Veonetinib

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Veonetinib

👉CAS 1210828-09-3

MF C27H28FN3O4 MW 477.5 g/mol

5-[2-[4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxyethyl]-5-azaspiro[2.4]heptan-7-ol

5-AZASPIRO(2.4)HEPTAN-7-OL, 5-(2-((4-((4-FLUORO-2-METHYL-1H-INDOL-5-YL)OXY)-6-METHOXY-7-QUINOLINYL)OXY)ETHYL)-

5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

(7RS)-5-[2-({4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinolin7-yl}oxy)ethyl]-5-azaspiro[2.4]heptan-7-ol
tyrosine kinase inhibitor, antineoplastic, U7PA8S6XGJ

👉SYN

[WO2010021918]

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2010021918&_cid=P21-MN159E-69738-1

Example 3

5-(2-(4-(4-fluoro-2-methyl-lH-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT.

NaBH₄ (75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M + 1), 478

Patent Scope

Covers:
- Quinoline–indole kinase inhibitors
- VEGFR / angiogenesis targets
- Broad Markush structures

Fragment A: Indole Phenol

4-fluoro-2-methyl-1H-indol-5-ol

Typical Preparation

Fischer indole synthesis or substituted aniline cyclization
Fluorination / directed substitution
Hydroxyl introduction at C-5

Fragment B: Quinoline Electrophile

4-chloro-6-methoxy-7-(leaving group) quinoline

Typical Route

Start from 6-methoxyaniline
Skraup / Doebner–Miller → quinoline core
Chlorination at C-4
Functionalization at C-7 (OH or halide)

Fragment C: Chiral Spiro Amine

(R)-5-azaspiro[2.4]heptan-7-ol

Usually from:
- Chiral pool OR
- Resolution of racemate
Important: defines final stereochemistry

4. STEP-BY-STEP SYNTHESIS (PATENT-ALIGNED)

Step 1: Indole–Quinoline Ether Formation

Reaction: SNAr / Ullmann-type coupling

Indole phenol + 4-chloroquinoline → aryl ether

Conditions

Base: K2CO3 / Cs2CO3
Solvent: DMF / DMSO
Temp: 80–120°C

Forms:
Indole–O–quinoline core

Step 2: Introduction of Linker (C-7 substitution)

If quinoline has OH:

Quinoline–OH + Br–CH2–CH2–X → O–CH2CH2–X

If halide:Direct alkylation

Conditions

Base: NaH / K2CO3
Solvent: DMF
Temp: 50–90°C

Product:
Quinoline–O–CH2CH2–X

Step 3: Coupling with Spiro Amine

Quinoline–O–CH2CH2–X + spiro amine → final amine linkage

Reaction Type

SN2 substitution

Conditions

Base: DIPEA / Et3N
Solvent: ACN / DMF
Temp: 50–80°C

Step 4: Final Deprotection / Purification

Remove protecting groups (if any)
Chiral purity control
Crystallization

Step 1: Preparation of Indole–Quinoline Ether

Starting materials:

4-fluoro-2-methyl-1H-indol-5-ol
→ 1.00 equiv (e.g., 5.0 g, ~30 mmol)
4-chloro-6-methoxyquinoline
→ 1.10 equiv (~33 mmol)

Reagents:

Potassium carbonate (K₂CO₃) → 2.0 equiv (~60 mmol)
Solvent: DMF (50–60 mL)

Procedure:

Charge indole phenol and K₂CO₃ in DMF under nitrogen.
Add 4-chloroquinoline portionwise.
Heat to 100–110°C.
Stir for 8–12 h.

Workup:

Cool to RT
Pour into water (200 mL)
Extract with EtOAc (3×)
Wash with brine, dry (Na₂SO₄)
Concentrate

Purification:

Silica gel chromatography (EtOAc/hexane)

Yield: ~70–80%
Product: Indole–quinoline ether intermediate

Step 2: Installation of Ethylene Linker

Starting material: Step 1 product (~25 mmol)

Reagents:

1,2-dibromoethane → 1.5–2.0 equiv
Base: K₂CO₃ → 2 equiv
Solvent: DMF (40 mL)

Procedure:

Dissolve intermediate in DMF
Add K₂CO₃
Add dibromoethane
Heat to 80–90°C for 6–8 h

Workup:

Pour into water
Extract with EtOAc
Dry and concentrate

Product: Quinoline–O–CH₂CH₂–Br

Yield: ~65–75%

Step 3: Coupling with Chiral Spiro Amine

Starting materials:

Bromo intermediate → 1.0 equiv (~15–20 mmol)
(R)-5-azaspiro[2.4]heptan-7-ol → 1.2 equiv

