# US 9,434,680 B2 · Methods for synthesizing and purifying aminoalkyl tetracycline compounds

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- Number: US 9,434,680 B2
- Document ID: US9434680B2
- Status: Granted
- Kind: B2
- Application number: 12/110,627
- Filed: 2008-04-28
- Published: 2008-11-20
- Granted: 2016-09-06
- Earliest claimed: 2007-04-27
- Assignees: Paratek Pharmaceuticals, Inc.
- Applicants: Sean Johnston; Tadeusz Warchol
- Inventors: Sean Johnston; Tadeusz Warchol
- Web page: https://patentgrep.com/patent/US9434680B2

## CPC

- C07C 231/12: by reactions not involving the formation of carboxamide groups
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/12: Antidiarrhoeals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 9/14: Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/16: Central respiratory analeptics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- 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 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 231/24: Separation; Purification
- C07C 2603/46: 1,4,4a,5,5a,6,11,12a- Octahydronaphthacenes, e.g. tetracyclines
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Methods for the synthesis and purification of 9-amino alkyl tetracycline compounds are described.

## Claims

### Claim 1

A method for the synthesis of a 9-aminomethyl minocycline compound of the following structural formula:
the method comprising:
a) contacting minocycline with a N-hydroxymethyl pthalimide compound (Pht) in the presence of a water scavenger and an acid under a reaction temperature of 20-35° C. to form a first 9-aminomethyl minocycline intermediate of the following structural formula:
b) reacting said first 9-aminomethyl minocycline intermediate formed in step a) with methylamine in the presence of ether and alkyl alcohol to form a second 9-aminomethyl minocycline intermediate of the following structural formula:
and
c) treating said second 9-aminomethyl minocycline intermediate formed in step b) through hydrogenation to form said 9-aminomethyl minocycline compound.

### Claim 2 (depends on 1)

The method of claim 1, wherein said water scavenger is an acid chloride or an acid anhydride.

### Claim 3 (depends on 2)

The method of claim 2, wherein said acid anhydride is methylsulfonic anhydride.

### Claim 4 (depends on 1)

The method of claim 1, wherein said acid is triflic acid or methane sulfonic acid.

### Claim 5 (depends on 1)

The method of claim 1, wherein said first 9-aminomethyl minocycline intermediate is no more than 10% tris-alkylated.

### Claim 6 (depends on 1)

The method of claim 1, wherein said first 9-aminomethyl minocycline intermediate is dissolved in acetone before step b).

### Claim 7 (depends on 1)

The method of claim 1, wherein step b) comprises an inert atmosphere.

### Claim 8 (depends on 1)

The method of claim 1, further comprising purifying said second 9-aminomethyl minocycline intermediate by forming a hydrochloride salt of said second 9-aminomethyl minocycline intermediate.

### Claim 9 (depends on 8)

The method of claim 8, wherein said hydrochloride salt is formed in an alkyl alcohol followed by precipitation with an alkyl ether.

### Claim 10 (depends on 1)

The method of claim 1, wherein step c) comprises a Pd/C or Pd/C/S catalyst.

### Claim 11 (depends on 1)

The method of claim 1, wherein step c) comprises methanol and an aldehyde.

### Claim 12 (depends on 1)

The method of claim 1, wherein step c) comprises hydrogen gas.

### Claim 13 (depends on 1)

The method of claim 1, further comprising reacting said 9-aminomethyl minocycline compound with an aldehyde to form a substituted 9-aminomethyl minocycline compound of the formula

### Claim 14 (depends on 13)

The method of claim 13, wherein said reaction comprises a Pd/C or Pd/C/S catalyst.

### Claim 15 (depends on 13)

The method of claim 13, wherein said reaction comprises methanol and an aldehyde.

### Claim 16 (depends on 13)

The method of claim 13, wherein said reaction comprises hydrogen gas.

### Claim 17 (depends on 13)

The method of claim 13, wherein said substituted 9-aminomethyl minocycline compound is formed substantially free of over hydrogenated impurities.

### Claim 18 (depends on 13)

The method of claim 13, wherein said substituted 9-aminomethyl minocycline compound comprises less than 10% β isomer.

### Claim 19 (depends on 18)

The method of claim 18, wherein said substituted 9-aminomethyl minocycline compound comprises less than 5% β isomer.

### Claim 20 (depends on 4)

The method of claim 4, wherein said acid is triflic acid.

### Claim 21 (depends on 1)

The method of claim 1, wherein said ether is an alkyl ether or a cyclic ether.

### Claim 22 (depends on 1)

The method of claim 1, wherein step a) comprises a reaction time of 1-2 hours.

### Claim 23 (depends on 1)

The method of claim 1, wherein step a) is carried out under a reaction temperature of 20-25° C.

### Claim 24

A method for the synthesis of a 9-aminomethyl minocycline compound of the following structural formula:
the method comprising:
a) contacting minocycline with a N-hydroxymethyl pthalimide compound (Pht) in the presence of an acid under a reaction temperature of 20-35° C. to form a first 9-aminomethyl minocycline intermediate of the following structural formula:
b) reacting said first 9-aminomethyl minocycline intermediate formed in step a) with methylamine in the presence of ether and alkyl alcohol to form a second 9-aminomethyl minocycline intermediate of the following structural formula:
and
c) treating said second 9-aminomethyl minocycline intermediate formed in step b) through hydrogenation to form said 9-aminomethyl minocycline compound.

### Claim 25 (depends on 24)

The method of claim 24, wherein said acid is triflic acid or methane sulfonic acid.

### Claim 26 (depends on 24)

The method of claim 24, wherein said first 9-aminomethyl minocycline intermediate is no more than 10% tris-alkylated.

### Claim 27 (depends on 24)

The method of claim 24, wherein said first 9-aminomethyl minocycline intermediate is dissolved in acetone before step b).

### Claim 28 (depends on 24)

The method of claim 24, wherein step b) comprises an inert atmosphere.

### Claim 29 (depends on 24)

The method of claim 24, further comprising purifying said second 9-aminomethyl minocycline intermediate by forming a hydrochloride salt of said second 9-aminomethyl minocycline intermediate.

### Claim 30 (depends on 29)

The method of claim 29, wherein said hydrochloride salt is formed in an alkyl alcohol followed by precipitation with an alkyl ether.

### Claim 31 (depends on 24)

The method of claim 24, wherein step c) comprises a Pd/C or Pd/C/S catalyst.

### Claim 32 (depends on 24)

The method of claim 24, wherein step c) comprises methanol and an aldehyde.

### Claim 33 (depends on 24)

The method of claim 24, wherein step c) comprises hydrogen gas.

### Claim 34 (depends on 24)

The method of claim 24, further comprising reacting said 9-aminomethyl minocycline compound with an aldehyde to form a substituted 9-aminomethyl minocycline compound of the formula

### Claim 35 (depends on 34)

The method of claim 34, wherein said reaction comprises a Pd/C or Pd/C/S catalyst.

### Claim 36 (depends on 34)

The method of claim 34, wherein said reaction comprises methanol and an aldehyde.

### Claim 37 (depends on 34)

The method of claim 34, wherein said reaction comprises hydrogen gas.

### Claim 38 (depends on 34)

The method of claim 34, wherein said substituted 9-aminomethyl minocycline compound is formed substantially free of over hydrogenated impurities.

### Claim 39 (depends on 34)

The method of claim 34, wherein said substituted 9-aminomethyl minocycline compound comprises less than 10% β isomer.

### Claim 40 (depends on 39)

The method of claim 39, wherein said substituted 9-aminomethyl minocycline compound comprises less than 5% β isomer.

### Claim 41 (depends on 25)

The method of claim 25, wherein said acid is triflic acid.

### Claim 42 (depends on 24)

The method of claim 24, wherein said ether is an alkyl ether or a cyclic ether.

### Claim 43 (depends on 24)

The method of claim 24, wherein step a) comprises a reaction time of 1-2 hours.

### Claim 44 (depends on 24)

The method of claim 24, wherein step a) is carried out under a reaction temperature of 20-25° C.