Diethylamine → ((r)-2-{(s)-2-[(r)-2-(9h-Fluoren-9-ylmethoxycarbonylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl ester

HRID 1012853

Reaction equation

HRID 1012853 reaction equation
[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:8]([CH3:10])[CH3:9].[NH:56](CC)CC.[C:61]([NH:78][C@@H:79]([C:81](O)=[O:82])[CH3:80])([O:63][CH2:64][CH:65]1[C:77]2[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=2)[C:71]2[C:66]1=[CH:67][CH:68]=[CH:69][CH:70]=2)=[O:62].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CC#N.CCCCCCC>[CH3:1][O:2][C:3](=[O:55])[CH2:4][NH:5][C:6](=[O:54])[C@H:7]([NH:11][C:12](=[O:53])[C@H:13]([NH:56][C:81](=[O:82])[C@H:79]([NH:78][C:61]([O:63][CH2:64][CH:65]1[C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=2[C:76]2[C:77]1=[CH:72][CH:73]=[CH:74][CH:75]=2)=[O:62])[CH3:80])[CH2:14][S:15][C:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH:8]([CH3:10])[CH3:9]

Participants

9

Reactant 6

HCID 8021DiethylamineHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 2724627(2R)-2-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}propanoic acidHCID 57696983{(R)-2-[(S)-2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionylamino]-3-methyl-butyrylamino}-acetic acid methyl ester

Product 1

HCID 57696991((r)-2-{(s)-2-[(r)-2-(9h-Fluoren-9-ylmethoxycarbonylamino)-propionylamino]-3-tritylsulfanyl-propionylamino}-3-methyl-butyrylamino)-acetic acid methyl esterYield 81%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolvent2×HCID 8900HeptaneSolvent

Procedure

To a stirred solution of 3 (400 mg, 0.53 mmol) in CH3CN (30 mL) at rt was added Et2NH (1.5 mL). After stirring for 3 h at rt the reaction mixture was diluted with heptane (60 mL) and concentrated to give the crude amine as a colourless oil. To a stirred solution of Fmoc-D-alanine (198 mg, 0.636 mmol) in CH3CN (25 mL) was added EDAC.HCl (122.0 mg, 0.634 mmol), HOBt (86 mg, 0.636 mmol) and DIEA (502 μl, 1.91 mmol). After stirring at rt for 15 minutes the crude amine was then added and the reaction mixture stirred for 18 h, solvent removed and the residue dissolved up in CH2Cl2 (50 mL), washed with water (15 mL) 10% HCl (15 mL), 5% NaHCO3 (15 mL) and sat NaCl (15 mL) solutions, dried (Na2SO4), filtered, and solvent removed to give a off white solid which was recrystallised from CH3CN to give 4 as a white solid (670 mg, 81%): mp=195-197° C.; [α]22D +5.1 (c 0.50, CHCl3); IR νmax 3267, 3054, 1744, 1706, 1635, 1531.1 cm−1; 1H NMR 400 MHz 7.75 (d, J=7.5 Hz, 2H), 7.52 (d, J=7.0 Hz, 2H), 7.39 (m, 7H), 7.26-7.15 (m, 13H), 6.79 (s, 1H), 6.62 (s, 1H), 5.47 (s, 1H), 4.43-4.28 (m, 4H), 4.13 (m, 1H), 4.01 (m, 1H), 3.88 (s, 2H), 3.63 (s, 3H), 2.81 (m, 1H), 2.52 (m, 1H), 2.26, (m, 1H), 1.30 (d, J=6.0 Hz, 3H), 0.94 (d, J=6.0 Hz, 3H), 0.89 (d, J=7.0 Hz, 3H); 13C NMR 100 MHz 172.7, 171.1, 170.2, 156.1, 144.4, 143.9, 143.8, 141.4, 129.6, 128.3, 127.9, 127.2, 127.1, 125.1, 120.1, 58.5, 52.7, 52.3, 50.8, 47.2, 41.0, 33.5, 30.4, 19.3, 19.0, 17.7; MS m/z 849.2 (M+Na)+, 865.1 (M+K)+.

Workup

  1. concentrationconcentrated
  2. customto give the crude amine as a colourless oil
  3. additionwas then added
  4. stirringthe reaction mixture stirred for 18 h
  5. customsolvent removed
  6. dissolutionthe residue dissolved up in CH2Cl2 (50 mL)
  7. washwashed with water (15 mL) 10% HCl (15 mL), 5% NaHCO3 (15 mL)
  8. dry with materialdried (Na2SO4)
  9. filtrationfiltered
  10. customsolvent removed
  11. customto give a off white solid which
  12. customwas recrystallised from CH3CN

Sources & evidence

ORD record
ord-ceb26b04a94b449fb019573950f22ed5
Source dataset
uspto-grants-2011_07
Patent number
US07977304B2

Linked notes

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