CH605873A5 - Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. - Google Patents
Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn.Info
- Publication number
- CH605873A5 CH605873A5 CH1588975A CH1588975A CH605873A5 CH 605873 A5 CH605873 A5 CH 605873A5 CH 1588975 A CH1588975 A CH 1588975A CH 1588975 A CH1588975 A CH 1588975A CH 605873 A5 CH605873 A5 CH 605873A5
- Authority
- CH
- Switzerland
- Prior art keywords
- piperazine
- solution
- benzhydryl
- mol
- formic acid
- Prior art date
Links
- DERZBLKQOCDDDZ-JLHYYAGUSA-N cinnarizine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1C\C=C\C1=CC=CC=C1 DERZBLKQOCDDDZ-JLHYYAGUSA-N 0.000 title claims abstract description 12
- 230000001387 anti-histamine Effects 0.000 title claims abstract description 4
- 239000000739 antihistaminic agent Substances 0.000 title claims abstract description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 26
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000019253 formic acid Nutrition 0.000 claims abstract description 13
- NWVNXDKZIQLBNM-UHFFFAOYSA-N diphenylmethylpiperazine Chemical compound C1CNCCN1C(C=1C=CC=CC=1)C1=CC=CC=C1 NWVNXDKZIQLBNM-UHFFFAOYSA-N 0.000 claims abstract description 12
- KJPRLNWUNMBNBZ-QPJJXVBHSA-N (E)-cinnamaldehyde Chemical compound O=C\C=C\C1=CC=CC=C1 KJPRLNWUNMBNBZ-QPJJXVBHSA-N 0.000 claims abstract description 9
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims abstract description 9
- KJPRLNWUNMBNBZ-UHFFFAOYSA-N cinnamic aldehyde Natural products O=CC=CC1=CC=CC=C1 KJPRLNWUNMBNBZ-UHFFFAOYSA-N 0.000 claims abstract description 9
- 229940117916 cinnamic aldehyde Drugs 0.000 claims abstract description 9
- 239000008096 xylene Substances 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 7
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000012442 inert solvent Substances 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- -1 lithium aluminum hydride Chemical compound 0.000 claims description 6
- 239000002244 precipitate Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 4
- 238000002844 melting Methods 0.000 claims description 4
- 230000008018 melting Effects 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- WBYWAXJHAXSJNI-VOTSOKGWSA-M .beta-Phenylacrylic acid Natural products [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 2
- DERZBLKQOCDDDZ-UHFFFAOYSA-N 1-(diphenylmethyl)-4-(3-phenylprop-2-enyl)piperazine Chemical compound C1CN(C(C=2C=CC=CC=2)C=2C=CC=CC=2)CCN1CC=CC1=CC=CC=C1 DERZBLKQOCDDDZ-UHFFFAOYSA-N 0.000 claims description 2
- WGEIOMTZIIOUMA-QPJJXVBHSA-N 1-[(e)-3-phenylprop-2-enyl]piperazine Chemical compound C1CNCCN1C\C=C\C1=CC=CC=C1 WGEIOMTZIIOUMA-QPJJXVBHSA-N 0.000 claims description 2
- WBYWAXJHAXSJNI-SREVYHEPSA-N Cinnamic acid Chemical compound OC(=O)\C=C/C1=CC=CC=C1 WBYWAXJHAXSJNI-SREVYHEPSA-N 0.000 claims description 2
- ZDVDCDLBOLSVGM-UHFFFAOYSA-N [chloro(phenyl)methyl]benzene Chemical compound C=1C=CC=CC=1C(Cl)C1=CC=CC=C1 ZDVDCDLBOLSVGM-UHFFFAOYSA-N 0.000 claims description 2
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 230000017531 blood circulation Effects 0.000 claims description 2
- 238000002512 chemotherapy Methods 0.000 claims description 2
- 229930016911 cinnamic acid Natural products 0.000 claims description 2
- 235000013985 cinnamic acid Nutrition 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 230000005494 condensation Effects 0.000 claims description 2
- 239000003623 enhancer Substances 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000015320 potassium carbonate Nutrition 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000000047 product Substances 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 2
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 230000004936 stimulating effect Effects 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
- C07D295/03—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring with the ring nitrogen atoms directly attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/023—Preparation; Separation; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Prodn. of 1-benzhydryl-4-cinnamyl-piperazine (I) comprises reacting benzhydrylpiperazine (II) with cinnamaldehyde (III) in the presence of formic acid. Reaction is pref. in an inert solvent, e.g. xylene Reaction without solvent is pref. at 120-150 degrees C.(I) has antihistamine and blood circulatory stimulating activities.
Description
Das Benzhydryl4cinnamyl-piperazin findet in der Chemotherapie als Antihistamin und durchblutungsförderndes Mittel Anwendung. Seine Herstellung ist in der belgischen Patentschrift Nr. 556 791 (1957) beschrieben. Gemäss diesem Patent wird entweder Benzhydrylpiperazinmit Zimtsäure chlond kondensiert und das entstandene l-zenznyaryle-cmna- moyl-piperazin mit Lithiumaluminiumhydrid zu 1-Benzhydryl4-cinnamyl-piperazin reduziert, oder die Kondensation erfolgt zwischen Cinnamylpiperazin und Benzhydrylchlorid.
Beide Verfahren sind ziemlich kompliziert, wozu sich noch im ersten Falle die Gefährlichkeit des Lithiumaluminiumhydrids gesellt.
Wir haben nun gefunden, dass das 1-Benzhydryl4-cinnamyl-piperazin auf einfache Art aus billigeren Rohmaterialien in guter Ausbeute hergestellt werden kann. Zu diesem Zwecke werden Benzhydrylpiperazin und Zimtaldehyd in Anwesenheit von Ameisensäure, mit oder ohne Lösungsmittel, kondensiert. Das Verhältnis der Komponenten ist allgemein äquimolekular, kann jedoch leicht variiert werden (z. B. 10% Überschuss an Ameisensäure). Die glatt verlaufende Reaktion ermöglicht die sofortige Abtrennung eines verhältnismässig reinen Produktes, entweder in Form seiner Base, oder eines Salzes mit organischen oder anorganischen Säuren.
Beispiel 1
Zu einer Lösung von 50,5 g (0,2 Mol) Benzhydrylpiperazin (F. 91-92 ) in 400 ml Xylol werden 26,5 g (0,2 Mol) Zimtaldehyd gegeben, wobei unter Exothermie ein weisser Niederschlag entsteht. Man gibt zu diesem Gemisch 10 g (0,22 Mol) 98-100%ige Ameisensäure und erhitzt langsam zum Sieden.
Die Reaktion verläuft unter CO2-Entwicklung und der Niederschlag geht allmählich in Lösung. Nachdem das Gemisch während 8-12 Stunden am Rückfluss gekocht wurde, wird die Reaktionslösung abgekühlt und zur Entfernung der überschüssigen Ameisensäure mit stark verdünnter NaOH- oder NH3-Lösung, dann mit Wasser neutral gewaschen. Die abgetrennte Xylollösung wird über K2CO3 getrocknet, filtriert und durch Eindampfen des Lösungsmittels im Vakuum und Umkristallisieren des Rückstandes aus Athanol das 1-Benzhydryl4cinnamyl-piperazin rein erhalten.
Schmelzpunkt: 118-120". Ausbeute: 75-85% der Theorie.
Aus der getrockneten und filtrierten Xylollösung kann, durch Zugabe der nötigen Menge einer alkoholischen Salzsäurelösung das Dichlorhyd,rat des 1-Benzhydryl4-cinnamylpiperazins gefällt werden, das dann aus Äthanol oder Isopropanol umkristallisiert wird.
Schmelzpunkt: 190-192". Ausbeute: 85-90% der Theorie.
Beispiel 2
Ein Gemisch aus 50,5 g (0,2 Mol) Benzhydrylpiperazin, 26,5 g (0,2 Mol) Zimtaldehyd und 10 g (0,22 Mol) 98-lOO0Ioige Ameisensäure wird langsam aufgeheizt, wobei unter CO2-Entwicklung eine Schmelze entsteht, die dann während 8-12 Stunden auf 120-130 erhitzt wird. Die abgekühlte Schmelze wird dann mit wenig verdünnter NaOH-Lösung digeriert, wobei ein kristalliner Niederschlag entsteht, der dann aus Äthanol umkristallisiert das reine 1-Benzhydryl4-cinnamyl-piperazin liefert. Diese Base kann mit äthanolischer Salzsäurelösung in ihr Dichlorhydrat übergeführt werden;
PATENTANSPRUCH
Verfahren zur Herstellung von 1-Benzhydryl4-cinnamylpiperazin, dadurch gekennzeichnet, dass Benzhydrylpiperazin mit Zimtaldehyd in Anwesenheit von Ameisensäure umgesetzt wird.
