EP1425261A2

EP1425261A2 - Method for producing 4-amino-1-naphthol ethers

Info

Publication number: EP1425261A2
Application number: EP02797591A
Authority: EP
Inventors: Joachim Komoschinski; Herbert Diehl
Original assignee: Bayer Chemicals AG
Current assignee: Saltigo GmbH
Priority date: 2001-08-31
Filing date: 2002-08-19
Publication date: 2004-06-09
Also published as: WO2003020686A3; US6964963B2; US20030083525A1; US20050261498A1; AU2002333464A1; CN1315781C; WO2003020686A2; CN1547568A

Abstract

The invention relates to a method for producing 4-amino-1-naphthol ethers which is characterized in that naphthol ethers are firstly produced from 1-naphthols, are subsequently transformed into corresponding 4-acetamino-1-naphthol ethers, whereupon the acyl group is then split off. The invention also concerns certain 4-acetamino-1-naphthol ethers.

Description

Nerfahren for the production of 4-Ammo-l-naphthoIethern

The present invention relates to a ner process for the preparation of 4-amino-1-naphthol ethers and new intermediates.

4-Amino-1-naphthol ethers are valuable intermediates in the production of active pharmaceutical ingredients (see, for example, WO 00/43384; B. Bachman, J. Wetzel, J. Org. Chem., 11, 1946, pp. 454-462; R. Herbst, P. Johnson, J. Org. Chem. 17, 1952, pp. 693-697). The e.g. from WO 00/43384 known synthetic route starts from 4-amino-1-naphthol hydrochloride and includes the conversion of the amine into a protected derivative, the alkylation of the hydroxy group and then the elimination of the protective group. This process has the disadvantage that both the starting material and the protective group reagents used are very expensive and the overfilling into the desired 4-amino-naphthol ether still requires three stages. The synthesis of 4-amino-l-methoxynaphtalin according to B. Bachman, J. Wetzel, J. Org. Chem., 11, 1946, pp. 454-462 also proceeds analogously and therefore has the same disadvantages.

There was therefore a need to develop an efficient ner driving which, based on inexpensive 1-aphthols, enables the production of 4-amino-1-naphthol ethers in a few steps.

A ner process for the preparation of 4-amino-1-naphthol ethers has now been found, which is characterized in that

a) substituted or unsubstituted 1-Νaphthols are reacted with reactive alkyl compounds, optionally in the presence of a base, to give 1-naphthol ethers, b) the 1-naphthol ethers are then converted with hydroxylammonium salts and carboxylic acids into the corresponding 4-acylamino-1-naphthol ethers and

c) these 4-acylamino-1-naphthol ethers are converted into the free 4-amino-1-naphthol ethers or analogous ammonium salts by cleavage of acid or basic acyl groups.

For step a) of the nerfalirene according to the invention, preference is given to using substituted or unsubstituted 1-α-phthols of the general formula (I)

in the

R represents hydrogen, halogen or Ci-C ₄ alkyl and

R represents hydrogen, halogen, Ci-C ₄ alkyl or C ₁ -C ₄ alkoxy and

n stands for zero, one, two, three or four

R ⁴ each independently of one another for halogen, nitro, cyano, protected formyl, -Cs-alkyl, C ₇ -C ₁₀ arylalkyl, CrCs-hydroxyalkyl, -Cs-haloalkyl or C ₆ -C ₁₀ aryl or substituents of the general Formula (II),

D-E-F (II)

in the independently of each other D is absent or represents a -Cs alkylene radical and

E represents a carbonyl group or sulfonyl group and

F represents R ^δ , OR ⁶ , NH ₂ , SR ⁶ , NHR ⁶ or NR ⁶ R ⁷ ,

and where

R and R each independently represent substituted or unsubstituted d-Cs-alkyl, CrCg-Halpgenalkyl, C ₇ -C ₁₂ arylalkyl or C ₆ - C ₁₀ aryl or

NR ⁶ R ⁷ as a whole represents a 5- to 8-membered heterocycle.

In the contexts mentioned, alkyl or alkylene each independently denotes a straight-chain, cyclic, branched or unbranched alkyl or alkylene radical. The same applies to the alkyl part of an arylalkyl radical.

Examples of -CC alkyl radicals are methyl, ethyl, n-propyl, isopropyl or n-butyl, for d-Cs-alkyl radicals also n-pentyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl and iso-octyl.

