# US 2017/0283368 A1 · Methods for synthesizing substituted tetracycline compounds

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- Number: US 2017/0283368 A1
- Document ID: US20170283368A1
- Status: Published application
- Kind: A1
- Application number: 15/351,700
- Filed: 2016-11-15
- Published: 2017-10-05
- Earliest claimed: 2007-07-06
- Assignees: Paratek Pharmaceuticals, Inc.
- Applicants: Paratek Pharmaceuticals, Inc.
- Inventors: Farzaneh Seyedi; Tadeusz Warchol; Mark Grier
- Web page: https://patentgrep.com/patent/US20170283368A1

## CPC

- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07C 2603/44: Naphthacenes; Hydrogenated naphthacenes
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Methods of synthesizing substituted tetracycline compounds are provided.

## Claims

### Claim at position 1

1-20. (canceled)

### Claim 21

A method for synthesizing a 9-substituted tetracycline compound, the method comprising:
a) reacting a 9-halogenated tetracycline compound with carbon monoxide, a first palladium catalyst, a silane and a base to generate a 9-carboxaldehyde substituted tetracycline compound; and
b) reacting said 9-carboxaldehyde substituted tetracycline compound with a primary or secondary amine under hydrogenolysis or reductive amination conditions to generate said 9-substituted tetracycline compound, or a pharmaceutically acceptable salt or ester thereof.

### Claim 22 (depends on 21)

The method of claim 21, wherein said 9-halogenated tetracycline compound is 9-halogenated minocycline.

### Claim 23 (depends on 22)

The method of claim 22, wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline, a 9-chlorine substituted minocycline, or a 9-bromine substituted minocycline.

### Claim 24 (depends on 23)

The method of claim 23, wherein said 9-halogenated minocycline is a 9-iodine substituted minocycline.

### Claim 25 (depends on 21)

The method of claim 21, wherein said hydrogenolysis conditions comprise a second palladium catalyst, an ammonium compound and one or more solvents; and wherein said reductive amination conditions comprise a reducing agent and a solvent.

### Claim 26 (depends on 21)

The method of claim 21, wherein said first palladium catalyst is Pd(OAc)2, PdCl(tBu2PhP)2 [dichlorobis(di-tert-butylphenylphosphine palladium (II)] or PdCl2(DPEPhos) [bis(diphenylphosphinophenyl)ether palladium (II) chloride].

### Claim 27 (depends on 26)

The method of claim 26, wherein said first palladium catalyst is Pd(OAc)2 or PdCl2(tBu2PhP)2.

### Claim 28 (depends on 21)

The method of claim 21, wherein the silane is a compound represented by the chemical formula R2SiH2 or R3SiH, wherein each R is independently C1-C10 branched or straight chain alkyl or C5-C14 aryl.

### Claim 29 (depends on 28)

The method of claim 28, wherein the silane is selected from the group consisting of tripropylsilane (Pr3SiH), triisopropylsilane (iPr3SiH), benzyldimethylsilane, di-tert-butylsilane (tBu2SiH2), triethylsilane (Et3SiH), cyclohexyldimethylsilane, dimethylphenylsilane, diethylisopropylsilane, methylphenylsilane, dimethylisopropylsilane, diethylmethylsilane, dimethylethylsilane, diethylsilane (Et2SiH2), trioctylsilane, dimethyloctadecylsilane, trihexylsilane, triphenylsilane (Ph3SiH), diisopropyloctylsilane, methyldiphenylsilane, triisobutylsilane (iBu3SiH), tributylsilane (Bu3SiH), diphenylsilane (Ph2SiH2) and dimethylphenethylsilane.

### Claim 30 (depends on 29)

The method of claim 29, wherein the silane is Et3SiH.

### Claim 31 (depends on 21)

The method of claim 21, wherein the base is a carbonate base.

### Claim 32 (depends on 31)

The method of claim 31, wherein the carbonate base is selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate, strontium carbonate and lanthanum carbonate.

### Claim 33 (depends on 32)

The method of claim 32, wherein the base is sodium carbonate.

### Claim 34 (depends on 21)

The method of claim 21, wherein the base is a trialkylamine.

### Claim 35 (depends on 34)

The method of claim 34, wherein the base is selected from the group consisting of trimethylamine, triethylamine, tributylamine, triisopropylamine, dimethylethylamine, diisopropylethylamine, diethylmethylamine, dimethylisopropylamine and dimethylbutylamine.

### Claim 36 (depends on 32)

The method of claim 32, wherein the base is diisopropylethylamine.

### Claim 37 (depends on 21)

The method of claim 21, wherein the reaction in step a) comprises a Lewis acid.

### Claim 38 (depends on 37)

The method of claim 37, wherein the Lewis acid is InCl3.