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

HRID 1096850Notes

Reaction equation

HRID 1096850 reaction equation
[Cl:1][C:2]([Cl:45])([Cl:44])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](O)=[O:35])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[CH:46]1([NH:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=2[Cl:58])[CH2:48][CH2:47]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:44][C:2]([Cl:1])([Cl:45])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34](=[O:35])[N:49]([CH:46]3[CH2:47][CH2:48]3)[CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[C:53]([Cl:57])[C:52]=3[Cl:58])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:13]2)=[O:8])([CH3:4])[CH3:5]

Participants

8

Reactant 5

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 834599Cyclopropyl-(2,3-dichloro-benzyl)-amineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 866370667-{3-[3-(tert-Butyldimethylsilanyloxy)propyl]isoxazol-5-yl}-3,9-diazabicyclo[3.3.1]non-6-ene-3,6,9-tricarboxylic acid 3-tert-butyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) ester

Product 1

HCID 866370697-{3-[3-(tert-Butyldimethylsilanyloxy)propyl]isoxazol-5-yl}-6-[cyclopropyl-(2,3-dichlorobenzyl)carbamoyl]-3,9-diazabicyclo[3.3.1]non-6-ene-3,9-dicarboxylic acid 3-tert-butyl ester 9-(2,2,2-trichloro-1,1-dimethylethyl) esterYield 35.2%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent2×

Procedure

A mixture of compound D3 (355 mg, 0.500 mmol), cyclopropyl-(2,3-dichlorobenzyl)-amine (prepared from 2,3-dichlorobenzaldehyde and cyclopropylamine by reductive amination, 324 mg, 1.50 mmol), DIPEA (0.342 mL, 2.00 mmol), DMAP (15.3 mg, 0.125 mmol), HOBt (101 mg, 0.75 mmol) and EDC.HCl (288 mg, 1.50 mmol) in CH2Cl2 (7 mL) was stirred at rt for 2 weeks. The mixture was diluted with more CH2Cl2, and washed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×). The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1) yielded the title compound (160 mg, 35%). LC-MS: tR=1.34 min, ES+: 909.35.

Workup

  1. washwashed with aq. 1M HCl (3×) and aq. sat. NaHCO3 (1×)
  2. dry with materialextracts were dried over MgSO4
  3. filtrationfiltered
  4. customthe solvents were removed under reduced pressure
  5. customPurification of the residue by FC (EtOAc/heptane 1:9→2:8 3:7→4:6→1:1)

Sources & evidence

ORD record
ord-e2e4601b702b421bad68d107514d8a5b
Source dataset
uspto-grants-2012_03
Patent number
US08138340B2

Reaction notes

Loading…