Examples of d-Cg-alkylene radicals are methylene, 1,1-ethylene, 1,2-ethylene, 1,2-

Propylene, 1,3-propylene, 1,4-butylene or 1,2-cyclohexylene.

Examples of C ₇ -C ₁₂ arylalkyl radicals are benzyl or p-methylbenzyl.

Examples of C ₁ -C ₄ alkoxy radicals are methoxy, ethoxy, n-propoxy, iso-propoxy or n-butoxy. The term aryl stands for both carbocyclic and heteroaromatic radicals in which none, one, two or three carbon atoms per cycle, but in the rest of at least one carbon atom, is substituted by heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.

Furthermore, the carbocyclic aromatic radicals or heteroaromatic radicals can be substituted with up to five identical or different substituents per cycle, selected from the group bromine, chlorine, fluorine, nitro, cyano, free or protected formyl, dC ₈ alkyl, d-Cs- Hydroxyalkyl or radicals of the general formula (II) with the meaning given there.

Carbocyclic, aromatic radicals or heteroaromatic radicals can, for example, be substituted or unsubstituted phenyl, pyridyl, imidazolyl, or pyrazolyl.

The same applies to the aryl part of an arylalkyl radical.

Halogen means fluorine, chlorine, bromine or iodine in the contexts mentioned.

Haloalkyl in the abovementioned contexts means in each case independently straight-chain, cyclic, branched or unbranched alkyl radicals which can be substituted by one, more or completely selected from the group fluorine, chlorine or bromine independently of one another by halogen atoms.

Examples of C 1 -C ₈ haloalkyl radicals are trifluoromethyl, pentafluoroethyl, 2,2,2-

Trifluoroethyl, trichloromethyl or 2-chloroethyl.

In the contexts mentioned, hydroxyalkyl in each case means independently straight-chain, cyclic, branched or unbranched alkyl radicals which are substituted with one or more hydroxy groups in such a way that each carbon atom of the radical carries at most one oxygen, sulfur or nitrogen atom. Examples of d-Cs-hydroxyalkyl radicals are hydroxymethyl or 2-hydroxyethyl.

Protected formyl means a formyl radical which is protected by conversion into an aminal, acetal or a mixed aminal acetal, the aminals,

Acetals and mixed amino acetals can be acyclic or cyclic.

5- to 8-membered heterocycle stands for heterocycles which, in addition to nitrogen, can also contain up to 3 further heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur.

Examples of such heterocycles are unsubstituted or substituted pyrrolidines, piperidines or morpholines.

Particularly preferred for step a) of the process according to the invention as substituted or unsubstituted 1-naphthols are those of the general formula (I) used in the

R, 2 for hydrogen and

R ³ for hydrogen and

n stands for zero, one or two and

R ⁴ each independently of one another for halogen, nitro, cyano, dC ₈ alkyl, C _\ -

C ₈ haloalkyl or substituents of the general formula (LU) are independent of one another

D is missing and

E represents a carbonyl group or sulfonyl group and F represents R ⁶ , OR ^δ , NH ₂ , NHR ⁶ or NR ⁶ R ⁷ and where

each independently represent substituted or unsubstituted C ₁ -C alkyl.

1-Naphthol is very particularly preferably used for step a).

In step a), the substituted or unsubstituted 1-naphthols are optionally added in the presence of a base with reactive alkyl compounds

1-naphthol ethers implemented.

Reactive alkyl compounds are, for example, those compounds of the general formula (purple) or (IIIb),

R ^] -Y (slide)

(R ¹ -O) ₂ SO ₂ (Illb)

in which, for example

R ^{1 represents} C ₃ -C ₁₂ alkyl, C ₂ -C ₈ haloalkyl, C ₇ -C ₁₃ arylalkyl or substituents of the general formula (IN),

A-B (IN)

in the

A for C ₂ -C ₈ alkylene, C ₂ -C ₈ haloalkylene and

B represents ΝR ⁶ R ⁷ , SR ⁶ or OR ⁶ in which

R and R each independently represent substituted or unsubstituted dC ₈ -alkyl, Ci-C ₈ -haloalkyl, C -C ₁₂ arylalkyl or C ₆ -do-aryl or

£ 7

NR R as a whole represents a 5- to 8-membered heterocycle and

Y represents chlorine, bromine, iodine, or a sulfonate.

