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GB1571278A - 2,3-alkylene bis(oxy)benzoic acids - Google Patents

2,3-alkylene bis(oxy)benzoic acids Download PDF

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GB1571278A
GB1571278A GB44877/78A GB4487778A GB1571278A GB 1571278 A GB1571278 A GB 1571278A GB 44877/78 A GB44877/78 A GB 44877/78A GB 4487778 A GB4487778 A GB 4487778A GB 1571278 A GB1571278 A GB 1571278A
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alkyl
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opt
carboxylic acid
benzodioxane
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SOC D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-
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SOC D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-
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Priority to JP9405777A priority Critical patent/JPS5328181A/en
Priority claimed from JP9405777A external-priority patent/JPS5328181A/en
Priority claimed from GB4487/78A external-priority patent/GB1567290A/en
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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

PATENT SPECIFICATION ( 11) 1 571 278
at ( 21) Application No 44877/78 ( 22) Filed I Aug 1977 ( 62) Divided out of No1571447 1 ( 31) Convention Application No7623835 ( 9 " pm 4 ( 32) Filed 4 Aug 1976 in L' ( 33) France (FR) ( 44) Complete Specification published 9 July 1980 ( 51) INT CL 3 C 07 D 319/18 321/10 491/02 (C 07 D 491/02 249/04 319/18) ( 52) Index at acceptance C 2 C 1230 145 X 1693 175 X 213 221 225 22 Y 247 253 255 25 Y 271 281 29 X 29 Y 305 30 Y 313 314 31 Y 321 32 Y 332 337 342 34 Y 364 366 367 36 Y 37 X 385 396 440 453 45 Y 470 471 510 511 51 X 536 537 538 552 601 614 620 621 624 628 62 X 630 631 670 671 672 678 AA BC BE KK LS ML QS SJ ( 72) Inventors MICHEL THOMINET, GERARD BULTEAU, JACQUES ACHER and CLOUDE COLLIGNON ( 54) 2,3-ALKYLENE BIS(OXY) BENZOIC ACIDS ( 71) We, SOCIETE D'ETUDES SCIENTIFIQUES ET INDUSTRIELLES DE L'ILE-DE-FRANCE, a French body corporate, of 46 Boulevard de Latour-Maubourg, 75 Paris ( 7), France, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following 5
statement:-
This invention provides novel substitution 2,3-alkylene bis (oxy) benzoic acids of general formula:
COO/t X r o / ( 1) in which A is an ethylene or propylene group; 10 X represents a hydrogen or halogen atom, or a hydroxy, nitro, amino, substituted amino, C,_ 4 alkoxy or C,_ 4 alkyl group, Y represents a hydrogen or halogen atom, a hydroxy, amino, substituted amino, nitro, C_ 4 alkoxy, C_ 4 alkylsulphonyl adamantylsulphonyl, or cycloalkyl sulphonyl group or a group of formula SO 2 NR 3 R 4 in which each of R 3 and R 4, 15 which can be identical or different, is a hydrogen atom or a C,_ 4 alkyl, C 2 _ 4 alkenyl, C 2,4 alkynyl, phenyl, benzyl, cycloalkyl, cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, pyrimidinyl or pyrazinyl group or an alkyl group having a hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio substituent, or R 3 and R 4, together with the nitrogen atom to which they are attached, form a heterocycle 20 which may optionally contain another heteroatom; Z represents a hydrogen or halogen atom or a hydroxy, amino, substituted amino, nitro, or a C,_ 4 alkoxy group; or X and Y or Y and Z are connected together through a substituted or unsubstituted carbon chain or through a heteroatom to form a ring such as 25 substituted or unsubstituted triazole, imidazole, oxazole, thiadiazole, pyrazine, piperazine or diazepine ring or an oxide thereof; with the proviso that when A is an ethylene group and X and Z are hydrogen atoms, Y cannot be a hydrogen or bromine atom.
The amides of such acids, which are claimed in the specification of our 30 copending application No 32117/77, (Serial No 1571447) are pharmaceutically valuable.
