Process for the preparation of aniline-derived thyroid receptor ligands

• US 6,806,381 B2
• Filed: 10/17/2002
• Issued: 10/19/2004
• Est. Priority Date: 11/02/2001
• Status: Expired due to Fees

• Current Assignee: Karo Pharma AB
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Chidambaram, Ramakrishnan, Yu, Jurong, Kant, Joydeep, Ghosh, Arun, Weaver, Raymond E.
• Primary Examiner(s): Desai, Rita
• Assistant Examiner(s): Reyes, Hector M.
• Application Number:
  US10/273,268
• Publication Number:
  US 20030157671A1
• Time in Patent Office: 733 Days
• Field of Search: 560/41, 560/43, 562/455, 514/522, 514/539
• US Class Current: 560/41
• CPC Class Codes: C07C 201/12 by reactions not involving the formation of nitro groups
• CPC Class Codes: C07C 205/12 the six-membered aromatic ring or a condensed ring system containing that ring being substituted by halogen atoms
• CPC Class Codes: C07C 205/37 the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
• CPC Class Codes: C07C 205/38 the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. nitrodiphenyl ethers
• CPC Class Codes: C07C 205/43 to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
• CPC Class Codes: C07C 213/02 by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
• CPC Class Codes: C07C 217/90 the oxygen atom of at least one of the etherified hydroxy groups being further bound to a carbon atom of a six-membered aromatic ring, e.g. amino-diphenylethers
• CPC Class Codes: C07C 231/02 from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
• CPC Class Codes: C07C 233/25 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 309/24 of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 309/65 of a saturated carbon skeleton
• CPC Class Codes: C07C 45/00 Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
• CPC Class Codes: C07C 47/575 containing ether groups, groups, groups, or groups

Abstract

Provided are processes for the synthesis of aniline derivatives, specifically certain aniline derivatives which have activity as thyroid receptor ligands.

Claims

1. A process for synthesizing a compound of formula I

wherein

R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7 carbons;

R² and R⁵ are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R² and R³ being other than, hydrogen;

R⁴ represents hydrogen or a lower alkyl group;

R⁵ represents a carboxylic acid or an alkyl ester thereof; and

Y represents —

(CH₂)_n—

where n is an integer from 1 to 5, or a cis- or trans-ethylene group —

CH=CH—

;

and all stereoisomers thereof;

said process comprising the steps of;

a) reacting a compound of formula III with a phenol of formula A, wherein R¹, R², R³, and R⁴ are as defined above and G is a protecting group, in the presence of a base to produce a compound of formula IV;

b) deprotecting and reducing the compound of formula IV to form a compound of formula VI;

c) reacting the compound of formula VI with a compound of the formula XC(O)YR⁵, wherein X represents OH or a halogen and R⁵ is a carboxylic acid alkyl ester, in the presence of a base, to produce a compound of formula I wherein R⁵ is a carboxylic acid alkyl ester; and

(d) optionally de-esterifying the compound of formula I wherein R⁵ is a carboxylic acid alkyl ester to produce a compound of formula I wherein R⁵ is a carboxylic acid;

wherein the compound of Formula III is produced by reacting a compound of formula II

wherein L is a leaving group;

R² and R³ are the same or different and represent hydrogen, halogen, an alkyl group of 1 to 4 carbons, or a cycloalkyl group of 3 to 6 carbons, at least one of R² and R³ being other than hydrogen; and

R⁴ alkyl group;

with an iodinating agent.

2. The process of claim 1, wherein, in step a, the base is selected from the group consisting of potassium hexamethyldisilazide (KHMDS), lithium hexamethyldisilazide, sodium hexamethyldisilazide, alkyl lithiums, lithium diisopropylamine, Grignard reagents, alkali metal hydrides, alkali metal carbonates, alkali metal hydroxides, and alkali metal alkoxides.

3. The process of claim 2, wherein, in step a, the base is selected from the group consisting of potassium hexamethyldisilazide (KHMDS), potassium t-butoxide, potassium t-pentoxide, LiHMDS, or NaHMDS.

4. The process of claim 3, wherein, in step a, the base is potassium hexamethyldisilazide.

5. The process of claim 1, wherein, in step b, the deprotecting agent is selected from the group consisting of trialkylsilyl halides, mercaptans, boron halides, magnesium halides, alumnum halides, hydrogen over palladium catalyst, or iron halides.

