CH396031A - Process for the preparation of new hydrazine derivatives - Google Patents
Process for the preparation of new hydrazine derivativesInfo
- Publication number
- CH396031A CH396031A CH1315360A CH1315360A CH396031A CH 396031 A CH396031 A CH 396031A CH 1315360 A CH1315360 A CH 1315360A CH 1315360 A CH1315360 A CH 1315360A CH 396031 A CH396031 A CH 396031A
- Authority
- CH
- Switzerland
- Prior art keywords
- preparation
- hydrazine
- hydrazine derivatives
- derivatives
- hydrogenation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 8
- 150000002429 hydrazines Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 12
- 150000007857 hydrazones Chemical class 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 235000019441 ethanol Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 2-octanone Chemical compound CCCCCCC(C)=O ZPVFWPFBNIEHGJ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000608781 Eptesicus serotinus Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- -1 alkyl radical Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012154 double-distilled water Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Procédé de préparation de nouveaux dérivés hydraziniques
La présente invention a pour objet un procédé de préparation de nouveaux dérivés hydraziniques répondant à la formule générale:
EMI1.1
dans laquelle R est un radical alkyle et n est un nombre entier de 3 à 9, ces dérivés étant de préférence préparés sous la forme de sels avec des acides organiques ou minéraux.
Ces composés sont particulièrement intéressants en tant que produits thérapeutiques. Ils constituent en effet des stimulants du système nerveux central, en inhibant une enzyme: la monoamino-oxydase, qui décompose les amines stimulantes endogènes telles la noradrénaline, l'adrénaline, la sérotine, etc.
Parmi les composés de formule générale (I), on donne particulièrement la préférence à ceux dans lesquels R est un radical méthyle et n est égal à 4 ou 5.
Suivant le procédé de préparation des composés de formule générale (I) faisant l'objet de l'invention, on condense une cétone de formule: CH3 (CH) nCOR dans laquelle R et n ont les significations précitées, avec l'hydrogène, en obtenant ainsi une hydrazone, que l'on hydrogène ensuite ; et salifie ultérieurement.
La condensation est avantageusement effectuée au sein d'un solvant tel que l'alcool méthylique. Elle s'opère commodément à température ambiante, et peut être parachevée par un court chauffage au reflux.
L'hydrogénation de l'hydrazone peut être faite catalytiquement, le catalyseur étant, par exemple, du platine.
Le dérivé hydrazinique final est aisément isolé sous forme d'oxalate, que l'on peut convertir en un autre sel.
Les nouveaux composés préparés suivant l'invention peuvent être formulés, en vue de leur usage thérapeutique, sous forme de composition en association avec un véhicule inerte thérapeutiquement administrable.
Ce véhicule peut être l'un quelconque des excipients solides habituels destinés à la préparation de comprimés ou dragées administrables per os. Ce peut être également un liquide, tel que de l'eau bidistillée stérile additionnée d'un bactériostatique pour la préparation d'ampoules injectables ou buvables.
Les composés préparés suivant l'invention peuvent ainsi être administrés, sous forme des compositions précitées, à raison de 10 à 30 mg de principe actif par jour.
L'exemple suivant illustre l'invention.
Exemple
Préparation du sulfate d'hydrazino-2 octane:
EMI1.2
On dissout 100 g de méthylhexylcétone dans 100 cm3 d'alcool méthylique absolu et verse lentement dans une solution de 116 g d'hydrate d'hydrazine dans 116 cm3 d'alcool méthylique, en maintenant la température de la solution obtenue entre 28 et 300 C, puis la fait bouillir à reflux 10 minutes.
On évapore sous vide l'alcool et une partie de l'excès d'hydrazine.
Le résidu est extrait à l'éther qui dissout l'hydrazone formée et on chasse ensuite l'éther par distilla tion, sous vide. Le résidu formé par l'hydrazone brute est dissous dans 1000 cm3 d'alcool éthylique à 95o, on ajoute 100 cm3 d'acide acétique glacial et 4,6 g d'oxyde de platine.
Le tout est hydrogéné par de l'hydrogène à pression et température ordinaires, jusqu'à fin d'absorbtion (durée 1 h à 1 h 30 environ). On décante la solution, lave le platine avec un peu d'alcool, distille à sec sous vide. Le résidu (constitué par l'acétate d'hydrazino-2 octane, impur) est dissous dans 650 cm3 d'eau. A la solution obtenue, on ajoute 86 g d'aldéhyde benzoïque et chauffe le mélange pendant 10 minutes à 500 C en agitant mécaniquement.
On refroidit et extrait à l'éther.
Cette solution éthérée est mise en présence d'une solution aqueuse contenant 140 g d'acide oxalique et on entraine le tout à la vapeur d'eau.
I1 reste dans la solution aqueuse l'oxalate d'hydrazino-2 octane qui est ensuite laissé à cristalliser au réfrigérateur.
Ce produit recristallisé dans l'alcool absolu a un point de fusion instantané de 133-1340 C.
Quantité obtenue: 48 à 50 g environ.
L'oxalate ainsi obtenu est converti en sulfate de la manière suivante:
On dissout 15 g d'oxalate d'hydrazino-2 octane dans 120 cm3 de NaOH 0,5 N et amène le pH à 7 par addition de NaOH.
Lorsque tout est dissous, on ajoute 90 cm3 d'éther puis 135 cm3 de soude 0,5 N.
On épuise à l'éther, lave l'extrait à l'eau et le sèche sur sulfate de sodium.
On ajoute alors en maintenant à + 50 C, 6 g d'acide sulfurique pur, soit environ 1 molécule pour 1 molécule d'oxalate d'hydrazino-2 octane. Il se forme un précipité de sulfate d'hydrazino-2 octane qui est laissé une nuit au réfrigérateur.
