2-[(Tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid
[CAS# 878798-87-9]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Isoquinoline compound
• Name: 2-[(Tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid
• Synonyms: 2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1H-isoquinoline-8-carboxylic acid
• Molecular Formula: C₁₅H₁₉NO₄
• Molecular Weight: 277.32
• CAS Registry Number: 878798-87-9
• EC Number: 851-053-9
• SMILES: CC(C)(C)OC(=O)N1CCC2=C(C1)C(=CC=C2)C(=O)O

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 432.5±45.0 °C 760 mmHg (Calc.)^*
• Flash point: 215.4±28.7 °C (Calc.)^*
• Index of refraction: 1.563 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H319-H335
• Safety Statements: P261-P264-P264+P265-P270-P271-P280-P301+P317-P302+P352-P304+P340-P305+P351+P338-P319-P321-P330-P332+P317-P337+P317-P362+P364-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Specific target organ toxicity - single exposure	STOT SE	3	H335
Eye irritation	Eye Irrit.	2A	H319
Acute toxicity	Acute Tox.	4	H302
Skin irritation	Skin Irrit.	2	H315

Discovery and Applications

The chemical substance 2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid, commonly referred to as Boc-protected tetrahydroisoquinoline-8-carboxylic acid, is a key intermediate in organic synthesis, particularly in pharmaceutical chemistry. Its discovery and applications are well-established in the literature, rooted in the development of protecting group strategies and the synthesis of tetrahydroisoquinoline derivatives.

The origins of this compound are linked to the study of tetrahydroisoquinoline (THIQ), a bicyclic heterocycle containing a benzene ring fused to a piperidine ring, which has been explored since the early 20th century for its presence in alkaloids and pharmacological activity. The tert-butoxycarbonyl (Boc) protecting group, introduced in the 1950s by Louis Carpino, revolutionized amine protection due to its stability under basic conditions and ease of removal under mild acidic conditions. The specific functionalization of tetrahydroisoquinoline with a Boc-protected amine at the 2-position and a carboxylic acid at the 8-position emerged in the late 20th century, driven by the need for versatile intermediates in drug synthesis. Advances in regioselective functionalization, particularly carboxylation and protection strategies, enabled the precise construction of such molecules during the 1970s and 1980s.

Synthetically, 2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid is typically prepared from 1,2,3,4-tetrahydroisoquinoline or its derivatives. A common route involves protecting the nitrogen at the 2-position by reacting tetrahydroisoquinoline with di-tert-butyl dicarbonate under basic conditions to form the Boc-protected intermediate. The carboxylic acid group at the 8-position is introduced via regioselective functionalization, such as lithiation at the 8-position followed by quenching with carbon dioxide, or through oxidation of a precursor with a suitable functional group, like a methyl or aldehyde group. Alternatively, the synthesis may start from isoquinoline, which is reduced to tetrahydroisoquinoline, followed by protection and carboxylation. These steps rely on well-documented heterocyclic and protecting group chemistry, ensuring high yields and selectivity.

The primary application of this compound is as a synthetic intermediate in pharmaceutical chemistry. The tetrahydroisoquinoline core is a privileged scaffold in medicinal chemistry, found in numerous bioactive molecules, including analgesics, antihypertensives, and anticancer agents. The Boc group protects the nitrogen during synthetic manipulations, allowing selective reactions at the carboxylic acid or aromatic ring. The carboxylic acid at the 8-position serves as a handle for forming amides, esters, or other derivatives, which are critical for constructing drug candidates. For example, this compound is used in the synthesis of enzyme inhibitors and receptor modulators, where the tetrahydroisoquinoline framework enhances binding to biological targets, and the carboxylic acid enables further structural elaboration.

In addition to pharmaceuticals, the compound is utilized in academic research to study tetrahydroisoquinoline chemistry, including regioselective functionalization, conformational analysis, and the effects of Boc protection on reactivity. Its dual functionality—Boc-protected amine and carboxylic acid—makes it a valuable model for exploring peptide-like molecules and heterocyclic transformations. The compound also finds use in the synthesis of specialty chemicals, such as ligands or catalysts, where the rigid bicyclic structure and functional groups are advantageous.

The significance of 2-[(tert-butoxy)carbonyl]-1,2,3,4-tetrahydroisoquinoline-8-carboxylic acid lies in its role as a versatile building block that combines the biological relevance of tetrahydroisoquinoline with the synthetic utility of Boc protection and carboxylic acid functionality. Its development reflects progress in heterocyclic synthesis and protecting group strategies. By enabling the efficient synthesis of complex, biologically active molecules, it has become a critical tool in advancing pharmaceutical and chemical research.