In the definitions mentioned in the present specification, the principal values of C,_ 4 alkyl are methy, ethyl, propyl, isopropyl, butyl, isobutyl, and t-butyl; the principal values of C 2,4 alkenyl are vinyl and allyl; the principal values of C 2-4 5 alkynyl are ethynyl and propargyl; the principal values of C,_ 4 alkoxy are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and t-butoxy; halogen means chlorine, bromine, iodine or fluorine; the principal substituted amino groups are those monosubstituted or disubstituted by alkyl, acyl, aralkyl, furanyl, pyranyl or alkoxycarbonyl; preferred acyl groups are formyl, acetyl and phthaloyl 10 Preferred values of X are hydrogen, alkoxy, particularly methoxy, nitro, halogen, particularly chlorine, amino and acylamino, particularly acetamido; preferred values of Y are hydrogen, halogen, particularly bromine or chlorine, amino, acylamino, particularly acetamido, alkylsulphonyl, particularly ethylsulphonyl, sulphamoyl, sulphamoyl N-monosubstituted by alkyl, particularly 15 methyl, or by adamantyl, and sulphamoyl N,N-disubstituted by alkyl, particularly methyl and/or ethyl; preferred values of Z are hydrogen, halogen, particularly bromine or chlorine, nitro, acylamino, particularly acetamido, and amino.
The preferred pairs of values of the substituents in the disubstituted compounds are: 20 (a) X is alkoxy, especially methoxy, and Y is sulphamoyl; (b) X is acylamino, especially acetamido, and Y is nitro; (c) X and Y are joined together through a heteroatom to form a triazole ring; (d) X and Y are both amino; (e) X is halogen, especially chlorine, and Y is amino; 25 (f) X is amino and Y is acylamino, especially acetamido; (g) X and Y are both acylamino, especially acetamido; (h) Y and Z are both nitro; (i) Y and Z are both acylamino, especially acetamido; (j) Y and Z are both halogen, especially bromine; 30 (k) Y and Z are both amino groups; (I) Y and Z are joined together through a heteroatom to form a triazole ring.
The preferred values X, Y and Z in trisubstituted compounds are:
(a) X is nitro and Y and Z are both halogen, especially chlorine and/or bromine; 35 (b) X is halogen, especially chlorine and bromine, and Y and Z are both nitro; (c) X is nitro and Y and Z are both acylamino, especially acetamido.
The following Examples illustrate the preparation of compounds in accordance with the present invention.
EXAMPLE 1 40
7-methylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid 670 g of chlorosulphonic acid was introduced into a balloon flask provided with a condenser and a thermometer 173 g of 1,4 benzodioxane 5 carboxylic acid was added in portions, with the temperature being maintained at 5-10 C The 45 mixture was heated at 55 C then cooled and poured into ice The precipitate was dried off, washed and dried 250 g of 7 chlorosulphonyl 1,4 benzodioxane carboxylic acid was obtained (M P = 210-215 C; yield= 93 5,).
7-methylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 139 5 g of a 40 % methylamine aqueous solution and 139 5 cc of water were 50 introduced into a balloon flask provided with an agitator and a thermometer, then in portions, 250 g of 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid and a solution of 180 cc of 30 % soda lye in 180 cc of water were added The mixture was agitated and then poured into 2200 cc of water The solution was filtered, then treated with 139 cc of concentrated hydrochloric acid The precipitate was dried 55 off, washed and dried 190 5 g of 7 methylsulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 208-209 C; yield= 80 %).
EXAMPLE 2
7-sulphamoyl-1,4-benzodioxane-5-carboxylic acid 209 g of 34 % ammonia and 97 g of 7 chlorosulphonyl 1,4 benzodioxane 60 1,571,278 carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer, at a temperature of 5-10 C The mixture was agitated at ambient temperature, then the precipitate was dissolved in 415 cc of water The solution was filtered and treated with 140 cc of concentrated hydrochloric acid.
The crystals were dried off, washed with water and dried 78 g of 7 sulphamoyl 5 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 272-274 C; yield= 87 %).
