EP0134782A1 - Process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereof - Google Patents
Process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereofInfo
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- EP0134782A1 EP0134782A1 EP83902635A EP83902635A EP0134782A1 EP 0134782 A1 EP0134782 A1 EP 0134782A1 EP 83902635 A EP83902635 A EP 83902635A EP 83902635 A EP83902635 A EP 83902635A EP 0134782 A1 EP0134782 A1 EP 0134782A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
Definitions
- This invention relates to a process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereof. These compounds are of use in the production of antibiotics by fermentation.
- 3-Amino-5-hydroxybenzoic acid (1) is a naturally occurring amino acid [J J Kibby and R W Rickards, J. Antibiot., 34, 605 (1981)] which functions as a key intermediate in the formation of certain metabolic products of living systems.
- the amino acid (1) has been proved to be an intermediate in the biological synthesis by microorganisms of several important groups of antibiotics, such as antibiotics of the ansamycin [J J Kibby, I A McDonald, and R W Rickards, J. Chem. Soc, Chem. Commun. 768 (1980); 0 Ghisalba and J Niiesch,
- antibiotics include several clinically important representatives, such as the antitubercular agent rifampicin (which is a synthetic modification of the natural ansamycin antibiotic rifamycin S [K L Rinehart, Jr., and L S Shield, Fortschr. Chem. Org. Naturst., 33, 231 (1976)]) and the antitumor agent mitomycin C [R W Franck, Fortschr. Chem. Org. Naturst., 3_8_, 1 (1979)].
- rifampicin which is a synthetic modification of the natural ansamycin antibiotic rifamycin S [K L Rinehart, Jr., and L S Shield, Fortschr. Chem. Org. Naturst., 33, 231 (1976)]
- antitumor agent mitomycin C [R W Franck, Fortschr. Chem. Org. Naturst., 3_8_, 1 (1979)].
- OMPI amino-5-hydroxybenzoic acid In some fermentations th production of 3-amino-5-hydroxybenzoic acid may b limited, either nutritionally or genetically, to th extent that the full potential of the particula microorganism for antibiotic production may not b realised. In these circumstances, the addition o exogenous 3-amino-5-hydroxybenzoic acid to the nie may increase the resultant antibiotic yield.
- 3-alkylamino-5-hydroxybenzoic acids when added to the appropriate fermentation media, may give rise to the production of the corresponding N-alkylated homologues of the antibiotic normally produced from 3- amino-5-hydroxybenzoic acid itself.
- 3- hydroxy-5-methylaminobenzoic acid added to the fermentation media, may result in the increased production of antibiotics such as the maytansinoids [K L Rinehart, Jr., and L S Shield, Fortschr. Chem. Org. Naturst., 33, 231 (1976)], which themselves carry an N-methyl group derived biogenetically from the amino group of the acid (1).
- R 1 represents the radicals -OR2 or -NR3R4;
- R , R , R , R , R and R represent radicals separately selected from hydrogen and alkyl, or the acid addition salts thereof, comprising: a) the reaction of a 3 , 5-dihydroxybenzoic acid of general formula (3):
- R 2 represents alkyl and R3
- R 4 , R 5 , R ⁇ and R are as hereinbefore defined;
- alkyl is used to denote a straight- or branched-chain hydrocarbon radical of 1 to 10 carbon atoms.
- the pressure and temperature conditions required for the reaction of a 3 , 5-dihydroxybenzoic acid of the general formula (3) with a compound of the general formula (4) vary with the nature and quantity of reactants used. Generally, however, it has been found that a temperature range of about 100 C to about 300 C and a pressure range of about 15 p.s.i. to 500 p.s.i. have been satisfactory. In particular, a temperature of about 180 C and a pressure of about 320 p.s.i. have resulted in good yields of the required products.
- R , R and R are separately selected from the group consisting of hydrogen, methyl and ethyl.
- ammonia is replaced by an amine, mono- or disubstituted with alkyl radicals, such as methylamine, ethylamine, or dimethylamine
- alkyl radicals such as methylamine, ethylamine, or dimethylamine
- the corresponding N- alkylated homologues of 3-amino-5-hydroxybenzoic acid (for example, 3-methylamino-, 3-ethylamino-, or 3- dimethylamino-5-hydroxybenzoic acid) can be prepared.
- the preparation of the ester of general formula (2d) can, if desired, provide a means for obtaining pure acid of general formula (2c).
- the crude reaction mixture containing the amide of general formula (2b) or the acid of general formula (2c) is esterified, by conventional techniques, to produce the ester of general formula (2d) which in some cases may be more readily separated from impurities.
- the ester of general formula (2d) is then hydrolysed with acid or base. Adjustment of the pH of the hydrolysis solution precipitates the free amino acid of general formula (2c), or its acid addition salt.
- methanolic sulphuric acid is used to prepare a methyl ester, although other esters can, of course, be employed.
- R , R , R , R and R are as hereinbefore defined.
- antibiotic analogues may also be achieved by direct supplementation of fermentation media with esters of 3-amino-5-hydroxybenzoic acid (1) or its analogues (for example, 3-N-alkylamino-5-hydroxybenzoic acids).
- esters (2d) which are described above may be used directly without hydrolysis.
- OMPI aqueous hydrochloric acid 100ml
- the solutio heated at reflux temperature for 36 h.
- the acidic solution was extracted with ethyl acetate
- the combined organic phases were washed with cold I aqueous hydrochloric acid, then with brine. Dryin (MgSO.) and evaporation of the organic solvent gav starting material (962 mg, 48%).
- the combined aqueou solutions were adjusted to pH 4-5 with solid sodiu bicarbonate, saturated with sodium chloride an extracted with ethyl acetate. Evaporation of the drie extracts gave 3-hydroxy-5-methylaminobenzoic aci (1.052g, 48%), m.p.
- aqueous sodium hydroxide extracts were the acidified to pH 6 under ice-cooling with concentrate phosphoric acid, saturated with sodium chloride, an extracted with ethyl acetate (x 4) . Drying (Na-SO.) and evaporation of the solvent gave 3-hydroxy-5-methyl- aminobenzoic acid (1.17g, 54%), identical with the material described in Example 5.
- m/z_ 196 (M + + H, 15%), 195 (M + , 75), 5 180 (M + -CH 3 , 100), 164 (M + -OMe, 12), 136(10).
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Abstract
Procédé de préparation de composés de formule générale (2), où R1 représente les radicaux -OR2 ou -NR3R4; et où R2, R3, R4, R5, R6 et R7 représentent des radicaux choisis séparément entre hydrogène et alcoyle, ou leurs sels acides d'addition, comprenant: a) la réaction d'un acide 3,5-dihydroxybenzoïque de formule générale (3) avec un composé de formule générale (4), où R3, R4, R5, R6, et R7 sont définis comme auparavant, pour produire un composé de formule générale (2b), où R3, R4, R5, R6 et R7 sont définis comme auparavant; et, lorsqu'on prépare des composés de formule générale (2) où R1 représente le radical -OR2, comprenant en outre b) l'hydrolyse du composé de formule générale (2b) pour produire un acide carboxylique de formule générale (2c) où R3, R4, R5, R6 et R7 sont définis comme auparavant; et c) l'estérification de l'acide de formule générale (2c) pour produire un ester de formule génerale (2d) où R2 représente un alcoyle et R3, R4, R5, R6 et R7 sont définis comme auparavant; ou, lorsqu'on prépare des composés de formule générale (2) où R1 représente le radical -OR2 et R2 un alcoyle, comprenant d) l'estérification de l'amide de formule générale (2b) en milieu acide pour produire un ester de formule générale (2d).Process for the preparation of compounds of general formula (2), in which R1 represents the radicals -OR2 or -NR3R4; and where R2, R3, R4, R5, R6 and R7 represent radicals chosen separately from hydrogen and alkyl, or their acid addition salts, comprising: a) the reaction of a 3,5-dihydroxybenzoic acid of general formula ( 3) with a compound of general formula (4), where R3, R4, R5, R6, and R7 are defined as before, to produce a compound of general formula (2b), where R3, R4, R5, R6 and R7 are defined as before; and, when preparing compounds of general formula (2) where R1 represents the radical -OR2, further comprising b) hydrolysis of the compound of general formula (2b) to produce a carboxylic acid of general formula (2c) where R3, R4, R5, R6 and R7 are defined as before; and c) esterifying the acid of general formula (2c) to produce an ester of general formula (2d) where R2 represents an alkyl and R3, R4, R5, R6 and R7 are defined as before; or, when compounds of general formula (2) are prepared in which R1 represents the radical -OR2 and R2 an alkyl, comprising d) esterification of the amide of general formula (2b) in an acid medium to produce an ester of general formula (2d).
Description
TITLE :
PROCESS FOR THE PREPARATION OF 3-A INO-5-HYDROXYBENZOIC ACIDS AND DERIVATIVES AND ANALOGUES THEREOF
TECHNICAL FIELD
This invention relates to a process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereof. These compounds are of use in the production of antibiotics by fermentation.
BACKGROUND ART
3-Amino-5-hydroxybenzoic acid (1) is a naturally occurring amino acid [J J Kibby and R W Rickards, J. Antibiot., 34, 605 (1981)] which functions as a key intermediate in the formation of certain metabolic products of living systems.
