# US 9,434,691 B2 · Process for the preparation of a PDE4 inhibitor

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- Number: US 9,434,691 B2
- Document ID: US9434691B2
- Status: Granted
- Kind: B2
- Application number: 14/516,976
- Filed: 2014-10-17
- Published: 2015-04-23
- Granted: 2016-09-06
- Earliest claimed: 2013-10-22
- Assignees: Chiesi Farmaceutici S.p.A.
- Applicants: CHIESI FARMACEUTICI S.p.A.
- Inventors: Alessandro Falchi; Emilio Lutero; Emanuele Ferrari; Fausto Pivetti; Rocco Bussolati; Edoardo Mariani; Orsola Vecchi; Erhard Bappert; Caterina Ventrici
- Web page: https://patentgrep.com/patent/US9434691B2

## CPC

- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- C07C 205/59: the carbon skeleton being further substituted by singly-bound oxygen atoms
- C07C 311/08: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07D 213/61: Halogen atoms or nitro radicals
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- 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

The present invention relates to a process for the preparation of compounds endowed with phosphodiesterase (PDE4) inhibitory activity having formula (I). The invention also relates to the process for the isolation by crystallization of the compound (I) and to its use for the preparation of pharmaceutical compositions for inhalation in combination with suitable carriers or vehicles. The present invention also relates to solvates and crystal forms of a compound of formula (I). The synthesized product is suitable for use in pharmaceutical applications for instance in the treatment of respiratory diseases.

## Claims

### Claim 1

A process for preparing a compound of formula (I):
wherein n is 0 or 1, which process comprises:
(a) reacting a compound of formula (II):
wherein n is 0 or 1, with a compound of formula (III):
wherein X is —NHSO2Me or —NO2 and Z is —OH, chlorine, bromine, linear or branched (C1-C6)alkoxy, aryloxy, arylalkoxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy, or aryl(C1-C6)alkylcarbonyloxy, to obtain a compound of formula (I) wherein n is 0 or 1 or a compound of formula (IV):
wherein n has the above reported meanings and X is —NO2; and,
when a compound of formula (IV) is obtained in step (a):
(b) reducing said compound of formula (IV) to obtain a compound of formula (V):
wherein n is 0 or 1, and reacting said compound of formula (V) with methanesulfonyl halide to obtain a compound of formula (I) wherein n has the above reported meanings;
and wherein said compound of formula (II) is obtained according to any one of the alternative steps (c1) or (c2):
(c1) oxidizing a compound of formula (VI):
wherein n is 0 or 1 to obtain a compound of formula (VII):
wherein n is 0 or 1, and subsequently enantioselectively reducing said compound of formula (VII) to obtain a compound of formula (II) wherein n has the above reported meanings; or
(c2) chromatographically separating a compound of formula (VI) wherein n is 0 or 1, to obtain said compound of formula (II) and a compound of formula (VIII):
wherein n has the above reported meanings;
and optionally oxidizing said compound of formula (VIII) to a corresponding compound of formula (VII) which can may optionally subsequently reduced to said compound of formula (VI) wherein n is 0 or 1 and optionally subjected to said chromatographic separating;
and wherein all of said compounds of formula (I), (II), (IV), (V), (VI), (VII), or (VIII) wherein n is 1 can be obtained by oxidizing the corresponding compounds wherein n is 0.

### Claim 2 (depends on 1)

A process according to claim 1, wherein in said compound of formula (III), X is —NHSO2Me.

### Claim 3 (depends on 1)

A process according to claim 1, which comprises (a) reacting said compound of formula (II) with a compound of formula (III) wherein X is —NO2 to obtain a compound of formula (IV) and (b) reducing said compound of formula (IV) to said compound of formula (V), and reacting said compound of formula (V) with a methanesulfonyl halide to obtain said compound of formula (I).

### Claim 4 (depends on 1)

A process according to claim 1, wherein said compound of formula (II) is obtained by (c1) oxidizing said compound of formula (VI) to said compound of formula (VII) and enantioselectively reducing said compound of formula (VII) to said compound of formula (II).

### Claim 5 (depends on 1)

A process according to claim 1, wherein said compound of formula (II) is obtained by (c2) chromatographically separating said compound of formula (VI) to obtain said compound of formula (II) and said compound of formula (VIII).

### Claim 6 (depends on 1)

A process according to claim 1, which comprises oxidizing said compound of formula (I) wherein n is 0.