EXAMPLE 3
7-ethylsulphonyl-1,4-benzodioxane-5-carboxylic acid 7-mercapto-1,4-benzodioxane-5-carboxylic acid 10 243 g of 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid and 654 cc of acetic acid were introduced into a balloon flask provided with an agitator and a condenser The mixture was heated at 90 C and then cooled at 45 C 389 g of tin and 1744 cc of hydrochloric acid were then added The mixture was heated at 55-60 C, cooled and poured into water The precipitate was dried off, washed and 15 dried 166 g of 7 mercapto 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 191-192 C; yield= 90 %).
7-ethylthio 1,4-benzodioxane-5-carboxylic acid 166 g of 7 mercapto 1,4 benzodioxane 5 carboxylic acid, 242 cc of water, 215 cc of soda lye and 181 g of ethylsulphate were introduced into a balloon 20 flask provided with a condenser The mixture was heated under reflux, then cooled.
The solution was poured into 1 3 1 of water, filtered and treated with 110 cc of hydrochloric acid The precipitate was dried off, washed with water and dried 152 g of 7 ethylthio 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 153-154 C; yield= 81 %) 25 7-ethylsulphonyl-1,4-benzodioxane-5-carboxylic acid 152 g of 7 ethylthio 1,4 benzodioxane 5 carboxylic acid and 958 cc of acetic acid were introduced into a balloon flask provided with a condenser 398 cc of hydrogen peroxide was then added and the mixture was heated The crystals formed by cooling were dried off, washed and dried, 139 g of 7 ethylsulphonyl 30 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 217-2180 C; yield= 81 %).
EXAMPLE 4
7-dimethylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 500 cc of acetone and a solution of 99 g of dimethylamine in 250 cc of acetone 35 were introduced into a balloon flask provided with an agitator and a thermometer.
The mixture was cooled at O C and then 139 g of 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid was added The mixture was agitated at ambient temperature, the acetone distilled off and the residue dissolved in 1 1 of water The solution was rendered alkaline, filtered and treated with 70 cc of 40 hydrochloric acid The precipitate was dried off, washed and dried 128 g of 7 dimethylsulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M.P = 220-221 C; yield= 89 %).
EXAMPLE 5
2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 45 Methyl 2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylate 111 g of methyl 2,3-dihydroxybenzoate, 660 cc of methyl ethyl ketone, 167 g of 1,3-dibromopropane and 10 g of sodium iodide were introduced into a balloon flask provided with an agitator and a thermometer The mixture was heated at 40 C and 182 g of potassium carbonate was added The mixture was heated under reflux and 50 2 1 of water was added The oily phase was decanted and extracted by ether and the solution was washed with 10 % caustic soda and dried The ether was removed by distillation under vacuum 86 5 g of methyl 2 H 3,4 dihydro 1,5 benzodioxepin 5 carboxylate was obtained (Boiling point= 166-176 C under 8 mm/Hg; yield=-63 , 55 2 H-34-dihydro-1,5-benzodioxepin-6-carboxylic acid g of methyl 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylate and 388 cc of caustic soda were introduced into a balloon flask provided with a condenser The mixture was heated under reflux and then poured into 1 1 of water 1,571,278 and treated with 5 g of sodium metabisulphite The solution was filtered and treated with 77 cc of concentrated hydrochloric acid The precipitate was drained off, washed with water and dried 120 g of 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid was obtained (M P = 65-67 C; yield= 80 5 %).
