BG60383B2 - Catechol derivatives - Google Patents

Abstract

The compounds are used as pharmaceutical products. The catechol derivatives have the formula /formula/ where Ra , Rb and Rc have have the meaning shown in the description, their ester and ether derivatives which hydrolyze under physiological conditions and their pharmaceutically acceptable salts. They posses useful pharmacological properties, or in particular they inhibit the catechol -O-methyltransferase (COMT) enzyme which is soluble, is affected by magnesium and catalyze the transport of the methyl group of S-adenosylmethionine to the catechol substrate where the respective methyl esters are formed. Suitable substrates which can be O-methylated and desactivated by COMT are, for example, extraneuronal catecholaminites after which they can be applied as therapeutically active substrates of catechol structure.

Description

The invention is in addition to application cep.No 395 110, filed August 16, 1989, now abandoned, which is additional to Ser. No. 07/022 891, filed March 6, 1987, now abandoned.

The invention relates to catechol derivatives of general formula

R. on 1 ^b but- wherein ^R b Ra denotes nitro or

cyano, Rb is hydrogen or halogen, Rc is halogen, nitro, cyano or group

- / A / '- / Q / _m - R' or - / A / _ - Q -R ² ,

A is a vinyl group, optionally substituted by lower alkyl, η has an integer value, 0 or 1, m is an integer, 0 or 1, R * means the group COR ³ , an aromatic carbocyclic group or an aromatic or partially unsaturated heterocyclic group a group bonded by a carbon atom, R ² is hydrogen or optionally substituted, saturated or partially saturated lower hydrocarbon moiety, R ³ is a hydroxy, amino, optionally substituted, saturated or partially unsaturated lower hydrocarbon moiety linked by an oxygen atom or an imino- or lower alkylimino group, Does saturated N-containing heterocyclic group bonded via the ring nitrogen, Q is the group -CO- or> C _{"N - / Z / p -} R ^4, Z is an oxygen atom or an imino group, p is an integer 0 or 1 and R ⁴ is hydrogen or a saturated or partially unsaturated lower hydrocarbon moiety which is optionally substituted and optionally linked via a carbonyl group, their esters and ether derivatives, which are hydrolysable under physiological conditions and their pharmaceutically acceptable salts.

The compounds of formula Ia have valuable pharmacological properties, in particular inhibiting the catechol-O-methyltransferase enzyme (COMT), a magnesium-dependent enzyme that catalyzes the transfer of the S-adenosyl-methionine methyl group to the catechol substrate, the corresponding methyl esters. Suitable substrates that can be methylated by COMT and which can thus be deactivated are, for example, extraleuronal catecholamine, and exeheonally therapeutically active catechol structure substrates administered.

The compounds of formula Ia can be used accordingly for the prevention or control of diseases in which the deactivation of extraneuronal catecholamines by COMT is important, for example for the prevention or control of depression. In this case, the compounds of formula Ia may be administered alone or in combination with other therapeutically active substances which have a beneficial effect on the course of the disease. The compounds of formula Ia may also be used as an adjunct to other therapeutically active substances.

The compounds of formula Ia can be used to improve the prevention or control of diseases with therapeutically active substances having a catechol structure, for example in the treatment of Parkinson's disease and L-dopa parkinsonism with a catechol structure, it may be noted as an example. In such cases, the compounds of formula Ia may be used as an adjunct or in combination.

The compounds of formula Ia are used for diagnosis. After administration of ( ^ls F) -6fluoro-1-dopa, (p) Dopamine in the brain can be imaged using positron emission tomography. By the addition of a compound of formula Ia, COMT inhibits and prevents the formation of N-F--3-methyldopa. In the absence of a COMT inhibitor, the β-3-O-methyldopa penetrates the brain and results in a significant increase in background, which complicates diagnosis.

Detailed Description of the Invention wherein Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is halogen,

nitro, cyano or the group - / A / _n - / Q / _n -R 'or - / A / _n -QR ² , A is a vinyl group optionally substituted by lower alkyl, η has an integer value of 0 or 1 , m is an integer, 0 or I, R ¹ is the COR 'group, an aromatic carbocyclic group or an aromatic or partially unsaturated heterocyclic group linked by a carbon atom, R ² is hydrogen or optionally substituted, saturated or partially unsaturated lower hydrocarbon moiety , R ³ is hydroxy, amino, optionally substituted, unsaturated or partially unsaturated lower hydrocarbon residue attached via an oxygen atom H atom or an imino or lower alkiliminogrupa or saturated N-containing heterocyclic group bonded to the nitrogen atom of the ring, Q is a group -CO- or> Ο N - I'Ll- R ^4, Z is an oxygen atom or an imino group, p is an the number 0 or 1 R ⁴ is hydrogen or a saturated or partially unsaturated lower hydrocarbon moiety which is optionally substituted and optionally linked via a carbonyl group, including esters and ester derivatives, which are hydrolysable under physiological conditions and their pharmaceutically acceptable salts. The compounds of formula Ia have valuable pharmacological properties. In particular, these compounds inhibit the catechol-O-methyl-transferase enzyme (COMT), which is a soluble magnesium-dependent enzyme that catalyzes the transfer of the metal group from

S-adenosylmethionine to the catechol substrate to form the corresponding methyl esters. Suitable substrates that can be 0-methylated by COMT and thus can be deactivated are, for example, extraneuronal catecholamines and exogenously applicable therapeutically active substances of catechol structure.

The compounds of formula Ia above can be used to prevent or control diseases in which the deactivation of extraneuronal catecholamines by COMT is important, for example, to prevent or control depression. In this case, the compounds of formula Ia may be used as single compounds or in combination with other therapeutically active substances that have a beneficial effect on the course of the disease. The compounds of formula Ia can be used as an adjunct to other therapeutically active substances.

the compounds of formula Ia may be used to improve the prevention or control of diseases with therapeutically active substances having a catechol structure, for example in the treatment of Parkinson's disease or of L-dopa parkinsonism with a catechol structure. In such cases, the compounds of formula Ia may be used in the form of an additional drug or as combination preparations.

In the diagnosis, there is also another possibility of using the compounds of formula Ia. After administration of (18P) -6-fluorine-Edopa, (F) dopamine in the brain can be imaged by positron emission tomography. By the addition of a compound of formula Ia, COMT inhibits and prevents the formation of (R) -3-O-methyldopa. In the absence of the SMOT inhibitor, F / -3-0methyldopa penetrates the brain and causes a significant increase in background, making diagnosis difficult.

Formula Ia encompasses not only known compounds but also those which form part of the invention. The compounds of formula Ia are known and are included in the formula

in which Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is a nitro, cyano group or the - (A / _o- COOH or / A / _B -QH, A is a vinyl group optionally substituted by lower alkyl, η has a value of 0 or 1, Q is the group -CO or> C = N- / Z / pR ⁴ , Z is an oxygen atom or an amino group, p is a value of 0 or 1 and R * is hydrogen or a saturated or partially unsaturated lower carbon moiety, which is optionally substituted and which is optionally linked via a carbonyl group, with the restriction wherein Ra is a nitro group when Rc 'is cyano or a nitro group, their ester and ether pro derivatives which are hydrolyzable under physiological conditions and their pharmaceutically acceptable salts.

The compounds of formula Ia according to the invention have the formula

in which Ra is nitro or cyano, Rb is hydrogen or halogen, Rc is nitro, cyano or the group - / A / _n - / Q / _n- R "or - / A / _n - <) - P ²¹ , A is the vinyl group, optionally substituted by lower alkyl, η is 0 or 1, m is the number 0 or 1, R ¹¹ is the COR ³¹ group, an aromatic carbocyclic group or an aromatic or partially unsaturated heterocyclic group bonded by a carbon atom, R ²¹ is an optionally substituted unsaturated or partially unsaturated lower hydrocarbon radical, R ³ 'is hydroxy, amino, optionally substituted saturated or partially unsaturated lower hydrocarbon day residue attached via an oxygen atom or an imino or lower alkylamino group or a saturated N-containing heterocyclic group bonded via the nitrogen atom of the ring, Q is the group -CO- or> CN- / Z / _p -R ^4, Z is oxygen atom or imino group, p is 0 or 1 and R ⁴ is hydrogen or a saturated or partially unsaturated hydrocarbon residue, which is optionally substituted and optionally linked via a carbonyl group, with restriction where Ra is a cyano group when Rc 'is cyano or nitro, and R ^3' has the meanings different from hydroxy when m is one hundred ness 0, their ester and ether derivatives which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof.

It is an object of the invention to use said compounds of formula Ia and their derivatives as therapeutically active substances, to create drugs based on these compounds and their derivatives; the preparation of such drugs, the use of the compounds and their derivatives to prevent or control diseases, the use of the compounds and their derivatives to produce drugs that optionally inhibit the COMT enzyme as a desired side effect, the compounds of formula Ib, said derivatives thereof; preparation of these compounds and derivatives as well as intermediates for their preparation.

The term "lower" means residues and compounds with a maximum of 7, preferably a maximum of 4 carbon atoms. The term "alkyl" hereinafter used, or the terms "alkyl group", "alkoxy", "alkylthio" and "alkylimino" mean a straight or branched chain saturated hydrocarbon radical, for example methyl, ethyl, propyl, isopropyl, n-butyl , secondary butyl, iso-butyl, tertiary butyl and the like. The term "saturated or partially unsaturated lower hydrocarbon moiety" means an open chain and cyclic groups and combinations thereof. Examples of saturated and partially unsaturated hydrocarbon residues are lower alkyl groups as defined above; lower alkenyl groups, for example 2-propenyl, 2-butenyl,

3-butenyl and 2-methyl-2-propenyl; C _{3 7} cycloalkyl and C ₁₀ -bitsikloalkilni groups, optionally substituted by lower alkyl groups, for example cyclopropyl, cyclopentyl,

2-methylcyclopentyl, cyclohexyl and 3-methylcyclohexyl; lower cycloalkenyl groups optionally substituted by lower alkyl groups, for example 3-cyclopentyl, 1-methyl-3-cyclopentyl and 3-cyclohexyl, lower alkyl or alkenyl groups substituted by lower cycloalkyl or cycloalkenyl groups, for example cyclopropylmethyl, cyclopropylmethyl, , cyclohexylmethyl, 2cyclohexylmethyl 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.

Said lower hydrocarbon moieties have the following substituents: hydroxy, cyan, nitro, halogen, amine, lower alkylamine, di- (lower) -alkylamine, lower alkoxy, lower alkoxycarbonyl, arylcarbonyl, arylcarbonylamine, carboxylic acid di / lower alkyl / carbamoyl, lower alkylenedioxy, trifluoromethyl, carboxy, lower alkanoylmain, lower alkoxycarbonylamine and lower alkylthio. The saturated or partially unsaturated lower carbon moieties are preferably unsubstituted or mono- or disubstituted.

The term "aryl" means carbocyclic aromatic groups, preferably monoyl or bicyclic groups. Particularly preferred carbocyclic aromatic groups are phenyl or naphthyl, especially phenyl. these groups are optionally substituted by halogen, trifluoromethyl, nitro, amine, mono- or di- (lower alkyl) -amine, lower alkyl, lower alkoxy, lower alkylthio, lower alkanoyl, lower alkoxycarbonyl, carboxy, hydroxy, cyano, cyano, cyano alkanoyloxy carbamoyl, mono- or di- (lower alkyl) -carbamoyl, lower alkyldioxy, lower alkanoylamine or lower alkoxycarbonylamine. Carbocyclic aromatic groups are preferably unsubstituted or mono- or disubstituted.

The term "aromatic" or partially unsaturated heterocyclic group "preferably means a mono- or di- or tricyclic aromatic or partially unsaturated heterocyclic group having up to 5 heteroatoms from the nitrogen, sulfur and oxygen groups. The heterocyclic groups preferably contain 1-4 nitrogen atoms and / or an oxygen or sulfur atom, preferably mono- or bicyclic. The heteroatoms are preferably arranged in one or two rings, wherein the nitrogen atoms may simultaneously be components of 2 rings. The heterocyclic groups are preferably aromatic. They may be substituted and preferably mono-, di- or trisubstituted. Substitutes include halogen, trifluoromethyl, nitro, carboxy, amine, arylamine, lower alkyl, lower alkoxy, hydroxy, lower alkoxycarbonyl, lower alkanoyl, lower alkanoyloxy, oxo, lower alkyldioxy, mercaptoalkyl, n-alkyloalkyl, n-alkyloalkyl, n-alkyloalkyl, n-alkyloxyalkyl, n-alkyloxyalkyl, n-alkyloxy lower alkyl N-amine, C _1-7 -cycloalkylamine, C _{g 10} bicycloalkylamine, lower alkanoylamine, lower alkoxycarbonylamine, carbamoyl, mono- or di- (lower alkyl) -carbamoyl, cyano, aryl, aryl-narylalkylamine , heteroaryl, heteroaryl-lower alkyl, heteroarylamine and C _3-7 cycloalkyl. 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 with separated rings, preferably 5- or 6-membered.

The heterocyclic groups may be as follows: pyridyl, pyrazinyl, triazinyl, thiadiazinan, thiazolyl, oxazolyl, oxadiazolyl, pyrazolyl, tetrazolyl, imidazolyl, thienyl, quinolinyl, isoquinolinyl, dihtsdroizohinolinil, benzoxazinyl, quinoxalinyl, benzopyranyl, benzimidazolyl, indolyl, imidazothiazolyl, imidazotiadiazolil, imidazopyridyl , benzothiazinyl, benzoquinoxalinyl and imidazobenzothiazolyl.

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

The expression saturated N-containing heterocyclic group bonded via the nitrogen ring atom preferably means 3- to

A 7-membered, preferably 4- to 6-membered, saturated N-heterocycle which to the nitrogen atom may contain oxygen, sulfur or a nitrogen atom such as a second heteroatom. These saturated N-heterocycles can be monoyl or di-substituted by lower alkyl, hydroxy, lower alkoxy, lower alkanoyloxy, lower hydroxyalkyl, lower alkoxyalkyl, lower alkanoyloxyalkyl, lower alkoxycarbonyl, or carboxylic, -carbonyl, oxo and / or lower alkylenedioxy.

The N-containing heterocyclic groups may be the following: 4-morpholinyl, 1-pyrrolidinyl and 1-acetidinyl.

The ester and ether derivatives which are hydrolysable under physiological conditions are preferably compounds of formula Ia in which at most one of the phenolic hydroxyl groups is acylated by a lower fatty acid or tertiary by lower 1-alkoxycarbonyloxy-1-alkyl, lower

1-alkanoyloxy-1-alkyl or by lower 2-oxo-

1-alkyl group.

The substituent Ra is preferably nitro. The substituent Rb is preferably located at the p-position relative to the substituent Ra and is preferably hydrogen, chlorine or fluorine, with hydrogen being particularly preferred. The substituent Re 'is preferably the group -CO-R in which R ¹¹ is an aromatic monocyclic carbocyclic group or an aromatic monocyclic heterocyclic group of 1-3 nitrogen atoms as heterocycle members which are bonded via a carbon atom. Preferably R ¹¹ is a phenyl group optionally- or disubstituted by halogen, trifluoromethyl, cyano, hydroxy or lower alkyl or pyridyl group.

Particularly preferred compounds of the invention are the following: 3,4-dihydroxy-5-nitrobenzophenone 2'-fluoro-3,4-di6 hydroxy-5-norbibenzophenone and 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone.

The compounds of formula 16, their ester and ether derivatives, which are hydrolyzable under physiological conditions, and their pharmaceutically acceptable salts, can be prepared according to the invention by the following reactions:

a) cleavage of a lower alkyl ether group and / from a compound of formula 1b 'above with β-aminocarbonyl; or e) conversion of a carboxaldehyde group / and / into a compound of formula

CHO

in which one of the symbols R and R 'is lower alkyl and the other is hydrogen or lower alkyl, and Ra, Rb and Rc'nMaT have the meanings described above or b / the reaction of a compound of formula

in which X is a leaving group and Ra, Rb, A and η have the meanings described above with thioamide, thiourea, hydrazide and thiocarboxylic acid, thiosquemicarbazide, amidine, guanidine, amidrazone, aminoguanidine, cyclic amidine, 1,2-diamine, 1,2-diamine, 1,2-aminothiol or 1,2-amino alcohol and optionally dehydrogenating the cyclo-condensation product to be obtained or c) reacting a compound of formula wherein Rc 'is nitro; the cyano group or the group - / A / nR ¹² , and R ¹² is the -COR ³¹ group, an aromatic carbocyclic group, or an aromatic or partially unsaturated heterocyclic group bonded through a carbon atom, and Ra, Rb, A, η and R ³¹ have the above values, either in the di-O-lower alkali derivative in the cyano group (s) and / or is the interaction of the di-O-lower alkanoyl derivative of the carboxylic acid of the formula

or

in which R 'is lower alkyl and Ra, Rb, A and η have the above meanings, with 1,2 diamine, 1,2-aminothiol, 1,2-amino alcohol, semicarbazide, thiosemicarbazide, amidrazone or aminoguanidine and, if desired, dehydrogenation of the resulting cyclocondensation product or g / reaction of a compound in which Ra, Rb, A and η have the above meanings in the presence of a condensing agent or a reactive derivative or a di-O-lower alkanoyl carboxylic acid derivative of formula Ia ³ or 1b ³ with a compound of formula HO-R ' ^ν or

HNR'R ^{7 νι} in which R ⁵ is optionally substituted saturated or partially unsaturated lower hydrocarbon residue, R * is hydrogen or lower alkyl and R ⁷ is hydrogen or optionally substituted saturated or partially unsaturated 5 lower carbon residue or R ⁶ and R 'taken together with the nitrogen atom means a saturated N-containing heterocyclic group or g / hydrolysis of a compound of formula 1b ² or a compound of formula 10

1b in which R * is lower alkanoyl and Ra, Rb and Rc 'have the meanings indicated above, 3 / the reaction of a compound of formula

in which Ra Rb has the above meanings and R '' is hydrogen or lower alkyl or its di-lower alkanoyl derivative in the presence of a secondary amine with a compound of formula

CHjCO-R ^{13 vu} in which R ²³ is optionally substituted saturated or partially unsaturated lower carbon residue or and / reacting a compound of formula k / converting a compound of formula of an ester or ether derivative which is hydrolyzable under physiological conditions or pharmaceutically acceptable salt.

By the method of option a, the compounds of formula 16 can be prepared by cleaving the ether group (s) of a compound of formula II. This ether cleavage can be accomplished by known methods, for example, by treatment with hydrogen bromide in a suitable solvent. Suitable solvents are, for example, water, acetic acid and mixtures thereof. Preferably the reaction proceeds at elevated temperature, for example at a temperature of about 100 ° C to the reflux temperature of the reaction mixture. Preferably 48% hydrobromic acid or mixtures thereof with acetic acid are used.

The ether cleavage may also occur upon treatment with boron tribromide in a suitable solvent at a temperature of about -60 ° C to about room temperature. Particularly suitable solvents are halogenated with lower hydrocarbons such as methylene chloride, chloroform and the like. Other suitable methods are the following. Treatment with pyridine hydrochloride at a temperature of about 150 ° C to about 250 ° C and treatment with sodium iodide / tetrachlorosilane, for example at reflux temperature of the reaction mixture. Suitable solvents for the latter process are, for example, acetonitrile, aromatic hydrocarbons such as benzene or toluene, mixtures thereof and the like.

Compounds of formula may be prepared by the method of Option 6,

No

COOR in which Ra.Rb, A and η and R 'have in which Ra, Rb, A and η have the above meanings Q ¹ is a group of the formula above, with hydrazine or 45 amidine, or j / reacting a compound of formula 16 in which m is an integer 1 and Q is the group -CO- with a compound of formula

Η, Ν - / Z / p - R ^{4 v} '50

NHRf in which Z, p and R ⁴ have the above meanings and if desired

NHRf

N = N

A- / ^- “· '

N = N __Z \ - NHRf h

alkyl or heteroarilnissh alkyl, Rf is hydrogen, aryl, aryl-lower alkyl, lower alkyl, lower alkoxycarbonyl, heteroaryl, heteroarilnissh alkyl, C, _{| 0} -bizikloalkil or C ₃ - cycloalkyl, Rg and Rh independently of one another are hydrogen, cyano, lower alkyl, C _3-7 cycloalkyl, aryl, aryl-lower alkyl, heteroaryl or heteroaryl-lower alkyl or Rg and Rh taken together with the two carbon atoms to which they are attached denote an aromatic carbocyclic group or aromatic or partial aromatic unsaturated heterocyclic group having a free line is an optional bond, and Q ⁴ together with the carbon nitrogen atom means an aromatic or partially unsaturated heterocyclic group which contains at least one nitrogen atom as ring heteroatom.

Suitable solvents for this process are lower alcohols such as ethanol, n-butanol, nhexanol and ethylene glycol, open chain ethers and cyclic ethers which may contain free hydroxyl groups, for example tetrahydrofuran, dioxane, tert. butylmethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, ethylene glycol monomethyl ether and diethylene glycol monomethyl ether, acetonitrile, dimethylformamide, dimethylacetamide and dimethyl sulfoxide. The desired reaction can also be carried out without solvents by dry heating of the reaction components. The reaction preferably takes place at elevated temperature, for example from about 50 ° C to 150 ° C, where it preferably takes place at the reflux temperature of the solvent when carried out in the presence of a solvent and the reflux temperature is as indicated above .

According to the method of Embodiment c, compounds of formula or may be prepared

in which Ra, Rb A and η have the meanings given above and Q ² is a group of the formula wherein Re is hydrogen, C _3-7 alkyl, C _3-7 cycloalkyl, aryl, heteroaryl, aryl-lower

in which Re, Rf Rg, Rh and the free line have the meanings indicated above.

