tert-butyl 1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carboxylate 1268521-74-9 98% White to Off-White Solid Spirocyclic In

1. Product Overview

tert-Butyl 1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carboxylate (CAS 1268521-74-9) is a complex spirocyclic hybrid molecule featuring a fused indazole ring system connected via a spiro junction at the 5-position to a piperidine ring, which is further protected as a tert-butyl carbamate (Boc). The indazole core bears an N-isopropyl substituent and a 7-oxo (lactam) functionality. This intricate architecture is characteristic of highly potent, selective kinase inhibitors and GPCR modulators, where the spirocyclic constraint locks the molecule into a specific three-dimensional conformation, enhancing target binding affinity and metabolic stability. It is a critical intermediate in the synthesis of next-generation pharmaceutical agents targeting oncology, neurology, and inflammatory diseases.

2. Key Features and Benefits

• Conformationally Locked Spiro Architecture: The spiro[indazole-5,4'-piperidine] core provides a rigid, three-dimensional scaffold that pre-organizes the molecule for optimal interaction with biological targets, a key feature in modern structure-based drug design.

• Orthogonal Protecting Groups: The Boc (tert-butyloxycarbonyl) group on the piperidine nitrogen can be selectively removed under mild acidic conditions (e.g., TFA, HCl/dioxane) without affecting the lactam or the N-isopropyl group, enabling sequential, chemo-selective synthesis.

• Dual Pharmacophoric Elements: The 7-oxoindazole (lactam) acts as a hydrogen bond acceptor, while the piperidine nitrogen (upon deprotection) serves as a hydrogen bond donor/acceptor and a handle for further functionalization (alkylation, acylation, sulfonylation).

• High Lipophilicity & Metabolic Stability: The spirocyclic core and isopropyl group contribute to a high calculated LogP (~3.5), enhancing membrane permeability and oral bioavailability, while the rigid structure resists metabolic degradation compared to flexible acyclic analogs.

• High Purity & Batch-to-Batch Consistency: Supplied at ≥98% (HPLC), with full lot-specific Certificate of Analysis (CoA) including ¹H NMR verification, ensuring reproducibility in multi-step API synthesis.

3. Major Applications

• Kinase Inhibitor Synthesis: Serves as a core intermediate for developing selective inhibitors of PI3K, mTOR, EGFR, or JAK family kinases, where spirocyclic indazole scaffolds are known to occupy hydrophobic pockets in the ATP-binding site.

• GPCR-Targeted Drug Discovery: The spiro[indazole-piperidine] system is a privileged structure in designing modulators for 5-HT (serotonin), dopamine, and opioid receptors for CNS disorders.

• Medicinal Chemistry & SAR Studies: Used as a starting material for structure-activity relationship (SAR) exploration, where the C-7 oxo group and N-isopropyl can be modified to fine-tune potency, selectivity, and pharmacokinetics.

• Proteolysis-Targeting Chimera (PROTAC) Development: The Boc-protected piperidine nitrogen can be deprotected and linked to E3 ligase ligands (e.g., thalidomide, VHL ligands) to create targeted protein degraders.

• Academic Research: Investigated in studies of spirocyclic scaffold design, conformational analysis, and bioisosteric replacement strategies in drug discovery.

4. Technical Specifications

Item Description
Product Name tert-Butyl 1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carboxylate
Synonyms 1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester; Spiro[5H-indazole-5,4'-piperidine]-1'-carboxylic acid, 1,4,6,7-tetrahydro-1-(1-methylethyl)-7-oxo-, 1,1-dimethylethyl ester
CAS Number 1268521-74-9
Molecular Formula C₁₉H₂₉N₃O₃
Molecular Weight 347.45 g/mol
MDL Number MFCD31694047
PubChem CID 58252563
Assay (Purity) ≥95% / ≥98% (HPLC)
Appearance White to off-white crystalline solid or powder
Melting Point Not reported (typical for spirocyclic Boc-amines: 100–180 °C, batch-dependent)
Boiling Point ~483.9 °C (Predicted)
Density ~1.21 g/cm³ (Predicted)
pKa (Predicted) ~0.70 ± 0.20 (Lactam N-H); ~10.5 ± 0.30 (Piperidine N-Boc, upon deprotection)
Calculated LogP ~3.5
Polar Surface Area (PSA) ~64.4 Ų
Hydrogen Bond Donors 0 (as Boc-protected lactam)
Hydrogen Bond Acceptors 4
Rotatable Bonds 3
Solubility Soluble: DMSO (>50 mg/mL), DMF, Methanol (slightly), Ethanol (slightly), DCM, Chloroform, THF, Acetone.
Practically Insoluble:Water (high LogP); can be converted to water-soluble salt after Boc deprotection.
Spectral Data (Predicted) ¹H NMR (CDCl₃, 400 MHz): δ 1.10 (d, J≈6.5 Hz, 6H, CH(CH₃)₂), 1.45 (s, 9H, OC(CH₃)₃), 1.6–2.8 (m, 10H, piperidine-CH₂ + cyclohexane-type CH₂), 3.85–4.10 (m, 1H, N-CH(CH₃)₂), 6.75–7.15 (m, 2H, ArH), 10.5 (br s, 1H, lactam NH).
¹³C NMR (CDCl₃):δ 21.5 (CH(CH₃)₂), 28.5 (OC(CH₃)₃), 35–55 (piperidine + cyclohexane Cs), 79.5 (Cq, Boc), 110–145 (aromatic Cs), 154.5 (NCOO), 170.0 (lactam C=O).
SMILES C1(C)(C)OC(=O)N2CCC3(CC2)CC(=O)N(N=C3C)C(C)C
InChI Key JRQQDCDIUOWSDI-UHFFFAOYSA-N
Storage (Powder) 2–8 °C, sealed, protected from light & moisture; stable ≥18–24 months
Sensitivity Moisture-sensitive (Boc group); protect from strong acid
HS Code 2933.99.90 / 2934.99.90

