CH500162A - Prepn of d-4-dimethylamino-3-methyl-1,2- - diphenyl-2-butanol from the l-isomer - Google Patents
Prepn of d-4-dimethylamino-3-methyl-1,2- - diphenyl-2-butanol from the l-isomerInfo
- Publication number
- CH500162A CH500162A CH860168A CH860168A CH500162A CH 500162 A CH500162 A CH 500162A CH 860168 A CH860168 A CH 860168A CH 860168 A CH860168 A CH 860168A CH 500162 A CH500162 A CH 500162A
- Authority
- CH
- Switzerland
- Prior art keywords
- diphenyl
- methyl
- butanol
- dimethylamino
- compound
- Prior art date
Links
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-butanol Substances CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 claims abstract description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 15
- 230000000202 analgesic effect Effects 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 4
- TZCXTZWJZNENPQ-UHFFFAOYSA-L barium sulfate Chemical compound [Ba+2].[O-]S([O-])(=O)=O TZCXTZWJZNENPQ-UHFFFAOYSA-L 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 238000010992 reflux Methods 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 2
- 150000007513 acids Chemical class 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- WDIHJSXYQDMJHN-UHFFFAOYSA-L barium chloride Chemical compound [Cl-].[Cl-].[Ba+2] WDIHJSXYQDMJHN-UHFFFAOYSA-L 0.000 claims description 2
- 229910001626 barium chloride Inorganic materials 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 230000032050 esterification Effects 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 239000000706 filtrate Substances 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- YYFIGOPUHPDIBO-UHFFFAOYSA-N propanoic acid;hydrochloride Chemical compound Cl.CCC(O)=O YYFIGOPUHPDIBO-UHFFFAOYSA-N 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Prepn. of D-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol from the L-isomer Title cpd (I) is prepd. from is L-isomer by reaction with acetic anhydride then saponifying the product which results in a Warden Inversion. The D-(I)-propionate hydrochloride is an analgesic while the L form is inactive. This conversion enables the yield of analgesic from the racemic starting material to be doubled.
Description
Verfahren zur Herstellung von D-4-Dimethylamino-3-methyl-1 ,2-diphenyl-2-butanol aus L-4-Dimethylamino-3-methyl-1,2-diphenyl-2-butanol D-4-Dimethylamino-3-methyl- 1 ,2-diphenyl-2 butanol
EMI1.1
ist die Vorstufe zur Herstellung des therapeutisch und klinisch verwendeten Analgetikums D-4-Dimethylamino- 3 -methyl-l ,2-diphenyl-2'-butanol-propionat-hydroc-hlorids und durch Spaltung der entsprechenden Racemverbindung mit optisch aktiven Säuren leicht zugänglich.
Hierbei fällt jedoch zu 50% die analgetisch absolut unwirksame L-Verbindung an. Nach den Ausführungen in dem Lehrbuch der organischen Chemie von Paul Karrer, Ausgabe 1954, S. 302, kann man mitunter mittels der Waldenschen Umkehrung die optisch aktiven Formen ineinander überführen; jedoch ist diese Umwandlung nicht allgemein anwendbar und es ist nicht mit Sicherheit vorauszusagen, ob diese Reaktion anwendbar ist.
Überraschenderweise hat sich nun gezeigt, dass das bei der Racematspaltung anfallende L-4-Dimethylamino3-methyl-1,2-diphenyl-2-butanol glatt in die D-Verbindung umgewandelt werden kann, wodurch sich eine Verdoppelung der Ausbeute ergibt.
Erfindungsgemäss wird vorgeschlagen, die L-Verbindung mit einem Säureanhydrid zu behandeln und die entstandene Verbindung anschliessend zu verseifen. Nachstehend wird die Erfindung anhand eines Beispiels noch näher erläutert.
Beispiel 84 g L4-Dimethylamino-3 -methyl-l ,2-diphenyl-
2-butanol werden in 250 ml Essigsäureanhydrid gelöst. Hierzu gibt man eine kalt bereitete Lösung von
15 ml konzentrierter Schwefelsäure in 100 ml Essigsäureanhydrid und kocht das Ganze eine
Stunde unter Rückfluss. Anschliessend werden im
Vakuum etwa 200 ml abdestilliert.
Zum Rückstand gibt man 250 ml 4 %ige wässrige Schwefelsäure und kocht fünf
Stunden unter Rückfluss. Nach dem Abkühlen gibt man eine Lösung von 96g BaCl2 2H20 in 500 ml Wasser hinzu, saugt das ausgefallene BaSO4 ab, macht das Filtrat unter Kühlung ammoniakalisch und äthert aus. Der Äther wird mit Wasser ge waschen und im Vakuum-Rotationsverdampfer abdestilliert. Der Rückstand ist reines D-4-Di- methylamino-3-methyl-1 2-diphenyl-2-butanol.
