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[ CAS No. 136030-33-6 ] {[proInfo.proName]}

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Cat. No.: {[proInfo.prAm]}
Chemical Structure| 136030-33-6
Chemical Structure| 136030-33-6
Structure of 136030-33-6 * Storage: {[proInfo.prStorage]}
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Quality Control of [ 136030-33-6 ]

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Product Details of [ 136030-33-6 ]

CAS No. :136030-33-6 MDL No. :MFCD00144368
Formula : C25H21NO4 Boiling Point : -
Linear Structure Formula :- InChI Key :LIRBCUNCXDZOOU-QHCPKHFHSA-N
M.W : 399.44 Pubchem ID :978341
Synonyms :

Calculated chemistry of [ 136030-33-6 ]      Expand+

Physicochemical Properties

Num. heavy atoms : 30
Num. arom. heavy atoms : 18
Fraction Csp3 : 0.2
Num. rotatable bonds : 5
Num. H-bond acceptors : 4.0
Num. H-bond donors : 1.0
Molar Refractivity : 116.52
TPSA : 66.84 Ų

Pharmacokinetics

GI absorption : High
BBB permeant : Yes
P-gp substrate : Yes
CYP1A2 inhibitor : No
CYP2C19 inhibitor : No
CYP2C9 inhibitor : Yes
CYP2D6 inhibitor : No
CYP3A4 inhibitor : No
Log Kp (skin permeation) : -5.61 cm/s

Lipophilicity

Log Po/w (iLOGP) : 2.59
Log Po/w (XLOGP3) : 4.4
Log Po/w (WLOGP) : 3.91
Log Po/w (MLOGP) : 3.63
Log Po/w (SILICOS-IT) : 3.76
Consensus Log Po/w : 3.66

Druglikeness

Lipinski : 0.0
Ghose : None
Veber : 0.0
Egan : 0.0
Muegge : 0.0
Bioavailability Score : 0.56

Water Solubility

Log S (ESOL) : -5.2
Solubility : 0.00251 mg/ml ; 0.00000627 mol/l
Class : Moderately soluble
Log S (Ali) : -5.52
Solubility : 0.0012 mg/ml ; 0.00000301 mol/l
Class : Moderately soluble
Log S (SILICOS-IT) : -6.8
Solubility : 0.0000636 mg/ml ; 0.000000159 mol/l
Class : Poorly soluble

Medicinal Chemistry

PAINS : 0.0 alert
Brenk : 0.0 alert
Leadlikeness : 2.0
Synthetic accessibility : 3.94

Safety of [ 136030-33-6 ]

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:

Application In Synthesis of [ 136030-33-6 ]

* 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.

  • Downstream synthetic route of [ 136030-33-6 ]