Particular preference is given to using activated compounds of the general formula (purple) in which

R ^{1 represents} substituents of the general formula (IV) in which

A represents C ₂ -C ₄ alkylene or C ₂ -C ₄ haloalkylene and

B represents ΝR ⁶ R ⁷ or OR ⁶

in which

R and R each independently represent substituted or unsubstituted C ₁ -C ₄ alkyl or

NR ⁶ R ⁷ as a whole represents a 5- or 6-membered heterocycle and

Y represents chlorine, bromine, iodine, methanesulfonate, tosylate or trifluoromethanesulfonate. Such compounds of the general formula (purple) are very particularly preferably used as activated alkyl compounds in the

R represents substituents of the general formula (IV) in which

A stands for 1,2-ethylene and

B represents NR ⁶ R ⁷ or OR ⁶

in which

NR R as a whole represents pyrrolidinyl, piperidinyl or morpholinyl and

Y represents chlorine, bromine or trifluoromethanesulfonate.

Most preferred are N- (2-chloroethyl) morpholine, N- (2-bromoethyl) morpholine, N- (2-methanesulfonylethyl) morpholine, with N- (2-chloroethyl) morpholine being even more preferred ,

The compounds of the general formulas (IUa) and (IIIb), if they contain amine nitrogen, are preferably used in the form of their ammonium salts.

For example, N- (2-chloroethyl) morpholine can preferably be used in the form of the hydrochloride.

The compounds of the general formulas (purple) or (IIIb) can, for example, in a molar ratio of 0.8 to 2.0 based on the substituted one used or unsubstituted 1-naphthol, a ratio of 0.9 to 1.5 is preferred, a ratio of 1.0 to 1.4 is very particularly preferred.

The conversion of the substituted or unsubstituted 1-Naρhthole to the 1-Naphtholether can e.g. in the presence of base in a suitable solvent at a suitable temperature.

Suitable bases are, for example, hydroxides, alcoholates, hydrides, amides, carbonates or hydrogen carbonates of alkali metals or alkaline earth metals or amines.

The hydroxides or carbonates of the alkali metals are preferred, and sodium or potassium hydroxide or carbonate are particularly preferred. Sodium hydroxide is very particularly preferred.

Alkali metal hydroxides are preferably used in the form of an aqueous solution with a proportion of 30 to 70% by weight of base, and a solution of 30 to 70% by weight sodium hydroxide in water is particularly preferred.

The amount of base can be, for example, between 0.8 and 5.0 equivalents based on the substituted or unsubstituted 1-naphthol used, preferably 0.9 to 1.5 equivalents, very particularly preferably 0.9 to 1.2 equivalents.

If, for example, compounds of the general formulas (purple) or (IIIb) with amine nitrogen in the form of their ammonium salts are used, the amount of base must be increased correspondingly in molar.

Examples of suitable solvents for step a) of the process according to the invention are aliphatic or aromatic hydrocarbons such as toluene, xylene, or hexane, chlorinated hydrocarbons such as chlorobenzene or methylene chloride, ethers such as tetrahydrofuran or diethyl ether, alcohols such as for example methanol, ethanol or isopropanol, esters such as ethyl acetate or polar aprotic solvents such as dimethylformamide or dimethyl sulfoxide or mixtures of such solvents.

The reaction is preferably carried out in an alcohol.

Ethanol is very particularly preferred as solvent for step a).

The temperature for step a) can be chosen, for example, from 0 to 120 ° C., preferably from 20 to 80 ° C., particularly preferably from 40 to 80 ° C.

The pressure during the reaction is not critical, preferably at ambient pressure.

In a preferred embodiment of step a), for example, the substituted or unsubstituted 1-naphthol and as reactive alkyl compound, for example N- (2-chloroethyl) morpholine hydrochloride are introduced in ethanol and the sodium hydroxide at 40 to 60 ° C. as 30-70- % aqueous solution added.

According to the invention, 1-naphthol ethers of the general formula (V) are obtained, for example,

in the

R, R, R, R and n have the meanings given above with the preferred ranges mentioned. The acylamination of electron-rich aromatics such as. of 1-methoxy-naphthalene is known from T. Cablewski et al, 1 Org. Chem., 1994, 59, pp. 5814-5817, but the process described there is only slightly regio-selective.