Ausbeute: 91%
Durch Veresterung der Base in bekannter Weise, z. B. mit Propionsäureanhydrid, erhält man dar aus D-4-Dimethylamino-3-methyl-1,2-diphenyl
2-butanol-propionat, das als Chlorhydrat eine
Drehung von [a]20 (c = 20 in 1 zeiger wässriger
Lösung) + 548 besitzt.
Es ist möglich geworden, nach Inanspruchnahme des erfindungsgemässen Verfahrens durch Verdoppelung der Ausbeute die Herstellung des Analgetikums lukrativer zu gestalten.
PATENTANSPRUCH
Verfahren zur Herstellung von D-4-Dimethylamino 3-methyl-1,2-diphenyl-2-butanol aus der entsprechenden L-Verbindung, dadurch gekennzeichnet, dass man die L Verbindung mit einem Säureanhydrid behandelt und die entstandene Verbindung anschliessend verseift.
**WARNUNG** Ende DESC Feld konnte Anfang CLMS uberlappen**.
Process for the preparation of D-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol from L-4-dimethylamino-3-methyl-1,2-diphenyl-2-butanol D-4-dimethylamino-3 -methyl-1,2-diphenyl-2 butanol
EMI1.1
is the precursor for the production of the therapeutically and clinically used analgesic D-4-dimethylamino-3-methyl-1,2-diphenyl-2'-butanol propionate hydrochloride and easily accessible by cleavage of the corresponding racemic compound with optically active acids.
In this case, however, 50% of the L-connection, which is absolutely ineffective in analgesic terms, occurs. According to the explanations in the textbook of organic chemistry by Paul Karrer, 1954 edition, p. 302, one can sometimes convert the optically active forms into one another by means of Walden's inversion; however, this conversion is not generally applicable and it cannot be predicted with certainty whether this reaction is applicable.
Surprisingly, it has now been shown that the L-4-dimethylamino3-methyl-1,2-diphenyl-2-butanol obtained in the resolution can be converted smoothly into the D compound, which results in a doubling of the yield.
According to the invention, it is proposed to treat the L-compound with an acid anhydride and then to saponify the resulting compound. The invention is explained in more detail below using an example.
Example 84 g of L4-dimethylamino-3-methyl-1,2-diphenyl
2-butanol are dissolved in 250 ml of acetic anhydride. For this purpose, a cold solution of
15 ml of concentrated sulfuric acid in 100 ml of acetic anhydride and boil the whole thing
Hour under reflux. Then the
Vacuum distilled off about 200 ml.
250 ml of 4% strength aqueous sulfuric acid are added to the residue and five is boiled
Hours under reflux. After cooling, a solution of 96 g of BaCl2 2H20 in 500 ml of water is added, the precipitated BaSO4 is suctioned off, the filtrate is made ammoniacal and etherified with cooling. The ether is washed with water and distilled off in a vacuum rotary evaporator. The residue is pure D-4-dimethylamino-3-methyl-12-diphenyl-2-butanol.
Yield: 91%
By esterification of the base in a known manner, e.g. B. with propionic anhydride, is obtained from D-4-dimethylamino-3-methyl-1,2-diphenyl
2-butanol propionate, which is a
Rotation of [a] 20 (c = 20 in 1 pointer aqueous
Solution) + 548.
It has become possible to make the production of the analgesic more lucrative by doubling the yield after using the process according to the invention.
PATENT CLAIM
Process for the preparation of D-4-dimethylamino 3-methyl-1,2-diphenyl-2-butanol from the corresponding L compound, characterized in that the L compound is treated with an acid anhydride and the compound formed is then saponified.
** WARNING ** End of DESC field could overlap beginning of CLMS **.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE1768509 | 1968-05-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH500162A true CH500162A (en) | 1970-12-15 |
Family
ID=5699764
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH860168A CH500162A (en) | 1968-05-20 | 1968-06-10 | Prepn of d-4-dimethylamino-3-methyl-1,2- - diphenyl-2-butanol from the l-isomer |
Country Status (2)
| Country | Link |
|---|---|
| AT (1) | AT279585B (en) |
| CH (1) | CH500162A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080721A3 (en) * | 1981-11-30 | 1983-08-24 | Sumitomo Chemical Company, Limited | Diphenylalkanoamine derivatives, and their production and use |
| DE10048714A1 (en) * | 2000-09-30 | 2002-04-11 | Gruenenthal Gmbh | 5-amino-1-penlen-3-ol derivatives |
-
1968
- 1968-06-10 CH CH860168A patent/CH500162A/en not_active IP Right Cessation
- 1968-06-21 AT AT595068A patent/AT279585B/en active
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0080721A3 (en) * | 1981-11-30 | 1983-08-24 | Sumitomo Chemical Company, Limited | Diphenylalkanoamine derivatives, and their production and use |
| DE10048714A1 (en) * | 2000-09-30 | 2002-04-11 | Gruenenthal Gmbh | 5-amino-1-penlen-3-ol derivatives |
| US6815443B2 (en) | 2000-09-30 | 2004-11-09 | Gruenenthal Gmbh | 5-Amino-1-pentene-3-ol substituted derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| AT279585B (en) | 1970-03-10 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |