EP3802547A1

EP3802547A1 - Process for producing compounds containing an oxazolopyridinone functional group

Info

Publication number: EP3802547A1
Application number: EP19728382.3A
Authority: EP
Inventors: Morgan HANS
Original assignee: Biocidal Alternative Solutions
Current assignee: Biocidal Alternative Solutions
Priority date: 2018-05-31
Filing date: 2019-05-29
Publication date: 2021-04-14
Also published as: WO2019229141A1; EP3575305A1

Abstract

The invention relates to a process for producing compounds containing an oxazolopyridinone group (3) by reacting a compound comprising an ortho-aminohydroxypyridine functional group of formula (1) and a compound containing a diarylcarbonate group of formula (2).

Description

"PROCESS FOR PRODUCING COMPOUNDS COMPRISING A GROUP

FUNCTIONAL OXAZOLOPYRIDINONES »

Technical area

The present invention relates to a process for the manufacture of compounds comprising an oxazolopyridinone group.

Technological background of the invention

In a first aspect, the present invention thus relates to a process for the manufacture of compounds comprising an oxazoiopyridinone group of formula (3) which is optionally substituted:

by a reaction between a compound comprising an ortho-aminohydroxypyridine group of formula (1) optionally substituted:

and a compound comprising a diarylcarbonate group of formula (2) optionally substituted:

State of the art

Methods based on a reaction from an ortho-aminohydroxypyridine in the presence of a base and a carbonylating agent in a solvent are known as for example documents CN 105924454 and WO2009130487.

These processes involve triphosgene which is a safer substitute for phosgene. However, triphosgene remains a toxic product because it decomposes into phosgene by heating or by reaction with a nucleophile. In such a way that it is necessary to take the same safety precautions to involve triphosgene as phosgene.

Triphosgene is a solid and by its nature requires the addition of solvent that can contaminate the finished product and therefore requires one or more additional purification steps to remove any trace of these toxic contaminants.

Document US2012108809 discloses the use of phosgene, triphosgene, carbonyldiimidazole or diarylcarbonates as carbonyl group-donor reagents reacting with chlorine and fluorine-substituted butyn-2-ol compounds in order to obtain compounds of the type benzoxazine-2-one substituted with chlorine and fluorine for the manufacture of Efavirenz.

If according to this process the diaryl carbonates seem appropriate, the process requires the dissolution of a chlorine and fluorine-substituted amino alcohol derivative in an aprotic solvent such as tetrahydrofuran (THF) and the presence of a base such as that l, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) which deprotonates the molecule and makes it more nucleophilic therefore more able to react with the carbonyl donor.

However, it appears to be necessary to have a process for obtaining oxazolopyridinones which is cleaner, less expensive, industrially adaptable and faster while remaining flexible with respect to the types of starting compounds.

Summary of the invention The aim of the invention is to solve the aforementioned problems by providing a process for producing compounds comprising an optionally substituted oxazolopyridinone group of formula (3):

by a reaction between a compound comprising an ortho group

as indicated at the beginning, characterized in that it comprises a suspension and a reaction of said compound comprising an ortho-aminohydroxypyridine group of formula (1) in said compound comprising a diarylcarbonate group of formula (2) in a molten state .

Against all expectations, it has been observed according to the invention that it is possible to use the combination of an optionally substituted diaryl carbonate, in the molten state. Diaryl carbonates are on the one hand much cleaner, less toxic to the environment and health and on the other hand requiring neither solvent nor base.

According to the invention, the compound comprising an optionally substituted ortho-aminohydroxypyridine group is in a solid state when the compound comprising an optionally substituted diarylcarbonate group is in a molten state. There is thus formed a suspension of the compound comprising an optionally substituted ortho-aminohydroxypyridine group in the compound comprising an optionally substituted diarylcarbonate group, thus avoiding the contamination of the reaction medium with compounds that will have to be removed later.

Therefore, in the process according to the present invention, compounds comprising an oxazolopyridinone moiety are obtained by reducing the number of exogenous materials added.

The process according to the present invention is therefore cleaner, less expensive and particularly flexible and industriaiisable, the use of phosgene or triphosgene which are complicated products to handle and toxic is not necessary. It also makes it possible to dispense with 1,1'-carbonyldiimidazole which has a high cost and which is therefore difficult to adapt industrially.