UNTERANSPRÜCHE
1. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass obige Umsetzung in einem indifferenten Lösungsmittel wie z. B. Xylol durchgeführt wird.
2. Verfahren nach Patentanspruch, dadurch gekennzeichnet, dass die Umsetzung ohne Lösungsmittel bei einer Temperatur zwischen 120 und 1500 durchgeführt wird.
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
The benzhydryl4cinnamyl-piperazine is used in chemotherapy as an antihistamine and blood circulation enhancer. Its manufacture is described in Belgian patent specification No. 556 791 (1957). According to this patent, either benzhydrylpiperazine is condensed with cinnamic acid and the resulting l-zenznyaryle-cmna-moyl-piperazine is reduced with lithium aluminum hydride to 1-benzhydryl4-cinnamyl-piperazine, or the condensation takes place between cinnamylpiperazine and benzhydryl chloride.
Both processes are rather complicated, and in the first case there is also the danger of lithium aluminum hydride.
We have now found that 1-benzhydryl-4-cinnamyl-piperazine can be prepared in a simple manner from cheaper raw materials in good yield. For this purpose, benzhydrylpiperazine and cinnamaldehyde are condensed in the presence of formic acid, with or without a solvent. The ratio of the components is generally equimolecular, but can easily be varied (e.g. 10% excess of formic acid). The smooth reaction enables a relatively pure product to be separated off immediately, either in the form of its base or a salt with organic or inorganic acids.
example 1
26.5 g (0.2 mol) of cinnamaldehyde are added to a solution of 50.5 g (0.2 mol) of benzhydrylpiperazine (F. 91-92) in 400 ml of xylene, a white precipitate being formed with an exotherm. 10 g (0.22 mol) of 98-100% formic acid are added to this mixture and the mixture is slowly heated to the boil.
The reaction proceeds with evolution of CO2 and the precipitate gradually dissolves. After the mixture has been refluxed for 8-12 hours, the reaction solution is cooled and, to remove the excess formic acid, washed neutral with highly dilute NaOH or NH3 solution and then with water. The separated xylene solution is dried over K2CO3, filtered and the 1-benzhydryl-cinnamyl-piperazine is obtained in pure form by evaporating the solvent in vacuo and recrystallizing the residue from ethanol.
Melting point: 118-120 ". Yield: 75-85% of theory.
The dichlorohydrate of 1-benzhydryl-4-cinnamylpiperazine can be precipitated from the dried and filtered xylene solution by adding the necessary amount of an alcoholic hydrochloric acid solution, which is then recrystallized from ethanol or isopropanol.
Melting point: 190-192 ". Yield: 85-90% of theory.
Example 2
A mixture of 50.5 g (0.2 mol) of benzhydrylpiperazine, 26.5 g (0.2 mol) of cinnamaldehyde and 10 g (0.22 mol) of 98,000,000 formic acid is slowly heated, with the evolution of CO2 arises, which is then heated to 120-130 for 8-12 hours. The cooled melt is then digested with a little dilute NaOH solution, whereby a crystalline precipitate is formed, which then recrystallized from ethanol yields the pure 1-benzhydryl-4-cinnamyl-piperazine. This base can be converted into dichlorohydrate with an ethanolic hydrochloric acid solution;
PATENT CLAIM
Process for the preparation of 1-benzhydryl4-cinnamylpiperazine, characterized in that benzhydrylpiperazine is reacted with cinnamaldehyde in the presence of formic acid.
SUBCLAIMS
1. The method according to claim, characterized in that the above reaction in an inert solvent such. B. xylene is carried out.
2. The method according to claim, characterized in that the reaction is carried out at a temperature between 120 and 1500 without a solvent.
