NO165959B - ANALOGY PROCEDURE FOR THE PREPARATION OF 3,5-DISUBSTITUTED PYROCATIC COLD DERIVATIVES. - Google Patents

Description

The present invention relates to an analog method

in the preparation of therapeutically active compounds of the general formula

where Ra means nitro or cyano, Rb hydrogen or halogen,

Rc' nitro, cyano or the group -(A)n-(Q)^-R<11> or

-(A)n-Q-R<21>, A optionally with lower alkyl-substituted vinylene, n the number 0 or 1, m the number 0 or 1, R<11>

the group -COR<31>, a carbocyclic, aromatic group or an aromatic or partially unsaturated heterocyclic group bound through a carbon atom, R<21> an optionally substituted,

saturated or partially unsaturated lower hydrocarbon residue, R<31>

hydroxy, amino, one through an oxygen atom or an imino-

or lower alkylimino group attached optionally substituted,

saturated or partially unsaturated lower hydrocarbon residue, or a saturated N-containing heterocyclic group bonded through a ring nitrogen atom, the Q group -CO or >C=N-(Z)p-R<4>, Z

an oxygen atom or an imino group, p number 0 or 1,

and R<4> hydrogen or an optionally substituted and optionally bound through a carbonyl group, saturated or partially unsaturated, lower hydrocarbon residue, where Ra means cyano,

when Rc' means cyano or nitro, and R<31> has a different

meaning from hydroxy when m means the number 0,

and wherein the optionally substituted hydrocarbon residues are unsubstituted or substituted with lower alkoxycarbonyl,

halogen, amino, lower alkylamino, di(lower alkyl)-amino,

phenyl, hydroxyphenylcarbonyl or trifluoromethylphenylamino-

carbonyl, and the carbocyclic aromatic group means an optionally halogenated, trifluoromethyl, lower alkyl, hydroxy or cyano mono- or disubstituted phenyl or natyl group,

and the aromatic or partially unsaturated heterocyclic group

an optionally with halogen, trifluoromethyl, nitro, carboxy,

amino, anilino, lower alkyl, lower alkoxy, hydroxy, oxo, mercapto, 1-adamantylamino, 2-exo-bornylamino, cyano, phenyl, phenyl-lower alkyl, phenyl-lower alkylamino, pyridyl, pyridylamino, quinolinylamino or with trifluoromethylphenylaminocarbonyl-lower alkylamino mono-, di- or trisubstituted pyridyl-, pyrazinyl-, triazinyl-, thiadiazinyl-, thiazolyl-, oxazolyl-, oxadiazolyl-, pyrazolyl-, tetrazolyl-, imidazolyl-, thienyl-, quinolinyl-, isoquinolinyl-, dihydroisoquinolinyl-, benzoxazinyl, quinoxazinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazothiadiazolyl, imidazopyridyl, benzothiazinyl, benzoquinoxalinyl or imidazobenzothiazolyl group,

of ester and ether derivatives hydrolyzable under physiological conditions and of pharmaceutically acceptable salts thereof.

These compounds specifically inhibit the enzyme catechol-O-methyl-transferase (COMT), a soluble, magnesium-dependent enzyme, which catalyzes the transfer of the methyl group from S-adenosylmethionine to a catechol substrate, during which the corresponding methyl ether is formed. Suitable substrates that are O-methylated with COMT and thus deactivated are e.g. extraneuronal catecholamines and exogenously administered therapeutic agents with a catechol structure.

The above-mentioned compounds of formula Ib can consequently be used in the prevention or combating of diseases in which the deactivation of extraneuronal catecholamines by COMT plays a role, e.g. when preventing or combating depression. In this case, the compounds of the above-mentioned formula Ib can be used as single compounds or in combination with other therapeutic agents that favorably influence the course of the disease. However, the compounds of formula Ib can also be used as comedication to other therapeutic agents.

However, the compounds of formula Ib can also be used for the prevention or combating of diseases with therapeutic active substances that have a catechol structure. An example is the treatment of Parkinson's disease and Parkinsonism with L-dopa, a therapeutic agent with a catechol structure. In such cases, the compounds of formula Ib can be used in the form of a comedication or as combination preparations.

A further possibility for the use of the above-mentioned compounds of formula Ib lies in the area of diagnostics. After administration of [<18>F]-6-fluoro-L-dopa, [18F]-dopamine can be made visible in the brain using positron emission tomography. By adding a compound of the above formula Ib, COMT is inhibited and thus the formation of [<18>F]-3-0-methyldopa is prevented. Without a COMT inhibitor, the formed [<18>F]-3-0-methyldopa would penetrate the brain and lead to a strongly increased background, which would greatly complicate diagnostics.

The term "lower" denotes residues and compounds with a maximum of 7, preferably a maximum of 4 carbon atoms. The term "alkyl" taken alone or in combinations such as "alkyl groups", "alkoxy", "alkylthio" and "alkylimino" denotes straight chain or branched saturated hydrocarbon radicals, such as methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, i -butyl and t-butyl. The term "saturated or partially unsaturated, lower hydrocarbon residue" means open-chain and cyclic groups and combinations thereof. Examples of saturated and partially unsaturated lower hydrocarbon residues are: Lower alkyl groups as defined above; lower alkenyl groups such as 2-propenyl, 2-butenyl, 3-butenyl and 2-methyl-2-propenyl; optionally with lower alkyl groups substituted C3-7-cycloalkyl and C8-10-bicycloalkyl groups, such as cyclopropyl, cyclopentyl, 2-methylcyclopentyl, cyclohexyl and 3-methylcyclohexyl; optionally with lower alkyl groups substituted lower cycloalkenyl groups, such as 3-cyclopentenyl, 1-methyl-3-cyclopentenyl and 3-cyclohexenyl; with lower cycloalkyl or cycloalkenyl groups substituted lower alkyl or alkenyl groups, such as cyclopropylmethyl, cyclopropylethyl, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl and 3-cyclopropyl-2-propenyl. The lower alkenyl groups preferably contain 2-4 carbon atoms; the cycloalkyl and cycloalkenyl groups preferably contain 3-6 carbon atoms.

Substituents for the above-mentioned lower hydrocarbon residues include the following: hydroxy, cyano, nitro, halogen, amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, lower alkoxycarbonyl, aryl, arylaminocarbonyl, arylcarbonyl, arylcarbonylamino, lower alkanoyloxy, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylamino, lower alkoxycarbonylamino and lower alkylthio. The saturated or partially unsaturated lower hydrocarbon residues are preferably unsubstituted or mono- or disubstituted.

The term "aryl" means carbocyclic aromatic groups and preferably mono- or bicyclic groups. Particularly preferred carbocyclic aromatic groups are the phenyl and naphthyl groups, especially the phenyl groups. These groups are optionally substituted with: halogen, trifluoromethyl, nitro, amino, mono- or di(lower alkyl)amino, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, lower alkanoyloxy, carbamoyl , mono- or di(lower alkyl)carbamoyl, lower alkylenedioxy, lower alkanoylamino or lower alkoxycarbonylamino. The carbocyclic aromatic groups are preferably unsubstituted or mono- or disubstituted.

The term "aromatic or partially unsaturated, heterocyclic group" preferably denotes a mono-, di- or tricyclic, aromatic or partially unsaturated, heterocyclic group with up to 5 heteroatoms from the group consisting of nitrogen, sulfur and oxygen. These heterocyclic groups preferably contain 1-4 nitrogen atoms and/or an oxygen or sulfur atom. They are preferably mono- or bicyclic. The heteroatoms are preferably distributed over one or two rings, under which the nitrogen atoms can also be part of two rings at the same time. The heterocyclic groups are preferably aromatic. They can be substituted, whereby in these cases they are preferably mono-, di- or tri-substituted. Examples of substituents include: Halogen, trifluoromethyl, nitro, carboxy, amino, arylamino, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkylenedioxy, mercapto, lower alkylthio, lower alkylamino, di( lower alkyl)-amino, <C>3_7-cycloalkylamino, C8_10-bicycloalkylamino, lower alkanoylamino, lower alkoxycarbonylamino, carbamoyl, mono-or di(lower alkyl)carbamoyl, cyano, aryl, arvl-lower alkyl, aryl-lower alkylamino, heteroaryl , heteroaryl-lower alkyl, heteroarylamino and C3-7-cycloalkyl. The monocyclic heterocyclic groups are preferably 5- or 6-membered and contain a maximum of four heteroatoms. The bicyclic heterocyclic groups are preferably 8- to 10-membered, under which the individual rings are preferably 5- or 6-membered.

Examples of such heterocyclic groups include the following: pyridyl, pyrazinyl, triazinyl, thiadiazinyl, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazothiadiazolyl, imidazopyridyl, benzothiazinyl, benzoquinoxalinyl and imidazobenzothiazolyl.

The term "heteroaryl" means aromatic heterocyclic groups as defined above.

The expression "a saturated, N-containing heterocyclic group bound through a ring nitrogen atom" preferably denotes a 3- to 7-membered, preferably 4- to 6-membered, saturated N-heterocycle, which next to the mentioned nitrogen atom can also contain a oxygen, sulfur or nitrogen atom as second heteroatom. These saturated N-heterocycles may also be mono- or disubstituted; lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, mono- or di(lower alkyl)carbamoyl, oxo and/or lower alkylenedioxy.

The following are mentioned as examples of such N-containing heterocyclic groups: 4-morpholinyl, 1-pyrrolidinyl and 1-azetidinyl.

If they are hydrolyzable under physiological conditions

ester and ether derivatives are preferably compounds of formula Ib, in which at least one of the two phenolic hydroxy groups is acylated with a lower fatty acid or is etherified with a lower 1-Alkoxycarbonyloxy-1-alkyl-, lower 1-Alkanoyloxy-1- alkyl or with a lower 2-oxo-1-alkyl group.

The substituent Ra preferably means nitro. The substituent Rb is preferably in the p-position to the substituent Ra and preferably means hydrogen, chlorine or fluorine, under which the possibility of meaning hydrogen is particularly preferred. The substituent Rc' preferably means the group -CO-R<11>, where R<11> means an aromatic, mononuclear carbocyclic group or an aromatic, mononuclear heterocyclic group bound through a carbon atom with 1-3 nitrogen atoms as heterogeneous ring elements. In a particularly preferred embodiment, R<11> means a phenyl group optionally substituted with halogen, trifluoromethyl, cyano, hydroxy or lower alkyl or a pyridyl group.

Within the scope of the present invention, particularly preferred compounds are: 3,4-dihydroxy-5-nitrobenzophenone,

2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone and 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone.

The compounds of formula Ib, the hydrolyzable ester and ether derivatives under physiological conditions and the pharmaceutically acceptable salts thereof, can be prepared according to the invention by

a) in connection with the general formula

wherein one of the symbols R and R' means lower alkyl and that

others are hydrogen or lower alkyl, and Ra, Rb and Rc' have

above meaning,

cleaves the lower alkyl ether group(s), or

b) reacts a compound with the general formula

wherein X means a leaving group, and Ra, Rb, A and n have

above meaning,

with a thioamide, thiourea, thiocarbonic hydrazide, thiosemicarbazide, amidine, guanidine, amidrazone, aminoguanidine, cyclic amidine, 1,2-diamine, 1,2-aminothiol or a 1,2-amino alcohol, and if desired dehydrogenates the resulting cyclocondensation product, or

c) reacts a compound with the general formula

wherein R" means lower alkyl, and Ra, Rb, A and n have the above meaning, with a 1,2-diamine, 1,2-aminothiol, 1,2-aminoalcohol, semicarbazide, thiosemicarbazide, amidrazone or an aminoguanidine, and if dehydrogenates the resulting cyclocondensation product as desired, or d) reacts a compound of the above-mentioned formula Ib<1> with an ε-aminocarbonyl compound, or

e) in connection with the general formula

wherein Rc'" means nitro, cyano or the group -(A)n-R<12> and R<12 >the group -COR<31> a carbocyclic aromatic group or an aromatic or partially unsaturated heterocyclic group bonded through a carbon atom, and Ra, Rb, A, n and R<31> have

above meaning,

or in a di-O-lower alkanoyl derivative thereof transfers the carboxaldehyde group(s) into the cyano group(s), or

f) reacts a di-O-lower alkanoyl derivative of a carboxylic acid of the general formula

wherein Ra, Rb, A and n have the above meaning in the presence of a condensing agent or a reactive derivative of a di-O-lower alkanoyl derivative of a carboxylic acid of formula Ib<3> or Ib<3> with a compound of the general formula

in which R<5> means an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue, R<6> hydrogen or lower alkyl and R<7> hydrogen or an optionally substituted, saturated

or partially unsaturated, lower hydrocarbon residue or R<6> and R<7> together with the nitrogen atom mean a saturated N-containing heterocyclic group,

or

1 g) hydrolyzes a compound of the above formula Ib<2>

or the general formula

in which R<8> means lower alkanoyl and Ra, Rb and Rc' have the above meaning,

or

h) reacts a compound with the general formula

wherein Ra and Rb have the above meaning and R"' means

hydrogen or lower alkyl,

or a di-O-lower alkanoyl derivative thereof in the presence of a secondary amine with a compound of the general formula

in which R<23> means an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue,

or

i) reacts a compound with the general formula

in which Ra, Rb, A, n and R" have the above meaning, with a hydrazine or with an amidine, or

j) reacts a compound with the above-mentioned formula Ib, in which m means the number 1 and Q the group -CO-,

with a compound of the general formula

wherein Z, p and R<4> have the above meaning,

and, if desired,

k) transfers a compound of the above-mentioned formula Ib in an ester or ether derivative hydrolyzable under physiological conditions, or in a pharmaceutically acceptable salt thereof.

According to method variant a), the compounds of formula Ib can be prepared by cleaving the ether group(s) in a compound of formula II. This ether splitting can be carried out according to methods known per se and common to any person skilled in the art. The ether cleavage can e.g. obtained by treatment with hydrogen bromide in a suitable solvent. Suitable solvents are e.g. water, acetic acid and mixtures thereof. One preferably works at a higher temperature, e.g. in a temperature range from approx. 100°C to the boiling temperature of the reaction mixture. Preferably, 48% hydrogen bromide or mixtures thereof with acetic acid are used.

The ether cleavage can also be carried out by treatment with boron tribromide in a suitable solvent at temperatures from approx. -60°C to approx. room temperature. Suitable solvents are particularly halogenated lower hydrocarbons such as methylene chloride, chloroform etc. Other suitable methods are: Treatment with pyridinium hydrochloride at temperatures from approx. 150°C to approx. 250°C and treatment with sodium iodide/silicon tetrachloride in an inert organic solvent at a higher temperature, e.g. at the reflux temperature of the reaction mixture. Suitable solvents for the last method are e.g. acetonitrile, aromatic hydrocarbons such as benzene or toluene, mixtures thereof etc.

According to method variant b), compounds with the general formula can

is produced, where Ra, Rb, A and n have the above meaning, and Q<1> is a group with the formulas

Re is hydrogen, lower alkyl, C3_7-cycloalkyl, aryl, heteroaryl, aryl-lower alkyl or heteroaryl-lower alkyl, Rf hydrogen, aryl, aryl-lower alkyl, lower alkyl, lower alkoxycarbonyl, heteroaryl, heteroaryl-lower alkyl, C8_ 10 -bicycloalkyl or <C>3_7-cycloalkyl, Rg and Rh each hydrogen, cyano, lower alkyl, C3_7-cycloalkyl, aryl, aryl-lower alkyl, heteroaryl or heteroaryl-lower alkyl, or Rg and Rh together with the two hydrogen atoms form they are attached to a carboxycyclic aromatic group or an aromatic or partially unsaturated heterocyclic group, the dotted line has a facultative bond and Q<4> together with the carbon and nitrogen atom means an aromatic or partially unsaturated heterocyclic group, containing at least one nitrogen atom which heteroring element.

Suitable solvents for this process aspect are lower alcohols, such as ethanol, n-butanol, n-hexanol and ethylene glycol, open-chain and cyclic ethers which may also contain free hydroxy groups, such as tetrahydrofuran, dioxane, t-butyl methyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, acetonitrile, dimethylformamide, dimethylacetamide and dimethylsulfox-syd. The desired reaction can also be carried out without solvent by dry heating the reaction partners. The reaction is preferably carried out at a higher temperature, e.g. in an area from approx. 50°C to 150°C, below which one preferably works at the solvent's boiling temperature, provided one works in the presence of a solvent and the boiling point is in the aforementioned range.

According to method variant c), compounds with the general formula can

is prepared, wherein Ra, Rb, A and n have the above meaning and Q<2> means a group of formula

under which Re, Rf, Rg, Rh and the dotted line have the above meaning.

The reaction according to process variant c) can be carried out under the same reaction conditions as process variant b).

According to method variant d), compounds with the general formula can

is prepared in which Q<3> means the group of formula

and Ra, Rb, Re, Rf, Rg, Rh, A, n and the dotted line have the above meaning.

Process variant d) can also be carried out under the same reaction conditions as process variant b).

According to method variant e) compounds of formula Ib can be prepared, in which Ra means cyano, Rc' nitro, cyano or the group -(A)n-R<12> and R<12> the group -COR<31> a carbocyclic, aromatic group, or a through a carbon atom bonded, aromatic or partially unsaturated, heterocyclic group, and Rb, A, n and R<31 >have the above meaning. The transfer of the carboxaldehyde group(s) into the cyano group(s) can take place according to methods known per se and common to any person skilled in the art. One can e.g. treat a compound of formula Ib<2>, III or IV with hydroxylamine-O-sulfonic acid at a higher temperature, preferably using water as solvent. The reaction can be carried out in a temperature range from approx. 50°C to approx. 100°C.

According to process variant f) di-O-lower alkanoyl derivatives of compounds of formula Ib can be prepared, in which Rc' means the group -(A)n-(CO)m-COR<32> and R3<2>amino, either through an oxygen atom or an imino or lower alkylimino group attached, optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue, or a saturated, N-containing heterocyclic group attached through a ring nitrogen atom, and A, n and m have the above meaning. This reaction can also be carried out according to methods known per se and common to any person skilled in the art. Lower alkyl esters can e.g. is produced by treating the carboxylic acid in the presence of an acid with the corresponding lower alcohol, during which one as solvent preferably uses the corresponding lower alcohol. Suitable acids are e.g. mineral acids such as hydrogen chloride and organic sulphonic acids such as p-toluenesulphonic acid. The reaction temperature is preferably in a range from room temperature up to the boiling temperature of the chosen solvent.

The other esters and amides are preferably prepared from reactive carboxylic acid derivatives. Suitable reactive carboxylic acid derivatives are e.g. the corresponding carboxylic acid halides, in particular the carboxylic acid chlorides, corresponding carboxylic acid anhydrides and mixed anhydrides (e.g. with trifluoroacetic acid and organic sulphonic acids, such as mesitylenesulphonic acid and p-toluenesulphonic acid), corresponding carboxylic acid imidazolides etc. One works expediently in the presence of an acid binding agent and an inert organic solvent. Suitable acid binding agents are e.g. tertiary amines such as triethylamine and pyridine. In the production of amides, excess amine from formula VI can also be used as an acid-binding agent. Suitable solvents are e.g. open chain and cyclic ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol, dimethyl ether etc., halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, acetonitrile and dimethylformamide.

The hydrolyses of compounds of formula Ib<4> to the corresponding catechol derivatives according to method variant g) can also be carried out according to methods known per se and common to any person skilled in the art. The hydrolysis can e.g. is carried out by treatment with an alkali metal hydroxide such as sodium or potassium hydroxide in a suitable solvent. Suitable solvents are e.g. lower alcohols such as methanol and water or mixtures thereof. The hydrolysis can e.g. performed in a temperature range from approx. 0°C to the solvent's boiling temperature, below which, however, one preferably works at room temperature.

According to process variant h), compounds with the general formula can

wherein Ra, Rb, R<1>" and R<23> have the above meaning,

and the corresponding di-O-lower alkanoyl derivatives thereof are prepared. Cyclic amines such as pyrrolidine, piperidine, morpholine and thiomorpholine are preferably used as secondary amines. Suitable solvents for this method are e.g. open-chain and cyclic ethers, such as; tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol and dimethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloroethane, acetonitrile and dimethylformamide. The reaction temperature is suitably in a range from approx. 0°C to the boiling temperature of the chosen solvent, below which one preferably works at room temperature. In a particularly preferred embodiment, the reaction is carried out in the presence of an acid, preferably a carboxylic acid such as acetic acid.

