HK1095145B - Process for the preparation of n-arylmorpholinones - Google Patents

Description

Process for preparing N-aryl morpholinones

The invention relates to a method for preparing a compound of formula I and a salt thereof

Wherein

X represents

R¹Represents NO₂、CN、COOR³、CON(R³)₂、COR³、SO₂R⁴、SO₂N(R³)₂、CF₃F or Cl, or a salt of a compound of formula,

R²represents H, Hal, A, OR³、N(R³)₂、NO₂、CN、COOR³、CON(R³)₂、NR³COA、NR³CON(R³)₂、NR³COOR³、NR³SO₂A、-[C(R⁵)₂]_n-Ar、-[C(R⁵)₂]_n-Het、-[C(R⁵)₂]_n-cycloalkyl, COR³、SO₂N(R³)₂Or SO₂R⁴，

R³Represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁴Represents A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁵Represents H or A',

ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted with the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂Or S (O)_nA，

Het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂、S(O)_nA and/or carbonyl oxygen (═ O),

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 12C atoms in which one or two CH groups₂A group may be substituted by O or S atoms and/or by-CH ═ CH-groups, and/or a further 1 to 7H atoms may be substituted by F,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1, 2, 3 or 4,

it is characterized in that

a) A compound of formula II

X-NH₂ II

Wherein X has the same meaning as above,

with 5-chloro-2, 3-dihydro-1, 4-dioxadiene (dioxin)

To give the compound of the formula III

Wherein X has the same meaning as above,

b) then cyclizing the compound shown in the formula III to generate the compound shown in the formula I,

and is

c) By converting a base or acid of formula I into one of its salts, optionally converting the latter of b) into its salt.

It is an object of the present invention to find a new and improved process for the preparation of factor Xa inhibitor precursors.

Compared with the known methods in the prior art, the method provided by the invention is simpler and more effective.

Factor Xa inhibitors can be used to combat and prevent thromboembolic disorders such as thrombosis, myocardial infarction, arteriosclerosis, inflammation, stroke, angina pectoris, restenosis following angioplasty, and intermittent claudication.

Factor Xa is one of the proteases in this complex process of blood coagulation. Factor Xa catalyzes the conversion of prothrombin to thrombin. Thrombin splits fibrinogen into fibrin monomers, the cross-linking of which is the primary cause of contributing to thrombosis. Activation of thrombin can lead to the development of thromboembolic disorders. However, inhibition of thrombin inhibits fibrin formation during thrombosis.

Inhibition of thrombin is measurable, for example, using the method in G.F. Cousin et al "Circulation" 1996, 94, 1705-1712.

Inhibition of factor Xa prevents thrombin formation.

Factor Xa inhibition, anticoagulant assay, and antithrombotic activity can be measured by conventional in vitro or in vivo methods. Suitable methods are described in J.Hauptmann et al, "Thrombosisand Haemostasis" 1990, 63, 220-.

Inhibition of factor Xa is measurable, for example, using the method of T.Hara et al, "Thromb. Haemostas" 1994, 71, 314-319.

Upon binding of factor VIIa to tissue factor, an external coagulation cascade is initiated and activates factor X to form factor Xa. Inhibiting factor VIIa thus prevents the formation of factor Xa, which in turn prevents the formation of thrombin.

Factor VIIa inhibition, anticoagulant determination, and antithrombotic activity can be determined by conventional in vitro or in vivo methods. Conventional methods for determining factor VIIa inhibition are described in H.F.Ronning et al, "Thrombosis Research" 1996, 84, 73-81.

Factor IXa is produced in an internal coagulation cascade, which also activates factor X to form factor Xa. Thus, inhibition of factor IXa can prevent factor Xa formation in another way.

Factor IXa inhibition, anticoagulant assay, and antithrombotic activity can be measured by conventional in vitro or in vivo methods. Suitable methods are described in J.Chang et al, "Journal of biological Chemistry" 1998, 273, 12089-12094.

The correlation between tissue factor TF/factor VIIa and the development of various types of Cancer has been described by T.Taniguchi and N.R.Lemoine in "biomed.health Res." (2000), 41(Molecular characterization of functional Cancer), 57-59. The following publications describe the antitumor effect of various tumor types TF-VII and factor Xa inhibitors:

k.m.donnelly et al, "thromb.haemant." 1998; 79: 1041-1047;

e.g. fischer et al "clin.invest." 104: 1213-1221 (1999);

b.m.mueller et al "clin.invest." 101: 1372-1378 (1998);

m.e.bromberg et al, "thromb.haemos." 1999; 82: 88-92.

WO 02/057236 describes other methods and morpholinone precursors.

The following processes for the preparation of 2- (2-chloroethoxy) acetamide have been described in the literature:

such processes are described, for example, in US 3074939, BE776767 and DE 1922613.

This method is described, for example, in g.may, d.peteri, arzneim. -Forsch. (Drug Res.)23, 718 (1973).

This process is described, for example, in DE 2150075.

However, these methods have drawbacks. Therefore, many reaction steps are required or the starting materials are expensive.