The method according to the present invention uses an optionally substituted diarylcarbonate which is a cheap reagent, even for molecules whose cyclization is difficult to implement by their nature less nucleophilic.

For the purposes of the present invention, the term "compound comprising a diarylcarbonate group" means carbonate esters comprising diaryl carbonates, that is to say carbonates having two Arl aryl substituents in which Ar 1 represents an aryl group such as for example a phenyl group, a tolyl group, a xylyl group, a mesityl group, a naphthyl group, more particularly Arl represents a phenyl group. In another preferred embodiment according to the present invention, the method further comprises:

a solid state mixing step of said compound comprising an optionally substituted ortho-aminohydroxypyridine group of formula (1) and said compound comprising an optionally substituted diarylcarbonate (2) group, and

a step of heating said two compounds in a mixture at a temperature between 50 ° C and 170 ° C, preferably between 70 ° C and 150 ° C, preferably between

70 ° C and 120 ° C, in particular between 80 ° C and 100 ° C, until obtaining said suspension. In a variant according to the present invention, the method re:

a step of heating said compound comprising a diarylcarbonate group (2) optionally substituted with a solid state at a temperature of between 50 ° C and 170 ° C, preferably between 70 ° C and 150 ° C, advantageously between 70 ° C and 120 ° C ° C, in particular between 80 ° C and 100 ° C, and a step of introducing said compound comprising an ortho-aminohydroxypyridine group of formula (1) optionally substituted for a solid state in said compound comprising a diarylcarbonate group (2) optionally substituted for a molten state, so as to form said suspension.

In a preferred embodiment of the method according to the present invention, said heating step takes place between 1 h and 24 h. Advantageously, the process according to the present invention is characterized in that said heating step takes place for at least 1 h, advantageously at least 2h, in particular at least 3h, preferably at least 4h, advantageously at least 5h, preferably at least 6h, in particular at least 7h, preferably at least 8h, advantageously at least 9h, in particular at least lOh, preferably at least 11h, advantageously at least 12b, preferably at least 13h, in particular at least 14h, preferably at least 15h, advantageously at least 16h, in particular at least 17h, preferably at least 18h, advantageously at least 19h, preferably at least 20h, in particular at least 21b, preferably at least 22h, advantageously at least 23h, preferably at most 24h, advantageously at most 23h, in particular at most 22h, preferably at most 21h, advantageously at most 20h, preferably at most 19h, in particular at most 18h, preferably at most 17h, preferably at most 16h, preferably during at most 15h , advantageously at most 14h, in particular at most 13h, preferably at most 12h, advantageously at most 11h, preferably at most 10h, in particular at most 9h, preferably at most 8h, advantageously at most 7h, preferably at most 6h, preferably at most 5h, in particular at most 4h, preferably at most 3h, advantageously at most 2h. In another preferred embodiment according to the present invention, the process is characterized in that said compound comprising an ortho-aminohydroxypyridine group of formula (1) is 2-amino-3-hydroxypyridine or 3-amino-4-hydroxypyridine or 4-amino-3-hydroxypyridine or 3-amino-2-hydroxypyridine. Advantageously, said compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the pyridine ring respectively by one or more substituents chosen independently of each other from the group consisting of R, ORi, SRi and NR2R3 radicals. , NR4R5, C (O) R ₆ and SO ₂ R ₇ where: R represents independently a hydrogen atom or an alkyl, aryl, halogen or nitro group,

R 1 independently represents an alkyl, aryl or C (O) R _{2 group} ,

R ₂ independently represents an alkyl or aryl group,

R ₃ independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ ,

R ₅ independently represents a hydrogen atom or an alkyl or aryl group,

R ₆ independently represents a hydrogen atom or an alkyl, aryl, O ₂ or NR ₂ R _{3 group} ,

R ₇ independently represents an alkyl, aryl, NH ₂ or NR ₄ R ₅ group.

Advantageously, the process is characterized in that said compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the amino group by an alkyl group.

