CH642346A5 - Process for preparing (2,6-dichlorobenzylidene-amino)-guanidine - Google Patents
Process for preparing (2,6-dichlorobenzylidene-amino)-guanidine Download PDFInfo
- Publication number
- CH642346A5 CH642346A5 CH947979A CH947979A CH642346A5 CH 642346 A5 CH642346 A5 CH 642346A5 CH 947979 A CH947979 A CH 947979A CH 947979 A CH947979 A CH 947979A CH 642346 A5 CH642346 A5 CH 642346A5
- Authority
- CH
- Switzerland
- Prior art keywords
- guanidine
- amino
- preparing
- dichlorobenzylidene
- methyl
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- WDZVGELJXXEGPV-UHFFFAOYSA-N 2-[(2,6-dichlorophenyl)methylideneamino]guanidine Chemical compound NC(N)=NN=CC1=C(Cl)C=CC=C1Cl WDZVGELJXXEGPV-UHFFFAOYSA-N 0.000 title description 2
- SDDKIZNHOCEXTF-UHFFFAOYSA-N methyl carbamimidothioate Chemical compound CSC(N)=N SDDKIZNHOCEXTF-UHFFFAOYSA-N 0.000 abstract description 7
- DMIYKWPEFRFTPY-UHFFFAOYSA-N 2,6-dichlorobenzaldehyde Chemical compound ClC1=CC=CC(Cl)=C1C=O DMIYKWPEFRFTPY-UHFFFAOYSA-N 0.000 abstract description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 abstract description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 abstract description 4
- 150000007857 hydrazones Chemical class 0.000 abstract description 3
- 150000003839 salts Chemical class 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000047 product Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-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
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 230000036571 hydration Effects 0.000 description 2
- 238000006703 hydration reaction Methods 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VPIXQGUBUKFLRF-UHFFFAOYSA-N 3-(2-chloro-5,6-dihydrobenzo[b][1]benzazepin-11-yl)-N-methyl-1-propanamine Chemical compound C1CC2=CC=C(Cl)C=C2N(CCCNC)C2=CC=CC=C21 VPIXQGUBUKFLRF-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- XZMCDFZZKTWFGF-UHFFFAOYSA-N Cyanamide Chemical compound NC#N XZMCDFZZKTWFGF-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 208000021822 hypotensive Diseases 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/16—Compounds containing any of the groups, e.g. aminoguanidine
- C07C281/18—Compounds containing any of the groups, e.g. aminoguanidine the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
642 346 642 346
2 2
RIVENDICAZIONI 1. Processo per la preparazione della (2,6-diclorobenzili-den-amino)-guanidina di formula (I) CLAIMS 1. Process for the preparation of (2,6-dichlorobenzyl-den-amino) -guanidine of formula (I)
caratterizzata dal fatto che si fa reagire l'idrazone della 2,6-diclorobenzaldeide con un sale di S-metil-isotiouronio, secondo lo schema qui sotto riportato: characterized by the fact that the hydrazone of 2,6-dichlorobenzaldehyde is reacted with an S-methyl-isothiouronium salt, according to the scheme below:
CH=N-NH, CH = N-NH,
r r
CH.S-C-NIL CH.S-C-NIL
© ©
2. Processo secondo la rivendicazione 1 caratterizzato dal fatto che si opera con cloruro o bromuro di S-metil isomiscela dei reagenti. 2. Process according to claim 1 characterized in that the reagents are worked with S-methyl isomide chloride or bromide.
3. Processo secondo le rivendicazioni 1-2, caratterizzato da Ifatto che si opera con cloruro o bromuro di S-metil-iso-tiouronio. 3. Process according to claims 1-2, characterized in that it is carried out with S-methyl-iso-thiouronium chloride or bromide.
4. Processo secondo le rivendicazioni 1-3, caratterizzato dal fatto che si opera a temperature comprese fra 130 e 160°C. 4. Process according to claims 1-3, characterized in that it operates at temperatures between 130 and 160 ° C.
