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

HRID 1012855

Reaction equation

HRID 1012855 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.C(Cl)Cl.CCCCCCC.C(Cl)Cl>[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

10

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 82%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8900HeptaneSolventHCID 21877088Acetonitrile methylene chlorideSolvent

Procedure

To a stirred solution of 3A (900 mg, 1.19 mmol) in CH3CN/CH2Cl2 (1:1, 60 mL) at RT was added Et2NH (3 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 (529 mg, 1.7 mmol) in CH2Cl2 (30 mL) was added EDAC.HCl (326 mg, 1.7 mmol), HOBt (230 mg, 1.7 mmol) and DIEA (627 μl, 3.6 mmol). After stirring at RT for 10 minutes a solution of the crude amine in CH2Cl2 (20 mL) was then added and the reaction mixture stirred for 18 h. Whereupon the reaction was washed with water (15 mL), 10% HCl (15 mL), 5% NaHCO3 (15 mL) and sat NaCl (15 mL) solutions, dried (Na2SO4), filtered, and the solvent removed to give an off white solid which was recrystallised from CH3CN to give 4A as a white solid (810 mg, 0.98 mmol, 82%). 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, CDCl3) δ 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, CDCl3) δ 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; LRMS m/z 849.2 (100%, [M+Na]+), 865.1 (20%, [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. washWhereupon the reaction was washed with water (15 mL), 10% HCl (15 mL), 5% NaHCO3 (15 mL)
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. customthe solvent removed
  9. customto give an off white solid which
  10. customwas recrystallised from CH3CN

Sources & evidence

ORD record
ord-26748d412e514fadace338f9df92df73
Source dataset
uspto-grants-2011_07
Patent number
US07977304B2

Linked notes

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