According to method variant i), compounds with the general formula can

is produced, in which Q<5> means the group

and Ra, Rb, Re, Rf, A and n have the above meanings.

Suitable solvents for this method are e.g. lower alcohols such as methanol and ethanol, open chain and cyclic ethers such as tetrahydrofuran, diethyl ether, t-butyl methyl ether, dioxane, ethylene glycol and dimethyl ether, acetonitrile and dimethylformamide. One preferably works at a higher temperature, e.g. in a worm way from approx. 50°C to the boiling temperature of the chosen solvent, below which one preferably works at the boiling temperature of the chosen solvent.

According to method variant j), compounds with the general formula can

is prepared, in which Ri means the group -COR<31>, a carbocyclic, aromatic group or an aromatic or partially unsaturated, heterocyclic group bound through a carbon atom or an optionally substituted, saturated or partially unsaturated, lower hydrocarbon residue, and Ra, Rb, R <31>, R<4>, A, Z, n and p have the above meaning.

This procedure can also be carried out independently

methods known and common to any professional. Suitable solvents are e.g. lower alcohols such as methanol and ethanol, dimethylformamide and water. The reaction is conveniently carried out at room temperature.

The compounds of formula Ib can be converted into ester and ether derivatives hydrolyzable under physiological conditions. Suitable under physiological conditions hydrolysable ester derivatives are especially the compounds of formula Ib, in which at least one of the two phenolic hydroxy groups is acylated with a lower fatty acid.

These can be produced according to methods known in and of themselves and common to any expert. In a preferred embodiment, the acylation is carried out with the corresponding lower fatty acid anhydride in the presence of a catalytic amount of a strong acid, during which an excess of fatty acid anhydride is preferably used as solvent. Suitable acids are e.g. sulfuric acid and organic sulphonic acids, such as p-toluenesulphonic acid.

Hydrolyzable ether derivatives suitable under physiological conditions are e.g. compounds of formula Ib, in which at least one of the two phenolic hydroxy groups is etherified with a lower 1-alkoxycarbonyloxy-1-alkyl-, lower 1-alkanoyloxy-1-alkyl- or with a lower 2-oxo-1-alkyl group. The business can be carried out according to methods known in and of themselves and common to any person skilled in the art. One can e.g. reacting a compound of formula Ib with a lower 1-alkoxycarbonyloxy-1-alkyl-, a lower 1-alkanoyloxy-1-alkyl- or a lower 2-oxo-1-alkyl halide, wherein this etherification is conveniently carried out in the presence of a base.

As halides, the iodides in particular come into question. Suitable bases

is e.g. alkali metal hydroxides and alkali metal carbonates,

such as sodium hydroxide and sodium carbonate.

According to the latter method variant, compounds of the above-mentioned formula Ib can also be transferred in pharmaceutically acceptable salts. As salts, especially salts with the pharmaceutically acceptable bases come into consideration. Examples of such salts include alkali metal salts, such as the sodium and potassium salts.

These salts can be produced according to methods known per se and common to any person skilled in the art.

The various compounds used as starting materials are known or can be prepared according to methods known per se. The following examples contain detailed information regarding the production of these starting materials. As already mentioned at the outset, the compounds of formula Ib inhibit the enzyme COMT. This effect can be measured quantitatively as follows: Rat liver homogenate is incubated in the presence of a suitable substrate as described in J. Neurochem. 38, 191-195 (1982) and measures COMT activity. In a second series of experiments, the incubation is carried out in the presence of a compound of formula Ib. From the difference to the measured COMT activities, the IC50 can then be calculated. The IC50 is stated in nMol/1 and is the concentration in the incubation mixture that is necessary to reduce the COMT activity by 50%. In the following table, the IC50 values for some compounds of formula Ib are indicated. This table also contains information on the acute toxicity of these compounds (DL50 in mg/kg upon single oral administration to mice).

The substances described can be used as pharmaceuticals, e.g. in the form of pharmaceutical preparations for enteral or parenteral application. The compounds of formula Ib can e.g. given orally, e.g. in the form of tablets, varnish tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions.

The preparation of the pharmaceutical preparations can be carried out in the usual way for any person skilled in the art by bringing the compounds of formula Ib, possibly in combination with other therapeutically valuable substances, together with suitable, non-toxic, inert, therapeutically tolerable solid or liquid carrier materials and possibly the common pharmaceutical excipients in a galenic administration form.

As carrier materials, both inorganic and organic carrier materials are suitable. Thus, for tablets, varnish tablets, dragees and hard gelatin capsules, e.g. use lactose, corn starch or derivatives thereof, talc, stearic acid or their salts as carrier materials. For soft gelatin capsules suitable as a carrier e.g. vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient, however, carriers are unnecessary for soft gelatin capsules). For the production of solutions and syrups, suitable carrier materials are e.g. water, polyols, sucrose, invert sugar and glucose. Suitable for injection solutions as carrier materials are e.g. water, alcohols, polyols, glycerol and vegetable oils. Suitable for suppositories as carrier materials are e.g. natural or hardened oils, waxes, fats and semi-liquid or liquid polyols.

Pharmaceutical excipients include the usual preservatives, solvents, stabilizers, wetting agents, emulsifiers, flavor enhancers such as sweeteners and flavoring agents, coloring agents, salts for changing the osmotic pressure, buffers, coating agents and antioxidants.

The dosage of the described substances can, depending on the disease to be treated, vary within wide limits with the age and the individual condition of the patient and the method of application, and must of course be adapted to the individual circumstances in each individual case. In improving the treatment of Parkinson's disease and parkinsonism with L-dopa, a daily dose for adult patients of approx. 25 mg to approx. 1000 mg, especially approx. 100 mg to approx. 300 mg. Depending on the dosage, it is appropriate to give the daily dose in several dosage units.

The pharmaceutical preparations appropriately contain approx.

25 mg to approx. 300 mg, preferably approx. 50 mg to approx. 150 mg of a compound of formula Ib or an ester or ether derivative hydrolysable under physiological conditions or a pharmaceutically acceptable salt thereof.

The following examples shall illustrate the present invention in more detail, but without in any way limiting its scope. All temperatures are given in degrees Celsius.

Example 1

a) 17.1 g (86.7 mmol) of 4-hydroxy-3-methoxy-5-nitrobenzaldehyde are mixed with 170 ml of constant-boiling hydrogen bromide and heated in

3.5 hours during reflux. After cooling, the precipitate is filtered off, washed twice with ice water and taken up in vinegar. The organic phase is washed twice with 50 ml sodium chloride solution each time, dried over magnesium sulphate and evaporated in a water jet vacuum. The crystals obtained are taken up in methylene chloride, after which it is filtered through a tenfold amount of silica gel. The material obtained is crystallized from ethyl acetate/isopropyl ether. 3,4-Dihydroxy-5-nitrobenzaldehyde is obtained in the form of yellow crystals with m.p. 142-143°C.

b) A solution of 1.83 g (10 mmol) 3,4-dihydroxy-5-nitrobenzaldehyde in 25 ml of water is added to a solution of 1.7 g (15 mmol)

hydroxylamine-O-sulfonic acid in 6 ml of water, then stirs for 3.5 hours at 65°C, cools, filters off the precipitate and absorbs this in acetic acid. The organic phase is dried over sodium sulfate and evaporated in a water jet vacuum. The crystals obtained are recrystallized from ethyl acetate/n-hexane. 3,4-dihydroxy-5-nitrobenzonitrile is obtained in the form of yellow crystals with a melting point of 194-195°C.

Example 2

aa) To 4.1 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 40 ml of tetrahydrofuran is added dropwise at -70°C during 10 min. 10 ml tart. butyl lithium solution (1.4 M in hexane). After 2 hours of stirring at -70°C, 1 ml of pyridine-3-carbaldehyde is added over 5 minutes. The reaction mixture is stirred for 1 hour at -70°C and 2 hours at 0°C and poured onto 100 ml of 1N hydrochloric acid. It is extracted three times with 50 ml of ether each time. The combined ether phases are washed with 100 ml of 1 N hydrochloric acid and 20 ml of water. The combined aqueous phases are made alkaline with aqueous ammonia solution and extracted three times with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. Alpha-[4-(benzyloxy)-3-methoxyphenyl]-3-pyridinemethanol is obtained as an oil.

ab) In an analogous way, by using pyridine-4-carbaldehyde, alpha-[4-(benzyloxy)-3-methoxyphenyl]-4-pyridinemethanol is obtained as an oil.

ba) 3.2 g of alpha-[4-(benzyloxy)-5-methoxyphenyl]-3-pyridinemethanol suspended in 50 ml of water is mixed with 2.5 g of potassium permanganate, after which it is stirred for 30 min. at 90°C. After adding a further 1.0 g of potassium permanganate and stirring for a further 30 min. at 90°C, cool to room temperature and extract twice with 150 ml of acetic acid each time. The combined acetic ester phases are washed with sodium chloride solution, dried over sodium sulphate and evaporated. The residue thus obtained is chromatographed on 50 g of silica gel with acetic acid. After recrystallization from methylene chloride/hexane, 4-(benzyloxy)-3-methoxyphenyl-3-pyridyl ketone with m.p. 7 6°C.

bb) In an analogous manner, one obtains from alpha-[4-(benzyloxy)-3-methoxyphenyl)-4-pyridinemethanol 4-(benzyloxy)-3-methoxyphenyl 4-pyridyl ketone with m.p. 85-87°C (methylene chloride/hexane).

approx) To 20 g of 4-(benzyloxy)-3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride, 50 ml of 33% hydrogen bromide in acetic acid is added dropwise at 10°C over the course of 15 min. After 3 hours of stirring at 20°C the reaction mixture is poured onto a mixture of 100 ml conc. aqueous ammonia and ice. The pH is set to 6 by adding acetic acid. The methylene chloride phase is separated, the aqueous phase is extracted twice more with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulfate and evaporated. The residue is recrystallized from methylene chloride/hexane. 4-Hydroxy-3-methoxyphenyl 3-pyridyl ketone is obtained with m.p. 150-151°C.

cb) In an analogous manner, 4-(benzyloxy)-3-methoxyphenyl 4-pyridyl ketone is obtained from 4-hydroxy-3-methoxyphenyl 4-pyridyl ketone with m.p. 215-218°C (acetonitrile).

da) To 1.15 g of 4-hydroxy-3-methoxyphenyl-3-pyridyl ketone dissolved in 15 ml of acetic acid, add 0.38 ml of 65% nitric acid at room temperature

raw ride. After 2 hours of stirring, the reaction mixture is poured on

120 ml of ice water, after which the pH is adjusted to 5 with conc. ammonia and filters off the formed precipitate. The resulting residue is heated in 20 ml of acetonitrile under reflux, after which it is filtered off again. 4-hydroxy-3-methoxy-5-nitro-nyl-3-pyridyl ketone is obtained as brown crystals with m.p. 193°C.

db) In an analogous manner, 4-hydroxy-3-methoxy-4-pyridyl ketone is obtained from 4-hydroxy-3-methoxy-5-nitrophenyl-4-pyridyl ketone with m.p. 240°C.

e) 3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl-3-pyridyl ketone dissolved in 70 ml of 48% aqueous hydrogen bromide is stirred for 18 hours at

100°C. The reaction mixture is then evaporated under reduced pressure. The remainder is recrystallized from water. This gives 3,4-dihydroxy-5-nitrophenyl-3-pyridyl ketone hydrobromide with m.p. 265°C.

f) In an analogous way, 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone is obtained from 4-hydroxy-3-methoxy-5-nitro-nyl-4-pyridyl ketone with

m.p. 246°C (from water).

g) 13.2 g of 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone are suspended in 500 ml of methanol and mixed with stirring with 4.88 g of methanesulfonic acid. The suspension is heated for 60 min. during reflux. It is then cooled to 10°C, the crystals are filtered off and washed twice with 30 ml of methanol each time. This gives 3,4-dihydroxy-5-nitro-nyl-4-pyridyl ketone methanesulfonate with m.p. 260-261°C (decomposition).

Example 3

a) A solution of 2.6 g (12.2 mmol) of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26 ml of constant-boiling hydrogen bromide is heated 2

hours during reflux. After cooling, the solvent is distilled off in a water jet vacuum. The crystalline residue is recrystallized from 50 ml water at the boiling point. 3,4-dihydroxy-5-nitrobenzoic acid is obtained in the form of yellow crystals with m.p. 224-226°C.

b) 1.0 g (5 mmol) of 3,4-dihydroxy-5-nitrobenzoic acid is mixed with 20 ml of methanolic hydrochloric acid solution, stirred for 3 hours at 45°C and the residue taken up after removal of the solvent in methylene chloride. The organic phase is washed with sodium chloride solution, dried over sodium sulphate and evaporated. The crystalline product obtained is taken up in methylene chloride and filtered through a tenfold amount of silica gel. The material obtained is recrystallized from ethyl acetate/n-hexane. 3,4-dihydroxy-5-nitrobenzoic acid methyl ester is obtained in the form of yellow crystals with m.p. 144-145°C.

In an analogous way, the following esters are obtained from 3,4-dihydroxy-5-nitrobenzoic acid: c) 3,4-dihydroxy-5-nitrobenzoic acid ethyl ester with m.p. 106-107°C (from acetic ester/n-hexane), d) 3,4-dihydroxy-5-nitrobenzoic acid n-butyl ester with m.p. 73-74°C (from methylene chloride) and e) 3,4-dihydroxy-5-nitrobenzoic acid n-hexyl ester with m.p. 44-45°C (from isopropyl ether).

Example 4

a) To 10.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of tetrahydrofuran is added dropwise at -20°C during 15 min. 25 ml of 2 M-phenyllithium solution (in benzene/ether (7:3)), and the reaction mixture is stirred for 1 hour at 0°C and 2 hours at 20°C. Then mix with 150 ml of 2 N sulfuric acid and extract three times with 150 ml of ether. The combined ether phases are washed with sodium chloride solution, dried over sodium sulphate and evaporated. The residue thus obtained is chromatographed on 180 g of silica gel with methylene chloride. 3,4-dimethoxy-5-nitrobenzohydrol is obtained as an amorphous solid. b) 2.5 g of 3,4-dimethoxy-5-nitrobenzohydrol dissolved in 50 ml of methylene chloride are mixed with 2.2 g of pyridinium chlorochromate, after which

stir for 2 hours at room temperature. The undissolved components are then filtered off. The filtrate is evaporated and the residue is chromatographed on 60 g of silica gel with methylene chloride. This gives, after crystallization from methylene chloride/hexane, 3,4-dimethoxy-5-nitrobenzophenone with m.p. 78-80°C.

c) 0.5 g of 3,4-dimethoxy-5-nitrobenzophenone is stirred in a mixture of 4 ml of acetic acid and 4 ml of 48% aqueous hydrogen bromide for 30 hours

at 110°C. The reaction mixture is then evaporated to dryness. The rest

taken up in methylene chloride. It is washed with water, dried over sodium sulphate and evaporated. After recrystallization from methylene chloride/hexane, 3,4-dihydroxy-5-nitrobenzophenone is obtained with m.p. 132°C.

Example 5

a) 4.9 g (0.2 mol) magnesium is suspended in 15 ml of absolute ethanol and heated after adding 1 ml of carbon tetrachloride

until the reaction starts. A solution of 31.8 g (0.2 mol) of malonic acid diethyl ester in 19.9 ml of absolute ethanol and 80 ml of absolute toluene is then added dropwise with stirring so that the temperature is between 50°C and 60°C. Stirring is then continued at this temperature for 1 hour, after which the reaction mixture is cooled to -5°C, and a solution of 49.3 g (0.2 mol) 3,4-dimethoxy-5-nitrobenzoyl chloride (m.p. 82-85°C ) in 300 ml of absolute toluene and 50 ml of absolute tetrahydrofuran are added dropwise so that the temperature does not exceed -5°C. Then stir further overnight at room temperature. After distilling off the solvent, the residue is dissolved in 500 ml of vinegar. While stirring and cooling with ice, mix with an ice-cold solution of 12 ml of concentrated sulfuric acid in 80 ml of water. The organic phase is washed with sodium chloride solution, dried over magnesium sulphate and evaporated. The oil obtained is chromatographed on a tenfold amount of silica gel with methylene chloride. The crystalline material obtained is recrystallized from isopropyl ether. 3,4-dimethoxy-5-nitrobenzoyl-malonic acid diethyl ester is obtained in the form of light beige crystals with m.p. 70°C.

b) Dissolve 19.0 g (51.4 mmol) of 3,4-dimethoxy-5-nitrobenzoylmalonic acid diethyl ester in 100 ml of glacial acetic acid, add 5 drops

concentrated sulfuric acid and heat for 16 hours under reflux. The acetic acid is distilled off in a water jet vacuum at 60°C, and the residue is mixed three times with 250 ml of toluene each time, during which it is constantly evaporated. The crystalline residue is extracted with vinegar. The organic phase is washed with water, dried over magnesium sulphate and evaporated. The crystals obtained are chromatographed on the 30-fold amount of silica gel with toluene. The crystalline material obtained is recrystallized from isopropyl

ether. 3',4'-dimethoxy-5'-nitroacetophenone is obtained in the form of yellowish crystals with m.p. 86-87°C.

c) 2 g (8.9 mmol) of 3',4'-dimethoxy-5'-nitroacetophenone are mixed with 30 ml of constant boiling hydrogen bromide and stirred for 2.5 hours

at 140°C. After cooling, pour on 200 ml of ice water and extract three times with 100 ml of vinegar each time. The organic phase is washed twice with 25 ml sodium chloride solution each time, dried over sodium sulphate and evaporated. The product obtained is filtered with acetic acid over the 20-fold amount of silica gel. After recrystallization of the obtained material from water, 3',4'-dihydroxy-5'-nitroacetophenone is obtained in the form of yellowish crystals with m.p. 159-160°C.

The same compound is obtained from 4'-hydroxy-3'-methoxy-5'-nitroacetophenone by treatment with hydrogen bromide at the boiling point.

Example 6

a) 100 g (0.8 mol) Guajacol is dissolved in 136.4 g (0.86 mol) isobutyric anhydride, mixed with 120 g (0.88 mol) anhydrous

zinc chloride (during which everything goes into solution), heat the reaction mixture to 155°C and cool after three minutes. The residue is first subjected to steam distillation to remove the easily volatile components, and then extracted three times with 500 ml of ether each time. The organic phase is washed twice with 250 ml of water each time, once with 150 ml of saturated bicarbonate solution and again with 250 ml of water, dried over sodium sulphate and evaporated in a water jet vacuum. The obtained brown resin is distilled in high vacuum. The distillate with a boiling point of 105-120°C (6.67 Pa) is dissolved in ether, after which it is mixed with n-hexane until crystallization begins. The crystals obtained are recrystallized from ether/hexane. 4'-Hydroxy-3'-methoxy-2-methylpropiophenone is obtained in the form of colorless crystals with m.p. 86-87°C.

b) 15.0 g (77.2 mmol) of 4'-hydroxy-3'-methoxy-2-methyl-propiophenone are dissolved in 300 ml of glacial acetic acid and added dropwise while stirring in

within 15 min. 7.65 ml of 50.5% nitric acid (11.2 N) in 40 ml of glacial acetic acid. After 15 min. the reaction mixture is poured onto ice water, and

the precipitated crystals are filtered off, washed with water and dissolved in methylene chloride. The solution is dried over sodium sulfate and evaporated. The crude product obtained is taken up in methylene chloride and filtered through 100 g of silica gel. The crystals thus obtained are recrystallized from methylene chloride/n-hexane. 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone is obtained in the form of yellow crystals with m.p. 85-87°C.

c) 8.0 g (33.4 mmol) of 4'-hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone are mixed with 64 g of pyridine hydrochloride and stirred for 45 min. at 180°C. After cooling, the reaction mixture is poured into 500 ml of ice water, after which it is acidified with 20 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. After recrystallization from methylene chloride/n-hexane, 3',4'-dihydroxy-2-methyl-5'-nitropropiophenone is obtained in the form of yellow crystals with m.p. 98-99°C.

Example 7

a) 100 g (805.5 mmol) Guajacol is dissolved in 136.4 g (86.2 mmol) butyric anhydride, mixed with 120 g (880 mmol) zinc chloride, heated as indicated in example 6.a for 3 min. and then processes as described therein. The crude product obtained after high vacuum distillation is chromatographed with toluene on 600 g of silica gel. After recrystallization from ether/n-hexane, 4'-hydroxy-3'-methoxybutyrophenone is obtained in the form of colorless crystals with m.p. 40-41°C. b) To a solution of 12.7 g (65.4 mmol) 4'-hydroxy-3'-methoxy-butyrophenone in 250 ml glacial acetic acid is added dropwise with stirring over the course of 10 min. 6.5 ml of 11.2 N nitric acid. The mixture is then stirred for 15 min., the reaction mixture is poured onto ice water, the precipitate that has formed is filtered off, this is washed with ice water and taken up in methylene chloride. The methylene chloride solution is then filtered through 50 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone is obtained in the form of yellow crystals with m.p. 92-93°C. c) 10.2 g (42.6 mmol) of 4'-hydroxy-3'-methoxy-5'-nitrobutyrophenone are mixed with 80 g of pyridine hydrochloride and stirred for 40 min.

at 200°C. After cooling, the reaction mixture is poured into 500 ml of ice water. It is mixed with 30 ml of 3 N hydrochloric acid and extracted with methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is chromatographed with methylene chloride on 150 g of silica gel. The material obtained is recrystallized from methylene chloride/n-hexane. 3',4'-dihydroxy-5'-nitrobutyrophenone is obtained in the form of yellow crystals with m.p. 88-90°C.

Example 8

a) 2.25 g (10 mmol) of 3,4-dihydroxy-5-nitrocinnamic acid are dissolved in 50 ml of methanol and hydrochloric acid gas is introduced into this solution for 10 min. After 1 hour, 50 ml of isopropyl ether is added and the precipitate that has formed is filtered off and washed with isopropyl ether. After recrystallization from methanol/ether, 3,4-dihydroxy-5-nitrocinnamic acid methyl ester is obtained in the form of yellow crystals with m.p. 186-187°C. b) In an analogous manner, from 3,4-dihydroxy-5-nitrocinnamic acid and butanol hydrochloric acid solution, the 3,4-dihydroxy-5-nitrocinnamic acid n-butyl ester is obtained in the form of yellow crystals with m.p. 129-130°C.

Example 9

5.0 g (13.5 mmol) of 3,4-dimethoxy-5-nitrobenzoyl-malonic acid diethyl ester are dissolved in 50 ml of absolute methylene chloride. After cooling to -20°C, a solution of 16.9 g (67.5 mmol) of boron tribromide in 30 ml of methylene chloride is added dropwise while stirring so that the temperature does not exceed -2 0°C. Then stir overnight at room temperature. After adding 80 ml of ethanol, stir for 30 min. at room temperature, and then the solvent is distilled off in a water jet vacuum. The residue is mixed with water and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. The crude product obtained is filtered over 50 g of silica gel with vinegar. The crystalline residue obtained is recrystallized from methylene chloride/n-hexane. 3,4-dihydroxy-5-nitro-benzoylacetic acid ethyl ester is obtained in the form of yellow crystals with m.p. 141-142°C.

Example 10

a) A solution of 1.49 g (12.3 mmol) of 2-phenylethylamine in 100 ml of methylene chloride is mixed with 1.26 g of triethylamine. Under stirring

a solution of 3.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride is added dropwise, after which the mixture is stirred for 15 min. The organic phase is then extracted twice with 50 ml of ice water each time, dried over sodium sulfate and evaporated in water jet vacuum. After recrystallization from methylene chloride/n-hexane, 3,4-dimethoxy-5-nitro-N-phenethylbenzamide is obtained in the form of light beige needles with m.p. 121-122°C.

b) 3.6 g (10.9 mmol) of 3,4-dimethoxy-5-nitro-N-phenethylbenzamide are heated with 36 ml of phosphorus oxychloride in a nitrogen atmosphere for 96 hours under reflux. After distillation of excess phosphorus oxychloride in a water jet vacuum at 60°C, it is mixed three times with 100 ml of toluene each time, during which the solvent is constantly distilled off. The remainder is taken up in methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. The red resin obtained is chromatographed with methylene chloride/acetic ester (1:1) on 120 g of silica gel. 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline is obtained in the form of a yellow resin.

c) 1.4 g (4.5 mmol) of 1-(3,4-dimethoxy-5-nitrophenyl)-3,4-dihydroisoquinoline are mixed with 15 ml of constantly boiling hydrogen bromide and

heat under nitrogen atmosphere for 1.5 hours under reflux at boiling. After distilling off the hydrogen bromide in a water jet vacuum, the crystalline residue is recrystallized from acetone. 5-(3,4-dihydro-1-isoquinolinyl)-3-nitropyrocatecol hydrobromide is obtained in the form of yellow crystals with m.p. >250°C (decomposition).

Example 11

a) Mix 5.0 g (27.7 mmol) of 4-hydroxy-5-methoxy-isophthalaldehyde with 50 ml of constantly boiling hydrogen bromide and heat

under an argon atmosphere for 3 hours at reflux and stirring at the boiling point. After cooling, 50 ml of ice water is added, and the

precipitate is filtered off and washed with water. The crude product is taken up in vinegar and filtered through 50 g of aluminum oxide (activity stage II). The crystalline material obtained is recrystallized from ethyl acetate/n-hexane. 4,5-Dihydroxy-sisophthalaldehyde is obtained in the form of slightly orange-coloured crystals with m.p. 201-202°C.

b) To a solution of 2.0 g (12.0 mmol) 4,5-dihydroxyisophtalaldehyde in 20 ml of water, while stirring at 30°C, add drop by drop a solution of

3.27 g (28.9 mmol) of hydroxylamine-O-sulfonic acid in 12 ml of water, after which the temperature is maintained at 65°C for 10 hours. After cooling, the precipitate is filtered off, washed with water and taken up in vinegar. The organic phase is washed with water, dried over sodium sulphate and evaporated in a water jet vacuum. After recrystallization from acetic ester, 4,5-dihydroxyisophthalonitrile is obtained in the form of yellow crystals which decompose above 300°C.

Example 12

a) A solution of 112.5 g of 2-bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml of glacial acetic acid is added dropwise with stirring over the course of 30 min. at 20-25°C a solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid. Thereby, yellow-brown crystals are secreted. After 90 min. the reaction mixture is poured onto 300 g of ice. The crystals are filtered off, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and the filtrate evaporated at 50°C in a water jet vacuum until crystallization begins. The crystallisate, which has cooled to room temperature, is filtered off and washed with a little methylene chloride. 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone is obtained with m.p. 147-149°C.

b) Method A:

ba) A suspension of 580.1 mg of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanol is mixed with 443.8 mg of selenium dioxide and heated for 71 hours under reflux. The reaction mixture is then filtered from the selenium and evaporated. One dissolves

the residue in methylene chloride, washing with saturated sodium chloride solution,

dried over sodium sulfate, filtered and evaporated. 4-Hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester with m.p. 165-167°C (from ethanol).

Analogously, you get:

bb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-butanol 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n-butyl ester with m.p. 105-107°C (from ethanol) and

bc) from 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-hexanol 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid hexyl ester with m.p. 103-105°C (from n-hexanol/petroleum ether).

c) Method B:

ca) A suspension of 29.01 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone is mixed in 300 ml of tert. butanol with 27.74 g of selenium dioxide and heating for 18 hours under reflux at the boiling point. The hot reaction mixture is filtered while washing with methylene chloride through a filter aid of diatomaceous earth. The filtrate is evaporated and the residue is suspended in 150 ml of hot methylene chloride. The crystalline precipitate is filtered off and washed with a little methylene chloride. 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid is obtained with m.p. 169-171°C.

2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid are dissolved in 25 ml of dry N,N-dimethylformamide, mixed at room temperature with 50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol, then cooled in an ice bath for 0°C and adds 2.27 g of N,N-dicyclohexylcarbodiimide. After 10 min. the ice bath is removed, and the reaction mixture is stirred again for 1 hour at room temperature. Then evaporate. The residue is dissolved in acetic acid, after which undissolved urea is filtered off, the filtrate is washed 4 times with water, dried over sodium sulphate, filtered and evaporated. 4-Hydroxy-3-methoxy-5-nitrophenylglyoxylic acid methyl ester is obtained with m.p. 155-157°C (from methylene chloride/ether).

Analogously, you get:

cb) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and ethanol 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester with m.p. 165-167°C (from ethanol) and

cc) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid and isopropanol 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid i-propyl ester with m.p. 99-101°C (from isopropanol).

d) A suspension of 17.2 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester is mixed in 100 ml of dry acetonitrile and

100 ml of dry toluene with 10.53 g of sodium iodide and 11.9 g of silicon tetrachloride and heat for 4 7 hours under reflux. The reaction mixture is then evaporated and the residue is distilled 6 times with 200 ml of toluene each time. The resulting residue is divided between water and ether and filtered through a filter aid of diatomaceous earth. The ether phase is washed 4 times with saturated sodium chloride solution, dried with sodium sulphate, filtered and evaporated. The oily residue is treated 3 times with ether and activated carbon. This gives 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester with m.p. 77-79°C (from ether/n hexane).

Analogously, you get:

e) From 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid methyl ester 3,4-dihydroxy-5-nitrophenylglyoxylic acid methyl ester as yellow

distillate at 145-150°C and 10.67 Pa,

f) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid isopropyl ester 3,4-dihydroxy-5-nitrophenylglyoxylic acid isopropyl ester which

yellow distillate at 155-160°C and 12.0 Pa,

g) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n-butyl ester 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-butyl ester as yellow

distillate at 160-165°C and 10.67 Pa and

h) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n-hexyl ester 3,4-dihydroxy-5-nitrophenylglyoxylic acid hexyl ester as yellow

distillate at 165-170°C and 12.0 Pa.

Example 13

236.1 mg of 3,4-dihydroxy-nitrophenylglyoxylic acid n-hexyl ester is dissolved in 15 ml of ethanol and mixed with 7.59 ml of 0.1 N sodium hydroxide solution. After 1 hour, the reddish-yellow solution is evaporated. The obtained sodium salt of 3,4-dihydroxy-5-nitro-nylglyoxylic acid-n-hexyl ester is crystallized from water and has a m.p. at ~ 300°C.

Example 14

A solution of 3.18 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester in 47.5 ml of ethanol is mixed with 1.11 g of 0-methyl-hydroxylamine hydrochloride, 1.95 g of sodium acetate and 2, 5 ml of water and heated for 5 hours under reflux by boiling. The reaction mixture is then evaporated and the residue is mixed with ether and water. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The residue is chromatographed on silica gel with methylene chloride. A 7:3 mixture of E- and Z-3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester 0-methyloxime is obtained as a reddish oil; 80 MHz NMR spectrum (CDC 13 ): Signal for O-methyl at 3.96 and 4.05 ppm.

Example 15

A solution of 5.1 g of 3,4-dihydroxy-5-nitro-nylglyoxylic acid ethyl ester is mixed in dry methylene chloride at -10°C over the course of 15 minutes. dropwise with 2 5 g of boron tribromide. The mixture is then stirred for 1 hour at -10°C and then for 17 hours at room temperature. The reaction mixture is then evaporated, the residue is carefully mixed with water and stirred for a further 30 min. at 50°C. After cooling to room temperature, the fuzzed precipitate is filtered off. The aqueous phase is acidified with 10 ml of 1N hydrochloric acid, extracted 4 times with ether, the combined organic extracts are washed 4 times with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The crude product is filtered 3 times in succession in ether through a filter aid of diatomaceous earth. This gives 3,4-dihydroxy-5-nitrophenylglyoxylic acid with m.p. 172-174°C (from isopropyl ether).

Example 16

a) A mixture of 3.93 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 1.38 g of 2-aminophenol is brought to melting

with stirring at 120°C. The melt crystallizes after 5 min. After 2 hours, cool and recrystallize from methanol. This gives 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one with m.p. 202-204°C.

Analogously, you get:

b) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 2-amino-p-cresol 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazine- 2-on with m.p. 233-235°C (from methanol/methylene chloride). c) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2-amino-4-propylphenol 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-1,4-benzoxazine- 2-on with m.p. 200-202°C (from methanol), d) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 3-amino-4-hydroxybenzoic acid 3-(3,4-dihydroxy-5-nitrophenyl)-2- oxo-2H-1,4-benzoxazine-6-carboxylic acid with m.p. 286-287°C (from acetone/petroleum ether), e) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 2-amino-4-chlorophenol 6-chloro-3-(3,4-dihydroxy-5 -nitrophenyl)-2H-1,4-benzoxazin-2-one with m.p. 241-243°C (from methanol), f) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 2-amino-4,6-dichlorophenol 6,8-dichloro-3-(3,4-dihydroxy -5-nitropho-nyl)-2H-1,4-benzoxazin-2-one with m.p. 237-239°C (from ethanol/ether) and g) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 2-amino-5-nitrophenol 3-(3,4-dihydroxy-5-nitrophenyl)- 7-nitro-2H-1,4-benzoxazin-2-one with m.p. 253-255°C (from acetonitrile/ethanol).

Example 17

a) A mixture of 396.0 mg of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 137.6 mg of 1,2-phenylenediamine is heated for 60 min. at 120°C. It is then suspended in methanol, filtered off and recrystallized from N,N-dimethylformamide/water. This gives 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone with m.p. >300°C.

Analogously, you get:

b) From 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and N-methyl-1,2-phenylenediamine l-methyl-3-(3,4-dihydroxy-5-nitro-nyl)-2(1H) -quinoxalinone with m.p. 271-273°C (from methanol), c) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and N-propyl-1,2-phenylenediamine l-propyl-3-(3,4-dihydroxy-5 -nitro-nyl)-2(1H)-quinoxalinone with m.p. 183-185°C (from methanol), d) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 4,5-dimethyl-1,2-phenylenediamine 3-(3,4-dihydroxy-5-nitrophenyl )-6,7-dimethyl-2(1H)-quinoxalinone with m.p. >300°C (from N,N-dimethylformamide/water), e) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 4,5-dichloro-1,2-phenylenediamine 6,7-dichloro-3 -(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone with m.p. >300°C (from N,N-dimethylformamide/water), f) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 3-chloro-5-trifluoromethyl-1,2-phenylenediamine a l:l- mixture of 8 (and 5)-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-6-(and 7)-trifluoromethyl-2-(1H)-quinoxalinone with m.p. >300°C (from N,N-dimethylformamide/water), g) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 4-methoxy-1,2-phenylenediamine a 1:1 mixture of 3- (3,4-dihydroxy-5-nitrophenyl)-6(and 7)-methoxy-2(1H)-quinoxalinone with m.p. >300°C (from ethanol/ether), h) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4-nitro-1,2-phenylenediamine a 1:1 mixture of 3-(3,4 -dihydroxy-5-nitrophenyl)-6(and 7)-nitro-2(1H)-quinoxalinone with m.p. >300°C (from N,N-dimethylformamide/water) and

i) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and N-hexyl-1,2-phenylenediamine l-hexyl-3-(3,4-dihydroxy-5-nitro-nyl)-2H-quinoxalinone with m.p. 152-154°C (from methanol).

Example 18

A solution of 1.07 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 696.3 mg of 2,3-diaminonaphthalene in 3 ml of 1-hexanol is heated for 3 hours under reflux to the boiling point. The reaction mixture is then cooled and diluted with methanol. The crude product is filtered off and recrystallized from N,N-dimethylformamide/water. This gives 3-(3,4-dihydroxy-5-nitrophenyl)benzo[f]-quinoxalin-2(1H)-one with m.p. >300°C.

Example 19

A suspension of 2.05 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 600.8 mg of thiosemicarbazide is stirred vigorously for 30 minutes. at 90°C. Then cool to 40°C and mix with a solution of 870.1 mg of sodium hydroxide in 15 ml of water. The solution is then heated for 30 min. to 90°C, cool the reaction mixture to room temperature and mix dropwise with 2 ml conc. hydrochloric acid. The crystallized product is filtered off and then dissolved in vinegar. Wash with saturated sodium chloride solution, dry over sodium sulphate, filter and evaporate. This gives 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one with m.p. 282-284°C (from ethanol).

Example 2 0

aaa) A suspension of 2.9 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 761.2 mg of thiourea in 170 ml of ethanol is mixed at 60°C with 820.3 mg of sodium acetate and stirring for 6 hours. The reaction mixture is then evaporated, the residue is mixed with 170 ml of water and heated for 30 min. to 60°C. After cooling, the product is filtered off and washed with water. 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol with m.p. 248-250°C (from ethanol).

Analogously, you get:

aab) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and N-phenylthiourea 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol with m.p. 185-187°C (from ether).

aba) 50 ml of 1,2-dichloroethane and 3.56 g of calcium carbonate are added to a solution of 4.88 g of 6-amino-4'-(trifluoromethyl)-hexanilide hydrochloride in 70 ml of water. The suspension is mixed within 60 minutes. with stirring at room temperature with a solution of 2.6 g of thiophosgene in 1.7 ml of toluene. After 16 hours, the precipitate is filtered off and the organic phase is washed with 1N hydrochloric acid and water. After drying over sodium sulphate and filtration, it is evaporated. Crude 4'-(trifluoromethyl)hexanilide-6-isothiocyanate is obtained.

abb) A solution of 5.2 g of crude 4'-(trifluoromethyl)hexanilide-6-isothiocyanate in 60 ml of ethanol is mixed with 100 ml of conc. ammonia solution. After 30 min. the reaction mixture is evaporated. The residue is dissolved in vinegar, washed with water, dried over sodium sulphate, filtered and evaporated. 1-[5-[(α,α,α-trifluoro-p-tolyl)carbamoyl]pentyl]-2-thiourea with m.p. 140-142°C (from ethanol).

abc) A suspension of 666.7 mg of 1-[5-[a ,a ,cx-trifluoro-p-tolyl)carbamoyl]pentyl]-2-thiourea and 58 0.2 mg of 2-bromo-4' is mixed -hydroxy-3'-methoxy-5'-nitroacetophenone in 50 ml of ethanol at 60°C with 164.2 mg of sodium acetate. A reddish-yellow solution is thereby formed. After 90 min. the reaction mixture is evaporated, the residue is mixed with water, the precipitate is filtered off and washed 4 times with 10 ml of water each time. 6-[[4-(4-hydroxy-3-methoxy-5-nitro-nyl)-2-thiazolyl]amino]-4'-(trifluoromethyl)hexanilide with m.p. 160-162°C (from ethanol).

ac) A solution of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 13.5 g of 2-aminoacetophenone in 250 ml of dry N,N-dimethylformamide is stirred at 90°C in 16 hours. The reaction mixture is then evaporated to approx. 2/3 and pour over ice. The separated crystals are filtered off and dissolved in methylene chloride. Wash with saturated sodium chloride solution, dry over sodium sulphate, filter and evaporate. This gives 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole with m.p. 195-197°C (from methylene chloride/methanol).

ada) A suspension of 14.5 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 5.41 g of 1,2-phenylenediamine in 350 ml of methanol is mixed with 4.92 g of sodium acetate and heating the mixture under reflux for 2 2 hours at the boiling point. The reaction mixture is then evaporated, the residue is dissolved in methylene chloride, this solution is washed 4 times with water, dried over sodium sulphate, filtered and evaporated. 2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline is obtained with m.p. 195-197°C (from methylene chloride/methanol) .

Analogously, you get:

adb) From 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and 4,5-dimethyl-1,2-phenylenediamine 6,7-dimethyl-2-(4-hydroxy-3-methoxy- 5-nitrophenyl)quinoxaline with m.p. 207-209°C (from methylene chloride/methanol).

b) A suspension of 267.3 mg of 4-(2-amino-4-thiazolyl)-2-methoxy-6-nitrophenol is mixed in 10 ml of dry methylene chloride at -20°C

with 1.25 g boron tribromide. After the addition, the mixture is stirred for another 1 hour at -2 0°C and without cooling at room temperature for 18 hours. The reaction mixture is then evaporated, the residue is carefully mixed with water and stirred for 30 min. at 50°C. After cooling to room temperature, the crude product is filtered off and washed with a little water. 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide with m.p. 244-246°C (from methanol).