In a variant according to the present invention, the process is characterized in that said compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the pyridine ring by one or more substituents chosen independently of one another in the group consisting of R, OR 1, SR 1, NR ₂ R ₃ , NR ₄ R ₅ , C (O) Re and SO ₂ R ₇ OÙ:

R represents independently a hydrogen atom or an alkyl, aryl, halogen or nitro group,

R 1 independently represents an alkyl, aryl or C (O) R _{2 group} , R ₂ independently represents an alkyl or aryl group,

Rs independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ ,

R ₅ independently represents a hydrogen atom or an alkyl or aryl group,

R ₆ independently represents a hydrogen atom or an alkyl, aryl, OR ₂ or NR ₂ R 3 group,

R ₇ independently represents an alkyl, aryl, NH ₂ or NR ₄ R _{5 group;}

Advantageously, the process is characterized in that the said compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the oxazolidinone ring at the 3-position, respectively, with one or more substituents chosen independently of one another in the group consisting of the radical R 'where R' independently represents:

An alkyl group,

A halomethyl group with the halogen chosen from chlorine (Cl) or bromine (Br),

A 1,2-dihaloethyl group with the halogen chosen from chlorine (Cl) or bromine (Br),

A vinyl group,

A hydroxymethyl group,

A group (CH ₂ ) _n -X (with X = P (O) OR "and R" chosen from H, alkyl; Br; CN; arylpiperazine),

A group CH ₂ SP (0) (0Me) ₂ ,

In another preferred embodiment according to the present invention, the method is characterized in that said compound comprising a diarylcarbonate group of formula (2) comprises at least one phenyl group, preferably two phenyl groups.

The invention also relates to the use of said compound prepared according to the present invention, for the preparation of Azamethiphos. Indeed, Azamethiphos is a molecule known to be insecticidal by acting on the nervous system of flying and crawling insects and animal parasites.

The invention relates to the use of said compound prepared according to the present invention for the preparation of analogues of osmidomycin.

Indeed, Fosmidomycin is known to be a herbicide but also as an antibiotic involved in the treatment of Malaria / Malaria.

The invention also relates to the use of said compound prepared according to the present invention for the preparation of analogs of 3- [(4-aryl-1-piperazinyl) alkyl] oxazolo [4,5-b] pyridin-2- (3H) -one or 1 - [(4-aryl-1-piperazinyl) alkyl] oxazolo [5,4-b] pyridin-2- (1H) -one or N-aminohydroxypyridine compounds -substituted.

Indeed, analogous compounds of 3 - [(4-aryl-1-piperazinyl) alkyl] oxazolo [4,5-b] pyridin-2- (3H) -one, 1 - [(4-aryl) 1-piperazinyl) alkyl] oxazolo [5,4-b] pyridin-2- (1H) -one or the N-substituted aminohydroxypyridine compounds act as analgesic compounds.

Advantageously, the process according to the present invention is characterized in that it further comprises a second aromatic chlorination reaction step of said first compound comprising an oxazolopyridinone group to form a second compound comprising an oxazolopyridinone group. In another preferred embodiment according to the present invention, the process is characterized in that said second aromatic chlorination reaction step is carried out in an aprotic polar solvent selected from the group consisting of acetone, acetonitrile, DM F, THF, NMP and ethyl acetate, with chlorine gas cold to form said second compound comprising an oxazolopyridinone moiety.

Advantageously, the process according to the present invention is characterized in that it further comprises a third reaction step of said second compound comprising an oxazolopyridinone group with paraformaldehyde to form a third compound comprising an oxazolopyridinone group.

Particularly advantageously, the process according to the present invention is characterized in that it comprises, in addition, a fourth reaction step of said third compound comprising an oxazolopyridinone group with thionyl chloride to form a fourth compound comprising an oxazolopyridinone group, of preferably said fourth compound comprising an oxazolopyridinone functional group is 6-chloro-3- (chloromethyl) oxazolo [4,5-b] pyridine-2 (3H) -one.

Advantageously, the process according to the present invention is characterized in that it further comprises a step of isolating said fourth compound comprising an oxazolopyridinone group, preferably by precipitation with water, which also makes it possible to isolate the product in order to increase its purity.

In another preferred embodiment according to the present invention, the process is characterized in that it further comprises a fifth reaction step of said fourth compound comprising an oxazolopyridinone moiety with sodium O, O'-dimethylphosphorothioate in a solvent. , preferably a polar solvent to form a fifth compound comprising an oxazolopyridinone group, such as Azamethiphos.

Advantageously, the process according to the present invention is characterized in that it further comprises a step of precipitating and purifying said fifth compound comprising an oxazolopyridinone group, preferably by recrystallization, which also makes it possible to purify the product in the process. purpose of increasing its purity.

Advantageously, the process according to the present invention is characterized in that it further comprises at least one chromatographic monitoring step, preferably after each reaction step.

The invention also relates to the use of said compound prepared according to the present invention, for the preparation of a medicament or an effective treatment for treating autoimmune diseases, melanoma, arthritis, rheumatoid arthritis, Parkinson's disease, asthma, dementia, Alzheimer's disease, leukemia, diabetes, psoriasis, heart failure and allergies.

Other embodiments of the derivatization process comprising an oxazolopyridinone moiety are indicated in the appended claims. It is understood that the present invention is in no way limited to the embodiments described above and that many modifications can be made without departing from the scope of the appended claims.

DESCRIPTION OF THE INVENTION The invention will now be described in more detail, with reference to the following reactions, which:

Reaction I is a direct reaction according to the process of the present invention between a compound comprising an ortho group aminohydroxypyridine of formula (1) optionally substituted and, a compound comprising a diarylcarbonate group of formula (2) optionally substituted to form a first compound of formula (3) optionally substituted comprising an oxazolopyridinone group and a compound comprising a phenol group of formula (4) ) as described above

The compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the pyridine ring by one or more substituents chosen independently of each other from the group consisting of R, ORi, SRi, R2R3, NR ₄ radicals. R ₅ , C (O) R ₆ and SO ₂ R ₇ where

R 1 independently represents an alkyl, aryl or C (O) R _{2 group} ,

R ₂ independently represents an alkyl or aryl group,

R3 independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ ,

R5 independently represents a hydrogen atom or an alkyl or aryl group,

R ₆ independently represents a hydrogen atom or an alkyl, aryl, OR ₂ or IMR ₂ R 3 group,

R7 independently represents an alkyl, aryl, NH ₂ or NR4R5 group ·

The compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the amino group by radical R 'where R' represents an alkyl group.

The first compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the pyridine ring by one or more substituents chosen independently of each other from the group consisting of the radicals R, ORi, SRi, NR2R3, R4R5, C (O) R6 and SO2R7 where:

R 1 independently represents an alkyl, aryl or C (O) R _{2 group} ,

R ₂ independently represents an alkyl or aryl group,

R ₃ independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ ,

R ₅ independently represents a hydrogen atom or an alkyl or aryl group,

Re independently represents a hydrogen atom or an alkyl, aryl, OR ₂ or NR ₂ R _{3 group} ,

R7 is independently alkyl, aryl, IMH2 or NR ₄ R 5.

The first compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the oxazolidinone ring at the 3-position, respectively, with one or more substituents chosen independently of each other from the group consisting of the radical R 'where R 'represents independently:

alkyl group, A halomethyl group with the halogen chosen from chlorine (Cl) or bromine (Br),

A wine group,

A hydroxymethyl group,

A CH ₂ 5P (O) (0Me) _{2 group} ,

The compound comprising an ortho-aminohydroxypyridine functional group of formula (1) is 2-amino-3-hydroxypyridine or 3-amino-4-hydroxypyridine or 4-amino-3-hydroxypyridine or 3-amino-2-hydroxypyridine .

In addition, the compound comprising a diarylcarbonate functional group of formula (2) comprises at least one phenyl group, preferably two phenyl groups.

Example 1 Preparation of Azamethiphos The compound comprising an ortho-aminohydroxypyridine group of formula (1) in which the substituent R is a hydrogen atom and the substituent R 'is a hydrogen atom, in a solid state and the compound comprising a diarylcarbonate group of formula (2) in which the Arl groups are phenyl groups in a solid state will be heated to at least 85 ° C with a step of mixing the compound comprising an ortho-aminohydroxypyridine group of formula (1) a solid state in said compound comprising a diarylcarbonate group of formula (2) in a molten state to form a first compound of formula (3) comprising an oxazolopyridinone group in which the substituent R is a hydrogen atom and the R 'substituent is a hydrogen atom, and phenol of formula (4) as described below:

oxazolopyridinone can be reacted according to the aromatic chlorination reaction II in a protic polar solvent selected from the group consisting of acetone, acetonitrile, DMF, THF, NMP and ethyl acetate, with chlorine gas cold to form a second compound of formula (5) comprising an oxazolopyridinone group as described below:

The second compound of formula (5) comprising an oxazolopyridinone group may react with paraformaldehyde according to reaction III to form a third compound of formula (6) comprising an oxazolopyridinone functional group as described below:

oxazolopyridinone group may react with thionyl chloride with increasing temperature according to reaction IV to form a fourth compound of formula (7) comprising an oxazolopyridinone group as described below:

Reaction II, Reaction III and Reaction IV may be carried out in a single reactor without isolation of intermediates, namely, the second compound of formula (5) comprising an oxazolopyridinone group and the third compound of formula (6) comprising a group oxazolopyridinone or carried out sequentially in separate reactors, after isolation of the intermediates.

The fourth compound of formula (7) comprising a moietyoxazolopyridinone is isolated by precipitation with water and can react with sodium O, O'-dimethylphosphorothioate in a polar solvent selected for example from the group consisting of primary aliphatic ketones such as acetone, methylethyl ketone, alkanols such as methanol, ethanol, isopropanol, esters such as ethyl acetate, nitriles, N-alkylated amide acids, cold according to a reaction V to form a fifth compound of formula (8) comprising an oxazolopyridinone group, Azamethiphos (8) as described below:

the entire reaction process is followed by chromatography to ensure that each step is complete and determine purity.

Example 2 Preparation of Oxazolopyridinone Compounds (US3929809) The first compound of formula (3) comprising an oxazolopyridinone group may be reacted according to the halogenation or nitration reaction VI on aromatic to form a sixth compound of formula (9) comprising a group oxazolopyridinone derivative with a moiety RI representing a chloro group , bromo or nitro as

oxazolopyridinone derivative with a chloro, bromo or nitro moiety may be substituted in accordance with reaction VII by a group A selected from the group of methyl halogen radicals, vinyls or 1,2-dihalogenoethyl radicals to form a seventh compound of formula (10 ) comprising an oxazolopyridinone group as described below:

oxazolopyridinone group may react according to an eighth reaction VIII with a phosphorus compound, optionally in the presence of an acidic linking agent, or with a salt to form an eighth compound of formula (11) comprising an oxazolopyridinone group as described below:

comprising an oxazolopyridinone group are the following: - 3-chloromethyl-oxazolo [4 _/ 5-b] pyridin-2- (3H) -one

3-chloromethyl-oxazolo [4,5-b] pyridin-2 (3H) -thione

3-chloromethyl-6-chloro-oxazolo [4,5-b] pyridin-2 (3H) -one 3-bromomethyl-6-chloro-oxazolo [4 _/ 5-b] pyridin-2 (3H) -one 3- chloromethyl-6-bromo-oxazolo [4,5-b] pyridin-2 (3H) -one 3-chloromethyl-6-nitrooxazolo [4,5-b] pyridin-2 (3H) -one

3-vinyl-oxazolo (4,5-b] pyridin-2 (3H) -one

3-vinyl-oxazolo [4,5-b] pyridin-2 (3H) -thione

3-vinyi-6-chloro-oxazolo [4,5-b] pyridin-2 (3H) -one

3-vinyl-6-bromo-oxazolo [4,5-b] pyridin-2 (3H) -one

3-vinyl-6-nitro-oxazolo [4,5-b] pyridin-2 (3H) -one

3- (l _'7 2'-dichloroethyl) -oxazolo [4,5-b] pyridin-2- (3H) -one 3- (l' ₇ 2'-dibromoethyl) -oxazolo [4,5-b] pyridin 2- (3H) -one 3- (2'-dichloroethyl) -oxazolo [4,5-b] pyridin-2 (3H) -thione 3- (1 ', 2'-dibromoethyl) -oxazolo [4, 5-b] pyridin-2 (3H) -thione 3- (l _'/ 2'-dichloroethyl) -6-chloro-oxazolo _[4/5-b] pyridin-2 (3H) - one

