# US 8,569,499 B2 · Process for making trans-1-((1R,3S)-6-chloro-3-phenylindan-1-yl)-3,3-dimethylpiperazine

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- Number: US 8,569,499 B2
- Document ID: US8569499B2
- Status: Granted
- Kind: B2
- Application number: 11/816,383
- Filed: 2006-02-14
- Published: 2008-06-26
- Granted: 2013-10-29
- Earliest claimed: 2005-02-16
- Assignees: H. Lundbeck A/S
- Applicants: Allan Carsten Dahl; Christina Wøhlk Nielsen; Christina Suteu; David Robin; Peter Brøsen
- Inventors: Allan Carsten Dahl; Christina Wøhlk Nielsen; Christina Suteu; David Robin; Peter Brøsen
- Web page: https://patentgrep.com/patent/US8569499B2

## CPC

- C07D 295/073: with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- A61P 25/06: Antimigraine agents
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- C07C 17/16: of hydroxyl groups
- C07C 25/22: with condensed rings
- C07C 29/143: of ketones
- C07C 45/292: {with chromium derivatives}
- C07C 45/67: by isomerisation; by change of size of the carbon skeleton
- C07C 45/78: Separation; Purification; Stabilisation; Use of additives
- C07C 49/697: containing six-membered aromatic rings
- C07B 2200/07: Optical isomers
- C07C 2602/08: the other ring being five-membered, e.g. indane
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Described is a method for making the trans-1-((1R,3S)-6-chloro-3-phenylin-dan-1-yl)-3,3-dimethylpiperazine (formula I) and salts thereof and a similar method for making 4-((1R,3S)-6-chloro-3-phenylin-dan-1-yl)-1,2,2-trimethylpiperazine (formula IX) and salts thereof, which method comprises conversion of a compound of formula IVa to the compound of formula I or the compound of formula IX, respectively.

## Claims

### Claim 1

A method for manufacturing a compound of formula I (Compound I) or a salt thereof, the method comprising:
resolving the racemic compound of formula (IV) (Compound IV) using chiral chromatography; and
converting the enantiomer of formula IVa (Compound IVa) obtained thereby to the compound of formula I, wherein formula I, formula IV and formula IVa are as follows:
the conversion includes the use of a 2,2-dimethylpiperazine analog.

### Claim 2 (depends on 1)

The method of claim 1, wherein the conversion includes the compound of formula IVa being converted into the corresponding alcohol Va having cis configuration, wherein formula Va is as follows:

### Claim 3 (depends on 2)

The method of claim 2, wherein the conversion includes converting the alcohol group of the cis-alcohol of formula Va to a leaving group LG, resulting in a compound of formula VI (Compound VI):

### Claim 4 (depends on 3)

The method of claim 3, wherein LG is a halogen or a sulfonate.

### Claim 5 (depends on 3)

The method of claim 3, wherein Compound VI is precipitated from a suitable solvent

### Claim 6 (depends on 5)

The method of claim 5, wherein LG is a halogen and the solvent is an alkane.

### Claim 7 (depends on 3)

The method of claim 3, wherein Compound VI is reacted with 2,2-dimethylpiperazine to obtain Compound I.

### Claim 8 (depends on 7)

The method of claim 7, wherein Compound I is precipitated as a salt.

### Claim 9 (depends on 8)

The method of claim 8, wherein the salt is a fumarate salt, a maleate salt or a hydrochloride salt of Compound I.

### Claim 10 (depends on 7)

The method of claim 7, wherein Compound 1 is isolated as a free base.

### Claim 11 (depends on 3)

The method of claim 3, comprising:
reacting Compound VI with 1-protected 2,2-dimethylpiperazine of formula VII (Compound VII), wherein PG is a protection group, thereby obtaining a compound of formula VIII (Compound VIII); and
deprotecting Compound VIII to obtain Compound I,
wherein Compound VII and Compound VIII are as follows:

### Claim 12 (depends on 1)

The method of claim 1, wherein compound IVa is obtained by resolution of a racemic compound IV using chiral chromatography.

### Claim 13 (depends on 12)

The method of claim 12, wherein the chiral chromatography is performed using chiral liquid chromatography.

### Claim 14 (depends on 12)

The method of claim 12, wherein the chiral chromatography is performed on a chiral stationary phase.

### Claim 15 (depends on 14)

The method of claim 14, wherein the chiral stationary phase is silica gel coated with modified amylose.

### Claim 16 (depends on 15)

The method of claim 15, wherein the modified amylase is amylose tris-[(S)-α-methylbenzylcarbamate].

### Claim 17 (depends on 16)

The method of claim 16 further comprising a solvent that comprises: a mixture of n-heptane and ethanol; and optionally N,N-diethylamine.

### Claim 18 (depends on 12)

The method of claim 12, wherein the chiral chromatography is performed using subcritical fluid chromatography or supercritical fluid chromatography.

### Claim 19 (depends on 18)

The method of claim 18, wherein the subcritical fluid chromatography or supercritical fluid chromatography is performed on a chiral stationary phase.

### Claim 20 (depends on 19)

The method of claim 19, wherein the chiral stationary phase is silica gel coated with a chiral polymer, silica gel with an immobilized chiral polymer, or silica gel with a covalently bound chiral monomer.

### Claim 21 (depends on 20)

The method of claim 20, wherein the chiral polymer of the coated silica gel is amylose tris (3,5-dimethylphenylcarbamate), amylose tris [(S)-α-methylbenzylcarbamate], cellulose tris (3,5-dimethylphenylcarbamate) or cellulose tris (4-methylbenzoate), the immobilized chiral polymer is amylose tris (3,5- dimethylphenylcarbamate), and the covalently bound chiral monomer is 3,5-dinitrobenzoyl tetrahydrophenanthrene amine.