### Claim 7 (depends on 1)

A process according to claim 1, which comprises reacting a compound of formula (II) with a compound of formula (III) wherein Z is —OH in the presence of a coupling reagent selected from the group consisting of DCC, CDI, HATU, HBTU, TBTU, DMTMM, COMU, EDCI, with or without HOBt, with or without an organic base selected from the group consisting of TEA, DIPEA, NMM, DBU, DBO, pyridine and DMAP, in a solvent selected from the group consisting of dimethyl sulfoxide, sulfolane, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and a mixture thereof.

### Claim 8 (depends on 1)

A process according to claim 1, wherein (a) said reacting is conducted in the presence of CDI and DBU in ethyl acetate.

### Claim 9 (depends on 1)

A process according to claim 1, wherein (a) said reacting is conducted in the presence of EDCI and DMAP in DMF.

### Claim 10 (depends on 1)

A process according to claim 1, wherein (b) said reducing is carried out with a reducing agent selected from the group consisting of hydrogen, cyclohexadiene, ammonium formate, formic acid, iron, tin dichloride, tin, nickel chloride, nickel, lithium aluminium hydride, sodium aluminium hydride, lithium borohydride, sodium borohydride, potassium borohydride, and sodium hydrosulfite.

### Claim 11 (depends on 10)

A process according to claim 10, wherein said reducing agent is selected from the group consisting of hydrogen, cyclohexadiene, ammonium formate and formic acid, and (b) said reducing is carried out in presence of a palladium- platinum- or nickel-based catalyst, or a catalyst selected from the group consisting of palladium on carbon, palladium sulfided on carbon, palladium on barium sulfate, palladium on calcium carbonate, and platinum on carbon.

### Claim 12 (depends on 10)

A process according to claim 10, wherein said reducing agent is formic acid, and (b) said reducing is carried out in presence of ammonia or an amine, in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene, xylene, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, and a mixture thereof.

### Claim 13 (depends on 10)

A process according to claim 10, wherein (b) said reducing is carried out with hydrogen with palladium 5% on activated carbon powder, Type A103038, sulfided in ethyl acetate.

### Claim 14 (depends on 1)

A process according to claim 1, wherein said reacting of said compound of formula (V) with methanesulfonyl halide is carried out in the presence of one or more solvents selected from the group consisting of toluene, benzene, xylene, tetrahydrofuran, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-buthylmethyl ether, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, chloroform, chlorobenzene, and a mixture thereof and a base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate, cesium hydroxide, cesium carbonate, cesium bicarbonate, TEA, DIPEA, NMM, DBO, pyridine, and DMAP;
or said reacting of said compound of formula (V) with methanesulfonyl halide is carried out in the presence of excess pyridine without any other solvent.

### Claim 15 (depends on 1)

A process according to claim 1, wherein said oxidizing said compound of formula (VI) to said compound of formula (VII) is carried out in the presence of an oxidizing agent selected from the group consisting of a metallic oxide, a hypervalent iodine, and a dimethylsulfoxide-based oxidant, in a solvent selected from the group consisting of water, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, dimethyl sulfoxide, sulfolane, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isopropyl acetate, acetonitrile, dichloromethane, THF, dioxane, and a mixture thereof.

### Claim 16 (depends on 1)

A process according to claim 1, wherein said enantioselectively reducing said compound of formula (VII) to said compound of formula (II) is carried out with a reducing agent which is hydrogen in presence of a heavy metal chiral complex pre-formed or formed in situ, wherein in situ formation may occur by reacting a Ru-, Rh- or Ir-complex selected from the group consisting of RuCl2(PPh3)3, [Ru (p-cymene)Cl2]2, [RhCI2(Cp*)]2 and [IrCl2(Cp*)]2 with a chiral ligand which is SL-N004-1 ((S)-4-tert-Butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl]oxazoline), SL-N003-1 ((R)-4-Isopropyl-2-[(R)-2-(diphenylphosphino)-ferrocen-1-yl]Oxazoline), (S,S)-Ts-DPEN ((1S,2S)-(−)-N-p-tosyl-1,2-diphenylethylenediamine), (S,S)-Ms-DPEN ((1S,2S)-(−)-N-Mesyl-1,2-diphenylethylenediamine), (R)-DAIPEN ((2R)-(−)-1,1-Bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine), or (1R,2S)-1-amino-2-indanol.

### Claim 17 (depends on 16)

A process according to claim 16, wherein said enantioselectively reducing is carried out in presence of a base selected from the group consisting of sodium hydroxide, sodium carbonate, sodium C1-C4 alcoholates, sodium bicarbonate, sodium hydride, potassium hydroxide, potassium carbonate, potassium C1-C4 alcoholates, potassium bicarbonate, lithium hydroxide, lithium carbonate, lithium C1-C4 alcoholates, caesium hydroxide, caesium carbonate, caesium bicarbonate, triethyl amine, pyridine, and 4-dimethylaminopyridine.