Analogously, you get:

c) From 4-(2-anilino-4-thiazolyl)-2-methoxy-6-nitrophenol 5-(2-anilino-4-thiazolyl)-3-nitropyrocatechol with m.p. 202-204°C (from

methanol),

d) from 6-[4-(4-hydroxy-3-methoxy-5-nitrophenyl)-2-thiazolyl)-amino]-4'-(trifluoromethyl)hexanilide 6-[[4-(3,4-dihydroxy- S-nitrophenyl)-2-thiazolyl]amino]-4'-(trifluoromethyl)hexanilide with m.p. 214-216°C (from methanol), e) from 2-(4-hydroxy-3-methoxy-5-nitrobenzoyl)-3-methylindole 5-bromo-2-(3,4-dihydroxy-5-nitrobenzoyl)- 3-methylindole with m.p. 265-267°C (from methanol), f) from 2-(4-hydroxy-3-methoxy-5-nitrophenyl)quinoxaline 2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline with m.p. 241-243°C (from

methanol) and

g) from 6,7-dimethyl-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-quinoxaline 6,7-dimethyl-2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline

with m.p. 274-276°C (from methanol).

Example 21

A mixture of 3.12 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 849.3 mg of thioacetamide in 40 ml of ethanol is heated under reflux at the boiling point for 18 hours. After cooling, the crystals are filtered off and recrystallized from methanol/isopropanol. 5-(2-methyl-4-thiazolyl)-3-nitropyrocatechol hydrobromide with m.p. 280-282°C.

Example 22

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 461 mg of thiosemicarbazide in 20 ml of n-butanol is heated for 60 min. under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butanol. 5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatechol hydrobromide with m.p. 265-267°C.

Example 2 3

A solution of 1.38 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 505.7 mg of 2-amino-1,3,4-thiadiazole in 25 ml of n-butanol is heated for 7 hours under reflux at the boiling point. The reaction mixture is then cooled to room temperature and the separated crystals are filtered off. 5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatechol with m.p. 278-280°C (from methanol).

Example 24

A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.01 g of 2-aminothiazole and 40 ml of ethanol is heated for 23 hours under reflux at the boiling point. The reaction mixture is then cooled to room temperature and the crystals are filtered off. 5-(Imidazo[2,1-b]thiazol-6-yl)-3-nitropyrocatechol hydrobromide with m.p. 286-288°C (from methanol).

Example 25

A mixture of 1.95 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.06 g of 2-aminobenzothiazole and 50 ml of ethanol is heated under reflux at the boiling point for 17 hours. The reaction mixture is then cooled to room temperature, after which the crystals are filtered off. 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyrocatechol with m.p. 303-305°C (from N,N-dimethylformamide/methanol).

Example 26

A mixture of 2.78 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone, 1.51 g of 2-aminothiophenol and 50 ml of ethanol is heated for 1 hour under reflux to the boiling point. The reaction mixture is then cooled to room temperature, after which the crystals are filtered off. 5-(2H,1,4-benzothiazin-3-yl)-3-nitropyrocatechol with m.p. 302-304°C (from N,N-dimethylformamide/methanol).

Example 27

A mixture of 987.5 mg of 2-bromo-3',4'-dihydroxy-5'-nitro-acetophenone and 1.01 g of 2-aminopyridine is melted at 110°C. After 30 min. mix with 15 ml of ethanol and heat for 3 hours under reflux at the boiling point. The reaction mixture is then cooled to room temperature and the crystals are filtered off. 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitropyrocatechol with m.p. 250-252°C (from N,N-dimethylformamide/methanol).

Example 28

a) 8.9 g of 1,1'-carbonyldiimidazole is added to a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture is then heated for 5 hours at

65-70°C. It is then cooled to room temperature and dripped over the course of 15 minutes. to a solution of 21.6 g of 6-aminohexyl-t-butyl carbamate in 50 ml of dry tetrahydrofuran. The reaction mixture is then heated for 18 hours to 65-70°C, evaporated, the residue is suspended in ethyl acetate, filtered off and the filtered material is chromatographed with acetone/methylene chloride (3:1) on silica gel. One obtains [6-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamate with m.p. 145-147°C (from isopropanol).

b) To a solution of 4.1 g of [6-(4-hydroxy-5-nitro-m-anis-amido)hexyl]-t<->butyl carbamate in 80 ml of glacial acetic acid, add

room temperature 5.8 ml hydrogen bromide in glacial acetic acid (£33%) . The mixture is stirred for 2 hours, the precipitated crystals are filtered off and washed with ether. N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamide hydrobromide with m.p. 207-209°C (from isopropanol).

c) To a suspension of 392.3 mg of N-(6-aminohexyl)-4-hydroxy-5-nitro-m-anisamide hydrobromide in 25 ml of dry methylene chloride put

one at -20°C 1.25 g boron tribromide. After addition, the mixture is stirred for 1 hour at -20°C and then for 17 hours at room temperature. The reaction mixture is then evaporated, the residue is mixed with 10 ml of water and stirred for 1 hour at room temperature. After evaporation of the water, the residue is chromatographed with toluene/ethanol (1:1) on Sephadex LH 20. N-6-aminohexyl-3,4-dihydroxy-5-nitrobenzamide hydrobromide is obtained with m.p. 205-207°C.

Example 29

. aa) A solution of 4.93 g of 5-nitrovanillin and 2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene is heated under reflux at the boiling point. After 15 min. crystals start to fall out of the red solution. After 18 hours, the reaction mixture is cooled to room temperature and diluted with 60 ml of methanol. The crystals are filtered off and washed with methanol. 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol with m.p. 198-200°C (from N,N-dimethylformamide/methanol).

Analogously, you get:

ab) From 5-nitrovanillin and 4,5-dichloro-1,2-phenylenediamine 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol with m.p. 258-260°C (from N,N-dimethylformamide/ether).

b) A suspension of 860.1 mg of 4-(2-benzimidazolyl)-2-methoxy-6-nitrophenol in 10 ml of glacial acetic acid and 10 ml of 48% hydrogen bromide

heated for 72 hours under reflux at the boiling point. It is then evaporated, and the residue is mixed 4 times with 50 ml of toluene each time, which is distilled off again. 5-(2-benzimidazolyl)-3-nitropyrocatechol with m.p. >300°C (from acetone/water).

Analogously, you get:

c) From 4-(5,6-dichloro-2-benzimidazolyl)-2-methoxy-6-nitrophenol 5-(5,6-dichloro-2-benzimidazolyl)-3-nitropyrocatechol with m.p. 282-284°C (from acetone/water).

Example 3 0

A suspension of 29.0 g of 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone is mixed in 700 ml of dry methylene chloride at -20°C over the course of 30 minutes. with a solution of 125.3 g of boron tribromide in 300 ml of dry methylene chloride. After the addition, the mixture is stirred for another hour at -20°C and 16 hours at room temperature, then evaporated, the residue is carefully mixed with water under ice cooling and stirred for 30 min. at 50°C. After cooling, extract with ether, wash the ether phase with water, dry over sodium sulphate, filter and evaporate. 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is obtained with m.p. 138-140°C (from methylene chloride).

Example 31

a) A solution of 3.6 g of 3,4-dihydroxy-5-nitro-nylglyoxylic acid ethyl ester in 30 ml of acetic anhydride is heated in the presence of a

catalytic amount of conc. sulfuric acid for 3 0 min. at 110°C, cool to room temperature, pour the reaction mixture into 150 ml of water and stir for 60 min. Extract with ether, wash with saturated sodium chloride solution, dry the combined organic extracts over sodium sulfate, filter and evaporate. This gives 3,4-diacetoxy-5-nitrophenylglyoxylic acid ethyl ester with m.p. 87-89°C (from ether/petroleum ether).

Analogously, you get:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxazin-2-one 3-(3,4-diacetoxy-5-nitrophenyl)-2H-1,4-benzoxazine -2-on with

m.p. 186-188°C (from methylene chloride/methanol),

c) from 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone 3-(3,4-diacetoxy-5-nitrophenyl)-2(1H)-quinoxalinone with m.p. 241-243°C (from methylene chloride/methanol), d) from 3,4-dihydroxy-5-nitrobenzophenone 3,4-diacetoxy-5-nitrobenzophenone with m.p. 141-143°C (from methylene chloride/ether), e) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone 3,4-diace-toxy-2'-fluoro-5-nitrobenzophenone with m.p. 122-124°C (from ether) and f) from 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone 3,4-diacetoxy-5-nitrophenyl-4-pyridyl ketone with m.p. 148-150°C (from

methylene chloride/ether).

Example 32

a) A solution of 2.0 g of 3,5-dinitropyrocatechol in 25 ml of propionic anhydride is heated in the presence of a catalytic amount of conc.

sulfuric acid for 18 hours at 110°C, distills off the excess anhydride at 70°C in high vacuum (1.33 Pa), dissolves the residue in methylene chloride, washes with water, dries over sodium sulfate, filters and evaporates. 1,2-dipropionyloxy-3,5-dinitrobenzene is obtained with m.p. 74-76°C (from methylene chloride/petroleum ether).

Analogously, you get:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxa-zin-2-one 3-(3,4-dipropionyloxy-5-nitrophenyl)-6- methyl-2H-1,4-benzoxazin-2-one with m.p. 158-160°C (from methylene chloride), c) from 6-chloro-3-(3,4-dihydroxy-5-nitrophenyl)-2H-1,4-benzoxa-zin-2-one 5-(6-chloro -2-oxo-2H-1,4-benzoxazin-3-yl)-3-nitro-o-phenylene-dipropionate with m.p. 148-150°C (from methylene chloride/ether), d) from 3-(3,4-dihydroxy-5-nitrophenyl)-7-nitro-2H-1,4-benzoxa-zin-2-one 3-nitro- 5-(7-nitro-2-oxo-2H-1,4-benzoxazin-3-yl)-o-phenylene dipropionate with m.p. 177-179°C (from methanol), e) from 3-(3,4-dihydroxy-5-nitrophenyl)-2-oxo-2H-1,4-benzoxazine-6-carboxylic acid 3-[3,4 -bis(propionyloxy)-5-nitrophenyl]-2-oxo-2H-1,4-benzoxazine-6-carboxylic acid with m.p. 192-194°C (from methylene chloride), f) from 3-nitro-5-(2-quinoxalinyl)pyrocatechol 3-nitro-5-(2-quinoxalinyl)-o-phenylene dipropionate with m.p. 152-154°C (from

methylene chloride/ether),

g) from 5-(2-benzimidazolyl)-3-nitropyrocatechol 5-(2-benzimidazolyl)-3-nitro-o-phenylene dipropionate with m.p. 179-181°C (from ether), h) from 6,7-dichloro-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone 5-(6,7-dichloro-3, 4-dihydro-3-oxo-2-quinoxalinyl)-3-nitro-o-phenylene dipropionate with m.p. 260-262°C (from methylene chloride),

i) from 5-bromo-2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole 5-bromo-2-(3,4-dipropionyloxy-5-nitrobenzoyl)-3-methylindole with m.p. 196-198°C (from ether) and

j) from 6-(3,4-dihydroxy-5-nitrophenyl)-3-mercapto-1,2,4-triazin-5(4H)-one 3-nitro-5-(2,3,4,5- tetrahydro-5-oxo-3-thioxo-as-triazin-6-yl)-o-phenylene-dipropionate with m.p. 237-239°C (from ether).

Example 3 3

a) A solution of 1.09 g of 3,4-dihydroxy-5-nitro-nylglyoxylic acid ethyl ester in 6 ml of isobutyric anhydride is heated in the presence of

a catalytic amount of conc. sulfuric acid for 17 hours at 110°C. The reaction mixture is then mixed 10 times with 10 ml of toluene each time, during which the mixture is continuously evaporated at 80°C and 18.7 mbar. The oily residue is distilled in a bubble tube at 175-180°C and 8.0 Pa. 3,4-diisobutyryloxy-5-nitrophenylglyoxylic acid ethyl ester is obtained.

Analogously, you get:

b) From 3,5-dinitropyrocatechol i,2-diisobutyryloxy-3,5-dinitro-benzene with m.p. 78-80°C (from ether), c) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxa-zin-2-one 3-(3,4 -diisobutyryloxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxazin-2-one with m.p. 142-144°C (from ether), d) from 2-(3,4-dihydroxy-5-nitrophenyl)quinoxaline 2-(3,4-diisobutyryloxy-5-nitrophenyl)quinoxaline with m.p. 155-157°C (from

ether),

e) from l-methyl-3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone l-methyl-3-(3,4-diisobutyryloxy-5-nitrophenyl)-2(1H )-quinoxa-linone with m.p. 138-140°C (from ether), f) from 5-(imidazo[2,1-b]-1,3,4-thiadiazol-6-yl)-3-nitropyrocatecol 5-(imidazo[2, 1-b]-1,3,4-thiadiazol-6-yl)-3-nitro-o-phenylene diisobutyrate with m.p. 169-171°C (from methylene chloride), g) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone 5-(bromoacetyl)-3-nitro-o-phenylene-diisobutyrate with m.p. 56-58°C (from

methylene chloride/hexane),

h) from 5-(2-amino-4-thiazolyl)-3-nitropyrocatechol hydrobromide 3-nitro-5-(2-isobutyramido-4-thiazolyl)-o-phenylene-diisobutyrate with

m.p. 157-159°C (from methylene chloride/ether),

i) from 5-(2-amino-6H-1,3,4-thiadiazin-5-yl)-3-nitropyrocatechol hydrobromide 3-nitro-5-(2-isobutyramido-4-isobutyryl-1,3,4 -thiadiazin-5-yl)-o-phenylene-diisobutyrate with m.p. 177-179°C (from ether),

j) from 3-(3,4-dihydroxy-5-nitrophenyl)-6-propyl-2H-1,4-benzoxazin-2-one 3-nitro-5-(2-oxo-6-propyl-2H -1,4-benzoxazin-3-yl)-o-phenylene-diisobutyrate with m.p. 131-133°C (from methanol),

k) from 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitropyrocatechol 5-(imidazo[1,2-a]pyridin-3-yl)-3-nitro-o-phenylene- diisobutyrate with m.p. 137-139°C (from ether),

1) from 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitropyrocatechol 5-(imidazo[2,1-b]benzothiazol-2-yl)-3-nitro-o-phenylene diisobutyrate with m.p. 197-199°C (from methylene chloride/ether) and

m) from 3,4-dihydroxy-5-nitrophenyl-2-pyridyl ketone hydrobromide 3-nitro-5-(2-pyridylcarbonyl)-o-phenylene diisobutyrate with m.p. 83-85°C (from ether/hexane).

Example 34

a) A solution of 613.0 mg of 3,4-dihydroxy-5-nitrophenylglyoxylic acid ethyl ester in 4 ml of pivaloyl anhydride is heated in

presence of a catalytic amount of conc. sulfuric acid for 17 hours at 100°C, dilute the cooled solution with ether, wash with saturated sodium chloride solution, dry over sodium sulfate, filter and evaporate. The residue is mixed 10 times with 10 ml of toluene each time, during which the mixture is again constantly evaporated. After ball-tube distillation (air bath) at 175-180°C and 4.0 Pa, 3,4-dipivaloyloxy-5-nitrophenylglyoxylic acid ethyl ester is obtained.

Analogously, you get:

b) From 3-(3,4-dihydroxy-5-nitrophenyl)-6-methyl-2H-1,4-benzoxa-zin-2-one 3-(3,4-dipivaloyloxy-5-nitrophenyl)-6- methyl-2H-1,4-benzoxazin-2-one with m.p. 180-182°C (from ether), c) from 3,4-dihydroxy-5-nitrobenzophenone 3,4-dipivaloyloxy-5-nitrobenzophenone with m.p. 101-103°C (from t-butyl methyl ether) and d) from 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone 3,4-dipiva-loyloxy-2'-fluorobenzophenone with m.p. 74-76°C (from petroleum ether

ts.) .

Example 3 5

A solution of 1.7 g of 3-(3,4-dihydroxy-5-nitrophenyl)-2(1H)-quinoxalinone in 17 ml of enonic anhydride is heated in the presence of a catalytic amount of conc. sulfuric acid for 17 hours at 110°c, then distills off the excess of anhydride under high vacuum, dissolves the residue in methylene chloride, washes the organic solution with water, dries it over sodium sulfate, filters and evaporates. 5-(1,2-dihydro-2-oxo-3-quinoxalinyl)-3-nitro-o-phenylene diheptanoate is obtained with m.p. 186-188°C (from methylene chloride/ether).

Example 3 6

a) To a solution of 1.35 g of 2-bromo-3',4'-dihydroxy-5'-nitro-acetophenone in 25 ml of alcohol, add 1.26 g of sodium acetate and

heats during reflux to the boiling point. After 6 hours, the separated sodium bromide is filtered from the reaction mixture and

is evaporated. The rest is dissolved in vinegar. Wash with saturated sodium chloride solution, dry over sodium sulphate, filter and evaporate at 50°C. This gives (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate with m.p. 166-168°C (from acetic acid/ether).

Analogously, you get:

b) From 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and sodium isobutyrate (3,4-dihydroxy-5-nitrobenzoyl)methyl isobutyrate with

m.p. 120-122°C (from acetic acid/ether) and

c) from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 3,4-dihydroxy-5-nitrophenylglyoxylic acid sodium salt 3,4-dihydroxy-S-nitrophenacyl (3,4-dihydroxy-5-nitrobenzoyl ) format with m.p. 224-226°C (from methanol/acetic acid).

Example 37

A suspension of 2.91 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 1.31 g of thionicotinamide in 50 ml of alcohol and heated for 2 hours under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from N,N-dimethylformamide/alcohol. 3-nitro-5-[2-(3-pyridyl)-4-thiazolyl]pyrocatechol with m.p. 279-281°C.

Example 38

A solution of 5.52 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 2.7 g of 2-aminoacetophenone in 100 ml of dry N,N-dimethylformamide is stirred at 90°C for 24 hours . The reaction mixture is evaporated, the residue is dissolved in acetic acid, washed with water, dried over sodium sulphate, filtered and evaporated. 2-(3,4-dihydroxy-5-nitrobenzoyl)-3-methylindole is obtained with m.p. 212-214°C (from n-butanol).

Example 3 9

A suspension of 7.32 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 4.06 g of 1-(3-pyridinyl)-2-thiourea in 100 ml of n-butanol and heated in 3 hours under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butanol. 3-nitro-5-[2-(3-pyridylamino)-4-thiazolyl]pyrocatechol hydrobromide with m.p.

>300°C.

Example 4 0

A suspension of 6.35 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 4.68 g of 1-(3-quinolinyl)-2-thiourea in 150 ml of n-butanol and heated in 3 hours under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butanol. 3-nitro-5-[2-(3-quinolinylamino)-4-thiazolyl]pyrocatechol hydrobromide with m.p. >300°C.

Example 41

A suspension of 8.28 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 6.37 g of rac-1-(2-exo-bornyl)-2-thiourea in 100 ml of n- butanol and heat for 3 hours under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butnol. Rac-3-nitro-5-[2-(2-exo-bornylamino)-4-thiazolyl]-pyrocatechol hydrobromide is obtained with m.p. 262-264°C.

Example 42

0.875 ml of pyrrolidine is mixed in 35 ml of tetrahydrofuran at 5°C with 0.605 ml of acetic acid and then with 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4'-(trifluoromethyl)heptanilide and stirring for 56 hours under argon at 2 3°C. The residue obtained after evaporation of the reaction mixture is distributed between ethyl acetate and 1N caustic soda. The combined caustic soda extracts are acidified with conc. hydrochloric acid, extract with ethyl acetate, wash the combined ethyl acetate extracts with saturated sodium chloride solution, dry over sodium sulphate, evaporate and chromatograph the residue on 120 g silica gel with methylene chloride/methanol (91:9). After recrystallization from ethyl acetate/petroleum ether, (E)-8-(3,4-dihydroxy-S-nitrophenyl)-6-oxo-4'-(trifluoromethyl)-7-octenanilide is obtained with m.p. 194-197°C.

