Azido-mono-amide-DOTA-tris(t-Bu ester) → (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate

HRID 1052317Notes

Reaction equation

HRID 1052317 reaction equation
[C:1]([O:5][C:6](=[O:79])[CH2:7][N:8]([CH2:71][C:72](=[O:78])[O:73][C:74]([CH3:77])([CH3:76])[CH3:75])[C:9](=[O:70])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:65]=[CH:64][C:63]([O:66][CH2:67][C:68]#[CH:69])=[CH:62][CH:61]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:4])([CH3:3])[CH3:2].[N:80]([CH2:83][CH2:84][CH2:85][NH:86][C:87](=[O:125])[CH2:88][N:89]1[CH2:100][CH2:99][N:98]([CH2:101][C:102]([O:104][C:105]([CH3:108])([CH3:107])[CH3:106])=[O:103])[CH2:97][CH2:96][N:95]([CH2:109][C:110]([O:112][C:113]([CH3:116])([CH3:115])[CH3:114])=[O:111])[CH2:94][CH2:93][N:92]([CH2:117][C:118]([O:120][C:121]([CH3:124])([CH3:123])[CH3:122])=[O:119])[CH2:91][CH2:90]1)=[N+:81]=[N-:82]>C1COCC1.O.CCOC(C)=O.[Cu].[O-]S([O-])(=O)=O.[Cu+2]>[C:74]([O:73][C:72](=[O:78])[CH2:71][N:8]([CH2:7][C:6](=[O:79])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:9](=[O:70])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:16][N:17]([CH2:59][C:60]1[CH:61]=[CH:62][C:63]([O:66][CH2:67][C:68]2[N:82]=[N:81][N:80]([CH2:83][CH2:84][CH2:85][NH:86][C:87](=[O:125])[CH2:88][N:89]3[CH2:90][CH2:91][N:92]([CH2:117][C:118](=[O:119])[O:120][C:121]([CH3:122])([CH3:123])[CH3:124])[CH2:93][CH2:94][N:95]([CH2:109][C:110](=[O:111])[O:112][C:113]([CH3:115])([CH3:116])[CH3:114])[CH2:96][CH2:97][N:98]([CH2:101][C:102]([O:104][C:105]([CH3:108])([CH3:107])[CH3:106])=[O:103])[CH2:99][CH2:100]3)[CH:69]=2)=[CH:64][CH:65]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:58])[NH:24][CH2:25][CH2:26][CH2:27][CH2:28][C@@H:29]([C:51]([O:53][C:54]([CH3:55])([CH3:56])[CH3:57])=[O:52])[NH:30][C:31](=[O:50])[NH:32][C@H:33]([C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])([CH3:77])([CH3:76])[CH3:75]

Participants

8

Reactant 2

HCID 59487518Azido-mono-amide-DOTA-tris(t-Bu ester)HCID 86676473(14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate

Product 1

HCID 86676474(14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylateYield 13.7%

Reagents, catalysts & solvents 5

HCID 23978CopperCatalystHCID 24462Copper SulfateCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of (14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-(prop-2-yn-1-yloxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (145 mg, 0.13 mmol), tri-tert-butyl 2,2′,2″-(10-(2-((3-azidopropyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (59 mg, 0.090 mmol) in THF (5.0 mL) and water (1.0 mL) was added copper powder (6.4 mg) and 1 N CuSO4 (0.01 mL). The mixture was stirred at room temperature for overnight under nitrogen, diluted with EtOAc, washed with an aqueous saturated solution of EDTA. The solvent was evaporated under reduce pressure to afford a residue, which was purified by Biotage SP4 to afford ((14S,18S)-tri-tert-butyl 1-(1-(2-(bis(2-(tert-butoxy)-2-oxoethyl)amino)-2-oxoethyl)-1H-imidazol-2-yl)-8,16-dioxo-2-(4-((1-(3-(2-(4,7,10-tris(2-(tert-butoxy)-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl)acetamido)propyl)-1H-1,2,3-triazol-4-yl)methoxy)benzyl)-2,9,15,17-tetraazaicosane-14,18,20-tricarboxylate (21.8 mg). MS (ESI), 883.2 (M/2+H)′.

Workup

  1. washwashed with an aqueous saturated solution of EDTA
  2. customThe solvent was evaporated
  3. customto afford a residue, which
  4. customwas purified by Biotage SP4

Sources & evidence

ORD record
ord-e890600e06ac4871b3dcf179c0bf188b
Source dataset
uspto-grants-2016_07
Patent number
US09388144B2

Reaction notes

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