CO.-H
(1) In particular, the amino acid (1) has been proved to be an intermediate in the biological synthesis by microorganisms of several important groups of antibiotics, such as antibiotics of the ansamycin [J J Kibby, I A McDonald, and R W Rickards, J. Chem. Soc, Chem. Commun. 768 (1980); 0 Ghisalba and J Niiesch,
J. Antibiot 34, 64 (1981 K L Rinehart, Jr
M Potgieter, W-Z Jin, C J Pearce, D A Wright, J L C Wright, J A Walter and A G Mclnnes, in Trends in
Antibiotic Research. Genetics, Biosyntheses, Actions and
__
New Substances. Ed., H Umezawa, A L Demain, T Hata and C R Hutchinson, pp. 171-184, Japan Antibiotics Research Association, Tokyo, 1982], maytansinoid [K Hatano, S Akiyama, M Asai and R W Rickards, J. Antibiot. , 35, 1415 (1982)] and mitomycin groups [M G Anderson, J J Kibby, R W Rickards and J M Rothschild, J. Chem. Soc, Chem. Commun., 1277 (1980)]. It may also be involved in the biosynthesis of other types of antibiotic [J J Kibby, I A McDonald and R W Rickards, J. Chem. Soc, Chem. Commun., 768 (1980)], for example, the asukamycin-manumycin type [K Kakinuma, N Ikekawa, A Nakagawa and S Omura, J. Am. Chem. Soc. , 101, 3402 (1979); K Schroder and A Zeeck, Tetrahedron Lett., 4995 (1973); L Slechta, J I Cialdella, S A Mizsak and H Hoeksema, J. Antibiot., 35, 556 (1982)].
These groups of antibiotics include several clinically important representatives, such as the antitubercular agent rifampicin (which is a synthetic modification of the natural ansamycin antibiotic rifamycin S [K L Rinehart, Jr., and L S Shield, Fortschr. Chem. Org. Naturst., 33, 231 (1976)]) and the antitumor agent mitomycin C [R W Franck, Fortschr. Chem. Org. Naturst., 3_8_, 1 (1979)].
The molecular complexity of antibiotics of all these types is such that their synthesis by laboratory chemical processes can only provide small amounts of material. The significant quantities required for clinical use and continued laboratory studies can, at present, only be produced by fermentation of the appropriate microorganism. Such fermentations are carried out under controlled conditions using a variety of nutrient media which permit growth and antibiotic production. A disadvantage of these fermentation procedures is that environmental conditions which would favour the production of the antibiotic do not necessarily favour the production of its precursor 3-
OMPI
amino-5-hydroxybenzoic acid. In some fermentations th production of 3-amino-5-hydroxybenzoic acid may b limited, either nutritionally or genetically, to th extent that the full potential of the particula microorganism for antibiotic production may not b realised. In these circumstances, the addition o exogenous 3-amino-5-hydroxybenzoic acid to the mediu may increase the resultant antibiotic yield. Fo example, supplementation of laboratory fermentatio media with the amino acid (1) has been shown by two o the present inventors to increase two to four fold th production of the mitomycin antibiotic porfiromycin an of the ansamycin antibiotics actamycin [A M Becker A J Herlt, G L Hilton, J J Kibby and R W Rickards J Antibiot. , submitted for publication] and mycotrienin Also, the production of the ansamycin antibioti rifa ycin B by a genetically impaired mutant wa restored to the level of the parent strain by th addition of 3-amino-5-hydroxybenzoic acid to th fermentation [0 Ghisalba and J Nϋesch, J. Antibiot., 3_4, 64 (1981)].
Further, 3-alkylamino-5-hydroxybenzoic acids, when added to the appropriate fermentation media, may give rise to the production of the corresponding N-alkylated homologues of the antibiotic normally produced from 3- amino-5-hydroxybenzoic acid itself. For example, 3- hydroxy-5-methylaminobenzoic acid, added to the fermentation media, may result in the increased production of antibiotics such as the maytansinoids [K L Rinehart, Jr., and L S Shield, Fortschr. Chem. Org. Naturst., 33, 231 (1976)], which themselves carry an N-methyl group derived biogenetically from the amino group of the acid (1).
Such stimulation of production when applied to a commercial rather than laboratory scale would necessitate access to large quantities of 3-amino-5-
OMPΓ -
hydroxybenzoic acid and its N-alkyl analogues. Although 3-amino-5-hydroxybenzoic acid is a natural microbial product, this amino acid has been detected only in trace quantities in one microorganism [J J Kibby and R W Rickards, J. Antibiot., 34, 605 (1981)]. There are two syntheses of 3-amino-5-hydroxybenzoic acid published in the chemical literature [H Bickel, P Mertens, V Prelog, J Seibl and A Walser, Tetrahedron, Suppl. 8, 171 (1966), subsequently modified by 0 Ghisalba and J Nϋesch, J. Antibiot., 34, 64 (1981); and A J Herlt, J J Kibby and R W Rickards, Aust. J. Chem. , 34, 1319 (1981)], both starting from the relatively expensive 3, 5-dinitrobenzoic acid. The former synthesis requires a lengthy sequence of reaction steps while the latter, although short, employs potentially toxic chemicals, the use of which would be undesirable on a large scale.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a convenient and direct process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereof which utilises cheap, non-toxic, readily available reagents, proceeds in high yield without complex purification stages, and is capable of providing commercial quantities of product.