The reaction by the method of variant c may proceed under the same reaction conditions as the method of variant b /.

According to the method of embodiment d, compounds of formula may be prepared

in which Q ³ is a group of formula

D 'and Ra, R6, Re, Rf, Rh, A, n and the free line have the meanings indicated above.

The method of variant d may proceed under the reaction conditions of the method of variant b.

By the method of Embodiment e, compounds of formula 16 can be prepared in which Ra is cyano, Re 'is nitro cyano or the group - / A / _n -R ₁₂ and R ¹² is the group -COR ³¹ , aromatic 10 carbocyclic group or aromatic or a partially unsaturated heterocyclic group attached by a carbon atom and Rb, A, η and R ³¹ have the meanings indicated above. The conversion of the carboxaldehyde group (s) and (15) into a cyano group (s) can be accomplished by known methods known to those skilled in the art. For example, a compound of formula Ia ² , III or IV may be treated with hydroxylamine 0-sulfonic acid at elevated temperature and with water as the preferred solvent. The reaction takes place at a temperature of about 50 ° C to about 100 ° C.

According to the method of embodiment, di-O-lower alkanoyl derivatives of the compounds of formula 16 can be obtained, in which Rc 'is the group - / A / _n - / CO / _B -COR ³² R ³² is an amine, optionally substituted a saturated or partially unsaturated lower hydrocarbon moiety attached by an oxygen atom or an imino or lower alkylimin group or a saturated N-containing heterocyclic group attached via the ring nitrogen atom and A, η and m have the meanings indicated above. This interaction can proceed by known methods. The lower alkyl esters can be prepared, for example, by reacting a carboxylic acid with the corresponding lower alcohol in the presence of an acid with the corresponding lower alcohol used as a solvent. Suitable acids are, for example, mineral acids, such as hydrogen chloride, and organic sulfonic acids, such as p-toluenesulfonic acid. The reaction temperature is preferably within room temperature to the reflux temperature of the selected solvent.

The other esters and amides are preferably prepared starting from a reactive carboxylic acid derivative. Suitable reactive carboxylic acid derivatives are, for example, the corresponding carboxylic acid halides, in particular carboxylic acid chlorides, corresponding carboxylic acid anhydrides, and a mixture of anhydrides, for example, trifluoroacetic acid and organic sulfonic acids, such as mesitylenesulfonic sulfonic acid, carboxylic acid imidazolides and the like. The reaction usually takes place in the presence of an acid binder and an inert organic solvent. Suitable acid binding agents are, for example, tertiary amines such as triethylamine and pyridine. In the preparation of amides, an amine of formula VI may be used as the acid binder. Suitable solvents are, for example, open-chain ethers and cyclic ethers such as tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dioxane, ethylene glycol, dimethyl ether, etc., halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dichloromethane.

The hydrolysis of compounds of formula 16 * to the corresponding catechal derivatives by the method of option g / can be carried out by known methods, for example, by treatment with alkali metal hydroxides such as sodium hydroxide or potassium hydroxide in a suitable solvent. Suitable solvents are, for example, lower alcohols such as methanol and water or mixtures thereof. The hydrolysis can take place, for example, at a temperature of about 0 ° C to the boiling point of the solvent, preferably at room temperature.

By the method of variant 3 /, compounds of formula are prepared

1 * BUT. γϊι 10 but- 1b C (R) - CH - CO - R

in which Ra, Rb '' HR ²³ has the above and their corresponding lower alkanoyl derivatives. Cyclic amines such as pyrrolidine, piperidine, morpholine and thiomorpholine are preferably used as the secondary amine. Suitable solvents for carrying out the process are, for example, open chain and cyclic ethers such as tetrahydrofuran, diethyl ether, tert-butyl methyl ether, dioxane, ethylene glycol and dimethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform and 1,2-dimethylformitri . Preferably, the reaction temperature is in the range of 0 ° C to the reflux temperature of the selected solvent. Preferably the reaction takes place 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.

By the method of variant and / the compounds of formula may be prepared

in which Q ⁵ is the group

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

Suitable solvents for carrying out the process are, for example, lower alcohols such as methanol and ethanol, open-chain ethers and cyclic ethers such as tetrahydrofuran, diethyl ether, tert-butyl methyl ester, dioxane, ethylene glycol and dimethyl ether, acenonitrile and dimethylformyl. Preferably, the reaction proceeds at elevated temperature, for example, in the range of about 50 ° C to the reflux temperature of the selected solvent. Preferably, it is carried out at the reflux temperature of the selected solvent.

Compounds of formula may be prepared by the method of embodiment j)

in which R1 is the -COR ³¹ group, an aromatic carboxyl group, or an aromatic or partially unsaturated heterocyclic group attached by a carbon atom or optionally substituted, saturated or partially unsaturated lower hydrocarbon moiety is Ra, R ³¹ , Rb, R ⁴ , A, Z , have the meanings given above.

The process can also be performed by known methods. Suitable solvents are, for example, lower alcohols such as methanol and ethanol, dimethylformamide and water. Typically, the reaction takes place at room temperature.

By the method of option k / the compounds of formula Ib can be converted into ester or ether derivatives which are hydrolyzable under physiological conditions. Suitable ester derivatives which are hydrolysable under physiological conditions are preferably the compounds of formula 1b, in which formula 1b at least one of the two hydroxyl groups to the phenolic nucleus is acylated with lower fatty acid. They can be prepared by known methods known to those skilled in the art, according to a preferred embodiment, the acylation is carried out with the corresponding lower fatty acid anhydride in the presence of catalytic amounts of a strong acid with excess fatty acid anhydride used as the solvent. Suitable acids are, for example, sulfuric acid and organic sulfonic acids such as p-toluenesulfonic acid.

Suitable ester derivatives which are hydrolysable under physiological conditions are, for example, compounds of formula 16, in which at least one of the two phenolic hydroxyl groups is esterified with lower 1-alkoxycarbonyl-oxo-1-alkyl, lower 1-alkanoyloxy-

1-alkyl or a lower 2-oxo-1-alkyl group. The esterification can be carried out by known methods.

For example, a compound of formula Ib may be reacted with lower 1-alkoxycarbonyl-

1-alkyl halide, lower 1-alkanoyloxy-2-alkyl halide or lower 2-oxo-1-alkyl halide, this esterification usually taking place in the presence of a base. Halides are especially iodides. Suitable bases are, for example, alkali metal hydroxides and alkali metal carbonates such as sodium hydroxide and sodium carbonate.

By the method of embodiment k / the compounds of formula Ib can be converted into pharmaceutically acceptable salts. Salts are particularly salts having pharmaceutically acceptable bases. For example, alkali metal salts such as sodium and potassium salts, which can be prepared by known methods, should be mentioned as salts.

The various compounds used as starting compounds are known or can be prepared according to known methods. The following examples describe in detail the preparation of said starting products.

As described above, the compounds of formula Ia inhibit the COMT enzyme. This activity can be quantified as follows. The rat liver homogenate is incubated in the presence of suitable substrates as described in

J. Neugochem, 38, 191-195 (1982), and COMT activity was measured. In a second series of experiments, the incubation is carried out in the presence of a compound of formula Ia. _IC10 can then be calculated from the difference of COMT activity that is determined. IC _J0 are given in mol / ί and this concentration in the incubation mixture, which is necessary to decrease COMT activity by 50%. The _IC10 values for some compounds of formula Ia are listed in the following table. The table also provides data on the acute toxicity of these compounds at LD50 in mg / kg in the case of single oral administration to mice.

Compound of formula la IC50, LD50, in nmol / ί in mg / kg p.o.

3,4-dihydroxy-5-nitro- 53,4 1250-2500 phenyl 2-pyridyl ketone 3,4-dihydroxy-5-nitro- 47,0 1000-2000 phenyl 3-pyridyl ketone 3,4-dihydroxy-5-nitro- 67.0 1000-2000 phenyl 4-pyridyl ketone 67.0 1000-2000 n-butyl ester of 3,4- 20,0 312-625 3,4-dihydroxy-5-nitrobenzoic acid n-butyl ester 25.9 2500-5000

dihydroxy-5-nitrocane12

hydrochloric acid 3,4-Dihydroxy-5-nitrophenylglyoxyl acid ethyl ester 48,1 1 250-2500 3,4-dihydroxy-5-nitro- benzophenone 48,0 500-1000 3,5-dinitropyracatechol 36,9 500-1000 2'-fluoro-3,4-dihydroxy- 5-nitrobenzophenone 42.0 312-625

The compounds of formula Ia, their ester and ether derivatives can be administered as medicaments, for example, in the form of pharmaceutical preparations for enteral or parenteral administration. The compounds of formula Ia may be administered, for example, orally, for example in the form of tablets, film tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories or parenterally, for example in the form of injectable solutions .

The preparation of the pharmaceutical preparations can be carried out by a known method by administering the compounds of formula Ia, optionally in combination with other therapeutically useful substances, in galenical forms together with suitable non-toxic inert therapeutically compatible solid or liquid carriers and, if desired, with conventional pharmaceuticals additives.

Inorganic and organic carriers are suitable as carriers. For tablets, film tablets, dragees and hard gelatin capsules, for example, lactose, corn starch or derivatives, talc, stearic acid or salts thereof may be used as carriers. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols. Depending on the nature of the active substances, carriers are not required in the case of soft gelatin capsules. Suitable carriers for the preparation of solutions and syrups are, for example, water, polyols, sucrose, inert sugar and glucose. Suitable carriers for injection solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. Suitable suppository carriers are, for example, natural or hardened oils, waxes, fats and obtained or liquid polyols.

Pharmaceutical additives are conventional preservatives, solubilizers, stabilizing agents, wetting agents, emulsifying agents, flavoring agents such as sweeteners, flavors, colorants, salts of osmotic pressure, buffers, envelopes and antioxidants.

The single dose of the compounds of formula Ia, their ester or ether or ether derivatives and their salts may vary widely, depending on the disease being treated, the age and individual condition of the patient and the mode of administration as may be administered. adapt to individual needs on a case by case basis. A daily dose of 25 mg to about 1000 mg, in particular 100 mg to about 300 mg, is recommended to improve the treatment of Parkinson's disease and L-dopa. Depending on the dosage, it is appropriate to administer the daily dose in several separate doses.

The pharmaceutical compositions of the invention contain about 25 mg to about 300 mg, preferably about 50 mg to about 150 mg, of a compound of formula Ia, or an ester or ether derivative thereof, which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof.

The following examples illustrate the invention. The temperature is measured in Celsius.

Example 1.

a / Treat 17 lg of 4-hydroxy-methoxy-5-nitrobenzaldehyde with 170 ml of hydrochloric acid at constant boiling point and reflux

3.5 h. After cooling, the precipitate was filtered off by suction, washed twice with ice water and mixed with ethyl acetate. The organic phase was washed twice with 50 ml of sodium chloride solution, dried over magnesium sulfate and evaporated in a water pump. The crystals are stirred with methylene chloride, the solution being filtered through ten times silica gel. The resulting product was crystallized from ethyl acetate / isopropyl ether. 3,4-Dihydroxy-5-nitrobenzaldehyde is obtained as yellow crystals, mp 142-143 ° C.

b / a solution of 1.7 g of hydroxylamine 0 sulfonic acid in 6 ml of water and added to a solution of 1.83 g of 3,4-dihydroxy-5-nitrobenzaldehyde in 25 ml of water, stirred at 65 ° C for 3.5 hours, cooled The precipitate was filtered off by suction and mixed with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated by a water pump. The crystals obtained were recrystallized from ethyl acetate / n-hexane. 3,4-dihydroxy-5-nitrobenzonitrile is obtained as yellow crystals with a melting point of 194-105 ° C.

Example 2.

aa (10 ml of a solution of butyllithium (1.4M in hexane) was added dropwise at 70 ° C for 10 min to 4, 4- (benzyloxy) -3-methoxy-bromobenzene dissolved in 40 ml of tetrahydrofuran. After stirring for 2 h at 70 ° C, 1 ml of pyridine-3-carbaldehyde was added for 5 min. The reaction mixture was stirred at -70 ° C for one hour and at 0 ° C for 2 hours and poured into 100 ml of 1N hydrochloric acid. The mixture was extracted three times with 50 ml of ether each time. The combined ether phases were washed with 100 ml of 1N hydrochloric acid and 20 ml of water. The combined aqueous phases were basified with aqueous ammonia and extracted three times with 100 ml of methylene chloride. The combined methylene chloride phases were dried over sodium sulfate and evaporated. Sea- (4- (benzyloxy) 3-methoxyphenyl) -3-pyridine methanol is obtained as an oil.

ab / Similarly, using pyridine-4-carbaldehyde gave α- (4- (benzyloxy) -3-methoxyphenyl) -4-pyridine methanol as an oil.

ba) 3.2 g of α- (4- (benzyloxy) -5-methoxyphenyl) -3-pyridine methanol were suspended in 50 ml of water and treated with 2.5 g of potassium permanganate, stirring the mixture at 90 ° C for 30 min. After the addition of 1.0 g of potassium permanganate and stirring for another 30 min at 90 ° C, the mixture was cooled to room temperature and extracted twice with 150 ml of ethyl acetate. The combined ethyl acetate phases were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The resulting residue was chromatographed on 50 g of silica gel with ethyl acetate. Recrystallization from methylene chloride / hexane is obtained

4- (benzyloxy) -3-methoxyphenyl-3-pyridyl ketone, m.p. 76 ° C.

cc / Similarly, α- (4-benzyloxy) -3-methoxyphenyl) -4-pyridinethanol yields 4- (benzyloxy) -3-methoxyphenyl

4-Pyridyl ketone, mp 85-87 ° C / methylene chloride / hexane.

are / 50 ml 33 percent hydrobromic acid in acetic acid is added dropwise over 15 minutes at 10 ° C to 20 g of 4- (benzyloxy) -3-methoxyphenyl 3-pyridyl ketone dissolved in 200 ml of methylene chloride. After stirring at 20 ° C for 3 h, the reaction mixture was poured into a mixture of 100 ml of conc. Ammonia and ice. The pH was adjusted to 6 by the addition of acetic acid. The methylene chloride phase was separated and extracted twice with more than 100 ml of methylene chloride. The combined methylene chloride phases were dried over sodium sulfate and evaporated. The residue was also crystallized from methylene chloride / hexane. 4hydroxy-3-methoxyphenyl 3-pyridyl ketone is obtained with a melting point of 150-151 ° C.

(c) Similarly, from 4- (benzyloxy) -3-methoxyphenyl 4-pyridyl ketone, 4-hydroxy-3-methoxyphenyl 4-pyridyl ketone is obtained with m.p.

da / 0.38 ml of 65% nitric acid was added dropwise at room temperature to 1.15 g of 4-hydroxy-3-methoxyphenyl 3-pyridyl ketone dissolved in 15 ml of acetic acid. After 2 h, stirring, the reaction mixture was poured into 120 ml of ice water, the mixture was adjusted to pH 5 with conc. Ammonia and the precipitate formed was filtered. The resulting residue was refluxed in 20 ml of acetonitrile and filtered again. 4-Hydroxy3-methoxy-5-nitrophenyl 3-pyridyl ketone is obtained as brown crystals with a melting point of 193 ° C.

de / Similarly to 4-hydroxy-

3-Methoxyphenyl 4-pyridyl ketone is obtained

4- hydroxy-3-methoxy-5-nitrophenyl 4-pyridyl ketone, mp 240 ° C.

e / 3.5 g of 4-hydroxy-3-methoxy-5-nitrophenyl 3-pyridyl ketone were dissolved in 70 ml of 48% aqueous hydrobromic acid and stirred at 100 ° C for 18 h. The reaction mixture was then evaporated under reduced pressure. . The residue was crystallized from water. 3,4-Dihydroxy-

5-Nitrophenyl 3-pyridyl ketone hydrobromide, m.p. 265 ° C.

f / Similarly to 4-hydroxy-

3-Methoxy-5-nitrophenyl 4-pyridyl ketone yields 3,4-dihydroxy-5-nitrophenyl 4-pyridyl ketone, m.p. 246 ° C (from water) g (13.2 g) 3,4-dihydroxy-5- nitrophenyl

The 4- pyridyl ketone was suspended in 500 ml of methanol and treated with 4.88 g of methanesulfonic acid with stirring. The suspension was refluxed for 60 minutes. It was then cooled to 10 ° C, the crystals were filtered off by suction and washed twice with 30 ml of methanol each. 3,4-Dihydroxy-5-nitrophenyl 4-pyridyl ketone methanesulfonate is obtained with a melting point of 260-261 ° C, decomposition.

Example 3. a / solution of 2.6 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 26 ml of hydrochloric acid with constant boiling point was heated at reflux for 2 hours. After cooling, the solvent was distilled off with a water pump. . The crystalline residue was crystallized from 50 ml of boiling water. 3,4-Dihydroxy-5-nitrobenzoic acid is obtained as yellow crystals, mp 224-226 ° C.

b / 1.0 g of 3,4-dihydroxy-5-nitrobenzoic acid were treated with 20 ml of methanolic hydrochloric acid, stirred at 45 ° C for 3 h and after removal of the solvent, the residue was mixed with methylene chloride. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and evaporated. The resulting crystalline product was combined with methylene chloride and filtered through ten times silica gel. The resulting product was recrystallized from ethyl acetate / n-hexane. 3,4-Dihydroxy- methyl ester is obtained

5- Nitrobenzoic acid as yellow crystals, mp 144-145 ° C.

The following esters are similarly prepared from 3,4-dihydroxy-5-nitrobenzoic acid:

c) 3,4-Dihydroxy-5-nitrobenzoic acid ethyl ester m.p. 106-107 ° C (from ethyl acetate (n-hexane), 3,4-dihydro-3,4-dihydroxy-

5-Nitrobenzoic acid with a melting point

73-74 ° C (from methylene chloride) and 3,4-dihydroxy-

5-Nitrobenzoic acid, m.p. 4445 ° C (from isopropyl ether).

Example 4 a (25 ml 2M solution of phenyllithium / in benzene / ether 7: 3) was added dropwise over 10 min to 10.0 g

3.4-dimethoxy-5-nitrobenzaldehyde dissolved in 150 ml of THF and the mixture was stirred at 0 ° C for 1 hour and at 20 ° C for 2 hours. The mixture was then treated with 150 ml of 2N sulfuric acid and extracted three times with 150 ml of ether each. The combined ether phases were washed with sodium chloride solution, dried over sodium sulfate and evaporated. The resulting residue was chromatographed on 180 g of silica gel with methylene chloride. 3,4-Dimethoxy-5-nitrobenzhydrol is obtained as an amorphous solid.

b / 2.5 g of 3,4-dimethoxy-5-nitrobenzhydrol dissolved in 50 ml of methylene chloride were treated with 2.2 g of pyridinium chlorochromate and the mixture was stirred at room temperature for 2 h. were filtered, the filtrate was evaporated and the residue was chromatographed on 60 g of silica gel with ethylene chloride. Crystallization from methylene chloride / hexane is obtained

3.4-dimethoxy-5-nitrobenzophenone, m.p. 78-80 ° C.

c / 0.5 g of 3,4-dimethoxy-5-nitrobenzophenone was stirred at 100 ° C for 30 h in a mixture of 4 ml of acetic acid and 4 ml of 48% aqueous hydrobromic acid. The reaction mixture was then evaporated to dryness. The residue was taken up in methylene chloride, washed with water, dried over sodium sulfate and evaporated. Recrystallization from methylene chloride / hexane afforded 3,4 dihydroxy-5-nitrobenzophenone with a melting point of 132 ° C.

Example 5. a / 4.9 g of magnesium was suspended in 15 ml of absolute ethanol and after the addition of 1 ml of tetrahydromethane was warmed up until the reaction began. 31.8 g of diethylmalonate in 19.9 ml of absolute ethanol and 80 ml of absolute toluene are then added dropwise with stirring so that the temperature is between 50 and 60 ° C. The reaction mixture was then stirred at this temperature for another 1 hour, cooled to -5 ° C and 49.3 g of 3,4-dimethoxy-5-nitrobenzoyl chloride / m were added dropwise. mp 82-85 ° C / in 300 ml absolute toluene and 50 ml absolute tetrahydrofuran so that the temperature does not exceed -5 ° C. The mixture was then stirred at room temperature overnight. After distillation of the solvent, the residue was dissolved in 500 I of ethyl acetate. The solution was treated with stirring and ice-cooling with an ice-cold solution of 12 ml of concentrated sulfuric acid in 80 ml of sulfuric acid. The organic phase was washed with sodium chloride solution, dried over magnesium sulfate and evaporated. The resulting oil was chromatographed on ten times silica gel with methylene chloride. The crystalline product obtained was recrystallized from isopropyl ether. 3,4-Dimethoxy-5-nitrobenzoylmalonic acid diethyl ester is obtained in the form of light beige crystals with a melting point of 70 ° C.

b / 19.0 g of 3,4-dimethoxy-5-nitrobenzoylmalonic acid diethyl ether was dissolved in 100 ml of glacial acetic acid, 5 drops of concentrated sulfuric acid were added thereto, and the mixture was refluxed for 16 h. is distilled at 60 ° C under vacuum in a water pump and the residue is treated three times with 250 ml of toluene, evaporating each time. The crystalline residue was extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and evaporated, and the resulting crystals were chromatographed on 30x silica gel with toluene. The crystalline product obtained was recrystallized from isopropyl ether. 3,4-Dimethoxy-5-nitroacetophenone is obtained as yellowish crystals with a melting point of 86-87 ° C.

c / 2 g 3 ', 4'-dimethoxy-5', nitroacetophenone was treated with 30 ml of hydrochloric acid at a constant boiling point and stirred at 140 ° C for 2.5 hours. After cooling, the mixture was poured into 200 ml of ice water and extracted three times with 100 mJ ethyl acetate. The organic phase was washed twice with 25 ml of sodium chloride solution, dried over sodium sulfate and evaporated. The resulting product was filtered with ethyl acetate over 20 times silica gel. Recrystallization of the product from water gave 3 ', 4'-dihydroxy-5'-nitroacetophenone as yellow crystals, mp 159-160 ° C.