[ 136030-33-6 ] Synthesis Path-Downstream   1~97

  • 1
  • [ 71989-18-9 ]
  • [ 136030-33-6 ]
  • [ 99953-00-1 ]
  • [ 76-05-1 ]
  • [ 845255-75-6 ]
  • (S)-4-({(S)-2-[(S)-2-Amino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionyl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-4-[(S)-1-carbamoyl-2-(6-dimethylamino-1,3-dioxo-1,3-dihydro-benzo[f]isoindol-2-yl)-ethylcarbamoyl]-butyric acid; compound with trifluoro-acetic acid [ No CAS ]
  • 2
  • [ 71989-26-9 ]
  • [ 136030-33-6 ]
  • C6H5CH2CH(NH2)C(O)O-2-ClTrt resin [ No CAS ]
  • C50H60N8O6 [ No CAS ]
  • 3
  • [ 119831-72-0 ]
  • [ 136030-33-6 ]
  • C6H5CH2CH(NH2)C(O)O-2-ClTrt resin [ No CAS ]
  • C50H58N10O8 [ No CAS ]
  • 4
  • [ 71989-18-9 ]
  • [ 136030-33-6 ]
  • [ 99953-00-1 ]
  • [ 88574-06-5 ]
  • [ 76-05-1 ]
  • Fmoc-α-amino-β-(6-N,N-dimethylamino naphthalimide)propanoic acid [ No CAS ]
  • C49H58N8O10*2C2HF3O2 [ No CAS ]
  • 5
  • [ 71989-26-9 ]
  • [ 136030-33-6 ]
  • (N-Boc-indol-3-yl)CH2CH(NH2)C(O)O-2-ClTrt resin [ No CAS ]
  • C54H62N10O6 [ No CAS ]
  • 6
  • [ 68858-20-8 ]
  • [ 35661-60-0 ]
  • [ 35661-39-3 ]
  • [ 136030-33-6 ]
  • Fmoc-Tyr(t-Bu)-OHN-Fmoc-3-aminomethylbenzoic acid [ No CAS ]
  • βALA-G(ΨCH2NH)Tic-(3-aminomethylbenzoic acid)-LTV [ No CAS ]
  • 7
  • [ 136030-33-6 ]
  • [ 839720-27-3 ]
  • 8
  • [ 136030-33-6 ]
  • [ 839720-28-4 ]
  • 9
  • [ 136030-33-6 ]
  • L-N-[3-[[4-[(3-aminopropyl)amino]butyl]amino]propyl]-2-(1-oxobutyl)isoquinoline-3-carboxylamide tris(trifluoroacetate) [ No CAS ]
  • 10
  • [ 136030-33-6 ]
  • 3-[3-(<i>tert</i>-butoxycarbonyl-{4-[<i>tert</i>-butoxycarbonyl-(3-<i>tert</i>-butoxycarbonylamino-propyl)-amino]-butyl}-amino)-propylcarbamoyl]-3,4-dihydro-1<i>H</i>-isoquinoline-2-carboxylic acid 9<i>H</i>-fluoren-9-ylmethyl ester [ No CAS ]
  • 11
  • [ 136030-33-6 ]
  • [ 166168-89-4 ]
  • 12
  • [ 136030-33-6 ]
  • [ 166168-91-8 ]
  • 13
  • [ 136030-33-6 ]
  • [ 166168-90-7 ]
  • 14
  • [ 136030-33-6 ]
  • (S)-2-({(S)-2-[(S)-2-(4-Chloro-2-hydroxy-benzoylamino)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-4-methylsulfanyl-butyric acid methyl ester [ No CAS ]
  • 15
  • [ 136030-33-6 ]
  • (S)-2-({(S)-2-[(S)-2-(5-Bromo-2-hydroxy-benzoylamino)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-4-methylsulfanyl-butyric acid [ No CAS ]
  • 16
  • [ 136030-33-6 ]
  • (S)-2-({(S)-2-[(S)-2-(4-Chloro-2-hydroxy-benzoylamino)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-4-methylsulfanyl-butyric acid [ No CAS ]
  • 17
  • [ 136030-33-6 ]
  • (S)-2-({(S)-2-[(S)-2-(5-Bromo-2-hydroxy-benzoylamino)-3-methyl-butyryl]-1,2,3,4-tetrahydro-isoquinoline-3-carbonyl}-amino)-4-methylsulfanyl-butyric acid methyl ester [ No CAS ]
  • 18
  • C30H35N4O3Pol [ No CAS ]
  • [ 136030-33-6 ]
  • C55H54N5O6Pol [ No CAS ]
  • 19
  • C26H29N2O2Pol [ No CAS ]
  • [ 136030-33-6 ]
  • C51H48N3O5Pol [ No CAS ]
  • 20
  • Fmoc-Arg(Pbf) [ No CAS ]
  • [ 103-72-0 ]
  • [ 136030-33-6 ]
  • [ 96-32-2 ]
  • [ 134-96-3 ]
  • [ 1194838-52-2 ]
  • 21
  • [ 68858-20-8 ]
  • [ 35661-40-6 ]
  • [ 71989-38-3 ]
  • [ 71989-26-9 ]
  • [ 103213-32-7 ]
  • [ 136030-33-6 ]
  • [ 143824-78-6 ]
  • Fmoc-S-trityl penicillamine [ No CAS ]
  • C58H74N10O10S2 [ No CAS ]
  • 22
  • [ 68858-20-8 ]
  • [ 35661-40-6 ]
  • [ 71989-38-3 ]
  • [ 103213-32-7 ]
  • [ 109425-55-0 ]
  • [ 136030-33-6 ]
  • 1-tert-butoxycarbonyl-N-[(9-fluorenyl)methoxycarbonyl]-D-tryptophan [ No CAS ]
  • Fmoc-S-trityl penicillamine [ No CAS ]
  • C57H72N10O10S2 [ No CAS ]
  • 23
  • knorr amide resin [ No CAS ]
  • [ 29022-11-5 ]
  • [ 68858-20-8 ]
  • [ 35661-60-0 ]
  • [ 71989-38-3 ]
  • [ 71989-26-9 ]
  • [ 103213-32-7 ]
  • [ 136030-33-6 ]
  • [ 109425-51-6 ]
  • [ 109425-56-1 ]
  • UGVCCGYKLCH[TIK]C-NH2; U = L-pyroglutamic acid; [TIK] = 1,2,3,4-L-tetrahydroisoquinoline-3-carboxylic acid [ No CAS ]
  • 24
  • [ 29022-11-5 ]
  • [ 35661-40-6 ]
  • [ 108-24-7 ]
  • [ 105047-45-8 ]
  • [ 136030-33-6 ]
  • 1‐fluorenylmethoxycarbonyl-(2S,3aS,7aS)‐octahydroindole‐2‐carboxylic acid [ No CAS ]
  • Ac-GF-Tic-Oic-GK-Tic-Oic-GF-Tic-Oic-GK-Tic-KKKK-CONH2 [ No CAS ]
  • 25
  • [ 29022-11-5 ]
  • [ 35661-60-0 ]
  • [ 71989-14-5 ]
  • [ 71989-38-3 ]
  • [ 136030-33-6 ]
  • [ 1273019-50-3 ]
  • 26
  • [ 29022-11-5 ]
  • [ 35661-60-0 ]
  • [ 71989-14-5 ]
  • [ 71989-38-3 ]
  • [ 136030-33-6 ]
  • [ 1273019-51-4 ]
  • 27
  • [ 2459-05-4 ]
  • C21H20N3O5Pol [ No CAS ]
  • [ 71989-31-6 ]
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • [ 1312616-96-8 ]
YieldReaction ConditionsOperation in experiment
General procedure: All aza-peptidyl inhibitors and probes were synthesized by following the previously reported procedures 1, 2 with slight modifications. Fmoc protecting groups from Rink SS resin (0.75 mmol/g) were removed by treatment with 20% piperidine in DMF for 15 min, followed by three washes with DMF. A 1.2 M solution of bromoacetic acid (10 eq) in NMP and DIC (10 eq) were added to the resin. The resin was shaken 1.5 hrs and washed three times. A solution of Mono-Fmoc protected hydrazide (3 eq) in NMP was added and shaken overnight. Resin loading was determined by Fmoc-quantification (0.2-0.3 mmol/g). A 0.5M solution of N-Fmoc-protected amino acid (3 eq.) and HOBt (3 eq.) in DMF and DIC (3 eq.) were added to the resin. The resin was shaken 1.5-2hrs. For each of the following steps, Fmoc-deprotection and coupling reactions were repeated as described above. Capping of N-terminal amine was achieved by shaking the resin with a 0.5 M solution of acetic anhydride (5 eq.) and DIEA (5 eq.) in DMF for 5 min.
  • 28
  • C21H22NO4Pol [ No CAS ]
  • [ 304697-38-9 ]
  • [ 29022-11-5 ]
  • [ 57618-17-4 ]
  • [ 71989-14-5 ]
  • [ 71989-18-9 ]
  • [ 71989-26-9 ]
  • [ 71989-35-0 ]
  • [ 136030-33-6 ]
  • [ 71989-31-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • C110H156N18O26S [ No CAS ]
  • 29
  • [ 503-74-2 ]
  • [ 1414927-98-2 ]
  • [ 136030-33-6 ]
  • [ 1414928-01-0 ]
YieldReaction ConditionsOperation in experiment
1.9 mg General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS.
  • 30
  • [ 140-77-2 ]
  • [ 1414927-98-2 ]
  • [ 136030-33-6 ]
  • [ 1414928-04-3 ]
YieldReaction ConditionsOperation in experiment
1.4 mg General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS.
  • 31
  • [ 1414927-98-2 ]
  • [ 136030-33-6 ]
  • [ 98-89-5 ]
  • [ 1414928-07-6 ]
YieldReaction ConditionsOperation in experiment
1.2 mg General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS.
  • 32
  • [ 112-05-0 ]
  • [ 1414927-98-2 ]
  • [ 136030-33-6 ]
  • [ 1414928-10-1 ]
YieldReaction ConditionsOperation in experiment
2.1 mg General procedure: The chlorosilyl resin was swollen in dry DCM (20 mL) under argon atmosphere. A solution of imidazole (1.16 g, 17.0 mmol) and diol 5 (10.7 g, 16.8 mmol) in DCM (20 mL) was subsequently added. The mixture was vortexed overnight at room temperature using a Burrell wrist-action shaker. The loaded resin was washed with DCM (3 × 75 mL) and dried overnight under vacuum to provide 7.3 g of resin 6 (loading of 0.40 mmol/g). IR (KBr): nu 3442 (OH, alcohol), 1702 (C=O, carbamate) cm-1. The free diol 5 (8.7 g) was easily recovered after flash chromatography using EtOAc/hexanes (1:1) as eluent. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. A solution of piperidine in DCM (20% v/v) (70 mL) was added to resin 6 (7.3 g, 0.4 mmol/g) and the suspension was vortexed using a Burrell wrist-action shaker for 1 h at room temperature. The resin was then filtered and washed successively with DCM (5 × 75 mL) and MeOH (5 × 75 mL), and finally dried overnight to provide 6.5 g of Fmoc deprotected resin. The resin was divided into portions (1.80 g, 0.4 mmol/g in a 50 mL peptide flask). To each portion was added a solution of the appropriate amino acid (Fmoc-l-proline-OH (2.5 g, 7.5 mmol), Fmoc-d-proline-OH (2.5 g, 7.5 mmol), Fmoc-l-phenylalanine-OH (2.9 g, 7.5 mmol), Fmoc-d-phenylalanine-OH (2.9 g, 7.5 mmol) or Fmoc-l-tetrahydro-isoquinoline-3-carboxylic acid (3.0 g, 7.5 mmol), benzotriazole-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP) (3.9 g, 7.5 mmol) and N-hydroxybenzotriazole (HOBt) (1.0 g, 7.5 mmol) in DMF (25 mL) under argon atmosphere. Diisopropylethylamine (DIPEA) (2.6 mL, 15 mmol) was added to the suspensions and the peptide flasks were vortexed with a Burrell wrist-action shaker for 5 h at room temperature. The resins were then filtered and washed successively with DCM (5 × 25 mL) and MeOH (5 × 25 mL), and finally dried overnight to give the resins 7. The coupling reaction was repeated a second time in each case in order to ensure complete coupling. To each of the resin-bound derivatives 8 was added 2 mL of an acid solution of 2 M methanolic HCl (AcCl + MeOH) in DCM (20:80, v/v) and the resulting suspensions were vortexed at 600 rpm for 1 h. DCM (1 mL) was added and the suspensions were filtered and the recovered filtrate was neutralized with 0.5 mL of 10% aqueous NaHCO3 (pH 8). The biphasic solution was filtered using a phase separator syringe (Biotage) and the resulting organic solution evaporated under reduced pressure. The 12 (3 × 4) crude amide compounds of library A (Table 2 ) were purified by filtration over a silica gel plug (10 mL) using EtOAc/hexanes (1:1) (15 mL) and then EtOAc (20 mL). In another experiment, the 28 (4 × 7) amide compounds of library B (Table 3 ) were evaporated to dryness and judged sufficiently pure by TLC and 1H NMR analyses for direct screening on HL-60 cells. All members of libraries A and B were analyzed by TLC, 1H NMR and LRMS.
  • 33
  • [ 1443251-62-4 ]
  • [ 136030-33-6 ]
  • 3-isobutyl-3-phenyl-5-((S)-1,2,3,4-tetrahydroisoquinoline-3-carbonyl)-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one [ No CAS ]
YieldReaction ConditionsOperation in experiment
68% To a solution of (S)-2-(((9H-fluoren-9- yl)methoxy)carbonyl)- l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (147 mg, 0.369 mmol), 3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin- l(3H)-one (50 mg, 0.184 mmol), and N,N'-diisopropylethylamine (112 mg, 0.870 mmol) in THF (5 mL) was added BOP reagent (144 mg, 0.326 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated to dryness, re-dissolved in 20% piperidine in DMF (5 mL), and stirred at room temperature for 1 hour. The crude reaction mixture was concentrated and purified by column chromatography (12 g, Si02, 0 to 100% ethyl acetate in hexanes) to provide 3-isobutyl-3-phenyl-5-((S)- l,2,3,4-tetrahydroisoquinoline-3-carbonyl)- 4,5,6,7-tetrahydrofuro[3,4-c]pyridin- l(3H)-one (54 mg, 68%) as a mixture of diastereoisomers in form of white solid: 1H NMR (300 MHz, CHLOROFORM- ) delta ppm 0.81 - 1.01 (m, 6 H), 1.59 - 1.74 (m, 1 H), 1.75 - 1.88 (m, 1 H), 2.26 - 2.52 (m, 3 H), 2.71 - 2.85 (m, 1 H), 2.87 - 3.10 (m, 1 H), 3.37 - 3.72 (m, 2 H), 3.76 - 3.99 (m, 2 H), 4.00 - 4.15 (m, 3 H), 4.62 - 4.86 (m, 1 H), 7.01 - 7.22 (m, 4 H), 7.28 - 7.45 (m, 5 H); MS m/z 431 (M+H) +, 429 (M-H)".
  • 34
  • [ 20260-53-1 ]
  • [ 114346-31-5 ]
  • [ 136030-33-6 ]
  • [ 82379-38-2 ]
  • p-MBHA resin [ No CAS ]
  • C38H36N5O9Pol [ No CAS ]
  • 35
  • [ 1013-24-7 ]
  • [ 4509-90-4 ]
  • [ 136030-33-6 ]
  • (S)-2-(5-(4-(2-(methylthio)phenyl)piperazin-1-yl)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 36
  • [ 35386-24-4 ]
  • [ 4509-90-4 ]
  • [ 136030-33-6 ]
  • (S)-2-(5-(4-(2-methoxyphenyl)piperazin-1-yl)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 37
  • [ 38212-33-8 ]
  • [ 4509-90-4 ]
  • [ 136030-33-6 ]
  • (S)-2-(5-(4-(4-chlorophenyl)piperazin-1-yl)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 38
  • [ 4509-90-4 ]
  • [ 136030-33-6 ]
  • [ 2252-63-3 ]
  • (S)-2-(5-(4-(4-fluorophenyl)piperazin-1-yl)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
33% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 39
  • [ 4509-90-4 ]
  • [ 87691-89-2 ]
  • [ 136030-33-6 ]
  • (S)-2-(5-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)pentanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 40
  • [ 1013-24-7 ]
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • (S)-2-(6-(4-(2-(methylthio)phenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 41
  • [ 35386-24-4 ]
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • (S)-2-(6-(4-(2-methoxyphenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 42
  • [ 1011-17-2 ]
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • (S)-2-(6-(4-(2-hydroxyphenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 43
  • [ 39512-50-0 ]
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • (S)-2-(6-(4-(2-chlorophenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 44
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • [ 6640-24-0 ]
  • (S)-2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 45
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • [ 2252-63-3 ]
  • (S)-2-(6-(4-(4-fluorophenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 46
  • [ 22809-37-6 ]
  • [ 136030-33-6 ]
  • [ 41202-77-1 ]
  • (S)-2-(6-(4-(2,3-dichlorophenyl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
32% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 47
  • [ 22809-37-6 ]
  • [ 87691-89-2 ]
  • [ 136030-33-6 ]
  • (S)-2-(6-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)hexanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
36% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 48
  • [ 1013-24-7 ]
  • [ 50733-91-0 ]
  • [ 136030-33-6 ]
  • (S)-2-(7-(4-(2-(methylthio)phenyl)piperazin-1-yl)heptanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 49
  • [ 50733-91-0 ]
  • [ 87691-89-2 ]
  • [ 136030-33-6 ]
  • (S)-2-(7-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl)heptanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
37% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 50
  • [ 1013-24-7 ]
  • [ 52780-16-2 ]
  • [ 136030-33-6 ]
  • (S)-2-(4-((4-(2-(methylthio)phenyl)piperazin-1-yl)methyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
35% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 51
  • [ 35386-24-4 ]
  • [ 52780-16-2 ]
  • [ 136030-33-6 ]
  • (S)-2-(4-((4-(2-methoxyphenyl)piperazin-1-yl)methyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
34% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 52
  • [ 52780-16-2 ]
  • [ 136030-33-6 ]
  • [ 41202-77-1 ]
  • (S)-2-(4-((4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)benzoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% General procedure: 4.2.1 Deprotection of rink amide resin and an amine group of the amino acid (0033) The resin (2.25g, 1.58mmol, 0.7mmolg-1) was treated with a 20% solution of piperidine in DMF and allowed to rotate for 3min. Subsequently, the beads were drained and washed with DMF (1×5mL). The procedure described above was repeated for another 15min. Next, the resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being dried under low vacuum. 