CH313473A - Process for the preparation of a new derivative of streptomycin - Google Patents
Process for the preparation of a new derivative of streptomycinInfo
- Publication number
- CH313473A CH313473A CH313473DA CH313473A CH 313473 A CH313473 A CH 313473A CH 313473D A CH313473D A CH 313473DA CH 313473 A CH313473 A CH 313473A
- Authority
- CH
- Switzerland
- Prior art keywords
- streptomycin
- salt
- reaction
- water
- carried out
- Prior art date
Links
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical class CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 title claims description 25
- 238000000034 method Methods 0.000 title claims description 9
- 229960005322 streptomycin Drugs 0.000 claims description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 8
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 5
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 4
- 239000012736 aqueous medium Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 2
- 238000007865 diluting Methods 0.000 claims 1
- 239000012429 reaction media Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 5
- 229910021653 sulphate ion Inorganic materials 0.000 description 5
- BLEQFIQOCMNEBW-UITAMQMPSA-N (z)-pyridin-4-ylmethylidenehydrazine Chemical compound N\N=C/C1=CC=NC=C1 BLEQFIQOCMNEBW-UITAMQMPSA-N 0.000 description 4
- WEEMDRWIKYCTQM-UHFFFAOYSA-N 2,6-dimethoxybenzenecarbothioamide Chemical compound COC1=CC=CC(OC)=C1C(N)=S WEEMDRWIKYCTQM-UHFFFAOYSA-N 0.000 description 3
- 150000007857 hydrazones Chemical class 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 229960002385 streptomycin sulfate Drugs 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 2
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 230000000845 anti-microbial effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 238000005266 casting Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- -1 hydrazone sulfate Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 201000008827 tuberculosis Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Procédé de préparation d'un nouveau dérivé de la streptomycine La présente invention a pour objet un procédé de préparation d'un nouveau dérivé de la streptomycine : un sel de l'isonicotinylhydrazone de la streptomycine, laquelle hydrazone a pour formule probable
EMI0001.0004
Ce nouveau dérivé possède des propriétés antimicrobiennes, en particulier contre le ba- cile tuberculeux, qui le rendent utilisable en thérapeutique humaine et vétérinaire.
Selon le procédé de l'invention, on obtient un sel de cette hydrazone en- faisant réagir l'isonicoty- nylhydrazide sur un sel de streptomycine.
La réaction est effectuée de préférence en milieu aqueux. Elle peut être conduite à tem pérature inférieure à 500, de préférence entre 0 et 100. On peut cependant sans inconvé nient opérer à des températures supérieures à 50o, par exemple en chauffant à reflux la solu tion aqueuse des réactifs ; de cette façon on réduit notablement le temps de réaction sans nuire ni à la pureté du produit obtenu ni au rendement.
Il est avantageux d'employer un excès d'isonicotinylhydrazide (1 à 5 fois la théorie). On peut ensuite précipiter le produit par addi tion d'un liquide dans lequel il est insoluble, tel que, par exemple, le méthanol.
On peut aùssi traiter le mélange réaction nel pour le concentrer avant précipitation par le liquide convenable ou éventuellement le déshydrater par azéotropie, par exemple avec du benzène, après concentration éventuelle.
Au lieu d'effectuer la réaction en milieu aqueux, on peut la conduire: en milieu orga nique, dans un solvant du sel (notamment le sulfate) de streptomycine, par exemple dans un glycol, et particulièrement dans le glycol éthylénique, à une température comprise en tre 0o et environ 100o.
Les exemples suivants montrent comment le procédé de l'invention peut être mis en aeuvre. <I>Exemple 1</I> Dans une solution refroidie par de l'eau glacée, de 34,25 g d'isonicotinylhydrazide dans 425 cm3 d'eau, on ajoute en agitant une solution de 36,45 g: de sulfate de streptomy cine dans 175 em3 d'eau. On continue l'agita tion pendant une demi-heure, puis laisse repo ser à -I- 50 pendant 48 heures. On coule, en agitant, la solution ainsi obtenue dans 3400 cm3 de méthanol refroidi à + 5() par de l'eau glacée.
