEA (1 mmol), andDMAP (0.1 mmol) in THF (2 mL) at 0-5 C. Then the reaction mixture wasstirred for 30 min followed by the addition of hydroxylamine hydrochloride inDMF (0.5 mL), DIPEA (1.5 mmol). The progress of the reaction was monitoredby TLC at room temperature. After completion of the reaction, the reactionmixture was concentrated using rotary evaporator and then diluted with15 mL of ethyl acetate and washed with 5% HCl (2 10 mL), 5% NaHCO3(2 10 mL), saturated NaCl solution (2 10 mL), and dried over anhydrousNa2SO4 and the evaporation of the solvent gave a residue that was purified onsilica gel column chromatography using hexane and ethyl acetate. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With trifluoroacetic acid; In hexane; isopropyl alcohol; at 25℃;Resolution of racemate; | Analysis was performed usingan HP series 1100 HPLC system (Palo Alto, CA, USA),consisting of a G1310A iso pump, an automatic sample injector, and an HP 1046A programmable fluorescencedetector. The chromatographic analysis was performedunder simultaneous UV 262 nm and fluorescence [excitation(Ex.) 264 and emission (Em.) 312 nm] detection. Allenantiomeric separations of alpha-amino acids and methyl estersas N-FMOC derivatives were performed using isocraticmobile phases [10 or 20% 2-propanol/hexane (v/v) with orwithout 0.1% TFA] at an ambient temperature (approximately25 C) with a flow rate of 1 mL/min. Three covalentlybonded CSPs, CSP 1 (Chiralpak ID), CSP 2 (Chiralpak IE),and CSP 3 (Chiralpak IF) (250 mm × 4.6 mm, I.D., 5 mum)having chiral selectors of amylose tris (3-chlorophenylcarbamate),amylose tris (3,5-dichlorophenylcarbamate), and amylosetris (3-chloro-4-methylphenylcarbamate), respectively,were purchased from the Daicel Company (Tokyo, Japan). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
Peptides were synthesized using standard 9- fluorenylmethoxycarbonyl method on a multispecific PSSM8 peptide synthesizer (Shimadzu Corporation Biotechnology, Kyoto, Japan) . The resin NovaSyn TGA (Merck, Darmstadt, Germany) (substitution 0.25 mmol/g) was used as support in solid phase, and synthesis were performed on a scale of 100 micromol. Ten equivalents of the first amino acid were coupled in the resin according to the N, N ' -Dicyclohexylcarbodiimide (DIC) /4- Dimethylaminopyridine (DMAP) method (10 equivalents of Fmoc amino acid, 5 equivalents of DIC, 0.1 equivalents of DMAP) . All subsequent amino acids, 4 equivalents relative to the resin, were coupled according to the method of N-hydroxybenzotriazole (HOBT) / 2 - Benzotriazole-3-tetramethyluronium tetrafluoroborate (TBTU) /Di-iso-propylethylamine (DIPEA) [1 equivalent of Fmoc amino acid, 1 equivalent of TBTU, one equivalent of HOBT (0.5 mM HOBT in NMP) , 2 equivalents of DIPEA (DIPEA 1 mM in N-methylpyrrolidone, NMP) ] . The Fmoc protecting group was removed with 30% piperidine in NMP (v/v) . The peptides were fully deprotected and cleaved from the resin by trifluoroacetic acid (TFA) with 5% thioanisole, 3% ethanedithiol , and 2% anisole as scavenger. The crude peptides were precipitated in ice in ethyl ether, filtered, dissolved in water, freeze dried and reduced with dithiothreitol (DTT) . The peptides were purified to homogeneity by chromatography on preparative reverse phase high pressure liquid (RP-HPLC) on chromatographic equipment Schimadzu Class-LC8A, equipped with a Lambda UV detector SPD-10A. Samples were injected on a C18 Phenomenex (column Phenomenex, Torrance, CA, USA) (22 mm x 25 cm, 5 mm) , eluted with a mixture of solvents consisting of H2O/0.1% TFA (A) and CH3CN/0.1% TFA (B) . A linear gradient from 5 to 50% of B for 17 min at a flow rate of 20 ml/min was used. The collected fractions were freeze-dried and analyzed by reversed phase HPLC on a Shimadzu Class-LCIO equipped