Oggetto della presente invenzione è un nuovo procedimento per la preparazione della (2,6-diclorobenzilidene-a-mino)-guanidina, di formula (I) The object of the present invention is a new process for the preparation of (2,6-dichlorobenzylidene-a-mino) -guanidine, of formula (I)
-CI -CI
CH=N-NH-C-NH CH = N-NH-C-NH
[| 2 [| 2
NH NH
(I) (THE)
Il composto I è dotato di interessanti caratteristiche farmacologiche. Esso esercita infatti attività ipotensiva o anti-iper-tensiva (brevetto britannico 1223492); antidepressiva (brevetto tedesco (1802364); antiemicranica (brevetto statunitense 3896232). Compound I has interesting pharmacological characteristics. In fact, it exercises hypotensive or anti-hyper-tensioning activity (British patent 1223492); antidepressant (German patent (1802364); anti-migraine (U.S. patent 3896232).
25 Secondo la tecnica sinora seguita, il composto (I) viene preparato per reazione della 2,6-diclorobenzaldeide con carbonato di aminoguanidina. Questo procedimento, che è apparentemente il più lineare, comporta tuttavia alcuni inconvenienti, che si rendono particolarmente sensibili specialmente so su scala industriale. Infatti, i rendimenti della reazione, che secondo l'esempio 1 del brevetto britannico 1223491 ammontano al 74%, su cariche di pochi grammi, diminuiscono sensibilmente all'atto della produzione su grande scala. Ciò che è peggio, il prodotto ottenuto industrialmente contiene quantità 35 non trascurabili di impurezza derivanti dalla ulteriore condensazione del composto (I) con aminoguanidina. Come è noto, la formazione di tali impurezze accompagna pressoché sistematicamente la preparazione di derivati della aminoguanidina. L'eliminazione delle impurezze in oggetto dal composto (I) 40 comporta notevoli complicazioni di carattere tecnico, e ulteriori diminuzioni di rendimento. 25 According to the technique followed heretofore, compound (I) is prepared by reaction of 2,6-dichlorobenzaldehyde with aminoguanidine carbonate. This process, which is apparently the most linear, however entails some drawbacks, which are particularly sensitive especially on an industrial scale. In fact, the yields of the reaction, which according to Example 1 of British patent 1223491 amount to 74%, on charges of a few grams, decrease significantly during large-scale production. Worse, the industrially obtained product contains non-negligible quantities 35 of impurities deriving from the further condensation of the compound (I) with aminoguanidine. As is known, the formation of these impurities almost systematically accompanies the preparation of aminoguanidine derivatives. The elimination of the impurities in question from the compound (I) 40 involves considerable technical complications, and further decreases in efficiency.
Analoghi inconvenienti si verificano per reazione dell'idra-zione della 2,6-dicluorobenzaldeide con cianammide. Secondo questa alternativa, la formazione di prodotti secondari è anzi 45 più accentuata. Similar drawbacks occur by reaction of the hydration of 2,6-dicluorobenzaldehyde with cyanamide. According to this alternative, the formation of secondary products is indeed 45 more pronounced.
Si è ora trovato che gli inconvenienti più sopra descritti possono essere evitati, e che si può ottenere il composto (I) con alte rese e allo stato di purezza assai elevata, facendo reagire l'idrazione della 2,6-diclorobenzaldeide con un sale di so S-metil-isotiouronio, secondo Io schema qui sotto riportato: It has now been found that the drawbacks described above can be avoided, and that compound (I) can be obtained with high yields and in a very high state of purity, by reacting the hydration of 2,6-dichlorobenzaldehyde with a salt of I know S-methyl-isothiouronium, according to the scheme below:
Ï THE
H H
CM-NH2 + CH S-C-NHg > (I) CM-NH2 + CH S-C-NHg> (I)
In questo modo, infatti, si evita completamente la forma-60 zione di sotto-prodotti. In this way, in fact, the formation of by-products is completely avoided.