According to the invention, step b), the conversion of the 1-naphthol ether into 4-acylamino-1-naphthol ether is carried out, for example,

that the 1-naphthol ethers are reacted with a hydroxylammonium salt and a carboxylic acid in the presence of polyphosphoric acid.

In the context of the invention, polyphosphoric acid is understood to mean, for example, those polyphosphoric acids which have a content of more than 100% based on orthophosphoric acid.

A content of 100% to 300% is preferred, particularly preferably 100% to 150%. Commercially available polyphosphoric acid with a content of 116% based on orthophosphoric acid is very particularly preferred.

The amount of polyphosphoric acid used can be, for example, 5 to 12 times, preferably 5 to 8 times, based on the molar ratio of the unsubstituted or substituted 1-naphthol ether used. The molar amount of polyphosphoric acid is given based on the content based on orthophosphoric acid.

Suitable hydroxylammonium salts can be, for example, hydroxylamine hydrochloride, hydrogen sulfate or dihydrogen phosphate.

Hydroxylamine hydrochloride is preferred.

Suitable carboxylic acids are, for example, those of the general formula (VI)

in the

R> 5 _Λ for _; r is dC ₆ alkyl or C ₁ -C ₄ haloalkyl or their analogs.

Acetic acid, trifluoroacetic acid, propionic acid and their anhydrides are preferred; acetic acid, propionic acid and trifluoroacetic acid are particularly preferred. Acetic acid is even more preferred.

The amount of the carboxylic acid of the general formula (VI) used can be, for example, 0.8 to 20 times based on the molar ratio to the unsubstituted or substituted 1-naphthol ether used, preferably 1.0 to 3.0 times, more preferably preferably 1.2 to 1.5 times.

The temperature during the reaction can be, for example, 50 to 130 ° C., 70 to 120 ° C. are preferred.

The total reaction time can be, for example, 1 to 48 hours, preferably 2 to 10 hours, particularly preferably 5 to 8 hours.

In a preferred embodiment of step b), carboxylic acid, hydroxylammonium salt and polyphosphoric acid are introduced, and the 1-naphthol ether at a temperature between 70 and 90 ° C. over a period of 0.5 to

8 hours, preferably 1 to 5 hours and particularly preferably 2 to 4 hours, and then heated to 100-120 ° C. for a period of 1 to 10 hours, preferably 1 to 4 hours. The work-up can preferably be carried out in such a way that the reaction mixture is brought together with ice and, if appropriate after addition of water, the pH is adjusted to a value of 9 to 10 with a base, preferably sodium hydroxide. The temperature is preferably kept below 40 ° C, particularly preferably at 25 ° C or less.

4-Acylamino-1-naphthol ether of the general formula (VIIa) is obtained in a manner according to the invention,

in the

R represents C -C ₁₂ alkyl, C ₂ -C ₈ haloalkyl, C -C ₁₃ arylalkyl or substituents of the general formula (IV),

A-B (IN)

in the

A for dd-alkylene, C ₂ -C ₈ haloalkylene and

B stands for ΝR ⁶ R ⁷ SR ⁶ or OR ⁶ .

in which fi 7

R and R each independently represent substituted or unsubstituted dC ₈ -alkyl, d-Cs-haloalkyl, C -Ci ₂ -arylalkyl or C ₆ -do-aryl or

as a whole represents a 5- to 8-membered heterocycle and

R ² for hydrogen, halogen or _. C ₁ -C alkyl and

R ^{3 represents} hydrogen, halogen, -CC ₄ alkyl or dC ₄ alkoxy and

n stands for zero, one, two, three or four

R ⁴ each independently of one another for halogen, nitro, cyano, protected formyl, dC ₈ alkyl, C ₇ -C ₁₀ arylalkyl, C 1 -C ₈ -hydroxyalkyl, C 1 -C ₈ haloalkyl or C ₆ -do-aryl or substituents of the general formula (II),

D-E-F (II)

in the independently of each other

D is absent or represents a dC ₈ alkylene radical and

E represents a carbonyl group or sulfonyl group and

represents R ⁶ , OR ⁶ , NH ₂ , SR ⁶ , NHR ⁶ or NR ⁶ R ⁷ ,

and where

R ⁶ and R ⁷ each independently of one another are substituted or unsubstituted Ci-Cg-alkyl, d-Cs-haloalkyl, C ₇ -C ₁₂ - arylalkyl or C ₆ -

C ₁₀ aryl or NR R as a whole represents a 5- to 8-membered heterocycle and

R ^{s is} dC ₆ alkyl or C ₁ -C ₄ haloalkyl.