6. The process of claim 5, wherein, in step b, the deprotecting agent is a trialkylsilyl halide or BBr₃.

7. The process of claim 6, wherein, in step b, the compound of formula IV is deprotected by reaction with BBr₃.

8. The process of claim 1, wherein, in step b, the reducing agent is selected from the group consisting of elemental metals;

hydrogen catalyzed by nickel, palladium or platinum;

alkali metal borohydrides;

magnesium-mediated, reductions;

iron carbonyls;

iron sulfate mediated reductions;

iron and HCl;

sodium hydrogen sulfite;

sodium dithionite;

tin and tin halide mediated reductions; and

alkali metal sulfides end polysulfides.

9. The process of claim 8, wherein, in step b, the reducing agent is selected from the group consisting of sodium hydrogen sulfite;

sodium dithionite; and

iron and HCl.

10. The process of claim 9, wherein, in step b, the reducing agent is sodium dithionite.

11. The process of claim 1, wherein, in step c, the base is selected from the group consisting of alkali metal hydroxides and alkoxides;

alkaline earth metal hydroxides and alkoxides;

alkyl amines; and

substituted alkyl amines.

12. The process of claim 11, wherein, in step c, the base is selected from the group consisting of alkali metal hydroxides and alkaline earth metal hydroxides.

13. The process of claim 12, wherein, in step c, the base is sodium hydroxide.

14. The process of claim 1, wherein, in step d, the de-esterifying agent is selected from the group consisting of enzymes;

hydrogen ever catalytic palladium;

lithium and ammonia;

zinc;

alkali metal hydroxides and alkoxides;

alkaline earth metal hydroxides and alkoxides;

sodium sulfide;

KSCN;

thioethers in combination with Lewis acids;

anions of alkyl thiols or selenols;

trialkyl silyl halides;

zinc dichloride;

mercury (II) acetate; and

strong protic acids.

15. The process of claim 14, wherein, in step d, the de-esterifying agent is an alkali metal hydroxide.

16. The process of claim 15, wherein, in step d, the de-esterifying agent is sodium hydroxide.

17. The process of claim 1, wherein the iodinating agent is selected from the group consisting of alkali metal iodides and tetraalkylammonium, iodides.

18. The process of claim 17, wherein the iodinating agent is selected from the group consisting of sodium iodide and potassium iodide.

19. The process of claim 17, wherein the iodinating agent is sodium iodide.

20. The process of claim 1 wherein the compound of formula IV is first deprotected to form a compound of formula V

and then reduced to form the compound of formula VI wherein the variables R1-R4 are defined as in claim 1.

21. The process of claim 1 wherein the compound of formula IV is first reduced to form a compound of formula VA

and then deprotected to form the compound of formula VI wherein the variables R1-R4 and G are defined as in claim 1.

22. The process of claim 1 for the preparation of a formula I compound wherein

Y represents —

(CH₂)_n—

where n is 1 or 2;

R¹ represents halogen, trifluorormethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl group of 3 to 7 carbons;

R² and R³ independently represent bromo, chloro, or methyl;

R⁴ represents hydrogen or methyl; and

R⁵ represents carboxyl.

23. The process of claim 1 for the preparation of a formula I compound wherein

Y represents —

(CH₂)_n—

where n is 1;

R¹ represents halogen, trifluoromethyl, an alkyl group of 1 to 6 carbons, or a cycloalkyl, group of 3 to 7 carbons;

R² and R² independently represent bromo or chloro;

R⁴ represents hydrogen or methyl; and

R⁵ represents carboxyl.

24. The process of claim 1 wherein the compound of formula I is selected from the group consisting of

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl—

phenyl]-malonamic acid;

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-succinamic acid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid;

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-2-methyl-phenyl]-malonamic acid; and

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-2-phenyl]-succinamic acid, and alkyl esters thereof.

25. The process of claim 1 wherein the compound of formula I is

N-[3,5-dibromo-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid, or

N-[3,5-dichloro-4-(4-hydroxy-3-isopropyl-phenoxy)-phenyl]-malonamic acid, and alkyl esters thereof.

26. The process of claim 1 wherein the compound of formula I is

and alkyl esters thereof.