CH269428A - Process for the preparation of a biguanide derivative. - Google Patents
Process for the preparation of a biguanide derivative.Info
- Publication number
- CH269428A CH269428A CH269428DA CH269428A CH 269428 A CH269428 A CH 269428A CH 269428D A CH269428D A CH 269428DA CH 269428 A CH269428 A CH 269428A
- Authority
- CH
- Switzerland
- Prior art keywords
- preparation
- biguanide
- isopropyl
- chlorophenyl
- salts
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000004283 biguanides Chemical class 0.000 title description 4
- POXAIQSXNOEQGM-UHFFFAOYSA-N propan-2-ylthiourea Chemical compound CC(C)NC(N)=S POXAIQSXNOEQGM-UHFFFAOYSA-N 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 7
- ZSJNJAJDBNFVCA-UHFFFAOYSA-N 2-(4-chlorophenyl)guanidine Chemical compound NC(=N)NC1=CC=C(Cl)C=C1 ZSJNJAJDBNFVCA-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000003009 desulfurizing effect Effects 0.000 claims description 3
- 238000002844 melting Methods 0.000 claims description 3
- 230000008018 melting Effects 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- 239000012458 free base Substances 0.000 claims description 2
- 239000000155 melt Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- NGMNYSASEGPPEO-UHFFFAOYSA-N C(C)(C)N=C(N(C1=CC=CC=C1)Cl)NC(=N)N Chemical compound C(C)(C)N=C(N(C1=CC=CC=C1)Cl)NC(=N)N NGMNYSASEGPPEO-UHFFFAOYSA-N 0.000 claims 1
- 230000000078 anti-malarial effect Effects 0.000 claims 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 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 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- VHBFEIBMZHEWSX-UHFFFAOYSA-N 2-isothiocyanatopropane Chemical compound CC(C)N=C=S VHBFEIBMZHEWSX-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 class 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
- 229960000583 acetic acid Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical class CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ISJBQSJDQZLCSF-UHFFFAOYSA-N (4-chlorophenyl)azanium;chloride Chemical compound [Cl-].[NH3+]C1=CC=C(Cl)C=C1 ISJBQSJDQZLCSF-UHFFFAOYSA-N 0.000 description 1
- SWHSXWLSBBYLGM-UHFFFAOYSA-N 2-[(2-carboxyphenoxy)methoxy]benzoic acid Chemical class OC(=O)C1=CC=CC=C1OCOC1=CC=CC=C1C(O)=O SWHSXWLSBBYLGM-UHFFFAOYSA-N 0.000 description 1
- OCISOSJGBCQHHN-UHFFFAOYSA-N 3-hydroxynaphthalene-1-carboxylic acid Chemical class C1=CC=C2C(C(=O)O)=CC(O)=CC2=C1 OCISOSJGBCQHHN-UHFFFAOYSA-N 0.000 description 1
- 229940123208 Biguanide Drugs 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
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Chemical class 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 239000011133 lead Substances 0.000 description 1
- 239000007788 liquid 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
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- -1 methylene-bis-2 Chemical class 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
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 239000007787 solid Substances 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)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (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 Biguanid-Derivates, nämlich des Nl-p-Chlor- phenyl-N"-isopropyl-biguanids, welches als chemotherapeutisches Mittel oder als Zwi schenprodukt für die Herstellung chemo therapeutischer Mittel wertvoll ist. Dieses Biguanid-Derivat ist insbesondere gegen Malariaparasiten hochwirksam.
Das erfindungsgemässe Verfahren ist da durch gekennzeichnet, dass man p-Chlor- phenylguanidin mit Isopropylthioharnstoff in Gegenwart eines Entsehwefelungsmittels zur Umsetzung bringt.
Der Isopropylthioharnstoff kann durch Umsetzung von Isopropyl-isothiocyanat mit Ammoniak nach dem von Jahn (Monats hefte, Bd.3, Seite<B>168)</B> beschriebenen Ver fahren hergestellt werden.
Das p-Chlorphenylguanidin kann durch Umsetzung von p-Chloranilin-hydroehlorid mit Cyanamid nach dem von Braun (Journal of the American Chemical Society, 1933, Bd.55, Seite 1282) beschriebenen Verfahren hergestellt werden.
Als Entschwefelungsmittel für das erfin dungsgemässe Verfahren 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 er hitzt, z. B. in Gegenwart eines Lösungs- oder Verdünnungsmittels, wie z. B. Methanol, Äthanol oder fl-Äthoxyäthanol. Der Isopropyl- thioharnstoff sowie das p-Chlorphenylguani- din können als solche oder in Form ihrer Salze, beispielsweise der Hydrochloride, ver wendet werden.
Im letzteren Falle kann der freie Isopropylthioharnstoff bzw. das p-Chlor- phenylguanidin in situ durch Zugabe einer äquivalenten Menge eines basisch machenden Mittels, wie z. B. Natriumäthoxyd oder Na- triummethoxyd, in Freiheit gesetzt werden.
Das nach dem. erfindungsgemässen Ver fahren erhaltene NI-p-Chlorphenyl-N@-isopro- pyl-biguanid ist eine starke Base, die mit organischen und anorganischen Säuren be ständige Salze bildet, welche in vielen Fäl len in Wasser leicht löslich sind.
Diese Salze können in, der Weise her gestellt werden, dass man das Nl-p-Chlor- phenyl-N'-isopropyl-biguanid in wässrigen Lösungen der Säure löst und das Wasser hierauf abdampft. Man stellt sie jedoch zweckmässiger trocken her, indem man die Komponenten in einem organischen Lösungs mittel, wie z. B. Aceton oder einem Alkohol, in welchem die Salze schwer löslich sind, ver mischt.