Example 43

a) Dissolve 26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde in 400 ml of acetic anhydride and 5 ml of pyridine. Stir for 8 hours at 80°C, then evaporate the reaction mixture, distribute the residue between ice water and methylene chloride, dry the organic phase over sodium sulfate, evaporate and recrystallize the residue from methylene chloride/petroleum ether. 2-Chloro-3-formyl-6-methoxyphenyl acetate is obtained with m.p. 48-50°C. b) 38 g of 2-chloro-3-formyl-6-methoxyphenyl-acetate are introduced at -5°C to -10°C during 15 minutes. portionwise in 150 ml 98% nitric acid. After 30 min. stirring at -5°C, the reaction mixture is poured into 1.5 l of ice water and extracted 3 times with 500 ml of methylene chloride. The combined organic phases are washed with ice water, dried over sodium sulphate and evaporated. The residue is crystallized from ether. 2-Chloro-3-formyl-6-methoxy-5-nitrophenyl acetate is obtained with m.p. 84-85°C. c) Dissolve 35.8 g of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate in 300 ml of methanol. After adding 145 ml of 1N caustic soda, stir for 1 hour at 23°C. After evaporation of the methanol, the residue is diluted with ice water, acidified with 2N hydrochloric acid and extracted twice with 400 ml of ethyl acetate each time. The organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. This gives 2-chloro-3-hydroxy-5-nitro-p-anisalde-hyde with m.p. 130°C. d) Dissolve 1.3 g of 2-chloro-3-hydroxy-5-nitro-p-anisaldehyde in 80 ml of methylene chloride, mix with 0.82 ml of boron tribromide, stir for 18 hours at 23°C, mix the reaction mixture under ice cooling with 5 ml of methanol, evaporate, dry the residue in high vacuum, triturate in water, filter and recrystallize from acetonitrile. 2-Chloro-3,4-dihydroxy-5-nitrobenzaldehyde is obtained with m.p. 193-195°C.

Example 44

a) A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml of ethanol is stirred in the presence of 12.3 g of hydroxylamine hydrochloride

for 4 hours at 70°C, then evaporate the reaction mixture, dry the residue under high vacuum and recrystallize from methanol/water. 2-Chloro-3-hydroxy-p-anisaldehyde oxime is obtained with m.p. 174-176°C.

b) 21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime is heated with 400 ml of acetic anhydride for 20 hours under reflux. Then

the reaction mixture is evaporated, the residue is mixed with 300 ml of ice water, stirred for 1 hour, decanted, the residue thus obtained is distributed between methylene chloride and water, the organic phase is dried over sodium sulfate, evaporated, the residue is dried in high vacuum, this is chromatographed on 200 g silica gel with methylene chloride and recrystallizes from methylene chloride/petroleum ether. 2-Chloro-3-cyano-6-methoxyphenyl acetate is obtained with m.p. 97-99°C. c) Analogous to examples 43b and 43c, 2-chloro-3-cyano-6-methoxyphenyl-acetate gives 2-chloro-3-hydroxy-5-nitro-p-anisonitrile with m.p. 157-159°C (methylene chloride/hexane). d) Analogous to example 4 3d, 2-chloro-3-hydroxy-5-nitro-p-anisonitrile yields 2-chloro-3,4-dihydroxy-5-nitrobenzonitrile

with m.p. 180°C (acetonitrile).

Example 45

a) 5.5 g of α-chloro-2-fluoro-3,4-dimethoxytoluene and 4.05 g of potassium acetate are stirred in 50 ml of dimethylformamide for 25 hours at 80°C. So

the reaction mixture is poured into 150 ml of ice water and extracted with ether. The ether layers are washed with sodium chloride solution, dried over sodium sulfate and evaporated. 2-fluoro-3,4-dimethoxybenzyl acetate is obtained as an oil. b) 5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate are heated together with 50 ml of methanol and 50 ml of 1N sodium hydroxide solution for 1.5 hours at 80°C.

After evaporation of the methanol, the residue is extracted with methylene chloride. The combined extracts are washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on 80 g of silica gel with methylene chloride/methanol (95:5). 2-fluoro-3,4-dimethoxybenzyl alcohol is obtained as an oil. c) 3.0 g of 2-fluoro-3,4-dimethoxybenzyl alcohol and 5.0 g of manganese dioxide are heated together with 50 ml of benzene for 1 hour under reflux. The insoluble parts are then filtered off while washing with methylene chloride. The filtrate is evaporated and the residue is recrystallized from methylene chloride/hexane. 2-Fluoro-3,4-dimethoxybenzaldehyde is obtained with m.p. 52-54°C. d) 4.4 g of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride are heated together with 30 ml of ethanol for 5 hours under reflux. The reaction mixture is then evaporated and the residue, which has been dried in a high vacuum at 23°C, is introduced into 40 ml of phosphorus oxychloride. After stirring for 2.5 hours at 23°C, the reaction mixture is evaporated, the residue is treated with ice water, the resulting precipitate is filtered off, washed with water, taken up in methylene chloride, the methylene chloride solution is dried over sodium sulfate and evaporated. Recrystallization of the residue from methylene chloride/hexane yields 2-fluoro-3,4-dimethoxybenzonitrile with m.p. 64-65°C.

e) Dissolve 2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile in 60 ml of methylene chloride, wash with 1.1 ml of boron tribromide, stir for 1 hour at

23°C, then mix with a further 1.0 ml of boron tribromide and stir for a further 80 min. at 23°C. The reaction mixture is then poured

gen on 100 ml of ice-cold saturated sodium hydrogencarbonate solution, after which you extract twice with 300 ml of ether, wash the combined ether phases twice with sodium chloride solution, dry over sodium sulfate, evaporate and chromatograph the residue on 50 g of silica gel with methylene chloride and methylene chloride/methanol (97:3 ). 2-Fluoro-3-hydroxy-p-anisonitrile is obtained with m.p. 198-200°C.

f) 0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile is dissolved in 10 ml of acetic anhydride and 0.5 ml of pyridine, after which it is stirred for 2 hours

at 120°C. The reaction mixture is then evaporated and the residue is distributed between ice water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. 3-cyano-2-fluoro-6-methoxyphenyl acetate is obtained with m.p. 90-91°C.

g) 0.8 g of 3-cyano-2-fluoro-6-methoxyphenyl-acetate is introduced in three portions at -15°C in 5 ml of 96% nitric acid, after which stirring

1 hour at -10°C. The reaction mixture is then poured onto 50 g of ice. The mixture is extracted twice with 70 ml of ethyl acetate each time. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue thus obtained is dissolved in 50 ml of 1 N sodium carbonate solution and 50 ml of methanol, after which it is stirred for 1 hour at 23°C, and the methanol is distilled off. The remaining aqueous phase is set at 0°C with conc. hydrochloric acid at pH 2 and extract twice with

100 ml ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, and the residue is chromatographed on 45 g of silica gel with methylene chloride/methanol (97:3). After recrystallization from ether/hexane, 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile with m.p. 112-113°C. h) 550 mg of 2-fluoro-3-hydroxy-5-nitro-p-anisonitrile is dissolved in 30 ml of methylene chloride, after which it is mixed with 0.44 ml of boron tribromide. After stirring for 6 hours at 23°C, a further 0.1 ml of boron tribromide is added, after which stirring is done for 1.5 hours at 23°C. 3 ml of ethanol are then added at -15°C. The reaction mixture is evaporated and the residue is dried at 23°C in a high vacuum. Recrystallization from ether/hexane yields 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile with m.p. 154°C.

Example 4 6

a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid are suspended in 95 ml of thionyl chloride. Stir for 1 hour at 80°C. At two times

evaporation with the addition of absolute toluene yields 10 g of 3,4-dimethoxy-5-nitrobenzoic acid chloride, which is dissolved in 100 ml of tetrahydrofuran. This solution is dripped into 300 ml of 28% aqueous ammonia. - Then stirred for 2 hours at 40°C and cooled to 5°C. The crystalline precipitate is filtered off. You get 3,4-dimethoxy-5-nitrobenzamide with m.p. 182-185°C.

b) During ice cooling, 2.46 g of chlorine are introduced into a mixture of 8.0 g of sodium hydroxide, 50 ml of water and 30 g of ice. Then added

slowly 6.5 g of 3,4-dimethoxy-5-nitrobenzamide, suspended in 5 ml of tetrahydrofuran. The reaction mixture is heated for 30 min. to 70°C, stir for 1 hour at 70°C, cool to 5°C and filter off the precipitated crystals. 3,4-dimethoxy-5-nitroaniline is obtained with m.p. 129-131°C. By extracting the filtrate with ethyl acetate, drying the extracts over sodium sulfate, evaporating and crystallizing the residue while adding ether, a further portion of 3,4-dimethoxy-5-nitroaniline can be obtained.

c) 10 g of finely powdered 3,4-dimethoxy-5-nitroaniline is suspended in 15 ml of 12 N-hydrochloric acid and 40 ml of water, after which it is stirred for 1 hour at

30°C. Then, at -5°C, 3.8 g of sodium nitrite dissolved in 20 ml of water are added dropwise over the course of 15 min. The mixture is stirred for 30 min. at -5°C and drips the cold diazonium salt solution over the course of 45 min. to 100 ml of pyridine at 40°C. Then stir for 1 hour at 70°C. The reaction mixture is evaporated and the residue is taken up in 300 ml of ethyl acetate. It is extracted three times with 200 ml of 2 N hydrochloric acid each time. The acidic water phase is adjusted to pH 9 with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts are dried over sodium sulphate and evaporated, and the residue is chromatographed on 250 g of silica gel with ethyl acetate. After crystallization from methylene chloride/hexane, 2-(3,4-dimethoxy-5-nitrophenyl)pyridine is obtained with m.p. 89-90°C.

d) 1.5 g of 2-(3,4-dimethoxy-5-nitrophenyl)pyridine is dissolved in 30 ml of 48% aqueous hydrogen bromide. The reaction mixture is stirred for 16 hours at 100°C and 18 hours at 23°C. The resulting precipitate is filtered off and recrystallized from methanol/ether. 3-nitro-5-(2-pyridyl)pyrocatechol hydrobromide with m.p. 239-240°C.

Example 4 7

a) 2.76 ml of 2-bromopyridine dissolved in 30 ml of absolute tetrahydrofuran are mixed at -60°C during 30 min. with 19.2 ml of 1.6 M n-butyllithium solution (in hexane), after which it is stirred for 30 min. at 60°C. Then 6.0 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise over the course of 30 minutes. at -40°C. The reaction mixture is heated to 0°C over 2 hours, poured onto ice water and extracted with ethyl acetate. The combined extracts are dried over sodium sulfate and evaporated, and the residue is chromatographed on 200 g of silica gel with ethyl acetate. α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol is obtained as a brown oil. b) Add 4.0 g of a-(3,4-dimethoxy-5-nitrophenyl)-2-pyridinemethanol dissolved in 100 ml of acetone under constant heating and

reflux over a period of 2.5 hours portionwise 7 g of manganese dioxide. It is then heated under reflux for a further 2 hours. The manganese salts are then filtered off and the residue obtained after evaporation is recrystallized from ether/hexane. 3,4-dimethoxy-5-nitrophenyl-2-pyridyl ketone is obtained with m.p. 113°C.

c) 1.5 g of 3,4-dimethoxy-5-nitrophenyl-2-pyridyl ketone dissolved in 30 ml of 48% hydrogen bromide is stirred for 18 hours at 100°C. Then

the reaction mixture is evaporated and the residue is recrystallized from acetonitrile/methanol. This gives 3,4-dihydroxy-5-nitrophenyl-2-pyridyl ketone hydrobromide with m.p. 213°C.

Example 4 8

a) 11.3 g of tin dichloride dihydrate is added to 2.25 g of 3',4'-dimethoxy-5'-nitroacetophenone dissolved in 50 ml of ethanol, after which

stirring 30 min. at 75°C. The reaction mixture is then poured onto 100 g of ice, neutralized with 300 ml of saturated sodium bicarbonate solution and mixed with 150 ml of methylene chloride. The methylene chloride phase is filtered and separated. This is dried over sodium sulfate

and evaporated, and the residue recrystallized from ether/petroleum ether. 5'-amino-3',4'-dimethoxyacetophenone is obtained with m.p. 63-65°C.

b) To 14.0 g of 5'-amino-3',4'-dimethoxyacetophenone dissolved in

155 ml of 1 N-hydrochloric acid is dripped at 0°C over 20 minutes. a solution

of 5.2 g of sodium nitrite in 20 ml of water. After 30 min. stirring at - 2°C, the cold diazonium salt solution is dripped over the course of 30 min. at 5-10°C to a solution of 8.7 g of copper (I) cyanide and 5.45 g of potassium cyanide in 60 ml of water. After the addition is complete, add 200 ml

methylene chloride, and the reaction mixture is stirred for 3 hours at 23°C and then filtered. The organic phase is separated, washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized from methylene chloride/petroleum ether. 5'-cyano-3',4'-dimethoxyacetophenone is obtained with m.p. 125-126°C.

c) 3.75 g of aluminum powder and 28.5 g of iodine are heated in 160 ml of absolute benzene for 2 hours under reflux. At 20°C add

then 3.0 g of 5'-cyano-3',4'-dimethoxyacetophenone and 0.5 g of tetra-n-butylammonium iodide, after which heating is done at reflux for 1 hour. Then mix at 20°C with 50 g of ice and filter. The residue is washed with ethyl acetate. The phases are separated, and the aqueous phase is again extracted twice with ethyl acetate. The combined organic phases are washed with 20% sodium thiosulphate solution, dried over sodium sulphate and evaporated. The resulting residue is dissolved in 20 ml of acetic anhydride and 0.5 ml of pyridine and stirred for 6 hours at 120°C. The mixture is then evaporated and the residue is distributed between methylene chloride and ice water. The methylene chloride phase is dried over sodium sulphate and evaporated, and the residue is chromatographed on 100 g of silica gel with methylene chloride. After recrystallization from ether, 5'-cyano-3',4'-diacetoxyacetophenone with m.p. 76-79°C.

Example 49

0.33 g of 5'-cyano-3',4'-diacetoxyacetophenone dissolved in 3.3 ml of methanol is mixed with 2.7 ml of 1.0 N caustic soda, and the reaction mixture is stirred for 45 min. at 23°C. Then acidify with 2N hydrochloric acid, dilute with 5 ml of saturated sodium chloride solution and extract twice with 30 ml of ethyl acetate each time. The combined ethyl acetate phases are dried over sodium sulfate and evaporated. The rest is recrystallized

from toluene/acetonitrile. 5'-cyano-3',4'-dihydroxyacetophenone is obtained as brownish crystals which decompose above 215°C.

Example 50

a) To 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30 ml of tetrahydrofuran is added dropwise at room temperature over 45 minutes. 3.48 g of phenyltrimethylammonium bromide-dibromide dissolved in 30 ml of tetrahydrofuran, after which it is stirred for 30 min. The reaction mixture is then poured into 120 ml of ice water and extracted three times with 70 ml of methylene chloride. The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulphate and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, 5-(bromoacetyl)-2,3-dimethoxybenzonitrile with m.p. 138-141°C. b) 1.45 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile and 1.12 g of selenium dioxide are stirred in 10 ml of n-hexanol for 18 hours at 120°C. After cooling to room temperature, dilute with 20 ml of methylene chloride and filter. The filtrate is washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on 70 g of silica gel with hexane/ether (2:1). Hexyl-(3-cyano-4,5-dimethoxyphenyl)-glyoxylate is obtained as an oil. c) To 4.0 g of hexyl-(3-cyano-4,5-dimethoxyphenyl)glyoxylate dissolved in 100 ml of methylene chloride is added dropwise under ice cooling during 20 min. 4.8 ml of boron tribromide dissolved in 20 ml of methylene chloride, and the reaction mixture is stirred for 18 hours at room temperature. Then 40 ml of methanol are added dropwise at -60°C, stirred for 1 hour at room temperature and evaporated. The rest is taken up in methanol. It is heated for 10 min. under reflux, evaporated to dryness and dried in high vacuum. The crude product thus obtained is recrystallized from acetonitrile. Methyl-(3-cyano-4,5-dihydroxyphenyl)glyoxylate with m.p. 252°C.

Example 51

1.075 g of methyl-(3-cyano-4,5-dihydroxyphenyl)glyoxylate and 0.60 g of 2-amino-p-cresol are stirred for 70 minutes. at 120°C in 2 ml of dimethylformamide. Then cool to room temperature and dilute with 15 ml of water. The precipitate is filtered off and dried for 6 hours at 80°C in a water jet vacuum. After recrystallization from acetonitrile, 2,3-dihydroxy-5-(6-methyl-2-oxo-2H-1,4-benzoxazin-3-yl)benzonitrile is obtained with m.p. 278-280°C.

Example 52

a) A solution of 2.5 g (10.2 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is mixed with 1.1 ml

isocyanoacetic acid ethyl ester and then a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred for 48 hours at room temperature. After distilling off the solvent, extract with vinegar/water. The crude product obtained after evaporation is chromatographed on the 20-fold amount of silica gel with acetic acid. After recrystallization from ethyl acetate/hexane, ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazole carboxylate is obtained in the form of yellow crystals with m.p. 109-110°C. b) 1.0 g (3.1 mmol) of ethyl 5-(3,4-dimethoxy-5-nitrophenyl)-4-oxazole carboxylate is mixed with 10 ml of constant boiling hydrogen bromide and stirred for 2 hours at 140°C. After distilling off the excess hydrogen bromide, the yellow residue is redissolved from ethanol/acetone. 2-amino-3',4'-dihydroxy-5'-nitroacetophenone hydrobromide is obtained in the form of yellow crystals with m.p. >250°C (decomposition) .

Example 53

a) 10 g (34 mmol) of ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetate are suspended in 100 ml of ethanol, mixed with 1.7 g (37 mmol) of methylhydrazine and heated for 16 hours under reflux. After distilling approx. 50 ml of ethanol are cooled to 0°C, and the precipitate that has formed is filtered off. After recrystallization from ethanol, 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol is obtained in the form of yellow crystals with m.p. 200-202°C. b) 2.0 g (7.2 mmol) of 3-(3,4-dimethoxy-5-nitrophenyl)-1-methylpyrazol-5-ol are suspended in 100 ml of methylene chloride. After cooling to -40°C, a solution of 4.9 ml of boron tribromide in 60 ml of methylene chloride is added dropwise over the course of one hour. then stirred at room temperature for 16 hours, cooled to -20°C and mixed with 100 ml of ethanol during 30 min. After stirring at room temperature for one hour, the solvent is distilled off in a water jet vacuum at 40°C. The residue is mixed three times with a mixture of 100 ml of ethanol/toluene each time, during which the solvent is constantly distilled off. The residue is recrystallized from ethanol. 5-(S-hydroxy-1-methylpyrazol-S-yl)-3-nitropyrocatechol hydrobromide is obtained in the form of yellow crystals at m.p. >250°C.

Example 54

a) 16.8 g (0.7 g atom) of magnesium are mixed with 15 ml of ethanol and after the addition of 2 ml of carbon tetrachloride, the reaction is started

during heating. While stirring, drip over the course of 30 min. a solution of 130.3 g of tert.butyl ethyl malonate in 70 ml of ethanol and 600 ml of absolute ether so that the reaction proceeds at reflux temperature. The mixture is then stirred for 3 hours at 50°C, and the solvent is distilled off at 40°C in a water jet vacuum. The residue is dissolved in 900 ml of tetrahydrofuran. A solution of 170 g (0.7 mol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 700 ml of absolute tetrahydrofuran is added dropwise while stirring at 50°C and stirred for one hour at the reflux temperature. The solvent is distilled off at 40°C in a water jet vacuum. The residue is mixed with 1 1 ether. While stirring and cooling, 260 ml of 3N sulfuric acid is added and stirred for 30 min. The aqueous phase is extracted twice with 600 ml of ether each time. The organic phase is washed neutral with water, dried over sodium sulfate and evaporated. The brown oil obtained is filtered with toluene over 1 kg of silica gel. The mixture obtained, which consists of ethyl tert-butyl-(3,4-dimethoxy-5-nitrobenzoyl)malonate and ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetate, is dissolved in 600 ml of methylene chloride and mixed under stirring during approx. 30 min. with 193 ml of trifluoroacetic acid. Then stir for 2 hours at 40°C and then evaporate at 40°C in a water jet vacuum. The oil obtained is extracted with ether/water. The organic phase is dried over sodium sulfate and evaporated. After dissolution in diisopropyl ether/hexane and cooling, the precipitated crystals are filtered off and recrystallized from diisopropyl ether. Ethyl-(3,4-dimethoxy-5-nitrobenzoyl)acetate is obtained in the form of slightly yellowish crystals with m.p. 67-68°C.

b) 10.0 g (33.6 mmol) of ethyl (3,4-dimethoxy-5-nitrobenzoyl)acetate is reacted analogously to example 53a with 4.0 g (37 mmol) of phenylhydrazine. After recrystallization from methylene chloride/ethanol, 3-(3,4-dimethoxy-5-nitrophenyl)-1-phenyl-2-pyrazolin-5-one is obtained in the form of

yellow crystals with m.p. 190-192°C.

c) Analogous to example 53b, with boron tribromide 5-(5-hydroxy-1-phenylpyrazol-3-yl)-3-nitropyrocatechol hydrobromide is obtained in

form of yellow crystals with m.p. >220°C (decomposition).

