SE453390B - SUBSTITUTED 2,3-ALKYLENE-BIS (OXI) -BENIC ACIDS FOR USE AS INTERMEDIATES FOR THE PREPARATION OF THERAPEUTIC VALUES, SUBSTITUTED 2,3-ALKYLENE-BIS (OXY) -BENZYES - Google Patents

Abstract

2,3-Alkylenedioxybenzamides of formula (I) and their acid -addn. salts, quat. ammonium salts, oxides and optical isomers are new. In (I), A is 1-3C alkylene opt. substd by 1-4C alkyl, 2-4C alkenyl or 1-4C hydroxyalkyl. R is H, 1-4C alkyl or -B-NR1R2; B is a direct bond or a 1-3C alkylene gp. opt. substd. by 1-4C alkyl or 2-4C alkenyl; R1 is H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, substd. alkyl, or forms a heterocyclic ring with B, and R2 is H, 1-4C alkyl, 2-4C alkenyl or alkynyl, substd. alkyl, an opt. substd. heterocyclic gp., or a phenyl, adamantyl, cycloalkyl, bicycloalkyl or cycloalkenyl gp. bonded directly to the N atom or via an opt. substd. alkylene chain, or NR1R2 is a heterocycle opt. contg. other heteroatoms (including NR'', where R'' is H- 1-4C alkyl, 2-4C alkenyl or alkynyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, adamantyl, bicycloalkyl or alkyl substd by OH, SH, acyl, thioacyl, alkoxy or alkylthio). - R' is H, 1-4c alkyl, 2-4C alkenyl or alkynyl, adamantyl, pyrimidinyl, pyrazinyl, diazepinyl, quinuclidinyl, azabicycloalkyl, diazabicycloalkyl, bicycloalkyl, or opt. substd. phenyl or aralkyl, or R'+B forms an opt. substd. heterocycle contg. a single N atom, or R'+R1 forms an opt. substd. heterocycle contg. two heteroatoms, X is H, halogen, OH, 1-4C alkoxy, 1-4C alkyl, amino opt. mono- or disubstd. by 1-4C alkyl, acyl, aralkyl, furyl, pyranyl or alkoxycacarbonyl, or forms an A' chain with Y. Y is as defined for X or is NO2, 1-4C alkylsulphonyl, adamantyl-sulphonyl, cycloalkyl sulphonyl or SO2NR3R'; R3 and R4 are H, 1-4C alkyl, 2-4C alkenyl, 2-4C alkynyl, phenyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, bicycloalkyl, adamantyl, pyrimidinyl, pyrazinyl, or alkyl substd. by OH, SH, acyl, thioacyl, alkoxy or alkylthio, or NR3R4 is an opt. substd. heterocycle opt. congt. another heteroatom; or Y forms an A chain with X or Z. Z is as defined for X or is NO2, or forms an A chain with Y. A is a carbon chain opt. substd. or opt. interrupted by one or more opt. substd. heteroatoms. - Cpds. (I) have anxiolytic, antidepressant and antiemetic activity with little or no cataleptic activity. A typical cpd. of N-(1-allyl-2-pyrrolidinylmethyl)-7-methylsulphamoyl-1, 4-benzodioxan-5-carboxamide. In an example, this is prepd. from 1,4-benzodioxan-5-carboxylic acid.

Description

N (II) wherein B represents a single bond or an alkylene chain having 1-5 carbon atoms, mainly when methylene, ethylene or propylene, R 1 represents alkyl having 1-U carbon atoms, or is connected with B to form a pyrrolidinyl or piperidinyl group.

R 2 represents alkyl of 1-H carbon atoms, alkenyl of 2-H carbon atoms, alkynyl of 2-H carbon atoms, or pyrimidinyl, benzyl or cycloalkyl, and Å H 2 and R 1 may be connected to form a piperidinyl or U-alkyl- piperazinyl group, R 'represents hydrogen, alkyl having 1-H carbon atoms, especially when methyl, ethyl, propyl, isopropyl, butyl, isobutyl or t-butyl, adamantyl, pyrimidinyl, or benzyl, and R' may be attached with R 1 to form a piperazinyl group, or with R 1 and R 2 to form a diazabicycloalkyl- EPUPP- These therapeutically valuable compounds can be prepared by a compound of the general formula COD Z \\ Q \\ AY / 0 / (III) wherein A, X , Y and Z are as previously defined, and D is a hydroxy group, a halogen atom or an alkoxy or phthalimidoxy group, are reacted with an amine having the general / R HN \ R, wherein R and R 'are as previously defined. meaning, or with any of the formula: (IV) its reactive derivative.