M.j.astle, j.d.welks, j.org.chem.26, 4325(1961) disclose the following reaction:

r is alkyl or phenyl

We have surprisingly found that, provided the pK of the aromatic amine is_aA value less than or equal to 3, which also reacts with 5-chloro-2, 3-dihydro-1, 4-dioxadiene (2-chlorodioxene) to form 2- (2-chloroethoxy) acetamide.

In view of m.j.attle, j.d.welks, j.org.chem.26, 4325(1961), this reaction is unpredictable because amines such as ammonia, benzylamine, 8-amino-quinoline or 4-methoxyaniline do not react or do not react sufficiently.

pK_aComparison of values:

benzylamine 9.5

Ammonia 9.24

8-amino-quinoline 0.7(NH2 group) and 4.0 (quinoline nitrogen).

Basic quinoline nitrogen prevents the reaction.

4-Methoxyaniline 5.4

4-Nitro-aniline 1.0

4-Cyanoanilines 1.7

3-Nitro-anilines 2.5

2-methyl-4-nitroaniline 1.04

4-Aminobenzoic acid methyl ester 1.5

4-aminobenzophenone 2.2

2-Nitro-aniline-0.23

In this reaction, the addition of, for example, Bronsted acid facilitates the reaction, such as hydrochloric acid, or Lewis acid, or the addition of 2, 2-dichlorodioxine (2, 2-dichlorodioxine) which is a compound mentioned in the literature (R.K. Summerbell, H.E.Lunk, J.Am.chem.Soc.79, P.4802, 1957) and which readily decomposes into hydrogen chloride and 5-chloro-2, 3-dihydro-1, 4-dioxine. The reaction can be carried out in a number of solvents, for example toluene, acetonitrile, dioxane, or in solid (in mass), i.e. without addition of a solvent. Typical reaction temperatures are from 0 to 150 ℃, usually about 80 ℃, for example between 70 and 90 ℃.

The process has the advantage that 5-chloro-2, 3-dihydro-1, 4-dioxadiene or 2, 2-dichlorodioxane is easily prepared.

The preparation of 2, 3-dichlorodioxane has been described, for example, in M.Lyoda et al "Heterocycles", 54, P.833, 2001. The thermal elimination of hydrogen chloride is described in US 2756240. These processes produce 5-chloro-2, 3-dihydro-1, 4-dioxadienes that contain a proportion of 2, 2-dichlorodioxane impurity (typically 5% to 50%).

N.v. kuznetsov, i.i. krasvsov, sov. prog.chem. (engl. trans.) 44, p.77, 1987 describes a process for the preparation of 5-chloro-2, 3-dihydro-1, 4-dioxadiene from 2, 3-dichlorodioxane using sodium hydroxide.

The cyclisation of chloroethoxyacetamides to morpholinones has hitherto been described in two publications: DE922613 and l.fumagalli et al "Pharmazie" 30, 78 (1975).

Both examples relate to triiodobenzoic acid and triiodophenylalkanoic acid derivatives.

However, this method is only applicable to water-soluble reactants, as described in the above-mentioned documents, where R always contains one free carboxyl group.

We have found that chloroethoxyacetamides can preferably be cyclized to morpholinones using a weak base such as cesium carbonate or potassium carbonate in a suitable solvent such as acetonitrile.

Hereinbefore and hereinafter, a represents an alkyl group, either unbranched (straight chain) or branched structure having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10C atoms. A preferably represents methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore pentyl, 1-, 2-or 3-methylbutyl, 1, 1-, 1, 2-or 2, 2-dimethyl-propyl, 1-ethylpropyl, hexyl, 1-, 2-, 3-or 4-methylpentyl, 1, 1-, 1, 2-, 1, 3-, 2, 2-, 2, 3-or 3, 3-dimethylbutyl, 1-or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1, 1, 2-or 1, 2, 2-trimethylpropyl, may preferably also represent, for example, trifluoromethyl.

A very particularly preferably represents alkyl having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

A' preferably represents an alkyl group having 1, 2, 3, 4, 5 or 6C atoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

Cycloalkyl has 3 to 7C atoms and preferably represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Hal preferably represents F, Cl, Br or I.

R¹Preferably represents NO₂、CN、COOH、COOR³、COR³Or Cl.

R²Preferably represents H, Hal or A.

R³Preferably represents H, A' or- [ C (R)⁵)₂]_n-Ar。

R⁴Preferably represents A.

Ar represents, for example, phenyl, o-, m-or p-tolyl, o-, m-or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m-or p-isopropylphenyl, o-, m-or p-tert-butyl-phenyl, o-, m-or p-hydroxyphenyl, o-, m-or p-nitrophenyl, o-, m-or p-aminophenyl, o-, m-or p- (N-methylamino) -phenyl, o-, m-or p- (N-methyl-aminocarbonyl) -phenyl, o-, m-or p-acetamidophenyl, o-, m-or p-methoxy-phenyl, o-, m-or p-ethoxyphenyl, o-, m-or p-ethoxycarbonylphenyl, o-, m-or p- (N, N-dimethylamino) -phenyl, o-, m-or p- (N, N-dimethylaminocarbonyl) -phenyl, o-, m-or p- (N-ethylamino) -phenyl, o-, m-or p- (N, N-diethylamino) -phenyl, o-, m-or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m-or p-chlorophenyl, o-, m-or p- (methylsulphonamido) phenyl, o-, m-or p- (methylsulphonyl) phenyl, and preferably also represents 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-difluorophenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dichlorophenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-or 3, 5-dibromophenyl, 2, 4-or 2, 5-dinitrophenyl, 2, 5-or 3, 4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-, 2-amino-5-chloro-or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino-or 3-nitro-4-N, N-dimethylaminophenyl, 2, 3-diaminophenyl, 2, 3, 4-, 2, 3, 5-, 2, 3, 6-, 2, 4, 6-or 3, 4, 5-trichlorophenyl, 2, 4, 6-trimethoxyphenyl, 2-hydroxy-3, 5-dichlorophenyl, p-iodophenyl, 3, 6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2, 5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-4-acetylaminophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetylaminophenyl or 2, 5-dimethyl-4-chlorophenyl.

