DE1093368B - Process for the preparation of piperazine derivatives - Google Patents
Process for the preparation of piperazine derivativesInfo
- Publication number
- DE1093368B DE1093368B DEM40246A DEM0040246A DE1093368B DE 1093368 B DE1093368 B DE 1093368B DE M40246 A DEM40246 A DE M40246A DE M0040246 A DEM0040246 A DE M0040246A DE 1093368 B DE1093368 B DE 1093368B
- Authority
- DE
- Germany
- Prior art keywords
- preparation
- piperazine
- solution
- ecm
- piperazine derivatives
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000004885 piperazines Chemical class 0.000 title description 3
- 229940066771 systemic antihistamines piperazine derivative Drugs 0.000 title description 2
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 claims description 4
- 230000000954 anitussive effect Effects 0.000 claims description 3
- KTACZRWRTSQVNO-UHFFFAOYSA-N 1-phenyl-2-piperazin-1-ylethanone Chemical compound C=1C=CC=CC=1C(=O)CN1CCNCC1 KTACZRWRTSQVNO-UHFFFAOYSA-N 0.000 claims description 2
- 229940124584 antitussives Drugs 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical compound C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims 1
- 150000004820 halides Chemical class 0.000 claims 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 6
- -1 1-phenacyl-4- (2,2-dimethylol-3-hydroxypropyl) piperazine Chemical compound 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 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
- 229960004126 codeine Drugs 0.000 description 3
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- UXQHRRWIFFJGMQ-UHFFFAOYSA-N 3-piperazin-1-ylpropane-1,2-diol Chemical compound OCC(O)CN1CCNCC1 UXQHRRWIFFJGMQ-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- DGPGLGUNXIOESS-UHFFFAOYSA-N OCC(CN1CCN(CC(C2=CC=CC=C2)=O)CC1)O Chemical compound OCC(CN1CCN(CC(C2=CC=CC=C2)=O)CC1)O DGPGLGUNXIOESS-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- JMSRBKPMLUGHCR-UHFFFAOYSA-N bromohydrin Chemical compound BrC[C]1CO1 JMSRBKPMLUGHCR-UHFFFAOYSA-N 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000011121 sodium hydroxide Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DEUTSCHESGERMAN
KL. 12 ρ bKL. 12 ρ b
INTERNAT. KL. C 07 dINTERNAT. KL. C 07 d
PATENTAMTPATENT OFFICE
M 40246 IVb/12pM 40246 IVb / 12p
ANMKLDETAG: 20. JANUAR 1959 NOTICE DATE: JANUARY 20, 1959
BEKANNTMACHUNG DER ANMELDUNG UND AUSGABE DER AUSLEGESCHRIFT: 24. NOVEMBER 1960NOTICE THE REGISTRATION AND ISSUE OF THE EDITORIAL: NOVEMBER 24, 1960
Die Erfindung bezieht sich auf ein Verfahren zur Herstellung von hustenreizstillend wirkenden Phenacylpiperazinen der allgemeinen FormelThe invention relates to a process for the preparation of cough-relieving phenacylpiperazines the general formula
Verfahren zur Herstellung von PiperazinderivatenProcess for the preparation of piperazine derivatives
>— CO-CH9-N'> - CO-CH 9 -N '
N —RNO
in der R einen durch mindestens zwei Hydroxylgruppen substituierten Alkylrest darstellt.in which R represents an alkyl radical substituted by at least two hydroxyl groups.
Die Produkte sind in pharmakologischer Hinsicht wegen ihrer hustenreizstillenden Wirkung und ihrer sehr geringen Giftigkeit von Bedeutung.The products are pharmacological because of their antitussive effect and their very low levels Toxicity matters.
Wie aus der folgenden Tabelle hervorgeht, ist die hustenreizstillende Wirksamkeit der Verfahrensprodukte nicht nur derjenigen des Codeins, sondern auch den gemäß Patent 1070186 erhältlichen Piperazinen überlegen. As can be seen from the following table, the antitussive efficacy of the process products superior not only to that of codeine, but also to the piperazines obtainable according to patent 1070186.
Anmelder:
Henri Morren, Forest, Brüssel (Belgien)Applicant:
Henri Morren, Forest, Brussels (Belgium)
Vertreter: Dr.-Ing. A. van der Werth, Patentanwalt, Hamburg-Harburg I1 Wilstorfer Str. 32Representative: Dr.-Ing. A. van der Werth, patent attorney, Hamburg-Harburg I 1 Wilstorfer Str. 32
Beanspruchte Priorität: Belgien vom 21. Januar, 14. Juli und 16. August 1958Claimed priority: Belgium from January 21, July 14 and August 16, 1958
Henri Morren, Forest, Brüssel (Belgien), ist als Erfinder genannt wordenHenri Morren, Forest, Brussels (Belgium), has been named as the inventor
Dabei ist die Giftigkeit der neuen Produkte deutlich geringer als diejenige des Codeins.The toxicity of the new products is significantly lower than that of codeine.
Erfindungsgemäß kann man diese Stoffe herstellen, indem man Phenacylchlorid mit einem R-Piperazin unter sich bekannten Bedingungen umsetzt.According to the invention, these substances can be prepared by reacting phenacyl chloride with an R-piperazine implemented under known conditions.
Man kann sie auch synthetisieren, indem man in der Wärme ein 1-Phenacylpiperazin mit einem R-Halogenid reagieren läßt, wobei R die in der allgemeinen Formel angegebene Bedeutung hat.They can also be synthesized by warming a 1-phenacylpiperazine with an R-halide lets react, where R has the meaning given in the general formula.
Die anorganischen und organischen Salze dieser Stoffe sind in üblicher Weise erhältlich.The inorganic and organic salts of these substances can be obtained in the usual way.
l-Phenacyl-4-(2,2-dimethylol-3-hydroxypropyl)-piperazin 1-phenacyl-4- (2,2-dimethylol-3-hydroxypropyl) piperazine
CH,OHCH, OH
CO-CH2-N N-CH2-C-CH2OHCO-CH 2 -N N-CH 2 -C-CH 2 OH
CH2OHCH 2 OH
Zu 0,11 Mol 1-Phenacylpiperazin-dimaleat setzt man eine wäßrige Lösung von Ätznatron zu. Die freigesetzteTo 0.11 mol of 1-phenacylpiperazine dimaleate is added an aqueous solution of caustic soda too. The released
009 649/404009 649/404
Base wird dreimal mit 100 ecm Benzol ausgezogen und die benzolische Extraktionslösung mit Kaliumcarbonat getrocknet. Man vertreibt dann das Lösungsmittel und löst den Rückstand in 100 ecm n-Butanol auf. Zu dieser Lösung setzt man eine Lösung von 0,1 Mol Pentaerythritbromhydrin in 50 ecm n-Butanol zu und erwärmt dann unter Rückfluß 10 Stunden. Dann kühlt man das Reaktionsgemisch ab und setzt 300 ecm wasserfreien Äther zu. Unter gutem Rühren läßt man dann stehen, dekantiert die Lösung und filtriert sie über Tierkohle. Man verdampft das Lösungsmittel im Vakuum und löst den Rückstand in siedendem Äthanol. Nach dem Abkühlen erhält man l-Phenacyl-4-(2,2-dimethylol-3-hydroxypropyl)-piperazin mit einem Schmelzpunkt von 1290C. Ausbeute 25%.Base is extracted three times with 100 ecm of benzene and the benzene extraction solution is dried with potassium carbonate. The solvent is then driven off and the residue is dissolved in 100 ecm of n-butanol. A solution of 0.1 mol of pentaerythritol bromohydrin in 50 ecm of n-butanol is added to this solution and the mixture is then heated under reflux for 10 hours. The reaction mixture is then cooled and 300 ecm of anhydrous ether is added. The solution is then allowed to stand with thorough stirring, decanted and filtered through animal charcoal. The solvent is evaporated off in vacuo and the residue is dissolved in boiling ethanol. After cooling, l-phenacyl-4 is obtained (2,2-dimethylol-3-hydroxypropyl) -piperazine having a melting point of 129 0 C. Yield 25%.
Die Analyse hat folgendes ergeben:The analysis showed the following:
Berechnet
gefundenCalculated
found
N 8,69 %;
N 8,62%.N 8.69%;
N 8.62%.
