CH267604A - Process for the preparation of a biguanide derivative. - Google Patents
Process for the preparation of a biguanide derivative.Info
- Publication number
- CH267604A CH267604A CH267604DA CH267604A CH 267604 A CH267604 A CH 267604A CH 267604D A CH267604D A CH 267604DA CH 267604 A CH267604 A CH 267604A
- Authority
- CH
- Switzerland
- Prior art keywords
- preparation
- salts
- biguanide
- isopropyl
- isothiourea
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000004283 biguanides Chemical class 0.000 title description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 7
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 claims description 2
- 229940123208 Biguanide Drugs 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 230000000078 anti-malarial effect Effects 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 239000002246 antineoplastic agent Substances 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 239000002585 base Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SWHSXWLSBBYLGM-UHFFFAOYSA-N 2-[(2-carboxyphenoxy)methoxy]benzoic acid Chemical compound OC(=O)C1=CC=CC=C1OCOC1=CC=CC=C1C(O)=O SWHSXWLSBBYLGM-UHFFFAOYSA-N 0.000 description 1
- -1 3,4-dichlorophenylguanyl-S-methyl-isothiourea-hydroiodide Chemical compound 0.000 description 1
- OCISOSJGBCQHHN-UHFFFAOYSA-N 3-hydroxynaphthalene-1-carboxylic acid Chemical compound C1=CC=C2C(C(=O)O)=CC(O)=CC2=C1 OCISOSJGBCQHHN-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
- C07C279/24—Y being a hetero atom
- C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Verfahren zur Herstellung eines Biguanid-Derivates. Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung eines Bi guanid-Derivates, nämlich des N1-3,4-Diehlor- phenyl - N - isopropyl - biguaiiids, welches als Chemotherapeutikum oder als Zwischenpro dukt für die Herstellung von Chemothera- peutika nützlich ist..
Das erfindungsgemässe Verfahren ist da durch gekennzeichnet, da.ss man einen 3,4-Di- chlor - phenylguanyl - S - alky 1- isothioharnstoff mit Isopropylamin zur Umsetzung bringt.
Der als AtLsgangsniaterial für das erfin dungsgemässe Verfahren verwendete 3,4-Di- ehlor - phenylguany 1- S - alkyl-isothioliarnstoff kann durch Alky lierung des entsprechenden Thioharnstoffes hergestellt werden.
Bei der Ausführung des erfindungsgemässen Verfahrens werden die Reaktionsteilnehmer vorzugsweise zusammen erhitzt, und zwar zweckmässig in Gegenwart eines Lösungs- bzw. Verdünnungsmittels. Der 3,4=Diehlorphenyl- guanyl-S-alkyl-isothioharnstoff kann in freier Form oder in Form seiner Salze, beispiels weise des Hydrochlorids, verwendet werden. Im letzteren Fall wird der Isothioharnstoff zweckmässig in situ durch Zugabe einer äqui valenten Menge einer basischen Substanz, wie z. B. Natriummethylat oder Natriumäthylat, in Freiheit gesetzt.
Ausserdem kann man auch das Isopropylamin, sofern dies erwünscht ist, in Form eines Salzes verwenden.
Das N1-3,4-Diclilor-phenyl-N'-isopropyl-bi- guanid, welches nach dem erfindungsgemässen Verfahren erhalten wird, ist als Chemothera- peutikum oder als Zwischenprodukt für Chemotherapeutika nützlich. Es ist insbeson dere als Antimalariamittel wertvoll. Es ist eine starke Base, die mit organischen und an organischen Säuren beständige Salze bildet, die in vielen Fällen in Wasser leicht löslich sind. Diese Salze können dadurch erhalten werden, dass man das Biguanid in einer wäs serigen Lösung der Säure löst und hierauf das Wasser abdampft.
Zweckmässiger wer den sie jedoch in trockener Form erhalten, indem man die Komponenten in einem or ganischen Lösungsmittel, beispielsweise in Aceton oder in einem Alkohol, in welchem die Salze schwer löslich sind, vermischt. Auf diese Weise kann man leicht beispielsweise die Salze mit Essigsäure, Milchsäure, Methan sulfonsäure, Methy lendisalicylsäure, Methy- len-bis 2,3-oxynaphthoesäure und Salzsäure herstellen.
Im folgenden Beispiel bedeuten die Teile Gewichtsteile.