Auf diese Weise lassen sich leicht beispielsweise die Salze der Essigsäure, Milchsäure, Methansulfonsäure, Methylen- disalicylsäiire, Methylen-bis-2,3-oxynaphthoe- säure und Salzsäure herstellen. Im folgenden Beispiel sind unter Teile Gewichtsteile zu verstehen.
Beispiel: 3,4 Teile p-Chlorphenylguanidin, 2 Teile Isopropylthioharnstoff, 8,9 Teile Bleiglätte und 50 Teile Äthanol werden gerührt und während 18 Stunden am Rückfluss erhitzt. Das Reaktionsgemisch wird abfiltriert und der Rückstand mit Äthanol gewaschen. Die Filtrate und Waschflüssigkeiten werden ver einigt und auf dem Wasserbad eingedampft. Der Rückstand wird in 7%iger Salzsäure gelöst, die Lösung filtriert und einem über schuss einer 8%igen Natr iumhydroxydlösung zugesetzt. Der feste Körper, der ausfällt, wird abfiltriert und in Benzol gelöst.
Die Lösung wird getrocknet und das Benzol abgedampft. Der Rückstand wird in trockenem Äthylessig- ester gelöst und mit so viel Eisessig versetzt, bis die Lösung gegen Lackmus gerade sauer reagiert. Der ausgeschiedene Körper wird ab filtriert, mit Äthylessigester gewaschen und bei 60 C getrocknet. Er besteht aus N'-p- Chlorphenyl - NI - isopropyl - diguanidinacetat vom Smp. 188 C.
Die freie Base vom Smp. 129 C wird nach gewöhnlichen Methoden der Basifizierung erhalten. Ihr Hydrochlorid schmilzt bei 243-244 C.
Process for the preparation of a biguanide derivative. The present invention relates to a process for the preparation of a biguanide derivative, namely Nl-p-chlorophenyl-N "-isopropyl-biguanide, which is valuable as a chemotherapeutic agent or as an intermediate for the preparation of chemotherapeutic agents. This biguanide -The derivative is particularly effective against malaria parasites.
The process according to the invention is characterized in that p-chlorophenylguanidine is reacted with isopropylthiourea 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 booklet, volume 3, page 168).
The p-chlorophenylguanidine can be prepared by reacting p-chloroaniline hydrochloride with cyanamide according to the process described by Braun (Journal of the American Chemical Society, 1933, vol. 55, page 1282).
Suitable desulfurizing agents for the process according to the invention are, for example, the oxides and the salts of heavy metals, in particular those of lead, copper, silver and mercury.
To carry out the reaction of the method according to the invention, the reaction participants are expediently heated together, e.g. B. in the presence of a solvent or diluent, such as. B. methanol, ethanol or fl-ethoxyethanol. The isopropyl thiourea and p-chlorophenylguanidine 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 p-chlorophenylguanidine can be added in situ by adding an equivalent amount of a basicizing agent, such as. B. sodium ethoxide or sodium methoxide, are set free.
That after. NI-p-chlorophenyl-N @ -isopropyl-biguanide obtained according to the invention is a strong base which forms permanent salts with organic and inorganic acids, which in many cases are readily soluble in water.
These salts can be prepared in such a way that the Nl-p-chlorophenyl-N'-isopropyl-biguanide is dissolved in aqueous solutions of the acid and the water is then evaporated off. However, they are more conveniently dry by putting the components in an organic solvent such as. B. acetone or an alcohol in which the salts are sparingly soluble, mixed ver.
In this way, for example, the salts of acetic acid, lactic acid, methanesulfonic acid, methylene disalicylic acid, methylene-bis-2,3-oxynaphthoic acid and hydrochloric acid can easily be prepared. In the following example, parts are to be understood as parts by weight.
Example: 3.4 parts of p-chlorophenylguanidine, 2 parts of isopropylthiourea, 8.9 parts of black lead and 50 parts of ethanol are stirred and refluxed for 18 hours. The reaction mixture is filtered off and the residue is washed with ethanol. The filtrates and washing liquids are combined and evaporated on the water bath. The residue is dissolved in 7% hydrochloric acid, the solution is filtered and an excess of 8% sodium hydroxide solution is added. The solid that precipitates is filtered off and dissolved in benzene.
The solution is dried and the benzene evaporated. The residue is dissolved in dry ethyl acetate and mixed with glacial acetic acid until the solution just reacts acidic to litmus. The excreted body is filtered off, washed with ethyl acetate and dried at 60.degree. It consists of N'-p-chlorophenyl - NI - isopropyl - diguanidine acetate with a melting point of 188 C.
The free base of melting point 129 ° C. is obtained by customary basification methods. Their hydrochloride melts at 243-244 C.
Claims (1)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB256511X | 1946-01-25 | ||
| GB269428X | 1946-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH269428A true CH269428A (en) | 1950-06-30 |
Family
ID=32964104
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH269428D CH269428A (en) | 1946-01-25 | 1947-01-24 | Process for the preparation of a biguanide derivative. |
| CH256511D CH256511A (en) | 1946-01-25 | 1947-01-24 | Process for the preparation of a biguanide derivative. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH256511D CH256511A (en) | 1946-01-25 | 1947-01-24 | Process for the preparation of a biguanide derivative. |
Country Status (1)
| Country | Link |
|---|---|
| CH (2) | CH269428A (en) |
-
1947
- 1947-01-24 CH CH269428D patent/CH269428A/en unknown
- 1947-01-24 CH CH256511D patent/CH256511A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CH256511A (en) | 1948-08-31 |
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