3- (1 ', 2'-dibromoethyl) -6-chloro-oxazolo [4 _; 5-b] pyridin-2 (3H) -one

3- (1 ', 2'-dichloroethyl) -6-bromo-oxazolo [4,5-b] pyridin-2 (3H) -one

3- (l ', 2'-dibromoethyl) -6-bromo-oxazolo [4,5-b] pyridin

2 (3H) -one

3- (2'-dichloroethyl) -6-nitro-oxazolo [4,5-b] pyridin-2 (3H) -one

3- (2'-dibromoethyl) -6-nitrooxazolo [4,5-b] pyridin-2 (3H) -one Examples of the phosphorus compound are as follows, and may be made from known methods: dimethyl-dithiophosphoric

dimethyl-monothiophosphoric

-diethyl dithiophosphoric

-diethyl-monothiophosphoric

0.0-diisopropyl dithiophosphoric acid

O-methyl-O-ethyl-dithiophosphoric

O-methyl-O-isopropyl-dithiophosphoric O-methyl-O-isopropyl-dithiophosphoric

- 0,0-Diallyl-dithiophosphoric acid

eu

ethyl-thiophosphoric-ethyl amide

methyl-thiophosphoric dimethyl amide

ethyl-thiophosphoric dimethyl amide

methyl-thiophosphoric diethyl amide

ethyl-thiophosphoric-diethyl amide

methyl-dithiophosphoric dimethyl amide-ethyl-di-thiophosphoric dimethyl amide

methyl-dithiophosphoric diethyl amide

ethyl-dithiophosphoric-diethyl amide isopropyl-dithiophosphoric dimethyl amide

The phosphorus compound reacts with the seventh compound of formula (10) comprising an oxazolopyridinone group without temperature constraints between 0 ° C and 120 ° C, preferably between 10 ° C and 70 ° C. The possible polar solvents are chosen, for example, from the group consisting of

Primary aliphatic ketones such as acetone, methylethyl ketone;

Alkanols such as methanol, ethanol, isopropanol;

Esters such as ethyl acetate;

Nitriles;

N-alkylated amide acids; s radicals R1, R2, R3, R4, X and Y previously mentioned the following group:

RI represents a hydrogen atom, a halogen or a nitro group;

R2 represents a hydrogen atom or a methyl, chloromethyl or bromomethyl group;

R3 represents an alkyl, alkoxy, alkenyloxy, alkynyloxy, alkoxyalkoxy, hexyalkoxy, phenyl, amino, monoalkylamino or dialkylamino group; R4 represents an alkyl, alkenyl, alkynyl, alkoxyalkyl or helogenalkyl group;

X represents an oxygen or sulfur atom;

Y represents an oxygen or sulfur atom;

Example 3 Preparation of Similar Fosmidomycin Compounds

The first compound of formula (3) comprising an oxazolopyridinone group may be reacted according to a ninth reaction IX with EtONa in EtOH for 1h at room temperature and then with diethyl-bromopropylphosphonate in an aprotic polar solvent selected from the group consisting of acetone, acetonitrile, DMF, THF, NMP and ethyl acetate, at reflux overnight to form a sixteenth compound of formula (19) comprising an oxazolopyridinone moiety such as

Which sixteenth compound of formula (19) comprising an oxazolopyridinone group may be reacted according to a tenth reaction X with (CH ₃ ) 3SiBr in CH ₂ Cl ₂ , cold to form a seventeenth compound of formula (20) comprising a group oxazolopyridinone, analogue of Fosmidomycin as mentioned below:

Example 4 Preparation of N-Substituted Aminohydroxypyridine Compounds

The first compound of formula (3) comprising an oxazolopyridinone group may be reacted according to an eleventh reaction XI with Br- (CH ₂ ) _n -Br in the presence of NaH in DMF at 110 ° C. to form an eighteenth compound of formula (21) comprising an oxazolopyridinone group such

Which eighteenth compound of formula (21) comprising an oxazolopyridinone group may be reacted according to a twelfth reaction XII with KCN and Kl in DMSO to form a nineteenth compound of formula (22) comprising an oxazolopyridinone group as mentioned

Which nineteenth compound of formula (22) comprising an oxazolopyridinone group may react according to a thirteenth reaction XIII with 10% NaOH and then HCl to form a twentieth compound of formula (23) comprising an aminohydroxypyridine group as mentioned hereinabove.

an oxazolopyridinone group can react according to a fourteenth reaction XIV with arylpiperazine, in the presence of diisoproprylethylamine (iPr) ₂ NEt in CH ₃ CN to form a twenty-first compound of formula (24) comprising an oxazolopyridinone group such as mentioned below:

an oxazolopyridinone group can react according to a fifteenth reaction XV with 10% NaOH and then HCl to form a twenty-second compound of formula (25) comprising an aminohydroxypyridine group as mentioned below:

Example 5 Comparison of the Process According to the Invention with and Without Solvents and / or Additives

The yield depends on the isolation technique used.

