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1,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochloride → 9H-fluoren-9-ylmethyl N-[(2S)-1-[[(2S)-1-[[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-[4-(4-methylpiperazin-1-yl)phenyl]-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 1057080
Notes
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Reaction equation

HRID 1057080 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:83][CH3:84])=[CH:48][C:49]5[C:55](=[O:56])[N:54]6[CH:57]=[C:58]([C:60]7[CH:65]=[CH:64][C:63]([N:66]8[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]8)=[CH:62][CH:61]=7)[CH2:59][C@H:53]6[C:52](=[O:73])[N:51]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:81])([CH3:80])[CH3:79])[C:50]=5[CH:82]=4)[C:37]([O:39][CH3:40])=[CH:38][C:22]=3[C:21](=[O:85])[N:20]2[CH:86]=1.[CH:87]1[C:99]2[CH:98]([CH2:100][O:101][C:102]([NH:104][C@@H:105]([CH:114]([CH3:116])[CH3:115])[C:106]([NH:108][C@@H:109]([CH3:113])[C:110](O)=[O:111])=[O:107])=[O:103])[C:97]3[C:92](=[CH:93][CH:94]=[CH:95][CH:96]=3)[C:91]=2[CH:90]=[CH:89][CH:88]=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:83][CH3:84])=[CH:48][C:49]3[C:55](=[O:56])[N:54]4[CH:57]=[C:58]([C:60]5[CH:61]=[CH:62][C:63]([N:66]6[CH2:71][CH2:70][N:69]([CH3:72])[CH2:68][CH2:67]6)=[CH:64][CH:65]=5)[CH2:59][C@H:53]4[C:52](=[O:73])[N:51]([CH2:74][O:75][CH2:76][CH2:77][Si:78]([CH3:80])([CH3:79])[CH3:81])[C:50]=3[CH:82]=2)=[CH:35][C:23]2[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:25](=[O:26])[C@@H:19]3[CH2:18][C:17](/[CH:16]=[CH:15]/[CH2:14][NH:13][C:110](=[O:111])[C@@H:109]([NH:108][C:106](=[O:107])[C@@H:105]([NH:104][C:102](=[O:103])[O:101][CH2:100][CH:98]4[C:99]5[CH:87]=[CH:88][CH:89]=[CH:90][C:91]=5[C:92]5[C:97]4=[CH:96][CH:95]=[CH:94][CH:93]=5)[CH:114]([CH3:116])[CH3:115])[CH3:113])=[CH:86][N:20]3[C:21](=[O:85])[C:22]=2[CH:38]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

5

Reactant 3

HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 11165770Fmoc-Val-Ala-OHHCID 90409067(S)-2-((E)-3-aminoprop-1-enyl)-7-methoxy-8-(3-((S)-7-methoxy-2-(4-(4-methylpiperazin-1-yl)phenyl)-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 131736461
9H-fluoren-9-ylmethyl N-[(2S)-1-[[(2S)-1-[[(E)-3-[(6aS)-3-[3-[[(6aS)-2-methoxy-8-[4-(4-methylpiperazin-1-yl)phenyl]-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
Yield 60.2%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.0541 g, 0.282 mmol, 1.0 eq.) was added to a solution of allylamine 17e (assumed 100% yield, 0.296 g, 0.282 mmol, 1.0 eq.) and HO-Ala-Val-Fmoc 12 (0.116 g, 0.282 mmol, 1.0 eq.) in dry dichloromethane (18 mL). The reaction mixture was stirred for 80 minutes at room temperature when the reaction mixture was diluted with dichloromethane (30 mL) and washed sequentially with water (30 mL) and brine (30 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; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the product as a yellow solid (0.245 g, 60%). LC/MS (2.706 min (ES+)), m/z: 721.5 ½[M+2H]+.

Workup

  1. washwashed sequentially with water (30 mL) and brine (30 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; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH)

Sources & evidence

ORD record
ord-ff3580e6c9684c618402bbb2c60815af
Source dataset
uspto-grants-2016_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09399073B2

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes