# US 2008/0188659 A1 · Method for Preparing Halogenated Amines

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- Number: US 2008/0188659 A1
- Document ID: US20080188659A1
- Status: Published application
- Kind: A1
- Application number: 12/027,412
- Filed: 2008-02-07
- Published: 2008-08-07
- Earliest claimed: 2007-02-07
- Assignees: Wyeth
- Inventors: Eddine Saiah; Huan-Qiu Li; Adrian Huang
- Web page: https://patentgrep.com/patent/US20080188659A1

## CPC

- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/46: for decreasing, blocking or antagonising the activity of glucocorticosteroids
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/06: for tuberculosis
- A61P 31/12: Antivirals
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07C 303/40: by reactions not involving the formation of sulfonamide groups
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

This invention relates to methods for preparing halogenated amines.

## Claims

### Claim 1

A method for preparing an organic compound or a salt thereof having one or more substituents of formula (A):
wherein:
(i) each of RF1 and RF2 is, independently, optionally substituted C1-C6 fluoroalkyl;
(ii) each of R3 and R4 is, independently, hydrogen, Ra, —C(O)H, —C(O)Ra, —C(O)ORa, or —SO2Ra, wherein Ra at each occurrence is, independently, any organic group, selected from alkyl, cycloalkyl, aralkyl, heterocyclyl, aryl, or heteroaryl, each of which is optionally substituted; and
(iii) the organic compound comprises as part of its structure any one or more of the following substructures:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally substituted; or
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is optionally substituted; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally substituted;
each of which, when two or more substructures are present, is connected to one another by a direct bond or a heteroatom-containing linker;
the method comprising reacting a nitrile-containing organic compound with a fluoroalkylating agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein RF1 and RF2 are the same.

### Claim 3 (depends on 1)

The method of claim 1, wherein each of RF1 and RF2 is, independently, optionally substituted C1-C4 perfluoroalkyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein each of RF1 and RF2 is CF3.

### Claim 5 (depends on 1)

The method of claim 1, wherein each of R3 and R4 is hydrogen.

### Claim 6 (depends on 1)

The method of claim 1, wherein the organic compound having one or more substituents of formula (A) is a compound of formula (I) or a salt thereof:
wherein:
R is:
(i) C6-C18 aryl or heteroaryl including 5-16 atoms, each of which is optionally substituted;
(ii) C7-C20 aralkyl or heteroaralkyl including 6-20 atoms, each of which is optionally substituted; or
(iii) C3-C10 cycloalkyl, C3-C10 cycloalkenyl, heterocyclyl including 3-10 atoms, or heterocycloalkenyl including 3-10 atoms, each of which is optionally substituted; or
(iv) C1-C12 alkyl, C2-C12 alkenyl or C2-C12 alkynyl, each of which is optionally substituted;
each of RF1 and RF2 is, independently, optionally substituted C1-C6 fluoroalkyl; and
each of R3 and R4 is, independently, hydrogen, Ra, —C(O)H, —C(O)Ra, —C(O)ORa, or —SO2Ra, wherein Ra at each occurrence is, independently, as defined above for R;
and the nitrile-containing organic compound is a compound of formula (II):
wherein R is as defined above.

### Claim 7 (depends on 6)

The method of claim 6, wherein R is optionally substituted C6-C10 aryl.

### Claim 8 (depends on 6)

The method of claim 6, wherein R is optionally substituted phenyl.

### Claim 9 (depends on 6)

The method of claim 6, wherein R is optionally substituted C7-C12 aralkyl.

### Claim 10 (depends on 6)

The method of claim 6, wherein R is optionally substituted benzyl.

### Claim 11 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a perfluoroalkylating agent.

### Claim 12 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a trifluoromethylating agent.

### Claim 13 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a compound having formula (III):
wherein:
RF is C1-C6 fluoroalkyl; and
each of Rb, Rc, and Rd is, independently, C1-C12 alkyl or C2-C12 alkenyl, each of which is optionally substituted.

### Claim 14 (depends on 13)

The method of claim 13, wherein a fluoride ion is present during the reacting of the compound of formula (II) and the compound of formula (III).

### Claim 15 (depends on 13)

The method of claim 13, wherein each of Rb, Rc, and Rd is, independently, C1-C4 alkyl.

### Claim 16 (depends on 13)

The method of claim 13, wherein each of Rb, Rc, and Rd is —CH3.

### Claim 17 (depends on 13)

The method of claim 13, wherein each of Rb, Rc, and Rd is —CH2CH3.

### Claim 18 (depends on 13)

The method of claim 13, wherein one of Rb, Rc, and Rd is C2-C4 alkenyl, and the other two are each, independently, C1-C4 alkyl.

### Claim 19 (depends on 13)

The method of claim 13, wherein one of Rb, Rc, and Rd is —CH═CH2, and the other two are each —CH3.

### Claim 20 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a fluoroalkyl-containing salt or ionic complex.

### Claim 21 (depends on 20)

The method of claim 20, wherein the method further comprises reacting a compound having formula (IV):
RF—X
wherein RF is C1-C6 fluoroalkyl; and X is halo;
with a reducing agent.

### Claim 22 (depends on 21)

The method of claim 21, wherein the reducing agent is tetrakis(dimethylamino)ethylene (TDAE).

### Claim 23 (depends on 21)

The method of claim 21, wherein X is iodo.

### Claim 24 (depends on 21)

The method of claim 21, wherein RF is CF3, CF2CF3, or (CF2)3CF3.

### Claim 25 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a compound having formula (V):
wherein:
RF is C1-C6 fluoroalkyl; and
ring A is optionally substituted morpholinyl or piperazinyl.

### Claim 26 (depends on 25)

The method of claim 25, wherein a base is present during the reacting of the compound of formula (II) and the compound of formula (V).

### Claim 27 (depends on 26)

The method of claim 26, wherein the base is a metal salt of a C1-C6 alkoxide.

### Claim 28 (depends on 25)

The method of claim 25, wherein RF is CF3.

### Claim 29 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is a compound having formula (VI): Ar—S(O)x—RF;
wherein:
Ar is optionally substituted phenyl;
x is 1 or 2; and
RF is C1-C6 fluoroalkyl.

### Claim 30 (depends on 29)

The method of claim 29, wherein a base is present during the reacting of the compound of formula (II) and the compound of formula (VI).

### Claim 31 (depends on 30)

The method of claim 30, wherein the base is a metal salt of a C1-C6 alkoxide.

### Claim 32 (depends on 29)

The method of claim 29, wherein RF is CF3.

### Claim 33 (depends on 29)

The method of claim 29, wherein x is 2.

### Claim 34 (depends on 1)

The method of claim 1, wherein the fluoroalkylating agent is CF3H.

### Claim 35 (depends on 1)

The method of claim 1, wherein the compound of formula (II) further comprises a substituent having a formula —C(O)Re, wherein Re is C1-C6 alkyl.

### Claim 36 (depends on 35)

The method of claim 35, wherein Re is CH3.

### Claim 37

A method for preparing a compound of formula (VII) or a salt thereof:
wherein:
each of m and n is, independently, 0 or 1, provided that one of m and n is 1;
each of RF1, RF2, RF1′, and RF2′ is, independently, optionally substituted C1-C6 fluoroalkyl;
each of R3, R4, R3′, and R4′ is, independently, hydrogen, C1-C6 alkyl, —C(O)H, or —C(O)ORa, wherein Ra is C7-C20 aralkyl or C1-C6 alkyl, each of which is optionally substituted;
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally further substituted with from 1-5 substituents independently selected from halo; NRfRg; hydroxyl; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; optionally substituted C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is optionally substituted; C6-C10 aryloxy or heteroaryloxy including 5-12 atoms, each of which is optionally substituted; heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including 6-12 atoms, each of which is optionally substituted; —C(O)ORh; —C(O)NRfRg; or —NRiC(O)Rj;
each of Rf, Rg, and Rh, at each occurrence is, independently:
(i) hydrogen; or
(ii) C1-C12 alkyl or C1-C12 haloalkyl; each of which is optionally substituted; or
(iii) C7-C20 aralkyl; C3-C16 cycloalkyl; heteroaralkyl including 6-20 atoms; C3-C16 cycloalkenyl; heterocyclyl including 3-16 atoms; or heterocycloalkenyl including 3-16 atoms; each of which is optionally substituted; or
(iv) C2-C20 alkenyl or C2-C20 alkynyl; or
(v) C6-C16 aryl or heteroaryl including 5-16 atoms, each of which is optionally substituted;
Rj is Rh; ORh; or NRfRg;
W is C1-C4 alkyl; and
ring C is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally further substituted with from 1-5 substituents independently selected from halo; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; or C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is optionally substituted;
from a compound of formula (VIII):
wherein:
ring B is C6-C10 aryl or heteroaryl including 5-10 atoms, each of which is optionally further substituted with from 1-5 substituents independently selected from halo; NRfRg; hydroxyl; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; optionally substituted C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is optionally substituted; C6-C10 aryloxy or heteroaryloxy including 5-12 atoms, each of which is optionally substituted; heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including 6-12 atoms, each of which is optionally substituted; —C(O)Re, wherein Re is C1-C6 alkyl; —C(O)NRfRg; or —NRiC(O)Rj; and
m, n, ring C, and W are as defined above in conjunction with formula (VII);
the method comprising reacting the compound of formula (VIII) with a fluoroalkylating agent.

### Claim 38 (depends on 37)

The method of claim 37, wherein m in formulas (VII) and (VIII) is 1, and n in formulas (VII) and (VIII) is 0.

### Claim 39 (depends on 38)

The method of claim 38, wherein each of RF1 and RF2 in formula (VII) is CF3.

### Claim 40 (depends on 38)

The method of claim 38, wherein each of R3 and R4 in formula (VII) is hydrogen.

### Claim 41 (depends on 38)

The method of claim 38, wherein ring C in formula (VII) has formula (IX):
wherein two of Rc22, Rc23, Rc24, Rc25, and Rc26 are each, independently, halo; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; or C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is optionally substituted; and the others are hydrogen.

### Claim 42 (depends on 41)

The method of claim 41, wherein Rc22 is CF3 or fluoro; and Rc24 is fluoro, chloro, CF3, or optionally substituted heteroaryl.

### Claim 43 (depends on 37)

The method of claim 37, wherein m in formulas (VII) and (VIII) is 0, and n in formulas (VII) and (VIII) is 1.

### Claim 44 (depends on 43)

The method of claim 43, wherein each of RF1′ and RF2′ in formula (VII) is CF3.

### Claim 45 (depends on 43)

The method of claim 43, wherein each of R3′ and R4′ in formula (VII) is hydrogen.

### Claim 46 (depends on 43)

The method of claim 43, wherein ring B in formula (VII) has formula (X):
wherein one of Ra2, Ra3, and Ra4 is halo; NRfRg; hydroxyl; C1-C12 alkyl or C1-C12 haloalkyl, each of which is optionally substituted; optionally substituted C1-C12 alkoxy; C1-C12 haloalkoxy; nitro; C6-C10 aryl or heteroaryl including 5-12 atoms, each of which is optionally substituted; C6-C10 aryloxy or heteroaryloxy including 5-12 atoms, each of which is optionally substituted; heterocyclyl including 3-10 atoms, C3-C10 cycloalkyl, C7-C12 aralkoxy or heteroaralkoxy including 6-12 atoms, each of which is optionally substituted; —C(O)ORh; —C(O)NRfRg; or —NRiC(O)Rj; and the others are hydrogen.

### Claim 47 (depends on 46)

The method of claim 46, wherein Ra3 or Ra4 is 1,1,1-trifluoro-2-hydroxy-2-propyl.

### Claim 48 (depends on 43)

The method of claim 43, wherein ring B in formula (VIII) is substituted with —C(O)Re, wherein Re is C1-C4 alkyl.

### Claim 49 (depends on 37)

The method of claim 37, wherein the fluoroalkylating agent is a compound having formula (III):
wherein:
RF is C1-C6 fluoroalkyl; and
each of Rb, Rc, and Rd is, independently, C1-C12 alkyl or C2-C12 alkenyl, each of which is optionally substituted.

### Claim 50 (depends on 49)

The method of claim 49, wherein a fluoride ion is present during the reacting of the formula (VII) and the compound of formula (III).

### Claim 51 (depends on 49)

The method of claim 49, wherein each of Rb, Rc, and Rd is, independently, C1-C4 alkyl.

### Claim 52 (depends on 49)

The method of claim 49, wherein each of Rb, Rc, and Rd is —CH3.

### Claim 53 (depends on 49)

The method of claim 49, wherein each of Rb, Rc, and Rd is —CH2CH3.

### Claim 54 (depends on 49)

The method of claim 49, wherein one of Rb, Rc, and Rd is C2-C4 alkenyl, and the other two are each, independently, C1-C4 alkyl.

### Claim 55 (depends on 49)

The method of claim 49, wherein one of Rb, Rc, and Rd is —CH═CH2, and the other two are each —CH3.

### Claim 56

A compound selected from the group consisting of:
2-(3-{[(2R)-4-{6-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridin-3-yl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol;
2-(3-{[(2R)-4-{4-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)phenyl}-2-methylpiperazin-1-yl]sulfonyl}phenyl)-1,1,1-trifluoropropan-2-ol;
2-[4-({(2R)-4-[4-[1-amino-2,2,2-trifluoro-1-(trifluoromethyl)ethyl]-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]-1,1,1-trifluoropropan-2-ol;
1,1,1,3,3,3-hexafluoro-2-[4-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-amine; and
1,1,1,3,3,3-hexafluoro-2-[3-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)phenyl]propan-2-amine; or a pharmaceutically acceptable salt thereof.

### Claim 57

A compound selected from the group consisting of the title compounds of Examples 1-13, or a pharmaceutically acceptable salt thereof.