tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate Chemical Properties

Boiling point:

403.7±45.0 °C(Predicted)

Density 

1.153±0.06 g/cm3(Predicted)

storage temp. 

2-8°C

pka

14.44±0.10(Predicted)

Appearance

White to off-white Solid

tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate Usage And Synthesis

Uses

N-Boc-6-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline is an intermediate used to prepare phosphonate-substituted HIV protease inhibitors for treatment of AIDS and other viral infections. It is also used in the synthesis of immunosuppressant heterocyclic compdounds for treating or preventing diseases assocd. with EDG receptor mediated signal transduction.

Synthesis

General procedure for the synthesis of tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate from 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid: In Example 16, tert-butyl 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2- carboxylate (D-1 ), the intermediate 6-bromomethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid, was prepared as follows: firstly, under nitrogen protection, the Borane-THF complex (99.17 mL, 99.17 mmol) was slowly added to a solution of 2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (12.50 g, 45.08 mmol) in anhydrous THF (125.0 mL) via a syringe, and the reaction lasted for 16 h at 25 °C. Subsequently, water (10.0 mL) was slowly added followed by 2.0 M Na2CO3 solution (15.0 mL). The mixture was stirred for 15 min and then diluted with EtOAc to separate the organic layer. The organic layer was washed with 1 M HCl, dried over MgSO4 and concentrated under reduced pressure to give an oil. The oily substance was purified by silica gel chromatography to give the intermediate D-1-1 (11.8 g, 99.3% yield) as a white solid. Next, D-1-1 (9.50 g, 36.1 mmol) and N,N-diisopropylethylamine (9.43 mL, 54.1 mmol) were dissolved in dichloromethane (200.0 mL), triphenylphosphine dibromide (23.79 g, 54.11 mmol) was added, and the reaction was stirred for 1 hr and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography to afford the target product D-1 (8.74 g, 74% yield) as a white solid.

References

[1] Patent: US2016/24059, 2016, A1. Location in patent: Paragraph 0308-0309
[2] Patent: WO2012/122340, 2012, A1. Location in patent: Page/Page column 77
[3] Patent: US2014/73629, 2014, A1. Location in patent: Paragraph 0100; 0101
[4] Patent: WO2017/160632, 2017, A1. Location in patent: Page/Page column 78; 79
[5] Patent: WO2017/216726, 2017, A1. Location in patent: Page/Page column 643-644