4.2.2 Preparation of solid-supported carboxamides (0034) The amine resin was placed into 3 reactors for coupling with different Fmoc-protected amino acids. The resin was swelled in CH2Cl2 (10mL) for 30min and then washed with CH2Cl2-DMF (80/20, v/v). Fmoc-amino acid 2{1-3} (5.4mmol, 5equiv), HBTU (0.88g, 5.4mmol, 5equiv) in DMF (8mL), and DIEA (1.8mL, 10.8mmol, 10equiv) were then added to the resin (0.6g, 1.08mmol, 1.8mmolg-1). The reaction mixture was agitated with an orbital shaker for 2h. The resin-bound amino acid was then drained and washed with DMF (4×5mL), MeOH (1×5mL), and DCM (4×5mL). The procedure described above was repeated. The washed resin was dried under low vacuum for 12h. 4.2.3 Acylation using arylacyl chlorides (0035) The deprotected resin (140mg, 0.08mmol, 0.57mmolg-1) was swelled in 2mL of DCM for 30min; DIEA (0.08mL, 0.45mmol, 6equiv) was added to the resin, followed by a solution of acyl chloride 4{1-4} in 0.25mL of DCM and DMAP (10.3mg, 0.08mmol, 1equiv). The reaction mixture was allowed to rotate for 4h. The resin was drained and washed with DMF (4×), MeOH (1×), and DCM (4×) before being allowed to dry in open air. 4.2.4 Nucleophilic displacement with arylpiperazine derivatives (0036) The air-dried resin was placed into glass vials containing 1.5mL of 1M solution of secondary amine 6{1-10} in DMF. The resulting reaction mixture was heated to 75C for 24h. The resulting resin-bound product was drained and sequentially washed with a 10% solution of AcOH in DMF (2×), DMF (4×), MeOH (1×), and DCM (4×) before being dried in open air. 4.3 General procedure for the cleavage of the final products (0037) Two milliliters of a TFA/DCM (80/20, v/v) mixture was added to the resin, and the cleavage reaction was carried out for 2h. Subsequently, the reaction was filtered and washed with a small volume of DCM; the collected filtrates were concentrated in a stream of argon to yield the target compounds.
  • 53
  • [ 108-24-7 ]
  • [ 86123-10-6 ]
  • [ 136030-33-6 ]
  • [ 109425-51-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • [ 485805-31-0 ]
  • 54
  • [ 108-24-7 ]
  • [ 86123-10-6 ]
  • [ 136030-33-6 ]
  • [ 109425-51-6 ]
  • [ 143824-78-6 ]
  • [ 1609537-61-2 ]
  • 55
  • [ 108-24-7 ]
  • [ 86123-10-6 ]
  • [ 136030-33-6 ]
  • [ 143824-78-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • Ac-Tic-D-Phe-Arg-Trp-NH<SUB>2</SUB> [ No CAS ]
  • 56
  • Phe-Wang resin [ No CAS ]
  • [ 1059690-89-9 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • C47H53N4O8Pol [ No CAS ]
  • 57
  • Phe-Wang resin [ No CAS ]
  • [ 35661-40-6 ]
  • [ 76757-93-2 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-propyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 58
  • Phe-Wang resin [ No CAS ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 85676-48-8 ]
  • [ 76-05-1 ]
  • H-Tyr(O-butyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 59
  • Phe-Wang resin [ No CAS ]
  • [ 1497169-70-6 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-pentyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 60
  • Phe-Wang resin [ No CAS ]
  • [ 1497426-34-2 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-hexyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 61
  • Phe-Wang resin [ No CAS ]
  • [ 1497151-88-8 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-heptyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 62
  • Phe-Wang resin [ No CAS ]
  • [ 141537-18-0 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-octyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 63
  • Phe-Wang resin [ No CAS ]
  • [ 1613393-41-1 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-nonyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 64
  • Phe-Wang resin [ No CAS ]
  • [ 1613393-42-2 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-decyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 65
  • Phe-Wang resin [ No CAS ]
  • [ 1613393-43-3 ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr(O-undecyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 66
  • Fmoc-Phe-Wang resin [ No CAS ]
  • [ 35661-40-6 ]
  • [ 127132-38-1 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • C40H42N4O6*C2HF3O2 [ No CAS ]
  • 67
  • Boc-Tyr(O-hept-2-enyl)-OH [ No CAS ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • [ 76-05-1 ]
  • H-Tyr-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • H-Tyr(O-hept-2-enyl)-Tic-Phe-Phe-OH*TFA [ No CAS ]
  • 68
  • Boc-Tyr(O-hept-2-enyl)-OH [ No CAS ]
  • [ 35661-40-6 ]
  • [ 136030-33-6 ]
  • Boc-Tyr(O-hept-2-enyl)-Tic-Phe-Phe-OH [ No CAS ]
  • 69
  • [ 560088-66-6 ]
  • Wang-Fmoc-Lys(Mtt)-OH resin [ No CAS ]
  • [ 136030-33-6 ]
  • [ 99953-00-1 ]
  • fmoc-S-4-methoxytrityl-L-cysteine [ No CAS ]
  • [ 170908-81-3 ]
  • C49H72N10O16S [ No CAS ]
YieldReaction ConditionsOperation in experiment
This was achieved from Wang resin, which was mesylated using an 8-fold excess of MsCI at 0C to activate OH groups, followed by coupling with Fmoc-Lys(Mtt)-OH. In a 50 mL bottle containing 1 g of Wang resin (0.93 mmol/g) with a magnetic stir bar, dry CH2CI2 was added to swell the resin for 1 h. The solvent was removed, the bottle closed with a septum and flushed with nitrogen, and /'Pr2NEt (9 equiv, 1.4 mL) in 15 mL of CH2CI2 was added. The resin slurry was cooled to 0C followed by dropwise addition of MsCI (8 equiv, 0.57 mL) in 2 mL of CH2CI2. The reaction was stirred for 20 min, the ice-bath was removed, and the stirring was continued for another 20 min (rt). The resin was then transferred to a syringe reactor and washed with dry CH2CI2 and dry DMF. Fmoc-Lys(Mtt)-OH (2 equiv, 1 .2g), Csl (2 equiv, 0.5g), /'Pr2NEt (2 equiv, 0.32 mL) in ca. 10 mL of dry DMF were added, and the reaction was stirred overnight at rt. The NR-Fmoc protection from 3 was removed with piperidine in DMF, and Fmoc- Tic-OH was coupled using standard NR-Fmoc/iBu strategy of solid-phase peptide synthesis to give