CH269432A - Process for the preparation of a biguanide derivative. - Google Patents
Process for the preparation of a biguanide derivative.Info
- Publication number
- CH269432A CH269432A CH269432DA CH269432A CH 269432 A CH269432 A CH 269432A CH 269432D A CH269432D A CH 269432DA CH 269432 A CH269432 A CH 269432A
- Authority
- CH
- Switzerland
- Prior art keywords
- preparation
- biguanide
- isopropyl
- salts
- derivative
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 3
- 150000004283 biguanides Chemical class 0.000 title description 3
- POXAIQSXNOEQGM-UHFFFAOYSA-N propan-2-ylthiourea Chemical compound CC(C)NC(N)=S POXAIQSXNOEQGM-UHFFFAOYSA-N 0.000 claims description 10
- 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
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- 239000012458 free base Substances 0.000 claims description 2
- 230000000078 anti-malarial effect Effects 0.000 claims 1
- 239000000155 melt Substances 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical class CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- NNRSVGLUJAPMQD-UHFFFAOYSA-N 2-(3,4-dichlorophenyl)guanidine Chemical compound NC(N)=NC1=CC=C(Cl)C(Cl)=C1 NNRSVGLUJAPMQD-UHFFFAOYSA-N 0.000 description 2
- VHBFEIBMZHEWSX-UHFFFAOYSA-N 2-isothiocyanatopropane Chemical compound CC(C)N=C=S VHBFEIBMZHEWSX-UHFFFAOYSA-N 0.000 description 2
- 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
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000003009 desulfurizing effect Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XANZVOMCLKMKMV-UHFFFAOYSA-N 3,4-dichloroaniline;hydrochloride Chemical compound Cl.NC1=CC=C(Cl)C(Cl)=C1 XANZVOMCLKMKMV-UHFFFAOYSA-N 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229940123208 Biguanide Drugs 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical class CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- ISZNZKHCRKXXAU-UHFFFAOYSA-N chlorproguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C(Cl)=C1 ISZNZKHCRKXXAU-UHFFFAOYSA-N 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000011133 lead Substances 0.000 description 1
- 201000004792 malaria Diseases 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 125000000325 methylidene group Chemical class [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 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
- 238000005406 washing Methods 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)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Verfahren zur Herstellung eines Biguanid-Derivates. Gegenstand der vorliegenden Erfindung ist ein Verfahren zur Herstellung eines Bi- nuanid-Derivates, nämlich des N1-3,4-Dichlor- plienyl-N,-isopropyl-biguanids, welches als chernotherapeutisehes Mittel oder als Zwi- schenprodukt für die Herstellung chemot.hera- peutiseher Mittel wertvoll ist. Dieses Bigua- nid-Derivat ist insbesondere gegen Malaria parasiten hochwirksam.
Das erfindungsgemässe Verfahren ist da durch gekennzeichnet, dass man 3,4-Dichlor- plienyl-g2ianidin mit Isopropyl.-thibliarnstoff in Gegenwart eines Entschwefelungsmittels zur Umsetzung bringt.
Der Isopropylthioharnstoff kann durch Umsetzung von Isopropyl-isothiocyanat mit Ammoniak nach dem von Jahn (Monatshefte, Bd. 3, Seite 168) beschriebenen Verfahren her gestellt werden.
Das 3,4-Diehlorphenylguanidin kann durch Umsetzung von 3,4-Dichloranilin-hydrochlorid mit Cyanamid nach dem von Braun (Journal of the American Chemical Society, 1933, Bd.55, Seite 1282) beschriebenen Verfahren hergestellt werden.
Als Entschwefelungsmittel eignen sich bei spielsweise die Oxyde und die Salze von Schwermetallen, insbesondere diejenigen von Blei, Kupfer, Silber und Quecksilber.
Zur Ausführung der Reaktion des erfin dungsgemässen Verfahrens werden die Reak tionsteilnehmer zweckmässig zusammen erhitzt, z. B. in Gegenwart eines Lösungs- oder Ver dünnungsmittels, wie z. B. Methanol, Äthanol oder Ätlioxyäthanol. Der Isopropylthioharn- stoff sowie das 3,4-Diehlorphenyl-guanidin können als solche oder in Form ihrer Salze, beispielsweise der Hydrochloride, verwendet werden.