Das als Ausgangsprodukt verwendete 1-Phenacylpiperazin-dimaleat war folgendermaßen hergestellt worden: The 1-phenacylpiperazine dimaleate used as the starting product was made as follows:
Man erwärmt eine Lösung von 3 Mol Piperazin in 11 Toluol, setzt in der Wärme und unter Rühren eine Lösung von 1 Mol Phenacylchlorid in 250 ecm Toluol zu und erwärmt am Rückfluß 10 Stunden. Dann läßt man über Nacht stehen und filtriert den erhaltenen Niederschlag ab. Das Toluolfiltrat wird zweimal mit WasserA solution of 3 moles of piperazine in 11 is heated Toluene, puts a solution of 1 mole of phenacyl chloride in 250 ecm of toluene in the heat and with stirring and heated to reflux for 10 hours. The mixture is then left to stand overnight and the precipitate obtained is filtered off away. The toluene filtrate is washed twice with water
xo gewaschen. Man trocknet das Toluol und dampft es im Vakuum ab. Den hierbei erhaltenen Rückstand löst man in 500 ecm Äthanol und gießt die erwärmte Lösung in eine warme Lösung von 2 Mol Maleinsäure in 900 ecm Äthanol. Man läßt kristallisieren und erhält so 305 g Dimaleat des 1-Phenacylpiperazins mit einem Schmelzpunkt von 1600C unter Zersetzung.xo washed. The toluene is dried and evaporated in vacuo. The residue obtained in this way is dissolved in 500 ecm of ethanol and the heated solution is poured into a warm solution of 2 moles of maleic acid in 900 ecm of ethanol. It is allowed to crystallize and are thus obtained 305 g of 1-dimaleate Phenacylpiperazins having a melting point of 160 0 C with decomposition.
Die Analyse hat folgendes ergeben:The analysis showed the following:
Berechnet
gefundenCalculated
found
N 6,42%;
N 6,36%.N 6.42%;
N 6.36%.
Beispiel 2 1 -Phenacyl-4-(2,3-dihydroxypropyl) -piperazin-HydrochloridExample 2 1 -Phenacyl-4- (2,3-dihydroxypropyl) -piperazine hydrochloride
C8H8 C 8 H 8
!_. \J \_s JtT ο ' jLN! _. \ J \ _s JtT ο 'jLN
N-CH2-CHOH-CH2OH · HClN-CH 2 -CHOH-CH 2 OH · HCl
Zu einer Lösung von 2 Mol l-(2,3-Dihydroxypropyl)-piperazin in 11 warmem n-Butanol setzt man langsam und unter mechanischem Rühren eine Lösung von 2 Mol Phenacylchlorid in 500 ecm n-Butanol zu. Man erwärmt dann unter Rückfluß 5 Stunden, kühlt ab und läßt kristallisieren. Die Kristalle werden abfiltriert und aus 3,51 siedendem Methanol umkristallisiert. Man erhält mit einer Ausbeute von 76% das Chlorhydrat des 1 -Phenacyl-4-(2,3-dihydroxypropyl)-piperazins. Schmelzpunkt 172° C.It is slowly added to a solution of 2 mol of 1- (2,3-dihydroxypropyl) piperazine in 11% of warm n-butanol and with mechanical stirring a solution of 2 mol of phenacyl chloride in 500 ecm of n-butanol. One warms up then reflux for 5 hours, cool and allow to crystallize. The crystals are filtered off and off 3.51 boiling methanol recrystallized. You get the chlorohydrate of 1-phenacyl-4- (2,3-dihydroxypropyl) piperazine with a yield of 76%. Melting point 172 ° C.
Claims (1)
Deutsches Patent Nr. 1 070 186.Legacy Patents Considered:
German Patent No. 1 070 186.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| BE1093368X | 1958-01-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1093368B true DE1093368B (en) | 1960-11-24 |
Family
ID=3893290
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DEM40246A Pending DE1093368B (en) | 1958-01-21 | 1959-01-20 | Process for the preparation of piperazine derivatives |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE1093368B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1070186B (en) | 1959-12-03 | Morren Forest Brüssel Henri (Belgien) | I Process for the production of antitussive 1,4-disubstituted piperazms |
-
1959
- 1959-01-20 DE DEM40246A patent/DE1093368B/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1070186B (en) | 1959-12-03 | Morren Forest Brüssel Henri (Belgien) | I Process for the production of antitussive 1,4-disubstituted piperazms |
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