1-Hydroxybenzotriazole → 7-{2-[2-(tert-Butyldimethylsilanyloxy)ethoxymethyl]thiazol-5-yl}-6-[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl ester

HRID 1096858Notes

Reaction equation

HRID 1096858 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])=[N:29][CH:28]=3)=[C:13]2[C:24](O)=[O:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH:75]1([NH:78][CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([Cl:86])[C:81]=2[Cl:87])[CH2:77][CH2:76]1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][O:33][CH2:34][CH2:35][O:36][Si:37]([C:40]([CH3:43])([CH3:41])[CH3:42])([CH3:38])[CH3:39])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:78]([CH:75]2[CH2:76][CH2:77]2)[CH2:79][C:80]2[CH:85]=[CH:84][CH:83]=[C:82]([Cl:86])[C:81]=2[Cl:87])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 834599Cyclopropyl-(2,3-dichloro-benzyl)-amine2×HCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 685735637-{2-[2-(tert-Butyldimethylsilanyloxy)ethoxymethyl]thiazol-5-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester

Product 1

HCID 685707897-{2-[2-(tert-Butyldimethylsilanyloxy)ethoxymethyl]thiazol-5-yl}-6-[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl esterYield 12.1%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a stirred sol. of compound D8 (0.38 g, 0.594 mmol) in CH2Cl2 (3.0 mL) were added EDC.HCl (0.285 g, 1.49 mmol), HOBt (0.109 g, 0.713 mmol), DMAP (2.0 mg, 0.15 mmol) and DIPEA (0.467 mL, 2.67 mmol). After 15 min cyclopropyl-(2,3-dichloro-benzyl)amine (0.257 g, 1.19 mmol) was added and stirring was continued for 7 days. Every day cyclopropyl-(2,3-dichlorobenzyl)amine (prepared by reductive amination from 2,3-dichlorobenzaldehyde and cyclopropylamine, 0.128 g, 0.59 mmol) was added. The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated, washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification of the crude by FC (heptane/EtOAc 7/3→1/1) yielded the title product (60 mg, 12%) as a yellow oil. LC-MS: tR=1.28 min, ES+: 837.48.

Workup

  1. customThe reaction mixture was partitioned between aq. 1M HCl and CH2Cl2
  2. customthe phases were separated
  3. washwashed with aq. sat. NaHCO3
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. customthe solvents were removed in vacuo
  7. customPurification of the crude by FC (heptane/EtOAc 7/3→1/1)

Sources & evidence

ORD record
ord-8ac95e8aceab44728a31653e054e6a40
Source dataset
uspto-grants-2012_03
Patent number
US08138340B2

Reaction notes

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