1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 9H-fluoren-9-ylmethyl N-[(2R)-1-[[(2S)-1-[[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-methyl-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enyl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamate

HRID 1057078Notes

Reaction equation

HRID 1057078 reaction equation
Cl.C(N=C=NCCCN(C)C)C.[NH2:13][CH2:14]/[CH:15]=[CH:16]/[C:17]1[CH2:18][C@H:19]2[C:25](=[O:26])[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:23]3[CH:35]=[C:36]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]4[C:47]([O:71][CH3:72])=[CH:48][C:49]5[C:55](=[O:56])[N:54]6[CH:57]=[C:58]([CH3:60])[CH2:59][C@H:53]6[C:52](=[O:61])[N:51]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:69])([CH3:68])[CH3:67])[C:50]=5[CH:70]=4)[C:37]([O:39][CH3:40])=[CH:38][C:22]=3[C:21](=[O:73])[N:20]2[CH:74]=1.[CH:75]1[C:87]2[CH:86]([CH2:88][O:89][C:90]([NH:92][C@@H:93]([CH:102]([CH3:104])[CH3:103])[C:94]([NH:96][C@@H:97]([CH3:101])[C:98](O)=[O:99])=[O:95])=[O:91])[C:85]3[C:80](=[CH:81][CH:82]=[CH:83][CH:84]=3)[C:79]=2[CH:78]=[CH:77][CH:76]=1>ClCCl>[CH3:40][O:39][C:37]1[C:36]([O:41][CH2:42][CH2:43][CH2:44][O:45][C:46]2[C:47]([O:71][CH3:72])=[CH:48][C:49]3[C:55](=[O:56])[N:54]4[CH:57]=[C:58]([CH3:60])[CH2:59][C@H:53]4[C:52](=[O:61])[N:51]([CH2:62][O:63][CH2:64][CH2:65][Si:66]([CH3:68])([CH3:67])[CH3:69])[C:50]=3[CH:70]=2)=[CH:35][C:23]2[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:25](=[O:26])[C@@H:19]3[CH2:18][C:17](/[CH:16]=[CH:15]/[CH2:14][NH:13][C:98](=[O:99])[C@@H:97]([NH:96][C:94](=[O:95])[C@H:93]([NH:92][C:90](=[O:91])[O:89][CH2:88][CH:86]4[C:87]5[CH:75]=[CH:76][CH:77]=[CH:78][C:79]=5[C:80]5[C:85]4=[CH:84][CH:83]=[CH:82][CH:81]=5)[CH:102]([CH3:104])[CH3:103])[CH3:101])=[CH:74][N:20]3[C:21](=[O:73])[C:22]=2[CH:38]=1

Participants

5

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 11165770Fmoc-Val-Ala-OHHCID 90407865(S)-2-((E)-3-aminoprop-1-enyl)-7-methoxy-8-(3-((S)-7-methoxy-2-methyl-5,11-dioxo-10-((2-(trimethylsilyl)ethoxy)methyl)-5,10,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yloxy)propoxy)-10-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione

Product 1

HCID 1317364599H-fluoren-9-ylmethyl N-[(2R)-1-[[(2S)-1-[[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-methyl-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]prop-2-enyl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]carbamateYield 41%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.018 g, 0.095 mmol, 1.0 eq.) was added to a solution of allylamine 17a (assumed 100% yield, 0.100 g, 0.095 mmol, 1.0 eq.) and HO-Ala-Val-Fmoc 12 (0.036 g, 0.095 mmol, 1.0 eq.) in dry dichloromethane (6 mL). The reaction mixture was stirred for 120 minutes at room temperature when the reaction mixture was diluted with dichloromethane (10 mL) and washed sequentially with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4, filtered and excess dichloromethane removed under reduced pressure. The resulting residue was purified by flash chromatography (silica gel; 100:1 v/v DCM/MeOH to 40:1 v/v DCM/MeOH) to afford the product as a yellow solid (0.050 g, 35%). LC/MS (3.677 min (ES+)), m/z: 1281.42 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.76 (d, 2H, J=7.7 Hz), 7.58 (m, 2H), 7.40 (t, 2H, J=7.6 Hz), 7.34 (d, 2H, J=5.7 Hz), 7.31 (m, 3H), 7.25 (m, 2H), 6.93 (s, 1H), 6.68 (m, 1H), 6.34 (m, 3H), 5.58 (m, 1H), 5.49 (m, 2H), 4.71 (m, 2H), 4.45 (m, 5H), 4.27 (m, 4H), 4.22 (t, 1H, J=7.0 Hz), 3.97 (m, 2H), 3.89 (m, 7H), 3.75 (m, 2H), 3.65 (m, 3H), 3.44 (m, 1H), 2.77 (m, 2H), 2.43 (m, 2H), 2.14 (m, 1H), 1.83 (d, 3H, J=1.0 Hz), 1.40 (d, 3H, J=6.9 Hz), 0.99-0.91 (m, 10H), 0.01 (s, 9H), 0.00 (s, 9H).

Workup

  1. washwashed sequentially with water (10 mL) and brine (10 mL)
  2. dry with materialThe organic layer was dried over MgSO4
  3. filtrationfiltered
  4. customexcess dichloromethane removed under reduced pressure
  5. customThe resulting residue was purified by flash chromatography (silica gel; 100:1 v/v DCM/MeOH to 40:1 v/v DCM/MeOH)

Sources & evidence

ORD record
ord-758f38aa81794056943047559f520a70
Source dataset
uspto-grants-2016_07
Patent number
US09399073B2

Reaction notes

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