Ar preferably represents, for example, phenyl, which is unsubstituted or mono-, di-or trisubstituted by the following substituents: hal, A, OR⁵、SO₂A、COOR⁵Or CN. Ar particularly preferably represents, for example, phenyl, which is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OA, SO₂A、SO₂NH₂、COOR⁵Or CN. For example phenyl, 2-methylsulfonylphenyl, 2-aminosulfonylphenyl, 2-, 3-or 4-chlorophenyl, 4-methylphenyl, 4-bromophenyl, 3-fluoro-4-methoxyphenyl, 4-trifluoromethoxyphenyl, 4-ethoxyphenyl, 2-methoxyphenyl, 3-cyanophenyl or 4-ethoxycarbonyl-phenyl.

Ar very particularly preferably represents unsubstituted phenyl.

Het is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂、S(O)_nA and/or carbonyl oxygen (═ O) and represents, for example, 2-or 3-furyl, 2-or 3-thienyl, 1-, 2-or 3-pyrrolyl, 1-, 2, 4-or 5-imidazolyl, 1-, 3-, 4-or 5-pyrazolyl, 2-, 4-or 5-oxazolyl, 3-, 4-or 5-isoxazolyl, 2-, 4-or 5-thiazolyl, 3-, 4-or 5-isothiazolyl, 2-, 3-or 4-pyridyl, 2-, 4-, 5-or 6-pyrimidinyl, preferably also 1, 2, 3-triazol-1-, -4-or-5-yl, 1, 2, 4-triazol-1-, -3-or 5-yl, 1-or 5-tetrazolyl, 1, 2, 3-oxadiazol-4-or-5-yl, 1, 2, 4-oxadiazol-3-or-5-yl, 1, 3, 4-thiadiazol-2-or-5-yl, 1, 2, 4-thiadiazol-3-or-5-yl, 1, 2, 3-thiadiazol-4-or-5-yl, 3-or 4-pyridazinyl, pyrazinyl, 1-, 2-, 3-, 4-, 5-, 6-or 7-indolyl, 4-or 5-isoindolyl, 1-, (meth) acrylic acid or methacrylic acid, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6-or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6-or 7-benzisoxazolyl, 2-, 4-, 5-, 6-or 7-benzothiazolyl, 2-, 4-, 5-, 6-or 7-benzisothiazolyl7-benzo-2, 1, 3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7-or 8-quinazolinyl, 5-or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7-or 8-2H-benzo-1, 4-oxazinyl, preferably also 1, 3-benzodioxolin-5-yl, optionally also optionally substituted, optionally, 1, 4-benzodioxan-6-yl, 2, 1, 3-benzothiadiazol-4-or-5-yl or 2, 1, 3-benzoxadiazol-5-yl.

The heterocyclic groups may also be partially or fully hydrogenated. Het may also represent, for example, 2, 3-dihydro-2-, -3-, -4-or-5-furyl, 2, 5-dihydro-2-, -3-, -4-or-5-furyl, tetrahydro-2-or-3-furyl, 1, 3-dioxolan-4-yl, tetrahydro-2-or-3-thienyl, 2, 3-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 2, 5-dihydro-1-, -2-, -3-, -4-or-5-pyrrolyl, 1-, 1-, or, 2-or 3-pyrrolidinyl, tetrahydro-1-, -2-or 4-imidazolyl, 2, 3-dihydro-1-, -2-, -3-, -4-or 5-pyrazolyl, tetrahydro-1-, -3-or 4-pyrazolyl, 1, 4-dihydro-1-, -2-, -3-or 4-pyridyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-or 6-pyridyl, 1-, 2-, 3-or 4-piperidyl, 2-, 3-or 4-morpholinyl, tetrahydro-2-, -3-or 4-pyranyl, 1, 4-dioxane-yl, 1, 3-dioxane-2-, -4-or 5-yl, hexahydro-1-, -3-or 4-pyridazinyl, hexahydro-1-, -2-, -4-or 5-pyrimidinyl, 1-, 2-or 3-piperazinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or 8-quinolinyl, 1, 2, 3, 4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7-or-8-isoquinolinyl, 2-, 3-, 5-, 6-, 7-or 8-3, 4-dihydro-2H-benzo-1, 4-oxazinyl, still more preferably 2, 3-methylenedihydroxyphenyl, 3, 4-methylenedihydroxyphenyl, 2, 3-ethylenedihydroxyphenyl, 3, 4- (difluoromethylenedihydroxy) phenyl, 2, 3-dihydrobenzofuran-5-or 6-yl, 2, 3- (2-oxomethylenedihydroxy) -phenyl or 3, 4-dihydro-2H-1, 5-benzodiazepines-6-or-7-yl, further preferably 2, 3-dihydrobenzofuranyl or 2, 3-dihydro-2-oxo-a furyl group.

n preferably represents 0 or 1.

m preferably represents 0, 1 or 2.