EXAMPLE 6 5
8-methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 8-chlorosulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylic acid 1092 cc of chlorosulphonic acid was introduced into a balloon flask provided with an agitator, a condenser and a thermometer Then, in portions, 106 g of 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid was added, with the 10 temperature being maintained at from 5 to 10 C The mixture was agitated at ambient temperature and then poured onto ice The crystals were dried off, washed with water and dried 146 g of 8 chlorosulphonyl 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid were obtained (M P = 114-115 C; yield= 91 %) 15 8-methylsulphamoyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 233 g of an aqueous solution of methylamine was introduced into a balloon flask provided with an agitator and a thermometer; then, in portions, 146 g of 8 chlorosulphonyl 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid was added, with the temperature being maintained at from 5 to 10 C The mixture 20 was agitated and the precipitate was then dissolved in water The solution was filtered and treated with 150 cc of concentrated hydrochloric acid The crystals were dried off, washed and dried 122 g of 8 methylsulphamoyl 2 H 11 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid was obtained (M P = 145146 C; yield= 78 %) 25 EXAMPLE 7
7-nitro-1,4-benzodioxane-5-carboxylic acid ml of acetic acid, 160 ml of acetic anhydride and 100 g of 1,4 benzodioxane 5 carboxylic acid were introduced into a balloon flask provided with an agitator and a thermometer 30 The mixture was heated and a solution of 40 ml of nitric acid in 40 ml of acetic acid was added The mixture was agitated at 40-45 C, then cooled The crystals were dried off, washed and dried 34 g of 7 nitro 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 246 C; yield= 27 %).
EXAMPLE 8 35
7-( 1-adamantyl)sulphamoyl 1,4-benzodioxane-5-carboxylic acid 187 5 g of adamantylamine hydrochloride, 500 ml of caustic soda and 1000 ml of triethylamine were introduced into a balloon flask provided with an agitator and a thermometer 280 g of 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid was then added at a temperature below 15 C The mixture was agitated at 40 ambient temperature and treated with 1 5 1 of methylene chloride The organic phase was separated and the solvent removed The residue was treated with 1200 ml of water and 150 ml of hydrochloric acid, then the precipitate was dissolved in 1200 ml of water and 120 ml of soda The solution was filtered and treated with 150 ml of hydrochloric acid The crystals were dried off, washed and dried 200 g of 7 45 ( 1 adamantyl)sulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 205 C; yield= 51 %).
EXAMPLE 9
7-amino-1,4-benzodioxane-5-carboxylic acid 56 g of 7 nitro 1,4 benzodioxane S carboxylic acid, 560 ml of absolute 50 ethanol and Raney nickel were introduced into an autoclave, then hydrogen under a pressure of 65 kg/cm 2 was introduced while heating The mixture was then agitated at 60 C and treated with a solution of 50 ml of caustic soda in 450 ml of water The solution was filtered and treated with 50 ml of hydrochloric acid The precipitate was dried off, washed with water and dried 36 5 g of 7 amino 1,4 55 benzodioxane 5 carboxylic acid was obtained (M P = 220 C; yield= 75 %/).
EXAMPLE 10
7-chloro-1,4-benzodioxane-5-carboxylic acid 49 g of 7 amino 1,4 benzodioxane 5 carboxylic acid, 200 ml of water 1,571,278 1,571,278 5 and 50 ml of hydrochloric acid were introduced into a balloon flask provided with an agitator and a thermometer The mixture was cooled to 5 C, then 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 cuprous chloride in 75 ml of hydrochloric acid The precipitate was dried off, washed and dissolved in a 5 solution of 42 g of sodium bicarbonate in 420 ml of water The solution was filtered and treated with 100 ml of hydrochloric acid 50 g of 7 chloro 1,4benzodioxane 5 carboxylic acid was obtained (M P = 180 C; yield= 92 7 %).
EXAMPLE 11
8-methoxy-1,4-benzodioxane-5-carboxylic acid 10 171 5 g of 2,3 dihydroxy 4 methoxybenzoic acid, 515 cc of ethanol, 280 cc of caustic soda and 175 g of ethylene bromide were introduced into a balloon flask provided with an agitator, a thermometer and an inlet pipe for nitrogen The mixture was heated under reflux, then cooled and poured into 2 8 1 of water The solution was filtered and treated with 85 cc of concentrated hydrochloric acid The 15 precipitate was dried off, washed and dried After recrystallisation in dimethylformamide, 110 g of 8 methoxy 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 224-226 C; yield= 57 %).
EXAMPLE 12
8-methoxy-7-sulphamoyl-1,4-benzodioxane-5-carboxylic acid 20 8-methoxy-7-chlorosulphonyl-1,4-benzodioxane-5-carboxylic acid 1045 cc of chlorosulphonic acid was introduced into a balloon flask provided with an agitator, a thermometer and condenser, then, in portions, 110 g of 8 methoxy 1,4 benzodioxane 5 carboxylic acid was added with the temperature being maintained at from 5 to 10 C The mixture was agitated at 25 ambient temperature and then poured onto ice The precipitate was dried off, washed and dried 159 g of 8 methoxy 7 chlorosulphonyl 1,4benzodioxane 5 carboxylic acid was obtained (yield= 98 %).