Im letzteren Falle kann der freie Isopropylthioharnstoff bzw. das 3,4-Dichlor- phenyl-guanidin in situ durch Zugabe einer äquivalenten Menge eines basisehen Mittels, wie z. B. Natriumäthoxyd oder Natrium methoxyd, in Freiheit gesetzt werden.
Das nach dem erfindungsgemässen Verfah ren erhaltene N1-3,4-Dichlorphenyl-N1-isopro- pyl-biguanid ist eine starke Base, die mit organischen und anorganischen Säuren be ständige Salze bildet, welche in vielen Fällen in 'Wasser leicht löslich sind. Diese Salze kön nen in der Weise hergestellt werden, dass man das N1-3,4-Dichlorphenyl-N5-isopropyl-bigua- nid in wässrigen Lösungen der Säure löst und das Wasser hierauf abdampft. Es ist jedoch zweckmässiger, sie trocken herzustellen, indem man die Komponenten in einem organischen Lösungsmittel, wie z. B. Aceton oder einem Alkohol, in welchem die Salze schwer löslich sind, vermischt.
Auf diese Weise lassen sich leicht beispielsweise die Salze der Essigsäure, Milchsäure, Methansulfonsäure, Methylen- disalieylsäure, Methylen-bis-2,3-oxynaphthoe- säure und Salzsäure herstellen.
Im folgenden Beispiel bedeuten Teile Gewichtsteile. <I>Beispiel:</I> 4,1 Teile 3,4-Dichlorphenyl-guanidin, 2 Teile Isopropylthioharnstoff, 8,9 Teile Bleiglätte und 50 Teile Äthanol werden zusammen wäh rend 18 Stunden am Rüekfluss gerührt und erhitzt. Man filtriert das Reaktionsgemisch, wäscht den Rückstand mit Äthanol und dampft die vereinigten Filtrate und Wasch wasser auf dem Wasserbad ein. Man löst den Rückstand in 7 % iger Salzsäure, filtriert die Lösung und trägt diese in einen Überschuss von 8 % iger Natriumhydroxydlösung ein.
Die gefällte feste Substanz wird abfiltriert und in Benzol gelöst. Man trocknet die Lösung und dampft das Benzol ab. Man löst den Rückstand in trockenem Essigsäureäthylester und versetzt die Lösung mit Essigsäure, bis die Lösung gegen Lackmus gerade alkalisch reagiert. Die abgeschiedene farblose, feste Substanz wird abfiltriert, mit Essigsäure- äthylester gewaschen und dann bei<B>60'C</B> ge- trocknet.
Sie besteht aus NI-3,4-Dichlorphenyl- N6-isopropzTl-biguanid-acetat, welches nach den gewöhnlichen Methoden der Basifizierung in die freie Base vom Smp. 124-126 C über geführt wird. Die Base liefert mit Salzsäure ein Hydrochlorid vom Smp. 248-249'C.
Process for the preparation of a biguanide derivative. The present invention relates to a process for the production of a binuanide derivative, namely N1-3,4-dichloroplienyl-N, -isopropyl-biguanide, which is used as a chemotherapeutic agent or as an intermediate for the production of chemot.hera - peutic means is valuable. This biguanide derivative is particularly effective against malaria parasites.
The process according to the invention is characterized in that 3,4-dichloroplienyl-g2ianidine is reacted with isopropyl-thibliurea in the presence of a desulfurizing agent.
The isopropylthiourea can be prepared by reacting isopropyl isothiocyanate with ammonia according to the method described by Jahn (MONTHS, Vol. 3, page 168).
The 3,4-diehlophenylguanidine can be prepared by reacting 3,4-dichloroaniline hydrochloride with cyanamide according to the process described by Braun (Journal of the American Chemical Society, 1933, vol. 55, page 1282).
Suitable desulfurizing agents are, for example, the oxides and the salts of heavy metals, especially those of lead, copper, silver and mercury.
To carry out the reaction of the process according to the invention, the reaction participants are advantageously heated together, for. B. in the presence of a solvent or United diluent such. B. methanol, ethanol or Ätlioxyäthanol. Isopropylthiourea and 3,4-diehlophenylguanidine can be used as such or in the form of their salts, for example the hydrochlorides.
In the latter case, the free isopropylthiourea or the 3,4-dichloro-phenyl-guanidine can be added in situ by adding an equivalent amount of a basic agent, such as. B. sodium ethoxide or sodium methoxide, are set free.