The first isolation technique is an extraction of phenol with boiling heptane for which 87.4% yield is obtained.

The second isolation technique is a distillation of phenol and extraction of the remaining phenol with boiling heptane for which 96.8% yield is obtained.

² the expected effect was the decrease in reaction time, which was not observed. a) Process according to the invention without solvent, without additives: It is observed that the reaction process I according to the invention between a compound comprising an ortho-aminohydroxypyridine group of formula (1) in which the substituent R is a hydrogen atom and the substituent R 'is a hydrogen atom and a compound comprising a diarylcarbonate group of formula (2) in which the groups Ari are phenyl groups to form a first compound of formula (3) comprising an oxazolopyridinone group in which the substituent R is a hydrogen atom and the substituent R ' is a hydrogen atom, and phenol of formula (4), under conditions without solvents and without additives at a conversion rate of 99.5% after 24 hours and a yield of 87.4 to 96.8% according to the isolation technique used. b) Method according to the invention with addition of Na ₂ CO ₃

It is observed that the process according to the invention with the addition of Na ₂ CO ₃ at a conversion level of 99.5% after 24 h while the addition of Na ₂ CO ₃ should result in a reduction of the reaction time with respect to the process according to US Pat. invention without solvent or additives. c) Method according to the invention with addition of Et ₃ N:

It is observed that the process according to the invention with the addition of Et ₃ N at a conversion level of 99.5% after 24 hours while the addition of triethylamine should result in a reduction of the reaction time compared to the process according to the invention without solvent. neither additives. dj Comparison of the process according to the invention without solvents, without additives with the process according to the invention with the addition of THF:

It is observed that the process according to the invention with addition of tetrahydrofuran as a solvent at a conversion of 68% while the process according to the invention without solvent has a conversion rate. 99.5%, it is observed that the addition of solvent leads to a decrease in the conversion and the addition of exogenous material removal steps. e) Comparison of the process according to the invention without solvents, without additives with the process according to the invention with addition of EtOAc:

It is observed that the process according to the invention with the addition of ethyl acetate as a solvent at a conversion level of 57% while the process according to the invention without solvent has a conversion level of 99.5%, it is observed that addition of solvent leads to a decrease in conversion and the addition of exogenous material removal steps. f) Comparison of the process according to the invention without solvents, without additives with the process according to the invention with addition of 1,4-dioxane;

It is observed that the process according to the invention with addition of 1,4-dioxane as a solvent at a conversion rate of 90% and a yield of 56% while the process according to the invention without solvent has a conversion rate of 99.5. % and a yield between 87.4% and 96.8%, it is observed that the addition of solvent leads to a decrease in conversion and yield and the addition of exogenous material removal steps.

Claims

"CLAIMS"

A process for the manufacture of compounds comprising an optionally substituted oxazolopyridinone group of formula (3):

characterized in that it comprises a suspension and a reaction of said compound comprising an ortho-aminohydroxypyridine group of formula

(1) in said compound comprising a diarylcarbonate group of formula

(2) in a molten state.

2. Method according to claim 1, further comprising: - a step of solid state mixing said compound comprising an ortho-aminohydroxypyridine group of formula (1) optionally substituted and said compound comprising an optionally substituted diarylcarbonate (2) group, and

a step of heating said two compounds in a mixture at a temperature of between 50 ° C. and 170 ° C., preferably between 70 ° C. and 150 ° C., advantageously between 70 ° C. and 120 ° C., in particular between 80 ° C. and 100 ° C., until said suspension is obtained.

