# US 2022/0033428 A1 · Large scale preparation of pseudo-trisaccharide aminoglycosides and of intermediates thereof

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- Number: US 2022/0033428 A1
- Document ID: US20220033428A1
- Status: Published application
- Kind: A1
- Application number: 17/493,672
- Filed: 2021-10-04
- Published: 2022-02-03
- Earliest claimed: 2017-03-15
- Assignees: Eloxox Pharmaceuticals Ltd.
- Applicants: Eloxox Pharmaceuticals Ltd.
- Inventors: Michael MIZHIRITSKII; Mani Bushan KOTALA; Ravinder PALADI
- Web page: https://patentgrep.com/patent/US20220033428A1

## CPC

- C07H 15/224: with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
- C07H 1/00: Processes for the preparation of sugar derivatives
- C07H 13/12: by acids having the group -X-C(=X)-X-, or halides thereof, in which each X means nitrogen, oxygen, sulfur, selenium or tellurium, e.g. carbonic acid, carbamic acid
- C07H 15/23: with only two saccharide radicals in the molecule, e.g. ambutyrosin, butyrosin, xylostatin, ribostamycin
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- 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)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Synthetic pathways for preparing pseudo-trisaccharide aminoglycoside compounds represented by Formula I or Ia as defined in the specification and donor and acceptor compounds useful for preparing such compounds are provided. A process of stereoselectively preparing compounds represented by Formula III as defined in the specification, while avoiding chromatographic separation of stereoisomers are also provided. Compounds prepared by the described processes and uses thereof are also provided.

## Claims

### Claim 1

A process of preparing a compound represented by Formula III:
wherein: OT1 and OT2 are each independently a protected hydroxyl group;
R8 is alkyl; and
D is a protected amino group,
the process comprising:
reacting a compound represented by Formula IIIa:
with a Grignard reagent represented by a Formula R8MgX, wherein X is halide, to thereby obtain stereoselectively a compound represented by Formula IIIb:
converting said compound represented by Formula IIIb to a compound represented by Formula IIIc:
reacting said compound represented by Formula IIIc with an amino-protecting group to thereby form said D; and
reacting said compound represented by Formula IIIc with hydroxy protecting groups to thereby form said OT1 and OT2,
thereby preparing the compound represented by Formula III.

### Claim 2 (depends on 1)

The process of claim 1, wherein said amino-protecting group is N-benzyloxycarbonyl and/or each of said hydroxy-protecting groups is benzoyl.

### Claim 3 (depends on 1)

The process of claim 1, wherein said compound represented by Formula IIIa is prepared by:
converting D-ribose to a dioxolane-protected D-ribose;
oxidizing a hydroxy group at position 5″ to a respective aldehyde; and
reacting said aldehyde with N-Benzyl hydroxyl amine hydrochloride.

### Claim 4 (depends on 1)

The process of claim 1, wherein D is an N-benzyloxycarbonyl (CBz)-protected amino group and each of T1 and T2 is benzoyl.

### Claim 5 (depends on 4)

The process of claim 4, wherein preparing said compound represented by Formula IIIa from D-ribose, reacting said compound represented by Formula IIIa with said Grignard reagent, converting said compound represented by Formula IIIb to said compound represented by Formula IIIc and reacting said compound represented by Formula IIIc with an amino-protecting group to thereby form said D, are performed in one reactor.

### Claim 6 (depends on 1)

A process of preparing a pseudo-trisaccharide aminoglycoside compound represented by Formula Ia:
or a pharmaceutically acceptable salt thereof, wherein:
the dashed line represents an optional S-configuration or an R-configuration at position 6′;
R1 is selected from hydrogen, alkyl, cycloalkyl or aryl;
R2 is selected from a substituted or unsubstituted alkyl, OR′ and NR′R″, wherein each of R′ and R″ is independently selected from hydrogen, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted alkaryl, and an acyl;
R4 is selected from hydrogen, acyl, an amino-substituted alpha-hydroxy acyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted alkaryl, and a cell-permealizable group; and
R8 is alkyl,
the process comprising:
preparing a compound represented by Formula III, according to claim 1;
converting said compound of Formula III to an activated form; and
coupling said activated form of the compound represented by Formula III with a compound represented by Formula IIb:
wherein:
the dashed line represents an optional S-configuration or an R-configuration at position 6′;
OP is a protected hydroxyl group;
AP is a protected amino group;
A is a protected hydroxyl group, when R2 in Formula Ia is OR′ and R′ is hydrogen; a protected amino group, when R2 is Formula Ia is NR′R″ and at least one of R′ and R″ is hydrogen; or is a protected or unprotected form of a group defining R2 when R2 is other than OH, NH2, NHR′ or NHR″;
B is a protected amine group, when R4 is Formula Ia is hydrogen, or a protected or unprotected form of a group defining R4 when R4 is other than hydrogen;
de-protecting said protected hydroxyl groups;
de-protecting said protected amino groups; and
de-protecting said protected form of a group defining R2 and/or said protected form of a group defining R4, if present,
thereby preparing a compound represented by Formula Ia.

### Claim 7 (depends on 6)

The process of claim 6, wherein said converting said compound of Formula III to said activated form is performed in situ, without isolating said activated form.

### Claim 8 (depends on 6)

The process of claim 6, wherein each OP is O-acetyl.

### Claim 9 (depends on 6)

The process of claim 6, wherein each AP is an N-benzyloxycarbonyl (CBz)-protected amino group.

### Claim 10 (depends on 6)

The process of claim 6, wherein the compound of Formula Ia is a sulfate salt, the process further comprising converting a compound represented by Formula Ia in a form of a free base thereof to said sulfate salt.

### Claim 11 (depends on 8)

The process of claim 8, wherein when A is a protected hydroxyl group, A is O-acetyl.

### Claim 12 (depends on 9)

The process of claim 9, wherein when A is a protected amino group, A is CBz-protected amino group.

### Claim 13 (depends on 8)

The process of claim 8, wherein de-protecting OP is effected in a methanolic ammonia solution.

### Claim 14 (depends on 10)

The process of claim 10, wherein said converting is performed by contacting a compound represented by Formula Ia in a form of a free base thereof with a methanolic solution of sulfuric acid (H2SO4).