8-methoxy-7-sulphamoyl 1,4-benzodioxane-5-carboxylic acid 300 g of 34 % ammonia was introduced into a balloon flask provided with an 30 agitator and a thermometer and 159 g of 8 methoxy 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid was added in portions, the temperature being maintained at from 0 to 5 C The mixture was agitated; then the precipitate was dissolved in water The solution was filtered and treated with 280 cc of concentrated hydrochloric acid The precipitate was dried off, washed and dried 35 118 g of 8 methoxy 7 sulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 247-248 C; yield= 82 %).
EXAMPLE 13
7-diethylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 200 ml of water, 100 ml of diethylamine and 200 ml of triethylamine were 40 introduced into a balloon flask provided with an agitator and a thermometer Then g of 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid was added in portions, the temperature being maintained at from 20 to 30 C.
The mixture was agitated at ambient temperature and 500 ml of water was added The solution was filtered and treated with 300 ml of hydrochloric acid The 45 precipitate was dried off, washed and dried 117 g of 7 diethylsulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 149 C; yield= 74 %).
EXAMPLE 14
8-ethylsulphonyl-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 8-mercapto-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 50 A solution of 106 g of 8 chlorosulphonyl 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid in 273 ml of acetic acid, together with 159 5 g of tin, was introduced into a balloon flask provided with an agitator and a thermometer The mixture was agitated with heating at 40-45 C, then 705 ml of concentrated hydrochloric acid was added After heating at 55-60 C the solution 55 was cooled The precipitate was dried off, washed and dried 65 g of 8 mercapto 2 H 3,4 dihydro 1,5 benzodioxepin 6 carboxylic acid was obtained (M.P = 99 5-100 C; yield= 80 %).
8-ethylthio-2 H-3,4-dihydro-1,5-benzodioxepin-6-carboxylic acid 86 g of 8 mercapto 211 3,4 dihydro 1,5 benzodioxepin 6carboxylic acid, 152 ml of water, 76 ml of caustic soda and 58 5 g of ethylsulphate were introduced into a balloon flask provided with a condenser The mixture was heated under reflux then cooled 150 ml of water was added and the solution was 5 filtered and treated with 60 ml of hydrochloric acid The precipitate was dried off, washed and dried 88 g of 8 ethylthio 2 H 3,4 dihydro 1,5benzodioxepin 6 carboxylic acid was obtained (M P = 66-67 C; yield= 91 %) .
8-ethylsulphonyl-2 H-3,4-dihydro 1,5-benzodioxepin-6-carboxylic acid 88 g of 8 ethylthio 2 H 3,4 dihydro 1,5 benzodioxepin 6 10 carboxylic acid in 528 ml of acetic acid was introduced into a balloon flask provided with a condenser, then 210 ml of hydrogen peroxide was added in portions The solution was heated and the acetic acid removed under vacuum The residue was dissolved in 180 ml of water and cooled The precipitate was dried off, washed and dried 90 g of 8 ethylsulphonyl 2 H 3,4 dihydro 1,5 15 benzodioxepin -6 carboxylic acid was obtained (M P = 142-143 C; yield= 91,).