In the definitions given in the present description, by alkyl having 1 to 1 carbon atoms is meant mainly methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. The alkyl of 1-3 carbon atoms essentially comprises methylene, ethylene and propylene. Alkenyl having 2-U carbon atoms comprises mainly vinyl ε and allyl, while alkynyl having 2-U carbon atoms mainly comprises ethynyl and propargyl. Alkoxy with 1-H carbon atoms mainly comprises methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy. Halogen essentially includes chlorine, bromine iodine and fluorine.

The preferred meanings for the substituents are as follows: -For'X: -For Y: -for Z: The preferred meanings for the substituents in the disubstituted compounds are the following: AH P <q »<w» <x hydrogen, methoxy, nitro, halogen, mainly chlorine, amino and acetylamino hydrogen, halogen, mainly bromine or chlorine, amino, acetylamino, and sulfamoyl, alkylsulfamoyl, especially then dimethylsulfamoyl and diethylsulfamoyl, ethylsulfonyl, or adamantylsulfamoyl. hydrogen, halogen, mainly bromine or chlorine, nitro, and acetylamino. = alkoxy, mainly methoxy = sulfamoyl '= acetylamino = nitro, and Y forms an azimido group Y = amino = halogen, mainly chlorine = amino = amino = acetylamino = Y = acetylamino = X = nitro = Z = acetylamino = Z = halogen, mainly bromine and Z form an azimido group. 453 390 4 The preferred meanings for the substituents in the trisubstituted compounds are as follows: i: nitro Z = halogen, mainly chlorine or bromine Il halogen, mainly chlorine or bromine> <|| Z = nitro I- <u nitro 'x Y Z = acetylamino.

The compounds of the invention may be prepared by reacting a compound of the general formula: COD (III) O / X wherein A, X, Y and Z are as previously defined and D represents hydroxy, halogen or an organic group with an amine with the general formula: (IV) \ R. wherein R and R 'are as previously defined, or by reaction of their active derivatives.

In the starting compound, the organic group comprises groups which can form reactive acid derivatives. These may be lower alkyl esters, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl or isopentyl, reactive acid esters, such as the methoxymethyl ester or the oyanomethyl ester, substituted or unsubstituted aromatic esters or N- hydroxyimide esters, acid azides, acid hydrazides, symmetrical anhydrides, mixed anhydrides, such as those formed from carboxylic acid esters and haloformic acid esters, azolides, such as triazolides, tetrazolides and especially imidazolides, substituents, α-oxobenzeneacetonitriles, ï ass 390 ring, or other equivalent groups, or the compound of the general formula: z Y oo -_c = cn-co-NH-c2H5 X. / _ ° -A S031; (formed from the acid and an isoxazolium salt). In the above formula, A, X, Y and Z are as previously defined. However, the invention is not limited to only the reactive derivatives mentioned above.

According to the invention, the amine can react in the form of one of its reactive derivatives. Examples of these are the reaction products of the amine with phosphorus chlorides, phosphorus oxychloride, dialkyl, diaryl and orthophenylene chlorophosphites, alkyl or aryl dichlorophosphites or isothiocyanate of the amine, or the symmetrical or asymmetrical sulphamide amide corresponding to the amine , the corresponding enamines or any other equivalent compound.

The above reactive derivatives can react with the acid in situ or after prior isolation. However, the invention is not limited to only the reactive derivatives mentioned above.

Furthermore, it is also possible to carry out the reaction between the free acid and the free amine in the presence of a condensing agent, such as silicon tetrachloride, phosphoric acid anhydride or a carbodiimide, such as diocylohexylcarbodiimide, or alkoxyethylene, such as methoxy or ethoxyacetylene. Among the processes described for the preparation of the compounds of the invention, the use of an acid halide is particularly suitable for compounds which are unsubstituted in the benzene ring, and compounds which are monosubstituted by halogen, nitro, alkylsulfonyl, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, adam or cycloalkylsulfamoyl. The use of alkyl esters, activated acid esters or aromatic esters is particularly suitable for compounds in which the benzene ring is substituted by hydroxy, amino, acetylamino, alkylsulfonyl or sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl-adamantyl-salfamoyl or q-doalkylsulfones , in which two groups X and Y or Y and Z are connected to an azimido group. A A The use of mixed anhydrides (prepared in situ by reaction between the starting benzoic acid and haloformic acid esters, especially chloroformic acid esters) is particularly suitable for compounds which are substituted by nitro, acetylamino or by sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, adamantulfloylsulfamo.

