# US 8,541,593 B2 · Process for making substituted 2-amino-thiazolones

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- Number: US 8,541,593 B2
- Document ID: US8541593B2
- Status: Granted
- Kind: B2
- Application number: 12/665,405
- Filed: 2008-06-20
- Published: 2010-11-04
- Granted: 2013-09-24
- Earliest claimed: 2007-06-21
- Assignees: Amgen Inc.
- Applicants: George A. Moniz; Matthew J. Frizzle; Charles Bernard; Michael Martinelli; Margaret M. Faul; Roger Nani; Jay Larrow
- Inventors: George A. Moniz; Matthew J. Frizzle; Charles Bernard; Michael Martinelli; Margaret M. Faul; Roger Nani; Jay Larrow
- Web page: https://patentgrep.com/patent/US8541593B2

## CPC

- C07D 277/42: Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/12: Antihypertensives
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/10: for osteoporosis
- 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 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to methods of making compounds that inhibit 11-hydroxysteroid dehydrogenase type 1 enzyme (11-HSD1). One method comprises (a) contacting a compound of formula (II) sequentially with a chiral base in the presence of an amine, and an alkylating agent R3-LG, (b) contacting the product of (a) with an acid to form a salt, and (c) reacting the salt with a base to form the compound of formula (I), wherein Z, R1, R2, and R3 are defined herein.

## Claims

### Claim 1

A process for the preparation of a compound according to formula I, or a tautomer, stereoisomer, geometric isomer, or optical isomer thereof:
comprising
(a) asymmetrically alkylating a compound of formula II by contacting a compound of formula II
with a chiral base selected from the group consisting of
wherein
X is selected from O, N, S, and C1-8-alkylene;
Y is selected from C1-8-alkyl, aryl, and heterocyclyl;
is selected from Li, Na, K, Cs, Cu, Zn, and Mg; and
Ar is an aryl;
and an alkylating agent R3-LG in the presence of an amine, whereby the compound of formula II is asymmetrically alkylated;
wherein:
Z is S or O;
R1 is selected from C1-8 alkyl, C2-8 alkenyl, C3-10-cycloalkyl, C3-10-cycloalkenyl, C3-10-cycloalkyl-C1-8-alkyl, C3-10-cycloalkenyl-C1-8-alkyl, aryl, aryl-C1-8-alkyl, heterocyclyl, heterocyclyl-C1-8-alkyl and haloalkyl;
wherein any aryl, cycloalkyl, or heterocyclyl residue is optionally independently substituted by one or more C1-8-alkyl, aryl, halogen, halo-C1-C8-alkyl, HO—C1-C8-alkyl, R4R5N—C1-C8-alkyl, C1-C8-alkyl-OR6, —OR6, (C3-C10)-cycloalkyl or C1-C8-alkyl-sulfonyl;
R2 and R3 are independently selected from C1-8-alkyl, C1-8-alkoxy, C3-10-cycloalkyl, heterocyclyl, C3-10-cycloalkyl-C1-8-alkyl, CN—C1-8-alkyl, aryl, aryl-C1-8-alkyl, heterocyclyl-C1-8-alkyl and haloalkyl;
wherein any aryl, cycloalkyl, or heterocyclyl residue is optionally independently substituted by one or more C1-8-alkyl, aryl, halogen, halo-C1-C8-alkyl, HO—C1-C8-alkyl, R4R5N—C1-C8-alkyl, C1-C8-alkyl-OR6, —OR6, (C3-C10)-cycloalkyl or C1-C8-alkyl-sulfonyl;
R4 and R5 are each independently selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, —NR6R6, —S—(C1-C8)alkyl, aryl and heterocyclyl;
where in the definition of R4 and R5 any alkyl, alkoxy, heterocyclyl or aryl may be substituted with one to three substituents selected from -halo, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkoxy, unsubstituted C1-C8 thioalkoxy and unsubstituted aryl(C1-C4)alkyl
R6 is independently selected from hydrogen, C1-C8 alkyl, aryl-C1-C8 alkyl, C1-C8 alkoxy, —S—(C1-C8)alkyl, heterocyclyl and aryl;
where in the definition of R6 any alkyl, heterocyclyl or aryl may be substituted with one to three substituents selected from -halo, unsubstituted C1-C8 alkyl, unsubstituted C1-C8 alkoxy, unsubstituted C1-C8 thioalkoxy and unsubstituted aryl(C1-C4)alkyl
LG is a leaving group; and
(b) contacting the product of (a) with an acid HB to form a salt of formula I′, then isolating the salt of formula I′,
wherein B is an organic or inorganic anion selected from the group consisting of acetate, 4,4-diaminostilbene-2,2-disulfonate, benzenesulfonate, benzonate, bicarbonate, bisulfate, borate, bromide, butyrate, carbonate, chloride, citrate, edetate, edisylate, estolate, esylate, fiunarate, fumarate, glycolate, glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydroxynaphthoate, iodide, isothionate, laurate, malate, maleate, mesylate, methylbromide, methylnitrate, methylsulfate, napsylate, nitrate, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, 1,1-methene-bis-2-hydroxy-3-naphthoate, phosphate, diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, subacetate, succinate, sulfate, sulfosaliculate, suramate, teoclate, tosylate, triethiodide, trifluoroacetate, and valerate; and
(c) reacting the salt of formula I′ that was isolated in step (b) with a base to form the compound of formula I
wherein the disastereomeric excess (de) of the compound of formula I is at least 85%.