EXAMPLE 15
6,7-dibromo-1,4-benzodioxane-5-carboxylic acid 1440 ml of acetic acid and 360 g of 1,4 benzodioxane 5 carboxylic acid were introduced into a balloon flask provided with an agitator, an introduction 20 funnel and a condenser The mixture was heated to 55 C, then a solution of 700 g of bromine in 360 ml of acetic acid was added in portions The mixture was heated to C, then cooled to 15 C The precipitate was dried off, washed with acetic acid and dried 332 g of 6,7 dibromo 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 212 C) The structure was confirmed by NMR analysis 25 EXAMPLE 16
6,7-dibromo-8-nitro-1,4-benzodioxane-5-carboxylic acid 166 g of 6,7 dibromo 1,4 benzodioxane 5 carboxylic acid and 500 ml of acetic acid were introduced into a balloon flask The mixture was heated to 37 C and a solution of 60 ml of nitric acid (specific gravity= 1 49) in 60 ml of acetic acid, 30 together with sulphuric acid as catalyst, was added After heating at 50 C, the mixture was poured in cold water, under agitation The precipitate was dried off, washed with water and dried 107 g of 6,7 dibromo 8 nitro 1,4benzodioxane 5 carboxylic acid was obtained (M P = 237 C) The acid was purified by treatment with a solution of 50 g of sodium bicarbonate in 500 ml of 35 water and precipitation by hydrochloric acid The precipitate was dried off, washed and dried Crystals were obtained (M P = 238 C; yield= 51 %) The structure was confirmed by NMR analysis.
EXAMPLE 17
8-amino-1,4-benzodioxane-5-carboxylic acid 40 400 ml of water, 98 5 of 6,7 dibromo 8 nitro 1,4 benzodioxane 5 carboxylic acid, 100 ml of caustic soda and 10 g of Pd/C were introduced into an autoclave, then hydrogen under a pressure of 40 kg/cm 2 was introduced while heating at 50 C The mixture was filtered, then treated with 95 ml of hydrochloric acid The precipitate was dried off, washed and dried 42 g of 8 amino 1,4 45 benzodioxane 5 carboxylic acid was obtained (M P = 186 C; yield= 83 7 %).
EXAMPLE 18
8-chloro-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 introduced into a balloon flask provided with 50 an agitator and a thermometer The mixture was heated to 40 C and then cooled to C, and a solution of 10 5 g of sodium nitrite in 20 ml of water was added in portions, with the temperature being maintained at from 5 to 10 C The mixture was agitated and then poured into a solution of 12 g of cuprous chloride in 45 ml of hydrochloric acid (specific gravity=l 18), with the temperature being maintained 55 below 30 C The precipitate was dried off, washed with hydrochloric acid and water, and dissolved in 300 ml of water and 25 g of sodium bicarbonate The solution was filtered and treated with hydrochloric acid The precipitate was dried off, washed with water and dried 20 g of 8 chloro 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 195 C; yield= 62 %) 60 1,571,278 EXAMPLE 19
8-acetamido-1,4-benzodioxane-5-carboxylic acid 43 g of 8 amino 1,4 benzodioxane 5 carboxylic acid and 72 ml of acetic acid were introduced into a balloon flask and 24 5 ml of acetic anhydride was added in portions The mixture was heated at 60-70 C, then cooled The 5 precipitate was dried off, washed with acetic acid and water and dried 44 g of 8 acetamido 1,4 benzodioxane 5 carboxylic acid was obtained (M P = 233 C; yield= 84 %,).
EXAMPLE 20
7,8-azimido-1,4-benzodioxane-5-carboxylic acid 10 13 g of a 50 % mixture of 7 nitro 8 acetamido 1,4 benzodioxane 5 carboxylic acid and 6 nitro 8 acetamido 1,4 benzodioxane 5carboxylic acid, 90 ml of water, 45 ml of sodium hydroxide, some Raney nickel, and hydrogen under a 50 kg/cm 2 pressure were introduced into an autoclave At the end of the hydrogen absorption the nickel was filtered off and the solution was treated 15 with 12 ml of hydrochloric acid and then with a solution of 3 5 g of sodium nitrite in ml of water, at a temperature of from 20 to 25 C The resulting precipitate was dried off, washed, and then treated with an aqueous sodium hydroxide solution.
The mixture was acidified and the resulting precipitate was dried off, washed and dried 3 g of 7,8 azimido 1,4 benzodioxane 5 carboxylic acid was obtained 20 (M.P = 260 C with decomposition; yield= 59 %).
