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Hydrochloric Acid → [1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3h-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1h-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester

HRID 79999
Notes
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Reaction equation

HRID 79999 reaction equation
C([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[C:30]([C:35]6[NH:36][C:37]([CH:40]7[CH2:46][C:43]8([CH2:45][CH2:44]8)[CH2:42][N:41]7[C:47](=[O:57])[CH:48]([NH:52]C(OC)=O)[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=6)[CH:31]=5)[CH:26]=4)=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:58][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.CN1C[CH2:65][O:64][CH2:63]C1.[CH3:67][O:68][C:69]([NH:71][CH:72]([CH2:76][CH3:77])C(O)=O)=[O:70].CN(C([O:85]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CO.CN(C=O)C>[CH3:63][O:64][C:65](=[O:85])[NH:52][CH:48]([C:47]([N:41]1[CH:40]([C:37]2[NH:36][C:35]([C:30]3[CH:29]=[CH:28][C:27]4[C:32](=[CH:33][CH:34]=[C:25]([C:22]5[CH:21]=[CH:20][C:19]([C:16]6[NH:15][C:14]([CH:13]7[CH:12]8[CH2:58][CH:9]([CH2:10][CH2:11]8)[N:8]7[C:6](=[O:5])[CH:72]([NH:71][C:69]([O:68][CH3:67])=[O:70])[CH2:76][CH3:77])=[N:18][CH:17]=6)=[CH:24][CH:23]=5)[CH:26]=4)[CH:31]=3)=[CH:39][N:38]=2)[CH2:46][C:43]2([CH2:44][CH2:45]2)[CH2:42]1)=[O:57])[CH:49]([CH3:50])[CH3:51]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 79724-MethylmorpholineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 434699742-Methoxycarbonylamino-butyric acidHCID 66620794
3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl]-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

Product 1

HCID 66620756[1-(6-{5-[6-(4-{2-[2-(2-Methoxycarbonylamino-butyryl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3h-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1h-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl esterYield 80.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6228DimethylformamideSolvent

Procedure

To 3-{5-[4-(6-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (60 mg, 0.077 mmol) in dioxanes (2 mL) and MeOH (0.5 mL) was added 4N HCl in dioxanes (160 μL). The suspension was stirred for 2 h then concentrated to afford the HCL salt of the crude amine. To the crude amine in DMF (1 mL) was added N-methylmorpholine (34 μL, 0.31 mmol), 2-methoxycarbonylamino-butyric acid (19 mg, 0.11 mmol) and HATU (35 mg, 0.09 mmol). After stirring for overnight the reaction was quenched with formic acid then purified by reverse phase preparative HPLC (5-45% MeCN—H2O; 0.1% formic acid modifier) to afford the title product (51 mg, 0.062 mmol, 80% yield). LCMS-ESI+: calc'd for C47H55N8O6: 827.4 (M+H+). Found: 827.4 (M+H+).

Workup

  1. concentrationthen concentrated
  2. customto afford the HCL salt of the crude amine
  3. stirringAfter stirring for overnight the reaction
  4. customwas quenched with formic acid
  5. customthen purified by reverse phase preparative HPLC (5-45% MeCN—H2O; 0.1% formic acid modifier)

Sources & evidence

ORD record
ord-557ac123ec6e4cd69a721a0a2e337988
Source dataset
uspto-grants-2014_09
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08841278B2

Reaction notes

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