The compounds of the general formula (VIIa) are also the subject of the invention.

Examples of individual compounds are 4- (2- [l] -naphthyloxy- [4] -acetamino-ethyl) -morpholine, 4- (2- [l] -naphthyloxy- [4] -propionylamino-ethyl) -mo holin and 4

(2- [l] -naphthyloxy- [4] -trifluoroacetamino-ethyl) -moφholin called.

The compounds of the general formula (VIIa) can either be stored or reacted further.

Further implementation is preferred. If the compounds of the general formula (VIIIa) are to be stored and R ¹ also contains amine nitrogen, the compounds can also be converted into their analogous ammonium compounds.

For example, 4- (2- [l] -naphthyloxy- [4] -acetamino-ethyl) -morpholine, 4-

Convert (2- [1] -naphthyloxy- [4] -propionylamino-ethyl) -morpholine and 4- (2- [1] -naphthyl-oxy- [4] -trifluoroacetamino-ethyl) -morpholine into the corresponding morpholinium salts by optionally reacting the compounds in a solvent with an equivalent of an acid H-An.

Accordingly, the compounds of the general formula (VIIIb)

detected,

in which

R> 5 for a dC ₆ alkyl or -CC ₄ haloalkyl

and to ^"

stands for the anion of an acid.

Preferred acids H-An are mineral acids such as e.g. Sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, tetrafluoroboric acid, hydrogen halides such as e.g. Hydrogen chloride, hydrogen bromide, carboxylic acids such as those of the general

Formula (VI), where R ^{5 has} the broadest meaning mentioned there, or sulfonic acids such as methanesulfonic acid. The anions An are derived accordingly from the acids H-An.

According to step c), the 4-acylamino-1-naphthol ethers can be converted into the corresponding 4-

Amino-1-naphthol ether are transferred. This step can be carried out analogously to the literature (e.g. to B. Bachman, J. Wetzel, J. Org. Chem., 11, 1946, pp. 454-462), for example by acidic or alkaline acyl group elimination, saponification with an acid is preferred , where the 4-amino-1-naphthol ether in the form of their ammonium salts attack. When using radicals R ¹ which contain amine nitrogen, the 4-amino-1-naphthol ethers are obtained in the form of the diammonium salts.

Examples of suitable acids are those which have a pKa of 2 or less. For example, these are hydrogen halides such as hydrogen chloride, hydrogen bromide or hydrogen iodide, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or organic sulfonic acids such as methanesulfonic acid or mixtures of such acids.

Hydrochloric acid and sulfuric acid are preferred, and concentrated hydrochloric acid is very particularly preferred.

After step c), 4-amino-1-naphthol ethers of the general formula (Villa) or their ammonium salts of the general formula (VHIb)

(VIIIb)

in which

R ¹ , R ² , R ³ , R ⁴ and n have the meaning given under formula (VIIa)

own and

X stands for an anion of an acid. If the radical R ^{1 has} amine nitrogen, the formula (VIIIb) also includes its ammonium salts.

4- (2- [l] -naphthyloxy- [4] -amino-ethyl) -mo-pholine-di-hydrochloride may be mentioned as a single compound.

The compounds of the general formulas (Vlla), (VHb), (Villa) and (Vlllb) are particularly suitable for use in a process for the preparation of medicaments.

The process according to the invention is characterized in particular by the fact that it uses the inexpensive 1-naphthols as starting substances and leads selectively to the desired 4-amino-1-naphthol ethers or their ammonium salts in high yields in a few steps.

Examples

example 1

Preparation of 4- (2- [l] -naphthyloxy-ethyl) morpholine

441 g of 1-naphthol and 648 g of N- (2-chloroethyl) morpholine hydrochloride are placed in 2680 ml of ethanol at 50 ° C. For this purpose, 554 g of 50% sodium hydroxide solution are added dropwise within 3 h. The mixture is then stirred at 50 ° C for 3 h and then at reflux for 1 h.