La coulée dure environ une heure ; on continue à agiter pendant encore une demi-heure, puis essore et sèche sous vide en présence d'acide sulfurique. On obtient ainsi 41 g de sulfate d'isonicotinylhydrazone de la streptomycine qui a un pouvoir rotatoire
EMI0002.0020
<U>24</U> <SEP> D <SEP> = <SEP> - <SEP> 70 <SEP> (c <SEP> = <SEP> 2 <SEP> % <SEP> dans <SEP> l'eau).
<tb> [ ]. <I>Exemple 2</I> On chauffe à 600 pendant 3 heures la so lution obtenue en mélangeant une solution de 13,7 g d'isonicotinylhydrazide dans 150 cm3 d'eau avec une solution de 14,6 g de sulfate de streptomycine dans 50 cms d'eau.
On coule, en agitant, le mélange réactionnel ainsi obtenu dans 3 litres de méthanol refroidi à -;- 50. On laisse reposer pendant une nuit, fil tre, lave avec 1 litre de méthanol et sèche sous vide en présence d'acide sulfurique. On ob tient ainsi 15,5 g de sulfate d'isonicotinyl- hydrazone de la streptomycine identique à celui préparé selon l'exemple 1. <I>Exemple 3</I> On opère comme dans l'exemple 2, mais en chauffant à reflux (1000) au bain d'huile pendant 2 heures.
En traitant le mélange réactionnel comme indiqué dans l'exemple 2, on obtient 15,4 g de sulfate d'isonicotinyl- hydrazone de la streptomycine. <I>Exemple 4</I> A une solution de 300 g de sulfate de streptomycine dans 500 cm3 d'eau, on ajoute une solution tiède de 141 g d'isonicotinyl- hydrazide -dans 500 cm3 d'eau. On chauffe à reflux pendant 3 heures, puis concentre sous vide jusqu'à un volume de 750 cm3. On verse la solution ainsi obtenue dans 10 litres de méthanol refroidi à -I- 50.
On laisse reposer pendant 2 heures et filtre le précipité qui s'est formé, on lave avec 5 litres de méthanol et sèche sous vide en présence d'acide sulfuri que. On obtient ainsi 336 g de sulfate d'isoni- cotinylhydrazone de la streptomycine. <I>Exemple 5</I> On chauffe à reflux pendant 2 heures une solution de 36,5 g de sulfate de streptomycine et de 6,85 g d'isonicotinylhydrazide dans 100 cm3 d'eau. On chasse ensuite l'eau sous vide à 600 jusqu'à obtention d'une meringue.
On reprend ensuite par 75 cm3 de benzène et on achève la déshydratation par distillation azéotropique, puis chasse l'excès de benzène au bain-marie sous vide. On obtient ainsi 41,3 g de sulfate d'isonicotinylhydrazone de la streptomycine.
<I>Exemple 6</I> On chauffe au bain d'huile à 1000 pen dant 3 heures un mélange de 36,45 g de sul fate de streptomycine et de 13,5 g d'isonico- tinylhydrazide dans 100 cm3 de glycol éthylé- nique. Après refroidissement vers 50,on ajoute en une heure, en agitant, 500 cm3 de métha nol, On continue à agiter pendant environ une demi-heure, filtre,
lave avec 150 cm3 de méthanol et sèche sous vide en présence d'acide sulfurique. On obtient ainsi 38 g de sulfate d'isonicotiny1hydrazone de la strepto mycine.
Process for preparing a new derivative of streptomycin The present invention relates to a process for preparing a new derivative of streptomycin: a salt of isicotinyl hydrazone of streptomycin, which hydrazone has the probable formula
EMI0001.0004
This new derivative has antimicrobial properties, in particular against tuberculosis bacillus, which make it usable in human and veterinary therapy.
According to the process of the invention, a salt of this hydrazone is obtained by reacting isonicotynyl hydrazide with a salt of streptomycin.
The reaction is preferably carried out in an aqueous medium. It can be carried out at a temperature below 500, preferably between 0 and 100. However, it is possible without disadvantage to operate at temperatures above 50 °, for example by heating the aqueous solution of the reagents to reflux; in this way the reaction time is significantly reduced without harming either the purity of the product obtained or the yield.
It is advantageous to use an excess of isonicotinyl hydrazide (1 to 5 times the theory). The product can then be precipitated by adding a liquid in which it is insoluble, such as, for example, methanol.