5. Storage and Handling

• Storage: Store in a tightly sealed container at 2–8 °C, protected from light and moisture. For long-term storage (>12 months), keep in a desiccator under an inert atmosphere (N₂ or Ar). The Boc-protected spirocyclic scaffold is stable under these conditions for at least 18–24 months.

• Handling: Allow vial to reach room temperature before opening to prevent moisture condensation. Dissolve in anhydrous DMSO, DMF, DCM, or MeOH as required. Minimize exposure to strong acids or protic solvents to prevent premature Boc deprotection.

• Boc Deprotection: The tert-butyl carbamate can be cleanly removed with 4 M HCl in dioxane, TFA/DCM (1:1 v/v), or 10% trifluoroacetic acid in DCM at room temperature for 30–60 minutes. After evaporation, the resulting piperidine hydrochloride salt is ready for further N-functionalization.

• Lactam Stability: The 7-oxoindazole (lactam) ring is generally stable to mild acid/base and heat (<100 °C) but may hydrolyze under strongly acidic (6 M HCl, reflux) or strongly basic (2 M NaOH, heat) conditions.

• Solution Stability: Prepare fresh for critical couplings. DMSO stocks may degrade over time; store aliquots at -20 °C for up to 1–2 months. Avoid repeated freeze-thaw cycles.

6. Safety Summary (Full SDS Highlights)

• GHS Classification: GHS07 – Warning

• Signal Word: Warning

• Hazard Statements:

• H302: Harmful if swallowed.

• H315: Causes skin irritation.

• H319: Causes serious eye irritation.

• H335: May cause respiratory irritation.

• Precautionary Statements:

• P261: Avoid breathing dust/mist/vapors. Use only in a well-ventilated area or fume hood.

• P264: Wash hands, forearms, and face thoroughly after handling.

• P270: Do not eat, drink, or smoke in areas where this material is used.

• P271: Use only outdoors or in a well-ventilated area.

• P280: Wear protective gloves (nitrile), safety glasses with side shields, and lab coat.

• P301+P312: IF SWALLOWED: Call a POISON CENTER or physician if you feel unwell.

• P302+P352: IF ON SKIN: Wash with plenty of soap and water.

• P304+P340: IF INHALED: Remove person to fresh air and keep comfortable for breathing.

• P305+P351+P338: IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses if present and easy to do. Continue rinsing.

• P330: Rinse mouth if swallowed.

• P337+P313: If eye irritation persists: Get medical advice/attention.

• P403+P233: Store in a well-ventilated place. Keep container tightly closed.

• P501: Dispose of contents/container in accordance with local, regional, and national regulations.

• First Aid Measures:

• Inhalation: Remove to fresh air. If breathing difficult, administer oxygen and seek medical attention.

• Skin Contact: Immediately wash with plenty of soap and water. Remove contaminated clothing. Seek medical advice if irritation or rash develops.

• Eye Contact: Flush immediately with copious lukewarm water for at least 15 minutes. Remove contact lenses if possible. Seek medical attention.

• Ingestion: Rinse mouth. Do NOT induce vomiting. Give water to drink if conscious. Seek medical advice.

• Fire-Fighting Measures:

• Suitable Extinguishing Media: Water spray, alcohol-resistant foam, dry chemical, or CO₂.

• Special Hazards: Combustion may produce irritating/acrid smoke (CO, NOₓ). Nitrogen oxides are toxic.

• Protective Equipment: Wear self-contained breathing apparatus (SCBA) and full protective clothing.

• Spill Response:

• Avoid dust generation. Sweep up and place in a suitable closed container for disposal. Do not allow entry to drains or waterways. Ventilate area after cleanup.

• Handling & Storage:

• Handle in fume hood. Keep container closed when not in use. Store at 2–8 °C, protected from light and moisture. Keep away from strong oxidizers and strong acids (Boc group sensitive to acid).

• Hazardous Decomposition Products: Nitrogen oxides (NOₓ), carbon monoxide (CO), carbon dioxide (CO₂), tert-butanol vapor.

• Intended Use: For laboratory research and development ONLY. Not for human or veterinary therapeutic, diagnostic, or food use.

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