The salt formed is filtered off and washed with ethanol. The combined filtrates are evaporated to dryness on a rotary evaporator in the bath and 10 mbar at 80 ° C. The cooled residue is dissolved in 1200 ml of diethyl ether and first with 180 ml of water, then twice with 450 ml of 5% sodium hydroxide solution and finally twice The Etheiphase is dried with sodium sulfate and concentrated to dryness at 60 ° C and 10 mbar.

Yield: 741g 4- (2- [l] -naphthyloxy-ethyl) -morpholine with a purity of 97.7% (GC). This corresponds to 93.8% of theory based on 1-naphthol.

Example 2

Preparation of 4- (2- [l] -naphthyloxy- [4] -acetamido-ethyl) -morpholine

376 g of glacial acetic acid and 224 g of hydroxylammonium chloride in 2090 g of polyphosphoric acid are placed in a stirred flask at 80.degree. 830 g of 4- (2- [l] -naphthyloxy-ethyl) -morpholine are metered in with good stirring within 3 h. The temperature should not rise above 90 ° C during dosing. The mixture is subsequently stirred at 80-90 ° C. for 1 hour and then at 115 ° C. for a further 3 hours. The reaction mixture is allowed to cool to 80 ° C. and stirred with 1800 g of ice. The temperature is allowed to drop to 30 - 35 ° C. After adding 9.75 l of water, it is precipitated with 50% sodium hydroxide solution (2005 g) to a pH of 4-5. The temperature should not exceed 25 ° C during the precipitation. The mixture is stirred for 30 min and then filtered off. The filter cake comes with little

Washed water.

The filter cake is suspended in 10 liters of water and dissolved with heating to 90 ° C. The solution is clarified with activated carbon. 530 g of 50% sodium hydroxide solution are added with stirring in 1 h until a pH of 10 is reached. The

Crystal suspension is filtered off at 50 ° C and the filter cake washed neutral with plenty of water. The filter cake is then dried in a vacuum drying cabinet.

Weight: 846 g of 4- (2- [l] -naphthyloxy- [4] -acetamido-ethyl) -morpholine

with a purity of 99.3% (HPLC). This corresponds to 85.1% of theory calculated on 4- (2- [1] -naphthyloxy-ethyl) -morpholine

Elemental analysis:

Theor. Values: C = 68.77% H = 7.05% N = 8.91%

Found values: C = 68.65% H = 6.9% N = 8.8%

Example 3

4- (2- [l] -Naphthyloxy- [4] amino-ethyl) -morpholine dihydrochloride

846 g of 4- [2- [l] -naphthyloxy- [4] -acetamido-ethyl] -morpholine are mixed with 1340 ml

Suspended water and stirred with 2470 g of 37% hydrochloric acid. Then saponified at 95 ° C for 5 h. At the end of the reaction time, 1600 g of isopropanol are added and the suspension is cooled with stirring. The crystals are filtered off and washed with 4530 g of isopropanol until the filtrate is largely colorless. The product is then recrystallized from ethanol and dried in a vacuum drying cabinet.

Yield: 839 g of 4- (2- [l] -naphthyloxy- [4] amino-ethyl) -morpholine dihydrochloride.

Example 4

Preparation of the free 4- (2- [l] -naphthyloxy- [4] amino-ethyl) -morpholine

839 g of the dihydrochloride from Example 3 are dissolved in 5600 ml of water. In a beaker, 450 ml of water with 50% sodium hydroxide solution are brought to a pH

Value of 12 set. After the generation of seed crystals in the sodium hydroxide solution introduced, the remaining solution is simultaneously added dropwise with 50% sodium hydroxide solution in such a way that a pH of 10-12 is maintained. 390 g of 50% sodium hydroxide solution are consumed. The crystals are filtered off and washed with 3300 ml of water until the filtrate has a pH of 8. The filter cake is then dried in a vacuum drying cabinet. The yield of free amine is almost quantitative (620 g), with a purity of 99.4% (HPLC).

Claims

claims

Process for the preparation of 4-amino-1-naphthol ethers, characterized in that

a) substituted or unsubstituted 1-naphthols are reacted with reactive alkyl compounds to give 1-naphthol ethers,

b) the 1-naphthol ethers are then converted with hydroxylammonium salts and carboxylic acids into the corresponding 4-acylamino-1-naphthol ethers and

c) the 4-acylamino-1-naphthol ethers are converted into the free 4-amino-1-naphthol ethers or analogous ammonium salts by cleavage of acid or basic acyl groups.

