# US 10,766,868 B2 · Methods for preparing substituted 5,6-dihydro-6-phenylbenzo[f]isoquinolin-2-amine

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- Number: US 10,766,868 B2
- Document ID: US10766868B2
- Status: Granted
- Kind: B2
- Application number: 16/390,205
- Filed: 2019-04-22
- Published: 2019-08-08
- Granted: 2020-09-08
- Earliest claimed: 2015-12-17
- Assignees: ArQule, Inc.
- Applicants: ArQule, Inc.
- Inventors: Craig Bates; Jianmin Mao; David P. Reed
- Web page: https://patentgrep.com/patent/US10766868B2

## CPC

- C07D 239/84: Nitrogen atoms
- A61P 35/00: Antineoplastic agents
- C07D 239/70: condensed with carbocyclic rings or ring systems
- 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 application relates to methods of preparing Compound A: or a salt thereof, and a polymorph of Compound A dihydrochloride salt:

## Claims

### Claim 1

A method of making Compound A:
or a salt thereof, comprising
Step 2: reacting Compound 2:
with Compound 3:
to form Compound 4:

### Claim 2 (depends on 1)

The method of claim 1, further comprising one or more steps selected from:
Step 1: reacting Compound 1:
with N,N-dimethylformamide dimethyl acetal (DMF-DMA), to form Compound 2:
Step 3: reacting Compound 4:
with methanesulfonyl chloride (MsCl) to form Compound 5:
and
Step 4: reacting Compound 5:
with methoxyethylamine to form Compound A:

### Claim 3 (depends on 2)

The method of claim 2, wherein Step 1 comprises:
1a. adding DMF-DMA, optionally together with a protic solvent to Compound 1; and
1b. reacting Compound 1 with DMF-DMA, optionally in the presence of a protic solvent at a temperature below 100° C.

### Claim 4 (depends on 3)

The method of claim 3, further comprising:
1c. cooling the reaction between Compound 1 and DMF-DMA; and
1d. adding a hydrocarbon solvent to the reaction to generate a slurry.

### Claim 5 (depends on 4)

The method of claim 4, further comprising one or more steps selected from:
1e. stirring the slurry from 1d;
1f. adding a hydrocarbon solvent to the slurry from 1d or 1e;
1g. cooling the slurry from 1d, 1e, or 1f, optionally followed by stirring the slurry;
1h. further cooling the slurry from 1g, optionally followed by stirring the slurry; and
1i. filtering the slurry from 1d, 1e, 1f, 1g, or 1h to produce solid Compound 2.

### Claim 6 (depends on 1)

The method of claim 1, wherein Step 2 comprises:
2a. adding Compound 2 to Compound 3, optionally preceded by the addition of 2-MeTHF and a base to Compound 3;
2b. reacting Compound 2 and Compound 3 at a temperature between about 75° C. and about 80° C.;
2c. adding HCl after the reaction between Compound 2 and Compound 3; and
2d. optionally adding a seed Compound 4 to generate a slurry.

### Claim 7 (depends on 6)

The method of claim 6, further comprising, after 2b and before 2c, one or more steps selected from:
2ab1. cooling the reaction between Compound 2 and Compound 3, and optionally washing the reaction with a NaCl solution after the cooling;
2ab2. distilling the organic phase generated in the reaction between Compound 2 and Compound 3;
2ab3. adding 2-MeTHF to the organic phase and distilling the organic phase to generate a dried 2-MeTHF solution; and
2ab4. adding water to the dried 2-MeTHF solution, and optionally heating the solution.

### Claim 8 (depends on 6)

The method of claim 6, further comprising, after 2d, one or more steps selected from:
2e. stirring the slurry from 2d;
2f. adding HCl to the slurry from 2d or 2e;
2g. cooling the slurry from 2d, 2e, or 2f;
2h. stirring the slurry from 2g; and
2i. filtering the slurry from 2d, 2e, 2f, 2g, or 2h to produce solid Compound 4.

### Claim 9 (depends on 2)

The method of claim 2, wherein Step 3 comprises:
3a. adding a base to Compound 4, optionally preceded by forming a Compound 4 slurry in 2-MeTHF;
3b. adding triethylamine, and optionally cooling the mixture; and
3c. adding MsCl, and optionally heating the mixture.

### Claim 10 (depends on 9)

The method of claim 9, further comprising, after 3a and before 3b, one or more steps selected from:
3ab1. after adding the base to Compound 4, stirring the resulting mixture;
3ab2. after the stirring, removing the aqueous phase and keeping the organic phase; and
3ab3. concentrating the organic phase, and adding 2-MeTHF to and distilling the organic phase.

### Claim 11 (depends on 9)

The method of claim 9, further comprising, after 3c, one or more steps selected from:
3d. adding additional triethylamine and MsCl to the mixture, for once, twice, or more times, and after each additional addition of triethylamine and MsCl, optionally stirring the mixture;
3e. after the reaction between Compound 4 and MsCl, adding water to the reaction mixture, optionally stirring the mixture, and collecting the aqueous phase; and
3f. extracting the aqueous phase with 2-MeTHF, and collecting the organic phase.

### Claim 12 (depends on 2)

The method of claim 2, wherein Step 4 comprises adding methoxyethylamine to Compound 5 and heating the mixture.

### Claim 13 (depends on 12)

The method of claim 12, wherein the mixture is heated to a temperature below 90° C.

### Claim 14 (depends on 12)

The method of claim 12, further comprising one or more steps selected from:
adding a solvent and water to the reaction mixture;
collecting the aqueous phase;
extracting the aqueous phase with a solvent;
collecting the organic phase; and
distilling the organic phase to form a slurry.

### Claim 15 (depends on 14)

The method of claim 14, further comprising one or more steps selected from:
adding a non-polar hydrocarbon solvent to the slurry;
stirring the slurry; and
filtering the slurry.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising Compound A or a salt thereof prepared according to the method of claim 1.

### Claim 17 (depends on 1)

A method of making a pharmaceutical composition comprising Compound A:
or a salt thereof, comprising the step of making Compound A or a salt thereof of claim 1, and a step of combining Compound A or a salt thereof with at least one pharmaceutically acceptable excipient or carrier.