The same compound was prepared by starting from 4'-hydroxy-3'-methoxy-5'-nitroacetophenone by boiling with hydrobromic acid.

Example 6

a / 100 g guaiacol was dissolved in 136.4 g isobutyric anhydride, treated with 120 g anhydrous zinc chloride, all of which was carried out in solution, the reaction mixture was heated to 155 ° C and cooled after three minutes. it is first steam distilled to remove volatile components and then extracted three times with 500 ml of ether each time. The organic phase was washed twice with 250 ml of water each time, once with saturated bicarbonate solution of 150 ml and again with 250 ml of water, dried over sodium sulfate and evaporated in a water pump vacuum. The brown residue obtained was distilled under high vacuum. The distillate, boiling point 105-120 ⁰ C (6.67 Pa), was dissolved in ether and the solution was treated with n-hexane until crystallization began. The crystals obtained were recrystallized from ether / hexane. 4'-Hydroxy-3'-methoxy-2methylpropiophenone is obtained in the form of colorless crystals with a melting point of 86-87 ° C.

b / 15.0 g of 4'-hydroxy-3'-methoxy-2methylpropiophenone was dissolved in 300 ml of glacial acetic acid and 7.65 ml was added dropwise.

50.5% nitric acid (11.2N) in 40 ml glacial acetic acid with stirring for 15 min. After 15 min, the reaction mixture is poured into ice-water and the separated crystals are filtered off by suction, washed with water and are dissolved in methylene chloride. The solution was dried over sodium sulfate and evaporated. The crude product obtained is combined with methylene chloride and filtered through 100 g of silica gel. The crystals thus obtained were recrystallized from methylene chloride / n-hexane. 4'-Hydroxy-3'-methoxy-2-methyl-5'-nitropropiophenone was obtained as yellow crystals, mp 85-87 ° C.

c / 8.0 g of 4'-hydroxy-3'-methoxy-2-methyl5'-nitropropiophenone was treated with 64 g of pyridine hydrochloride and stirred at 180 ° C for 45 minutes. After cooling, the reaction mixture was poured into 500 ml. glacier, acidified with 20 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum with a water pump. Crystallization from methylene chloride / n-hexane gave 3'-4'-dihydroxy-2-methyl-5'-nitropropiophenone as yellow crystals with a mp of 98-99 ° C.

Example 7.

a / 100 g guaiacol was dissolved in 136.4 g oily anhydride, treated with 120 g zinc chloride, heated for 3 min, and treated as described in Example 6a. The crude product obtained after distillation under high vacuum is chromatographed with toluene on 600 g of silica gel. Recrystallization from ether / n-hexane gave 4'-hydroxy-3'-methoxybutyrophenone as colorless crystals with a melting point of 40-41'C.

b / 6.5 ml of 11.2N nitric acid was added dropwise to a solution of 12.7 g of 4'hydroxy-3'-methoxybutyrophenone in 250 ml of glacial acetic acid with stirring for 10 min. The reaction mixture was then stirred. for another 15 min, poured into ice-water, the precipitated precipitate was filtered off by suction, washed with ice water and mixed with methylene chloride. The methylene chloride solution was filtered through 50 g of silica gel. The resulting product was recrystallized from methylene chloride / n-hexane. 4'-Hydroxy3'-methoxy-5'-nitrobutyrophenone is obtained as yellow crystals, mp 92-93 ° C.

c / 10.2 g of 4'-hydroxy-3'-methoxy-5'nitrobutyrophenone was treated with 80 g of pyridine hydrochloride and stirred at 200 ° C for 40 min. After cooling, the reaction mixture was poured into 500 ml of ice. The mixture was treated with 30 ml of 3N hydrochloric acid and extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated. The resulting crude product was chromatographed with CH2 Cl2 on 150 g of silica gel. The resulting product was recrystallized from methylene chloride / hexane. 3 ', 4'hydroxy-5'-nitrobutyrophenone is obtained as yellow crystals with a melting point of 88-90 ° C.

Example 8.

a) 2.25 g of 3,4-dihydroxy-5-nitrocannelic acid were dissolved in 50 ml and hydrogen chloride was added to the solution for 10 minutes. After 1 hour 50 ml of isopropyl ether was added and the precipitate was filtered off by suction and washed with isopropyl ether. Recrystallization from methanol / ether afforded 3,4 dihydroxy-5-nitrocannelic acid methyl ester as yellow crystals, mp 186-187 ° C.

b / Similarly, 3,4-dihydroxy-5-nitrocannelic acid and butanol hydrochloric acid obtain 3,4-dihydroxy-5-nitrocannelic acid butyl ester as yellow crystals with a melting point of 129-130 °. S.

Example 9.

Dissolve 5,0 g of 3,4-dimethoxy-5-nitrobenzoylmalonic acid diethyl ester in 50 ml of absolute methylene chloride. After cooling to -20 ° C, a solution of 16.9 g of boron tribromide in 30 ml of methylene chloride was added dropwise with stirring so that the temperature did not exceed -20 ° C. The mixture was then stirred at room temperature overnight. After the addition of 80 ml of ethanol, the mixture was stirred at room temperature for 30 min and the solvent was then distilled in vacuo with a water pump. The residue was treated with water and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated. The resulting crude product was filtered with ethyl acetate through 50 g of silica gel. The resulting crystalline residue was recrystallized from methylene chloride / n-hexane. 3.4-Dihydroxy5-nitrobenzoyl acetate ethyl ester was obtained as yellow crystals, mp 141-142 ° C.

Example 10.

a) A solution of 1.49 g of 2-phenylethylamine in 100 ml of methylene chloride was treated with 1.26 g of triethylamine. A solution of 3.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 100 ml of methylene chloride was added dropwise with stirring, then the mixture was stirred for another 15 minutes. The organic phase was then extracted twice with 500 ml of ice-water each. , dried over sodium sulfate and evaporated under vacuum in a pump. Recrystallization from methylene chloride / n-hexane gave 3,4-dimethoxy-5-nitro-phenylbenzamide as light beige needles with a melting point of 121-122 ° C.

b / 3.6 g of 3,4-dimethoxy-5-nitro-phenylbenzamide was refluxed with 35 ml of phosphorus oxychloride under a nitrogen atmosphere for 96 h. After distillation of excess phosphorus oxychloride under vacuum at 60 ° C C, treat the residue three times with 100 ml of toluene each, distilling the solvent each time. The residue was mixed with methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum with a water pump. The resulting red gum was chromatographed on 120 g of silica gel with methylene chloride (ethyl acetate (1: 1)). 1- (3,4-Dimethoxy-5-nitrophenyl) -3,4-dihydroisoquinoline is obtained as a yellow gum.

c / 1.4 g of 1- (3,4-dimethoxy-5-nitrophenyl) -3,4-dihydroisoquinoline was treated with 15 ml of hydrochloric acid at a constant boiling point and heated to reflux under a nitrogen atmosphere. 1.5 hours. After distilling the hydrobromic acid under vacuum in a water pump, the crystalline residue was recrystallized from acetone. 5- (3,4-Dihydro-1-isoquinolinyl) -3-nitropyrocatechol hydrobromide is obtained in the form of yellow crystals with a melting point> 250 ° C (decomposition).

Example 11.

a / 5.0 g of 4-hydroxy-5-methoxy-isophthaladdehyde was treated with 50 ml of constant boiling point of hydrobromic acid and heated at reflux with stirring under argon for 3 h. 50 ml of ice-water was added and the precipitate formed was filtered off by suction and washed with water. The crude product was combined with ethyl acetate and filtered on 50 g of alumina (activity grade II). The crystalline product obtained was recrystallized from ethyl acetate / hexane. 4,5-Dihydroxyisophthalaldehyde is obtained as pale orange crystals with a melting point of 201-202 ° C.

b / A solution of 3.27 g of hydroxylamine 0-sulfonic acid in 12 ml of water was added dropwise at 30 ° C and stirred to a solution of 2.0 g of 4,5-dihydroxyisophthalaldehyde in 20 ml of water, keeping the mixture at 65 ° C for 10 h. After cooling, the precipitate was filtered off by suction, washed with water and mixed with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated under vacuum with a water pump. Recrystallization from ethyl acetate afforded 4,5 dihydroxyisophthalonitrile as yellow crystals, which decomposed above 300 ° C.

Example 12.

a) A solution of 38 g of fuming nitric acid (96%) in 50 ml of glacial acetic acid was added dropwise with stirring and for 30 min at 20-25 ° C to a solution of 112.5 g

2-Bromo-4'-hydroxy-3'-methoxyacetophenone in 560 ml glacial acetic acid. Separate yellow-brown crystals. After 90 minutes, the reaction mixture was poured onto 300 g of ice. The crystals were filtered off by suction, washed with 1000 ml of water and dissolved in 1000 ml of methylene chloride. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was evaporated at 50 ° C under vacuum with a water pump until crystallization began. Crystallizate, cooled to room temperature, was removed by suction filtration and washed with a small amount of methylene chloride. 2-Bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone was obtained, m.p. 147-149 ° C.

b / Method A.b / Suspension of 580.1 mg

2-Bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 10 ml of ethanol was treated with 443.8 mg of selenium dioxide and refluxed for 71 hours. The selenium was then removed by filtration and the filtrate was evaporated. The residue was dissolved in methylene chloride, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 4-Hydroxy-3-methoxy-5-nitrophenylglyoxyl acid ethyl ester was obtained, mp 165167 ° C (from ethanol).

Similarly:

bb / 2-Bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-butanol give 4-hydroxy-3-methoxy-5-nitrophenylglyoxic acid n-butyl ester with a melting point of 105-107 ° C (from ethanol) and 6b) from 2-bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone and n-hexanol teach 4-hydroxy-3-methoxy-5-nitrophenylglyoxyl acid hexyl ester with melting point 103 -105 ° C (from n-hexanol / petroleum ether).

c) Method B. va / A suspension of 29.1 g of 2bromo-4'-hydroxy-3'-methoxy-5'-nitroacetophenone in 300 ml of tert-butanol is treated with

27.74 g of selenium dioxide and refluxed for 18 h.

The hot reaction mixture was filtered by suction through a diatomaceous earth filter layer, washing with methylene chloride. The filtrate was evaporated and the residue was suspended in 150 l of hot methylene chloride. The crystalline precipitate was filtered off by suction and washed with a small amount of methylene chloride. 4-Hydroxy-3-methoxy-5-nitrophenylglyoxyl acid is obtained with a melting point of 169-171 ° C.

2.42 g of 4-hydroxy-3-methoxy-5-nitrophenylglyoxic acid were dissolved in 25 ml of dry N, N-dimethylformamide, treated at room temperature with 50 mg of 4-dimethylaminopyridine and 920 mg of dry methanol, then cooled to 0 ° C with an ice bath and 2.27 g of N, N-dicyclohexylcarbodiimide was added. After 10 min, the ice bath was removed and the reaction mixture was stirred for another hour at room temperature. The mixture was then evaporated. The residue was dissolved in ethyl acetate, the insoluble urea filtered off, the filtrate washed four times with water, dried over sodium sulfate, filtered and evaporated. 4-Hydroxy-3-methoxy-5-nitrophenylglyoxyl acid methyl ester is obtained, mp 155-157 ° C (methylene chloride / ether).

Similarly:

c) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxyl acid and ethanol, 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid ethyl ester is obtained, m.p. 165-167 ° C (from ethanol) and cc. (from 4-hydroxy-3-methoxy-5-nitrophenylglyoxyl acid and isopropanol, 4-hydroxy-3-methoxy-5-nitrophenylglyoxyl acid isopropyl ester is obtained, m.p. 99-101 ° C (from isopropanol).

d / Suspension of 17.2 g of ethyl ester of

4-Hydroxy-3-methoxy-5-nitrophenylglyoxyl acid in 100 ml of dry acetonitrile and 100 mg of dry toluene was treated with 10.53 g of sodium iodide and 11.9 g of tetrachlorosilane and refluxed for 47 hours. the mixture was then evaporated and the residue was distilled six times with 200 ml of toluene each time. The resulting residue was partitioned between water and ether and filtered through a filter pad of diatomaceous earth. The ether phase was washed four times with saturated sodium chloride solution, filtered and evaporated. The oily residue is treated three times with ester and activated carbon.

3,4-Dihydroxy-5-nitrophenylglyoxyl acid ethyl ester was obtained, mp 77-79 ° C (from ether (n-hexane)).

Similarly:

e) 4-Hydroxy-3-methoxy-5-nitrophenylglyoxyl acid methyl ester gives 3,4-dihydroxy-5-nitrophenylglyoxyl acid methyl ester as a yellow distillate at 145-150 ° C and 10.67 Pa.

f) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxyl acid isopropyl ester, 3,4-dihydroxy-5-nitrophenylglyoxyl acid isopropyl ester was obtained as a yellow distillate at 155-160 ° C and 12.0 Pa.

g) from 4-hydroxy-3-methoxy-5-nitrophenylglyoxylic acid n -bugyl ester gives 3,4-dihydroxy- n -butyl ester.

5-nitrophenylglyoxyl acid as a yellow distillate at 160-165 ° C and 10.67 Pa.

h) 4-Hydroxy3-methoxy-5-nitrophenylglyoxylic acid n-hexyl ester gave 3,4-dihydroxy5-nitrophenylglyoxyl acid hexyl ester as a yellow distillate at 165-170 ° C and 12.0 Pa.

Example 13 Dissolve 236.1 mg of 3,4-dihydroxynitrophenylglyoxylic acid hexyl ester in 15 ml of ethanol and treat with 7.59 ml of 0.1 N sodium hydroxide solution. After 1 hour the reddish yellow solution was evaporated. The resulting 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester sodium salt crystallizes from water and has a melting point of 300 ° C.

Example 14. A solution of 3.18 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester in 47.5 ml of ethanol was treated with 1.11 g of 0-methylenehydroxyamine hydrochloride, 1.95 g of sodium acetate and 2 , 5 ml of water and refluxed for 5 hours. The reaction mixture was then evaporated and the residue treated with ether and water. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on silica gel with methylene chloride. A mixture of n- hexyl ester of E- and r-3,4-dihydroxy5-nitrophenylglyoxyl acid 0-methyl oxime in a ratio of 7: 3 was obtained as a reddish oil: 80 MHz NMR spectrum (CDC1 ₃ ): 0-methyl signal at 3.96 and 4.05 ppm.

Example 15. A solution of 5.1 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid ethyl ester in dry methylene chloride was treated dropwise at -10 ° C for 15 min with 25 g of boron tribromide. The mixture was then stirred at -10 ° C for 1 hour and then at room temperature for 17 hours. The reaction mixture was then evaporated and the residue was carefully treated with water and stirred at 50 ° C for an additional 30 min. After cooling to room temperature, the rag sediment is filtered off by suction. The aqueous phase was acidified with 10 ml of 1N hydrochloric acid, extracted four times with ether, the combined organic extracts washed four times with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The crude product was filtered three times by suction in ether through a diatomaceous earth filter layer. 3,4-Dihydroxy-5-nitrophenylglyoxyl acid is obtained with a melting point of 172-174 ° C (from isopropyl ether).

Example 16. A mixture of 3.93 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 1.38 g of 2-aminophenyl was dissolved at 120 ° C with stirring. The melt crystallizes after 5 min. After 2 h it is cooled and recrystallized from methanol. 3- (3,4-Dihydroxy-5-nitrophenyl) -2H-1,4-benzoxazin-2-one is obtained with a melting point of 202204 ° C.

Similarly:

c) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2-amino-p-cresol 3- (3,4-dihydroxy5-nitrophenyl) -6-methyl-2H-1,4-benzoxazine- 2on, mp 233-235 ° C (methanol / methylene chloride).

c) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 2-amino-4-propylphenol give 3- (3,4-dihydroxy-5-nitrophenyl) -6-propyl-2H-1,4benzoxazine-2- mp 200-202 ° C / methanol.

d) 3,4-Dihydroxy-5-nitrophenylglyoxyl acid and 3-amino-4-hydroxybenzoic acid n-hexyl ester gives 3- (3,4-dihydroxy-5-nitrophenyl) -2ox-2H-1,4-benzoxazine -6- carboxylic acid, m.p. 286-287 ° C (from acetone (petroleum ether)).

e) 3,4-Dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 2-amino-4-chlorophenol give 6-chloro-3- (3,4-dihydroxy-5-nitrophenyl) 2H-1,4-benzoxazine -2-one, mp 241-243 ° C (from methanol).

f) from 3,4-dihydroxy-5-nitrophenyl glyoxyl acid n-hexyl ester and 2-amino-4,6-dichlorophenol give 6,8-dichloro-3- (3,4-dihydroxy-5-) nitrophenyl / -2H-

1,4-benzoxazin-2-one, 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 yields 3- (3,4-dihydroxy-5-nitrophenyl) -7-nitro-2H-2,4-benzoxazin-2-one, m.p. 253-255 ° C (from acetonitrile (ethanol).

Example 17.

a) A mixture of 396.0 mg n-hexyl ester of 3,4-dihydroxy-5-nitrophenylglyoxyl acid and 137.6 mg of 1,2-phenylenediamine was heated to 120 ° for 60 min. Then the mixture was suspended in methanol, it is filtered off by suction and recrystallized from Ν, мети dimethylformamide / water. 3- (3,4dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone is obtained with a melting point of> 300®C.

Similarly:

c) from 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and -N-methyl-1,2-phenylenediamine are obtained

1-methyl-3- (3,4-dihydroxy-5-nitrophenyl) -2 (1H) -quinoxalinone, m.p. 271-273 ° C (from methanol).

c / from 3,4-Dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and N-propyl-1,2-phenylenediamine is obtained 1-propyl-

3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone, m.p. 183-185 ° C (from methanol).

d) 3,4-Dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 4,5-dimethyl-1,2-phenylenediamine are obtained

3- (3,4-dihydroxy-5-nitrophenyl) -6,7-dimethyl-2- (1H) -quinoxalinone with a melting point> 300 ° C (of N, N-dimethylformamide (water)).

e) from 3,4-dihydroxy-5-nitrophenylglyoxylic acid n-hexyl ester and 4,5-dichloro-2-phenylenediamine was obtained 6,720 dichloro-3- (3,4-dihydroxy-5-nitrophenyl) -2- / 1H (-phenoxalinone with a melting point> 300 ° C) of N, N -dimethylformamide (water).

f) from 3,4-Dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 3-chloro-5-trifluoromethyl-1,2-phenylenediamine a mixture of 8 / and 5-chloro-3- (3,4- dihydroxy-5-nitrophenyl-6- (7) -trifluoromethyl-2- (1H) -quinoxalinone in a 1: 1 ratio and melting point> 30 ° C (from Ν, ди-dimethylformamide (water)).

g) of 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 4-methoxy-1,2-phenylenediamine a mixture of

3- (3,4-dihydroxy-5-nitrophenyl) -6 (S) -methoxy-2- (1H) -quinoxalinone in a 1: 1 ratio, and with a melting point> 300 ° C (from ethanol / ether) h) 3,4-Dihydroxy-5-nitrophenylglyoxyl acid and 4-nitro-1,2-phenylenediamine n-hexyl ester give a 1: 1 mixture of 3- (3,4-dihydroxy-5-nitrophenyl) -6 (and 7) -nitro-2- (1H) -quinoxalinone in a ratio of 1: 1 and with a melting point> 300 ° C (of Ν, Ν-dimethylformamide) and water and i) of n-hexyl ester of 3 4-Dihydroxy-5-nitrophenylglyoxyl acid and N-hexyl-1,2-phenylenediamine give 1-hexyl-

3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone, m.p. 152-154'C (im methanol).

Example 18

A solution of 1.07 g of n-hexyl ester

3,4-Dihydroxy-5-nitrophenylglyoxyl acid and 696.3 mg of 2,3-diavinonaphthalene in 3 ml of 1-hexanol were refluxed for 3 hours. The reaction mixture was then cooled and diluted with methanol. . The crude product was filtered off by suction and recrystallized from N, N-dimethylformamide / water. 3- (3,4-Dihydroxy-5-nitrophenyl) -benzo (g) -XHHokcanHH-2- (1H) -one is obtained with a melting point> 300 ° K.

Example 19. A suspension of 2.05 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 600.8 mg of thiosemicarbazide was stirred vigorously at 90 ° C for 30 min. The mixture was then cooled to 40 And treated with a solution of 870.1 mg of sodium hydroxide in 15 ml of water. The solution was then heated to 90 ° C for 30 min, cooled to room temperature and treated dropwise with 2 ml conc. hydrochloric acid. The crystallized product was filtered off by suction and then dissolved in ethyl acetate. The solution was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 6 (3,4-Dihydroxy-5-nitrophenyl) -3-mercapto-1,2,4-triazin-5- (4H) -OH is obtained, m.p. 282-284 ° C (from ethanol).

Example 20.

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 was treated at 60 ° C with 820.3 mg of sodium acetate and The reaction mixture was then evaporated, the residue treated with 170 ml of water and heated at 60 ° C for 30 min. After cooling, the product was filtered by suction and washed with water. It turns out

4- (2-amino-4-thiazolyl) -2-methoxy-6-nitrophenol, m.p. 248-250 ° C (from ethanol).

Similarly:

aaB] from 2-bromo-4'-hydroxy-3'-methoxy5'-nitroacetophenone and N-phenylthiocarbamide gave 4- (2-aniline-4-thiazolyl) -2-methoxy-

6-nitrophenol, 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-amine-4 '- (trifluoromethyl) -hexanylide dihydrochloride in 70 ml of water. The suspension was treated for 60 min with stirring at room temperature with a solution of 2.6 g thiophosgene in 1.7 ml toluene. After 16 h, the precipitate was removed by suction filtration and the organic phase was washed with 1N hydrochloric acid and water. After drying over sodium sulfate and filtration, the filtrate was evaporated. Crude 4 '- (trifluoromethyl) -hexananilide-6-isothiocyanate is obtained.

abb (A solution of 5.2 g of crude 4 '(trifluoromethyl) -hexane-anilide-6-isothiocyanate in 60 ml of ethanol was treated with 100 ml of conc. ammonium solution. After 30 min, the reaction mixture was evaporated. The residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated. 1- (5 - [[alpha], [alpha], [alpha], -trifluoro-tololyl) -carbamoyl] -pentyl] -2-thiourea was obtained, m.p. 140-142 [deg.] C. (from ethanol).

abc (Suspension of 666.7 mg 1- (5-) a, a, a, -trifluoro-p-toluyl) -carbamoyl (phenyl) -2-thiourea and 580.2 mg 2-bromo-4'-hydroxy3'- methoxy-5'-nitroacetophenone in 50 ml of ethanol was treated at 60 ° C with 164.2 mg of sodium acetate. A reddish-yellow solution is obtained. After 90 minutes the reaction mixture was evaporated, the residue was treated with water, the precipitate was filtered off with suction and washed four times with 10 ml of water each. 6 - [(4-Hydroxy-3-methoxy-5-nitrophenyl) -2-thiazolyl] -amino (-4'-trifluoromethyl) hexananilide was obtained, m.p. 160-162 ° C (from ethanol).

ac / A solution of 29.0 g of 2-bromo-4'-hydroxy3'-methoxy-5'-nitroacetophenone and 13.5 g of 2-aminoacetophenone in 250 ml of dry Ν, мети, dimethylformamide was stirred at 90 ° C for at 16 h. The reaction mixture was then evaporated to about two thirds and poured onto ice. The separated crystals were filtered off by suction and dissolved in methylene chloride. The solution was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. 2- (4-Hydroxy-3-methoxy-5-nitrobenzoyl) -3-methylindole is obtained, m.p. 195-197 ° C (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 was treated with 4.92 g of sodium acetate and the mixture was stirred. reflux for 22 hours. The reaction mixture was then evaporated, the residue was dissolved in methylene chloride, this solution was washed four times with water, dried over sodium sulfate, filtered and evaporated to give 2- [4-hydroxy-

3-methoxy-5-nitrophenyl / -quinoxaline m.p. 195-197 ° C (from methylene chloride methanol)

Similarly: from abd (from 2-bromo-4'-hydroxy-3'-methoxy5'-nitroacetophenone and 4,5-dimethyl-1,2-phenylenediamine 6,7-dimethyl-2-) were obtained.

4- hydroxy-3-methoxy-5-nitrophenyl) -quinoxaline m.p. 207-209 ° C / methylene chloride / methanol.

B) A suspension of 267.3 mg of 4- (2-amino-4-thiazolyl) -2-methoxy-6-nitrophenol in 10 ml of dry methylene chloride was treated at -20 ° C with 1.25 g of boron tribromide. After the addition, the mixture was stirred at -20 ° C for another hour at room temperature without cooling for

The reaction mixture was then evaporated, the residue carefully treated with water and stirred at 50 ° C for 30 min. After cooling at room temperature, the mixture was sucked off and the crude product was removed by filtration and washed with a small amount of water. . 5- (2amino-4-thiazolyl) -3-nitropyracatechol hydrobromide was obtained with mp 244-246 ° C (from methanol).

Similarly:

with 4- (2-aniline-4-thiazolyl) -2-methoxy-6-nitrophenol yields 5- (2-aniline).

4-Thiazolyl (-3-nitropyracatechol, m.p. 202-204 ° C) from methanol-d (6- (4- (4-hydroxy-3-methoxy-5-nitrophenyl) -2-thiazolyl) -amine) - 4 '- (trifluoromethyl) -hexananilide is obtained 6 - //

4- (3,4-dihydroxy-5-nitrophenyl) -2-thiazolyl) -amine (-4 '- (trifluoromethyl) -hexananilide, m.p. 214-216 ° C (from methanol).

e) 2- (4-Hydroxy-3-methoxy-5-nitrobenzoyl) -3-methylindole gives 5-bromo-

2- (3,4-dihydroxy-5-nitrobenzoyl) -3-methylindole, m.p. 265-267 ° C (from methanol).

f) 2- (3,4-dihydroxy-5-nitrophenyl) -quinoxaline was obtained from 2- (4-hydroxy-3-methoxy-5-nitrophenyl) -quinoxaline, 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 is obtained with melting point 274276 ° With methanol.

Example 21 A mixture of 3.12 g of 2-bromo-3 ', 4'dihydroxy-5'-nitroacetophenone and 849.3 mg of thioacetamide was refluxed for 18 h in 40 ml of ethanol. After cooling, the crystals were filtered off by suction and recrystallized from methanol / isopropanol. 5- (2-methyl-4-thiazolyl) -3-nitropyrocatechol hydrobromide is obtained with melting point 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 was refluxed for 60 minutes. After cooling to room temperature. the crystals are filtered off by suction and recrystallized from n-butanol.

5- (2-Amino-6H-1,3,4-thiadiazine) is obtained

5-yl / -3-nitropyracatechol hydrobromide, m.p. 265-267 ° C.

Example 23. A solution of 1.38 g of 2-bromo 3 ', 4'-dihydroxy-5'-nitroacetophenone and 505.7 mg

2-Amino-1,3,4-thiadiazole in 25 ml n-butanol was refluxed for 7 hours. The reaction mixture was then cooled to room temperature and the separated crystals were filtered off by suction. 5- (imidazo- [2,1-6] -) is obtained.

1,3,4-thiadiazol-6-yl (-3-nitropyrocatechol 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 was refluxed for 23 hours. it is then cooled to room temperature and the crystals are removed by suction filtration. 5-imidazo- [2,1-6] -thiazol-6-yl (3-nitropyrocatechol hydrobromide was obtained 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 was heated to reflux for 17 h. The reaction mixture was then cooled to room temperature and the crystals were removed by suction filtration. 5- (imidazo [2,1-6] -benzothiazol-2-yl- (3-nitropyracatechol) with m.p. 303-3050C (from N, N-dimethylformamide (methanol) is obtained.

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 and refluxed for 1 hour . The reaction mixture was then cooled to room temperature and the crystals were removed by suction filtration. 5- (2H-1,4-benzothiazin-3-yl) -3-nitropyracatechol was obtained with mp 3O2-3O4 ° C (from N, N-dimethylformamide (methanol).

Example 27. A mixture of 987.5 mg 2, bromo 3 ', 4'-dihydroxy-5'-nitroacetophenone and 1.01 g

The 2-aminopyridine was melted at 110 ° C. After 30 min, the melt was treated with 15 ml of ethanol and refluxed for 3 h. The reaction mixture was then cooled to room temperature and the crystals were removed by suction filtration. 5- (imidazo- [1,2-a] pyridin-3-or (-3-nitropyracatechol) was obtained with a melting point of 250-252 ° C (from N, N-dimethylformamide (methanol).

Example 28.

a) 8.9 g of N, N-carbonyldiimidazole was added to a solution of 10.7 g of 4-hydroxy-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture was then heated to 65-70 &lt; 0 &gt; C It was then cooled to room temperature and a solution of 21.6 g of 6-aminohexyl-tert-butyl carbamate in 50 ml of tetrahydrofuran was added dropwise over 15 min. The reaction mixture was then heated to 6570 ° C for 18 h, evaporated and the residue suspended in ethyl acetate, filtered by suction and the resulting product chromatographed on silica gel with acetone (methylene chloride (3: 1).

(6-/4- Hydroxy-5- nitro-tetanisamide) -hexyl/- tert-butyl carbamate was obtained with melting point 145-147 (C) from isopropanol.

B / 5.8 ml of hydrobromic acid in glacial acetic acid (= 33%) was added at room temperature to a solution of 4.1 g (6- (4-hydroxy-5-nitro-6-anisamide / hexyl) -tert. butylcarbamate in 80 ml glacial acetic acid. The mixture was stirred for 2 h, the separated crystals were removed by suction filtration and washed with ether. N- (6-aminohexyl) -4-hydroxy-5-nitro-t-anisamide hydrobromide is obtained with m.p. 207-209 ° C (from isopropanol).

c / 1.25 g of boron tribromide was added at -20 ° C to a suspension of 392.2 mg of N- (6aminohexyl) -4-hydroxy-5-nitroanisamide hydrobromide in 25 ml of dry methylene chloride. After the addition, the mixture was stirred at -20 ° C for 1 hour and then at room temperature for 17 hours. The reaction mixture was then evaporated and the residue was treated with 10 ml of water and stirred at room temperature for 1 hour. 1 hour. After removal of water, the residue was chromatographed on Sephadex LH 20 with toluene / ethanol (1: 1). Nb-aminohexyl-3,4-dihydroxy-5-nitrobenzamide hydrobromide was obtained with a melting point of 205-207 ° C (from ethanol).

Example 29.

aa / A solution of 4.93 g of 5-nitroaniline and

2.7 g of 1,2-phenylenediamine in 45 ml of methanol and 15 ml of nitrobenzene are heated to reflux. After 15 min, crystals from the red solution begin to separate. After 18 hours, the reaction mixture was cooled to room temperature and diluted with 60 ml of methanol. The crystals were filtered off by suction and washed with methanol. 4- (2-Benzimidazolyl) -2-methoxy-6-nitrophenol was obtained with a melting point of 198-200 ° C (from N, N-dimethylformamide (methanol).

Similarly:

b) from 5-nitrovaniline and 4,5-dichloro-1,2-phenylenediamine yields 4- (5,6-dichloro-2-benzimidazolyl) -2-methoxy-6-nitrophenol, m.p. 258-260 ° C / from Ν , N-dimethylformamide (ether).

b / Suspension of 860.1 ml of 4- (2-benzimidazolyl) -2-methoxy-6-nitrophenol in 10 ml of glacial acetic acid and 10 ml of 48% hydrobromic acid was refluxed for 72 hours. it is then evaporated and the residue is treated four times with 50 ml of toluene, which is distilled each time. 5- (2-Benzimidazolyl) -3-nitropyracatechol is obtained with a melting point> 300 ° C / of acetone / water.

Similarly:

c) 4- (5,6-Dichloro-2-benzimidazolyl) -2-methoxy-6-nitrophenol yields 5- (5,6-dichloro-2-benzimidazolyl) -3-nitropyracatechol with mp 282-284 ° With / from acetone / water /.

Example 30. A suspension of 29.0 g of 2-bromo4'-dihydroxy-3'-methoxy-5'-nitroacetophenone in 700 ml of dry methylene chloride was treated at -20 ° C for 30 min with a solution of 125.3 g of boron tribromide in 300 ml of dry methylene chloride. After the addition, the mixture was stirred at 20 ° C for another hour and at room temperature for 16 h, then evaporated, the residue was carefully treated with water under ice-cooling and stirred at 50 ° C for 30 minutes. After cooling, the mixture was extracted with ester, the ether phase was washed with water, dried over sodium sulfate, filtered and evaporated. Obtained 2-bromo-3 ', 4'-dihydroxy5'-nitroacetophenone, m.p. 138-140'C (methylene chloride).

Example 31

a / A solution of 3.6 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid ethyl ester in 30 ml of acetic anhydride was heated at 110 ° C for 30 min in the presence of a catalytic amount of concentrated sulfuric acid, cooled to room temperature , the reaction mixture was poured into 150 ml of water and stirred for 60 min. The mixture was extracted with ether, washed with saturated sodium chloride solution, the combined organic extracts dried over sodium sulfate, filtered and evaporated. 3,4-Diazoethoxy-5-nitrophenylglyoxyl acid ethyl ester is obtained, mp 87-89 ° C (from ether (petroleum ether)).

Similarly:

B) from 3- (3,4-dihydroxy-5-nitrophenyl) -2H-1,4-benzoxazazin-2-one to give 3- (3,4-diazoethoxy-5-nitrophenyl) 2H-1,4-benzoxazin-2 -one melting point 186-188 ° C (from methyl enchloride (methanol).

c) from 3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone to give 3- (3,4-diacetoxy-5-nitrophenyl) -2- (1H-quinoxalinone) m.p. 243 ° C (methylene chloride / methanol).

d) from 3,4-dihydroxy-5-nitrobenzophenone gave 3,4-diazoethoxy-5 nitrobenzophenone with m.p. 141-143 ° C (from methylene chloride / ether).

e) 2-Fluoro-3,4-dihydroxy-5-nitrobenzophenone yields 3,4-diacetoxy2'-fluoro-5-nitrobenzophenone with a melting point

122-124 ° C (from ether) and f) from 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone yields 3,4-dihydroxy-5-nitrophenyl-4-pyridylketone with a melting point of 148-150 ° C / from methylene chloride / ether /.

Example 32

a / A solution of 2.0 g of 3,5-dinitropyracatechol in 25 ml of propine anhydride was heated at 110 ° C for 18 h in the presence of catalytic amounts of concentrated sulfuric acid, the excess anhydride was distilled at 70 ° C under high vacuum (1, 3Pa), the residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. 1,2 Dipropionyloxy-3,5-dinitrobenzene is obtained, m.p. 74-76 ° C (from methylene chloride (petroleum ether)).

Similarly:

B) from 3- (3,4-dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one

3- (3,4-dipropionyloxy-5-nitrophenyl-2H-

1.4- Benzoxazin-2-one melted 158-160'C / methylene chloride /.

c) from 6-chloro-3- (3,4-dihydroxy-5-nitrophenyl) 2H-1,4-benzoxazin-2-one to give 5- (6-chloro-2-oxo-2H-1,4-benzoxazine). 3-yl (-3-nitro-o-phenylenedipropionate, m.p. 148-150 ° C) (methylene chloride (ether)).

d) from 3- (3,4-dihydroxy-5-nitrophenyl) -7-nitro-2H-1,4-benzoxazin-2-one

3-Nitro-5- (7-nitro-2-oxo-2H-1,4-benzoxazin-3-yl) -o-phenylenedipropionate, m.p. 177-179 ° C (from methanol).

e) 3- (3,4-Benzoxazine-6-carboxylic acid) is obtained from 3- (3,4-dihydroxy-5-nitrophenyl) -2-oxo-2H-1,4-benzoxazine-6-carboxylic acid (3,4-bis) propionyloxy (-5-nitrophenyl) -2-oxo-2H-

1.4-benzoxazine-6-carboxylic acid, m.p. 192-194 ° C (from methylene chloride).

f) from 3-nitro-5- (2-quinoxalinyl) pyrocatechol gave 3-nitro-5- (2-quinoxalinyl) -o-phenylenedipropionate, m.p. 152-154 ° C (from methylene chloride / ether).

g) from 5- (2-benzimidazolyl) -3-nitropyracatechol afforded 5- (2-benzimidazolyl) (3-nitro-o-phenylenedipropionate) m.p. 179-181 ° C (from ether).

h) from 6,7-dichloro-3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone yields 5- (6,7-dihydro-3,4-dihydro-3-oxo-2-quinoxalinyl) (-3-nitro-o-phenylenedipropionate melting point 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 was obtained, m.p. 196198 ° C. (from ether) and j) from 6- (3,4-dihydroxy-5-nitrophenyl) -3-mercapto-1,2,4-triazin-5- (4H) -one yields 3-nitro-5- 2,3,4,5-tetrahydro-5-oxo-3-thioxo-8-triazin-6-yl) -o-phenylenedipropionate, m.p. 237-239 ° C (from ether).

Example 33.

a) A solution of 1.09 * 3,4-dihydroxy-5-nitrophenylglyoxyl acid ethyl ester in 6 ml of isobutyric anhydride was heated at 110 ° C for 17 h in the presence of catalytic amounts of concentrated sulfuric acid. The reaction mixture was then treated ten times with 10 ml of toluene, evaporating at 80 ° C and 18.7 mbar each time. The oily residue was distilled into a spherical expansion tube at 175180 ° C and 8.0 Pa. Obtained ethyl ester of

3,4-Diisobutyryloxy-5-nitrophenylglyoxyl acid.

Similarly:

B) from 3,5-dinitropyracatechol, 1,2-diisobutyryloxy-3,5-dinitrobenzene was obtained, m.p. 78-80 ° C (from ether).

c) from 3- (3,4-dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one

3- (3,4-diisobutyryloxy-5-nitrophenyl) -6methyl-2H-1,4-benzoxazin-2-one, m.p. 142-144 ° C (from ether).

d) 2- (3,4-dihydroxy-5-nitrophenyl) quinoxaline gave 2- (3,4-diisobutyryloxy-5-nitrophenyl) -quinoxaline, mp 155-157 ° C (from ether).

e) from 1-methyl-3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone to obtain 1-methyl-3- (3,4-diisobutyryloxy-5-nitrophenyl) -2- (1H) - quinoxalinone, mp 138-140'C (from ether).

f / from 5 - / imidazo [2,1-c] -1,3,4-thiadiazole-

6-yl / -3-nitropyracatechol yields 5- (imidazo [2,1-b] -1,3,4-thiadiazol-6-yl) -3-nitro-o-phenylene diisobutyrate with melting point 169-171 ' C (methylene chloride).

g) from 2-bromo-3'4'-dihydroxy-5'nitroacetophenone 5-bromoacetyl (-3-nitro-o-phenylenediisobutyrate) is obtained with a melting point of 56-58 ° C (methylene chloride / hexane).

B) from 5- (2-amino-4-thiazolyl) -3-nitropyracatechol hydrobromide gave 3-nitro-5- (2-isobutyramide-4-thiazolyl) -ophenylene diisobutyrate, m.p. 157-159 ° C (from methylene chloride) ether /.

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

3- (3,4-Dihydroxy-5-nitrophenyl) -6-propyl-2H-1,4-benzoxazin-2-one is obtained 3-nitro-5- (2-oxo-6-propyl-2H) -1,425 benzoxazin-3-yl] -o-phenylene diisobutyrate, mp 131-133 ° C (from methanol).

to (from 5- (imidazo) 1,2-a) pyridin-3-yl) -

3-Nitropyracatechol is obtained 5- (imidazo)

1,2-a (pyridin-3-yl) -3-nitro-o-phenylene diisobutyrate with mp 137-139 ° C (from ether)

1) from 5- (imidazo) - (2,1-6) -benzothiazole-

2-yl (-3-nitropyracatechol is obtained 5- (imidazo- (2,1-b) -benzothiazol-2-yl) -3-nitro-phenyl diisobutyrate melting point 197-199 ° C (from methylene chloride) ether and N, from 3,4-dihydroxy-5-nitrophenyl-2-pyridyl ketone hydrobromide, 3-nitro-5- (2-pyridylcarbonyl) -o-phenylene diisobutyrate is obtained with a melting point of 83-85 ° C (from ether / hexane). .

Example 34. a / A solution of 613.0 mg of 3,4-dihydroxy-5-nitrophenylglyoxyl acid ethyl ester in 4 ml pivaloyl anhydride was heated at 100 ° C for 17 h in the presence of a catalytic amount of concentrated sulfuric acid, cooled the solution was diluted with ether, washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated. The residue was treated ten times with 10 ml of toluene, which was evaporated each time. Distillation into a spherical expansion tube / air bath / fever 175-180 ° C and 4.0 Pa gave ethyl ester of 3,4-dipivaloyloxy-5-nitrophenylglyoxyl acid.

Similarly:

c) from 3- (3,4-dihydroxy-5-nitrophenyl) -6-methyl-2H-1,4-benzoxazin-2-one

3- (3,4-dipivaloyloxy-5-nitrophenyl) -6methyl-2H-benzoxazin-2-one, mp 180192 ° C (from ether).

c) from 3,4-dihydroxy-5-nitrobenzophenone yields 3,4-dipivaloyloxy-5-nitrobenzophenone with a melting point of 101-1030C (from tert-butyl methyl ether) and d) from 2'-fluoro-3,4 -dihydroxy-5nitrobenzophenone yields 3,4-dipivaloyloxy-2'-fluorobenzophenone with a melting point

74-76 ° C (from low boiling petroleum ether).

Example 35 A solution of 1.7 g of 3- (3,4-dihydroxy-5-nitrophenyl) -2- (1H) -quinoxalinone in 17 ml of enanthic anhydride was heated to 110 ° C for 17 h in the presence of a catalytic amount conc. sulfuric acid, the excess anhydride is then distilled off under high vacuum, the residue is dissolved in methylene chloride, the organic solution is washed with water, dried over sodium sulfate, filtered and evaporated to give 5- / 1,2-dihydro- 2-oxo-3-quinoxalinyl (-3-nitro-o-phenylene diheptanoate) m.p. 186-188 ° C (methylene chloride (ether)).

Example 36

a) 1.26 g of sodium acetate was added to a solution of 1.35 g of 2-bromo-3'-4'-dihydroxy-5'nitroacetophenone in 25 ml of alcohol and heated to reflux. After 6 h, the reaction mixture was filtered from the separated sodium bromide and evaporated. The residue was dissolved in ethyl acetate. The solution was washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated at 50 ° C. (3,4-Dihydroxy-5-nitrobenzoyl) -methyl acetate was obtained with m.p. 166168 ° C (from ethyl acetate (ether)).

Similarly:

c) from 2-bromo-3'-4'-dihydroxy-5'nitroacetophenone and sodium isobutyrate (3,4-dihydroxy-5-nitrobenzoyl) methylisobutyrate with melting point 120-122 ° C (ethyl acetate) ether and c) from 2-bromo-3-4'-dihydroxy-5'nitroacetophenone and sodium 3,4-dihydroxy-

5-Nitrophenylglyoxylate gives 3,4-dihydroxy-5-nitrophenacyl- / 3,4-dihydroxy-

5-Nitrobenzoyl (m.p.) m.p. 224224 (R) (methanol (ethyl acetate)).

Example 37 A suspension of 2.91 g of 2-bromo''-4'-dihydroxy-5'-nitroacetophenone was treated with 1.31 g of thionicotinamide in 50 ml of alcohol and heated to reflux for 2 hours. cooling to room temperature the crystals were filtered off with suction and recrystallized from N, N-dimethylformamide / alcohol. 3-Nitro-5- (2- (3-pyridyl) -4-thiazolyl) -pyrocatechol was obtained, m.p. 279281 ° C.

Example 38 A solution of 552 g of 2-bromo 3 ', 4 * dihydroxy-5'-nitroacetophenone and 2.7 g of 2aminoacetophenone in 100 ml of dry N, N-dimethylformamide was stirred at 90 * C for 24 h. evaporated, the residue was dissolved in ethyl acetate, washed with water, dried over sodium sulfate, filtered and evaporated. Obtained 2- /

3,4-dihydroxy-5-nitrobenzoyl (-3-methyl26 indole) m.p. 212-214 ° C (from n-butanol).

Example 39 A suspension of 7.32 g of 2-bromo 3 ', - 4'-dihydroxy-5'-nitroacetophenone was treated with 4.06 g of 1- (3-pyridinyl) -2-thiourea in 100 ml of n-butanol and heated to refluxed for 3 hours. After cooling to room temperature, the crystals were filtered off by suction and recrystallized from n-butanol. 3-Nitro-5- (2- (3-pyridylamino) -4-thiazolyl) -pyrocatechol hydrobromide is obtained with a melting point> 30 ° C.

Example 40 A suspension of 6.35 g of 2-bromo 3 ', 4'-dihydroxy-5'-nitroacetophenone was treated with 4.68 g of 1- (3-quinolinyl) -2-thiourea in 150 ml of n-butanol and heated to reflux. At reflux for 3 hours. After cooling to room temperature, the crystals were filtered off by suction and recrystallized from n-butanol. 3-Nitro-5- (2- (3-quinolinylamino) -4-thiazolyl) -pyrocatechol hydrobromide is obtained with a melting point> 300 ° C.

Example 41 A suspension of 8.28 g of 2-bromo 3 ', 4'-dihydroxy-5'-nitroacetophenone was treated with 6.37 g of racemic 1- (2-exobornyl) -2-thiourea in 100 ml of n-butanol and heated. to reflux for 3 h. After cooling to room temperature, the crystals were filtered off by suction and recrystallized from n-butanol. Racemic 3-nitro-5- is obtained

2- (2-exo-borylamino) -4-thiazolyl) -pyracatechol hydrobromide, m.p. 262-264 ° C.

Example 42 Process with 0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran with 0.605 ml of acetic acid at 5 ° C and then 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4 ' - (Trifluoromethyl) -heptananilide and stirred at 23 ° C under argon for 56 h. The residue obtained after evaporation of the reaction mixture was partitioned between ethyl acetate and 1N sodium hydroxide solution. The combined sodium hydroxide extracts were acidified with conc. hydrochloric acid, ethyl acetate extracted, the combined ethyl acetate extracts washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and the residue chromatographed on 120 g silica gel with methylene chloride (methanol (91: 9). Recrystallization from ethyl acetate / petroleum ether gave (E) -8- (3,4-dihydroxy-5-nitrophenyl) -6-oxo-4 '- (trifluoromethyl) -7-octenanilide, mp 194-197 ° C.

Example 43

a) 26.0 g of 2-chloro-3-hydroxy-p-anisaldehyde was dissolved in 400 ml of acetic anhydride and 5 ml of pyridine. The solution was stirred at 80 ° C for 8 h, then evaporated, the residue partitioned between ice water and methylene chloride, the organic phase dried over sodium sulfate, evaporated and the residue was recrystallized from methylene chloride / petroleum ether. 2chloro-3-formyl-6-methoxyphenyl acetate is obtained with a melting point of 48-50 ° C.

b / 38 g of 2-chloro-3-formyl-6-methoxyphenyl acetate were added portionwise at -5 ° C to -10 ° C for 15 min to 150 ml of 98% nitric acid. After stirring at 5 ° C for 30 min, the reaction mixture was poured into 1.51 ice water and extracted three times with 500 ml of methylene chloride. The combined organic phases were washed with ice water, dried over sodium sulfate and evaporated. The residue was crystallized from ether. 2-Chloro-3-formyl-6-methoxy-

5-nitrophenyl acetate, mp 84-85 ° C.

c) 35.8 g of 2-chloro-3-formyl-6-methoxy-5-nitrophenyl acetate were dissolved in 300 ml of methanol. After the addition of 145 ml of 1N sodium hydroxide solution, the mixture was stirred at 23 ° C for one hour. After evaporation of the methanol, the residue was diluted with ice water, acidified with 2N hydrochloric acid and extracted twice with 400 ml of ethyl acetate each time. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue was recrystallized from methylene chloride / petroleum ether. 2-Chloro-3-hydroxy5-nitro-p-anisaldehyde is obtained with a melting point of 130 ° C.

d / 1.3 g of 2-chloro-3-hydroxy-5-nitro-ranisaldehyde were dissolved in 80 ml of methylene chloride, treated with 0.82 ml of boron tribromide, stirred at 23 ° C for 18 h. treated with 5 ml of methanol under ice-cooling, evaporated, the residue was dried under high vacuum, stirred with water, filtered and recrystallized from acetonitrile. 2-Chloro-3,4-dihydroxy-5-nitrobenzaldehyde was obtained with a melting point of 193-195 ° C.

Example 44

a / A mixture of 30 g of 2-chloro-3-hydroxy-ranisaldehyde and 230 ml of ethanol was stirred at 70 ° C for 4 h in the presence of

12.3 g hydroxylamine hydrochloride, the reaction mixture was then evaporated, the residue was dried in vacuo and recrystallized from methanol / water. 2-Chloro-3-hydroxy-anisaldehyde oxime is obtained with a melting point of 174-176 ° C.

b / 21 g of 2-chloro-3-hydroxy-p-anisaldehyde oxime was refluxed for 20 h with 400 ml of acetic anhydride. The reaction mixture was then evaporated, the residue treated with 300 ml ice water, stirred for one hour, decanted, the cooled residue partitioned between methylene chloride and water, the organic phase dried over sodium sulfate, evaporated, the residue dried in vacuo , chromatographed on 200 g of methylene chloride silica gel and recrystallized from methylene chloride / petroleum ether. 2-Chloro-3-cyan-6-methoxyphenyl acetate was obtained with a melting point of 97-99 ° C.

c / As described in Examples 43b and 43c, 2-chloro-3-hydroxy-5-nitro-ranisonitrile was obtained from 2-chloro-3-cyan-6-methoxyphenyl acetate, m.p. 157-159 ° C. methylene chloride (hexane).

d / As described in Examples 43d, 2-chloro-3,4-dihydroxy-5-nitrobenzonitrile with m.p. 180 ° C (acetonitrile) was obtained from 2chloro-3-hydroxy-5-nitro-p-anisonitrile.

Example 45

a) 5.5 g-chloro-2-fluoro-3,4-dimethoxytoluene and 4.5 g potassium acetate were stirred at 80 ° C for 25 h in 50 ml of dimethylformamide. The reaction mixture was then poured onto 150 ml of ice water and extracted with ether. The ether phases were washed with sodium chloride solution, dried over sodium sulfate and evaporated. Obtained 2fluoro-3,4-dimethoxybenzyl acetate as an oil.

c) 5.4 g of 2-fluoro-3,4-dimethoxybenzyl acetate were heated at 80 ° C for 1.5 h with 50 ml of methanol and 50 ml of 1N sodium hydroxide solution. After evaporation of the methanol, the residue was extracted with methylene chloride. The combined extracts were washed with water, dried over sodium sulfate and evaporated. The residue was 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 magnesium dioxide were refluxed for one hour with 50 ml of benzene. The insoluble components are filtered off by washing with methylene chloride. The filtrate was evaporated and recrystallized from methylene chloride / hexane. 2fluoro-3,4-dimethoxybenzaldehyde is obtained with a melting point of 52-54 ° C.

d / 4.4 G of 2-fluoro-3,4-dimethoxybenzaldehyde and 1.83 g of hydroxylamine hydrochloride were refluxed for 5 h with 30 ml of ethanol. The reaction mixture was then evaporated and the residue dried under high vacuum at 23 ° C was introduced into 40 ml of phosphorus oxychloride. After stirring at 23 ° C for 2.5 h, the reaction mixture was evaporated, the residue was treated with ice water, the precipitate formed, filtered, washed with water, stirred with methylene chloride, the methylene chloride solution dried over sodium. sulfate and evaporated. Recrystallization of the methylene chloride / hexane residue afforded 2-fluoro-3,4-dimethoxybenzonitrile with a melting point of 64-65 ° C.

c / 2.0 g of 2-fluoro-3,4-dimethoxybenzonitrile was dissolved in 60 ml of methylene chloride, treated with 1.1 ml of boron tribromide, stirred at 23 ° C for 1 hour, then treated with more 1.0 ml of boron tribromide and stirred at 23 ° C for another 80 min. Then the reaction mixture was poured into 100 ml of ice-cold saturated sodium bicarbonate solution, then the mixture was extracted twice with 300 ml of ether, the combined ether phases washed twice with sodium chloride solution, dried over sodium sulfate, evaporated and the residue chromatographed on 50 g of silica gel with methylene chloride and methylene chloride (methanol / 97: 3). 2-Fluoro-3-hydroxy-ranisonitrile was obtained, mp 198-200 ° C.

f / 0.9 g of 2-fluoro-3-hydroxy-p-anisonitrile was dissolved in 10 ml of acetic anhydride and 0.5 ml of pyridine, then the mixture was stirred at 120 ° C for two hours. The reaction mixture was then evaporated and the residue partitioned between ice water and methylene chloride. The organic phase was dried over sodium sulfate and evaporated, the residue was recrystallized from methylene chloride / hexane. 3-Cyan-2-fluoro-6-methoxyphenyl acetate was obtained with a melting point of 90-91 ° C.

g / 0.8 g of 3-cyan-2-fluoro-6-methoxyphenyl acetate was introduced in three portions at 15 ° C in 5 ml of 96% nitric acid, then the mixture was stirred at -10 ° C for one hour. The reaction mixture was poured onto 50 g of ice and the mixture was extracted twice with 70 ml of ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. The residue thus obtained is dissolved in 50 ml of 1N sodium carbonate solution and 50 ml of methanol, the solution being stirred at 23 ° C for one hour and the methanol distilled. The remaining aqueous phase was adjusted to pH 2 at 0 ° C with conc. hydrochloric acid and extracted twice with 100ml ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated, and the residue was chromatographed on 45 g of silica gel with methylene chloride (methanol (97: 3). Recrystallization from ether / hexane afforded 2fluoro-3-hydroxy-5-nitro-p-anisonitrile, m.p. 112-113 ° C.

h / 550 mg 2-fluoro-3-hydroxy-5-nitro-anisonitrile was dissolved in 30 ml of methylene chloride and the solution was treated with 0.44 ml of boron tribromide. After stirring at 23 ° C for 6 h, an additional 0.1 ml of boron tribromide was added and the mixture was stirred at 23 ° C for 1.5 h. Then 3 ml of ethanol at -15 ° C was added. The reaction mixture was evaporated and the residue was dried under high vacuum at 23 ° C. Recrystallization from ether / hexane gave 2-fluoro-3,4-dihydroxy-5-nitrobenzonitrile, m.p. 154 ° C.

Example 46

a) 9.5 g of 3,4-dimethoxy-5-nitrobenzoic acid were suspended in 95 ml of thionyl chloride. The suspension was stirred at 80 ° C for one hour. Evaporation by additional addition of absolute toluene gave 10 g of 3,4-dimethoxy-5-nitrobenzoyl chloride, which was dissolved in 100 ml of THF. This solution was added dropwise to 300 ml of 28% ammonia. The mixture was then stirred at 40 ° C for two hours and cooled to 5 ° C. The crystalline precipitate was filtered off. 3,4-Dimethoxy-5-nitrobenzamide is obtained with melting point 182-185®C.

b / 2.46 g of chlorine were introduced under ice-cooling into a mixture of 8.0 g of sodium hydroxide, 50 ml of water and 30 g of ice. Then slowly add

6.5 g of 3,4-dimethoxy-5-nitrobenzamide suspended in 5 ml of tetrahydrofuran. The reaction mixture was then heated to 70 ° C for 30 min, stirred at 70 ° for 1 hour, cooled to 5 ° C and the separated crystals filtered. 3,4-Dimethoxy-5-nitroaniline is obtained with a melting point of 129131 ° C. Further extraction of 3,4-dimethoxy-5-nitroaniline can be obtained by extracting the filtrate with ethyl acetate, drying the extract over sodium sulfate, concentrating and crystallizing the residue with ether.

c / 10 g of finely divided 3,4-dimethoxy5-nitroaniline was suspended in 15 ml of 12N hydrochloric acid and 40 ml of water, then the suspension was stirred at 30 ° C for 1 hour. 3.8 g of sodium nitrite dissolved in 20 ml of water were added dropwise at -5 ° C for 15 min. The solution was stirred at -5 ° C for 30 min and the cold solution of diazonium salt was added at dropwise over 45 min to 100 ml of pyridine at 40 ° C. The mixture was then stirred at 70 ° C for 1 hour. The reaction mixture was evaporated and the residue was stirred with 300 ml ethyl acetate. It is extracted three times with 200 ml of 2N hydrochloric acid each time. The acidic aqueous phase was adjusted to pH 9 with conc. ammonia and extracted with methylene chloride. The combined methylene chloride extracts were dried over sodium sulfate and evaporated and the residue was chromatographed on 250 g of silica gel with ethyl acetate. Crystallization from methylene chloride / hexane gave 2- (3,4-dimethoxy5-nitrophenyl) -pyridine with a melting point of 89-90 ° C.

d / 1.5 g of 2- (3,4-dimethoxy-5-nitrophenyl) -pyridine was dissolved in 30 ml of 48% aqueous hydrobromic acid. The reaction mixture was stirred at 100 ° C for 16 hours and at 23 ° C for 18 hours. The precipitate which formed formed was filtered and recrystallized from methanol / ether. 3-Nitro-5- (2-pyridyl) -pyrocatechol hydrobromide is obtained with a melting point of 230-240 ° C.

Example 47

a) 2.76 ml of 2-bromopyridine was dissolved in 30 ml of absolute tetrahydrofuran and treated at -60 ° C for 30 minutes with 19.2 ml of 1.6M n-butyllithium solution (in hexane), then the mixture was stirred at -60 ° C for 30 minutes. Dissolve 6,0 g

3,4-dimethoxy-5-nitrobenzaldehyde in 50 ml of tetrahydrofuran and then added dropwise at -40 ° C for 30 min to said mixture. The reaction mixture was warmed to 0 ° C for 2 h, poured into ice water and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and evaporated and the residue was chromatographed on 200 g of silica gel with ethyl acetate. Obtained - (3,4-dimethoxy-5-nitrophenyl) -2-pyridine-methanol as a brown oil.

b / 7 g of magnesium dioxide was added in portions to 4.0 g of - (3,4-dimethoxy-5-nitrophenyl) -2-pyridine methanol dissolved in 100 ml of acetone, heated at reflux for 2.5 h. The mixture was then refluxed for a further 2 hours. The magnesium salt was then filtered and the residue obtained after evaporation was recrystallized from ether / hexane. 3,4-Dimethoxy-5-nitrophenyl-2-pyridyl ketone is obtained with a melting point of 113 ° C.

c / 1.5 g of 3,4-dimethoxy-5-nitrophenyl-2-pyridyl ketone dissolved in 30 ml of 48% hydrobromic acid was stirred at 100 ° C for 18 h. The reaction mixture was then evaporated and the residue was evaporated. recrystallized from acetonitrile / methanol. 3,4-Dihydroxy-5-nitrophenyl-2-pyridyl ketone hydrobromide is obtained with a melting point of 213 ° C.

Example 48

a) 11.3 g of tin dichloride dihydrate was added to 2.25 g of 3 ', 4'-dimethoxy-5'nitroacetophenone dissolved in 501 ethanol, then the mixture was stirred at 74 ° C for 30 min. The reaction mixture was poured onto 100 g of ice, neutralized with about 300 ml of saturated sodium bicarbonate solution, and treated with 150 ml of methylene chloride. The mixture was filtered and the methylene chloride phase was separated, dried over sodium sulfate and evaporated, and the residue was recrystallized from ether / petroleum ether.

Obtained S'-aMHHO-S '^ .'- aHMeTokcHacetophenone, mp 63-65 ° C.

b / A solution of 5.2 g of sodium nitrite in 20 ml of water was added dropwise at 0 ° C for 20 min to 14.0 g of 5'-amino-3 ', 4'-dimethoxyacetophenone dissolved in 155 ml of 1N hydrochloric acid . After stirring at -2 ° C for 3 min, a cooled solution of diazonium salt for 30 min at 5-10 ° C was added dropwise to a solution of 8.7 g of copper / 1 / cyanide and 5.45 g of potassium cyanide in 60 ml. water. After the solution was added, 200 ml of methylene chloride was added and the reaction mixture was stirred at 23 ° C for 3 h and then filtered. The organic phase was separated, washed with water, dried over sodium sulfate and evaporated. The residue was recrystallized from methylene chloride / petroleum ether. 5'-cyan-3'4 'dimethoxyacetophenone was obtained, mp 125-126 ° C.

c / 3.75 g of aluminum powder and 28.5 g of iodine were refluxed for 2 h in 160 ml of absolute benzene. 3, -0 g of 5'-cyan-3 ', 4'-dimethoxyacetophenone and 0.5 g of tetra-butylammonium iodide are then added at 20 ° C, and the mixture is refluxed for 1 hour. was treated at 20 ° C with 50 g of ice and filtered. The residue was washed with ethyl acetate. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with 20% sodium thiosulphate solution, dried over sodium sulfate and evaporated. The residue thus obtained was dissolved in 20 ml of acetic anhydride and 0.5 ml of pyridine and stirred at 120 ° C for 6 hours. The mixture was then evaporated and the residue partitioned between methylene chloride and ice water. The methylene chloride phase was dried over sodium sulfate and evaporated and the residue was chromatographed on 100 g of silica gel with methylene chloride. Recrystallization from ether gave 5'-cyan-3 ', 4'-diacetoxyacetophenone, mp 76-79 ° C.

Example 49.0.33 g of 5'-cyan-3'4'-diacetoxyacetophenone dissolved in 3.3 ml of methanol was treated with 2.7 ml of 1.0 N sodium hydroxide solution and the reaction mixture was stirred at 23 ° C for 45 min. The mixture was then acidified with 2N hydrochloric acid, diluted with 5 ml of saturated sodium chloride solution and extracted twice with 30 ml of ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and evaporated. The residue was recrystallized from toluene / acetonitrile. 5'-cyan-3, '4'-dihydroxyacetophenone is obtained as brownish crystals, which are melting with decomposition at 215 ° C.

Example 50

a) 3.48 g of phenyltrimethylammonium bromide dibromide dissolved in 30 ml of tetrahydrofuran was added dropwise at room temperature for 45 min to 1.9 g of 5'-cyan-3 ', 4'-dimethoxyacetophenone dissolved in 30 ml of tetrahydrofuran, the mixture was stirred for 30 min. The reaction mixture was then poured into 120 ml of ice water and extracted three times with 70 ml of methylene chloride. The combined methylene chloride phases were washed with 2N sulfuric acid, dried over sodium sulfate and evaporated. The residue was chromatographed on 20 g of silica gel with methylene chloride. Recrystallization from methylene chloride / hexane gave 5- (bromoacetyl) -2,3-dimethoxybenzonitrile, m.p. 138-141 ° C.

c) 1.45 g of 5- (bromoacetyl) -2,3-diethoxybenzonitrile and 1.12 g of selenium dioxide were stirred at 120 ° C for 18 h in 10 ml of n-hexanol. After cooling to room temperature, the mixture was diluted with 20 ml of methylene chloride and filtered. The filtrate was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on 70 g of silica gel with hexane (ether (2: 1) to give (3-cyan-4,5-dimethoxyphenyl) -glyoxylic acid hexyl ester as an oil.

c / 4.8 ml of boron tribromide was dissolved in 20 ml of methylene chloride and added dropwise under ice-cooling for 20 min to 4.0 g of (3-cyan-4,5-dimethoxyphenyl) -glyoxylic acid hexyl ester dissolved in 100 L of methylene chloride, and the reaction mixture was stirred at room temperature for 18 h. Then 40 ml of methanol at -60 ° C was added dropwise, the mixture was stirred at room temperature for 1 hour and evaporated. The residue was mixed with methanol. It was refluxed for 10 minutes, evaporated to dryness and dried in high vacuum. The crude product thus obtained was recrystallized from acetonitrile. (3-Cyan-4,5-dihydroxyphenyl) -glyoxyl acid methyl ester was obtained with a melting point of 252 ° C.

Example 51. 1.075 g of (3-cyan-4,5-dihydroxyphenyl) -glyoxylic acid methyl ester and 0.60 g of 2-amino-p-cresol were stirred at 120 ° C for 7 min in 2 ml of dimethylformamide. The mixture was then cooled to room temperature and diluted with 15 ml of water. The precipitate was filtered off and dried in an aqueous vacuum pump at 80 ° C for 6 hours. Recrystallization from acetonitrile gave 2,3-dihydroxy-5- (6-methyl-2oxo-2H-1,4-benzoxazin-3-yl N -benzonitrile, mp 278-280 ° C.

Example 52

a / A solution of 2.5 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute tetrahydrofuran is treated with 1.1 ml of isocyanacetic acid ethyl ester and then with a solution of 3.0 ml of triethylamine in 10 ml of tetrahydrofuran and stirred at room temperature for 48 hours. After distilling the solvent, the residue was extracted with ethyl acetate / water. The crude product obtained after evaporation was chromatographed on 20x silica gel with ethyl acetate. Recrystallization from ethyl acetate / hexane gave 5- (3,4-dimethoxy-5-nitrophenyl) -4-oxazolecarboxylic acid ethyl ester as yellow crystals, mp 109110 ° C.

b / 1.0 g of 5- (3,4-dimethoxy-5-nitrophenyl) -4-oxazolecarboxylic acid ethyl ester was treated with 10 ml of hydrochloric acid at a constant boiling point and stirred at 140 ° C for 2 h. After distillation of the excess hydrobromic acid, the yellow residue was recrystallized from ethanol / acetone. 2-Amino-3,4'-dihydroxy-5'nitroacetophenone hydrobromide is obtained as yellow crystals with a melting point> 250 ° C (decomposition).

Example 53

a) 10 g of 3,4-dimethoxy-5-nitrobenzoyl-acetic acid ethyl ester was suspended in 100 ml of ethanol, treated with 1.7 g of methylhydrazine and refluxed for 16 h. After distilling about 50 ml ethanol, the mixture was cooled to 0 ° C and the precipitated precipitate was filtered off by suction. Recrystallization from ethanol gave 3- (3,4dimethoxy-5-nitrophenyl) -1-methylpyrazol-5ol as yellow crystals with a melting point of 200-202 ° C.

b) 2.0 g of 3- (3,4-dimethoxy-5-nitrophenyl) -1-methylpyrazol-5-ol were 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 was added dropwise over 1 hour. The mixture was then stirred at room temperature for 16 h, cooled to -20 ° C and treated for 30 min with 100 ml of ethanol. After stirring at room temperature for one hour, the solvent was removed by distillation of a water vacuum pump at 40 ° C. The residue was treated three times with 100 ml of ethanol / toluene each time, the solvent being removed each time. The residue was crystallized from ethanol. 5- (5-Hydroxy-1-methylpyrazol-3yl) -3-nitropyracatechol hydrobromide was obtained as yellow crystals with a melting point> 250 ° C.

Example 54.

a) 16.8 g / 0.7 g atom / magnesium was treated with 15 ml ethanol and after the addition of 2 ml tetrachloromethane, the reaction was initiated by heating. A solution of 130.3 g of tert -butylielmalonate in 70 ml of ethanol and 600 ml of absolute ether was added dropwise with stirring for about 30 minutes so that the reaction was refluxed. The mixture was then stirred at 50 ° C for another three hours and the solvent distilled at 40 ° C in a water vacuum pump. The residue was dissolved in 900 ml of tetrahydrofuran. To this solution was added dropwise with stirring at 50 ° C a solution of 170 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 700 ml of absolute THF and the mixture was stirred at reflux for 1 hour. The solvent was distilled at 40 ° C in a water vacuum pump. The residue was treated with 11 ether, 260 ml of 3N sulfuric acid was added under cooling and stirring, and the mixture was stirred for 30 min. The aqueous phase was extracted twice with 600 ml of ether each time. The organic phase was washed to neutral with water, dried over sodium sulfate and evaporated. The brown oil obtained was filtered through 1 kg of silica gel with toluene. The resulting mixture containing 3,4-dimethoxy-5-nitrobenzoyl / malonic acid ethyltetrabutyl ester and (3,4-dimethoxy-5-nitrobenzoyl) -acetic acid ethyl ester was dissolved in 600 l of methylene chloride and treated with stirring for about 30 min with 193 ml of trifluoroacetic acid. The mixture was then stirred at 40 ° C for 2 h and then evaporated at 40 ° C in a water vacuum pump. The resulting oil was extracted with ether / water. The organic phase was dried over sodium sulfate and evaporated. After dissolving in diisopropyl ether / hexane and cooling, the separated crystals are filtered off by suction and recrystallized from diisopropyl ether. (3,4-Dimethoxy-5-nitrobenzoylacetic acid ethyl ester) is obtained as light yellowish crystals with a melting point of 67-68 ° C.

c) 10.0 g of (3,4dimethoxy-5-nitrobenzoyl) -acetic acid ethyl ester was reacted with 4.0 g of phenylhydrazine analogously to example 53a. Recrystallization from methylene chloride / ethanol gave 3- (3,4-dimethoxy-5-nitrophenyl) -1phenyl-2-pyrazolin-5-one as yellow crystals, mp 190-192 ° C.

c) As described in Example 53b, boron tribromide gave 5- (5-hydroxy-1-phenylpyrazol-3-yl) -3-nitropyracatechol hydrobromide as yellow crystals with a melting point> 220 ° C (decomposition).

Example 55 Dissolve 20.1 g of (3,4-dimethoxy-5-nitrobenzoyl) malonic acid diethyl ester in 200 ml of methylene chloride, cooling the solution at -20 ° C and at this temperature dropwise and stirring for 15 hours. a solution of 68.1 g of boron tribromide in 120 ml of methylene chloride was added over a minute. The mixture was then stirred at room temperature overnight. After cooling to -20 ° C, the mixture was treated with 300 ml of ethanol and stirred at room temperature for 30 minutes. The solvent was distilled off in a water vacuum pump at 40 ° C. The residue was treated with 300 ml of ice water and methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated. The crude product obtained is chromatographed on 10x silica gel with toluene. Crystallization from methylene chloride / hexane gave (3,4-dihydroxy-5-nitrobenzoyl) -acetic acid ethyl ester as yellow crystals, mp 136-137 ° C.

EXAMPLE 56 Suspended 2.0 g of (3,4-dihydroxy-5-nitrobenzoyl) acetic acid ethyl ester in 50 ml of ethanol. After treatment with 0.4 g of hydrazine hydrate, the mixture was kept at reflux for 16 h. After distilling the solvent, the residue was maintained at reflux for 5 min with 50 ml of ethyl acetate. The separated precipitate was filtered off with suction and the filtrate was concentrated to 10 ml. The crystals, which are separated in cold, are filtered off by suction. 5- (5-Hydroxypyrazol-3-yl) -3-nitropyracatechol was obtained as orange crystals with a melting point of 228 ° C (decomposition).

Example 57. 7.3 g of 3,4-dihydroxy-5-nitrobenzoic acid with 30 ml of acetic anhydride were treated, keeping the mixture at reflux for 8 hours. The reaction mixture was poured onto ice. The separated precipitate was filtered off by suction, washed with water and stirred with methylene chloride. The organic phase was dried over sodium sulfate and evaporated. The resulting residue was recrystallized from methylene chloride / n-hexane in cold. 3,4diacetoxy-5-nitrobenzoic acid is obtained with a melting point of 126-127 ° C.

Example 58.

a) 9.7 g of 3,4-diacetoxy-5-nitrobenzoic acid were treated with 12.5 ml of thionyl chloride, whereby the mixture was stirred at 100 ° C for 1.5 h. After distillation of excess thionyl chloride was distilled 5 - (chlorocarbonyl) -2-nitro-o-phenylene diacetate with boiling point 160 ° C (26.7 Pa).

b) 3.2 g of 5- (chlorocarbonyl) -2-nitro-phenylenediacetate was dissolved in 50 ml of dimethylformamide. The cooled solution was treated with stirring with a solution of 2.2 ml diethylamine in 20 ml dimethylformamide. The mixture was then stirred at room temperature for 1 hour, the solvent being distilled off in a water vacuum pump at 50 ° C. The residue obtained is treated with water and methylene chloride. The organic phase was dried over sodium sulfate and evaporated. The yellow resin obtained was crystallized from methylene chloride / ether. N, N-diethyl-3,4-dihydroxy-5-nitrobenzamide is obtained as yellow crystals with a melting point of 145-146 ^° C.

Example 59 Dissolve 3.2 g of 5- (chlorocarbonyl) -2-nitro-o-phenylenediacetate in 50 ml of dimethylformamide and treat the solution at 0-5 ° with stirring for 40 min with a solution of 3.02 ml 2 , 2-dimethylaminoethylamine in 20 ml of dimethylformamide. The mixture was then stirred at room temperature for 30 minutes. The solvent was distilled off in a water vacuum pump at 60 ° C. The residue was distilled twice with 20 ml each time, dissolved in hot ethanol and treated with excess ethanol hydrochloric acid, after which the mixture was evaporated. Recrystallization from ethanol (ethyl acetate) gave N- (2- (dimethylamino) N-ethyl) 3,4-dihydroxy-5-nitrobenzamide hydrochloride as yellow crystals, mp 139 ° C (decomposition).

Example 60.

a) 10.0 g of 2,3-dimethoxy-5-nitrobenzaldehyde are treated with 50 ml of glacial acetic acid and 50 ml of hydrochloric acid at a constant boiling point and maintained at reflux for 7 hours. The separated precipitate is filtered off by suction, washed with water and stirred with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The resulting crude product was filtered through silica gel with ethyl acetate. Crystallization from ethyl acetate / hexane gave 2,3-dihydroxy-5-nitrobenzaldehyde as brownish crystals with a melting point of 226228 ° C.

b / 4.5 g of 2,3-dihydroxy-5-nitrobenzaldehyde were suspended in 75 ml of water. After treatment with 4.2 g of hydroxylamine o-sulfonic acid, the mixture was stirred at 65 ° C for 16 h. After cooling, the separated crystals were filtered off with suction and washed with water. The filtrate was extracted with ethyl acetate. The crystals and the dry organic phase were combined, the mixture was evaporated and the residue was recrystallized from diisopropyl ether. 2,3 Dihydroxy-5-nitrobenzonitrile is obtained as yellow crystals, mp 186-188 ° C.

Example 61

a) 4.0 g of 3,4-dimethoxy-5-nitrobenzonitrile were dissolved in 50 ml of dimethylformamide and the solution was treated with 1.66 g of ammonium chloride and 2.02 g of sodium azide and stirred at 125 ° C for 31 h. After 8 and 15 h, the same amount of ammonium chloride and sodium azide are added. After cooling, the mixture is poured onto ice. The separated precipitate was filtered off by suction, washed with water and dried. 2-Methoxy-65-nitro (1H-tetrazol N-5-yl) -phenol was obtained as orange crystals with a melting point of> 240 ° C (decomposition).

b / 4.0 g of 2-methoxy-6-nitro- (1H-tetrazol-5-yl) -phenol was treated with 40 ml of hydrochloric acid at a constant boiling point and the mixture was stirred at 140 ° C for 8 h under atmosphere of nitrogen. After cooling, the mixture is poured onto ice. The separated precipitate was filtered off by suction and recrystallized from ether. 3-Nitro-5- (1H-tetrazol-5-yl) pyrocatechol was obtained in the form of orange crystals with a melting point> 240 ° C (decomposition).

Example 62 A total of 7.2 g of 3,4-dihydroxy-5-nitro-benzonitrile was added portionwise in 130 ml of conc. of sulfuric acid with stirring for 10 min, after which the mixture was heated at 50 ° C for 4 h. The reaction mixture was poured into 800 ml of ice water. The separated precipitate was filtered off by suction, washed with water and mixed with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. Recrystallization from acetone / ethyl acetate is obtained

3,4-dihydroxy-5-nitrobenzamide in the form of orange crystals, mp 235-236'C.

Example 63

a / A solution of 11.25 g of 2-hydroxyacetophenone in 100 ml of absolute dimethylformamide was added dropwise under an argon atmosphere for 15 min to a suspension of 3.6 g of 55% sodium chloride as a dispersion in 50 ml of absolute dimethylformamide and the mixture stirred at room temperature for one hour. After cooling to 0 ° C, a solution of 20.3 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 10 ml of absolute dimethylformlamide was added dropwise over 20 minutes and the mixture was stirred at room temperature overnight. The reaction water was poured into ice water, then the mixture was extracted twice with 250 ml of ethyl acetate. The organic phase was extracted twice with 100 ml of sodium chloride solution each time, dried over sodium sulfate and evaporated.

The brown oil obtained was heated in 100 ml of toluene. The separated precipitate was filtered off by suction and the filtrate was chromatographed on 30x silica gel with toluene (ethyl acetate (4: 1)). Recrystallization from ethyl acetate / hexane afforded 3,4-dimethoxy-5-nitrobenzoic acid o-acetylphenyl ester as yellow crystals, mp 108-109 ° C.

b / 10.0 g of 3,4-methoxy-5-nitrobenzoic acid o-acetylphenyl ether was dissolved in 50 ml of toluene. After treatment with 8.12 g of ground and dried potassium hydroxide, the mixture was stirred at 80 ° C for 5 minutes. After cooling, the mixture is poured onto ice. The aqueous solution was acidified with 3N hydrochloric acid. The separated precipitate is removed by suction filtration. Recrystallization from ethyl acetate / hexane gave 1- (o-hydroxyphenyl) -3- (3,4 dimethoxy-5-nitrophenyl) -1,3-propanedione as yellowish crystals, mp 188-189 ° C.

c) A solution of 1.82 g of boron tribromide in 20 ml of methylene chloride was added dropwise over about 20 minutes to a solution of 500 mg of 1- (ohydroxyphenyl) -3- (3,4-dimethoxy-5nitrophenyl) -1,3-propanedione in 50 ml of methylene chloride with stirring and under argon atmosphere at -20C, after which the mixture was stirred at room temperature overnight. After cooling to -20 ° C, the mixture was treated dropwise with 25 ml of ethanol and evaporated at 40 ° C in a water vacuum pump. Recrystallization from ethanol is obtained

1- (3,4-dihydroxy-5-nitrophenyl) -3- (ohydroxyphenyl) -1,3-propanedione in the form of yellow crystals, mp 251-252 ⁰ C.

Example 64.

a / A solution of 2.0 g of 3,4-dimethoxy-5-nitrobenzoic acid o-acetylphenyl ester in 12.5 ml of glacial acetic acid is treated with 0.94 g of sodium acetate and kept at reflux for a further at 4 h. After cooling, the mixture was poured into ice-water. The separated crystals are filtered off by suction. Recrystallization from ethyl acetate / hexane is obtained

2- (3,4-dimethoxy-5-nitrophenyl) -4H-1-benzopyran-4-one as colorless crystals with a melting point of 216-217 ° C.

b) A solution of 10 ml of boron tribromide in ml of methylene chloride is added dropwise over 30 minutes at -10 ° C to a solution of 1.0 g of 2- (3,4-dimethoxy-5-nitrophenyl) -4H-1-benzopyran-4one in 100 ml of methylene chloride under argon, after which the mixture was stirred at room temperature overnight. After cooling to -20 ° C, 20 ml of ethanol was added dropwise. The mixture was then evaporated on a water vacuum pump. The resulting yellow residue was extracted with water / ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated. Recrystallization from ethanol / ethyl acetate gave 2- (3,4-dihydroxy-5-nitrophenyl) -4H-1-benzopyran-

4-one as yellow crystals with a melting point> 240 ° C (decomposition).

Example 65

a (92 ml solution of n-butyllithium (1.6M in hexane) was added dropwise at -70 ° C for 20 min to 33.0 g 4bromobenzotrifluoride (dissolved in 150 ml tetrahydrofuran). After stirring at 70 ° C for 45 min, 36 g of 3-methoxy-4-benzyloxybenzaldehyde (dissolved in 100 ml of tetrahydrofuran) were added dropwise at between -70 and -60 ° C. The reaction mixture was stirred at -70 ° C for 2 h and at 0 ° C for one hour, poured into a mixture of ice and 100 ml of 2N sulfuric acid and extracted twice with 500 ml of ether. The combined ether phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 4- (Benzyloxy) -3-methoxy-4 '- (trifluoromethyl) -benzyl chloride is obtained, which can be used directly in the next reaction step.

c) 52.6 g of 4- (benzyloxy) -3-methoxy-4 '(trifluoromethyl) -benzhydrol (dissolved in 500 ml of methylene chloride) was treated with 30.6 g of pyridine chlorochromate for 10 min at 20 ° C and stirred. at 20 ° C for 2 h. The precipitate formed is then filtered and washed with methylene chloride. The filtrate was evaporated and the residue was chromatographed on 150 g of silica gel with methylene chloride. Recrystallization from methylene chloride / hexane gave 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) benzophenone with a melting point of 101 ° C.

c) 70 ml of 33% hydrobromic acid in acetic acid was added within 15 min at 10 ° C to 20 g of 4- (benzyloxy) -3-methoxy-4 '- (trifluoromethyl) benzophenone dissolved in 150 ml of methylene chloride. /. After stirring at 20 ° C for 1.5 h, the reaction mixture was poured onto 600 ml of ice-water, the methylene chloride phase was separated and the aqueous phase was extracted more than twice with 100 ml of methylene chloride. The combined methylene chloride phases were washed with 600 ml of water, dried over sodium sulfate and evaporated. The residue was chromatographed on 150 g of silica gel with methylene chloride. Recrystallization from methylene chloride / hexane gave 4hydroxy-3-methoxy-4 '- (trifluoromethyl) benzophenone with a melting point of 97 ° C.

d / 3.2 ml of 65% nitric acid was added dropwise over 10 min at 20 ° C to 12.8 g of 4-hydroxy-3-methoxy-4 '(trifluoromethyl) -benzophenone dissolved in 160 ml of acetic acid acid. After stirring for 1.5 h, the reaction mixture was poured into 600 ml of ice-water and the precipitate formed was filtered, washed with water and dissolved in methylene chloride. The methylene chloride solution was dried over sodium sulfate and evaporated, and the residue was recrystallized from methylene chloride / hexane. 4-Hydroxy-3-methoxy-5-nitro-4 '- (trifluoromethyl) -benzophenone was obtained, m.p. 172 ° C.

e) 2.0 g of 4-hydroxy-3-methoxy-5-nitro 4 '- (trifluoromethyl) -benzophenone dissolved in 20 ml of 33% hydrobromic acid in glacial acetic acid was stirred at 90 ° C for 18 h 20 ml of 48% aqueous hydrobromic acid was added and the mixture was stirred at 110 ° C for an additional 18 h. The reaction mixture was then evaporated under reduced pressure and the residue was recrystallized from water. 3,4 Dihydroxy-5-nitro-4 '- (trifluoromethyl) benzophenone is obtained, m.p. 116-118 ° C.

Example 66.

a) 18.7 g of 4-hydroxy-3-methoxy-5-nitro4 '- (trifluoromethyl) -benzophenone dissolved in 250 ml of tetrahydrofuran is treated at room temperature with 27.5 ml of 2N potassium hydride solution and then the mixture evaporated. The residue was treated with 200 ml of toluene and the mixture was evaporated again. The mixture was heated with 400 ml of toluene for 4 hours under water and refluxed. Separate 100 ml of toluene by distillation and add 10 ml of dimethylformamide and 20 ml of dimethyl sulfate freshly distilled, then reflux for 5 h. Then 300 ml of 1N sodium hydroxide solution is added at 20 ° C. The reaction mixture was stirred for 30 min and treated with 200 ml of ether. The organic phase was separated, the aqueous phase was extracted more than twice with 100 ml of ether, the combined ether phases were dried over sodium sulfate and evaporated, and the residue was chromatographed on 70 g of silica gel with methylene chloride. Recrystallization from methylene chloride / hexane afforded 3,4 dimethoxy-5-nitro-4 '- (trifluoromethyl) benzophenone with a melting point of 115 ° C.

c) 49.5 g of tin dichloride was added to 16.0 g of 3,4-dimethoxy-5-nitro-4 '- (trifluoromethyl) -benzophenone dissolved in 300 ml of ethanol, then the mixture was stirred at 75 ° C in The reaction mixture was then poured into 800 ml of ice-water. It is neutralized with a 28% solution of sodium hydroxide and extracted three times with 600 ml of methylene chloride. The combined methylene chloride phases were washed with water, dried over sodium sulfate and evaporated. Recrystallization from methylene chloride / hexane afforded 5-amino-3,4-dimethoxy-4 '- (trifluoromethyl) -benzophenone, m.p. 9596 ° C.

c) 3.25 g of 5-amino-3,4-dimethoxy-4 '(trifluoromethyl) -benzophenone dissolved in 50 ml of acetone were evaporated under reduced pressure after the addition of 15 ml of 2N sulfuric acid. The residue thus obtained is suspended in 20 ml of acetic acid, diluted with 100 ml of water and treated at 5 ° C with a solution of 700 mg of sodium nitrite in 10 ml of water, stirring at 5 ° C for 1 hour. The diazonium salt solution was 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 at 5 ° C for 1 hour . Then 200 ml of methylene chloride was added. Insoluble components are filtered. The phases were separated, the aqueous phase was extracted more than twice with 100 l of methylene chloride. The combined methylene chloride phases were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on 30 g of silica gel with methylene chloride. Recrystallization from methylene chloride / hexane gave 5-cyan-3,4-dimethoxy-4 '- (trifluoromethyl) -benzophenone with a melting point of 130 ° C. d / 1.5 g of 5-cyan-3,4-dimethoxy-4 '- (trifluoromethyl) -benzophenone dissolved in 75 ml of methylene chloride was treated at 5 ° C with 2.18 ml of boron tribromide, then the mixture was stirred. at room temperature for 18 h. The reaction mixture was then diluted with 50 ml of methylene chloride. The mixture was refluxed for a further 4 h, treated at -70 ° C with 15 ml of methanol, stirred at room temperature for 2 h, evaporated, the residue dried in vacuo and partitioned between ethyl acetate and ice water. . The aqueous phase was extracted more than twice with ethyl acetate. The combined ethyl acetate phases were dried over sodium sulfate and evaporated. The product thus obtained was stirred at 130 ° C for 6 h with 10 ml of acetic anhydride and 1 ml of pyridine. The mixture was evaporated and the residue partitioned between ice-water and methylene chloride. The methylene chloride phase was dried over sodium sulfate and evaporated and the residue was chromatographed on 30 g of silica gel with methylene chloride. The diacetate thus obtained was dissolved in 10 ml of methanol. The solution was treated with 4.2 ml of a 1N sodium hydroxide solution, stirred at 0 ° C for 1 hour, neutralized with acetic acid, evaporated and partitioned between ethyl acetate and saturated sodium chloride solution. The ethyl acetate phase was dried over sodium sulfate and evaporated and the residue was recrystallized from methylene chloride. 5-Cyan-3,4-dihydroxy-4 '- (trifluoromethyl) -benzophenone is obtained, mp 204-206 ° C.

