# US 9,085,553 B2 · LFA-1 inhibitor and methods of preparation and polymorph thereof

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- Number: US 9,085,553 B2
- Document ID: US9085553B2
- Status: Granted
- Kind: B2
- Application number: 13/950,807
- Filed: 2013-07-25
- Published: 2014-01-30
- Granted: 2015-07-21
- Earliest claimed: 2012-07-25
- Assignees: Sarcode Bioscience Inc.
- Applicants: SARcode Bioscience Inc.
- Inventors: James Robert Zeller; Sripathy Venkatraman; Elisabeth C. A. Brot; Subashree Iyer; Michael Hall
- Web page: https://patentgrep.com/patent/US9085553B2

## CPC

- C07D 407/06: linked by a carbon chain containing only aliphatic carbon atoms
- 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 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07B 63/00: Purification; Separation (separation of optically-active compounds C07B57/00); Stabilisation; Use of additives
- 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

Methods of preparation and purification of a compound of Formula I, intermediates thereof, a polymorph thereof, and related compounds are disclosed. Formulations and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed.

## Claims

### Claim 1

A method of synthesizing a compound of Formula I:
or a salt thereof, comprising the steps:
a) performing hydrolysis of Formula AA with a base under biphasic conditions:
wherein R is a carbon-containing moiety or a silyl-containing moiety; and
b) isolating said compound of Formula I or a salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the biphasic conditions include aqueous acetone.

### Claim 3 (depends on 2)

The method of claim 2, wherein the aqueous acetone is about 30% aqueous acetone.

### Claim 4 (depends on 2)

The method of claim 2, wherein the aqueous acetone is present in an amount ranging from about 1:1 to about 5:1 by weight with respect to Formula AA.

### Claim 5 (depends on 1)

The method of claim 1, wherein the base is sodium hydroxide.

### Claim 6 (depends on 5)

The method of claim 5, wherein the sodium hydroxide is added in an amount ranging from about 1.0 to about 1.5 equivalents.

### Claim 7 (depends on 6)

The method of claim 6, wherein the sodium hydroxide is added in an amount of about 1.2 equivalents.

### Claim 8 (depends on 1)

The method of claim 1, further comprising a phase transfer catalyst.

### Claim 9 (depends on 8)

The method of claim 8, wherein said phase transfer catalyst is a quaternary ammonium salt.

### Claim 10 (depends on 9)

The method of claim 9, wherein said quaternary ammonium salt is tetrabutylammonium hydroxide.

### Claim 11 (depends on 8)

The method of claim 8, wherein said phase transfer catalyst is present in an amount ranging from about 0.01 equivalents to about 0.5 equivalents.

### Claim 12 (depends on 1)

The method of claim 1, wherein R is a substituted or unsubstituted group selected from lower alkyl, lower alkenyl, lower alkynyl, cyclo(lower)alkyl, cyclo(lower)alkenyl, aryl, aralkyl, heterocyclyl, and heteroaryl groups.

### Claim 13 (depends on 1)

The method of claim 1, wherein Formula AA is:

### Claim 14 (depends on 1)

The method of claim 1, further comprising purifying said compound of Formula I by recrystallization.

### Claim 15 (depends on 14)

The method of claim 14, wherein said recrystallization is performed with aqueous acetone.

### Claim 16

A composition comprising a compound of Formula I:
wherein said compound is synthesized by a process comprising the following steps:
a) performing hydrolysis of Formula AA with a base under biphasic conditions:
wherein R is a carbon-containing moiety or a silyl-containing moiety; and
b) isolating said compound of Formula I or a salt thereof, and further wherein said compound has an optical purity of >98%.