### Claim 2 (depends on 1)

The process according to claim 1, wherein Z is S.

### Claim 3 (depends on 1)

The process according to claim 1, wherein R1 is selected from the group consisting of

### Claim 4 (depends on 3)

The process according to claim 3, wherein R1 is

### Claim 5 (depends on 1)

The process according to claim 1, wherein, R2 and R3 are independently selected from methyl, isopropyl, and propyl.

### Claim 6 (depends on 5)

The process according to claim 5, wherein R2 is methyl and R3 is isopropyl.

### Claim 7 (depends on 1)

The process according to claim 1, wherein the chiral base is
wherein Ar is aryl.

### Claim 8 (depends on 7)

The process according to claim 7, wherein the chiral base is

### Claim 9 (depends on 1)

The process according to claim 1, wherein the leaving group LG is selected from the group consisting of Cl, Br, I, —OS(O)2CH3, —OS(O)2C4F9, —OS(O)2CF3, and —OS(O)2(4-CH3-phenyl).

### Claim 10 (depends on 1)

The process according to claim 1, wherein the amine is selected from triethylamine, trimethylamine, triisopropyl amine, N,N,N′N′-tetramethylethylenediamine (TMEDA), N,N,N′N′-tetramethylpropylenediamine (TMPDA), and N,N,N′N′-tetramethylbutylenediamine (TMBDA).

### Claim 11 (depends on 10)

The process according to claim 10, where the amine is TMEDA.

### Claim 12 (depends on 1)

The process according to claim 1, wherein step (a) is performed in the presence of a solvent selected from the group consisting of benzene, toluene, trifluorotoluene, xylene, chlorobenzene, dialkyl ethers, THF, dioxane, DMF, halogenated hydrocarbon solvents, ester solvents, and mixtures thereof.

### Claim 13 (depends on 12)

The process according to claim 12, wherein the solvent is toluene.

### Claim 14 (depends on 1)

The process according to claim 1, wherein HB in step (b) is selected from the group consisting of HCl, H2SO4, CH3C(O)OH, CF3C(O)OH, MeSO3H, and C6H5SO3H.

### Claim 15 (depends on 14)

The process according to claim 14, wherein HB is MeSO3H.

### Claim 16 (depends on 1)

The process according to claim 1, wherein the base in step (c) is selected from the group consisting of LiOH, NaOH, KOH, and sodium acetate.

### Claim 17 (depends on 1)

The process according to claim 1, wherein the de is at least 90%.

### Claim 18 (depends on 17)

The process according to claim 17, wherein the de is at least 95%.

### Claim 19 (depends on 18)

The process according to claim 18, wherein the de is at least 98%.

### Claim 20

A process for the preparation of a compound according to formula III:
comprising
(a) asymmetrically alkylating a compound of formula IV by contacting a compound of formula (IV)
with a chiral base of the formula
in the presence of TMEDA, whereby the compound of formula IV is asymmetrically alkylated; and
(b) reacting the product of step (a) with isopropyl iodide;
(c) contacting the product of step (b) with MeSO3H to form a mesylate salt; then isolating the mesylate salt, and
(d) reacting the mesylate salt from that was isolated in step (c) with NaOH to yield the compound of formula III;
wherein the de of the compound of formula III is at least 80%.

### Claim 21 (depends on 20)

The process according to claim 20, wherein the de is at least 90%.

### Claim 22 (depends on 21)

The process according to claim 21, wherein the de is at least 95%.

### Claim 23 (depends on 22)

The process according to claim 22, wherein the de is at least 98%.

### Claim 24 (depends on 20)

The process according to claim 20, wherein the de of the compound of formula III is at least 99%.