On sépare, lave à l'éther et sèche.
On obtient 13 g environ de sulfate d'hydrazino-2 octane de point de fusion instantané 78 à 800 C.
Process for the preparation of new hydrazine derivatives
The subject of the present invention is a process for preparing novel hydrazine derivatives corresponding to the general formula:
EMI1.1
in which R is an alkyl radical and n is an integer from 3 to 9, these derivatives preferably being prepared in the form of salts with organic or mineral acids.
These compounds are of particular interest as therapeutic products. They constitute in fact stimulants of the central nervous system, by inhibiting an enzyme: monoamino-oxidase, which breaks down endogenous stimulating amines such as norepinephrine, adrenaline, serotine, etc.
Among the compounds of general formula (I), preference is particularly given to those in which R is a methyl radical and n is equal to 4 or 5.
According to the process for preparing the compounds of general formula (I) forming the subject of the invention, a ketone of formula: CH3 (CH) nCOR in which R and n have the aforementioned meanings, is condensed with hydrogen, in thus obtaining a hydrazone, which is then hydrogenated; and salifies later.
The condensation is advantageously carried out in a solvent such as methyl alcohol. It is conveniently carried out at room temperature, and can be completed by short heating to reflux.
The hydrogenation of the hydrazone can be done catalytically, the catalyst being, for example, platinum.
The final hydrazine derivative is easily isolated as an oxalate, which can be converted to another salt.
The new compounds prepared according to the invention can be formulated, with a view to their therapeutic use, in the form of a composition in association with an inert therapeutically administrable vehicle.
This vehicle can be any of the usual solid excipients intended for the preparation of tablets or dragees which can be administered orally. It can also be a liquid, such as sterile double-distilled water with the addition of a bacteriostatic for the preparation of injectable or drinkable ampoules.
The compounds prepared according to the invention can thus be administered, in the form of the aforementioned compositions, at a rate of 10 to 30 mg of active principle per day.
The following example illustrates the invention.
Example
Preparation of 2-hydrazinoctane sulfate:
EMI1.2
100 g of methyl hexyl ketone are dissolved in 100 cm3 of absolute methyl alcohol and slowly poured into a solution of 116 g of hydrazine hydrate in 116 cm3 of methyl alcohol, maintaining the temperature of the solution obtained between 28 and 300 C. , then boil it under reflux for 10 minutes.
The alcohol and part of the excess hydrazine are evaporated off in vacuo.
The residue is extracted with ether which dissolves the hydrazone formed and the ether is then removed by distillation in vacuo. The residue formed by the crude hydrazone is dissolved in 1000 cm3 of 95o ethyl alcohol, 100 cm3 of glacial acetic acid and 4.6 g of platinum oxide are added.
The whole is hydrogenated with hydrogen at ordinary pressure and temperature, until the absorption is complete (duration approximately 1 hour to 1 hour 30 minutes). The solution is decanted, the platinum washed with a little alcohol, vacuum distilled to dryness. The residue (consisting of 2-hydrazinoctane acetate, impure) is dissolved in 650 cm3 of water. To the solution obtained, 86 g of benzoic aldehyde are added and the mixture is heated for 10 minutes at 500 ° C. while stirring mechanically.
Cooled and extracted with ether.
This ethereal solution is brought into contact with an aqueous solution containing 140 g of oxalic acid and the whole is entrained with water vapor.
There remains in the aqueous solution the 2-hydrazinoctane oxalate which is then left to crystallize in the refrigerator.
This product recrystallized from absolute alcohol has an instantaneous melting point of 133-1340 C.
Quantity obtained: 48 to 50 g approximately.
The oxalate thus obtained is converted into sulphate as follows:
15 g of 2-hydrazinoctane oxalate are dissolved in 120 cm3 of 0.5N NaOH and the pH is brought to 7 by addition of NaOH.
When everything is dissolved, 90 cm3 of ether are added then 135 cm3 of 0.5N sodium hydroxide.
Exhausted with ether, the extract is washed with water and dried over sodium sulphate.
6 g of pure sulfuric acid, ie approximately 1 molecule per 1 molecule of 2-hydrazinoctane oxalate, are then added while maintaining at + 50 ° C. A precipitate of 2-hydrazinoctane sulfate forms, which is left overnight in the refrigerator.
Separated, washed with ether and dried.
About 13 g of 2-hydrazinoctane sulphate of instantaneous melting point 78 to 800 C.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB40162/59A GB899385A (en) | 1959-11-26 | 1959-11-26 | Improvements in or relating to new hydrazine derivatives and process for their preparation |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH396031A true CH396031A (en) | 1965-07-31 |
Family
ID=10413493
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1315360A CH396031A (en) | 1959-11-26 | 1960-11-24 | Process for the preparation of new hydrazine derivatives |
Country Status (4)
| Country | Link |
|---|---|
| BE (1) | BE597420A (en) |
| CH (1) | CH396031A (en) |
| FR (1) | FR787M (en) |
| GB (1) | GB899385A (en) |
-
1959
- 1959-11-26 GB GB40162/59A patent/GB899385A/en not_active Expired
-
1960
- 1960-11-23 BE BE597420A patent/BE597420A/en unknown
- 1960-11-24 CH CH1315360A patent/CH396031A/en unknown
- 1960-11-24 FR FR844949A patent/FR787M/fr active Active
Also Published As
| Publication number | Publication date |
|---|---|
| GB899385A (en) | 1962-06-20 |
| BE597420A (en) | 1961-03-15 |
| FR787M (en) | 1961-09-04 |
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