with SPD- M10AVP Diode Array Detector using a Phenomenex C18 analytical column (4.6 x 250 mm, 5 mm) . The identity of purified peptides was confirmed by liquid chromatography/mass spectrometry (LC-MS ESI) using a Thermo Electron Surveyor MSQ. Results The yield of the obtained peptides was between 20 and 30% in the purified product to 99%. As known to the skilled in the field, such yield is very good for the synthesis of peptides of a similar length; furthermore, the synthesis and purification procedure resulted to be extremely reproducible. All homologue peptides containing modified amino acid residues were obtained by solid phase synthesis with similar methodologies to native sequences, appropriate changes to the synthetic strategy, also known to the skilled in the field. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Unless otherwise noted all peptides were synthesised using solid phase Fmoc chemistry on a Multisyntech Syro I automated peptide synthesiser. Couplings were performed using 4 eq protected amino acid, 4 eq O-benzotriazole-N,N,N?,N?-tetramethyl-uronium-hexafluoro-phosphate (HBTU) ), 4 eq hydroxybenzotriazole (HOBt) and 8 eq N,N-diisopropylethylamine (DIPEA) in N,N-dimethylformamide (DMF) and with double coupling. Removal of Fmoc protecting groups was achieved using piperidine (20% in DMF) 3 x 10 min. Amino acids were dissolved in NMP at 0.69 M with the exception of arginine which was dissolved in DMF. DIPEA was prepared at 2M in NMP and HBTU/HOBt at 0.45 M in DMF. Couplings proceeded for 25 min followed by washing with DMF and repetition of coupling. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
General procedure: Unless otherwise noted all peptides were synthesised using solid phase Fmoc chemistry on a Multisyntech Syro I automated peptide synthesiser. Couplings were performed using 4 eq protected amino acid, 4 eq O-benzotriazole-N,N,N?,N?-tetramethyl-uronium-hexafluoro-phosphate (HBTU) ), 4 eq hydroxybenzotriazole (HOBt) and 8 eq N,N-diisopropylethylamine (DIPEA) in N,N-dimethylformamide (DMF) and with double coupling. Removal of Fmoc protecting groups was achieved using piperidine (20% in DMF) 3 x 10 min. Amino acids were dissolved in NMP at 0.69 M with the exception of arginine which was dissolved in DMF. DIPEA was prepared at 2M in NMP and HBTU/HOBt at 0.45 M in DMF. Couplings proceeded for 25 min followed by washing with DMF and repetition of coupling. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
90% | With triethylamine; In N,N-dimethyl-formamide; at 20℃; for 12h;Cooling with ice; | To a ice cooled solution of <strong>[126727-04-6](((9H-fluoren-9-yl)methoxy)carbonyl)phenylalanine</strong> (18) (0.5 g, 1.290 mmol) and TEA (0.181 mL, 1.290 mmol) in DMF (5 mL) was added 2-iodoacetonitrile (0.093 mL, 1.290 mmol) drop-wise and the resulting solution was stirred at room temperature for 12 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (50 mL), saturated brine solution (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford brown gummy liquid crude product. The crude compound was purified by silica-gel flash column chromatography (eluted with ethyl-acetate/pet-ether = 2/10) to afford Cyanomethyl (((9H-fluoren-9-yl)methoxy)carbonyl) phenylalaninate (1e) (0.5 g, 90%) as off-white solid. 1H NMR (400 MHz, DMSO-d6): delta 7.87 (d, 2H), 7.61 (d, 2H), 7.44-7.21 (m, 9H), 5.01 (s, 2H), 4.34 (d, 2H), 4.30 (t, 2H), 4.25 (t, 1H), 3.06-2.89 (m, 2H). 13C NMR (100 MHz, DMSO-d6): delta 171.4, 156.3,144.1, 141.1, 137.4, 129.6, 128.7, 128.1, 127.5, 127.0, 125.6, 120.5, 116.1, 66.1, 55.6, 49.9, 47.0, 36.5. MS (ESI): 444.2 as [M+H2O] in +Ve mode. |
[ 371770-32-0 ]
(S)-2-((((9H-Fluoren-9-yl)methoxy)carbonyl)amino)-3-cyclopentylpropanoic acid
Similarity: 0.99
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