The present invention preferably relates to a process for the preparation of compounds of the formula I as claimed in claim 1, wherein

R¹Represents NO₂、CN、COOR³、COR³Or a combination of Cl and a base,

R²represents H, Hal or A.

Also preferred is a process for the preparation of a compound of formula I according to claim 1 or 2, wherein

R¹Represents NO₂、CN、COOR³、CON(R³)₂、COR³、SO₂R⁴、SO₂N(R³)₂、CF₃F or Cl, or a salt of a compound of formula,

R²the expression H, Hal or A is used,

R³represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het。

Also preferred is a process for the preparation of a compound of formula I according to claim 1, wherein Ar represents phenyl.

Also preferred is a process for the preparation of a compound of formula I, wherein R⁴Represents A.

Preference is also given to processes for the preparation of compounds of the formula I, in which

R¹Represents NO₂、CN、COOR³、CON(R³)₂、COR³、CF₃F or Cl, or a salt of a compound of formula,

R²represents H, Hal or A',

R³represents H, A' or- [ C (R)⁵)₂]_n-Ar，

Ar represents a phenyl group, and Ar represents a phenyl group,

R⁵represents H or A',

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2.

Very particularly preferred is a process for the preparation of the compounds according to claim 1, selected from

1)4- (4-nitrophenyl) -3-oxomorpholine,

2)4- (3-nitrophenyl) -3-oxomorpholine,

3)4- (2-nitrophenyl) -3-oxomorpholine,

4) 2-methyl-4- (4-nitrophenyl) -3-oxomorpholine,

5)4- (4-methoxycarbonylphenyl) -3-oxomorpholine,

6)4- (4-benzoylphenyl) -oxomorpholine.

Also preferred is a process for the preparation of compounds of the formula I according to one or more of claims 1 to 6, wherein the pK of the amine of the formula II_aThe value is less than or equal to 3.

The compounds of the formula I can preferably be prepared by reacting, in step a), a compound of the formula II with 5-chloro-2, 3-dihydro-1, 4-dioxadiene to give a compound of the formula III.

The reaction is usually carried out in an inert solvent, but may be carried out in a solid without a solvent.

In this reaction, the addition of, for example, Bronsted acid favors the reaction, like hydrochloric acid, or Lewis acids, or the addition of the compound 2, 2-dichlorodioxanone mentioned in the literature (R.K. Summerbell, H.E.Lunk, J.Am.chem.Soc.79, P.4802, 1957), which is readily decomposed to hydrogen chloride and 5-chloro-2, 3-dihydro-1, 4-dioxadiene.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, preferably between 1 and 10 hours, and the reaction temperature is between 0 ℃ and 150 ℃, generally between 20 ℃ and 130 ℃, preferably between 60 ℃ and 110 ℃, most preferably between 70 ℃ and 90 ℃.

Suitable inert solvents such as water; hydrocarbons such as hexane, petroleum ether, benzene, toluene, xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the above solvents. Acetonitrile is particularly preferred.

In a second step b), the compound of formula III is cyclized to give the compound of formula I.

The reaction is generally carried out in an inert solvent, preferably an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate. Most preferred are weak bases such as cesium carbonate or potassium carbonate.

Depending on the conditions used, the reaction time is between a few minutes and 14 days, preferably between 1 and 20 hours, and the reaction temperature is between 0 ℃ and 150 ℃, generally between 0 ℃ and 90 ℃, preferably between 10 ℃ and 70 ℃, more preferably between 20 ℃ and 50 ℃.

Suitable inert solvents are, for example, hydrocarbons, such as hexane, petroleum ether, benzene, toluene, xylene; chlorinated hydrocarbons, such as trichloroethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, Tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide or Dimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the above solvents. Acetonitrile is particularly preferred.

Steps a) and b) can also be carried out as a one-pot reaction. When the reaction of the amine with 5-chloro-2, 3-dihydro-1, 4-dioxadiene is complete, the solution temperature decreases. At this point, an excess of alkali metal carbonate (typically 1.5 to 4 equivalents) is added and the reaction mixture is stirred until conversion is complete.

The base of formula I may be converted to the relevant acid addition salt with an acid, for example by reacting an equivalent amount of the base with the acid in an inert solvent such as ethanol, followed by evaporation. Acids suitable for this reaction are in particular acids which form physiologically acceptable salts. Thus, use may be made of inorganic acids, such as sulfuric acid, nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromic acid, phosphoric acids, such as orthophosphoric acid, sulfamic acid, and also organic acids, in particular fatty acids, cycloaliphatic acids, aromatic acids (araliphatic acids), aromatic or heterocyclic mono-or polycarboxylic acids, sulfonic acids or sulfuric acids, such as formic acid, acetic acid, propionic acid, trimethylacetic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane-or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and naphthalenedisulfonic acid, lauryl sulfuric acid. Physiologically unacceptable salts, such as picrates, can be used to isolate and/or purify the compounds of formula I.