Example 55

20.1 g of diethyl-(3,4-dimethoxy-5-nitrobenzoyl)malonate are dissolved in 200 ml of methylene chloride, after which it is cooled to -20°C and at this temperature with stirring for 15 min. drops to a solution of 68.1 g of boron tribromide in 120 ml of methylene chloride. Then stir overnight at room temperature. After cooling to -20°C, mix with 300 ml of ethanol and stir for 30 min. at room temperature. The solvent is distilled off in a water jet vacuum at 40°C. The residue is mixed with 300 ml of ice water and methylene chloride. The organic phase is washed with water, dried over sodium sulphate and evaporated. The crude product obtained is chromatographed on the 10-fold amount of silica gel with toluene. After recrystallization from methylene chloride/hexane, ethyl-(3,4-dihydroxy-5-nitrobenzoyl)acetate is obtained in the form of yellow crystals with m.p. 136-137°C.

Example 56

2.0 g (7.4 mmol) of ethyl-(3,4-dihydroxy-5-nitrobenzoyl)acetate are suspended in 50 ml of ethanol. After mixing with 0.4 g of hydrazine hydrate, the temperature is maintained at the reflux temperature for 16 hours. After the solvent has been distilled off, the residue is boiled together with 50 ml of acetic acid for 5 min. The precipitate that has formed is filtered off, and the filtrate is evaporated to 10 ml. The crystals that fall out cold are filtered off. 5-(5-Hydroxypyrazol-3-yl)-3-nitropyrocatechol is obtained in the form of orange crystals with m.p. 228°C (decomposition).

Example 57

7.3 g (36.66 mmol) of 3,4-dihydroxy-5-nitrobenzoic acid are mixed with 30 ml of acetic anhydride, after which it is heated for 8 hours at reflux temperature. The reaction mixture is poured onto ice. The precipitate is filtered off, washed with water and taken up in methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The residue obtained is recrystallized from cold methylene chloride/n-hexane. 3,4-diacetoxy-5-nitrobenzoic acid is obtained in the form of colorless crystals with m.p. 126-127°C.

Example 58

a) 9.7 g (32.2 mmol) of 3,4-diacetoxy-5-nitrobenzoic acid are mixed with 12.5 ml of thionyl chloride, after which it is stirred for 1.5 hours at

100°C. After distillation of excess thionyl chloride, 5-(chlorocarbonyl)-2-nitro-o-phenylenediacetate, boiling point 160°C (26.7 Pa), is distilled.

b) 3.2 g (10.6 mmol) of 5-(chlorocarbonyl)-2-nitro-o-phenylene diacetate are dissolved in 50 ml of dimethylformamide. The ice-cold solution is mixed

while stirring with a solution of 2.2 ml of diethylamine in 20 ml of dimethylformamide. The mixture is then stirred for 1 hour at room temperature, after which the solvent is distilled off in a water jet vacuum at 50°C. The obtained residue is mixed with water and methylene chloride. The organic phase is dried over sodium sulfate and evaporated. The yellow resin obtained crystallizes from methylene chloride/ether. N,N-diethyl-3,4-dihydroxy-5-nitrobenzamide is obtained in the form of yellow crystals with m.p. 145-146°C.

Example 59

3.2 g (10.6 mmol) of 5-(chlorocarbonyl)-2-nitro-o-phenylene diacetate are dissolved in 50 ml of dimethylformamide, after which at 0-5°C with stirring and during 40 min. mixing with a solution of 3.02 ml of 2,2-diethylaminoethylamine in 20 ml of dimethylformamide. Then stir for 30 min. at room temperature. The solvent is distilled off at 60°C in a water jet vacuum. The residue is extracted twice with 20 ml of ethanol each time, dissolved in hot ethanol and mixed with an excess of an ethanolic hydrochloric acid, after which it is evaporated. After recrystallization from ethanol/acetic acid, N-[2-(diethylamino)ethyl]-

3,4-dihydroxy-5-nitrobenzamide hydrochloride in form 1 of yellow crystals with m.p. 139°C (decomposition).

Example 60

a) 10.0 g (47.4 mmol) of 2,3-dimethoxy-5-nitrobenzaldehyde is mixed with 50 ml of glacial acetic acid and 50 ml of constant-boiling hydrogen bromide and

kept for 7 hours at reflux temperature. After mixing with ice, the precipitate is filtered off, washed with water and absorbed in vinegar. The organic phase is dried over sodium sulfate and evaporated. The crude product obtained is filtered with vinegar through silica gel. After crystallization from ethyl acetate/hexane, 2,3-dihydroxy-5-nitrobenzaldehyde is obtained in the form of brownish crystals with m.p. 226-228°C.

b) 4.5 g of 2,3-dihydroxy-5-nitrobenzaldehyde is suspended in 75 ml of water. After mixing with 4.2 g of hydroxylamine-o-sulfonic acid, stir

for 16 hours at 65°C. After cooling, the precipitated crystals are filtered off and washed with water. The filtrate is extracted with vinegar. The crystals and the dried organic phase are combined, after which the residue is evaporated and recrystallized from diisopropyl ether. 2,3-dihydroxy-5-nitrobenzonitrile is obtained in the form of yellow crystals with m.p. 186-188°C.

Example 61

a) 4.0 g (19.2 mmol) of 3,4-dimethoxy-5-nitro-benzonitrile is dissolved in 50 ml of dimethylformamide, after which it is mixed with 1.66 g

ammonium chloride and 2.02 g of sodium azide and stir for 31 hours at 125°C. After respectively 8 and 15 hours, the same amount of ammonium chloride and sodium azide is added once more. After cooling, pour over ice.

The precipitate is filtered off, washed with water and dried. 2-Methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenol is obtained in the form of orange crystals with m.p. >240°C (decomposition). b) 4.0 g (16.9 mmol) of 2-methoxy-6-nitro-4-(1H-tetrazol-5-yl)phenyl is mixed with 40 ml of constant-boiling hydrogen bromide, after which it is stirred for 8 hours at 140°C under nitrogen atmosphere. After cooling, pour over ice. The precipitate is filtered off and recrystallized from ether. 3-nitro-5-(1H-tetrazol-5-yl)pyrocatechol is obtained in the form of orange crystals with m.p. >240°C (decomposition).

Example 62

To 13 0 ml conc. sulfuric acid is introduced while stirring during 10 min. in portions, a total of 7.2 g (40 mmol) of 3,4-dihydroxy-5-nitrobenzonitrile, after which it is stirred for 4 hours at 50°C. The reaction mixture is poured into 800 ml of ice water. The precipitate is filtered off, washed with water and taken up in vinegar. The organic phase is dried over sodium sulfate and evaporated. After recrystallization from acetone/acetic ester, 3,4-dihydroxy-5-nitrobenzamide is obtained in the form of orange crystals with m.p. 235-236°C.

Example 63

a) To a suspension of 3.6 g (82.5 mmol) of a 55% sodium hydride dispersion in 50 ml of absolute dimethylformamide, dropwise under

argon atmosphere within 15 min. a solution of 11.25 g (82.6 mmol) of 2-hydroxyacetophenone in 100 ml of absolute dimethylformamide and stir for one hour at room temperature. After cooling to 0°C, drip within 20 min. a solution of 20.3 g (82.6 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of absolute dimethylformamide to this and stir overnight at room temperature. The reaction mixture is poured onto ice water, after which it is extracted twice with 250 ml of acetic acid each time. The organic phase is washed twice with 100 ml of sodium chloride solution each time, dried over sodium sulfate and evaporated. The brown oil obtained is heated in 100 ml of toluene. The precipitate that precipitates is filtered off, and the filtrate is chromatographed on the 30-fold amount of silica gel with toluene/acetic ester (4:1). After recrystallization from ethyl acetate/hexane, o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate is obtained in the form of yellowish crystals with m.p. 108-109°C.

b) Dissolve 10.0 g (29 mmol) of o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate in 50 ml of pyridine. After mixing with 8.12 g (144 mmol)

powdered and dried potassium hydroxide is stirred for 5 min. at 80°C.

After cooling, the whole thing is poured over ice. The aqueous solution is acidified by mixing with 3N hydrochloric acid. The precipitate is filtered off. After recrystallization from ethyl acetate/hexane, 1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione is obtained in the form of yellowish crystals with m.p. 188-189°C.

c) To a solution of 500 mg (1.45 mmol) 1-(o-hydroxyphenyl)-3-(3,4-dimethoxy-5-nitrophenyl)-1,3-propanedione in 50 ml methylene chloride

a solution of 1.82 g (0.7 ml) of boron tribromide in 20 ml of methylene chloride is added dropwise with stirring and an argon atmosphere at -20°C over approx. 20 min., after which it is stirred overnight at room temperature. After cooling to -20°C, mix dropwise with 25 ml of ethanol and evaporate in a water jet vacuum at 40°C. After redissolving from ethanol, 1-(3,4-dihydroxy-5-nitrophenyl)-3-(o-hydroxyphenyl)-1,3-propanedione is obtained in the form of yellow crystals with m.p. 251-252°C.

Example 64

a) A solution of 2.0 g (5.79 mmol) of o-acetylphenyl-3,4-dimethoxy-5-nitrobenzoate in 12.5 ml of glacial acetic acid is mixed with 0.94 g of sodium acetate

and kept at reflux temperature for 4 hours. After cooling, pour over ice water. The precipitated crystals are filtered off. After recrystallization from ethyl acetate/hexane, 2-(3,4-dimethoxy-5-nitrophenyl)-4H-1-benzopyran-4-one is obtained in the form of colorless crystals with m.p. 216-217°C.

b) Add dropwise to a solution of 1.0 g (2.9 mmol) 2-(3,4-dimethoxy-S-nitrophenyl)-4H-1-benzopyran-4-one in 100 ml methylene chloride

at -10°C under an argon atmosphere, a solution of 10 ml of boron tribromide in 50 ml of methylene chloride during 30 min., after which it is stirred overnight at room temperature. After cooling to -20°C, 20 ml of ethanol are added dropwise. Then evaporate at 40°C in a water jet vacuum. The resulting yellow residue is extracted with water/acetic acid. The organic phase is washed with water, dried over sodium sulphate and evaporated. After recrystallization from ethanol/acetic ester, 2-(3,4-dihydroxy-5-nitrophenyl)-4H-1-benzopyran 4-one is obtained in the form of yellow crystals with m.p. >240°C (decomposition).

Example 65

a) To 33.0 g of 4-bromobenzotrifluoride (dissolved in 150 ml of tetrahydrofuran) is added dropwise at -70°C during 20 min. 92 ml of n-butyl lithium solution (1.6 M in hexane). After 45 min. stirring at -70°C, 3 6 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran) are added dropwise between -70°C and -60°C. The reaction mixture is stirred for 2 hours at -70°C and 1 hour at 0°C, poured onto a mixture of ice and 100 ml of 2N sulfuric acid and extracted twice with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. 4-(Benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol is obtained, which can be used directly in the subsequent reaction step.

b) 52.6 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzhydrol (dissolved in 500 ml of methylene chloride) are mixed during 10 minutes. by

20°C with 30.6 g of pyridinium chlorochromate and stirred for 2 hours at 20°C. The formed precipitate is then filtered off and washed with methylene chloride. The filtrate is evaporated, and the residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone with a melting point of 101°C is obtained.

c) To 20 g of 4-(benzyloxy)-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 150 ml methylene chloride (put at 10°C 70 ml 33-%

hydrogen bromide in acetic acid during 15 min. After stirring for 1.5 hours at 20°C, the reaction mixture is poured into 600 ml of ice water, the methylene chloride phase is separated and the aqueous phase is extracted twice more with 100 ml of methylene chloride. The combined methylene chloride phases are washed with 600 ml of water, dried over sodium sulphate and

is evaporated. The residue is chromatographed on 150 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone with a melting point of 97°C is obtained.

d) To 12.8 g of 4-hydroxy-3-methoxy-4'-(trifluoromethyl)benzophenone (dissolved in 160 ml of acetic acid) is added dropwise over the course of 10 min. at 20°C

3.2 ml of 65% nitric acid. After stirring for 1.5 hours, the reaction mixture is poured into 600 ml of ice water, and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride/hexane. You get 4-hydroxy-

3-Methoxy-5-nitro-4(trifluoromethyl)benzophenone with melting point 172°C.

e) 2.0 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzo-phenone (dissolved in 20 ml of 33% hydrogen bromide in acetic acid) is stirred for 18

hours at 90°C. Then 20 ml of 48% aqueous hydrogen bromide is added, after which it is stirred for a further 18 hours at 110°C. The reaction mixture is then evaporated under reduced pressure, and the residue is crystallized from water. This gives 3,4-dihydroxy-5-nitro-4'-(trifluoromethyl)benzophenone with m.p. 116-118°C.

Example 66

a) 18.7 g of 4-hydroxy-3-methoxy-5-nitro-4'-(trifluoromethyl)benzo-phenone (dissolved in 250 ml of tetrahydrofuran) is mixed at room temperature with 27.5 ml of 2N potassium hydroxide solution, after which it is evaporated . The residue is mixed with 200 ml of toluene, after which it is evaporated again. It is then heated with 400 ml of toluene for 4 hours under water separation and under reflux. 100 ml of toluene is distilled off again and 10 ml of dimethylformamide and 20 ml of dimethylsulphate (freshly distilled) are added, after which it is heated for 5 hours under reflux. Then 300 ml of 1N caustic soda is added at 20°C. The reaction mixture is stirred for 30 min. and mixed with 200 ml of ether. The organic phase is separated; the aqueous phase is extracted twice more with 100 ml of ether; the combined ether phases are dried over sodium sulfate and evaporated, and the residue is chromatographed on 70 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, 3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone with m.p. 115°C. b) 49.5 g of tin dichloride dihydrate is added to 16.0 g of 3,4-dimethoxy-5-nitro-4'-(trifluoromethyl)benzophenone (dissolved in 300 ml of ethanol), after which it is stirred for 30 min. at 75°C. The reaction mixture is then poured into 800 ml of ice water. It is neutralized with 28% sodium hydroxide solution and extracted three times with 600 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and evaporated. After recrystallization from methylene chloride/hexane, 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone with m.p. 95-96°C. c) 3.25 g of 5-amino-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone (dissolved in 50 ml of acetone) is evaporated after adding 15 ml of 2N-sulfuric acid under reduced pressure. The residue thus obtained is suspended in 20 ml of acetic acid, diluted with 100 ml of water and mixed at 5°C with a solution of 700 mg of sodium nitrite in 10 ml of water. It is stirred for 1 hour at 5°C. The diazonium salt solution is then filtered, added at 5°C to a solution of 2.0 g of sodium cyanide and 1.0 g of copper (I) cyanide in 20 ml of water and stirred for 1 hour at

5°C. 200 ml of methylene chloride is then added. Insoluble parts are filtered out. The phases are separated, the aqueous phase is extracted twice more with 100 ml of methylene chloride. The combined methylene chloride phases are washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on 30 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane, 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone with m.p. 130°C.

d) 1.5 g of 5-cyano-3,4-dimethoxy-4'-(trifluoromethyl)benzophenone (dissolved in 75 ml of methylene chloride) is mixed at 5°C with 2.18 ml

boron tribromide, after which it is stirred for 18 hours at room temperature. The reaction mixture is then diluted with 50 ml of methylene chloride. It is heated for a further 4 hours under reflux, mixed at -70°C with 15 ml of methanol, stirred for 2 hours at room temperature, evaporated, the residue dried in a vacuum and distributed between ethyl acetate and ice water. The aqueous phase is extracted twice more with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulphate and evaporated. The material thus obtained is stirred with 10 ml of acetic anhydride and 1 ml of pyridine for 6 hours at 130°C. It is evaporated and the residue is distributed between ice water <p>g methylene chloride. The methylene chloride phase is dried over sodium sulphate and evaporated, and the residue is chromatographed on 30 g of silica gel with methylene chloride. The diacetate thus obtained is dissolved in 10 ml of methanol. It is mixed with 4.2 ml of 1N caustic soda, stirred for 1 hour at 0°C, neutralized with acetic acid, evaporated and distributed between ethyl acetate and saturated sodium chloride solution. The ethyl acetate phases are dried over sodium sulfate and evaporated, and the residue is recrystallized from methylene chloride. 5-cyano-3,4-dihydroxy-4'-(trifluoromethyl)benzophenone is obtained with m.p. 204-206°C.

Analogously, you get:

al) From 2-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone with m.p. 86-88°C (from ether/petroleum ether, ts.),

bl) from 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone 5-amino-3,4-dimethoxy-2'-fluorobenzophenone with m.p. 93-95°C (from ether/petroleum ether, ts.),

cl) from 5-amino-3,4-dimethoxy-2'-fluorobenzophenone 5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile with m.p. 132-134°c (from methylene chloride/petroleum ether, ts) and

dl) from 5-benzoyl-2,3-dimethoxy-2'-fluorobenzonitrile 5-benzoyl-2,3-dihydroxy-2'-fluorobenzonitrile with m.p. 228-230°C (from ether/petroleum ether, ts.).

Analogously, you get:

b2) From 3,4-dimethoxy-5-nitrobenzophenone 5-amino-3,4-dimethoxy-benzophenone as an amorphous solid,

c2) from 5-amino-3,4-dimethoxybenzophenone 5-benzoyl-2,3-dimethoxy-benzonitrile with m.p. 98-100°C (from ether/hexane) and

d2) from 5-benzoyl-2,3-dimethoxybenzonitrile 5-benzoyl-2,3-dihydroxybenzonitrile with m.p. 212-214°C (from acetic acid/ether).

Example 67

a) To a solution of 2.68 g (32.64 mmol) 1-methylimidazole and

A solution of 6.6 g (65.14 mmol) triethylamine in 80 ml pyridine is added dropwise

of 16.0 g (65.14 mmol) of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine, after which it is stirred for 3 hours at 60°C. After mixing with 1.70 ml of 3N caustic soda, it is stirred for a further 1 hour and then poured into ice water. The precipitated gray crystals are filtered off and taken up in vinegar, after which the organic phase is dried over magnesium sulphate and the solvent is distilled away. After

recrystallization from ethyl acetate/hexane gives 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl)ketone in the form of colorless crystals with m.p. 144-145°C.

b) 5.0 g (17.17 mmol) of 3,4-dimethoxy-5-nitrophenyl (1-methylimidazol-2-yl) ketone are mixed with 50 ml of hydrogen bromide (48%), after which

stirring for 2 hours at reflux temperature. After cooling, the precipitate is filtered off, washed with ice water and recrystallized from ethanol. 3,4-dihydroxy-5-nitrophenyl (1-methylimidazol-2-yl)ketone hydrobromide is obtained in the form of yellow crystals with a cleavage point >24 0°C.

Example 68

Analogous to example 67, from 3,4-dimethoxy-5-nitro-benzoyl chloride and 1-benzylimidazole, 1-benzylimidazol-2-yl (3,4-dimethoxy-5-nitrophenyl)ketone is obtained in the form of colorless crystals with m.p. 134-135°C (from methylene chloride/hexane) and thence with hydrogen bromide 1-benzylimidazol-2-yl (3,4-dihydroxy-5-nitrophenyl)ketone hydrobromide as yellow crystals with m.p. 218-219°C (decomposition).