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1588975A CH605873A5 (en) | 1975-12-02 | 1975-12-02 | Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1588975A CH605873A5 (en) | 1975-12-02 | 1975-12-02 | Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH605873A5 true CH605873A5 (en) | 1978-10-13 |
Family
ID=4412811
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1588975A CH605873A5 (en) | 1975-12-02 | 1975-12-02 | Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH605873A5 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703048A (en) * | 1985-01-11 | 1987-10-27 | Kanebo Ltd. | Novel 1-benzhydryl-4-cinnamylpiperazine derivatives, and pharmaceutical compositions comprising said compounds as active ingredient for treating a cerebrovascular disease |
| US4792553A (en) * | 1986-02-04 | 1988-12-20 | Terumo Kabushiki Kaisha | Diene derivatives and vasodilators containing the same |
| CN103254152A (en) * | 2013-03-19 | 2013-08-21 | 珠海保税区丽珠合成制药有限公司 | New synthesis method of cinnarizine |
-
1975
- 1975-12-02 CH CH1588975A patent/CH605873A5/en not_active IP Right Cessation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4703048A (en) * | 1985-01-11 | 1987-10-27 | Kanebo Ltd. | Novel 1-benzhydryl-4-cinnamylpiperazine derivatives, and pharmaceutical compositions comprising said compounds as active ingredient for treating a cerebrovascular disease |
| US4792553A (en) * | 1986-02-04 | 1988-12-20 | Terumo Kabushiki Kaisha | Diene derivatives and vasodilators containing the same |
| CN103254152A (en) * | 2013-03-19 | 2013-08-21 | 珠海保税区丽珠合成制药有限公司 | New synthesis method of cinnarizine |
| CN103254152B (en) * | 2013-03-19 | 2016-01-27 | 珠海保税区丽珠合成制药有限公司 | A kind of novel method of synthesizing CN |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE1695753A1 (en) | Improvements in the preparation of 4-oxopiperidine compounds and certain new 4-oxopiperidine compounds | |
| DE3737825C2 (en) | ||
| DE1073662B (en) | Process for the production of cyanine dyes | |
| CH605873A5 (en) | Antihistaminic 1-benzhydryl-4-cinnamyl-piperazine prodn. | |
| DE60312543T2 (en) | PREPARATION OF CODEIN FROM MORPHINE | |
| DE1026322B (en) | Process for the preparation of 4,4'-bis (dialkylamino) diphenylmethanes | |
| DE952811C (en) | Process for the production of ditetrazole or its salts | |
| DE2636549A1 (en) | PROCESS FOR THE PREPARATION OF 3- (3,5-DICHLOROPHENYL) -HYDANTOIN | |
| DE2626894A1 (en) | PROCESS FOR THE PREPARATION OF 5-ALKYLPICOLIC ACID | |
| AT275518B (en) | Process for the preparation of new 1- (4-oxo-4-phenyl-butyl) -piperidines substituted in the 4-position and of their acid addition salts | |
| AT238174B (en) | Process for the preparation of N- (2,3-dimethylphenyl) anthranilic acid and its salts | |
| AT204045B (en) | Process for the production of new piperazine derivatives and their salts | |
| AT202940B (en) | Process for the preparation of new, racemic or optically active morpholine derivatives and their salts | |
| AT225183B (en) | Process for the preparation of phenylalanine derivatives | |
| AT276439B (en) | Process for the production of new xylitol nicotinates | |
| DE1470120C3 (en) | 1 square bracket to 1- (3-benzoylpropyl) -4-piperidyl square bracket to - and 1 square bracket to 1- (3-benzoylpropyl) -1,2,5,6-tetrahydro-4pyridyl square bracket to -2-benzimidazolinone derivatives. their acid addition salts and processes for their preparation | |
| AT69808B (en) | Process for the preparation of carbazole monosulfonic acids. | |
| AT218526B (en) | Process for the production of new phenthiazine derivatives | |
| CH353736A (en) | Process for the preparation of 3-methylamino-isocamphane | |
| DE1745780C3 (en) | l-Sulfonyläthyl ^ -methyl-S-nitroimidazole and process for their preparation | |
| DE922824C (en) | Process for the preparation of basic compounds | |
| AT230882B (en) | Process for the production of 6-aminochryses | |
| DE2518516C3 (en) | 2- (3,45-trimethoxybenzyl) -3,4-dimethylpyridine | |
| CH412887A (en) | Process for the preparation of addition salts of 1-methyl-3- (di-2-thienylmethylene) piperidine | |
| DE1205105B (en) | Process for the preparation of new heterocyclic compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased | ||
| PL | Patent ceased |