On the other hand, the compounds of the formula I can be converted with bases into the corresponding metal salts, in particular alkali metal salts or alkaline earth metal salts, or the corresponding ammonium salts (e.g.sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate).

It is also possible to use physiologically acceptable organic bases, such as ethanolamine.

The invention also relates to intermediate compounds of formula III and salts thereof

Wherein

X represents

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal, A, OR³、N(R³)₂、NO₂、CN、COOR³、CON(R³)₂、NR³COA、NR³CON(R³)₂、NR³COOR³、NR³SO₂A、-[C(R⁵)₂]_n-Ar、-[C(R⁵)₂]_n-Het、-[C(R⁵)₂]_n-cycloalkyl, COR³、SO₂N(R³)₂Or SO₂R⁴，

R³Represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁴Represents A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁵Represents H or A',

ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted with the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂Or S (O)_nA，

Het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂、S(O)_nA and/or carbonyl oxygen (═ O),

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 12C atoms in which one or two CH groups₂A group may be substituted by O or S atoms and/or by-CH ═ CH-groups, and/or a further 1 to 7H atoms may be substituted by F,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1, 2, 3 or 4.

The intermediate compounds are important for the preparation of the compounds of formula I.

Preferred meanings of the corresponding groups are as described above, unless otherwise indicated.

The invention also relates to intermediate compounds according to claim 15 and salts thereof, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal or A.

Also preferred are intermediate compounds according to claim 15 and salts thereof, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²the expression H, Hal or A is used,

R³represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het。

Also preferred are intermediate compounds according to claim 15, 16 or 17 and salts thereof, wherein

Ar represents phenyl.

Also preferred are intermediate compounds and salts thereof according to one or more of claims 15 to 18, wherein

R⁴Represents A.

Especially preferred are intermediate compounds and salts thereof according to one or more of claims 15 to 19, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal or A',

R³represents H, A' or- [ C (R)⁵)₂]_n-Ar，

Ar represents a phenyl group, and Ar represents a phenyl group,

R⁵represents H or A',

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1 or 2.

Especially preferred are intermediate compounds according to claim 20 and salts thereof, wherein

R¹Represents NO₂，

R²Represents HHal or A',

R³represents H, A' or- [ C (R)⁵)₂]_n-Ar，

Ar represents a phenyl group, and Ar represents a phenyl group,

R⁵represents H or A',

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1 or 2.

The invention also relates to a preparation method of the intermediate compound of the formula III and the salt thereof

Wherein

X represents

R¹Represents NO₂、CN、COOR³、CON(R³)₂、COR³、SO₂R⁴、SO₂N(R³)₂、CF₃F or Cl, or a salt of a compound of formula,

R²represents H, Hal, A, OR³、N(R³)₂、NO₂、CN、COOR³、CON(R³)₂、NR³COA、NR³CON(R³)₂、NR³COOR³、NR³SO₂A、-[C(R⁵)₂]_n-Ar、-[C(R⁵)₂]_n-Het、-[C(R⁵)₂]_n-cycloalkyl, COR³、SO₂N(R³)₂Or SO₂R⁴，

R³Represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁴Represents A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁵Represents H or A',

ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted with the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂Or S (O)_nA，

Het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂、S(O)_nA and/or carbonyl oxygen (═ O),

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 12C atoms in which one or two CH groups₂A group may be substituted by O or S atoms and/or by-CH ═ CH-groups, and/or a further 1 to 7H atoms may be substituted by F,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1, 2, 3 or 4,

it is characterized in that

a) A compound of formula II

X-NH₂ II

Wherein X has the same meaning as above,

reaction with 5-chloro-2, 3-dihydro-1, 4-dioxadiene

And is

The compound of formula III is optionally converted to a salt thereof.

The reaction conditions of this process are particularly preferably the same as those described above for the preparation of the compounds of formula I.

Preferred meanings of the corresponding groups are as described above, unless otherwise indicated.

A process for the preparation of an intermediate compound of formula III, preferably according to claim 22, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal, A, OR³、N(R³)₂、NO₂、CN、COOR³、CON(R³)₂、NR³COA、NR³CON(R³)₂、NR³COOR³、NR³SO₂A、-[C(R⁵)₂]_n-Ar、-[C(R⁵)₂]_n-Het、-[C(R⁵)₂]_n-cycloalkyl, COR³、SO₂N(R³)₂Or SO₂R⁴，

R³Represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁴Represents A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het，

R⁵Represents H or A',

ar represents phenyl, which is unsubstituted or mono-, di-or trisubstituted with the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂Or S (O)_nA，

Het represents a monocyclic or bicyclic saturated, unsaturated or aromatic heterocycle having 1 to 4N, O and/or S atoms, which is unsubstituted or mono-or disubstituted by the following substituents: hal, A, OR⁵、N(R⁵)₂、NO₂、CN、COOR⁵、CON(R⁵)₂、NR⁵COA、NR⁵SO₂A、COR⁵、SO₂N(R⁵)₂、S(O)_nA and/or carbonyl oxygen (═ O),

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 12C atoms in which one or two CH groups₂A group may be substituted by O or S atoms and/or by-CH ═ CH-groups, and/or a further 1 to 7H atoms may be substituted by F,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1, 2, 3 or 4.