3. Process according to claim 1, further comprising: a step of heating said compound comprising a diarylcarbonate group (2) optionally substituted with a solid state at a temperature of between 50 ° C and 170 ° C, preferably between 70 ° C and 150 ° C, advantageously between 70 ° C and 120 ° C, in particular between 80 ° C and 10 ° C, and a step of introducing said compound comprising an ortho-aminohydroxypyridine group of formula

(1) optionally substituted for a solid state in said compound comprising a diarylcarbonate group (2) optionally substituted for a molten state, so as to form said suspension.

4. Method according to claim 2 or 3, wherein said heating step takes place between 1h and 24h.

5. Process according to any one of claims 1 to 4, wherein said compound comprising an ortho-aminohydroxypyridine group of formula (1) is 2-amino-3-hydroxypyridine or 3-amino-4-hydrooxypyridine or 4-amino-3-hydroxypyridine or 3-amino-2-hydroxypyridine.

6. Process according to any one of claims 1 to 5, wherein said compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the pyridine ring respectively by one or more substituents chosen independently from one of the other in the group consisting of R, OR 1, SR 1, NR ₂ R ₃ , NR ₄ R ₅ , C (O) R 6 and SO 2 R 7 where:

R represents independently a hydrogen atom or an alkyl, aryl, halogen or nitro group, R 1 independently represents an alkyl, aryl or C (O) R _{2 group} ,

R ₂ independently represents an alkyl or aryl group,

R ₃ independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ ,

R ₅ independently represents a hydrogen atom or an alkyl or aryl group,

R ₆ independently represents a hydrogen atom or an alkyl, aryl, OR ₂ or N R2R3 group,

R ₇ independently represents an alkyl, aryl, NH ₂ or NR ₄ R ₅ group.

7. A process according to any one of claims 1 to 6, wherein said compound comprising an ortho-aminohydroxypyridine group of formula (1) may be substituted on the amino group by an alkyl group.

The process according to any one of claims 1 to 7, wherein said compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the pyridine ring by one or more substituents independently selected from one of other in the group consisting of R, OR 1, SR 1, NR 2 R _3, NR ₄ R ₅ , C (O) R ₆ and SO ₂ R ₇ where:

R 1 independently represents an alkyl, aryl or C (O) R _{2 group} ,

R ₂ independently represents an alkyl or aryl group,

R3 independently represents an alkyl or aryl group,

R ₄ represents a group C (O) R ₂ , R ₅ independently represents a hydrogen atom or an alkyl or aryl group,

- R ₇ independently represents an alkyl, aryl, NH ₂ or NR ₄ R _{5 group} .

9. Process according to any one of claims 1 to 8, wherein said compound comprising an oxazolopyridinone group of formula (3) may subsequently be substituted on the oxazolidinone ring at the 3-position, respectively, with one or more substituents chosen independently. one of the other in the group consisting of the radical R 'where R' independently represents:

An alkyl group,

A halomethyl group with the halogen chosen from chlorine (Cl) or bromine (Br),

A 1,2-dihalo-halo group with the halogen chosen from chlorine (Cl) or bromine (Br),

A vinyl group,

A hydroxymethyl group,

A group (CH ₂ ) _n -X (with X = P (Q) OR "and R" chosen from H, alkyl; Br; CN; arylpiperazine),

A group CH ₂ SP (0) (0Me) ₂ ,

10. Process according to any one of the preceding claims, wherein said compound comprising a diarylcarbonate group of formula (2) comprises at least one phenyl group, preferably two phenyl groups.

11. Use of said compound prepared according to any one of claims 1 to 10 for the preparation of Azamethiphos.

12. Use of said compound prepared according to any one of claims 1 to 10 for the preparation of analogues of the

Fosmidomycin.

13. Use of said compound prepared according to any one of claims 1 to 10 for the preparation of analogs of 3- [(4-aryl-1-piperazinyl) alkyl] oxazolo [4,5-b] pyridine 2- (3H) -one or 1 - [(4-aryl-1-piperazinyl) alkyl] oxazolo [5,4-b] pyridin-2- (1H) -one or N-substituted aminohydroxypyridine compounds .

14. Use of said compound prepared according to any one of claims 1 to 10, for the preparation of a drug or an effective treatment for treating autoimmune diseases, melanoma, arthritis, rheumatoid arthritis, Parkinson's disease, asthma, tumors, dementia, Alzheimer's disease, leukemia, diabetes, psoriasis, heart failure and allergies.