A method according to claim 1, characterized in that substituted or unsubstituted 1-naphthols of the general formula (I) are used in step a),

in the

R> 2 represents hydrogen, halogen or dC ₄ alkyl and

R represents hydrogen, halogen, C ₁ -C -alkyl or dC -alkoxy and n stands for zero, one, two, three or four

R ⁴ each independently of one another for halogen, nitro, cyano, protected formyl, dC ₈ alkyl, C ₇ -C ₁₀ arylalkyl, dC ₈ hydroxyalkyl, dC ₈ haloalkyl or C ₆ -C ₁₀ aryl or substituents of general formula (II),

D-E-F (II)

in the independently of each other

D is absent or represents a d-Cs-alkylene radical and

E represents a carbonyl group or sulfonyl group and

represents R ⁶ , OR ⁶ , NH ₂ , SR ⁶ , NHR ⁶ or NR ⁶ R ⁷ ,

and where

each independently represent substituted or unsubstituted dC ₈ alkyl, dC ₈ haloalkyl, C -C ₁₂ arylalkyl or C ₆ -C ₁₀ aryl or

NR ⁶ R ⁷ as a whole represents a 5- to 8-membered heterocycle.

Method according to one or more of claims 1 to 2, characterized in that substituted or unsubstituted 1-naphthols of the general formula (I) are used in step a),

in the R ² for hydrogen and

R for hydrogen and

n stands for zero, one or two and

R ⁴ each independently of one another represent halogen, nitro, cyano, dC ₈ -alkyl, dC ₈ -haloalkyl or substituents of the general formula (II),

in the independently of each other

D is missing and

E represents a carbonyl group or sulfonyl group and

F represents R ⁶ , OR ⁶ , NH ₂ , NHR ⁶ or NR ⁶ R ⁷ and where

each independently represent substituted or unsubstituted d-Gr alkyl.

4. The method according to one or more of claims 1 to 3, characterized in that 1-naphthol is used in step a).

5. The method according to one or more of claims 1 to 4, characterized in that in step a) the substituted or unsubstituted 1-naphthols are reacted with reactive alkyl compounds of the general formula (purple) or (Illb),

R ^! -Y (purple)

in which

R ^{1 is} C ₃ -C ₁₂ alkyl, C ₂ -C ₈ haloalkyl, C ₇ -C ₁₃ arylalkyl or

Is substituent of the general formula (IV),

A-B (IV)

in the

A for C ₂ -C ₈ alkylene, C ₂ -C ₈ haloalkylene and

B represents NR ⁶ R ⁷ SR ⁶ or OR ⁶

in which

independently represent substituted or unsubstituted dC ₈ alkyl, dC ₈ haloalkyl, C ₇ -C ₁₂ arylalkyl or C ₆ -C ₁₀ aryl or

NR ⁶ R ⁷ as a whole represents a 5- to 8-membered heterocycle and

Y represents chlorine, bromine, iodine, or a sulfonate.

6. The method according to one or more of claims 1 to 5, characterized in that in step a) the substituted or unsubstituted 1-naphthols are reacted with reactive alkyl compounds of the general formula (purple),

in which R ^{1 represents} substituents of the general formula (TV) in which

A represents C ₂ -C ₄ alkylene or C ₂ -C ₄ haloalkylene and

B represents NR ⁶ R ⁷ or OR ⁶ and

in which

R ⁶ and R ⁷ each independently represent substituted or unsubstituted C ₁ -C alkyl or

NR ⁶ R ⁷ as a whole represents a 5- or 6-membered heterocycle

and

Y represents chlorine, bromine, iodine, methanesulfonate, tosylate or trifluoromethanesulfonate.

7. The method according to one or more of claims 1 to 6, characterized in that 2-N-morpholinyl ethyl chloride, bromide or methanesulfonate, or their ammonium salts are used as reactive alkyl compounds in step a).

8. The method according to one or more of claims 1 to 7, characterized in that in step a) N- (2-chloroethyl) - morpholine hydrochloride is used as the reactive alkyl compound.

9. The method according to one or more of claims 1 to 8, characterized in that step a) is carried out in the presence of a base.

10. The method according to one or more of claims 1 to 9, characterized in that step a) in the presence of an aqueous solution of sodium hydroxide with a content of 30 to 70 wt .-%.

11. The method according to one or melxreren of claims 1 to 10, characterized in that step a) is performed diirch in ethanol.