EXAMPLE 21
6-nitro-1,4-benzodioxane-5-carboxylic acid 1600 ml of acetic acid, 1600 ml of acetic anhydride and 1000 g of 1,4 benzodioxane 5 carboxylic acid were introduced into a 6-liter balloon flask 25 provided with an agitator and a thermometer The mixture was heated to 40 C and a solution of 400 ml of nitric acid in 400 ml of acetic acid was added After the introduction, the mixture was stirred at 40-45 C for 2 hours, then cooled to 5 C.
The precipitate was dried off, washed with 600 ml of acetic acid and then with water, and dried at 40 C700 g of 7 nitro 1,4 benzodioxane 5 carboxylic 30 acid was collected, the structure of which was confirmed by NMR (M P 246 C).
The mother-liquors were diluted with 25 liters of water, and the resulting precipitate was dried off, washed with water and dried to produce 6 nitro 1,4 benzodioxane 5 carboxylic acid (M P 188 C).
EXAMPLE 22 35
6-chloro-1,4-benzodioxane-5-carboxylic acid 6-amino-1,4-benzodioxane-5-carboxylic acid hydrochloride g of 6 nitro 1,4 benzodioxane 5 carboxylic acid, 1950 ml of ethanol and some Raney nickel were introduced into an autoclave The mixture was hydrogenated under a hydrogen pressure of 35 kg/cm 2 at 60 C for one hour, 40 then cooled The nickel was filtered off and the solution was acidified with 150 ml of an ethanolic solution of hydrochloric acid ( 23 g/100 ml) The precipitate was filtered and dried 115 g of 6 amino 1,4 benzodioxane 5 carboxylic acid hydrochloride was obtained (M P 160 C; yield 57 5 %).
6-chloro-1,4-benzodioxane-5-carboxylic acid 45 58 g of 6 amino 1,4 benzodioxane 5 carboxylic acid hydrochloride and 116 ml of water were introduced in a 500 ml balloon flask provided with a stirrer, a thermometer and a dropping funnel 28 ml of hydrochloric acid (specific gravity= 1 18) was added and the mixture was cooled to a temperature of from O to 5 C 50 A solution of 17 5 g of sodium nitrite in 38 ml of water was added at a temperature within the range 0 to 5 C The mixture was stirred for one hour 20 g of cuprous chloride and 75 ml of hydrochloric acid were then added The mixture was allowed to stand overnight and then filtered.
The solid was washed with water, dried at 50 C and purified by treatment with 55 carbon black in alkaline solution ( 200 ml of water and 25 ml of 36 B 6 caustic soda), then addition of 25 ml of hydrochloric acid 40 g of 6 chloro 1,4 benzodioxane 6 carboxylic acid was obtained (M P 162 C; yield 74 %).
1,571,278 EXAMPLE 23
7-cyclohexylsulphamoyl-1,4-benzodioxane-5-carboxylic acid 250 ml of water and 300 ml of cyclohexylamine were placed in a I liter balloon flask 139 g of moist 7 chlorosulphonyl 1,4 benzodioxane 5 carboxylic acid was added portionwise, the temperature being maintained at from 20 to 30 C The 5 mixture was stirred at room temperature for 3 hours and then the solution was treated with 30 g of carbon black 3 S After filtration, 300 ml of hydrochloric acid (specific gravity= 1 18) was added The precipitate was recrystallized, washed with water and dried 92 g of 7 cyclohexylsulphamoyl 1,4 benzodioxane 5 carboxylic acid was obtained (M P 150 C) 10 EXAMPLE 24
6,7-dinitro-1,4-benzodioxane-5-carboxylic acid ml of nitric acid (specific gravity=l 49) was placed in a 500 ml balloon flask provided with a mechanical stirrer and a thermometer 90 g of 1,4benzodioxane 5 carboxylic acid was added at -10 C The mixture was 15 maintained for 2 hours at room temperature, then 1 liter of iced water was added.
The precipitate was filtered off, washed with water, dried at 50 C, and purified by recrystallization from acetic acid 87 g of 6,7 dinitro 1,4 benzodioxane 5 carboxylic acid was collected (M P 211 C).
