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

HRID 1096857Notes

Reaction equation

HRID 1096857 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][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37])=[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:74]1([NH:77][CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:76][CH2:75]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])([CH3:22])[CH3:23])=[O:18])[CH:10]([CH2:11][C:12]([C:27]3[S:31][C:30]([CH2:32][CH2:33][CH2:34][O:35][Si:36]([C:39]([CH3:41])([CH3:40])[CH3:42])([CH3:38])[CH3:37])=[N:29][CH:28]=3)=[C:13]2[C:24](=[O:25])[N:77]([CH:74]2[CH2:76][CH2:75]2)[CH2:78][C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH3:86])[C:80]=2[CH3:87])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

8

Reactant 5

HCID 757711-Hydroxybenzotriazole2×HCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 58006030Cyclopropyl-(2-methyl-3-methoxybenzyl)amine2×HCID 685729567-{2-[3-(tert-Butyldimethylsilanyloxy)propyl]thiazol-5-yl}-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3,9-di-tert-butyl ester

Product 1

HCID 685705247{2-[3-(tert-Butyldimethylsilanyloxy)propyl]thiazol-5-yl}-6-[cyclopropyl-(3-methoxy-2-methylbenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid di-tert-butyl esterYield 56.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent

Procedure

To a stirred sol. of compound D6 (2.66 g, 4.26 mmol) in CH2Cl2 (45 mL) were added EDC.HCl (2.04 g, 10.6 mmol), HOBt (783 mg, 5.11 mmol), DMAP (13 mg, 0.107 mmol), and DIPEA (3.35 mL, 19.19 mmol). After 15 min cyclopropyl-(3-methoxy-2-methyl-benzyl)amine (prepared by reductive amination from 3-methoxy-2-methylbenzaldehyde, Comins, D. L.; Brown, J. D., J. Org. Chem., 1989, 54, 3730 and cyclopropylamine, 2.45 g, 12.80 mmol) was added and stirring was continued over 6 days. Three times were added cyclopropyl-(3-methoxy-2-methyl-benzyl)amine (817 mg, 4.27 mmol) and HOBt (392 mg, 2.55 mmol). The reaction mixture was partitioned between aq. 1M HCl and CH2Cl2, and the phases were separated. The org. layer was washed with aq. sat. NaHCO3, dried over MgSO4, filtered, and the solvents were removed in vacuo. Purification by FC (heptane/EtOAc 7/3→1/1) yielded the title product (1.91 g, 56%). LC-MS: tR=1.27 min, ES+: 797.59.

Workup

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

Sources & evidence

ORD record
ord-29f2028576194208930c6f2c8fd494e2
Source dataset
uspto-grants-2012_03
Patent number
US08138340B2

Reaction notes

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