12. The method according to one or more of claims 1 to 11, characterized in that step a) is carried out at a temperature of 0 to 120 ° C.

13. The method according to one or more of claims 1 to 12, characterized in that step b) is carried out in the presence of polyphosphoric acid.

14. The method according to one or more of claims 1 to 13, characterized in that the molar ratio of polyphosphoric acid to 1-naphthol ether is 5.0 to 12.0.

15. The method according to one or more of claims 1 to 14, characterized in that hydroxylamine hydrochloride is used as the hydroxylammonium salt.

16. The method according to one or more of claims 1 to 15, characterized in that acetic acid, propionic acid or trifluoroacetic acid is used as the carboxylic acid.

17. The method according to one or more of claims 1 to 16, characterized in that in step b) the temperature is 50 to 130 ° C.

18. The method according to one or more of claims 1 to 17, characterized in that in step c) the 4-acylamino-1-naphthol ethers are converted into the ammonium salts of 4-amino-1-naphthol ethers by acid hydrolysis.

19. The method according to one or more of claims 1 to 18, characterized in that in step c) the acidic saponification is carried out in the presence of acids with a pKa value of 2 or below.

20. The method according to one or more of claims 1 to 19, characterized in that the acidic hydrolysis is carried out in the presence of concentrated hydrochloric acid.

21. 4- acylamino-1-naphthol ether of the general formula (VIIa),

in the

R ^{1 represents} C ₃ -C ₁₂ alkyl, C ₂ -C ₈ haloalkyl, C ₇ -C ₁₃ arylalkyl or substituents of the general formula (TV),

A-B (IV)

in the A for C ₂ -C ₈ alkylene, C ₂ -C ₈ haloalkylene and

B stands for NR ⁶ R ⁷ SR ° or OR °

in which

R and R ⁷ each independently represent substituted or unsubstituted dC ₈ alkyl, dC ₈ haloalkyl, C ₇ -C ₁₂ arylalkyl or C ₆ -C ₁₀ aryl or

NR R as a whole represents a 5- to 8-membered heterocycle

and

R ^{2 represents} hydrogen, halogen or dC ₄ alkyl and

R ^{3 represents} hydrogen, halogen, dC ₄ alkyl or C ₁ -C ₄ alkoxy and

n stands for zero, one, two, three or four

R ⁴ each independently of one another for halogen, nitro, cyano, protected formyl, dC ₈ alkyl, C ₇ -C ₁₀ arylalkyl, dC ₈ hydroxyalkyl, d C ₈ haloalkyl or C ₆ -C ₁₀ aryl or substituents of general formula (II)

D-E-F (II)

in the independently of each other

D is absent or represents a -C ₈ alkylene radical and represents a carbonyl group or sulfonyl group and

stands for R> 6 °, r OvRo ö °, NH ₂ , SR °, NHR ° or NR 6 ° Rτ, 7 '

and where

R and R each independently represent substituted or unsubstituted dC ₈ alkyl, dC ₈ haloalkyl, C ₇ -C ₁₂ arylalkyl or C ₆ -C ₁₀ aryl or.

NR ι 6 Rr> 7 as a whole represents a 5- to 8-membered heterocycle and

R ^{5 represents} dC ₆ alkyl or C ₁ -C ₄ haloalkyl.

22. 4- (2- [l] -naphthyloxy- [4] -acetamino-ethyl) -morpholine,

4- (2- [l] -naphthyloxy- [4] -propionylamino-ethyl) -morpholine and 4- (2- [l] -naphthyloxy- [4] -trifluoroacetamino-ethyl) -morpholine.

23. Compounds of the general formula (VITb)

in the R represents a dC ₆ alkyl or dC ₄ haloalkyl radical

and on

stands for the anion of an acid.

24. Use of compounds of the formula (VIII) and (VIIIb), in which R ¹ , R ² , R, R ⁴ , R and n have the meaning given in claim 21 in a process for the preparation of medicaments or compounds of the general formulas (Villa) or (Vlllb).

25. Use of compounds of the general formulas (Villa) and (Vlllb),

(VIIIb)

in which

R ¹ , R ² , R ³ , R ⁴ and n have the meaning given under formula (VII) in claim 22 and X represents the anion of an acid

and

which were produced according to one or more of claims 1 to 20 in a process for the production of medicaments.