tert-butyl 5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate synthesis

9synthesis methods

Product Name:tert-butyl 5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate
CAS Number:1019890-58-4
Molecular formula:C19H29N3O2
Molecular Weight:331.45

109-01-3 Synthesis

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tert-butyl 5-((4-methylpiperazin-1-yl)methyl)isoindoline-2-carboxylate

1019890-58-4
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Yield:1019890-58-4 90%

Reaction Conditions:

Stage #1: 1-methyl-piperazine;5-formyl-1,2-dihydro-isoindole-2-carboxylic acid tertiary butyl esterwith acetic acid in dichloromethane at 20; for 0.166667 h;Inert atmosphere;
Stage #2: with sodium cyanoborohydride in dichloromethane at 20; for 3 h;Inert atmosphere;

Steps:

tert-Butyl 5-[(4-methylpiperazin-1-yl)methyl]-isoindoline-2-carboxylate (6)

To a mixture of 5 (1.83 g, 7.40 mmol) and 1-methylpiperazine (1.0 g, 10.0 mmol, 1.3 equiv) in DCM (45 mL) was added acetic acid (0.85 mL, 14.8 mmol, 2.0 equiv). The mixture was stirred at rt for 10 min, and then was added sodium triacetoxyborohydride (2.41 g, 11.4 mmol, 1.5 equiv). The mixture was stirred at rt under N₂ atmosphere for 3h. The reaction mixture was quenched by adding saturated NaHCO₃ solution, and the resulting mixture was extracted with DCM (3×100 mL). The combined organic phases were then washed with water (20 mL) and brine (2×30 mL) and dried (Na₂SO₄). After the solvent was removed in vacuo, the crude product was purified by flash column chromatography on silica gel (DCM/MeOH = 20:1) to give 6 (2.18 g, 6.6 mmol, 90%). mp 45-47 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.14-7.24 (m, 3H), 4.67 (s, 2H), 4.62 (s, 2H), 3.50 (s, 2H), 2.47 (brs, 8H), 2.29 (s, 3H), 1.51 (s, 9H); ¹³C NMR (125 MHz, CDCl₃) δ 155.19, 138.21 (+138.16, rotamer), 138.09, 137.74, 136.80 (+136.45), 129.03, 124.10 (+123.85), 123.10 (+122.86), 80.26, 63.46, 55.65, 53.63, 52.83 (+52.73), 52.53 (+52.42), 46.57, 29.17. HRMS/ESI : m/z [M+Na]⁺ calcd. for C₁₉H₂₉N₃NaO₂: 354.2152; found: 354.2159.

References:

Liang, Cuirong;Gu, Lingling;Yang, Yang;Chen, Xin [Synthetic Communications,2014,vol. 44,# 16,p. 2416 - 2425] Location in patent:supporting information