This objective is achieved by the reaction of a
3 ,5-dihydroxybenzoic acid with ammonia, or an amine, which is then followed either by hydrolysis and, when required, esterification, or is followed by direct esterification.
According to the present invention, there is provided a process for the preparation of compounds of the general formula (2):
( 2 )
wherein R 1 represents the radicals -OR2 or -NR3R4; and
R , R , R , R , R and R represent radicals separately selected from hydrogen and alkyl, or the acid addition salts thereof, comprising: a) the reaction of a 3 , 5-dihydroxybenzoic acid of general formula (3):
R-
(3) with a compound of the general formula (4
wherein R , R , R , R and R are as hereinbefore defined, to produce a compound of general formula (2b):
( 2b :
wherein R" R4, R5, R and R are as hereinbefore defined; and, when preparing compounds of general formula (2) wherein R represents the radical -OR further comprising:
b) hydrolysis of the compound of general formula (2b) to produce a carboxylic acid of general formula (2c):
(2c)
wherein R , R4, R5, R and R are as hereinbefore defined; and c) esterification of the acid of general formula (2c) to produce an ester of general formula (2d):
wherein R 2 represents alkyl and R3
R4, R5, R^ and R are as hereinbefore defined;
or, when preparing compounds of general formula { 2 wwhheerreeiinn RR 1 rreepprreesssents the radical -OR 2 and R 2 represents alkyl, comprising:
d) esterification of the amide of general formula (2b) in an acidic medium to produce an ester of general formula (2d) .
As used throughout the specification, the term "alkyl" is used to denote a straight- or branched-chain hydrocarbon radical of 1 to 10 carbon atoms.
The pressure and temperature conditions required for the reaction of a 3 , 5-dihydroxybenzoic acid of the general formula (3) with a compound of the general formula (4) vary with the nature and quantity of reactants used. Generally, however, it has been found that a temperature range of about 100 C to about 300 C and a pressure range of about 15 p.s.i. to 500 p.s.i. have been satisfactory. In particular, a temperature of about 180 C and a pressure of about 320 p.s.i. have resulted in good yields of the required products.
Compounds of general formulae (3) and (4) are either known, or can be prepared from known compounds by standard reactions well known in the art. For example, 3, 5-dihydroxybenzoic acid is commercially available, as is ammonia and a large number of mono- and dialkylamines.
Preferably, the radicals represented by R 2, R3, R4,
" f> 7
R , R and R are separately selected from the group consisting of hydrogen, methyl and ethyl.
More preferably, the radicals represented by R 2, R3,
R , R , R and R are all hydrogen. Thus the reaction of 3, 5-dihydroxybenzoic acid with ammonia, produces the amide (2e) :
( 2e )
Hydrolysis of the amide (2e) produces 3-amino-5- hydroxybenzoic acid (1).
If ammonia is replaced by an amine, mono- or disubstituted with alkyl radicals, such as methylamine, ethylamine, or dimethylamine, the corresponding N- alkylated homologues of 3-amino-5-hydroxybenzoic acid (for example, 3-methylamino-, 3-ethylamino-, or 3- dimethylamino-5-hydroxybenzoic acid) can be prepared.
The preparation of the ester of general formula (2d) can, if desired, provide a means for obtaining pure acid of general formula (2c). The crude reaction mixture containing the amide of general formula (2b) or the acid of general formula (2c) is esterified, by conventional techniques, to produce the ester of general formula (2d) which in some cases may be more readily separated from impurities. The ester of general formula (2d) is then hydrolysed with acid or base. Adjustment of the pH of the hydrolysis solution precipitates the free amino acid of general formula (2c), or its acid addition salt.
Preferably, methanolic sulphuric acid is used to prepare a methyl ester, although other esters can, of course, be employed.
It will be appreciated that, after the reaction of a 3,5-dihydroxybenzoic acid of general formula (3) with a compound of general formula (4), the amide of general
OMPI VΛ --. WIPO
& ?N'AT\0
formula ( 2b ) is not the sole product . Another product is the ammonium salt of a 3-amino-5-hydroxybenzoic acid as represented by the general formula ( 2f ) :
« 3 4®
CO -, NH2R R
wherein R , R , R , R and R are as hereinbefore defined.
It is not necessary to separate the salt of general formula (2f) from the amide of general formula (2b) as treatment of the crude product mixture with acid produces a single carboxylic acid of general formula (2c). Alternatively, esterification of the crude product mixture in an acidic medium produces a single ester of the general formula (2d).
Since many microorganisms used in antibiotic production have efficient esterase enzymes, increased antibiotic production, or the formation of antibiotic analogues as described above, may also be achieved by direct supplementation of fermentation media with esters of 3-amino-5-hydroxybenzoic acid (1) or its analogues (for example, 3-N-alkylamino-5-hydroxybenzoic acids). In this case the esters (2d) which are described above may be used directly without hydrolysis.
