(S)-Tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester
[CAS# 156699-39-7]

Identification

• Classification: Pharmaceutical intermediate >> Heterocyclic compound intermediate >> Pyridazine
• Name: (S)-Tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester
• Synonyms: (3S)-1,2-bis[(2-methylpropan-2-yl)oxycarbonyl]diazinane-3-carboxylic acid
• Molecular Formula: C₁₅H₂₆N₂O₆
• Molecular Weight: 330.38
• CAS Registry Number: 156699-39-7
• SMILES: CC(C)(C)OC(=O)N1CCC[C@H](N1C(=O)OC(C)(C)C)C(=O)O

Properties

• Density: 1.2±0.1 g/cm³ Calc.^*
• Boiling point: 422.0±55.0 ºC 760 mmHg (Calc.)^*
• Flash point: 209.0±31.5 ºC (Calc.)^*
• Index of refraction: 1.503 (Calc.)^*

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

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H312-H332
• Precautionary Statements: P261-P264-P270-P271-P280-P302+P352-P304+P340-P305+P351+P338-P312-P330-P362-P403+P233-P501

Discovory and Applicatios

The chemical substance (S)-tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester is a chiral, partially saturated pyridazine derivative with two tert-butyl ester protecting groups and a free carboxylic acid, valued as a synthetic intermediate in pharmaceutical and organic chemistry. Its discovery and applications are well-documented in the literature, rooted in the development of heterocyclic chemistry, chiral synthesis, and protecting group strategies.

The origins of this compound are linked to the study of pyridazines, six-membered heterocycles with two adjacent nitrogen atoms, explored since the 19th century for their presence in bioactive molecules. The tetrahydropyridazine core, a partially saturated pyridazine, gained attention in the mid-20th century for its flexibility and utility in medicinal chemistry. The introduction of three carboxylic acid groups, with two protected as tert-butyl esters and one free, along with (S)-chirality, became feasible in the late 20th century with advances in stereoselective synthesis and esterification techniques. The tert-butyl ester, popularized in the 1950s through the tert-butoxycarbonyl (Boc) protecting group by Louis Carpino, was adapted for carboxylic acid protection due to its stability and ease of removal under mild acidic conditions. This specific compound emerged to meet the pharmaceutical industry’s need for chiral, multifunctional heterocycles as building blocks for complex drug molecules.

Synthetically, (S)-tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester is prepared through a multi-step process. A typical route starts with a chiral precursor, such as an (S)-configured hydrazine derivative or a chiral diene, which is cyclized to form the tetrahydropyridazine ring via a Diels-Alder reaction or hydrazine condensation with a suitable dicarbonyl compound. The 3-position carboxylic acid is introduced or retained from the precursor, while the 1- and 2-positions are functionalized with carboxylic acids through oxidation or carboxylation reactions. The 1- and 2-carboxylic acids are selectively protected as tert-butyl esters using tert-butanol and a coupling agent like dicyclohexylcarbodiimide, or via tert-butyl chloroformate, leaving the 3-carboxylic acid free. The (S)-stereochemistry is established using a chiral starting material, auxiliary, or catalyst. These steps rely on well-established protocols in heterocyclic synthesis, chiral chemistry, and esterification, ensuring high enantiomeric purity and yields.

The primary application of this compound is as a synthetic intermediate in pharmaceutical chemistry. The tetrahydropyridazine core offers a flexible, polar scaffold that mimics peptide-like structures, making it valuable for designing enzyme inhibitors or receptor modulators. The free carboxylic acid at the 3-position serves as a handle for amide formation, esterification, or coupling reactions, while the 1,2-di-tert-butyl esters protect the other carboxylic acids, allowing selective transformations. The (S)-chirality is critical for stereospecific interactions with biological targets, enhancing drug efficacy. This compound is frequently used in the synthesis of drug candidates, such as antihypertensive agents, antiviral compounds, and peptide mimetics, where the chiral heterocycle and carboxylic functionalities optimize binding affinity and pharmacokinetic properties.

In academic research, the compound is employed to study tetrahydropyridazine synthesis, stereoselective functionalization, and the effects of selective ester protection. Its synthesis has contributed to advancements in chiral heterocyclic chemistry and esterification techniques. The compound also finds use in synthesizing specialty chemicals, such as chiral ligands or polymer precursors, where the multifunctional heterocycle is advantageous.

The significance of (S)-tetrahydropyridazine-1,2,3-tricarboxylic acid 1,2-di-tert-butyl ester lies in its role as a chiral, multifunctional intermediate that combines the biological relevance of tetrahydropyridazines with the synthetic versatility of selectively protected carboxylic acids. Its development reflects progress in stereoselective synthesis and protecting group chemistry. By enabling the efficient synthesis of enantiopure, biologically active molecules, it has become a critical tool in advancing pharmaceutical and chemical research.