EXAMPLE 25 20
6,7-diamino-1,4-benzodioxane-5-carboxylic acid g of 6,7 dinitro 1,4 benzodioxane 5 carboxylic acid, 500 ml of water and 50 ml of caustic soda were introduced into a 1 liter autoclave and hydrogenated under a 80 kg/cm 2 pressure in presence of Raney nickel The mixture was heated to 100 C for 2 hours, then cooled and filtered; the nickel was washed on 25 the filter with 200 ml of water and the filtrates were kept all together A sample was acidifed with hydrochloric acid to form 6,7 diamino 1,4 benzodioxane 5 carboxylic acid dihydrochloride, which was filtered, washed and dried (M P.
153 C).
EXAMPLE 26 30
6,7-azimido-1,4-benzodioxane-5-carboxylic acid The filtrate obtained in the preceding Example was introduced in a 2 liter balloon flask provided with a mechanical stirrer and a thermometer A solution of g of sodium nitrite in 70 ml of water was added dropwise at a temperaturefrom 20 to 25 C The crystallized product was filtered off, washed with water and dried 35 at 50 C 96 g of 6,7 azimido 1,4 benzodioxane 5 carboxylic acid was obtained (yield 87 %/) The structure was confirmed by NMR analysis.

Claims (3)

WHAT WE CLAIM IS:-
1 2,3 Alkylene bis (oxy) benzoic acids having the following general formula:
COOH (I) 40 X in which A is an ethylene or propylene group; X represents a hydrogen or halogen atom, or a hydroxy, nitro, amino, substituted amino, C 1 _ 4 alkoxy or C,_ 4 alkyl group; Y represents a hydrogen or halogen atom, a hydroxy, amino, substituted amino, nitro, C,_ 4 alkoxy, C,-4 alkylsulphonyl, adamantylsulphonyl, or cycloalkyl 45 sulphonyl group or a group of formula SO 2 NR 3 R 4 in which each of R 3 and R 4, which can be identical or different, is a hydrogen atom or a C,_ 4 alkyl, C 2-4 alkenyl, C 2 _ 4 alkynyl, phenyl, benzyl, cycloalkyl, cycloalkanealkyl, cycloalkenealkyl, bicycloalkyl, adamantyl, pyrimidinyl or pyrazinyl group or an alkyl group having a hydroxy, mercapto, acyl, thioacyl, alkoxy or alkylthio substituent, or R 3 and R 4, 50 together with the nitrogen atom to which they are attached, form a heterocycle which may optionally contain another heteroatom; 1,571,278 9 1,571,278 9 Z represents a hydrogen or halogen atom or a hydroxy, amino, substituted amino, nitro, or a C 14 alkoxy group: or X and Y or Y and Z are connected together through a substituted or unsubstituted carbon chain or through a heteroatom to form a ring; with the proviso that when A is an ethylene group and X and Z are hydrogen atoms, Y 5 cannot be a hydrogen or bromine atom.
2 Each and every compound as claimed in Claim 1 hereinbefore individually specified.
3 A method of preparing a compound as claimed in Claim 1, substantially as hereinbefore described in any one of the Examples 10 4 A compound as claimed in Claim 1, when prepared by a method substantially as hereinbefore described in any one of the Examples or an obvious chemical equivalent of such a method.
For the Applicants, D YOUNG & CO, Chartered Patent Agents, 9 & 10 Staple Inn, London, WCIV 7RD.
Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa 1980 Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.
GB44877/78A 1976-08-04 1977-08-01 2,3-alkylene bis(oxy)benzoic acids Expired GB1571278A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP9405777A JPS5328181A (en) 1976-08-04 1977-08-04 Production of nove substituted 2*33alkylenebis *oxy* benzoic acid

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR7623835A FR2360305A1 (en) 1976-08-04 1976-08-04 NEW 2,3-ALKYLENE BIS (OXY) BENZAMIDE SUBSTITUTES, THEIR DERIVATIVES AND THEIR PREPARATION METHODS
JP9405777A JPS5328181A (en) 1976-08-04 1977-08-04 Production of nove substituted 2*33alkylenebis *oxy* benzoic acid
GB4487/78A GB1567290A (en) 1977-02-17 1978-02-03 Preparation of vinyl chloride polymers

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