DETAILED DESCRIPTION OF EMBODIMENTS
Specific details of the compounds of the present invention and the reactions involved in the processes of this invention are illustrated by the following examples. In these examples, all temperatures are in
degrees Centigrade, and technical terms (e.g. chromatography, etc.,) have the usual meaning in the art. Crude reaction products can be purified by the means described herein, or by other means known in the art.
EXAMPLE 1
3-amino-5-hydroxybenzoic acid hydrochloride: METHOD 1
A mixture of 3, 5-dihydroxybenzoic acid (2g, 13mmol) , ammonium chloride (1.7g, 32mmol) and aqueous ammonia (28%, 6ml) was heated in a steel bomb at 180° for 40 h. After cooling the reaction solution was evaporated to dryness and the residue taken up in 6N aqueous hydrochloric acid (100ml). The solution was kept at reflux for 16 h, filtered and concentrated (ca. 25ml). On cooling 3-amino-5-hydroxybenzoic acid hydrochloride (1.72 g, 70%), pure by H n.m.r., was collected as greyish crystals. Treatment with charcoal and recrystallization from 6N aqueous hydrochloric acid gave the hydrochloride of (1) as white crystals, m.p. 200- 230 (dec), identical by spectroscopic and mixed m.p. comparison with an authentic sample [A J Herlt, J-J Kibby and R W Rickards, Aust. J. Chem, 34_, 1319 (1981)]. Extraction with ethyl acetate of the mother liquor of the original crystallization led to the recovery of starting material (288 mg, 14%).
EXAMPLE 2
3-amino-5-hydroxybenzoic acid hydrochloride: METHOD 2
Methyl 3-amino-5-hydroxybenzoate (200mg, 1.2mmol) prepared as in Example 4 in 6N aqueous hydrochloric acid
(5ml) was heated at reflux for 2 h. The solution on cooling deposited crystalline, analytically pure
3-amino-5-hydroxybenzoic acid hydrochloride (215mg, 95%), identical with an authentic sample [A J Herlt, J J Kibby and R W Rickards, Aust. J. Chem. , 34, 131 (1981)].
EXAMPLE 3
3-amino-5-hydroxybenzoic acid
To 3-amino-5-hydroxybenzoic acid hydrochloride (47mg, 0.25mmol) prepared as in Example 1 or 2 in water (0.8ml) was added 2N aqueous sodium hydroxide until the pH of the solution reached 4. The cooled solution yielded crystalline 3-amino-5-hydroxybenzoic acid (37mg, 96%), identical with an authentic sample [A J Herlt, J J Kibby, and R W Rickards, Aust. J. Chem. , 34, 1319 (1981)].
EXAMPLE 4
methyl 3-amino-5-hydroxybenzoate
3 , 5-Dihydroxybenzoic acid was reacted with ammonium chloride and aqueous ammonia as described under Example 1. The reaction mixture was evaporated to dryness and the residue taken up in methanol (100 ml). Concentrated sulphuric acid (3ml) was added dropwise and the solution kept at reflux temperature for 36 h. After cooling the solution was evaporated, the residue taken up in ice- cold water, and the aqueous solution extracted with ether (x 3). The combined extracts were washed with ice-cold IN aqueous sulphuric acid (x 2), then with brine. Drying (MgSO.) and evaporation of the ether gave the methyl ester of starting material (220mg, 10%) containing a small amount of methyl 3-( 3 ' -carbomethoxy-
5'-hydroxyphenylamino)-5-hydroxybenzoate (70mg, 2%),
H n.m.r. (dg-acetone) 68.5, 7.6, OH, NH; 7.27, 7.03,
6.88, 3 ArH; 3.81, COOCH 1,-3 .• m Ul//z <---. 317.0891 (M+, calc. for
C , ,H, cNO , : 317 , 16 15 6 0893 )
- tJRlT
OMPI
^ IPO ■
The aqueous solution and aqueous sulphuric acid washings were combined, adjusted to pH 7 with solid sodium bicarbonate and extracted with ethyl acetate (x 4). The extracts were washed with brine, dried 5 (MgSO.) and evaporated. Flash chromatography on silica with ethyl acetate-dichloromethane (2:3) as eluant or recrystallization from methyl acetate-chloroform to remove methyl 3,5-diaminobenzoate gave methyl 3-amino- 5-hydroxybenzoate (1.63g, 75%), m.p. 125-127 (Found: C,
10 57.5; H, 5.42; N, 8.18. CgHgNO.- requires C, 57.5; H, 5.43; N, 8.38%). ~E n.m.r. (dg-acetone) δ8.16, bs, OH; 6.88, m, C(2)-H; 6.80, m, C(6)-H; 6.42, m, C(4)-H; 4.73, bs, NH-; 3.80, s, COOCH-, . C n.m.r. (dg-acetone) ppm 167.71, s, COOCH3; 158.99, s, C(5); 150.66, s, C { 3 ) ;
15 132.68, s, C(l); 108.12, d, J = 161 Hz, and 105.82, d, J = 164 Hz, C(2) and C(6); 106.43, d, J = 156 Hz, C(4); 52.05, q, J = 147 Hz, COOCH-.. m/z 167 (M+, 100%), 136 (M+-OMe, 55), 109 (35), 108 (35). From flash chromatography there was also isolated methyl 3,5-
20 diaminobenzoate (162mg, 7%), m.p. 123-126 after sublimation. H n.m.r. (d,-acetone) 56.62, d, J = 2.5 Hz, C(2)-H and C(6)-H; 6.19, t, J = 2.5 Hz, C(4)-H; 4.42, bs, NH2 ; 3.75, s, COOCH-.. m/z 167 (M+ + H, 48%), 166 (M+, 100), 136(12), 135 (M+ -OMe, 27),
25 109(26), 108(67), 107(43).