### Claim 18 (depends on 1)

A process according to claim 1, wherein said enantioselectively reducing is carried out in presence of a reducing agent which is a borane chiral complex selected from the group consisting of a diisopinocampheylborane and an oxazaborolidine.

### Claim 19 (depends on 16)

A process according to claim 16, wherein said enantioselectively reducing is carried out in a solvent selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, t-butanol, dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, toluene, benzene, xylene, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, acetonitrile, and mixtures thereof.

### Claim 20 (depends on 1)

A process according to claim 1, wherein said enantioselectively reducing is carried out in the presence of a complex formed in situ by reacting RuCl2(PPh3)3 and the chiral ligand SL-N004-1, (S)-4-tert-butyl-2-[(S)-2-(bis(1-phenyl)phosphino)ferrocen-1-yl]oxazoline, in toluene and in presence of aqueous sodium hydroxide.

### Claim 21

A compound of formula (IV) or (V) wherein n is 0 or 1

### Claim 22

A compound of formula (III):
wherein X is —NHSO2Me and Z is —OH.

### Claim 23

A process for the preparation of a compound of formula (IX):
wherein n is 0 or 1, and R1 and R2 are independently H, linear or branched (C1-C6) alkyl, optionally substituted by one or more substituents selected from one or more halogen atoms, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C5-C7) cycloalkenyl, linear or branched (C2-C6) alkenyl, aryl(C2-C6)alkenyl and linear or branched (C2-C6) alkynyl,
which process comprises:
(a) reacting a compound of formula (X):
wherein n is 0 or 1, with a compound of formula (III):
wherein X is —NHSO2Me or —NO2 and Z is —OH, chlorine, bromine, linear or branched (C1-C6)alkoxy, aryloxy, arylalkoxy, (C1-C6)alkylcarbonyloxy, arylcarbonyloxy or aryl(C1-C6)alkylcarbonyloxy to obtain a compound of formula (XI) wherein n is 0 or 1 or a compound of formula (XII):
wherein R1, R2, and n have the above reported meanings; and
when a compound of formula (XII) is obtained in step (a):
(b) reducing said compound of formula (XII) to a compound of formula (XIII):
wherein R1, R2, and n have the above reported meanings, and reacting said compound of formula (XIII) with methanesulfonyl halide to obtain said compound of formula (XI) wherein n has the above reported meanings;
and wherein said compound of formula (X) in step (a) is obtained according to any one of the alternative steps (c1) or (c2):
(c1) oxidizing a compound of formula (XIV):
wherein n is 0 or 1 to obtain a compound of formula (XV):
wherein n is 0 or 1, and subsequently enantioselectively reducing said compound of formula (XV) to obtain said compound of formula (X) wherein n has the above reported meanings; or
(c2) chromatographically separating said compound of formula (XIV) wherein n is 0 or 1, to obtain said compound of formula (X) and a compound of formula (XVI)
wherein n has the above reported meanings;
and optionally oxidizing said compound of formula (XVI) to obtain said compound of formula (XV) and optionally subsequently reducing said compound of formula (XV) to said compound of formula (XIV) wherein n is 0 or 1 and which may be optionally chromatographically separated;
and wherein all of said compounds of formula (XI), (X), (XII), (XIII), (XIV), (XV), or (XVI) wherein n is 1 can be obtained by oxidizing the corresponding compounds wherein n is 0.

### Claim 24

A compound of formula (XII) and (XIII):
wherein n is 0 or 1, and R1 and R2 are independently H, linear or branched
(C1-C6) alkyl, optionally substituted by one or more substituents selected from halogen atoms, (C3-C7) cycloalkyl, (C5-C7)cycloalkenyl, (C5-C7) cycloalkenyl, linear or branched (C2-C6) alkenyl, aryl(C2-C6)alkenyl and linear or branched (C2-C6) alkynyl.

### Claim 25 (depends on 1)

process according to claim 1, which further comprises crystallizating or crushing said compound of formula (I) from one or more solvents selected from the group consisting of water, methanol, ethanol, isopropanol, n-butanol, t-butanol, toluene, benzene, xylene, acetone, isopropyl ketone, methyl ethyl ketone, methyl isobutyl ketone, THF, dioxane, 2-methoxyethyl ether, diethyl ether, isopropyl ether, t-butyl methyl ether, ethyl acetate, isopropyl acetate, dichloromethane, an aliphatic or aromatic hydrocarbon, preferably chosen from the group consisting of pentane, hexane, heptane, cyclohexane, methylcyclohexane, and a mixture thereof.

### Claim 26 (depends on 25)

A process according to claim 25, wherein said solvent is ethyl acetate with n-heptane.