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
- Publication number
- 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
- Authority
- EP
- European Patent Office
- Prior art keywords
- general formula
- acid
- amino
- produce
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- 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).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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
Claims
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 WO PCT/AU1983/000111 patent/WO1984000750A1/en not_active Application Discontinuation
- 1983-08-22 JP JP50274383A patent/JPS59501589A/en active Pending
- 1983-08-22 EP EP83902635A patent/EP0134782A1/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
No further relevant documents have been disclosed. * |
See also references of WO8400750A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPS59501589A (en) | 1984-09-06 |
WO1984000750A1 (en) | 1984-03-01 |
EP0134782A4 (en) | 1985-02-18 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19840918 |
|
AK | Designated contracting states |
Designated state(s): DE FR GB |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 19851114 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: BROWN, ROGER, FREDERICH, CHALLIS Inventor name: BECKER, ANNA, MARIA Inventor name: RICKARDS, RODNEY, WARREN |