The use of reactive amine derivatives, specially prepared with phosphorus chlorides, mainly phosphorus trichloride, or with alkyl ooh. arylchlorophosphites, is particularly suitable for primary amines and especially aliphatic amines.

The amidation reaction according to the invention can be carried out in the presence or absence of a solvent. Useful solvent systems which are inert to the amidation reaction are, for example, alcohols, polyols, benzene, toluene, dioxane, chloroform or diethylene glycol dimethyl ether, or xylene. It is also possible to use a surplus of the solvent used as a starting material. It may be appropriate to heat the reaction mixture during the amidation process, for example up to the boiling point of the indicated solvents. The invention is further illustrated by the following examples, which, however, are not intended to have any limiting meaning.

Example 1 7-Chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chloroulfonic acid were charged to a round bottom flask equipped with a condenser and thermometer, after which 173 μl of 4-benzodioxane-5-carboxylic acid were added in small portions while maintaining the temperature. at 5-10 ° C.

The mixture was heated to 5500, after which it was cooled and precipitated on ice. The precipitate formed was collected, washed and dried to give 250 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid in a yield of 93,596 and with a melting point of 21 DEG-215 DEG. 7-Methylsulfamoyl-1,4-benzodioxan-β-carboxylic acid 139.5 g of a 40% aqueous solution of methylamine and 139.5 ml of water were charged to a flask equipped with a stirrer and thermometer, after which 250 g of 7-chlorosulfonyl were added portionwise. , 4-benzodioxane-5-carboxylic acid and a solution of 180 ml of 30% sodium hydroxide solution in 180 ml of water. The mixture was stirred and then poured into 2200 ml of water. The solution was filtered and then treated with 139 ml of concentrated hydrochloric acid, after which the precipitate formed was filtered off, washed and dried. 190.5 g were obtained of 7-menylsulfamoyl-1,4-benzodioxane-5-carboxylic acid in a yield of 80% and with a melting point of 208 DEG-209 DEG.

Example 2 7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 209 g of 34% ammonia and 97 g of Zdchlorosulfonyl-1,4-benzodioxane-5-carboxylic acid are charged into a round flask equipped with a stirrer and thermometer at a temperature of 5-10 ° C. The mixture is stirred at room temperature, after which the precipitate formed is dissolved in 415 ml of water. The solution is filtered and treated with 1 ml of concentrated hydrochloric acid. The crystals are separated, washed with water and dried to give 78-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid in a yield of 87% and with a melting point of 272-274 ° C.

Exomgcl 3 7-Mercapto-1,4-benzodioxane-5-carboxylic acid 243 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid and 654 ml of acetic acid were charged to a round bottom flask equipped with a stirrer and condenser.

The mixture was heated to 90 ° C and then cooled to 45 ° C, after which 389 3 tin and 1744 ml of hydrochloric acid were added. The mixture was heated at; 55-6000, and cooled and poured into water. The precipitates formed were separated, washed and dried to give 166,3-mercaptc-1,4-benzodioxane-5-carboxylic acid in a yield of 90% and with a melting point of 191-192 ° C. 7-Ethylthio-1,4-benzodioxane-5-carboxylic acid 166 3 7-mercapto-1,4-benzodioxane-5-carboxylic acid, 242 ml of water, 216 ml of sodium hydroxide solution and 181 g of ethyl sulphate were charged to a round bottom flask equipped with cooler. The mixture was heated under reflux and then cooled. The solution was poured into 1.3 liters of water, filtered and treated with 10 ml of hydrochloric acid. The precipitate was separated, washed with water and dried to give 152 g of 7-ethylthio-1,4-benzodioxane-5-carboxylic acid in a yield of 81% and with a melting point of 153-15400. 7-Ethylsulfonyl-1,4-benzodioxane-carbonic acid 152 g of 7-ethylthio-1,4-benzodioxene-5-carboxylic acid and 958 ml of acetic acid were charged to a round bottom flask equipped with a condenser. 398 ml of hydrogen peroxide were then added, and the mixture was heated. The crystals formed on cooling were separated, washed and dried to give 139 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carboxylic acid in a yield of 81% and with a melting point of 217-218 ° C. V15 455 390 Exemgel 4 1-dimethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 500 ml of acetone and a solution of 99 8 dimethylamine 1 250 ml of β-teton were charged to a round-bottomed flask equipped with a stirrer and thermometer.