EXAMPLE 5
3-hydroxy-5-methylaminobenzoic acid: METHOD 1
30
3,5-Dihydroxybenzoic acid (2g, 13mmol) was added under vigorous stirring to a solution of sodium carbonate (1.033g, 9.75mmol) in water (5ml). Stirring was continued until no further carbon dioxide evolved
35 (4 h). After addition of 40% aqueous methylamine (5ml) under ice-cooling, the mixture was heated in a steel bomb at 180 for 16 h. The cooled reaction solution was evaporated to dryness, the residue taken up in 6N
OMPI
aqueous hydrochloric acid (100ml), and the solutio heated at reflux temperature for 36 h. After cooling, the acidic solution was extracted with ethyl acetate The combined organic phases were washed with cold I aqueous hydrochloric acid, then with brine. Dryin (MgSO.) and evaporation of the organic solvent gav starting material (962 mg, 48%). The combined aqueou solutions were adjusted to pH 4-5 with solid sodiu bicarbonate, saturated with sodium chloride an extracted with ethyl acetate. Evaporation of the drie extracts gave 3-hydroxy-5-methylaminobenzoic aci (1.052g, 48%), m.p. 205-208° (dec.) after recrystallization from ethyl acetate-hexane (Found: C, 57.6; H, 5.48; N, 8.13. CQHQNO-. requires C, 57.5; H, 5.43; N, 8.38%). 1H n.m.r. (d4~methanol) 66.82, m, C(2)-H and C(6)-H; 6.29, t, J = 2 Hz, C(4)-H; 2.75, s, NHCH3. m/z 167 (M+,100%), 166(85), 122 (M+- C00H, 12).
EXAMPLE 6
3-hydroxy-5-methylaminobenzoic acid: METHOD 2
Reaction of 3, 5-dihydroxybenzoic acid and sodium carbonate in aqueous methylamine, and subsequent hydrolysis with hydrochloric acid was carried out as described under Example 5. After removal of the aqueous solvent under vacuum, the residue was taken up in methanol (100ml). Concentrated sulphuric acid (3ml) was added dropwise and the solution kept at reflux for 16 h. The residue remaining on evaporation of the solvent was worked-up as described for Example 1, yielding methyl 3 , 5-dihydroxybenzoate (633mg, 29%) from the acidic fraction, and from the neutral fraction after flash chromatography methyl 3-hydroxy-5-methylaminobenzoate (1.32g, 56%), m.p. 51-53° from chloroform (Found: C, 59.5; H, 6.27; N, 7.49. CgH-^NO.. requires C, 59.7; H, 6.12; N, 7.73%). 1H n.m.r. (d6~acetone) 58.18, bs, OH;
OMPI ^y
6.78, d, J = 2 Hz, C(2)-H and C(6)-H; 6.31, t, J = 2 Hz, C(4)-H; 5.06, bs, NH; 3.80, s, COOCH3; 2.78, d, J = 5 Hz, NHCH3. m/z_ 181 (M+, 100%), 180(19), 150 (M+- OMe, 28), 123(41), 122(43).
Methyl 3-hydroxy-5-methylaminobenzoate (500mg, 2.76mmol) in 6N aqueous hydrochloric acid (4ml) was heated at reflux for 14 h. After cooling the crystals were filtered and dried to give 3-hydroxy-5- methylaminobenzoic acid hydrochloride (512mg, 91%), m.p. 190-193° (dec). XH n.m.r. (d4~methanol) 57.58, m, C(2)-H and C(6)-H; 7.19, m, C(4)-H; 3.07, s, NH-CH... m/z 167 (M+, 100%), 166(93), 122 (M+-COOH, 12).
To 3-hydroxy-5-methylaminobenzoic acid hydrochloride (500mg, 2.46mmol) in water (7ml) was added 2N aqueous sodium hydroxide until the pH of the solution reached 4. Saturation with sodium chloride and extraction with ethyl acetate gave 3-hydroxy-5-methylaminobenzoic acid (363mg, 88%) identical with the material described in Example 5.