Also preferred is a process for the preparation of an intermediate compound of formula III according to claim 23, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal or A.

Also preferred is a process for the preparation of an intermediate compound of formula III according to claim 23, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²the expression H, Hal or A is used,

R³represent H, A, - [ C (R)⁵)₂]_n-Ar or- [ C (R)⁵)₂]_n-Het。

Also preferred is a process for the preparation of an intermediate compound of formula III according to claim 23, wherein

Ar represents phenyl.

Also preferred is a process for the preparation of an intermediate compound of formula III according to claim 23, wherein

R⁴Represents A.

Especially preferred is a process for the preparation of an intermediate compound of formula III according to claim 23, wherein

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²represents H, Hal or A',

R³represents H, A' or- [ C (R)⁵)₂]_n-Ar，

Ar represents a phenyl group, and Ar represents a phenyl group,

R⁵represents H or A',

a' represents an unbranched or branched alkyl group having 1 to 6C atoms,

hal represents F, Cl, Br or I,

n represents 0, 1 or 2,

m represents 0, 1 or 2.

Above and below, all temperatures are referred to as ℃.

Mass Spectrometry (MS): EI (Electron impact ionization) M⁺；

ESI (Electron spray ionization) (M + H)⁺；

FAB (Rapid atom bombardment) (M + H)⁺

Example 1

4- (4-Nitrophenyl) -3-oxomorpholine

The preparation method is similar to the following scheme:

1.1 solvent-free:

a mixture of 1.53 g of 5-chloro-2, 3-dihydro-1, 4-dioxane and 2, 2-dichlorodioxane (molar ratio 1:1) is added to 1.00 g (7.24mmol) of 4-nitroaniline and the mixture is heated to 80 ℃ with stirring. A brown solid formed within 1 hour and became liquid again, followed by crystallization within 12 hours. The crude product is recrystallized from ethanol with water to give 1.80 g of 2- (2-chloroethoxy) -N- (4-nitrophenyl) acetamide ("Al") as pale yellow crystals having a melting point of

101-102℃.¹H-NMR(d⁶-DMSO)：δ＝3.82(m；4H)，4.23(s；2H)，7.91(d，J＝9Hz，2H)，8.23(d，J＝9Hz，2H)，10.34(s，1H)。

1.2 in acetonitrile:

a mixture of 310 mg of 5-chloro-2, 3-dihydro-1, 4-dioxane and 2, 2-dichlorodioxane (molar ratio 1:1) was added to a solution of 276 mg (2.00mmol) of 4-nitroaniline in 2 ml of acetonitrile and the solution was heated at 80 ℃ for 18 hours with stirring. The reaction mixture was evaporated and the residue recrystallized from ethanol/water: 360 mg of pale yellow crystals "A1".

1.3 at room temperature, 1 kg of "A1" was dissolved in 5L acetonitrile, 835 g of potassium carbonate was added, and the mixture was stirred at this temperature for 18 hours. The mixture was warmed to 50 ℃ and treated in a similar manner to example 6 to give 4- (4-nitrophenyl) -3-oxomorpholine ("A2"), melting point 150-.

Example 2

4- (4-Nitro-2-methylphenyl) -3-oxomorpholine

A mixture of 1.05 g of 5-chloro-2, 3-dihydro-1, 4-dioxane and 2, 2-dichlorodioxane (molar ratio 1:1) is added to a solution of 1.10 g (7.24mmol) of 2-methyl-4-nitroaniline in 20 ml of THF and the mixture is heated to boiling. The solvent was distilled off and the residue was a brown viscous liquid, heated to 80 ℃ and held for 18 hours. After cooling, the residue was recrystallized from toluene/tert-butyl methyl ether: 1.50 g of 2- (2-chloroethoxy) -N- (2-methyl-4-nitrophenyl) acetamide in the form of pale yellow crystals, m.p.

113-114℃.¹H-NMR(d⁶-DMSO)：δ＝2.35(s；3H)，3.82(m；4H)，4.23(s；2H)，8.05(d，J＝8Hz，1H)8.09(dd，J＝9Hz，J＝1Hz，1H)，8.16(d，J＝1Hz，1H)，9.33(s，1H).

Cyclization reaction similar to 1.3 was performed to give 4- (4-nitro-2-methylphenyl) -3-oxomorpholine, ESI 237.

Example 3

4- (2-nitrophenyl) -3-oxomorpholine

A mixture of 1.12 g of 5-chloro-2, 3-dihydro-1, 4-dioxane and 2, 2-dichlorodioxane (molar ratio 89:11) is added to a solution containing 1.12 g (8.12mmol) of 2-nitroaniline and the mixture is heated to 80 ℃ with stirring. Slime was formed and stirred for 3 hours. Cooling to room temperature and crystallization of the product: 2.1 g of 2- (2-chloroethoxy) -N- (2-nitrophenyl) acetamide in the form of pale yellow crystals.