<I>Beispiel:</I> 1,96 Teile 3,4-Dichlor-phenylguanyl-S-me- thyl-isothioharnstoff - hydrojodid werden mit 0,5 Teilen Isopropylamin und 1 Teil Wasser zu einer Paste vermischt. Das Gemisch wird allmählich auf 130 bis 135 C erhitzt und wäh rend 15 Stunden bei dieser Temperatur ge halten.
Die Schmelze wird hierauf mit einem überschuss an heisser 2n-Natriumhydroxyd- lösung behandelt, abgekühlt und mit Äther extrahiert. Dann extrahiert man den äthe rischen Extrakt mit 2n-Essigsäure und stellt den Extrakt mit Natriumhydroxyd alkalisch.
Die gefällte Base wird abfiltriert. Sie besitzt nach dem Umkristallisieren einen Smp. von 124 bis 126 C. Das aus der Base durch Lö sen in Äther, Extrahieren der ätherischen Lösung mit 2n-Salzsäure und Versetzen des Extraktes mit Ammoniak, bis er gegen Bril- lant-Gelb alkalisch reagiert, erhältliche Hy- drochlorid weist, aus Wasser umkristallisiert., einen Smp. von 248 bis 249 C auf.
Das Hy- droehlorid kann nach einer üblichen Methode wieder in die freie Base vom Smp. 124 bis 126 C übergeführt werden.
Process for the preparation of a biguanide derivative. The present invention relates to a process for producing a bi guanide derivative, namely N1-3,4-diehlorphenyl - N - isopropyl - biguaiiids, which is useful as a chemotherapeutic agent or as an intermediate product for the manufacture of chemotherapeutic agents. .
The process according to the invention is characterized in that a 3,4-dichloro-phenylguanyl-S-alky-1-isothiourea is reacted with isopropylamine.
The 3,4-di-chloro-phenylguany 1-S-alkyl-isothiolarea used as starting material for the process according to the invention can be prepared by alkylation of the corresponding thiourea.
When carrying out the process according to the invention, the reactants are preferably heated together, expediently in the presence of a solvent or diluent. The 3,4 = Diehlophenylguanyl-S-alkyl-isothiourea can be used in free form or in the form of its salts, for example the hydrochloride. In the latter case, the isothiourea is expediently in situ by adding an equi-valent amount of a basic substance, such as. B. sodium methylate or sodium ethylate, set free.
In addition, the isopropylamine can, if so desired, also be used in the form of a salt.
The N1-3,4-diclilor-phenyl-N'-isopropyl-biguanide which is obtained by the process according to the invention is useful as a chemotherapeutic agent or as an intermediate for chemotherapeutic agents. It is particularly valuable as an antimalarial agent. It is a strong base that forms salts with organic and organic acids, which in many cases are easily soluble in water. These salts can be obtained by dissolving the biguanide in an aqueous solution of the acid and then evaporating the water.
However, it is more practical to obtain them in dry form by mixing the components in an organic solvent, for example in acetone or in an alcohol in which the salts are sparingly soluble. In this way, for example, the salts with acetic acid, lactic acid, methanesulfonic acid, methylene disalicylic acid, methylene to 2,3-oxynaphthoic acid and hydrochloric acid can easily be prepared.
In the following example, the parts mean parts by weight.
<I> Example: </I> 1.96 parts of 3,4-dichlorophenylguanyl-S-methyl-isothiourea-hydroiodide are mixed with 0.5 part of isopropylamine and 1 part of water to form a paste. The mixture is gradually heated to 130 to 135 C and keep ge during 15 hours at this temperature.
The melt is then treated with an excess of hot 2N sodium hydroxide solution, cooled and extracted with ether. Then the ethereal extract is extracted with 2N acetic acid and the extract is made alkaline with sodium hydroxide.
The precipitated base is filtered off. After recrystallization, it has a m.p. of 124 to 126 C. This is obtained from the base by dissolving it in ether, extracting the ethereal solution with 2N hydrochloric acid and adding ammonia to the extract until it reacts alkaline against brilliant yellow, The hydrochloride available has, recrystallized from water, a melting point of 248 to 249.degree.
The hydrochloride can be converted back into the free base with a melting point of 124 to 126 ° C. by a customary method.
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB265196X | 1946-01-07 | ||
| GB267604X | 1946-01-07 | ||
| CH265196T | 1947-01-06 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH267604A true CH267604A (en) | 1950-03-31 |
Family
ID=27178096
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH267604D CH267604A (en) | 1946-01-07 | 1947-01-06 | Process for the preparation of a biguanide derivative. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH267604A (en) |
-
1947
- 1947-01-06 CH CH267604D patent/CH267604A/en unknown
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