Similarly:

al) from 2'-fluoro-4-hydroxy-3-methoxy-

5-Nitrobenzophenone yields 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone with a melting point of 86-88'C (from ether / low-petroleum ether).

(1) from 3,4-dimethoxy-2'-fluoro-5-nitrobenzophenone, 5-amino-3,4-dimethoxy-2'-fluorobenzophenone was obtained, m.p. 93-95 ° C (from ether (low boiling petroleum ether)).

c1) from 5-amino-3,4-dimethoxy-2'fluorobenzophenone gave 5-benzoyl-2,3dimethoxy-2'-fluorobenzonitrile, m.p. 132-134 ° C (from methylene chloride (low boiling petroleum ether)) and hr (m-5-benzoyl-2,3'-dimethoxy-2'-fluorobenzonitrile yields 5-benzoyl-2,3-dihydroxy-2'-fluorobenzonitrile with m.p. 228-230 ° C (from ether (low boiling petroleum ether)).

Similarly:

b2) from 3,4-dimethoxy-5-nitrobenzophenone yields 5-amino-3,4-dimethoxybenzophenone as an amorphous solid, c2) from 5-amino-3,4-dimethoxybenzophenone yields 5-benzoyl-2,3- dimethoxybenzonitrile with melting point 98-100'C (from ether (hexane) and d2) from 5-benzoyl-2,3-dimethoxybenzonitrile yields 5-benzoyl-2,3-dihydroxybenzonitrile with melting point 212-214 ° With (ethyl acetate / ether).

Example 67.

a) A solution of 16.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride in 80 ml of pyridine was added dropwise to a solution of 2.68 g of 1-methylimidazole and 6.6 g of triethylamine in 80 1 ml of pyridine, then the mixture was stirred at 60 ° C for 3 hours. After treatment with 1.70 ml of 3N sodium hydroxide solution, the mixture was stirred for an additional hour and then poured onto ice-water. The separated gray crystals were filtered off by suction and stirred with ethyl acetate, after which the organic phase was dried over magnesium sulfate and the solvent was distilled off. Recrystallization from ethyl acetate / hexane afforded 3,4-dimethoxy-5-nitrophenyl- (1-methylimidazol-2-yl) -ketone as colorless crystals, mp 144-145 ° C.

b / 5.0 g of 3,4-dimethoxy-5-nitrophenyl- /

The 1-methylimidazol-2-yl) -ketone was treated with 50 ml of hydrobromic acid (48%), then the mixture was stirred at reflux for 2 hours. After cooling, the precipitate was filtered off by suction, washed with ice-water and recrystallized from ethanol. 3,4-Hydroxy-5-nitrophenyl- (1-methylimidazol-2-yl) -ketone hydrobromide is obtained as yellow crystals with a melting point of decomposition> 240 ° C.

Example 68. As described in Example 67, of 3,4-dimethoxy-5-nitrobenzoyl chloride and

1- benzylimidazole gives 1-benzimidazole-

2-yl- (3,4-dimethoxy-5-nitrophenyl) -ketone in the form of colorless crystals with m.p. 134-135 &lt; 0 &gt; C (methylene chloride / hexane) to give 1-benzimidazol-2 with hydrogen bromide -yl- (3,4-dihydroxy-5-nitrophenyl) -ketone hydrobromide as yellow crystals, mp 218-219 ° C (decomposition).

Example 69.

a) A solution of 10.0 g of 1 - // benzyloxy (methyl) -imidazole in 50 ml of acetonitrile was added dropwise over 10 minutes under ice-cooling to a solution of 13.0 g of 3,4-dimethoxy-5-nitrobenzoyl chloride and 5 , 4 g of triethylamine in 80 ml of acetonitrile so that the temperature does not exceed 25C. The mixture was then stirred for a further 3 h, after which the solvent was distilled off. After treatment with water, the mixture was extracted with ethyl acetate. After washing twice with water, the organic phase is dried over sodium sulfate and evaporated. The resulting oil was chromatographed on 600 g of silica gel with toluene (ethyl acetate (95: 5). 1 - [(Benzyloxy) -methyl] -imidazol-2-yl- (3,4-dimethoxy-5-nitrophenyl) -ketone is obtained as a yellowish oil.

c) Worked as described in Example 67b, obtained after treatment with hydrobromic acid 3,4-dihydroxy-5-nitrophenyl- (imidazol-2-yl) -ketone hydrobromide as yellow crystals, mp 247-248 ° S.

Example 70.

a) A solution of 25.0 g of 3-bromoquinoline was dissolved in 200 ml of dry ether and cooled to 60 ° C. At this temperature, 75.1 ml of a 1.6 molar solution of n-butyllithium was added dropwise over 15 minutes, after which the mixture was stirred for 10 minutes. To this mixture was added dropwise at -60 ° C. , 5 g of vanillinbenzoyl ether in 250 ml of dry ether and the mixture was then stirred at room temperature for 3 h, poured into about 1.51 ice-water and extracted three times with 600 ml of ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated. The resulting oil was chromatographed on 1 kg of silica gel with methylene chloride (ethyl acetate / 1: 1). The crude crystalline product obtained was recrystallized from ethyl acetate. Obtained with - (4-) benzyloxy / -

3-methoxyphenyl / -3-quinolinethanol as colorless crystals, mp 124-125 ° C.

b / A solution of 6.2 g - (4-benzyloxy) -

3-Methoxyphenyl / -3-quinolinethanol in 200 ml of methylene chloride was treated with 62 g of magnesium dioxide and stirred at reflux for 2 hours. After cooling, the precipitate was filtered off with suction and washed with methylene chloride. The filtrate was evaporated and the resulting oil was dissolved in hot ether, after which the solution was treated with a small amount of pentane. The separated crystals are filtered off by suction. 4- (Benzyloxy) -3-methoxyphenyl (3-quinolinyl) ketone is obtained as colorless crystals with a melting point of 110-111 ° C.

c) 11.0 g of 4- (benzyloxy) -3-methoxyphenyl- (3-quinolinyl) -ketone was treated with 50 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 hours. After distillation of the trifluoroacetic acid, the residue is treated twice with 50 l of ethanol and the solvent is distilled off each time. The resulting oil crystallizes on ethanol treatment. Recrystallization from ethanol gave 4-hydroxy-3-methoxyphenyl- (3quinolinyl) -ketone as yellowish crystals, mp 196-197 ° C.

d / A solution of 1.91 ml of 65% nitric acid in 20 ml of glacial acetic acid was added dropwise to a solution of 5.5 g of 4-hydroxy-3-methoxyphenyl- (3-quinolinyl) ketone in 300 ml of glacial acetic acid at 150 ° C and the mixture was then stirred at this temperature for another 2 hours. The mixture was then poured into ice-water and extracted three times with 300 ml of ethyl acetate each time. The organic phase was washed five times with 100 ml of water each, dried over sodium sulfate and evaporated. Treatment of the residue with ethyl acetate gave 4-hydroxy-3-methoxy-5-nitrophenyl (3-quinolinyl) ketone as yellow crystals, mp 220-221 ° C (decomposition).

f) 820 mg of 4-hydroxy-3-methoxy-5-nitrophenyl- (3-quinolinyl) -ketone is treated with 50 ml of 48% hydrobromic acid and kept at reflux for 3 hours. After distilling the hydrobromic acid at 50 ° C, the residue is treated with 70 ml of hot water and the insoluble components are filtered off by suction. 3,4 Dihydroxy-5-nitrophenyl- (3-quinolinyl) ketone hydrobromide is obtained as yellow crystals with a melting point of 270 ° (decomposition).

Example 71. Worked as described in Example 70, but gave - (4-benzioxy) -3-methoxyphenyl) -4-quinolinethanol as colorless crystals, mp 117-118 ° C (ethyl acetate), from it trifluoroacetic acid yields 4-hydroxy-3-methoxyphenyl- (4-isoquinolinyl) -ketone as yellow crystals, mp 197.5-198.5 ° C and nitrated with nitric acid in glacial acetic acid and this treatment with hydrobromic acid gave 3,4-dihydroxy-5-nitrophenyl- (4-isoquinolinyl) -ketone hydrobromide as yellow crystals with a melting point of 256 ° C (decomposition).

Example 72. Worked as described in Example 70, but gave - (4- (benzyloxy) -3-methoxyphenyl) -2-naphthalen-methanol as colorless crystals (ethyl acetate / hexane), mp 113-114 ° C. from which magnesium dioxide gives 4- (benzyloxy) -3-methoxyphenyl- (2-naphthyl) -ketone as colorless crystals (ethyl acetate / hessane), mp 104-105 ° C, from which, by treatment with trifluoroacetic acid and nitration with glacial acetic acid to give 4-hydroxy-S-methoxy-5-nitrophenyl / -2naftil / ketones as yellow crystals of mp. 187-188 ⁰ C and from there by treatment with hydrobromic orodna acid was prepared 3,4dihidroksi-5-nitrophenyl / 2-naphthyl / ketones as yellow crystals with mp. 184-185 ° C.

Example 73

a / A solution of 20.0 g of 3-phenylpropyl bromide in 300 ml of ether was treated at 60 ° C with stirring for 15 min with a solution of

71.8 ml of tert -butyl lithium (1.4 molar). After 10 min, a solution of 22.14 g of vanillinbenzyl ether in 200 ml of ether was added dropwise at this temperature for 15 min, then the mixture was stirred for another 2 h. The mixture was poured into 1 l of ice-water and extracted for three times with 500 ml of ethyl acetate each. The organic phase was washed twice with 200 ml of water each time, dried over sodium sulfate and evaporated. The resulting oil was chromatographed on 1 kg of silica gel with methylene chloride. The crystals obtained were recrystallized from ether / pentane. 4- (Benzioxy) -3-methoxy- (3-phenylpropyl) -benzyl alcohol is obtained in the form of colorless crystals with a melting point of 71-73 (R).

b) A solution of 9.0 4- (benzyloxy) -3-methoxy- (3-phenylpropyl) -benzoyl alcohol in 250 ml of methylene chloride is treated with 90 g of magnesium dioxide and maintained at reflux for 2 hours. cooling the precipitate was filtered off by suction and washed with methylene chloride. The filtrate was evaporated and the residue was recrystallized from ethyl acetate / ether. 4 '- (Benzyloxy) -3'-methoxy-

4-Phenylbutyrophenone in the form of colorless crystals with a melting point of 81-82 ° C.

c) A solution of 7.0 g of 4 '- (benzyloxy) -3'methoxy-4-phenylbutyrophenone in 40 ml 33% hydrobromic acid in glacial acetic acid was stirred at room temperature for 5 h and then poured into 50 ml ice-water. The solution was adjusted to pH 6.0 by the addition of concentrated ammonia and extracted three times with 250 ml of ethyl acetate. The organic phase was washed three times with 50 l of water each, dried over sodium sulfate and evaporated. The resulting oil was dissolved in 20 ml of ether and then the solution was treated with hexane until it was cloudy and allowed to crystallize. Colorless 4'-hydroxy-3'-methoxy-

4-Phenylbutyrophenone, mp 91-92 ° C.

d / A solution of 0.79 ml of 65% nitric acid in 25 ml of glacial acetic acid is added dropwise to a solution of 2.2 g of 4'hydroxy-3'-methoxy-4-phenylbutyrophenone in 25 ml of glacial acetic acid and the mixture The mixture was poured into 150 ml of ice-water and after treatment with 20 ml of 3N hydrochloric acid was extracted three times with 75 ml of ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated. The resulting crude product was stirred with ethyl acetate and filtered through 75 g of silica gel. Recrystallization from acetonitrile gave 4'-hydroxy-3'methoxy-5'-nitro-4-phenylbutyrophenone as yellow crystals with mp 120-12PC.

e / 1.0 g of 4'-hydroxy-3'-methoxy-5'-nitro-

4-Phenylbutyrophenone was held at 200 ° C for 1 hour with 8 g of pyridine hydrochloride. The reaction mixture was poured into ice-water while still hot and extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and then with water, dried over sodium sulfate and evaporated. The resulting dark residue was chromatographed on 30x silica gel with ethyl acetate. Methylene chloride / hexane gave 3 ', 4'dihydroxy-5'-nitro-4-phenylbutyrophenone as yellow crystals, mp 118-119 ° C.

Example 74.

a / A solution of 14.68 g of potassium cyanide in 20 ml of water is added to a solution of 10.0 g

3.4-dimethoxy-5-nitrobenzaldehyde in 100 ml dioxane. Now 18.81 ml of 37% hydrochloric acid are added dropwise over 30 min with vigorous stirring. After the addition of 120 ml of ether, excess hydrogen cyanide gas is removed by passing argon through the mixture. The reaction mixture was filtered through a quartz soil filter and the organic phase was washed with water, dried over sodium sulfate and evaporated, -hydroxy-

3.4-dimethoxy-phenylacetonitrile (yellowish oil), which is formed, is dissolved in 200 ml of ether, after which the solution is treated with 20 ml of ethanol, cooled to 0 ° C and hydrogen chloride is allowed to pass for 30 minutes. the colorless precipitate was filtered off with suction and recrystallized from ethanol / ether. Ethyl / 3,4-dimethoxy-

5-nitrophenyl / -hydroxy-acetamide hydrochloride.

c) 19.7 g of ethyl (3,4-dimethoxy-5-nitrophenyl) -hydroxyacetamidate were dissolved in 500 ml of ethanol, 6.74 g of o-phenylenediamine was added, the mixture was stirred at room temperature for 2 hours and then stirred. kept at reflux overnight. After distillation of the solvent, the residue is treated with 50 ml of water, basified with sodium carbonate solution and extracted twice with 250 ml of methylene chloride. The organic phase was washed with water, dried over sodium sulfate and evaporated. The resulting orange residue was chromatographed on 400 g of silica gel with methylene chloride (ethyl acetate (1: 1)). Ether (hexane) gave - (3,4-dimethoxy-5-nitrophenyl) -2-benzimidazolmethanol in the form of yellowish crystals with a melting point of 50 ° C (decomposition).

with (13.2 g - (3,4-dimethoxy-5-nitrophenyl) -2-benzimidazole-methanol was dissolved in 200 ml of methylene chloride, after treatment with 130 g of magnesium dioxide, the mixture was stirred at reflux for 2 After the filtration the solvent is distilled off. 2benzimidazolyl- (3,4-dimethoxy-5-nitro39-phenyl) -ketone was obtained as yellowish crystals, mp 212-213 ° C.

d / 1.0 g of 2-benzimidazolyl- (3,4-dimethoxy-5-nitrophenyl) -ketone and 8.0 g of pyridine hydrochloride were maintained at 200 ° C for 60 minutes. The dark solution was poured while hot. , in ice-water and extracted three times with 100 ml of ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and evaporated. Recrystallization from ethyl acetate / hexane gave 2-benzimidazolyl- (3,4-dihydroxy-5-nitrophenyl) ketone as yellow crystals with a melting point of 240-250 ° C.

Example 75

a) 30.0 g of 3,4-dimethoxy-5-nitrobenzoic acid were dissolved in 250 ml of THF and after the addition of 21,85 1,1'-carbonyldiimidazole the mixture was stirred at reflux for 2 hours. is poured into 300 ml of ice-water and the precipitated crystals are filtered off by suction after stirring for 30 minutes. The crystals are stirred in methylene chloride, then the organic phase is washed with water, dried over sodium sulfate and evaporated. Crystallization from methylene chloride / hexane gave 1- (3,4dimethoxy-5-nitrobenzoyl) -imidazole as colorless crystals, mp 136-137 ° C.

b) 10.0 g of 1- (3,4-dimethoxy-5-nitrobenzoyl) -imidazole in 50 ml of dimethylformamide was treated with 6.95 g of acetamidoxime, after which the mixture was stirred at 70 ° C for 1 hour. After cooling, the mixture was poured into 500 ml of ice-water and stirred for 30 minutes. The separated crystals were filtered off by suction and washed with water. Crystallization from ethyl acetate gave N '[3,4-dimethoxy-5-nitrobenzoyl] -oxy] acetamidine as colorless crystals, mp 165-166 ° C.

c / 2.0 g of M '- // 3,4-dimethoxy-5-nitrobenzoyl (oxy) acetamidine was refluxed for 1 hour in 20 ml of glacial acetic acid. After distilling the acetic acid, the crystalline residue was recrystallized from ether / hexane. It turns out

5- (3,4-dimethoxy-5-nitrophenyl) -3-methyl-

1,2,4-Oxadiazole as colorless crystals with a melting point of 111 ° C.

d / 2.5 g of 5- (3,4-dimethoxy-5-nitrophenyl) -3-methyl-1,2,4-oxadiazole was dissolved in 70 ml of methylene chloride. After cooling to 60 ° C, a solution of 2.3.62 g of boron tribromide in 50 ml of methylene chloride was added dropwise over 20 minutes, after which the mixture was refluxed for 48 hours. After cooling to -60 ° C, the mixture was treated with 60 ml of ethanol and then stirred at room temperature for 30 minutes. The yellow solution was evaporated to dryness and then the residue was treated three times with 100 ml of toluene / ethanol / 1: 1 / each and the solvent is distilled each time. Crystallization from ethanol gave 5- (3-methyl-1,24-oxadiazol-5-yl) -

3-nitropyracatechol as yellow crystals, mp 201-202 ° C.

Example 76

a) 143.8 ml of n-butyllithium solution (1.53M in hexane) was added dropwise at 70 ° C for 30 min to 35.0 g of 1-bromo-2fluorobenzene dissolved in 600 ml of tetrahydrofuran. After stirring at -70 ° C for 60 min, 48.5 g of 3-methoxy-

4- Benzyloxybenzaldehyde dissolved in 450 ml of THF was added dropwise over 30 min. The reaction mixture was stirred at -70 ° C for 2 h and at 0 ° C for 30 min, poured into a mixture of ice and 150 ml of 2N sulfuric acid and extracted three times with 500 ml of ether each. The combined ether phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated. 4- (Benzioloxy) -2'-fluoro-3'-methoxybenzhydrol is obtained as a yellowish oil, which can be used directly in the next reaction step.

Similarly:

A1) 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-fluoro benzene was obtained

4- (benzyloxy) -4'-fluoro-3-methoxybenzhydrol as an oil.

a3) from 3-methoxybenzhydrol as an oil. a4) from 3-methoxy-4-benzylxybenzaldehyde 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.

ab) 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 gave 4- (benzyloxy) -3-methoxy-2'-methylbenzhydrol as an oil.

a8) from 3-methoxy-4-benzyloxybenzaldehyde and 4-bromtoluene gave 4- (benzyloxy) -3-methoxy-4'-methylbenzhydrol as an oil.

9) from 3-methoxy-4-benzyloxybenzaldehyde and 1-bromobenzonitrile yields 4 (benzyloxy) -2'-cyan-3-methoxybenzhydrol as an oil.

and 10 / of 3-methoxy-4-benzyloxybenzaldehyde and 1-bromo-2-trifluoromethylbenzene gave 4- (benzyloxy) -3-methoxy-2 '- (trifluoromethyl) -benzhydrol as an oil.

b) 69.8 g 4- (benzyloxy) -2'-fluoro-3-methoxybenzhydrol dissolved in 600 ml of methylene chloride was treated for 30 min at 20 ° C with 45.3 g of pyridine chlorochromate and stirred at 20 ° C for 3 The precipitate formed is then filtered and washed with methylene chloride. The filtrate was evaporated and the residue filtered on 100 g of silica gel with ether. Recrystallization from ether gave 4- (benzyloxy) -2'-fluoro-3-methoxybenzophenone, mp 118-120 ° C.

Similarly:

61) from 4- (benzyloxy) -3'-fluoro-3methoxybenzhydrol yields 4- (benzyloxy) -3'-fluoro-3-methoxybenzophenone as an amorphous solid.

62) from 4- (benzyloxy) -4'-fluoro-3-methoxybenzhydrol yields 4- (benzyloxy) -4'-fluoro-3-methoxybenzophenone, m.p. 99-101 ° C (from ether / hexane).