intermediate 4. The resin was NR-Fmoc deprotected with piperidine/DMF (1 :4) and then washed with DMF, CH2CI2, 0.2 M HOBt/DMF, and DMF. Fmoc-Tic-OH (3 equiv), HOCt (3 equiv), and DIC (6 equiv) in DMF were then added, and the reaction was stirred for 2 h. For final coupling, Boc-Dmt-OH was used since a free N terminal peptide can be directly obtained after final acidic cleavage. Additionally, a choice of NR-terminal Boc protection prevents against premature Fmoc deprotection by free NH2 groups released on the side chain of lysine and any consequent cyclative elimination (dioxopiperazine) of Dmt- Tic from Dmt-Tic- Lys(R)-resin. (Caspasso, S.; Sica, F.; Mazzarella, L.; Balboni, G.; Guerrini, R.; Salvadori, S. Int. J. Pep. Protein Res. 1995, 45, 567-573) Lastly, Boc is smaller than Fmoc, facilitating a faster coupling rate. Despite that, Boc- Dmt coupling to the sterically hindered Tic-Lys(R)-resin was challenging. The coupling has to be mediated via strong HBTU activation accelerated by microwave. Boc-Dmt-OH (3 equiv), HBTU (3 equiv), and /'Pr2NEt (6 equiv) in DMF were added to the resin, and the reaction was heated in a household microwave for 3 s. The reaction was stirred until it cooled to rt; the heating was repeated (5x), and the resin was stirred for another 2 h. Also, there is a conceptual disadvantage of using an unprotected phenolic group on Dmt. The reaction leads to Dmt self-condensation, forming small amounts of Dmt-oligomers. Nonetheless, the formed phenolic esters are susceptible to mild aminolysis and can be selectively removed by treatment with 50% piperidine in CH2CI2:MeOH (5:1 ) before acidic cleavage. Following Dmt coupling to give intermediate 5, the coupling of dyes and chelating agents can be performed on the resin or in solution. For Cy5 labeling, more cost-effective conjugation of dye in solution was preferred via a thiolmaleimide reaction. 3-Mercaptopropionyl was chosen as a small linker for C-terminal attachment as the dye possesses a 12-atom linker with maleimide at the end. Thus, Trt-SCH2CH2COOH was coupled to 5 using HOCt/DIC protocol and then cleaved with acidic cocktail (82.5% TFA, 5% H20, 5% /'Pr3SiH, 5% thioanisole, and 2.5% ethanedithiol) to give ligand 6 (Scheme 2 shown in Figure 17). Following Dmt coupling to give intermediate 5, the coupling of dyes and chelating agents can be performed on the resin or in solution. For Cy5 labeling, more cost-effective conjugation of dye in solution was preferred via a thiolmaleimide reaction. 3-Mercaptopropionyl was chosen as a small linker for C-terminal attachment as the dye possesses a 12-atom linker with maleimide at the end. Thus, Trt-SCH2CH2COOH was coupled to 5 using HOCt/DIC protocol and then cleaved with acidic cocktail (82.5% TFA, 5% H20, 5% /'Pr3SiH, 5% thioanisole, and 2.5% ethanedithiol) to give ligand 6 (Scheme 2 shown in Figure 17). The compound was purified by preparative HPLC, and the Cy5 dye was conjugated to the peptide in solution to give ligand 1. Ligand 8 was dissolved in HEPES buffer (pH 7.2), and 1 .3 equiv of Cy5-maleimide was added in aliquots until full conversion was achieved as monitored on analytical HPLC. The labeled ligand was then separated with SPE.The on-resin labeling was tested by synthesizing a DOTA chelate as shown in Scheme 3 (Figure 18). The Mtt protection on lysine was removed with 3% TFA and 5% /'Pr3SiH in CH2CI2. Here the inventors employed a bifunctional handle to investigate its utility for coupling commonly available labeling moieties, for dual-modality labeling (e.g., optical/magnetic), for coupling to nanoparticles with lanthanide labels, and for preparing dimeric ligands at a later stage (unpublished data). For this purpose, the synthetic scheme was designed to incorporate orthogonally protected Fmoc-Cys(Mmt)-OH at the end of the Ado linker and coupled using standard NR-Fmoc/iBu strategy to give intermediate 7. T...
  • 70
  • Wang-Fmoc-Lys(Mtt)-OH resin [ No CAS ]
  • [ 27144-18-9 ]
  • [ 136030-33-6 ]
  • [ 99953-00-1 ]
  • [ 1160761-39-6 ]
YieldReaction ConditionsOperation in experiment
This was achieved from Wang resin, which was mesylated using an 8-fold excess of MsCI at 0C to activate OH groups, followed by coupling with Fmoc-Lys(Mtt)-OH. In a 50 mL bottle containing 1 g of Wang resin (0.93 mmol/g) with a magnetic stir bar, dry CH2CI2 was added to swell the resin for 1 h. The solvent was removed, the bottle closed with a septum and flushed with nitrogen, and /'Pr2NEt (9 equiv, 1.4 mL) in 15 mL of CH2CI2 was added. The resin slurry was cooled to 0C followed by dropwise addition of MsCI (8 equiv, 0.57 mL) in 2 mL of CH2CI2. The reaction was stirred for 20 min, the ice-bath was removed, and the stirring was continued for another 20 min (rt). The resin was then transferred to a syringe reactor and washed with dry CH2CI2 and dry DMF. Fmoc-Lys(Mtt)-OH (2 equiv, 1 .2g), Csl (2 equiv, 0.5g), /'Pr2NEt (2 equiv, 0.32 mL) in ca. 10 mL of dry DMF were added, and the reaction was stirred overnight at rt. The NR-Fmoc protection from 3 was removed with piperidine in DMF, and Fmoc- Tic-OH was coupled using standard NR-Fmoc/iBu strategy of solid-phase peptide synthesis to give intermediate 4. The resin was NR-Fmoc deprotected with piperidine/DMF (1 :4) and then washed with DMF, CH2CI2, 0.2 M HOBt/DMF, and DMF. Fmoc-Tic-OH (3 equiv), HOCt (3 equiv), and DIC (6 equiv) in DMF were then added, and the reaction was stirred for 2 h. For final coupling, Boc-Dmt-OH was used since a free N terminal peptide can be directly obtained after final acidic cleavage. Additionally, a choice of NR-terminal Boc protection prevents against premature Fmoc deprotection by free NH2 groups released on the side chain of lysine and any consequent cyclative elimination (dioxopiperazine) of Dmt- Tic from Dmt-Tic- Lys(R)-resin. (Caspasso, S.; Sica, F.; Mazzarella, L.; Balboni, G.; Guerrini, R.; Salvadori, S. Int. J. Pep. Protein Res. 1995, 45, 567-573) Lastly, Boc is smaller than Fmoc, facilitating a faster coupling rate. Despite that, Boc- Dmt coupling to the sterically hindered Tic-Lys(R)-resin was challenging. The coupling has to be mediated via strong HBTU activation accelerated by microwave. Boc-Dmt-OH (3 equiv), HBTU (3 equiv), and /'Pr2NEt (6 equiv) in DMF were added to the resin, and the reaction was heated in a household microwave for 3 s. The reaction was stirred until it cooled to rt; the heating was repeated (5x), and the resin was stirred for another 2 h. Also, there is a conceptual disadvantage of using an unprotected phenolic group on Dmt. The reaction leads to Dmt self-condensation, forming small amounts of Dmt-oligomers. Nonetheless, the formed phenolic esters are susceptible to mild aminolysis and can be selectively removed by treatment with 50% piperidine in CH2CI2:MeOH (5:1 ) before acidic cleavage. Following Dmt coupling to give intermediate 5, the coupling of dyes and chelating agents can be performed on the resin or in solution. For Cy5 labeling, more cost-effective conjugation of dye in solution was preferred via a thiolmaleimide reaction. 3-Mercaptopropionyl was chosen as a small linker for C-terminal attachment as the dye possesses a 12-atom linker with maleimide at the end. Thus, Trt-SCH2CH2COOH was coupled to 5 using HOCt/DIC protocol and then cleaved with acidic cocktail (82.5% TFA, 5% H20, 5% /'Pr3SiH, 5% thioanisole, and 2.5% ethanedithiol) to give ligand 6 (Scheme 2 shown in Figure 17).
  • 71
  • [ 29022-11-5 ]
  • [ 71989-33-8 ]
  • [ 136030-33-6 ]
  • [ 184962-88-7 ]
  • C26H31N4O8Pol [ No CAS ]
  • 72
  • [ 68858-20-8 ]
  • [ 71989-33-8 ]
  • [ 136030-33-6 ]
  • [ 184962-88-7 ]
  • C29H37N4O8Pol [ No CAS ]
  • 73
  • [ 35661-39-3 ]
  • [ 71989-31-6 ]
  • [ 71989-33-8 ]
  • [ 103213-32-7 ]
  • [ 71989-35-0 ]
  • [ 136030-33-6 ]
  • [ 143824-78-6 ]
  • PS(Tet)WATC-NH2 [ No CAS ]
  • 74
  • [ 10352-88-2 ]
  • [ 205526-24-5 ]
  • [ 35661-39-3 ]
  • C40H33ClNO4Pol [ No CAS ]
  • [ 71989-31-6 ]
  • [ 136030-33-6 ]
  • [ 111061-56-4 ]
  • C43H54F2N6O9 [ No CAS ]
  • 75
  • [ 68858-20-8 ]
  • [ 35661-40-6 ]
  • [ 71989-14-5 ]
  • [ 71989-26-9 ]
  • [ 103213-32-7 ]
  • [ 136030-33-6 ]
  • [ 143824-78-6 ]
  • Fmoc-[β-dimethylcysteine](Trt)-OH [ No CAS ]
  • H-Asp-c[Pen-Phe-Trp-Lys-Tic-Cys]-Val-OH [ No CAS ]
  • 76
  • [ 68858-20-8 ]
  • [ 35661-40-6 ]
  • [ 71989-14-5 ]
  • [ 103213-32-7 ]
  • [ 109425-55-0 ]
  • [ 136030-33-6 ]
  • 1-tert-butoxycarbonyl-N-[(9-fluorenyl)methoxycarbonyl]-D-tryptophan [ No CAS ]
  • Fmoc-[β-dimethylcysteine](Trt)-OH [ No CAS ]
  • H-Asp-c[Pen-Phe-D-Trp-Orn-Tic-Cys]-Val-OH [ No CAS ]
  • 77
  • C55H73N10O12Pol [ No CAS ]
  • [ 35661-40-6 ]
  • [ 108-24-7 ]
  • [ 71989-35-0 ]
  • [ 132388-59-1 ]
  • [ 136030-33-6 ]
  • Fmoc-D-Tyr(O-tBu)-OH [ No CAS ]
  • Ac-[D-Tyr46,Tic47,Thr49,azaGly51,Arg(Me)53,Trp54]metastin(46-54); Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid [ No CAS ]
  • 78
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Fmoc-β-(3-benzothienyl)-L-alanine [ No CAS ]
  • Ac-Tic-Arg-(pI)DPhe-3Bal-NH2 [ No CAS ]
  • 79
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Fmoc-β-(3-benzothienyl)-L-alanine [ No CAS ]
  • Ac-3Bal-Arg-(pI)DPhe-Tic-NH2 [ No CAS ]
  • 80
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • [ 199110-64-0 ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • C42H47IN8O5 [ No CAS ]
  • 81
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • [ 199110-64-0 ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • C42H47IN8O5 [ No CAS ]
  • 82
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • [ 109425-51-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-His-Arg-(pI)DPhe-Tic-NH<SUB>2</SUB> [ No CAS ]
  • 83
  • [ 35661-40-6 ]
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Phe-Arg-(pI)DPhe-Tic-NH2 [ No CAS ]
  • 84
  • [ 35661-40-6 ]
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Tic-Arg-(pI)DPhe-Phe-NH2 [ No CAS ]
  • 85
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine [ No CAS ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Nal(2)-Arg-(pI)DPhe-Tic-NH2 [ No CAS ]
  • 86
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • N-(9-fluorenylmethoxycarbonyl)-3-(β-naphthyl)-L-alanine [ No CAS ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Tic-Arg-(pI)DPhe-Nal(2')-NH2 [ No CAS ]
  • 87
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine [ No CAS ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-DNal(2)-Arg-(pI)DPhe-Tic-NH2 [ No CAS ]