EXAMPLE 7
3-hydroxy-5-methylaminobenzoic acid: METHOD 3
Reaction of 3, 5-dihydroxybenzoic acid and sodium carbonate with aqueous methylamine, subsequent hydrolysis with hydrochloric acid, esterification with methanol and sulphuric acid and the first stages of work-up were carried out as described under Example 6. The ether extracts from the neutralized aqueous solution, however, were not evaporated but extracted with cold 2N aqueous sodium hydroxide (x 2), washed with brine, dried (Na_SO. ) and evaporated to give crystalline methyl 3,5-di(methylamino)benzoate (254mg, 10%), m.p. 79-82° after sublimation (Found: C, 61.7; H, 7.32; N, 14.2. cιoH 14 N2°2 requires C, 61.8; H, 7.27; N, 14.4%).
"^H n.m.r. (d,-acetone) 56.58, d, J = 2 Hz, C(2) -H an
D
C(6)-H; 6.05, t, J = 2 Hz, C(4)-H; 4.82, bs, NH; 3.77, s, COOCH3; 2.75, d, J = 5 Hz, NHCH3. m z 194 (M+, 100%), 193(10), 163 (M+-OMe, 8), 136(33), 135(25) .
The aqueous sodium hydroxide extracts were the acidified to pH 6 under ice-cooling with concentrate phosphoric acid, saturated with sodium chloride, an extracted with ethyl acetate (x 4) . Drying (Na-SO.) and evaporation of the solvent gave 3-hydroxy-5-methyl- aminobenzoic acid (1.17g, 54%), identical with the material described in Example 5.
EXAMPLE 8
methyl 3-ethylamino-5-hydroxybenzoate
3 , 5-Dihydroxybenzoic acid (2.0g, 13mmol) and sodium carbonate (1.033g, 9.75mmol) in water (6ml) were reacted with ethylamine (5.1ml, 78mmol) following a similar procedure to that described in Example 5. Hydrolysis with hydrochloric acid, esterification with methanol and sulphuric acid followed by work-up gave methyl 3,5- dihydroxybenzoate (1.05g, 48%) which could be recycled after hydrolysis, and, after flash chromatography with ethyl acetate-dichloromethane (1:6), methyl 3,5- di (ethylamino)benzoate (57mg, 2%), m.p. 79-80° from chloroform-hexane (Found: C, 64.7; H, 8.30; N, 12.5.
C12H18N2°2 recϊuires c' 64.8; H, 8.16; N, 12.6%). H n.m.r. (dg-acetone) 56.59, d, J = 2.5 Hz, C( 2 ) -H and C(6)-H; 6.11, t, J = 2.5 Hz, C(4)-H; 4.70, bs, NH; 3.79, s, COOCH3; 3.15, bq, J = 7 Hz, NHCH_2CH3 ; 1.22, t, J = 7 Hz, CH2CH3. m/z 222 (M+, 67%), 207 (M+-CH3, 100), 191 (M -OMe, 10), 164(6), 163(6). The main product from flash chromatography was methyl 3-ethylamino-5-hydroxy- benzoate (940mg, 37%), m.p. 107-108° from chloroform (Found: C, 61.2; H, 6.82; N, 7.00. cιoHτ.3N03 requires C, 61.5; H, 6.71; N, 7.18%). 1H n.m.r. (dg-acetone)
OMPI ? WIPO
68.14, s, OH; 6.80, m, C(2)-H and C(6)-H; 6.34, t, J = 2.5 Hz, C(4)-H; 4.95, bs, NH; 3.81, s, COOCH3 ; 3.15, d x q, J = 5 Hz and J = 7 Hz, NHCH2CH3 ; 1.24, t, J = 7Hz, CH2CH3. m/z_ 196 (M+ + H, 15%), 195 (M+, 75), 5 180 (M+-CH3, 100), 164 (M+-OMe, 12), 136(10).
EXAMPLE 9
methyl 3-dimethylamino-5-hydroxybenzoate 0
A mixture of 3, 5-dihydroxybenzoic acid (2.0 g, 13 mmol), dimethylammonium chloride (2.65 g, 32.5 mmol) and aqueous dimethylamine (20%, 6 ml) was heated in a steel bomb at 180° for 40 h. After cooling the reaction 5 solution was evaporated to dryness and the residue taken up in methanol (100 ml). Concentrated sulphuric acid (3 ml) was added dropwise and the solution kept at reflux for 24 h. After cooling the solution was evaporated, the residue taken up in ice-cold water, and 0 the aqueous solution extracted with ether (x 3). The combined extracts were washed with ice-cold IN aqueous sulphuric acid (x 2), then with brine. Drying (MgSO.) and evaporation of the ether gave the methyl ester of starting material (1.3 g, 60%). 5
The aqueous solution and aqueous sulphuric acid washings were combined, adjusted to pH 7 with solid sodium bicarbonate and extracted with ether (x 3). The extracts were washed with brine, dried (MgSO.) and 0 evaporated. Flash chromatography on silica with ethyl acetate-dichloromethane (1:9) as eluant gave methyl 3-dimethylamino-5-hydroxybenzoate (510 mg, 20%), m.p. 126-129° after sublimation (Found: C, 61.8; H, 6.67; N, 6.84. C10H13NO3 requires C, 61.5; H, 6.71; N, 7.18%). 5 H n.m.r. (d,-acetone) 58.26, s, OH; 6.90, m, and 6.83, m, C(2)-H and C(6)-H; 6.42, t, C(4)-H; 3.80, s, COOCH3; 2.91, s, N(CH3)2. m/z 195 (M+, 100%), 194 (M+-H, 69), 164 (M+-OMe, 12), 137 (M+-C2H202, 7).136 (M+-C02Me, 15).
It will, of course, be appreciated that the abov examples are given by way of exemplification of th invention only, and that changes may be made to th details set out therein without departing from the scop of the invention.
Claims
\ S
1. A process for the preparation of compounds of the general formula (2):
COR"
wherein R 1 represents the radicals -OR2 or
-NR3R4; and R2, R3, R , R5, R6 and R7 represent radicals separately selected from hydrogen and alkyl, or the acid addition salts thereof, comprising:
a) the reaction of a 3, 5-dihydroxybenzoic acid of general formula (3):
with a compound of the general formula (4):
wherein R 3, R4, R5, R and R are as hereinbefore defined, to produce a compound of general formula (2b):
OMPI
3 4 CONR R
( 2b )
wherein R 3 , R 4 , R" c R6 and R7 are as hereinbefore defined ;
and, when preparing compounds of general formula
(2) wherein R 1 represents the radical -OR2, further comprising:
b) hydrolysis of the compound of general formula (2b) to produce a carboxylic acid of general formula (2c) :
wherein R , R , R , R and are as hereinbefore defined; and
c) esterification of the acid of general formula (2c) to produce an ester of general formula (2d):
(2d)
wherein R 2 represents alkyl and R3 , R4, R"
R6 and R7 are as hereinbefore defined;
or, when preparing compounds of general formula (2)
1 2 2 wherein R represents the radical -OR and R represents alkyl, comprising:
d) esterification of the amide of general formula (2b) in an acidic medium to produce an ester of general formula (2d).
2. A process as defined in claim 1 wherein the reaction of a 3, 5-hydroxybenzoic acid of general formula (3) with a compound of general formula (4) is carried out under pressure.
3. A process as defined in claim 2 wherein the pressure ranges from about 15 p.s.i. to 500 p.s.i.
4. A process as defined in claim 3 wherein the pressure is about 320 p.s.i.
5. A process as defined in any one of claims 1 to 4 wherein R,2", R„3" , „R4
R5, R and R are separately selected from the group consisting of hydrogen, methyl and ethyl.
A process as defined in claim 5 wherein R 2, R3, R4,
5 6 7 R , R and R all represent hydrogen.
OMPI IPO
7. Compounds of the general formula (2) as defined i claim 1, whenever prepared by a process as define in any one of claims 1 to 6.
8. A process as defined in claim 1 as hereinbefor described with reference to the Examples.
9. Compounds of the general formula (2) as defined i claim 1, whenever prepared by a process as define in claim 1, as hereinbefore described wit reference to the Examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU5512/82 | 1982-08-23 | ||
| AUPF551282 | 1982-08-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP0134782A4 EP0134782A4 (en) | 1985-02-18 |
| EP0134782A1 true EP0134782A1 (en) | 1985-03-27 |
Family
ID=3769709
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP83902635A Withdrawn EP0134782A1 (en) | 1982-08-23 | 1983-08-22 | Process for the preparation of 3-amino-5-hydroxybenzoic acids and derivatives and analogues thereof |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0134782A1 (en) |
| JP (1) | JPS59501589A (en) |
| WO (1) | WO1984000750A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5582980A (en) * | 1989-07-17 | 1996-12-10 | Tropix, Inc. | Chemiluminescent 1,2-dioxetanes |
| US8314250B2 (en) | 2009-11-24 | 2012-11-20 | Hoffmann-La Roche Inc. | Sultam derivatives |
-
1983
- 1983-08-22 EP EP83902635A patent/EP0134782A1/en not_active Withdrawn
- 1983-08-22 WO PCT/AU1983/000111 patent/WO1984000750A1/en not_active Application Discontinuation
- 1983-08-22 JP JP50274383A patent/JPS59501589A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| No further relevant documents have been disclosed. * |
| See also references of WO8400750A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0134782A4 (en) | 1985-02-18 |
| JPS59501589A (en) | 1984-09-06 |
| WO1984000750A1 (en) | 1984-03-01 |
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