The N1-3,4-dichlorophenyl-N1-isopropyl-biguanide obtained by the process according to the invention is a strong base which forms permanent salts with organic and inorganic acids, which in many cases are easily soluble in water. These salts can be prepared in such a way that the N1-3,4-dichlorophenyl-N5-isopropyl-biguanide is dissolved in aqueous solutions of the acid and the water is then evaporated off. However, it is more convenient to prepare them dry by placing the components in an organic solvent, such as. B. acetone or an alcohol in which the salts are sparingly soluble, mixed.
In this way, for example, the salts of acetic acid, lactic acid, methanesulphonic acid, methylene disalylic acid, methylene-bis-2,3-oxynaphthoic acid and hydrochloric acid can easily be prepared.
In the following example, parts mean parts by weight. <I> Example: </I> 4.1 parts of 3,4-dichlorophenylguanidine, 2 parts of isopropylthiourea, 8.9 parts of black lead and 50 parts of ethanol are stirred and heated together under reflux for 18 hours. The reaction mixture is filtered, the residue is washed with ethanol and the combined filtrates and washing water are evaporated on the water bath. The residue is dissolved in 7% hydrochloric acid, the solution is filtered and this is added to an excess of 8% sodium hydroxide solution.
The precipitated solid substance is filtered off and dissolved in benzene. The solution is dried and the benzene is evaporated off. The residue is dissolved in dry ethyl acetate and acetic acid is added to the solution until the solution just reacts alkaline to litmus. The deposited colorless, solid substance is filtered off, washed with ethyl acetate and then dried at <B> 60.degree. C. </B>.
It consists of NI-3,4-dichlorophenyl-N6-isopropzTl-biguanide acetate, which is converted into the free base with a melting point of 124-126 ° C. by the usual methods of basification. With hydrochloric acid, the base gives a hydrochloride with a melting point of 248-249'C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB269432X | 1946-01-25 | ||
| GB269428X | 1946-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH269432A true CH269432A (en) | 1950-06-30 |
Family
ID=32964123
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH269432D CH269432A (en) | 1946-01-25 | 1947-01-24 | Process for the preparation of a biguanide derivative. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH269432A (en) |
-
1947
- 1947-01-24 CH CH269432D patent/CH269432A/en unknown
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE1695780C3 (en) | New benzoxazine derivatives, processes for their preparation and pharmaceuticals | |
| CH269432A (en) | Process for the preparation of a biguanide derivative. | |
| CH269428A (en) | Process for the preparation of a biguanide derivative. | |
| CH269430A (en) | Process for the preparation of a biguanide derivative. | |
| CH269431A (en) | Process for the preparation of a biguanide derivative. | |
| CH267592A (en) | Process for the preparation of a biguanide derivative. | |
| CH267597A (en) | Process for the preparation of a biguanide derivative. | |
| CH267596A (en) | Process for the preparation of a biguanide derivative. | |
| DE864867C (en) | Process for the preparation of N-substituted monoethylene ureas or their homologues | |
| CH269427A (en) | Process for the preparation of a biguanide derivative. | |
| CH267593A (en) | Process for the preparation of a biguanide derivative. | |
| CH269429A (en) | Process for the preparation of a biguanide derivative. | |
| AT167100B (en) | Process for the preparation of imidazolines substituted in position 2 | |
| AT246720B (en) | Process for the preparation of new cyclic amines and their salts | |
| CH267603A (en) | Process for the preparation of a biguanide derivative. | |
| AT155475B (en) | Process for the preparation of amides of thioformic acid. | |
| CH267595A (en) | Process for the preparation of a biguanide derivative. | |
| AT235307B (en) | Process for the preparation of 4,4'-diisoamyloxy-thiocarbanilide | |
| CH267591A (en) | Process for the preparation of a biguanide derivative. | |
| CH267594A (en) | Process for the preparation of a biguanide derivative. | |
| CH265196A (en) | Process for the preparation of a biguanide derivative. | |
| CH267599A (en) | Process for the preparation of a biguanide derivative. | |
| CH269433A (en) | Process for the preparation of a biguanide derivative. | |
| CH259681A (en) | Process for the preparation of a biguanide derivative. | |
| CH283324A (en) | Process for the preparation of a biguanide derivative. |