Reagents:

DIPEA or Et₃N → 2 equiv
Solvent: Acetonitrile or DMF (30–40 mL)

Procedure:

Combine bromo intermediate and amine in solvent
Add DIPEA
Heat to 60–70°C
Stir 12–16 h

Workup:

Remove solvent
Dissolve in EtOAc
Wash with water + brine
Dry and concentrate

Yield: ~70–85%

Step 4: Final Purification

Purification options:

Silica chromatography OR
Recrystallization (EtOAc/hexane or IPA)

Optional:

Convert to pharmaceutically acceptable salt

Final Yield (overall): ~35–45%

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=US43556759&_cid=P21-MN152D-66699-1

EXAMPLE 1

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-[2-(5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane)ethoxy]quinoline

Preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline

Method A:

4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with DMAP (1.5 eq), 2-methyl-4-fluoro-5-hydroxyindole (WO0047212) (1 eq) in dioxane (20 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg).

Method B:

4-Chloro-7-benzyloxy-6-methoxy-quinoline (WO2008112407, 1.5 g) was mixed with 3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenol (WO0047212) (1.5 eq) in dioxane (30 ml). The reaction was refluxed for three days and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 7-(benzyloxy)-4-(3-(2,2-dimethoxypropyl)-2-fluoro-4-nitrophenoxy)-6-methoxyquinoline (650 mg). This product was mixed with 2NHCl (3 ml) and acetone (30 ml) and refluxed for 6 hours. The reaction was diluted with EtOAc and neutralized with saturated NaHCO ₃, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 1-(3-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-2-fluoro-6-nitrophenyl)propan-2-one (500 mg) which was mixed with iron (500 mg) and NH ₄Cl (50 mg) in EtOH/H ₂O (20 ml, 4/1). The reaction was refluxed for 4 hours, filter through Celite and evaporated. The residue was extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (250 mg).

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-benzyloxyquinoline (600 mg) was mixed with HCONH ₄(600 mg) and Pd/C (10%, 100 mg) followed by refluxing 30 min. The reaction was filtered while it was hot and the filtrate was evaporated and washed with water followed by filtration to give 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg).

Preparation of Title Compound

Method C:

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg) was mixed with 1,2-dibromoethane (2 eq) and K ₂CO ₃(2 eq) in DMF (5 ml). The reaction was heated at 100° C. for 5 hours and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column. The product was mixed with NaI (250 mg) in acetonitrile (15 ml) and refluxed for 30 min. The reaction was cooled, DIPEA (500 μL) and 5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane (300 mg) were added into the reaction which was refluxed overnight. The reaction was diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give title compound (150 mg). Mass: (M+1), 520

Method D:

4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline (400 mg) was mixed with 2-bromo-1,1-dimethoxyethane (2 eq) and K ₂CO ₃(2 eq) in DMF (5 ml). The reaction was heated at 100° C. for 8 hours and diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column. The product was mixed with 1NHCl (2 ml) in EtOH (10 ml) and refluxed for 5 hours. The reaction was evaporated and neutralized with saturated NaHCO ₃, further extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column to give the aldehye adduct (400 mg) which was mixed with 5,8-Dioxa-10-azadispiro[2.0.4.3]-undecane (200 mg) with NaBH(OAc)3 (2 eg) in DCM (10 ml). The reaction was stirred at RT for 2 hours then diluted with EtOAc, water and extracted with EtOAc three times. The combined organic layer was washed with water, brine and dried. The solution was evaporated and purified with silica gel column give title compound (250 mg). Mass: (M+1), 520,

EXAMPLE 2

5-(2-(4-(4-Fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-one

The above product from Example 1 (100 mg) was mixed with 1N HCl (4 ml) and acetone (20 ml). The reaction was refluxed overnight and evaporated. The solution was basified with 2N NaOH and extracted with EtOAc. The combined organic layer was washed with H ₂O followed by brine, dried over Na ₂SO ₄and evaporated. The residue was purified by column chromatography to give title compound (75 mg). Mass: (M+1), 476

EXAMPLE 3

5-(2-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxyquinolin-7-yloxy)ethyl)-5-azaspiro[2.4]-heptan-7-ol

The above product from Example 2 (75 mg) was dissolved into MeOH (8 ml) and stirred at RT. NaBH ₄(75 mg) was added to the reaction and stirred at RT for 30 min. The reaction was evaporated and purified by column chromatography to give title compound (60 mg). Mass: (M+1), 478

PAT

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2023239945&_cid=P21-MN15DA-71816-1