# US 10,501,417 B2 · Synthesis of indazoles

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- Number: US 10,501,417 B2
- Document ID: US10501417B2
- Status: Granted
- Kind: B2
- Application number: 16/097,065
- Filed: 2017-04-25
- Published: 2019-04-11
- Granted: 2019-12-10
- Earliest claimed: 2016-04-29
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Tobias Thaler; Johannes Platzek; Nicolas Guimond
- Web page: https://patentgrep.com/patent/US10501417B2

## CPC

- C07D 213/81: Amides; Imides
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/54: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

The present invention relates to a novel method of preparing a 2-substituted indazole of structure: (I), to intermediate compounds, and to the use of intermediate compounds for the preparation of said 2-substituted indazole.

## Claims

### Claim 1

A method of preparing a compound of formula (I):
comprising
reacting a compound of formula (V):
with a vinyl sulfone compound of formula (IX′):
wherein R is methyl, to provide the compound of formula (I).

### Claim 2 (depends on 1)

The method according to claim 1, wherein the compound of formula (V) is reacted with the compound of formula (IX′) in an aromatic hydrocarbon solvent.

### Claim 3 (depends on 1)

The method according to claim 1, further comprising
reacting a compound of formula (VI):
with a reductive methylating agent, to provide the compound of formula (V)

### Claim 4 (depends on 3)

The method according to claim 3, further comprising
reacting a compound of formula (VIII):
with a compound of formula (VII):
to provide the compound of formula (VI)

### Claim 5 (depends on 4)

The method according to claim 4,
wherein the compound of formula (V) and the compound of formula (IX′) are reacted in an aromatic hydrocarbon solvent, and
wherein the reductive methylating agent is methylmagnesium chloride.

### Claim 6 (depends on 5)

The method according to claim 5,
wherein the aromatic hydrocarbon solvent is toluene;
and
wherein the compound of formula (VI) is reacted with the reductive methylating agent in the presence of an alkali metal halide wherein the reductive methylating agent is methyl magnesium chloride and the alkali metal halide is lithium chloride.

### Claim 7 (depends on 1)

The method according to claim 1, wherein said compound of formula (I) is purified by crystallization.

### Claim 8 (depends on 7)

The method according to claim 7, wherein the compound of formula (I) is purified by crystallization from a solvent, and wherein said solvent is ethanol.

### Claim 9 (depends on 7)

The method according to claim 7, wherein the compound of formula (I) is purified by crystallization from a solvent, and wherein said solvent is isopropanol.

### Claim 10 (depends on 1)

The method according to claim 1, comprising reacting the compound of formula (V) with the compound of formula (IX′) in an aromatic hydrocarbon solvent at the reflux temperature of said solvent.

### Claim 11 (depends on 3)

The method according to claim 3, wherein the reductive methylating agent is a methylmetallic agent.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the methylmetallic agent is a methylmagnesium halide.

### Claim 13 (depends on 12)

The method according to claim 12, wherein the methylmagnesium halide is methylmagnesium chloride.

### Claim 14 (depends on 3)

The method according to claim 3, comprising reacting the compound of formula (VI) with the reductive methylating agent in the presence of an alkali metal halide.

### Claim 15 (depends on 4)

The method of claim 4, comprising reacting the compound of formula (VIII) with the compound of formula (VII) in the presence of an organic base.

### Claim 16 (depends on 15)

The method according to claim 15, wherein the organic base is a weak organic base.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the weak organic base is a tertiary amine.

### Claim 18 (depends on 4)

The method according to claim 4, comprising reacting the compound of formula (VIII) with the compound of formula (VII) in the presence of a coupling agent.

### Claim 19 (depends on 2)

The method of claim 2, wherein the aromatic hydrocarbon solvent is toluene.

### Claim 20 (depends on 14)

The method of claim 14, wherein the alkali metal halide is lithium chloride.

### Claim 21 (depends on 17)

The method of claim 17, wherein tertiary amine is N,N-diisopropylethylamine.

### Claim 22 (depends on 18)

The method of claim 18, wherein the coupling agent is 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P).