# US 9,751,908 B2 · Convergent processes for preparing macrolide antibacterial agents

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- Number: US 9,751,908 B2
- Document ID: US9751908B2
- Status: Granted
- Kind: B2
- Application number: 14/774,843
- Filed: 2014-03-15
- Published: 2016-02-18
- Granted: 2017-09-05
- Earliest claimed: 2013-03-15
- Assignees: Cempra Pharmaceuticals, Inc.
- Applicants: Cempra Pharmaceuticals, Inc.
- Inventors: David Eugene Pereira
- Web page: https://patentgrep.com/patent/US9751908B2

## CPC

- C07H 17/08: Hetero rings containing eight or more ring members, e.g. erythromycins
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)

## Abstract

The invention described herein relates to processes for preparing ketolide antibacterial agents. In particular, the invention relates to intermediates and processes for preparing ketolides that include a 1,2,3-triazole substituted side chain.

## Claims

### Claim 1

A process for preparing a compound of formula (I)
or a pharmaceutically acceptable salt thereof; wherein
R1 is a desosamine or a desosamine derivative;
A is —CH2—, —C(O)—, —C(O)O—, —C(O)NH—, —S(O)2—, —S(O)2NH—, or —C(O)NHS(O)2—;
B is saturated C0-C10; or B is unsaturated C2-C10; or -A-B- taken together is alkylene, alkenylene, cycloalkylene, or arylene;
C represents 2 substituents independently selected in each instance from the group consisting of hydrogen, halogen, hydroxy, acyl, acyloxy, sulfonyl, ureyl, and carbamoyl, and alkyl, alkoxy, heteroalkyl, aryl, heteroaryl, arylalkyl, and heteroarylalkyl, each of which is optionally substituted; and
W is hydrogen, F, Cl, Br, I, or OH;
the process comprising (A) contacting a compound of formula
or a salt thereof, where R100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula
or a salt thereof, where C is as defined herein, and CP is a protected form of C, and a base, to prepare a compound of formula
or a salt thereof; or
(C) contacting a compound of formula
or a salt thereof, with an acid to prepare a compound of formula
or a salt thereof; or
(E) contacting a compound of formula
or a salt thereof, with an oxidizing agent to prepare a compound of formula
or a salt thereof; or
(F) contacting a compound of formula
or a salt thereof, with a hydroxylating or halogenating agent to prepare a compound of formula
or a salt thereof, wherein W is F, Cl, Br, I, or OH;
any combination of the foregoing.

### Claim 2 (depends on 1)

The process of claim 1 comprising
(a) contacting a compound of formula
or a salt thereof, where R100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula
or a salt thereof, where NP is a protected amine, and a base; to prepare a compound of formula
or a salt thereof; or
(c) contacting a compound of formula
or a salt thereof, with an acid to prepare a compound of formula
or a salt thereof; or
(e) contacting a compound of formula
or a salt thereof, with an oxidizing agent to prepare a compound of formula
or a salt thereof; or
(g) contacting a compound of formula
or a salt thereof, with a fluorinating agent to prepare a compound of formula
or a salt thereof; or
any combination of the foregoing.

### Claim 3 (depends on 2)

The process of claim 2 wherein NP is NHC(O)CF3.

### Claim 4 (depends on 1)

The process of claim 1 comprising
(a′) contacting a compound of formula
or a salt thereof, where R100 is a hydroxyl protecting group, and L is a leaving group, with a compound of formula
or a salt thereof, and a base; to prepare a compound of formula
or a salt thereof; or
(b′) contacting a compound of formula
or a salt thereof, with an acid to prepare a compound of formula
or a salt thereof; or
(c′) contacting a compound of formula
or a salt thereof, with an oxidizing agent to prepare a compound of formula
or a salt thereof; or
(d′) contacting a compound of formula
or a salt thereof, with a fluorinating agent to prepare a compound of formula
or a salt thereof; or
any combination of the foregoing.

### Claim 5 (depends on 1)

The process of claim 1 wherein the leaving group is halo, pentafluorophenoxy, a sulfonate, a hydroxyamino, or imidazol-1-yl.

### Claim 6 (depends on 1)

The process of claim 1 wherein the base is DBU.

### Claim 7 (depends on 1)

The process of claim 1 wherein the halogenating agent is NFSI, F-TEDA, or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate).

### Claim 8 (depends on 1)

The process of claim 1 wherein C is aryl, heteroaryl, arylalkyl, or heteroarylalkyl, each of which is optionally substituted.

### Claim 9 (depends on 1)

The process of claim 1 wherein A is CH2.

### Claim 10 (depends on 1)

The process of claim 1 wherein B is (CH2)n and n is an integer from 2 to 6.

### Claim 11 (depends on 1)

The process of claim 1 wherein B is (CH2)n, and n is 2, 3, or 4.

### Claim 12 (depends on 1)

The process of claim 1 wherein B is (CH2)n, and n is 3.

### Claim 13 (depends on 1)

The process of claim 1 wherein R100 is acyl.

### Claim 14 (depends on 1)

The process of claim 1 wherein R100 is alkylcarbonyl or optionally substituted benzoyl.

### Claim 15 (depends on 1)

The process of claim 1 wherein R100 is acetyl or benzoyl.

### Claim 16 (depends on 1)

The process of claim 1 wherein W is H or F.

### Claim 17 (depends on 1)

The process of claim 1 wherein W is F.