63 / from 4- (benzyloxy) -2 ', 6'-difluoro-3methoxybenzophenone, m.p. 139-141'C / methylene chloride / ether /.

64 (from 4-benzyloxy) -2'-chloro-3-methoxybenzhydrol yields 4- (benzyloxy) -2'-chloro-3-methoxybenzophenone, mp 128130 ° C (from ether).

65) from 4- (benzyloxy) -3'-chloro-3-methoxybenzylhydrol gives 4-benzyloxy] -3'-chloro-3-methoxybenzophenone as an amorphous solid.

66) from 4- (benzyloxy) -4'-chloro-3methoxybenzhydrol gives 4- (benzyloxy) -4'-chloro-3-methoxybenzophenone, m.p. 106-108 ° C (from methylene chloride (hexane)).

67 (4- (Benzyloxy-3-methoxy-2'-methylbenzhydrol) gives 4- (benzyloxy) -3-methoxy-2'-methylbenzophenone, mp 86-88 ° C (from isopropyl ether).

68 (from 4- (benzyloxy) -3-methoxy-4'-methylbenzhydrol gives 4- (benzyloxy) -3-methoxy-4'-methylbenzophenone, m.p. 79-81 ° C) (from ether (hexane)).

69) from 4- (benzyloxy) -2'-cyan-3-methoxybenzhydrol yields 4- (benzyloxy) -2'-cyan-3-methoxybenzophenone as an amorphous solid and

610) of 4- (benzyloxy) -3-methoxy-2 '- (trifluoromethyl) -benzhydrol yields 4- (benzyloxy) -3-methoxy-2' - (trifluoromethyl) benzophenone, mp 103-105 ° C. / from the ethers /.

c / 170 ml 33% hydrochloric acid in glacial acetic acid was added at 2015 ° C for 20 min to 42.4 g of 4- (benzyloxy) -2'-fluoro-3-methoxybenzophenone dissolved in 450 ml of methylene chloride. After stirring at 20 ° C for 1.5 h, the reaction mixture is poured into 750 ml of ice-water, the methylene chloride phase is separated and the aqueous phase is extracted more than twice with 200 ml of methylene chloride. The combined methylene chloride phases were washed with 1200 ml of water, dried over sodium sulfate and evaporated. To remove the benzyl bromide obtained, the oily residue was treated with hexane and decanted. 2'-Fluoro-4-hydroxy-

3-Methoxybenzophenone as a yellowish oil that can be used directly in the next reaction step.

Similarly:

1 / from 4- (benzyloxy) -3'-fluoro-3-methoxybenzophenone gave 3'-fluoro-4-hydroxy-3-methoxybenzophenone, mp 133-135 ° C (from methylene chloride (low boiling petroleum ether)).

c2 (from 4- (benzyloxy) -4'-fluoro-3-methoxybenzophenone gave 4'-fluoro-4-hydroxy-3-methoxybenzophenone with a melting point of 139-141 ^° C (from ether).

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

c4) from 4- (benzyloxy) -2'-chloro-3-methoxy-benzophenone gave 2'-chloro-4'-hydroxy-3-methoxybenzophenone as an amorphous solid.

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

cb) from 4- (benzyloxy) -4'-chloro-3-methoxybenzophenone gave 4'-chloro-4-hydroxy-3-methoxybenzophenone, m.p. 114-116 (C) from methylene chloride (low boiling petroleum ether).

c7 (from 4- (benzyloxy) 3-methoxy-2'methylbenzophenone 4-hydroxy-methoxy-2'-methylbenzophenone was obtained, m.p. 103105 ° C (from isopropyl ether)).

c8 (from 4- (benzyloxy) -3-methoxy-4'methylbenzophenone m.p. 103-105 ° C) from ether (low boiling petroleum ether).

c9 (from 4- (benzyloxy) -2'-cyan-3-methoxybenzophenone yields 2'-cyan-4-hydroxy-3-methoxybenzophenone with a melting point of 124-126 (C) from ether (n-hexane).

c 10 (from 4- (benzyloxy) -3-methoxy-2 '- (trifluoromethyl) -benzophenone gave 4hydroxy-3-methoxy-2' - (trifluoromethyl) benzophenone, m.p. 115-117 (C) from ether) .

d / 7.8 ml 65% nitric acid was added dropwise at 20 ° C for 20 min to

29.4 g of 2'-fluoro-4-hydroxy-3-methoxybenzophenone (dissolved in 450 ml of acetic acid). After stirring for 1.5 h, the reaction mixture was poured into 2 L of ice-water and the precipitate formed was filtered, washed with water and dissolved in methylene chloride. The methylene chloride solution was washed with water, dried over sodium sulfate and evaporated. The residue was crystallized from methanol. 2'-Fluoro-4-hydroxy-3-methoxy-

5-Nitrobenzophenone mp 127-129'C.

Similarly:

dl / from 3-fluoro-4-hydroxy-3-methoxybenzophenone gave 3'-fluoro-4-hydroxy3-methoxy-5-nitrobenzophenone, m.p. 168-170 ° C (from methanol).

d2) from 4'-fluoro-4-hydroxy-3-methoxybenzophenone gave 4'-fluoro-4-hydroxy-

3-methoxy-5-nitrobenzophenone, m.p. 126-128 ° C (from ether).

d3 / from 2 ', 6'-difluoro-4-hydroxy-3methoxybenzophenone gave 2', 6'-difluoro-

4- hydroxy-3-methoxy-5-nitrobenzophenone, mp 147-149 ° C (from methanol).

d4) from 2'-chloro-4-hydroxy-3-methoxybenzophenone gives 2'-chloro-4-hydroxy3-methoxy-5-nitrobenzophenone with a melting point

123-125 ° C (from ethers).

d5 (from 3'-chloro-4-hydroxy-3-methoxybenzophenone gave 3-chloro-4-hydroxy3-methoxy-5-nitrobenzophenone, m.p. 152-154 (C) from methanol).

d6) from 4'-chloro-4-hydroxy-3-methoxybenzophenone gave 4'-chloro-4-hydroxy3-methoxy-5-nitrobenzophenone, mp 128-131 ° C (from methylene chloride (low boiling petroleum ether)).

d7 (from 4-hydroxy-3-methoxy-2'methylbenzophenone gave 4-hydroxy-3-methoxy-2'-methyl-5-nitrophenophenone melting point 125-127 (C) from ethanol).

d8) from 4-hydroxy-3-methoxy-4'-methoxybenzophenone gave 4-hydroxy-

3-methoxy-4'-methyl-5-nitrobenzophenone, m.p. 137-139'C / methylene chloride / ether /.

d9 (from 2'-cyan-4-hydroxy-3-methoxybenzophenone gave 2'-cyan-4-hydroxy3-methoxy-5-nitrobenzophenone, m.p. 163-164 ° C (from methanol).

dlO) from 4-hydroxy-3-methoxy-2 '- (trifluoromethyl) -benzophenone yields 4hydroxy-3-methoxy-5-nitro-2' - (trifluoromethyl) -benzophenone with mp 138-140 (C). methylene chloride (low boiling petroleum ether).

dll) from 4-hydroxy-3 ', 4'-dimethoxybenzophenone yields 4-hydroxy-3', 4'-dimethoxy-5-nitrobenzophenone with melting point 134-136 ° (from methanol) and dl2 / from 4-hydroxy -3,3 ', 4'-trimethoxybenzophenone gave 4-hydroxy-5-nitro3,3', 4'-trimethoxybenzophenone, m.p. 178-180'C (from methanol).

units / 24.8 g of 2'-fluoro-4-hydroxy-3-methoxy-5-nitrobenzophenone dissolved in 120 ml of glacial acetic acid, 1001 33% hydrobromic acid in glacial acetic acid and 68 ml of 48% aqueous hydrobromic acid The mixture is then refluxed for 4 hours. The reaction mixture is then evaporated under reduced pressure and the residue is distilled off with toluene. The residue was dissolved in methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated. The product was crystallized from methylene chloride / low boiling petroleum ether. 2'-Fluoro-3,4-dihydroxy-5-nitrobenzophenone was obtained, m.p. 169-171 ° C.

Similarly:

e1) from 3'-fluoro-4-hydroxy-3-methoxy-

5-Nitrobenzophenone provides 3-fluoro-3,4-dihydroxy-5-nitrobenzophenone with a melting point

124-126 ° C (methylene chloride).

e2 / from 4'-fluoro-4-hydroxy-3-methoxy-

5-Nitrobenzophenone gave 4'-fluoro-3,4-dihydroxy-5-nitrobenzophenone, m.p. 171-173 ° C (from methylene chloride).

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

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

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

eb) from 4'-chloro-4-hydroxy-3-methoxybenzophenone gave 4'-chloro-3,4-dihydroxybenzophenone, m.p. 174-176 _O (methylene chloride).

e7 / from 4-hydroxy-3-methoxy-2'-methyl-

5-Nitrobenzophenone gave 3,4-dihydroxy-2'-methyl-5-nitrobenzophenone, m.p. 164-166 ° C (from methylene chloride).

e8) from 4-hydroxy-3-methoxy-4'-methyl-

5-Nitrobenzophenone yields 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, m.p. 146-148 ° C (from methylene chloride).

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

is 10 / of 4-hydroxy-3-methoxy-5-nitro2 '- (trifluoromethyl) -benzophenone is obtained

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

ell) from 4-hydroxy-3,4'-dimethoxy-5-nitrobenzophenone afforded 5-nitro-3,4,4'-trihydroxybenzophenone, m.p. 212214 ° C (from methanol (methylene chloride).

e12 (from 4-hydroxy-3,3 ', 4'-trimethoxybenzophenone afforded 5-nitro3,3', 4,4'-tetrahydroxybenzophenone, mp 222-224 ° C (from ether).

Example 77 A suspension of 13.8 g of 2-bromo 3 ', 4'-dihydroxy-5'-nitroacetophenone was treated with 9.0 g of 1- (phenethyl) -2-thiourea in 150 ml of n-butanol and the mixture was heated to refluxed for 3 hours. After cooling to room temperature, the crystals were filtered off with suction and crystallized from n-butanol. 3nitro-5- (2- (phenethylamino) -4-thiazolyl) pyrocatechol hydrobromide was obtained with mp 249251 ° C.

Example 78. Worked as described in Example 38, but 2- (3,4-dihydroxy-5-nitrobenzoyl) - was obtained from 2-bromo-3 ', 4'-dihydroxy-5'-nitroacetophenone and 2-aminobenzophenone - 3-Phenylindole m.p. 196-198 ° C (from isopropanol).

Example 79 A suspension of 2-bromo-3 ', 4'dihydroxy-5'-nitroacetophenone was treated with 1- (1-adamantyl) -2-thiourea in 90 ml of butanol, and the mixture was refluxed. 4 h. After cooling to room temperature, the crystals were filtered off with suction and recrystallized from n-butanol. 5- (2- (1-adamantylamino) -5-thiazolyl) -3-nitropyracatechol hydrobromide was obtained with mp 245247 ° C.

Example 80 A suspension of 2.6 g (3,4 dihydroxy-5-nitrobenzoyl) -methyl acetate in 20 ml ethanol and 20 ml 1N hydrochloric acid was refluxed for 5 hours. The reaction mixture was then evaporated, the residue distilled with toluene and then recrystallized from ethanol. Obtained 2,3'4'-trihydroxy-5'-nitroacetophenone, mp 208-210 ° C.

Example 81 A solution of 4.0 g of 3,4-dihydroxy-5-nitrophenylglyoxyl acid n-hexyl ester and 1.5 g of diaminomaleonitrile in 35 ml of ethanol was refluxed for 24 hours. is distilled off, the residue is dissolved in ether, washed with water, dried over sodium sulfate, filtered and evaporated. 6-Hydroxy-5- (3,4, dihydroxy-5-nitrophenyl) -2,3-pyrazinecarbonitrile is obtained with a melting point> 300 ° C (from ethyl (methylene chloride)).

Example 82

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

b) 3.8 g 5- (bromoacetyl) -2,3-dihydroxybenzonitrile dissolved in 25 ml of N, N-dimethylformamide was treated with N-phenylthiourea and stirred at 100 ° C for 5

The solvent is then removed by evaporation. The residue was treated with 200 ml of 1N sodium carbonate solution, extracted three times with 100 ml of methylene chloride. The combined organic phases were washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed on 30 g of silica gel with ethyl acetate. The crude product obtained is treated with 40 ml of 1N hydrochloric acid, evaporated and crystallized from acetone. 5- (2-Aniline-4-thiazolyl) -2,3-dihydroxybenzonitrile hydrochloride was obtained with mp 245-247 ° C.

Example 83

a (25 ml solution of t-butyllithium (1.4M in hexane) was added dropwise at -70 ° C for 10 min to 10 g of 4-benzyloxy-bromobenzene dissolved in 100 ml of tetrahydrofuran. After stirring at -70 ° C for 1 hour, 5 g of quinoline-4-carbaldehyde dissolved in 50 ml of tetrahydrofuran was added dropwise over 30 minutes. The reaction mixture was stirred at -40 ° C for 1 hour. and at -5 ° C, also for one hour, was poured into 200 ml of water and the pH was adjusted to 4 with glacial acetic acid. The mixture was extracted three times with 50 ml of ether each. The combined ether phases were washed with water, dried over sodium sulfate and evaporated.

Α- (4- (benzioxy) -3-methoxyphenyl) -4-quinolinethanol is obtained as an amorphous solid.

b) 9.4 g of α- (4- (benzyloxy) -3-methoxyphenyl) -4-quinolinethanol dissolved in 200 ml of methylene chloride was treated with 6.5 g of pyridine chlorochromate and the mixture was stirred at room temperature for 3 h. The insoluble components are then filtered. The filtrate was evaporated and the residue was chromatographed on 150 g of silica gel with ethyl acetate. 4- (Benzyloxy) -3-methoxyphenyl-4-quinolyl ketone is obtained as an amorphous solid.

c / 15 ml 33% hydrobromic acid in glacial acetic acid was added dropwise over 5 min at room temperature to 7.5 g of 4- (benzyloxy) -3-methoxyphenyl-4-quinolyl ketone dissolved in 150 ml of methylene chloride. After stirring at 20 ° C for 45 h, the reaction mixture was poured into 250 saturated sodium bicarbonate solution. The methylene chloride phase was separated, the aqueous phase was extracted three times with 100 ml of methylene chloride. The combined methylene chloride phases were dried over sodium sulfate and evaporated. The residue was recrystallized from methylene chloride / hexane. 4-Hydroxy-3-methoxyphenyl-4-quinoline ketone is obtained with a melting point of 190-192 ° C.

d / 0.37 ml 65% nitric acid was added dropwise at room temperature

1.3 g of 4-hydroxy-3-methoxyphenyl 4-quinolyl ketone. The reaction mixture was stirred for 3 h, then poured into an iceberg, adjusted to pH 6 with concentrated ammonia and the precipitate formed filtered. The residue thus obtained is heated under reflux in 20 ml of acetonitrile, after which the crystals are filtered at 0 ° C. 4-Hydroxy-3-methoxy-5-nitrophenyl-4-quinolyl ketone is obtained with a melting point of 246248 ° C.

e / 1 g of 4-hydroxy-5-nitrophenyl-4quinolyl ketone dissolved in 30 ml of 48% aqueous hydrobromic acid was stirred at 100 ° C for 18 h. After cooling to room temperature, the reaction mixture was diluted with 30 ml. water and precipitate are filtered off by suction. 3,4-Dihydroxy-5-nitrophenyl-4-quinolyl which hydrobromide is obtained with a melting point of 273-275 ° C (from acetonitrile).

Example 84

a) 18.8 ml solution of n-butyllithium (1.6 M in hexane) was added dropwise at -50 ° C for 10 min to 4.03 g thiophene dissolved in 40 ml tetrahydrofuran. After stirring at -50 ° C for 30 min, 6.3 g of 3,4-dimethoxy-

5-Nitrobenzaldehyde dissolved in 100 l of tetrahydrofuran at 30 min interval. The reaction mixture was stirred at -50 ° C for 1 hour, at 0 ° C for 30 min and poured into 100 ml of 2N sulfuric acid. . The mixture was extracted three times with 100 ml of ether each time, the combined ether phases were washed with sodium chloride solution, dried over sodium sulfate, filtered and evaporated. Α- (3,4-Dimethoxy-5-nitrophenyl) -2-thiophen-methanol was obtained with m.p. 79-81 ° C (from methylene chloride (hexane)).

b) 9.9 g (3,4-dimethoxy-5-nitrophenyl) -2-thiophen-methanol dissolved in 300 ml of acetone, treated with 90 g of magnesium dioxide and refluxed for 4 hours. removed by suction filtration and the filtrate evaporated. There were obtained 3,4-dimethoxy-5-nitrophenyl-2-thienyl ketone, m.p. 102104 ° C (from methylene chloride (hexane)).

c / 2 g of 3,4-dimethoxy-5-nitrophenyl / -2-thienyl ketone was stirred at 100 ° C for 8 h in a mixture of 20 ml of 20-33% hydrochloric acid in glacial acetic acid and 20 ml of 48% hydrobromic acid . The reaction mixture was then evaporated to dryness. The residue was stirred with ethyl acetate, washed with water, dried over sodium sulfate and filtered and the filtrate evaporated. Recrystallization from ethyl acetate / hexane is obtained

3,4-dihydroxy-5-nitrophenyl-2-thienyl ketone, m.p. 155-157 ° C.

Example A.

By a known method, closable gelatin capsules of the following composition may be obtained.

3,4-dihydroxy-nitrophenyl-

4-Pyridyl ketone25

Gelatin1

Magnesium stearate1

Avicel93,7

Mannitol100

Capsule Weight 350 mg

Claims (22)

Claims A compound of the formula wherein R a represents a nitro or cyano group, R b is hydrogen or halogen, R c 'is a CO-R group in which R ¹ ' is a phenyl group, optionally mono- or di-substituted with halogen, cyan, hydroxy or a lower alkyl group, and an ester or ether derivative thereof which is hydrolyzable under physiological conditions, a pharmaceutically acceptable salt thereof. The compound of claim 1, wherein Rb is at the β-position relative to Ra. The compound of claim 2, wherein Ra is a nitro group. The compound of claim 3, wherein Rb is hydrogen, chlorine or fluorine. 5. The compound of claim 4, wherein Rb is hydrogen. The compound of claim 1, which is 3,4-dihydroxy-5-nitrobenzophenone. The compound of claim 1, which is 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone. A pharmaceutical composition comprising a compound of formula Components Quantity in mg / capsule L-dopa 100 Z 29,3 in which Ra is a nitro or cyano group Rb is hydrogen or halogen, Rc is CO-R ¹ , where R ¹ is a phenyl group, optionally mono- or disubstituted with halogen, cyan, hydroxy or lower alkyl, an ester or ether derivative thereof which is hydrolyzable under physiological conditions, a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. The pharmaceutical composition of claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrobenzophenone. 5 The pharmaceutical composition of claim 8, wherein the compound of formula Ia is 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone. A pharmaceutical composition comprising Ldopa, a peripheral decarboxylase inhibitor, 10 a compound of formula wherein Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is a CO-R ^{1 group} , and R ¹ is a phenyl group, optionally ₂ o mono- or disubstituted with halogen, cyano, hydroxy or a lower alkyl group or an ester or ether derivative which is hydrolyzable under physiological conditions or a pharmaceutically acceptable salt thereof and ₂ 5 a therapeutically inert carrier. The pharmaceutical composition of claim 11, wherein the compound of formula Ia is 3,4-dihydroxy-5-nitrobenzophenone. A pharmaceutical composition according to ₃ θ cavity 11, in which a compound of formula 1a is 2'-fluoro-3,4-dihydroxy-5-nitrobenzophenone. The compound of claim 1, wherein said compound is 4-dihydroxy-35 5'-methyl-5-nitrobenzophenone. The pharmaceutical composition of claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. The pharmaceutical composition of claim 49, wherein the compound of formula 1a is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. 17. A pharmaceutical composition for treating depression containing an effective amount of 45 of a compound of formula wherein Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is CO-R ¹ , and R ¹ is a phenyl group, optionally mono - either substituted by halogen, cyan, hydroxy or lower alkyl, or an ester or ether derivative thereof, which is hydrolyzable under physiological conditions, or a pharmaceutically acceptable salt and therapeutically inert carrier thereof. The pharmaceutical composition of claim 17, wherein the compound of formula Ia is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. 19. A pharmaceutical composition for treating Parkinson's disease comprising L-dopa, a peripheral decarboxylase inhibitor, a compound of formula wherein Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is CO-R ¹ , with R'e being a phenyl group optionally mono- or disubstituted with halogen, cyan, hydroxy or lower alkyl, its ester or ether derivative which is hydrolyzable under physiological conditions, or a pharmaceutically acceptable salt and therapeutically inert carrier thereof. The pharmaceutical composition of claim 19, wherein the compound of formula Ia is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. 21. A pharmaceutical composition for inhibiting catechol-O-methyltransferase, comprising catechol-O-methyltransferase, inhibiting an amount of a compound of formula wherein Ra is a nitro or cyano group, Rb is hydrogen or halogen, Rc is CO-R ¹ , wherein R ¹ is a phenyl group, optionally mono- or di-substituted with a halogen, cyan, hydroxy or lower alkyl group, or an ester or ether derivative thereof, which is hydrolyzable under physiological conditions, or a pharmaceutically acceptable salt and therapeutically inert carrier thereof. The pharmaceutical composition of claim 8, wherein the compound of formula Ia is 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone. Publication of the Patent Office of the Republic of Bulgaria 1113 Sofia, Dr. Γ Blvd. M. Dimitrov 52-B