The mixture was cooled to 0 ° C, after which 139 g of 7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were added. The whole was stirred at room temperature, after which the acetone was distilled off and the residue was dissolved in 1 liter of water. The solution was made alkaline, filtered and treated with 70 ml of hydrochloric acid, and the precipitate formed was separated, washed and dried. 28 g of 7-dimethylsulfamoyl-1,4-benzodioxane-5-carbonic acid were obtained in 89% yield and with a melting point of 220 DEG-212 DEG C.

Example 5 Methylene-3,4-dihydro-1,5-benzodioxepine-6-carbokygac 11 g of methyl 2,3-dihydroxybenzoate, 660 ml of methyl ethyl ketone, 167 g of 1,3-dibromopropane and 10 g of sodium iodide were charged to a round bottom flask. , equipped with a stirrer and thermometer. The mixture was heated at HOOC, after which low potassium carbonate was added. The whole was heated under reflux, and 2 liters of water were added. The oil phase was decanted off and extracted with ether, and the solution was washed with 10% soda, and dried. The ether was evaporated by vacuum distillation to give 86.5 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate in 63% yield and boiling point 166-176 ° C below 1.0 kPa. 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 160 g of methyl 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylate and 388 ml of soda were charged to a round-bottomed flask equipped with a condenser . The mixture was heated under reflux, then poured into 1 liter of water, and treated with 5 g of sodium metabisulfite. The solution was filtered and treated with 77 ml of concentrated hydrochloric acid, and the precipitate formed was filtered off, washed with water and dried, 120 g of 2H-3,4-dihydric-1,5-benzodioxepine-6-carboxylic acid obtained in 80.5% yield and with melting point 65-67 ° c.

Example gel 6 8-Chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxegine-6-carboxylic acid 1092 ml of chlorosulfonic acid was charged to a round bottom flask equipped with a stirrer, condenser and thermometer, followed by 106 g of 2H-3,4-dihydro- 1,5-Benzodioxepine-6-carbonic acid was added in small portions, keeping the temperature at 5-10 ° C. The mixture was stirred at room temperature and then poured onto ice, and the crystals formed were separated, washed with water and dried. 146 g were obtained from 8-chlorosulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 91% yield, m.p. 114-115 ° C. 8-Methylsulfamoyl-2H-3,4-dihydro-1,5-benzodiolepin-6-carbonic acid I - 233 g of aqueous solution of methylamine were charged to a round bottom flask equipped with a stirrer and thermometer, after which 146 g of 8-chlorosulfonyl-2H- 3,4-Dihydro-1,5-benzodioxepine-6-carboxylic acid was added, keeping the temperature at 5-10 ° C. The mixture was stirred, and the precipitate formed was then dissolved in 1 water. The solution was filtered and treated with 150 ml of concentrated hydrochloric acid, and the crystals formed were separated, washed and dried. 12 g were obtained from 8-methylsulphamoyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 78% yield and with a melting point of 145-1h6 ° C.

Example 7 7-Nitrc-1,4-beneodioxane-5-carboxylic acid 160 ml of acetic acid, 160 ml of acetic anhydride and 100 l of .alpha.-benzodioxane-5-carboxylic acid were charged into a round flask equipped with a stirrer and thermometer. The mixture was heated, and a solution of 40 ml of nitric acid 1 RO ml of acetic acid was added, after which the whole was stirred at 40-45 ° C and then cooled. The resulting crystals were separated, washed and dried to give 34 g of 7-nitro-1,4-benzodioxane-carbonic acid in 27% yield and with enamel point 2n6 ° C.

Example B 7- (1-adamantyl) -sulfamoyl-1,4-benzodioxane-5-carboxylic acid ~ 187.5 5 adamantylamine hydrochloride, 500 ml of soda and 1000 ml of triethylamine were charged to a round bottom flask equipped with a stirrer and thermometer, after which 280 7-Chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid was added at a temperature below 15 ° C. The mixture was stirred at room temperature and treated with 1.5 liters of methylene chloride, after which the organic phase was separated and the solvent was evaporated. The residue was treated with 1200 ml of water and 150 ml of hydrochloric acid, after which the precipitate formed was dissolved in 1200 ml of water and 120 ml of soda ash.

The solution was filtered and treated with 150 ml of hydrochloric acid, and the crystals formed were separated, washed and dried. 200 g were obtained of 7- (1-adamantyl) sulfamoyl-1,4-benzodioxane-5-carboxylic acid in 51% yield and with a melting point of 205 ° 0. 4šs san Example 9 I-amino-1,4-benzodioxane-5-carboxylic acid 56 g of 7-nitro-1,4-benzodioxane-5-carboxylic acid, 560 ml of absolute ethanol and Raney nickel were charged to an autoclave, then hydrogen gas under a pressure of 6.4 MPa was initiated during heating. Mixture X was then stirred at 6000, and treated with a solution of 50 ml of sodium hydroxide solution in 450 ml of water. The solution was filtered and treated with 50 ml of hydrochloric acid, and the precipitate formed was separated, washed with water and dried. 36.5 g were obtained of 7-amino-1,4-benzodioxane-5-carboxylic acid in 75% yield and with a melting point of 220 ° C. 1-Chloro-1,4-benzodioxane-5-carboxylic acid 49 g of 7-amino-1,4-benzodioxane-5-carboxylic acid, 200 ml of water and 50 ml of hydrochloric acid were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was cooled to 5 ° C, after which a solution of 17.5 g of sodium nitrite in 38 ml of water was added. The suspension was then poured into a solution of 20 g of copper (I) chloride in 75 ml of hydrochloric acid. The precipitate formed was separated, washed and dissolved in a solution of 42 g of sodium bicarbonate in 420 ml of water. The solution was filtered and treated with 100 ml of hydrochloric acid to give 50 g of 7-chloro-1,4-benzodioxane-5-carboxylic acid in 92.75 yield and with a melting point of 180 ° C.

Example 10 - 8-Methoxy-1,4-benzodioxane-4-carbonic acid 171,3,3-Dihydroxy-4-methoxybenzoic acid, 515 ml of alcohol, 280 ml of sodium hydroxide solution and 175 8 ethylene bromide were charged to a round bottom flask equipped with a stirrer, thermometer and inlet pipe for nitrogen gas. The mixture was heated under reflux, after which it was cooled and held in 2.8 liters of water. The solution was filtered and treated with 85 ml of concentrated hydrochloric acid, and the precipitate formed was separated, washed and dried. After recrystallization from dimethylformamide, 10 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were obtained in 57% yield and melting point 224 DEG-226 DEG.

Example gel 11 ~ 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane fi-carboxylic acid 1045 ml of chlorosulfonic acid was charged to a round bottom flask equipped with a stirrer, thermometer and condenser, then 110 g of 8-methoxy-1,4-benzodioxane -5-Carboxylic acid was added portionwise while maintaining the temperature at 5-10 ° C. The mixture was stirred at room temperature and then poured onto ice. The precipitate formed was separated, washed with ef-.w-nm-fw »wtaa-fm-w fl wwa-.Nsfaqamawla and was dried to give 159,358-methoxy-7-chlorosulfonyl-1,4-benzodioxane -5-Carboxylic acid 1 98% yield. 8-Methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid 300 g of 34% ammonia were charged to a round bottom flask equipped with a stirrer and thermometer, then 159,3 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane -5-Carboxylic acid was added portionwise, keeping the temperature at 0-5 ° C. The mixture was stirred, after which the precipitate formed was dissolved in water, and the solution was filtered and treated with 280 ml of concentrated hydrochloric acid. The precipitate formed was separated, washed and dried to give 118 g of 8-methoxy-7-sulfamoyl-1,4-benzodioxane-5-carboxylic acid in 82% yield and with a melting point of 247-248 ° C. Example 12 7-Diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid 200 ml of water, 10 ml of diethylamine and 200 ml of triethylamine were charged to a round flask equipped with a stirrer and thermometer, then 140 g of 7-chlorosulfonyl-1,4 -benzodioxane-5-carboxylic acid was added in portions, keeping the temperature at 20-30 ° C. The mixture was stirred at room temperature, after which 500 ml of water were added, and the solution was filtered and heated with 300 ml of hydrochloric acid. The precipitate formed was separated, washed and dried to give ll? 7-Diethylsulfamoyl-1,4-benzodioxane-5-carboxylic acid in 74% yield and with a melting point of 149 ° C.

Example 13 -n- w- fl ... 8-Mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid A solution of 105 g of 8-chlorosulfonyl-2H-3,4-dihydro-1 5-Benzodioxepine-6-carboxylic acid 1 273 ml of acetic acid and 159.5 g of tin were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was stirred under heating at 40-45 ° C, after which 705 ml of concentrated hydrochloric acid were added. After heating at 55-60 ° C, the solution was cooled, and the precipitate was separated, washed and dried. 65 3 was obtained from 8-mercapto-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 80% yield and with a melting point of 99.5-100 ° C. 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 86 5 8-mercapto-2H-3,1-dihydro-1,5-benzodioxepine-6-carboxylic acid, 152 ml water, 76 ml of soda and 58.5 g of ethyl sulphate were charged to a round-bottomed flask equipped with a condenser. The mixture was heated under reflux and then cooled, after which 150 ml of water were added and the solution was filtered and treated with 50 ml of hydrochloric acid. The resulting precipitate was separated, washed and dried to give 88 g of 8-ethylthio- '10 40 "M" MMÜ "" "" i = 2äÉ3É === ““ = “=“ * "" '- IIIIIIIIIIIIIIIII-IIIIIIIIIIIIIIIIIIIIIIIIII' 4s3 390 12 2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 91% yield and with a melting point of 66-67 ° C. 8-Ethylsulfonyl-2H-3,1-dihydro-1,5-benzodioxepine-6-carboxylic acid 688 g of 8-ethylthio-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid 1,528 ml of acetic acid were charged In a round bottom flask equipped with a condenser, after which 210 ml of hydrogen peroxide were added in portions. The solution was heated, and the acetic acid was evaporated in vacuo, after which the residue was dissolved in 180 ml of water and cooled. The precipitate formed was separated, washed and dried to give 90 g of 8-ethylsulfonyl-2H-3,4-dihydro-1,5-benzodioxepine-6-carboxylic acid in 91% yield, m.p. 142-143 ° C.

Example 14 6,7-Dibromo-1,4-benzodioxan-5-carboxylic acid - 14 ml of acetic acid and 360 g of 1,4-benzodioxane-5-carboxylic acid were charged to a round bottom flask equipped with a stirrer, starter funnel and condenser. the slurry was heated to 55 ° C, after which a solution of 70 g of brem in 360 ml of acetic acid was added in 1 portions. The whole was heated to 12,000 ° C to 155 ° C, after which the precipitate formed was separated, washed with acetic acid and dried. 332 g were obtained of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid, m.p. 212 ° C. The structure was confirmed by NMR analysis. 6,7-Dibromo-8-nitro-1,4-benzodioxane-5-carbonic acid 166 g of 6,7-dibromo-1,4-benzodioxane-5-carboxylic acid and 500 ml of acetic acid were saturated in a round bottom flask and the mixture was heated to 37 °. C, after which a solution of 60 ml of nitric acid (d - 1.49) in 60 ml of acetic acid and sulfuric acid as catalyst was added. After heating at 150 DEG C., the mixture is stirred into cold water while stirring; the precipitate formed was separated, washed with water and dried. 107 g were obtained of 6,7-dibromo-8-nitro-1,4-benzodioxene-5-carboxylic acid, m.p. 237 ° C. The acid was purified by treatment with a solution of 50 g of sodium bicarbonate in 1,500 ml of water and precipitating with hydrochloric acid. The precipitate was separated, washed and dried to give crystals in 61% yield and melting point 238 ° C.

The structure was confirmed by NMR analysis.

Example gel 15 '8-Amino-1,4-benzodioxane-5-carboxylic acid 400 ml water, 98.5 g 6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid, 100 ml soda and 10 g palladium-on-carbon was charged to an autoclave, after which hydrogen gas with a high pressure of 3.9 MPa was introduced and the whole was heated at 50 ° C. The mixture was filtered and then treated with 95 ml of hydrochloric acid, and the precipitate formed was separated, washed and dried; 42 g were obtained of 8-amino-1,4-benzodioxane-carboxylic acid in 83.7% yield and with a melting point of 186 ° C.

In Example Gel 16 Bachloro-1,4-benzodioxane-5-carboxylic acid 29.3 g of 8-amino-1,4-benzodioxane-5-carboxylic acid, 120 ml of water and 30 ml of hydrochloric acid were charged to a round bottom flask equipped with a stirrer and thermometer. The mixture was heated to 40 ° C and then cooled to 500, and a solution of 10.5 g of sodium nitrite in 20 ml of water was added portionwise while maintaining the temperature at 5-10 ° C.

The mixture was stirred and then poured into a solution of 12 g of copper (I) chloride in 45 ml of hydrochloric acid (d = 1.18), the temperature being below 30 ° C. The resulting compound was treated with hydrochloric acid and water, and then dissolved in 300 ml of water and 25 g of sodium bicarbonate. The solution was filtered and treated with hydrochloric acid, and the resulting precipitate was separated, washed with water and dried to give 20 g of 8-chloro-1,4-benzodioxane-xarbeneyrene in 62% yield with emaicpunk 195 ° C.

Example 17 8-Acetamino-1,4-benzodioxane-5-carboxylic acid 43 8-Amino-1,4-benzodioxane-5-carboxylic acid and 72 ml of acetic acid were charged to a round bottom flask, after which 24.5 ml of acetohydride were added in portions. The mixture was heated at 60-70 ° C and then cooled, and the precipitate was separated, washed with acetic acid and water and dried. 44 3 of 8-acetamino-1,4-benzodioxane-5-carboxylic acid were obtained in 84% yield with a melting point of 233 ° C.

Example 18 1,8-azimido-1,4-benzodioxane-5-carboxylic acid 13 g of a 50/50 mixture of 7-nitro-8-acetamino-1,4-benzodioxane-5-carboxylic acid and 6-nitro- 8-Acetamino-1, H-benzodioxane-5-carboxylic acid, 90 ml of water, 4.5 ml of sodium hydroxide, some Raney nickel and hydrogen at a pressure of 4.9 MPa were charged to an autoclave. After complete uptake of hydrogen, nickel was filtered off, and the solution was treated with 12 ml of hydrochloric acid and then with a solution of 3.5 U sodium nitrite in 10 ml of water at a temperature of 20-25 ° C. The precipitate formed was separated, washed and then treated with an aqueous solution of sodium hydroxide. The mixture was acidified, after which the formed compound was separated, washed and dried. 3 g of 20 g of 5,814 were obtained from 7,8-azimido-1,4-benzodioxane-5-carboxylic acid in 59% yield and with a melting point of 260 ° C with decomposition.

Example 19 6-Nitro-1,4-benzodioxane-5-carboxylic acid 1600 ml acetic acid, 1600 ml acetane hydride and 1000 g 1,4-benzodioxane-Carboxylic acid were charged to a 6 liter round bottom flask equipped with a stirrer and thermometer. The mixture was heated to 40 ° C, and a solution of 400 ml of nitric acid in 100 ml of acetic acid was added. After the addition, the mixture was stirred at 40-45 ° C for 2 hours, after which it was cooled to 500. The precipitate formed was washed, washed with 600 ml of acetic acid and then with water, and dried at 4000. 700 g of 7-nitro-1 were obtained. u-sensealoxane-5-carbonic acid (ssalcpunxt 246 ° c), the structure of which was confirmed by NMR. The mother liquors were diluted with 25 liters of water, and the resulting precipitate was separated, washed with water and dried to give 6-nitro-1,4-benzodioxane-5-carbonic acid, m.p. 188 ° C. 6-Amino-1,4-benzodioxane-5-carboxylic acid hydrochloride 195 g of 6-nitro-1,1-benzodioxane-5-carboxylic acid, 1950 ml of ethanol and some Raney nickel were charged to an autoclave, and the mixture was hydrogenated at a hydrogen pressure of 3 .4 MPa and 60 ° C for 1 hour, after which it was cooled. Nickel was filtered off, and the solution was acidified with 150 ml of ethanolic hydrochloric acid (23 3/100 ml). The precipitate formed was filtered off and dried, yielding 115 g of 6-amino-1,4-benzodioxane-5-carbonic acid hydrochloride in 57.5% yield, m.p. 6-Chloro-1,4-benzodioxane-5-carboxylic acid 58 g of 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride and 16 ml of water were charged to a 500 ml round bottom flask equipped with a stirrer, thermometer and dropping funnel. 28 ml of hydrochloric acid (d = 1.18) were added and the mixture was cooled to a temperature of 0-5 ° C. A solution of 17.5 g of sodium nitrite in 38 ml of water was added at a temperature in the range of 0-5 ° C, and the mixture was stirred for 1 hour. 20 g of copper (I) chloride and 75 ml of hydrochloric acid were then added, and the mixture was allowed to stand overnight, after which it was filtered. The solid product was washed with water, dried at 50 ° C and purified by treatment with carbon black in alkaline solution (200 ml of water and 25 ml of 30% sodium hydroxide solution), after which 25 ml of hydrochloric acid were added. 40 g were obtained of 6-chloro-1,4-benzodioxane-5-carboxylic acid in 74% yield and with melting point Q 162 ° C. 7,453,390 Exemgel 20 7-Cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid, 250 ml of water and 300 ml of cyclohexylamine were charged to a 1 liter round flask, and 139 g of moist 7-chlorosulfonyl-1,4-benzodioxane-5 Carboxylic acid was added in small portions, keeping the temperature at 20-30 ° C.

The mixture was stirred at room temperature for 3 hours, after which the solution was treated with 30 g of carbon black 3 S. After filtration, 300 ml of hydrochloric acid (d = 1.18) were added, and the precipitate formed was recrystallized, washed with water and dried. 92 g were obtained of 7-cyclohexylsulfamoyl-1,4-benzodioxane-5-carboxylic acid with a melting point of 15 ° C.

Example 21 21,4-Benzodioxane-6,7-dinitro-5-carboxylic acid 165 ml of nitric acid (d = 1.49) were charged to a 500 ml round bottom flask equipped with a mechanical stirrer and thermometer, followed by 90 μl of 4-benzodioxane-5 -carboxylic acid was added at -10 ° C. The mixture was kept for 2 hours at room temperature, after which 1 liter of ice water was added. The precipitate was filtered off, washed with water and dried at 50 ° C, after which it was purified by recrystallization from acetic acid. 87 g were obtained of 1,4-beneodioxane-6,7-dinitro-5-carboxylic acid with a melting point of 211 ° C. . 1,4-Benzodioxane-6,7-diemino-5-carboxylic acid 135 5 1,4-Beneodioxane-6,7-dinitro-5-carboxylic acid, 500 ml of water and 50 ml of sodium hydroxide solution were charged into a 1-liter autoclave and hydrogenated. was formed at a hydrogen pressure of 7.85 MPa in the presence of Raney nickel.

The mixture was heated at 100 ° C for 2 hours, after which it was cooled and filtered. Pre-filtered nickel was washed on the filters with 200 ml of water, and all the filtrates were combined. A sample was acidified with hydrochloric acid to give 1,4-benzodioxane-6,7-diamino-5-carboxylic acid dihydrochloride, which was filtered, washed and dried (m.p. 135 ° C). 1,4-Benzodioxane-6,7-azimido-5-carboxylic acid The filtrate obtained in the previous step was charged to a 2 liter round bottom flask equipped with a mechanical stirrer and thermometer, and a solution of 35 g of sodium nitrite in 70 ml of water was added dropwise. at a temperature of 20 to 25 ° C. The crystallized product was filtered off, washed with water and dried at 50 ° C to give 96 g of 1,4-benzodioxane-6,7-azimido-5-carboxylic acid in 87% yield.

The structure was confirmed by NMR analysis. - ~ - _ - _ _-

Claims (1)

1. Substitution of 2,3-alkylene bis-substitution as intermediates for the preparation of therapeutically valuable, substituted, 2,3-alkylene-bie (oxy) benaemides, characterized by the general formula : COOH in (V) wherein A represents an alkylene chain having 1-3 carbon atoms, mainly those of methylene, ethylene or propylene, X represents hydrogen, halogen, methoxy, nitro, amino or acetamino, or Y represents hydrogen, halogen, nitro, amino or acetamino, ethylulfonyl, eulfamoyl, C 1 -C 4 -alkylultamoyl, C 1 -C 4 -alkylr eulfamcyl, adamantyleulfamoyl or cyclalkylulfemoyl or ¿is attached to X to form an azimido group, and I 2 represents hydrogen, halogen, Y to form an azimido group, with the conditions that - when A represents methylene or ethylene and Z represents hydrogen, X and Y do not simultaneously represent hydrogen, - when X and Z represent hydrogen and A represents methylene or ethylene, Y is different from a bromine atom, - when X and Z betec hydrogen atoms and A represents a methylene group, Y does not represent nitro, acetamino or amino, - when Y and Z represent hydrogen atoms and A represents a methylene group, X does not represent a methoxy group, and - when A represents a methylene group and X and Y represent F hydrogen , Z does not simultaneously denote nitro. per, w - «, -». v. _ _ “" "'*“' "“ '-. .. ~ f, »v r-. Ir Mn” __, ____m_