La reazione secondo l'invenzione viene opportunamente effettuata per fusione utilizzando cloruro o bromuro di S-me-tilsotiouronio, preferibilmente bromuro, a temperature comprese fra 130-160°C. Al termine della reazione, che viene 65 condotta con i reagenti in rapporto stechiometrico, si addiziona una soluzione al 5% di NaHC03 e quindi si estrae con acetato di etile. Gli estratti organici, dopo lavaggio con acqua, sono essicati e concentrati fino a cristallizzazione incipiente The reaction according to the invention is suitably carried out by fusion using S-methylsothiouronium bromide or chloride, preferably bromide, at temperatures ranging from 130-160 ° C. At the end of the reaction, which is carried out with the reagents in a stoichiometric ratio, a 5% solution of NaHCO3 is added and then extracted with ethyl acetate. The organic extracts, after washing with water, are dried and concentrated until incipient crystallization
3 3
642 346 642 346
della (2,6-diclorobenziliden-amino)-guanidina. Quest'ultima, dopo filtrazione, è trasformata nel corrispondente acetato per cristallizzazione da acido acetico. L'invenzione verrà illustrata dall'esempio che segue. of (2,6-dichlorobenzyliden-amino) -guanidine. The latter, after filtration, is transformed into the corresponding acetate by crystallization from acetic acid. The invention will be illustrated by the following example.
Esempio Example
La miscela di 3,76 kg (20 moli) di idrazone della 2,6-diclorobenzaldeide e 3,42 kg (20 moli) di bromidrato di S-metili-sotiouronio in polvere fine è efficacemente mescolata e quindi riscaldata alla fusione che inizia attorno ai 100°C. Si lascia sotto agitazione a 140°C per 150 minuti quindi dopo raffreddamento a 90 °C, si aggiungono, sempre sotto agitazione, 41 litri di soluzione acquosa di NaHCOa al 5%. La sospensione acquosa così ottenuta è estratta con acetato di etile (40 litri). The mixture of 3.76 kg (20 moles) of hydrazone of 2,6-dichlorobenzaldehyde and 3,42 kg (20 moles) of S-methyl-sothiouronium hydrochloride in fine powder is effectively mixed and then heated to the melting that starts around at 100 ° C. The mixture is left under stirring at 140 ° C for 150 minutes, then after cooling to 90 ° C, 41 liters of 5% NaHCOa aqueous solution are added under stirring. The aqueous suspension thus obtained is extracted with ethyl acetate (40 liters).
Il solvente di estrazione viene essicato su solfato di sodio ani-, dro e concentrato a circa 10 litri. Dopo riposo a 0-5°C per 4 ore si filtra (4,1 kg). La base così ottenuta è sciolta a caldo in acido acetico (12 1). Si aggiunge etere etilico (12 1) quindi 5 si lascia a riposo a 5°C per 10 ore. Si filtra ottenendo 5,1 kg di acetato di (2,6-diclorobenziIiden-amino)-guanidina che, The extraction solvent is dried over anhydrous sodium sulphate and concentrated to about 10 liters. After resting at 0-5 ° C for 4 hours, it is filtered (4.1 kg). The base thus obtained is hot dissolved in acetic acid (12 1). Ethyl ether (12 1) is added, then 5 is left to rest at 5 ° C for 10 hours. It is filtered obtaining 5.1 kg of (2,6-dichlorobenziiden-amino) -guanidine acetate which,
dopo essiccamento sotto vuoto a 60 °C, fonde con decomposizione a 193-195°C. Il prodotto si rivela unitario alla cromatografia su strato sottile. I dati analitici e spettroscopici coinci-io dono con quelli previsti per la formula (I); al tempo stesso non si osserva depressione di punto di fusione con un campione di prodotto preparato secondo la tecnica nota. after drying under vacuum at 60 ° C, it melts with decomposition at 193-195 ° C. The product turns out to be unitary to thin layer chromatography. The analytical and spectroscopic data coincide with those provided for the formula (I); at the same time, no melting point depression is observed with a product sample prepared according to the prior art.
Risultati perfettamente analoghi si ottengono su cariche 10 e 100 volte superiori. Perfectly similar results are obtained on fillers 10 and 100 times higher.
v v
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT30942/78A IT1160360B (en) | 1978-12-18 | 1978-12-18 | PROCESS FOR THE PREPARATION OF (2,6-DICHLOROBENZYLIDENE-AMINO) -GUANIDINE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH642346A5 true CH642346A5 (en) | 1984-04-13 |
Family
ID=11232810
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH947979A CH642346A5 (en) | 1978-12-18 | 1979-10-23 | Process for preparing (2,6-dichlorobenzylidene-amino)-guanidine |
Country Status (7)
| Country | Link |
|---|---|
| AR (1) | AR217924A1 (en) |
| BR (1) | BR7903439A (en) |
| CH (1) | CH642346A5 (en) |
| ES (1) | ES481058A1 (en) |
| GR (1) | GR67642B (en) |
| IT (1) | IT1160360B (en) |
| PT (1) | PT69571A (en) |
-
1978
- 1978-12-18 IT IT30942/78A patent/IT1160360B/en active
-
1979
- 1979-05-04 PT PT69571A patent/PT69571A/en unknown
- 1979-05-15 AR AR276524A patent/AR217924A1/en active
- 1979-05-30 GR GR59219A patent/GR67642B/el unknown
- 1979-05-30 ES ES481058A patent/ES481058A1/en not_active Expired
- 1979-05-31 BR BR7903439A patent/BR7903439A/en unknown
- 1979-10-23 CH CH947979A patent/CH642346A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AR217924A1 (en) | 1980-04-30 |
| GR67642B (en) | 1981-09-01 |
| ES481058A1 (en) | 1980-02-01 |
| IT1160360B (en) | 1987-03-11 |
| IT7830942A0 (en) | 1978-12-18 |
| BR7903439A (en) | 1980-10-07 |
| PT69571A (en) | 1979-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US2938053A (en) | Amino acid analogues | |
| US5312973A (en) | Process for producing n-phosphono-methyl-imino-diacetic acid | |
| ATE125544T1 (en) | METHOD FOR PRODUCING AMIKACIN. | |
| KR20210065120A (en) | Method for preparing calcium alpha-ketoglutarate | |
| PL179578B1 (en) | Synthesis of n-acetloneuraminic acid derivatives | |
| US5162584A (en) | Fluorobenzene derivatives | |
| CH642346A5 (en) | Process for preparing (2,6-dichlorobenzylidene-amino)-guanidine | |
| ATE68478T1 (en) | PROCESS FOR THE PRODUCTION OF 1,6-DI(N3-CYANO-N1-GUANIDINO)HEXANE. | |
| US4978784A (en) | Process for industrial manufacture of sodium parahydroxymandelate | |
| US4650864A (en) | Process for preparing 5-deoxy-L-arabinose | |
| FI67538C (en) | PROCEDURE FOR FRAMSTATION OF AV (Z) -1,2-DIPHENYL-1- (4- (2- (N N-DIMETHYLAMINO) ETHOXY) PHENYL) -1-BUTEN | |
| EP0057889A1 (en) | Process for preparing 1-alkyl-2-chloro-5-nitro-benzene-4-sulphonic acids | |
| US4371472A (en) | Process for preparing cysteamine-S-substituted compounds and derivatives thereof | |
| US4298760A (en) | Process for preparing 1-aminocyclopropane-1-carboxylic acid | |
| US4313894A (en) | Process for the production of 3-cyanopropionamide | |
| US3419616A (en) | Preparation of ninhydrin | |
| RU1836334C (en) | Method for obtaining methyl ether of 3-aminocrotonic acid | |
| US5596099A (en) | Process for the preparation of N-(2-sulfatoethyl)-piperazine in high purity | |
| EP0070467B1 (en) | Process for synthesising n-isopropyl-n'-o-carbomethoxyphenylsulphamide | |
| US4595751A (en) | Perhydro-[2,3-c]-oxazolo-1,4-oxazines and their process of preparation | |
| JPS6127980A (en) | Preparation of hydroxyflavan compound | |
| US4559409A (en) | Process for manufacturing guanylurea sulfamate | |
| US4173581A (en) | Process for the preparation of alkylthiosemicarbazides | |
| US4332958A (en) | Benzylidene glycine ester derivatives | |
| HU9902375D0 (en) | Novel process for producing 2-methoxi-4(n-t-buthylaminocarbonyl)benzosulfochloride |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PUE | Assignment |
Owner name: BIEX SOLARIS AG |
|
| PUE | Assignment |
Owner name: HELSINN S.A. |
|
| PL | Patent ceased |