### Claim 22 (depends on 20)

The method of claim 20, wherein the chiral polymer of the coated silica gel is amylose tris (3,5-dimethylphenylcarbamate).

### Claim 23 (depends on 19)

The method of claim 19, further comprising an eluent having a modifier selected from the group consisting of methanol, ethanol, isopropanol, and acetonitrile; and optionally having diethylamine.

### Claim 24 (depends on 1)

The method of claim 1, further comprising recycling Compound IVb by converting enantiomerically enriched compound Wb into essentially racemic compound IV, wherein IVb and IV are:

### Claim 25 (depends on 24)

The method of claim 24, wherein the conversion is obtained by using a base or a mixture of two or more bases.

### Claim 26 (depends on 24)

The method of claim 24, wherein the conversion is obtained by using one or more equivalent of a non-nucleophilic base, followed by adding a catalytic amount, or one or more equivalent, of the same or another base.

### Claim 27

A method for the conversion of an enantiomerically enriched compound IVb into essentially racemic compound IV, wherein IVb and IV are:
the conversion is obtained by using one or more equivalent of a non-nucleophilic base, followed by adding a catalytic amount, or one or more equivalent, of the same or another base.

### Claim 28 (depends on 26)

The method of claim 26, wherein the conversion is obtained by using one or more equivalent of a non-nucleophilic base selected from the group consisting of an amide, a metal bis-silylamide, and an metal alkoxide, followed by adding a catalytic amount, or one or more equivalent, of the same or another base selected from the group consisting of an amide, a metal bis-silylamide, an metal alkoxide, an alkyl metal, and a mixture thereof.

### Claim 29 (depends on 28)

The method of claim 28, wherein the non-nucleophilic base is selected from the group consisting of lithium diisopropylamide (LDA), lithium bis(trimethylsilyl)amide (LiHMDS), and lithium tert-butoxide.

### Claim 30 (depends on 28)

The method of claim 28, wherein the non-nucleophilic base is selected from the group consisting of lithium diisopropylamide (LDA), potassium tert-butoxide, butyl lithium, and tert-butyl lithium.

### Claim 31 (depends on 24)

The method of claim 24, wherein non-nucleophilic base and the same or another base are present from the start of the method.

### Claim 32 (depends on 24)

The method of claim 24, wherein the essentially racemic compound IV is recrystallized from a suitable solvent.

### Claim 33 (depends on 1)

The method of claim 1, wherein Compound I is replaced by Compound IX of formula (IX):

### Claim 34 (depends on 33)

The method according to claim 33, wherein Compound DC is precipitated as a succinate salt or a malonate salt of Compound IX.

### Claim 35 (depends on 34)

The method according to claim 34, wherein the salt is crystalline.

### Claim 36 (depends on 35)

The method of claim 35, wherein the salt is formulated into a pharmaceutical composition.

### Claim 37 (depends on 4)

The method of claim 4, wherein the halogen is Cl or Br.

### Claim 38 (depends on 37)

The method of claim 37, wherein the halogen is Cl.

### Claim 39 (depends on 4)

The method of claim 4, wherein the sulfonate is a tosylate or a mesylate.

### Claim 40 (depends on 6)

The method of claim 6, wherein the halogen is Cl and the solvent is heptane.

### Claim 41 (depends on 18)

The method of claim 18, wherein the chiral chromatography is performed using supercritical fluid chromatography.

### Claim 42 (depends on 23)

The method of claim 23, wherein diethylamine is present in an amount of about 0.1%.

### Claim 43 (depends on 28)

The method of claim 28, wherein the amide is a dialkylamide.

### Claim 44 (depends on 43)

The method of claim 43, wherein the dialkylamide is selected from the group consisting of a lithium diethylamide, a lithium diisopropylamide, a lithium tetramethylpiperidide, and a suitable lithium diisopropylamide (LDA).

### Claim 45 (depends on 28)

The method of claim 28, wherein the metal bis-silylamide is an alkali bis(trimethylsily)amide.

### Claim 46 (depends on 45)

The method of claim 45, wherein the alkali bis(trimethylsilyl)amide is lithium bis-silylamide or a suitable lithium bis(trimethylsilyl)amide.

### Claim 47 (depends on 28)

The method of claim 28, wherein the metal alkoxide is a metal methoxide, a metal ethoxide, a metal tert-butoxide, or a suitable alkali alkoxide.

### Claim 48 (depends on 47)

The method of claim 47, wherein the suitable alkali alkoxide is a lithium alkoxide or a potassium alkoxide.

### Claim 49 (depends on 48)

The method of claim 48, wherein the lithium alkoxide is lithium tert-butoxide.

### Claim 50 (depends on 48)

The method of claim 48, wherein the potassium alkoxide is potassium tert-butoxide.

### Claim 51 (depends on 28)

The method of claim 28, wherein the alkyl metal is a suitable alkyl lithium.

### Claim 52 (depends on 51)

The method of claim 51, wherein the suitable alkyl lithium is butyl lithium or tert-butyl lithium.

### Claim 53 (depends on 32)

The method of claim 32, wherein the suitable solvent is an alcohol.

### Claim 54 (depends on 53)

The method of claim 53, wherein the alcohol is a C1-6-alcohol.

### Claim 55 (depends on 54)

The method of claim 54, wherein the C1-6-alcohol is ethanol, 2-propanol or a mixture thereof.