¹H-NMR(d⁶-DMSO)：δ＝3.84(m；4H)，4.25(s；2H)，7.35(t，J＝8Hz，1H)，7.77(t，J＝8Hz，1H)，8.14(d，J＝8Hz，1H)，8.30(d，J＝8Hz，1H)，10.74(s，1H).

Cyclization reaction similar to 1.3 was performed to give 4- (2-nitrophenyl) -3-oxomorpholine, ESI 223.

Example 4

4- (4-cyanophenyl) -3-oxomorpholine

A mixture of 959 mg (8.12mmol) of 4-aminobenzonitrile, 1.12 g of 5-chloro-2, 3-dihydro-1, 4-dioxadiene and 2, 2-dichlorodioxane (molar ratio 89:11) was heated at 80 ℃ for 18 hours with stirring. Cooling to room temperature, and recrystallizing the product: 1.9 g of 2- (2-chloroethoxy) -N- (4-cyanophenyl) -acetamide in the form of pale yellow crystals.

¹H-NMR(d⁶-DMSO)：δ＝3.82(m；4H)，4.19(s；2H)，7.78(d，J＝8Hz，2H)，7.85(d，J＝8Hz，2H)，10.22(s，1H).

Cyclization reactions analogous to 1.3 were performed to give 4- (4-cyanophenyl) -3-oxomorpholine, ESI 203.

Example 5

4- (4-methoxycarbonylphenyl) -3-oxomorpholine

A mixture of 1.23 mg (8.12mmol) of methyl 4-aminobenzoate, 1.12 g of 5-chloro-2, 3-dihydro-1, 4-dioxadiene and 2, 2-dichlorodioxane (molar ratio 89:11) was heated at 80 ℃ for 18 hours with stirring. Cooling to room temperature, and recrystallizing the product: 2.2 g of methyl 4- [2- (2-chloroethoxy) acetylamino ] benzoate as pale yellow crystals.

¹H-NMR(d⁶-DMSO)：δ＝3.82(m；7H)，4.20(s；2H)，7.82(d，J＝8Hz，2H)，7.93(d，J＝8Hz，2H)，10.15(s，1H).

Cyclization was carried out in analogy to 1.3 to give 4- (4-methoxycarbonylphenyl) -3-oxomorpholine, ESI 236.

Example 6

One-pot reaction preparation of 'A2'

6.40 g of 5-chloro-2, 3-dihydro-1, 4-dioxane (containing 6% of 2, 2-dichlorodioxane) are added to a solution of 6.00 g (24.9mmol) of 4-nitroaniline in 40 ml of acetonitrile and the mixture is stirred at 80 ℃ for 18 hours. The reaction solution was cooled to 40 ℃ and 18.0 g (130mmol) of potassium carbonate was added, and the mixture was stirred at this temperature for 14 hours. The reaction mixture was filtered, the residue was washed thoroughly with acetonitrile and the filtrate was evaporated. The residue was recrystallized from acetonitrile: 8.2 g of brown crystals ("A2"), melting point

150-152℃.¹H-NMR(d⁶-DMSO)：δ＝3.86(t，J＝5Hz；2H)，4.02(t，J＝5Hz；2H)，4.28(s；2H)，7.77(d，J＝9Hz，2H)，8.28(d，J＝9Hz，2H).

Example 7

4- (3-nitrophenyl) -3-oxomorpholine

A mixture of 1.12 g (8.12mmol) of 3-nitroaniline and 1.11 g of 5-chloro-2, 3-dihydro-1, 4-dioxadiene (containing 6% of 2, 2-dichlorodioxane) was heated with stirring at 80 ℃ for 24 hours to give 2.1 g of 2- (2-chloroethoxy) -N- (3-nitrophenyl) -acetamide as a brown oil. ESI 259.

Cyclization reaction similar to 1.3 was performed to give 4- (3-nitrophenyl) -3-oxomorpholine, ESI 223.

Example 8

4- (4-benzoylphenyl) -3-oxomorpholine

A mixture of 1.60 g (8.12mmol) of 4-aminobenzophenone and 1.11 g of 5-chloro-2, 3-dihydro-1, 4-dioxadiene (containing 6% of 2, 2-dichlorodioxane) was heated at 80 ℃ with stirring for 24 hours to give 2.6 g of N- (4-benzoylphenyl) -2- (2-chloroethoxy) acetamide as a brown oil. ESI 318.

Cyclization was carried out in analogy to 1.3 to give 4- (4-benzoylphenyl) -3-oxomorpholine, ESI 282.

Example 9

4- (3-fluorophenyl) -3-oxomorpholine

A mixture of 12.0 g (108mmol) of 3-fluoroaniline and 16 g of 5-chloro-2, 3-dihydro-1, 4-dioxadiene (containing 6% of 2, 2-dichlorodioxane) was heated at 100 ℃ for 24 hours. The mixture was cooled and the excess 5-chloro-2, 3-dihydro-1, 4-dioxadiene was removed under reduced pressure to give 25 g of 2- (2-chloroethoxy) -N- (3-fluorophenyl) acetamide as a brown oil; ESI 232. The oil was dissolved in 400 ml of acetonitrile and 84.7 g (260mmol) of cesium carbonate were added. The resulting suspension was stirred at room temperature for 18 hours. The reaction mixture was filtered and the filtrate was evaporated to give 21.0 g of 4- (3-fluorophenyl) morpholin-3-one as a brown oil;

ESI196.¹H-NMR(d⁶-DMSO)：δ＝3.77(t，J＝5Hz；2H)，3.97(t，J＝5Hz；2H)，4.23(s；2H)，7.11(dddd，J₁＝8Hz，J₂＝8Hz，J₃＝2Hz，J₄＝0.5Hz，1H)，7.26(ddd，J₁＝8Hz，J₂＝2Hz，J₃＝0.5Hz，1H)，7.34(ddd，J₁＝10Hz，J₂＝2Hz，J₃＝2Hz，1H)，7.45(ddd，J₁＝8Hz，J₂＝8Hz，J₃＝7Hz，1H).

example 10

4- (3-methyl-4-nitrophenyl) -3-oxomorpholine

12.8 g of 5-chloro-2, 3-dihydro-1, 4-dioxane (containing 6% of 2, 2-dichlorodioxane) are added to a solution of 10.0 g (65.7mmol) of 3-methyl-4-nitroaniline in 250 ml of acetonitrile and the mixture is stirred at 80 ℃ for 66 hours. The reaction solution was cooled to room temperature, 42.8 g (13] mmol) of cesium carbonate was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered, the residue was washed thoroughly with acetonitrile and the filtrate was evaporated. The residue was recrystallized from a small amount of acetonitrile to give 12.8 g (83%) of 4- (3-methyl-4-nitrophenyl) morpholin-3-one as a pale yellow solid.

ESI 236.¹H-NMR(d⁶-DMSO)：δ＝2.54(s；2H)，δ＝3.82(t，J＝5Hz；2H)，4.00(t，J＝5Hz；2H)，-4.25(s；2H)，7.57(m；2H)，8.04(d，J.＝8Hz；1H).

4- (2-chloro-5-fluoro-4-nitrophenyl) -3-oxomorpholine are obtained in an analogous manner

Example 11

4- (2-bromo-5-nitrophenyl) -3-oxomorpholine is obtained in analogy to example 7

4- (2-Methoxycarbonyl-5-nitrophenyl) -3-oxomorpholine is obtained in analogy to example 7

Claims (11)

1. Preparation method of compound of formula I or salt thereof

Wherein

X represents

R¹Represents NO₂、CN、COOR³A benzoyl group, F or Cl,

R²the expression H, Hal or A is used,

R³represents the general formula of A and the general formula of A,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 4C atoms,

hal represents F, Cl, Br or I,

m represents 0, 1, 2, 3 or 4,

it is characterized in that

a) A compound of formula II

X-NH₂ II

Wherein X has the same meaning as above,

reaction with 5-chloro-2, 3-dihydro-1, 4-dioxadiene

To give the compound of the formula III

Wherein X has the same meaning as above,

b) then cyclizing the compound shown in the formula III to generate the compound shown in the formula I,

and optionally

c) Converting the compound of formula I into one of its salts.

2. The process of claim 1 for the preparation of a compound of formula I, wherein the pK of the amine of formula II_aThe value is less than or equal to 3.

3. The process of claim 1, wherein process steps a) and b) are carried out as a one-pot reaction.

4. The process of claim 1, wherein process step a) is carried out at from 0 ℃ to 150 ℃.

5. The process of claim 4, wherein process step a) is carried out at from 70 ℃ to 90 ℃.

6. The process of claim 1 wherein the cyclization reaction is carried out in the presence of an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate in an inert solvent or solvent mixture.

7. The process of claim 1, wherein the cyclization reaction is carried out in the presence of cesium carbonate or potassium carbonate.

8. The process of claim 1, wherein the process is carried out as a one-pot reaction in acetonitrile.

9. The process of claim 1 for preparing a compound or salt thereof selected from

(1)4- (4-Nitrophenyl) -3-oxomorpholine

(2)4- (3-nitrophenyl) -3-oxomorpholine

(3)4- (2-nitrophenyl) -3-oxomorpholine

(4)4- (4-Nitro-2-methylphenyl) -3-oxomorpholine

(5)4- (4-methoxycarbonylphenyl) -3-oxomorpholine

(6)4- (4-benzoylphenyl) -3-oxomorpholine.

10. An intermediate compound of formula III or a salt thereof

Wherein

X represents

R¹Represents NO₂Or the CN group is selected from the group consisting of,

R²the expression H, Hal or A is used,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 4C atoms,

hal represents F, Cl, Br or I,

m represents 0, 1, 2, 3 or 4.

11. Preparation method of intermediate compound of formula III or salt thereof

Wherein

X represents

R¹Represents NO₂、CN、COOR³A benzoyl group, F or Cl,

R²the expression H, Hal or A is used,

R³represents the general formula of A and the general formula of A,

a represents an unbranched, branched or cyclic alkyl radical having 1 to 4C atoms,

hal represents F, Cl, Br or I,

m represents 0, 1, 2, 3 or 4,

it is characterized in that

a) A compound of formula II

X-NH₂ II

Wherein X has the same meaning as above,

reaction with 5-chloro-2, 3-dihydro-1, 4-dioxadiene

And the compound of formula III is optionally converted to a salt thereof.