Example 69

a) To a solution of 13.0 g (53.13 mmol) 3,4-dimethoxy-5-nitrobenzoyl chloride and 5.4 g (53.13 mmol) triethylamine in 80 ml

acetonitrile is dripped over 10 min. a solution of 10.0 g (53.13 mmol) of 1-[(benzyloxy)methyl]imidazole in 50 ml of acetonitrile under ice-cooling so that the temperature does not exceed 25°C. It is then stirred for a further 3 hours, after which the solvent is distilled off. After mixing with water, extract with vinegar. After washing twice with water, the organic phase is dried over sodium sulphate and evaporated. The obtained oil is chromatographed on 600 g of silica gel with toluene/acetic ester (95:5). 1-[(benzyloxy)-methyl]imidazol-2-yl (3,4-dimethoxy-5-nitrophenyl)ketone is obtained as a yellowish oil. b) Analogous to example 67b), after treatment with hydrogen bromide 3,4-dihydroxy-5-nitrophenyl (imidazol-2-yl)ketone hydrobromide is obtained as yellow crystals with m.p. 247-248°C.

Example 7 0

a) A solution of 25.0 g (120.16 mmol) of 3-bromoquinoline is dissolved in 200 ml of dry ether and cooled to -60°C. At this temperature

is infused within 15 min. 75.1 ml (120.16 mmol) of a 1.6-molar solution of n-butyllithium, after which one stirs for 10 min. To this, at -60°C, a solution of 2 6.5 g (109 .2 mmol) vanillin benzyl ether in 250 ml of dry ether, then stir for 3 hours at room temperature, rather at approx. 1.5 1 ice water and extract three times with 600 ml of vinegar each time. The organic phase is washed with water, dried over sodium sulphate and evaporated. The oil obtained is chromatographed on 1 kg of silica gel with methylene chloride/acetic acid (1:1). The crystalline crude product obtained is redissolved from acetic acid. α-[4-(benzyloxy)-3-methoxyphenyl]-3-quinolinemethanol is obtained in the form of colorless crystals with m.p. 124-125°C.

b) A solution of 6.2 g (16.7 mmol) of α-[4-(benzyloxy)-3-methoxy-phenyl]-3-quinoline methanol in 200 ml of methylene chloride is stirred after

mixture with 62 g of manganese dioxide for 2 hours at reflux temperature. After cooling, the precipitate is filtered off and washed with methylene chloride. The filtrate is evaporated and the oil obtained is dissolved in hot ether, after which it is mixed with a little pentane. The precipitated crystals are filtered off. 4-(Benzyloxy)-3-methoxyphenyl (3-quinoline)ketone is obtained in the form of colorless crystals with m.p. 110-111°C.

c) 11.0 g (29.78 mmol) of 4-(benzyloxy)-3-methoxyphenyl (3-quinoline) ketone are mixed with 50 ml of trifluoroacetic acid, after which

stir for 2 hours at room temperature. After the trifluoroacetic acid has been distilled off, it is mixed twice with 50 ml of ethanol each time and the solvent is constantly distilled off. The oil obtained crystallizes when mixed with ethanol. After recrystallization from ethanol, 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone is obtained in the form of yellow crystals with m.p. 196-197°C.

d) To a solution of 5.5 g (19.69 mmol) of 4-hydroxy-3-methoxyphenyl (3-quinolinyl) ketone in 300 ml of glacial acetic acid, at 15°C a

solution of 1.91 ml of 65% nitric acid in 20 ml of glacial acetic acid and then stir

further for 2 hours at this temperature. The whole is then poured into ice water and extracted three times with 300 ml of vinegar each time. The organic phase is washed five times with 100 ml of water each time, dried over sodium sulphate and evaporated. After mixing the residue with ethyl acetate, 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone is obtained in the form of yellow crystals with m.p. 220-221°C (decomposition).

e) 820 mg (2.53 mmol) of 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone are mixed with 50 ml of 48% hydrogen bromide and kept for 3 hours at the reflux temperature. After the hydrogen bromide has been distilled off at 50°C, the residue is mixed with 70 ml of hot water, and the insoluble part is filtered off. 3,4-dihydroxy-5-nitrophenyl (3-quinolinyl)ketone hydrobromide is obtained in the form of yellow crystals with m.p. 270°C (decomposition).

Example 71

Analogous to example 70, α-[4-(benzyloxy)-3-methoxy-phenyl]-4-quinolinemethanol is obtained as colorless crystals with m.p. 117-118°C (acetic ester), hence with manganese dioxide 4-(benzyloxy)-3-methoxyphenyl (4-isoquinolinyl)ketone as colorless crystals with m.p. 126.5-127.5°C, hence with trifluoroacetic acid 4-hydroxy-3-methoxyphenyl (4-isoquinolinyl)ketone as yellow crystals with m.p. 197.5-198.5°C, and hence by nitration with nitric acid in glacial acetic acid and subsequent treatment with hydrogen bromide 3,4-dihydroxy-5-nitrophenyl (4-isoquinolinyl)ketone hydrobromide as yellow crystals with m.p. 256°C (decomposition).

Example 72

Analogous to example 70, α-[4-(benzyloxy)-3-methoxy-phenyl]-2-naphthalene methanol is obtained as colorless crystals (acetic ester/hexane) with m.p. 113-114°C, hence with manganese dioxide 4-(benzyl-oxy)-3-methoxyphenyl (2-naphthyl)ketone as colorless crystals (acetic ester/hexane) with m.p. 104-105°C, from this by treatment with trifluoroacetic acid and nitration with nitric acid in glacial acetic acid 4-hydroxy-3-methoxy-5-nitrophenyl (2-naphthyl) ketone as yellow crystals with m.p. 187-188°C, and hence on treatment with hydrogen bromide 3,4-dihydroxy-5-nitrophenyl (2-naphthyl)ketone as yellow crystals with m.p. 184-185°C.

Example 7 3

a) A solution of 20.0 g (100.5 mmol) of 3-phenylpropyl bromide in 300 ml of ether is mixed at -60°C with stirring during 15 min. with

a solution of 71.8 ml (100.5 mmol) of tert-butyllithium (1.4 molar) in pentane. After 10 min. at this temperature, a solution of 22.14 g (91.36 mmol) of vanillin benzyl ether in 200 ml of ether is added dropwise over the course of 15 min., after which stirring is continued for 2 hours. The batch is poured into 1 1 ice water and extracted three times with 500 ml of vinegar each time. The organic phase is washed twice with 200 ml of water each time, dried over sodium sulphate and evaporated. The oil obtained is chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained are redissolved from ether/pentane. 4-(Benzyloxy)-3-methoxy-c-(3-phenylpropyl)benzyl alcohol is obtained in the form of colorless crystals with m.p. 71-73°C.

b) A solution of 9.0 g (24.83 mmol) of 4-(benzyloxy)-3-methoxy-α-(3-phenylpropyl)benzyl alcohol in 250 ml of methylene chloride is mixed with

90 g of manganese dioxide and kept for 2 hours at reflux temperature. After cooling, the precipitate is filtered off and washed with methylene chloride. The filtrate is evaporated and the residue is recrystallized from ethyl acetate/ether. 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone is obtained in the form of colorless crystals with m.p. 81-82°C. c) A solution of 7.0 g (19.42 mmol) 4'-(benzyloxy)-3'-methoxy-4-phenylbutyrophenone in 40 ml of 33% hydrogen bromide in glacial acetic acid is stirred for 5 hours at room temperature and then poured into 500 ml ice water. After adding conc. ammonia, the pH is set to 6.0, and extraction is carried out three times with 250 ml of acetic acid each time. The organic phase is washed three times with 50 ml of water each time, dried over sodium sulphate and evaporated. The oil obtained is dissolved in 20 ml of ether, after which it is mixed with hexane until clear and allowed to crystallize. Colorless 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone is obtained with m.p. 91-92°C. d) To a solution of 2.2 g (8.14 mmol) 4'-hydroxy-3'-methoxy-4-phenylbutyrophenone in 25 ml of glacial acetic acid, a solution of 0.79 ml of 65% nitric acid in 25 ml of glacial acetic acid is added dropwise and stir for a further 2 hours at room temperature. The whole is poured into 150 ml of ice water, and after mixing with 20 ml of 3N hydrochloric acid, it is extracted three times with 75 ml of acetic acid each time. The organic phase is washed with water, dried over sodium sulphate and evaporated. The crude product obtained is taken up in vinegar and filtered through 75 g of silica gel. After recrystallization from acetonitrile, 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophenone is obtained in the form of yellow crystals with m.p. 120-121°C. e) 1.0 g (3.2 mmol) of 4'-hydroxy-3'-methoxy-5'-nitro-4-phenylbutyrophene is kept with 8 g of pyridine hydrochloride at 200°C for 1 hour.

The reaction mixture is poured onto ice water while it is still warm and extracted with vinegar. The organic phase is washed with 1N hydrochloric acid and then with water, dried over sodium sulphate and evaporated. The dark residue obtained is chromatographed on double the amount of silica gel with acetic acid. From methylene chloride/hexane, 3',4',dihydroxy-5'-nitro-4-phenylbutyrophenone is obtained in the form of yellow crystals with m.p. 118-119°C.

Example 74

a) To a solution of 10.0 g (47.4 mmol) of 3,4-dimethoxy-5-nitrobenzaldehyde in 100 ml of dioxane is added a solution of 14.68 g

(225.4 mmol) of potassium cyanide in 20 ml of water. Now you drip within 30 minutes. 18.81 ml (190.76 mmol) of 37% hydrochloric acid to this with vigorous stirring. After adding 120 ml of ether, excess hydrocyanic acid gas is expelled by blowing through argon. The reaction mixture is filtered over a filter aid of kieselguhr, and the organic phase is washed with water, dried over sodium sulfate and evaporated. The formed α-hydroxy-3,4-dimethoxyphenylacetonitrile (yellowish oil) is dissolved in 200 ml of ether, after which it is mixed with 20 ml of ethanol, cooled to 0°C and hydrochloric acid gas is introduced for 30 min. After 3 hours of stirring, it is filtered the precipitated colorless precipitate from and redissolved from ethanol/ether. Ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidate hydrochloride is obtained.

b) Dissolve 19.7 g (61.46 mmol) of ethyl (3,4-dimethoxy-5-nitrophenyl)hydroxyacetimidate hydrochloride in 500 ml of ethanol, after which

after adding 6.73 g (61.46 mmol) of o-phenylenediamine, stir for 2 hours at room temperature and then maintain the reflux temperature overnight. After distilling off the solvent, mix with

50 ml of water, made alkaline with soda solution and extracted twice with 250 ml of methylene chloride each time. The organic phase is washed with water, dried over sodium sulphate and evaporated. The orange residue obtained is chromatographed on 400 g of silica gel with methylene chloride/acetic acid (1:1). From ether/hexane, α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazole methanol is obtained in the form of yellowish crystals with m.p. 50°C (decomposition). c) 13.2 g (40.1 mmol) α-(3,4-dimethoxy-5-nitrophenyl)-2-benzimidazolemethanol is dissolved in 200 ml of methylene chloride, after which, after mixing with 130 g of manganese dioxide, it is stirred for 2 hours at return temperature. After filtration, the solvent is distilled off. 2-benzimidazolyl (3,4-dimethoxy-5-nitrophenyl)ketone is obtained in the form of yellowish crystals with m.p. 212-213°C. d) 1.0 g (3.05 mmol) of 2-benzimidazolyl (3,4-dimethoxy-5-nitro-nyl) ketone and 8.0 g of pyridine hydrochloride are kept at 200°C for 60 min. The dark solution poured onto ice water while it is still warm and extracted three times with 100 ml of vinegar each time. The organic phase is washed with water, dried over sodium sulphate and evaporated. After recrystallization from ethyl acetate/hexane, 2-benzimidazolyl (3,4-dihydroxy-5-nitrophenyl) ketone is obtained in the form of yellow crystals with m.p. 249-250°C.

Example 75

a) 30.0 g (132 mmol) of 3,4-dimethoxy-5-nitrobenzoic acid are dissolved in 250 ml of tetrahydrofuran, after which, after the addition of 21.85 g

(135 mmol) of 1,1'-carbonyldiimidazole is stirred for 2 hours at reflux temperature. The whole is poured into 300 ml of ice water, and the precipitated crystals are filtered off after 30 min. stirring. These are taken up in methylene chloride, after which the organic phase is washed with water, dried over sodium sulphate and evaporated. After crystallization

from methylene chloride/hexane gives 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in the form of colorless crystals with m.p. 136-137°C.

b) 10.0 g (36.1 mmol) 1-(3,4-dimethoxy-5-nitrobenzoyl)imidazole in 50 ml dimethylformamide is mixed with 6.95 g (93.8 mmol) acetamide oxime, after which stirring is 1 hour at 70°C. It is all poured

after cooling in 500 ml of ice water and stirred for 30 min. The precipitated crystals are filtered off and washed with water. After crystallization from acetic ester, N'-[(3,4-dimethoxy-5-nitrobenzoyl)-oxy]acetamidine is obtained in the form of colorless crystals with m.p. 165-166°C.

c) 2.0 g (7.2 mmol) of N'-[(3,4-dimethoxy-5-nitrobenzoyl)oxy]-acetamidine is kept in 20 ml of glacial acetic acid for 1 hour at reflux temperature. After distilling off the glacial acetic acid, the crystalline residue is dissolved from ether/hexane. 5-(3,4-dimethoxy-5-nitro-nyl)-3-methyl-1,2,4-oxadiazole] is obtained in the form of colorless crystals with m.p. 111°C. d) 2.5 g (9.43 mmol) of 5-(3,4-dimethoxy-5-nitrophenyl)-5-methyl-1,2,4-oxadiazole are dissolved in 70 ml of methylene chloride. After cooling to -60°C, add drop by drop over the course of 20 min. with stirring, a solution of 23.62 g (94.3 mmol) of boron tribromide in 50 ml of methylene chloride, after which the reflux temperature is maintained for 48 hours. After cooling to -60°C, mix with 60 ml of ethanol, and then stir at room temperature for 30 min. The yellow solution is evaporated to dryness, after which the residue is mixed three times with 100 ml of toluene/ethanol (1:1), and the solvent is distilled off each time. After crystallization from ethanol, 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitropyrocatechol is obtained in the form of yellow crystals with m.p. 201-202°C.

Example 76

a) To 35.0 g of 1-bromo-2-fluorobenzene (dissolved in 600 ml of tetrahydrofuran) is added dropwise at -70°C during 30 min. 143.8 ml of n-butyl lithium solution (1.53 M in hexane). After 60 min. stirring wood

-70°C, 48.5 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 450 ml of tetrahydrofuran) are added dropwise for 30 min.. Reaction mixture

stir for 2 hours at -70°C and 30 min. at 0°C, poured onto a mixture of ice and 150 ml of 2N sulfuric acid and extracted three times with 500 ml of ether. The combined ether phases are washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated. 2-(Benzyloxy)-2'-fluoro-3-methoxybenzhydrol is obtained as a yellowish oil, which can be used directly in the following reaction step.

Analogously, you get:

al) From 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-fluorobenzene 4-(benzyloxy)-3'-fluoro-3-methoxybenzhydrol as an oil;

a2) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-fluorobenzeh 4-(benzyloxy)-4'-fluoro-3-methoxybenzhydrol as an oil;

a3) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2,6-difluoro-benzene 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol as an oil;

a4) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-chlorobenzene 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol as an oil;

a5) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-3-chlorobenzene 4-(benzyloxy)-3'-chloro-3-methoxybenzhydrol as an oil;

a6) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-4-chlorobenzene 4-(benzyloxy)-4'-chloro-3-methoxybenzhydrol as an oil;

a7) from 4-benzyloxy-3-methoxybenzaldehyde and 2-bromotoluene 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol as an oil;

a8) from 3-methoxy-4-benzyloxybenzaldehyde and 4-bromotoluene 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol as an oil;

a9) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromobenzonitrile 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol as oil and

alO) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-trifluoromethylbenzene 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzhydrol as an oil.

b) 69.8 g of 4-(benzyloxy)-2'-fluoro-3-methoxybenzhydrol (dissolved in 600 ml of methylene chloride) are mixed during 30 min. at 20°C with

45.3 g of pyridinium chlorochromate and stirred for 3 hours at 20°C. The formed precipitate is then filtered off and washed with methylene chloride. The filtrate is evaporated, and the residue is filtered on 100 g of silica gel with ether. After recrystallization from ether, 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone with m.p. 118-120°C.

Analogously, you get:

bl) From 4-(benzyloxy)-3'-fluoro-3-methoxybenzhydrol 4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone as amorphous solid;

b2) from 4-(benzyloxy)-4'-fluoro-3-methoxybenzhydrol 4-(benzyloxy)-4'-fluoro-3-methoxybenzophenone with m.p. 99-101°C (from ether/hexane);

b3) from 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzhydrol 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzophenone with m.p. 139-141°C (from methylene chloride/ether);

b4) from 4-(benzyloxy)-2'-chloro-3-methoxybenzhydrol 4-(benzyloxy)-2'-chloro-3-methoxybenzophenone with m.p. 128-130°C (from ether);

b5) from 4-(benzyloxy)-3'-chloro-3-methoxybenzhydrol 4-(benzyloxy)-3'-chloro-3-methoxybenzophenone as amorphous solid;

b6) from 4-(benzyloxy)-4'-chloro-3-methoxybenzhydrol 4-(benzyloxy)-4'-chloro-3-methoxybenzophenone with m.p. 106-108°C (from methylene chloride/hexane);

b7) from 4-(benzyloxy)-3-methoxy-2'-methylbenzhydrol 4-(benzyloxy)-3-methoxy-2'-methylbenzophenone with m.p. 86-88°C (from isopropyl ether);

b8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzhydrol 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone with m.p. 79-81°C (from ether/hexane);

b9) from 4-(benzyloxy)-2'-cyano-3-methoxybenzhydrol 4-(benzyloxy)-2'. -cyano-3-methoxybenzophenone as an amorphous solid and

blO) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzhydrol 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzophenone with m.p. 103-105°C (from ether).

c) To 42.4 g of 4-(benzyloxy)-2'-fluoro-3-methoxybenzophenone (dissolved in 450 ml of methylene chloride) is added at 20-25°C 170 ml of 33%

hydrogen bromide in glacial acetic acid during 20 min. After 1.5 hours of stirring at 20°C, the reaction mixture is poured into 750 ml of ice water; the methylene chloride phase is separated, and the aqueous phase is extracted twice more with 200 ml of methylene chloride. The combined methylene chloride phases are washed with 1200 ml of water, dried over sodium sulphate and evaporated. To remove the benzyl bromide formed, the oily residue is mixed with hexane and decanted. 2'-Fluoro-4-hydroxy-3-methoxybenzophenone is obtained as a yellowish oil, which can be used directly in the subsequent reaction step.