  • 88
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • N-[(9-fluorenyl)methoxycarbonyl]-3-(2-naphthyl)-D-alanine [ No CAS ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Tic-Arg-(pI)DPhe-DNal(2')-NH2 [ No CAS ]
  • 89
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Arg-Arg-(pI)DPhe-Tic-NH<SUB>2</SUB> [ No CAS ]
  • 90
  • [ 108-24-7 ]
  • [ 136030-33-6 ]
  • Nα-(9-fluorenylmethyloxycarbonyl)-Nγ-2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl-L-arginine [ No CAS ]
  • (R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-iodophenyl)propanoic acid [ No CAS ]
  • Ac-Tic-Arg-(pI)DPhe-Tic-NH2 [ No CAS ]
  • 91
  • C84H94ClN10O13PolS [ No CAS ]
  • [ 136030-33-6 ]
  • C94H103ClN11O14PolS [ No CAS ]
  • 92
  • tert-butyl 4-amino-4-((2-chloro-3-methylphenyl)carbamoyl)piperidine-1-carboxylate [ No CAS ]
  • [ 136030-33-6 ]
  • tert-butyl (S)-4-((2-chloro-3-methylphenyl)carbamoyl)-4-(1.2.3 .4-tetrahydroisoquinoline-3-carboxamido)piperidine-1-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
38% With N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In dichloromethane; A solution of Intermediate 11B (95 mg, 0.26 mmol) and (S)-2-(((9H-fluoren-9- yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (155 mg, 0.39 mmol) in DCM (4 mL) was treated with DIEA (225 muL, 0.26 mmol) and HATU (295 mg, 0.8 mmol). After stirring overnight, the reaction mixture was partitioned between DCM and 1 M aqueous solution of HCl (5 mL each). The aqueous layer was re-extracted with DCM (5 mL). The combined organic layers were dried (MgSO4), filtered and concentrated and the crude product was purified by chromatography (EA/hexane) to afford 208 mg (38%) of Intermediate 11C. LCMS [m/z] calculated for C43H45ClN4O6: 748.3; found 771.0 [M+Na]+, tR=2.85 min (Method 4).
  • 93
  • tert-butyl (S)-3-amino-4-((4-chloro-3-methylphenyl)amino)-4-oxobutanoate [ No CAS ]
  • [ 136030-33-6 ]
  • (9H-fluoren-9-yl)methyl (S)-3-(((S)-4-(tert-butoxy)-1-((4-chloro-3-methylphenyl)amino)-1,4-dioxobutan-2-yl)carbamoyl)-3.4-dihydroisoquinoline-2(1H)carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
65% A solution of (S)-2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (10.5 g, 26.2 mmol) and Intermediate 17B (13 g, 24.9 mmol) in DCM (100 mL) at 0 C was treated with DIEA (17.4 ml, 100 mmol) and, after 10 min, HATU (18.96 g, 49.9 mmol) was added portionwise at 0 C. The reaction mixture was stirred at 0 C for 3 h. The reaction mixture was partitioned between DCM (200 mL) and an aqueous 1 M HCl solution (200 mL). The layers were separated and the organic layer was washed an aqueous 1 M HCl solution (2x200 mL) and brine (200 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated. The resulting crude material was purified by chromatography (EA/isohexane) to afford 13.6g (65%) of Intermediate 17C as a white foam. LCMS [m/z] calculated for C40H40ClN3O6: 693.3; found 716 [M+Na]+, tR=3.13 min (Method 4).
  • 94
  • (S)-tert-butyl (3-amino-4-((4-chloro-3-methylphenyl)amino)-4-oxobutyl)carbamate [ No CAS ]
  • [ 136030-33-6 ]
  • (9H-fluoren-9-yl)methyl (S)-3-(((S)-4-((tert-butoxycarbonyl)amino)-1-((4-chloro-3-methylphenyl)amino)-1-oxobutan-2-yl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate [ No CAS ]
YieldReaction ConditionsOperation in experiment
77% Into a solution of (S)-tert-butyl (3-amino-4-((4-chloro-3-methylphenyl)amino)- 4-oxobutyl)carbamate (2.06 g, 6.03 mmol) in DMF (20 mL) at 0C were added (S)- 2-(((9H-fluoren-9-yl)methoxy)carbonyl)-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (2.19 g, 5.48 mmol) and N-ethyl-N-isopropylpropan-2-amine (2.86 mL, 16.44 mmol). After 5 min, HATU (3.12 g, 8.22 mmol) was added portionwise and the mixture was stirred at 0 C for 2 h. Water (20 mL) was added and the resulting white precipitate was collected by filtration. The solid was dissolved in DCM, dried (MgSO4), filtered and concentrated to afford an orange oil. The crude product was purified by chromatography (EA / isohexane) to afford 3.2 g (77%) of Intermediate 10A as a white solid.1H NMR (400 MHz, DMSO-d6, 363 K) delta 9.49 (s, 1H), 7.92- 7.81 (m, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.68- 7.56 (m, 2H), 7.47- 7.37 (m, 3H), 7.37- 7.28 (m, 3H), 7.26 (d, J = 8.6 Hz, 1H), 7.23- 7.09 (m, 4H), 6.15 (s, 1H), 4.75 (t, J = 5.6 Hz, 1H), 4.64 (d, J = 15.7 Hz, 1H), 4.53 (d, J = 15.7 Hz, 1H), 4.48- 4.20 (m, 4H), 3.22- 3.09 (m, 2H), 2.95- 2.77 (m, 2H), 2.27 (s, 3H), 1.93- 1.78 (m, 1H), 1.71 (dtd, J = 13.9, 8.0, 6.1 Hz, 1H), 1.36 (s, 9H).
  • 95
  • [ 136030-33-6 ]
  • tert-butyl ((S)-4-((4-chloro-3-methylphenyl)amino)-4-oxo-3-((S)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)carbamate [ No CAS ]
  • 96
  • [ 136030-33-6 ]
  • tert-butyl ((S)-4-((4-chloro-3-methylphenyl)amino)-4-oxo-3-((S)-2-(4-oxo-4-(piperidin-1-yl)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamido)butyl)carbamate [ No CAS ]
  • 97
  • [ 136030-33-6 ]
  • (S)-N-((S)-4-amino-1-((4-chloro-3-methylphenyl)amino)-1-oxobutan-2-yl)-2-(4-oxo-4-(piperidin-1-yl)butanoyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide [ No CAS ]
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