# US 11,999,757 B2 · Synthesis of boronate ester derivatives and uses thereof

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- Number: US 11,999,757 B2
- Document ID: US11999757B2
- Status: Granted
- Kind: B2
- Application number: 16/760,369
- Filed: 2018-10-30
- Published: 2020-10-01
- Granted: 2024-06-04
- Earliest claimed: 2017-11-01
- Assignees: Melinta Subsidiary Corp.
- Applicants: Melinta Subsidiary Corp.
- Inventors: Serge Henri Boyer; Scott J. Hecker; Gerardus K. M. Verzijl; Petrus J. Hermsen
- Web page: https://patentgrep.com/patent/US11999757B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- B01J 23/462: {Ruthenium}
- C07C 67/31: by introduction of functional groups containing oxygen only in singly bound form
- C07C 69/675: of saturated hydroxy-carboxylic acids
- C07F 5/04: Esters of boric acids
- C12P 9/00: Preparation of organic compounds containing a metal or atom other than H, N, C, O, S or halogen {(phosphoglycerides, C12P7/6481)}
- C12P 41/002: {by oxidation/reduction reactions}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C12P: FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE {(brewing of beer C12C; producing vinegar C12J; producing specific peptides or proteins C07K; producing enzymes C12N9/00; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; measuring or testing processes involving enzymes or microorganisms C12Q; measuring or testing processes involving nucleic acid amplification reactions C12Q1/6844; fermentation processes to form a food composition, A21 or A23; compounds in general, see the relevant compound class, e.g. C01, C07)}

## Abstract

Disclosed herein are methods for the preparation of boronate derivatives in the synthesis of antimicrobial compounds and uses thereof. Disclosed herein includes method of making a compound of Formula (B) by reducing the ketone group of the keto-ester compound of Formula (A), and the reduction can be performed using a Ruthenium based catalyst system or using an alcohol dehydrogenase bioreduction system.

## Claims

### Claim 1

A compound having the structure of Formula (I):
wherein X is a halogen and m is 2, 4, 5, or 6.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X is Cl and m is 2.

### Claim 3

A compound having the structure of Formula (II):
or a salt thereof, wherein:
X is a halogen;
m is an integer between 2 and 6;
each of R1a and R1b is independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R1a and R1b together with intervening atoms optionally form a 5-7 membered boron ester ring; and
R2 is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein Xis Cl and each of R1a and R1b is a butyl group.

### Claim 5

A method of making a compound of Formula (B), comprising the steps of:
reducing the ketone group of a compound of Formula (A):
to form a compound of Formula (B):
wherein:
X is Cl;
m is 2;
the ketone group in the compound of Formula (A) is reduced using Ru(OAc)2((R)-SegPhos) and methanol; and
the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%.

### Claim 6

A method of making a compound of Formula (B), comprising the steps of:
reducing the ketone group of a compound of Formula (A):
to form a compound of Formula (B):
wherein:
X is Cl;
m is 2; and
the ketone group in the compound of Formula (A) is reduced with an alcohol dehydrogenase system, wherein
the alcohol dehydrogenase system comprises a reduced nicotinamide adenine dinucleotide (NADH), a reduced nicotinamide adenine dinucleotide phosphate (NADPH), and an alcohol,
the alcohol is isopropyl alcohol,
acetone is generated as a by-product,
the acetone is removed under vacuum, and
the compound of Formula (B) is produced in an enantiomeric excess of greater than 99%.

### Claim 7

A method of making a compound of Formula (C), comprising:
reacting a boronate compound B(OR4a)(OR4b)(OR4c) with a compound of Formula (B-1):
to form the compound of Formula (C):
wherein:
X is a halogen;
m is an integer between 2 and 6;
R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
R4a and R4b are independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring; and
R4c is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl.

### Claim 8 (depends on 7)

The method of claim 7, wherein X is Cl; m is 2; and R2, R4a, and R4b are each independently a butyl group.

### Claim 9

A method of making a compound of Formula (D), comprising:
reacting magnesium with a compound of Formula (C):
to form a first reaction intermediate; and
hydrolyzing the first reaction intermediate to form the compound of Formula (D):
wherein:
X is a halogen;
m is an integer between 2 and 6;
R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl; and
each of R4a and R4b is independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring.

### Claim 10 (depends on 9)

The method of claim 9, wherein Xis Cl; m is 2; and R2, R4a, and R4b are independently a butyl group.

### Claim 11 (depends on 9)

The method of claim 9, wherein the compound of Formula (D)

### Claim 12

A method of making a compound of Formula (E), comprising
reducing the ketone group of a keto-ester compound of Formula (A-1):
to form a compound of Formula (B-1):
reacting a boronate compound B(OR4a)(OR4b)(OR4c) with the compound of Formula (B-1) to form a compound of Formula (C):
reacting magnesium with the compound of Formula (C) to form a first reaction intermediate;
hydrolyzing the first reaction intermediate to form a compound of Formula (D):
and
reacting the compound of Formula (D) with a complexing agent of Formula (CL):
to form the compound of Formula (E):
wherein:
X is a halogen;
m is an integer between 2 and 6;
n is an integer between 0 and 6;
Y1 is O or N+R9R10;
Y2 is O or NR11;
R2 is selected from the group consisting of, an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
R4a and R4b are independently selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R4a and R4b together with intervening atoms optionally form a 5-8 membered boron ester ring;
R4c is selected from the group consisting of an optionally substituted C1-C12 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C2-C12 alkenyl, optionally substituted C2-C12 alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
each R5 and R6 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl, or R5 and R6 together with the atom to which they are attached, form ═O;
each R7 and R8 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl, or R5 and R7 together with the atom to which they are attached form an aryl or heteroaryl ring; or R7 and R8 together with the atom to which they are attached, form ═O; and
each R9, R10 and R11 is independently selected from the group consisting of H, optionally substituted phenyl, and optionally substituted C1-4 alkyl.

### Claim 13 (depends on 12)

The method of claim 12, wherein X is Cl, m is 2, and R2 is a butyl group.

### Claim 14 (depends on 12)

The method of claim 12, wherein the complexing agent of Formula (CL) is NH2(CH2)2OH.

### Claim 15 (depends on 12)

The method of claim 12, further comprising reacting the compound of Formula (E) with pinanediol to form a compound of Formula (F):
protecting the hydroxy group of the compound of Formula (F) with a PG group to form a compound of Formula (G):
reacting the compound of Formula (G) with n-butyllithium and dichloromethane to form a compound of Formula (H):
reacting the compound of Formula (H) with an LiN[Si(R12)3]2 to form a compound of Formula (J):
reacting the compound of Formula (J) with R13—COCl to form a compound of Formula (K):
and
removing the PG group on the compound of Formula (K) to form a compound of Formula (L):
wherein:
PG is a hydroxy protection group;
R12 is optionally substituted phenyl or optionally substituted C1-8 alkyl; and
R13 is selected from the group consisting of optionally substituted C1-8 alkyl, optionally substituted C0-4 alkyl-C6-10 aryl, optionally substituted C0-4 alkyl-5-10 membered heteroaryl, optionally substituted C0-4 alkyl-C3-10 carbocyclyl, and C0-4 alkyl-4-10 membered heterocyclyl.

### Claim 16 (depends on 15)

The method of claim 15, wherein R13 is