Analogously, you get:

cl) From 4-(benzyloxy)-3'-fluoro-3-methoxybenzophenone 3'-fluoro-4-hydroxy-3-methoxybenzophenone with m.p. 133-135°C (from methylene chloride/petroleum ether ts.);

c2) from 4-(benzyloxy)-4'-fluoro-3-methoxybenzophenone 4'-fluoro-4-hydroxy-3-methoxybenzophenone with m.p. 139-141°C (from ether);

c3) from 4-(benzyloxy)-2',6'-difluoro-3-methoxybenzophenone 2',6'-difluoro-4-hydroxy-3-methoxybenzophenone with m.p. 130-132°C (from methylene chloride/petroleum ether ts.);

c4) from 4-(benzyloxy)-2'-chloro-3-methoxybenzophenone 2'-chloro-4-hydroxy-3-methoxybenzophenone as amorphous solid;

c5) from 4-(benzyloxy)-3'-chloro-3-methoxybenzophenone 3'-chloro-4-hydroxy-3-methoxybenzophenone with m.p. 136-138°C (from methylene chloride);

c6) from 4-(benzyloxy)-4'-chloro-3-methoxybenzophenone 4'-chloro-4-hydroxy-3-methoxybenzophenone with m.p. 114-116°C (from methylene chloride/petroleum ether ts.);

cl) from 4-(benzyloxy)-3-methoxy-2'-methylbenzophenone 4-hydroxy-3-methoxy-2'-methylbenzophenone with m.p. 103-105°C (from isopropyl ether);

c8) from 4-(benzyloxy)-3-methoxy-4'-methylbenzophenone 4-hydroxy-3-methoxy-4'-methylbenzophenone with m.p. 103-105°C (from ether/petroleum ether ts) ;

c9) from 4-(benzyloxy)-2'-cyano-3-methoxybenzophenone 2'-cyano-4-hydroxy-3-methoxybenzophenone with m.p. 124-126°C (from ether/n-hexane) and

clO) from 4-(benzyloxy)-3-methoxy-2'-(trifluoromethyl)benzophenone 4-hydroxy-3-methoxy-2'-(trifluoromethyl)benzophenone with m.p. 115-117°C (from ether).

d) To 29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid) is added dropwise over the course of 20 min. at 20°C 7.8 ml

65% nitric acid. After stirring for 1.5 hours, the reaction mixture is poured into 2 l of ice water, and the precipitate formed is filtered off, washed with water and dissolved in methylene chloride. The methylene chloride solution is washed with water, dried over sodium sulphate and evaporated. The residue is recrystallized from methanol. This gives 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 127-129°C.

Analogously, you get:

dl) From 3'-fluoro-4-hydroxy-3-methoxybenzophenone 3'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 168-170°C (from methanol); d2) from 4'-fluoro-4-hydroxy-3-methoxybenzophenone 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 126-128°C (from ether); d3) from 2',6'-difluoro-4-hydroxy-3-methoxybenzophenone 2',6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 147-149°C (from methanol); d4) from 2'-chloro-4-hydroxy-3-methoxybenzophenone 2'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 123-125°C (from ether); d5) from 3'-chloro-4-hydroxy-3-methoxybenzophenone 3'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 152-154°C (from methanol); d6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone 4'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 129-131°C (from methylene chloride/petroleum ether ts); d7) from 4-hydroxy-3-methoxy-2'-methylbenzophenone 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenone with m.p. 125-127°C (from ethanol); d8) from 4-hydroxy-3-methoxy-4'-methylbenzophenone 4-hydroxy-3-methoxy-4-methyl-5-nitrobenzophenone with m.p. 137-139°C (from methylene chloride/ether); d9) from 2'-cyano-4-hydroxy-3-methoxybenzophenone 2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone with m.p. 163-164°C (from methanol); dlO) from 4-hydroxy-3-methoxy-2'-(trifluoromethyl)benzophenone 4-hydroxy-3-methoxy-5-nitro-2'-(trifluoromethyl)benzophenone with m.p. 138-140°C (from methylene chloride/petroleum ether ts); dll) from 4-hydroxy-3,4'-dimethoxybenzophenone 4-hydroxy-3,4-dimethoxy-5-nitrobenzophenone with m.p. 134-136°C (from methanol) and dl2) from 4-hydroxy-3,3',4'-trimethoxybenzophenone 4-hydroxy-5-nitro-3,3',4'-trimethoxybenzophenone with m.p. 178-180°C (from methanol). e) 24.8 g of 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone (dissolved in 120 ml of glacial acetic acid, 100 ml of 33% hydrogen bromide in glacial acetic acid and 68 ml of 48% aqueous hydrogen bromide) is boiled for 4 hours under reflux. The reaction mixture is then evaporated under reduced pressure and distilled off with toluene. The residue is dissolved in methylene chloride, washed with water, dried over sodium sulphate, filtered and evaporated. The product is crystallized from methylene chloride/petroleum ether ts. 2'-Fluoro-3,4-dihydroxy-5-nitrobenzophenone is obtained with m.p. 169-171°C.

Analogously, you get:

el) from 3'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone 3'-fluoro-3,4-dihydroxy-5-nitrobenzophenone with m.p. 124-126°C (from methylene chloride);

e2) from 4'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone 4'-fluoro-3,4-dihydroxy-5-nitrobenzophenone with m.p. 171-173°C (from methylene chloride);

e3) from 2',6'-difluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone 2',6'-difluoro-3,4-dihydroxy-5-nitrobenzophenone with m.p. 194-196°C (from methanol);

e4) from 2'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone 2'-chloro-3,4-dihydroxy-5-nitrobenzophenone with m.p. 129-131°C (from methylene chloride/petroleum ether ts);

e5) from 3'-chloro-4-hydroxy-3-methoxy-5-nitrobenzophenone 3'-chloro-3,4-dihydroxy-5-nitrobenzophenone with m.p. 143-145°C (from methylene chloride/petroleum ether ts) ;

e6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone 4'-chloro-3,4-dihydroxybenzophenone with m.p. 174-176°C (from methylene chloride);

e7) from 4-hydroxy-3-methoxy-2'-methyl-5-nitrobenzophenone 3,4-dihydroxy-2'-methyl-5-nitrobenzophenone with m.p. 164-166°C (from methylene chloride);

e8) from 4-hydroxy-3-methoxy-4'-methyl-5-nitrobenzophenone 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone with m.p. 146-148°C (from methylene chloride);

e9) from 2'-cyano-4-hydroxy-3-methoxy-5-nitrobenzophenone 2'-cyano-3,4-dihydroxy-5-nitrobenzophenone with m.p. 159-161°C (from methanol);

elO) from 4-hydroxy-3-methoxy-5-nitro-2'-(trifluoromethyl)benzophenone 3,4-dihydroxy-5-nitro-2'-(trifluoromethyl)benzophenone with m.p. 146-148°C (from methanol);

ell) from 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone 5-nitro-3,4,4'-trihydroxybenzophenone with m.p. 212-214°C (from methanol/methylene chloride) and

el2) from 4-hydroxy-5-nitro-3,3',4'-trimethoxybenzophenone 5-nitro-3,3',4,4'-tetrahydroxybenzophenone with m.p. 222-224°C (from ether).

Example 77

A suspension of 13.8 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 9.0 g of 1-(phenethyl)-2-thiourea in 150 ml of n-butanol and heated at boiling point 3 hours during reflux. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butanol. 3-nitro-5-[2-(phenethylamino)-4-thiazolyl]pyrocatechol hydrobromide with m.p. 249-251°C.

Example 7 8

Analogous to example 38, from 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone and 2-amnobenzophenone, 2-(3,4-dihydroxy-5-nitrobenzoyl)-3-phenylindole with m.p. 196-198°C (from isopropanol).

Example 79

A suspension of 8.3 g of 2-bromo-3',4'-dihydroxy-5'-nitroacetophenone is mixed with 1-(1-adamantyl)-2-thiourea in 90 ml of n-butanol bg heating for 4 hours under reflux at the boiling point. After cooling to room temperature, the crystals are filtered off and recrystallized from n-butanol. 5-[2-(1-adamantylamino)-5-thiazolyl]-3-nitropyrocatechol hydrobromide with m.p. 245-247°C.

Example 80

A suspension of 2.6 g of (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate in 20 ml of ethanol and 20 ml of 1N hydrochloric acid is heated for 5 hours under reflux at the boiling point. The reaction mixture is then evaporated, distilled again with toluene and the residue recrystallized from ethanol. 2,3',4'-trihydroxy-5'-nitroacetophenone is obtained with m.p. 208-210°C.

Example 81

A solution of 4.0 g of 3,4-dihydroxy-5-nitrophenylglyoxylic acid-n-hexyl ester and 1.5 g of diaminomaleic acid nitrile in 35 ml of ethanol is heated for 24 hours under reflux at the boiling point. The alcohol is then distilled off, the residue dissolved in ether, washed with water, dried over sodium sulphate, filtered and evaporated. 6-Hydroxy-5-(3,4-dihydroxy-5-nitrophenyl)-2,3-pyrazine dicarbonitrile with m.p. >300°C (from ether/methylene chloride).

Example 82

a) To 4.2 g of 5-(bromoacetyl)-2,3-dimethoxybenzonitrile dissolved in 150 ml of methylene chloride, add 8.9 ml of boron tribromide. The reaction mixture is stirred for 18 hours at 20°C. This is then poured onto 220 ml of saturated sodium bicarbonate solution and 100 g of ice, the pH is adjusted to 6 with glacial acetic acid and extracted with acetic acid. The organic phase is washed with water, dried over sodium sulphate and evaporated. 5-(Bromoacetyl)-2,3-dihydroxybenzonitrile is obtained as an amorphous solid.

b) 3.8 g of 5-(bromoacetyl)-2,3-dihydroxybenzonitrile, dissolved in 25 ml of N,N-dimethylformamide, are mixed with N-phenylthiourea and stirred for 5

hours at 100°C. The solvent is then evaporated. The residue is mixed with 200 ml of 1N sodium carbonate solution and extracted three times with 100 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulphate and evaporated. The residue is chromatographed on 30 g of silica gel with acetic acid. The crude product thus obtained is mixed with 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. 5-(2-anilino-4-thiazolyl)-2,3-dihydroxybenzonitrile hydrochloride with m.p. 245-247°C.

Example 83

a) To 10 g of 4-(benzyloxy)-3-methoxy-bromobenzene dissolved in 100 ml of tetrahydrofuran is added dropwise at -70°C during 10 min. 25 ml

tert-butyllithium solution (1.4M in hexane). After 1 hour of stirring at -70°C, 5 g of quinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran are added dropwise over the course of 30 min. The reaction mixture is stirred for 1 hour at -40°C and 1 hour at -5°C, poured into 200 ml of water and the pH is adjusted to pH 4 with glacial acetic acid. It is extracted three times with 50 ml of ether each time. The combined ether phases are washed with water, dried over sodium sulphate and evaporated. Q-[4-(benzyloxy)-3-methoxyphenyl]-4-quinolinemethanol is obtained as an amorphous solid.

b) 9.4 g of cx-[4-(benzyloxy)-3-methoxyphenyl]-4-quinoline methanol, dissolved in 200 ml of methylene chloride, is mixed with 6.5 g of pyridinium chlorochromate, after which it is stirred for 3 hours at room temperature. The insoluble components are then filtered off. The filtrate is evaporated and the residue is chromatographed on 150 g of silica gel with acetic acid. This gives 4-(benzyloxy)-3-methoxyphenyl-4-quinolyl ketone as an amorphous solid. c) To 7.5 g of 4-(benzyloxy)-3-methoxyphenyl-4-quinolyl ketone, dissolved in 150 ml of methylene chloride, at room temperature 15 ml of 33% hydrogen bromide in glacial acetic acid are added dropwise over the course of 5 min. After 4.5 hours of stirring at 20°C, the reaction mixture is poured portionwise onto 250 ml of saturated sodium bicarbonate solution. The methylene chloride phase is separated; the aqueous phase is extracted again twice with 100 ml of methylene chloride each time. The combined methylene chloride phases are dried over sodium sulphate and evaporated. The residue is recrystallized from methylene chloride/hexane. 4-Hydroxy-3-methoxyphenyl-4-quinolyl ketone is obtained with m.p. 190-192°C. d) 1.3 g of 4-hydroxy-3-methoxyphenyl-4-quinolyl ketone, dissolved in 25 ml of glacial acetic acid, is added dropwise to 0.37 ml of 65% nitric acid at room temperature. After 3 hours of stirring, the reaction mixture is poured onto ice water, after which the pH is adjusted to 6 with conc. ammonia and filters off the formed precipitate. The residue thus obtained is heated under reflux in 20 ml of acetonitrile, whereby the crystals are filtered off at 0°C. 4-hydroxy-3-methoxy-5-nitrophenyl-4-quinolyl ketone is obtained with m.p. 246-248°C. e) lg 4-hydroxy-3-methoxy-5-nitrophenyl-4-quinolyl ketone dissolved in 30 ml of 48% aqueous hydrogen bromide is stirred for 18 hours at 100°C.

After cooling to room temperature, the reaction product is diluted with 30 ml of water and the precipitate is filtered off. This gives 3,4-dihydroxy-5-nitrophenyl-4-quinolyl ketone hydrobromide with m.p. 273-275°C (from acetonitrile).

Example 84

a) To 4.03 g of thiophene dissolved in 40 ml of tetrahydrofuran is added dropwise at -50°C during 10 min. 18.8 ml of n-butyllithium solution (1.6M in

hexane). After 30 min. stirring at -50°C, 6.3 g of 3,4-dimethoxy-5-nitrobenzaldehyde dissolved in 100 ml of tetrahydrofuran are added dropwise over the course of 30 min. The reaction mixture is stirred for 1 hour at -50°C and 30 min. at 0°C and poured onto 100 ml of 2N sulfuric acid. It is extracted three times with 100 ml of ether each time; and the combined ether phases are washed with sodium chloride solution, dried over sodium sulphate, filtered and evaporated. One obtains c-(3,4-dimethoxy-5-nitrophenyl)-2-thiophene methanol with m.p. 79-81°C (from methylene chloride/hexane).

b) 9.9 g of α-(3,4-dimethoxy-5-nitrophenyl)-2-thiophene methanol, dissolved in 300 ml of acetone, is mixed with 90 g of brownstone and heated in

4 hours under reflux. The lignite is then filtered off, and the filtrate is evaporated. 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone is obtained with m.p. 102-104°C (from methylene chloride/hexane).

c) 2 g of 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone are stirred in a mixture of 20 ml of 30-33% hydrogen bromide in glacial acetic acid and 20 ml of 48%

aqueous hydrogen bromide for 8 hours at 100°C. The reaction mixture is then evaporated to dryness. The residue is taken up in ethyl acetate, washed with water, dried over sodium sulfate and filtered, and the filtrate is evaporated. After recrystallization from ethyl acetate/hexane, 3,4-dihydroxy-5-nitrophenyl-2-thienyl ketone is obtained with m.p. 155-157°C.

Example A

The gelatin stick capsules with the following composition can be produced in a manner known per se:

Claims (5)

1. Analogy method in the preparation of therapeutic active compounds of the general formula in which Ra means nitro or cyano, Rb hydrogen or halogen, Rc' nitro, cyano or the group - (A) n-(Q) m-Ri:L or - (A) n-Q-R<21>, A optionally with lower alkyl substituted vinylene, n the number 0 or 1, m the number 0 or 1, R<11> the group -COR<31>, a carbocyclic, aromatic group or an aromatic or partially unsaturated heterocyclic group bound through a carbon atom, R<21> an optionally substituted, saturated or partially unsaturated lower hydrocarbon residue, R<31> hydroxy, amino, one bonded through an oxygen atom or an imino- or lower alkylimino group optionally substituted, saturated or partially unsaturated lower hydrocarbon residue, or one bonded through a ring nitrogen atom, saturated, N-containing heterocyclic group, Q the group -CO- or >C=N-(Z)p-R<4>, Z an oxygen atom or an imino group, p the number 0 or 1 and R<4> hydrogen or an optionally substituted and optionally linked through a carbonyl group, saturated or partially unsaturated, lower hydrocarbon residue, wherein Ra means cyano, when Rc' means cyano or nitro, and R<31> has a different meaning from hydroxy when m means the number 0, and wherein the optionally substituted hydrocarbon residues are unsubstituted or substituted with lower alkoxycarbonyl, halogen, amino, lower alkylamino, di(lower alkyl)-amino, phenyl, hydroxyphenylcarbonyl or trifluoromethylphenylaminocarbonyl, and the carbocyclic aromatic group means an optionally with halogen, trifluoromethyl, lower alkyl , hydroxy or cyano mono- or disubstituted phenyl or naphthyl group, and the aromatic or partially unsaturated heterocyclic group optionally with halogen, trifluoromethyl, nitro, carboxy, amino, anilino, lower alkyl, lower alkoxy, hydroxy, oxo, mercapto, 1- adamantylamino, 2-exo-bornylamino, cyano, phenyl, phenyl-lower alkyl, phenyl-lower alkylamino, pyridyl, pyridylamino, quinolinylamino or with trifluoromethylphenylaminocarbonyl-lower alkylamino mono-, di- or trisubstituted pyridyl-, pyrazinyl-, triazinyl-, thiadiazinyl -, thiazolyl-, oxazolyl-, oxadiazolyl-, pyrazolyl-, tetrazolyl-, imidazolyl-, thienyl-, quinolinyl-, isoquinoliny l-, dihydroisoquinolinyl-, benzoxazinyl-, quinoxazinyl-, benzopyranyl-, benzimidazolyl-, indolyl-, imidazothiazolyl-, imidazothiadiazolyl-, imidazopyridyl-, benzothiazinyl-, benzoquinoxalinyl or imidazobenzothiazolyl group, of ester and ether derivatives hydrolyzable under physiological conditions and of pharmaceutically acceptable salts thereof, characterized in that one a) in a compound of the general formula in which one of the symbols R and R' means lower alkyl and the other hydrogen or lower alkyl, and Ra, Rb and Rc' have the above meaning, cleaves the lower alkyl ether group(s), or b) reacts a compound of the general formula in which X means a cleavable group, and Ra, Rb, A and n have the above meaning, with a thioamide, thiourea, thiocarbonic acid hydrazide, thiosemicarbazide, amidine, guanidine, amidrazone, aminoguanidine, cyclic amidine, 1,2-diamine, 1,2-aminothiol or a 1,2-amino alcohol, and optionally dehydrogenates the resulting cyclocondensation product, or c ) reacts a compound with the general formula wherein R" means lower alkyl, and Ra, Rb, A and n have the above meaning, with a 1,2-diamine, 1,2-aminothiol, 1,2-aminoalcohol, semicarbazide, thiosemicarbazide, amidrazone or an aminoguanidine and, if desired, dehydrogenates the cyclocondensation product obtained, or d) reacts a compound of the above formula Ib<1> with a 3-aminocarbonyl compound, or e) in a compound of the general formula wherein Rc"' means nitro, cyano or the group -(A)n-R<12> and R<12> the group -COR<31>, a carbocyclic, aromatic group or a through a carbon atom bonded aromatic or partially unsaturated heterocyclic group, and Ra, Rb, A, n and R<31> have the above meaning, or in a di-O-lower alkanoyl derivative thereof transfers the carboxaldehyde group(s) in the cyano group(s), or f) reacts a di-O-lower alkanoyl derivative of a carboxylic acid with the general formula wherein Ra, Rb, A and n have the above meaning, in the presence of a condensing agent or a reactive derivative of a di-O-lower alkanoyl derivative of a carboxylic acid of formula Ia<3> or Ib<3> with a compound of the general formula in which R<5> means an optionally substituted, saturated or partially unsaturated lower hydrocarbon residue, R<6> hydrogen or lower alkyl and R<7> hydrogen or an optionally substituted, saturated or partially unsaturated lower hydrocarbon residue or R<6> and R< 7 >together with the nitrogen atom a saturated N-containing hetercyclic group, or g) hydrolyzes a compound of the above formula Ib<2> or the general formula wherein R<8> means lower alkanoyl, and Ra, Rb and Rc' have the above meaning, or h) reacts with a compound of the general formula wherein Ra and Rb have the above meaning, and R"' means hydrogen or lower alkyl, or a di-O-lower alkanoyl derivative thereof in the presence of a secondary amine with a compound of the general formula in which R<23> means an optionally substituted, saturated or partially unsaturated lower hydrocarbon residue, or i) reacts with a compound of the general formula in which Ra, Rb, A, n and R" have the above meaning, with a hydrazine or an amidine, or j) reacts a compound of the general formula Ib, in which m means the number 1 and Q the group -CO-, with a compound of the general formula wherein Z, p and R<4> have the above meaning, and if desired transfers a compound of the above-mentioned formula Ib in an ester or ether derivative hydrolyzable under physiological conditions or in a pharmaceutically acceptable salt thereof. 2. Process according to claim 1 for the production of 3,4-dihydroxy-5-nitrobenzophenone, characterized by using correspondingly substituted starting materials. 3. Process according to claim 1 for the production of 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone, characterized in that correspondingly substituted starting materials are used. 4. Method according to claim 1 for the production of 3,4-dihydroxy-5-nitrophenyl-4-pyridyl ketone, characterized in that correspondingly substituted starting materials are used. 5. Process according to claim 1 for the production of 3,4-dihydroxy-4'-methyl-5-nitro-benzophenone, characterized in that correspondingly substituted starting materials are used.