The reaction mixture can also be treated in order to concentrate it before precipitation with the suitable liquid or optionally to dehydrate it by azeotropy, for example with benzene, after optional concentration.
Instead of carrying out the reaction in an aqueous medium, it can be carried out: in an organic medium, in a solvent for the salt (in particular the sulphate) of streptomycin, for example in a glycol, and particularly in ethylenic glycol, at a temperature between 0o and approximately 100o.
The following examples show how the process of the invention can be carried out. <I> Example 1 </I> In a solution cooled with ice-water, 34.25 g of isonicotinyl hydrazide in 425 cm3 of water is added with stirring a solution of 36.45 g of: streptomy cine in 175 em3 of water. Stirring is continued for half an hour, then allowed to stand at -I- 50 for 48 hours. The solution thus obtained is poured, with stirring, into 3400 cm3 of methanol cooled to + 5 () with ice-cold water.
The casting lasts about an hour; stirring is continued for a further half an hour, then filtered off and dried under vacuum in the presence of sulfuric acid. We thus obtain 41 g of isonicotinyl hydrazone sulphate of streptomycin which has a rotatory power.
EMI0002.0020
<U> 24 </U> <SEP> D <SEP> = <SEP> - <SEP> 70 <SEP> (c <SEP> = <SEP> 2 <SEP>% <SEP> in <SEP> l ' water).
<tb> []. <I> Example 2 </I> The solution obtained is heated at 600 for 3 hours by mixing a solution of 13.7 g of isonicotinyl hydrazide in 150 cm3 of water with a solution of 14.6 g of streptomycin sulfate in 50 cms of water.
The reaction mixture thus obtained is poured, with stirring, into 3 liters of methanol cooled to -; - 50. It is left to stand overnight, filtered, washed with 1 liter of methanol and dried under vacuum in the presence of sulfuric acid. This gives 15.5 g of isonicotinyl-hydrazone sulphate of streptomycin identical to that prepared according to Example 1. <I> Example 3 </I> The procedure is as in Example 2, but with heating at reflux (1000) in an oil bath for 2 hours.
By treating the reaction mixture as indicated in Example 2, 15.4 g of isonicotinyl-hydrazone streptomycin sulfate is obtained. <I> Example 4 </I> To a solution of 300 g of streptomycin sulphate in 500 cm3 of water is added a lukewarm solution of 141 g of isonicotinyl hydrazide in 500 cm3 of water. The mixture is refluxed for 3 hours, then concentrated in vacuo to a volume of 750 cm3. The solution thus obtained is poured into 10 liters of methanol cooled to -I-50.
The mixture is left to stand for 2 hours and the precipitate which has formed is filtered off, washed with 5 liters of methanol and dried under vacuum in the presence of sulfuric acid. In this way 336 g of streptomycin isonia-cotinyl hydrazone sulfate is obtained. <I> Example 5 </I> A solution of 36.5 g of streptomycin sulfate and 6.85 g of isonicotinyl hydrazide in 100 cm3 of water is refluxed for 2 hours. The water is then removed under vacuum at 600 until a meringue is obtained.
The residue is then taken up in 75 cm3 of benzene and the dehydration is completed by azeotropic distillation, then the excess benzene is removed in a water bath under vacuum. In this way 41.3 g of isonicotinylhydrazone sulphate of streptomycin is obtained.
<I> Example 6 </I> A mixture of 36.45 g of streptomycin sulphate and 13.5 g of isonicotinyl hydrazide in 100 cm3 of glycol is heated in an oil bath at 1000 for 3 hours. ethylene. After cooling to 50, 500 cm3 of methanol are added over one hour, with stirring, stirring is continued for about half an hour, filtered,
washed with 150 cm3 of methanol and dried under vacuum in the presence of sulfuric acid. In this way 38 g of isonicotiny1hydrazone sulphate from streptomycin are obtained.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR1042089T | 1951-09-11 | ||
| FR313473X | 1952-06-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH313473A true CH313473A (en) | 1956-04-15 |
Family
ID=26214522
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH313473D CH313473A (en) | 1951-09-11 | 1953-06-16 | Process for the preparation of a new derivative of streptomycin |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH313473A (en) |
-
1953
- 1953-06-16 CH CH313473D patent/CH313473A/en unknown
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