CH491103A - Process for the production of chroman derivatives - Google Patents
Process for the production of chroman derivativesInfo
- Publication number
- CH491103A CH491103A CH787069A CH787069A CH491103A CH 491103 A CH491103 A CH 491103A CH 787069 A CH787069 A CH 787069A CH 787069 A CH787069 A CH 787069A CH 491103 A CH491103 A CH 491103A
- Authority
- CH
- Switzerland
- Prior art keywords
- tocopherol
- chroman derivatives
- production
- formula
- alkanoyl
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 10
- VZWXIQHBIQLMPN-UHFFFAOYSA-N chromane Chemical class C1=CC=C2CCCOC2=C1 VZWXIQHBIQLMPN-UHFFFAOYSA-N 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title description 2
- -1 alkanoyl halide Chemical class 0.000 claims description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 3
- 239000012346 acetyl chloride Substances 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 230000001419 dependent effect Effects 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 15
- 239000011732 tocopherol Substances 0.000 description 12
- 229960001295 tocopherol Drugs 0.000 description 9
- 229930003427 Vitamin E Natural products 0.000 description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 6
- 229930003799 tocopherol Natural products 0.000 description 6
- 239000011709 vitamin E Substances 0.000 description 6
- 235000019165 vitamin E Nutrition 0.000 description 6
- 229940046009 vitamin E Drugs 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 235000010384 tocopherol Nutrition 0.000 description 3
- 235000019149 tocopherols Nutrition 0.000 description 3
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 3
- QUEDXNHFTDJVIY-UHFFFAOYSA-N γ-tocopherol Chemical class OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1 QUEDXNHFTDJVIY-UHFFFAOYSA-N 0.000 description 3
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- GVJHHUAWPYXKBD-QLVXXPONSA-N (S,R,R)-alpha-tocopherol Chemical compound [H][C@@](C)(CCCC(C)C)CCC[C@@]([H])(C)CCC[C@@]1(C)CCC2=C(O1)C(C)=C(C)C(O)=C2C GVJHHUAWPYXKBD-QLVXXPONSA-N 0.000 description 1
- LTVDFSLWFKLJDQ-IEOSBIPESA-N 2-[(3r,7r,11r)-3-hydroxy-3,7,11,15-tetramethylhexadecyl]-3,5,6-trimethylcyclohexa-2,5-diene-1,4-dione Chemical compound CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@](C)(O)CCC1=C(C)C(=O)C(C)=C(C)C1=O LTVDFSLWFKLJDQ-IEOSBIPESA-N 0.000 description 1
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- ZAKOWWREFLAJOT-ADUHFSDSSA-N [2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-yl] acetate Chemical group CC(=O)OC1=C(C)C(C)=C2OC(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-ADUHFSDSSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- ZAKOWWREFLAJOT-UHFFFAOYSA-N d-alpha-Tocopheryl acetate Natural products CC(=O)OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-UHFFFAOYSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000000687 hydroquinonyl group Chemical class C1(O)=C(C=C(O)C=C1)* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
- C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
- C07D311/72—3,4-Dihydro derivatives having in position 2 at least one methyl radical and in position 6 one oxygen atom, e.g. tocopherols
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrane Compounds (AREA)
Description
Verfahren zur Herstellung von Chromanderivaten
Die vorliegende Erfindung betrifft ein Verfahren zur Herstellung von Chromanderivaten der Formel
EMI1.1
in der R1 Halogen und R2 Alkanoyl bedeutet.
Das erfindungsgemässe Verfahren eröffnet einen Zugang zu Verbindungen der Formel I, die die absolute Konfiguration [2R, 4'R, 8'R] besitzen. In der Formel I ist die sterische Anordnung der an den asymmetrischen Kohlenstoffatomen sitzenden Substituenten bildlich dargestellt [siehe hierzu Experientia 12 (1956), S. 81].
In den Verbindungen der Formel I stellt der Substituent Ri insbesondere ein Chloratom und der Substituent R ; ; bevorzugt einen niederen Alkanoylrest mit bis zu 4 Kohlenstoffatomen, wie Acetyl oder Propionyl, dar.
Die erhaltenen in 5-Stellung durch einen Halogenmethylrest und in 6-Stellung durch eine Alkanoyloxygruppe substituierten Chromanderivate können gegebenenfalls in an sich bekannter Weise, z. B. durch Reduzieren in die entsprechenden Tocopherylester übergeführt und anschliessend gegebenenfalls durch Verseifen in [2R, 4'R, 8'R]-oc-Tocopherol umgewandelt werden.
Es ist bekannt, dass die verschiedenen in der Natur vorkommenden Tocopherole eine unterschiedliche Vitamin-E-Wirksamkeit haben. Setzt man beispielsweise die Vitamin-E-Aktivität des natürlichen [2R, 4'R, 8'RI-m- -Tocopherols gleich 100, so beträgt die Vitamin-E-Akti vität von d-, 8-Tocopherol 15, von d-y-Tocopherol 3 und von d-8-Tocopherol 2.
Aus diesem Grunde hat es nicht an Versuchen gefehlt, die weniger aktiven Tocopherole in m-Tocopherol zu überführen. Die in der Literatur beschriebenen Umwandlungsmethoden, bei denen die aus den betreffenden Tocopherolen durch Ringöffnung erhaltenen Hydrochinonderivate methyliert und anschliessend cyclisiert werden, liefern jedoch stets ein Gemisch zweier Epimeren bestehend aus : ca. 41% [2R, 4'R, 8'R]-α-Tocopherol und ca. 59% [2S, 4'R, 8'R]-a-Tocopherol.
Die Vitamin-E-Aktivität beträgt für [2RS, 4'R, 8'R]-x-Tocopherylacetat = 73 [2R, 4'R, 8'R]- > a-Tocopherylacetat = 100 [2S, 4'R, 8'R]-a-Tocopherylacetat = 42
Die präparative Auftrennung des Epimerengemisches und Isolierung des [2R, 4'R, 8'R]-a-Tocopherols mit der höchsten Vitamin-E-Aktivität ist schwer durchführbar und verlustreich.
Das durch die vorliegende Erfindung gekennzeichnete Verfahren macht es nunmehr möglich, das in der Konfi- guration des natürlichen x-Tocopherols vorliegende -To- copherylchinon mit einer Retention von über 90% zu Chromanderivaten mit [2R, 4'R, 8'R]-Konfiguration zu cyclisieren, welche in [2R, 4'R, 8'R]-a.-Tocopherol über- geführt werden können.
Das erfindungsgemässe Verfahren ist dadurch gekennzeichnet, dass man 2- ( [3R, 7R, llR]-3', 7', 11', 15'-Tetra- methyl-3'-hydroxy-hexadecyl)-trimethyl-p-benzochinon der Formel II
EMI2.1
in Gegenwart eines Alkanoylhalogenids cyclisiert.
Von den Alkanoylhalogeniden sind niedere Alkanoyl- halogenide bevorzugt, z. B. das Propionylchlorid und ins- besondere das Acetylchlorid. Die Alkanoylhalogenide können ohne Zusatz eines Lösungsmittels verwendet werden.
Die Cyclisierung wird vorzugsweise bei gemässigter Temperatur, z. B. bei 0-40 C, insbesondere bei Raumtemperatur durchgeführt. Es genügt im allgemeinen, das Alkanoylhalogenid auf das Chinon längere Zeit einwirken zu lassen.
Die so erhaltenen Chromanderivate, insbesondere das in der 5-Methylgruppe chlorsubstituierte [2R, 4'R, 8'R]-x-Tocopherylacetat sowie das daraus erhältliche [2R, 4'R, 8'R]-x-Tocopherol zeichnen sich durch eine hohe Vitamin-E-Aktivität aus.
Beispiel 11 g α-Tocophenylchinon werden in 55 ml Acetylchlorid gelöst und 16 Stunden bei Raumtemperatur aufbewahrt. Das Reaktionsgemisch wird dann auf Eis gegossen, mit Äther extrahiert, die lipophile Phase sechsmal mit Wasser gewaschen, mit Natriumsulfat getrocknet und eingedampft. Man erhält 5-Chlormethyl-Y-tocopherylace- tat in Form eines öls, das aus Methanol kristallisiert werden kann. U. V.-Absorptionsspektrum (in Feinsprit) : =294mtL ; E=53.
Process for the production of chroman derivatives
The present invention relates to a process for the preparation of chroman derivatives of the formula
EMI1.1
in which R1 is halogen and R2 is alkanoyl.
The process according to the invention opens up access to compounds of the formula I which have the absolute configuration [2R, 4'R, 8'R]. In formula I, the steric arrangement of the substituents located on the asymmetric carbon atoms is shown graphically [see Experientia 12 (1956), p. 81].
In the compounds of the formula I, the substituent Ri represents in particular a chlorine atom and the substituent R; ; preferably a lower alkanoyl radical with up to 4 carbon atoms, such as acetyl or propionyl.
The chroman derivatives obtained in the 5-position by a halomethyl radical and in the 6-position by an alkanoyloxy group can optionally be used in a manner known per se, for. B. converted into the corresponding tocopheryl esters by reducing and then optionally converted into [2R, 4'R, 8'R] -oc-tocopherol by saponification.
It is known that the various naturally occurring tocopherols have different levels of vitamin E activity. For example, if the vitamin E activity of the natural [2R, 4'R, 8'RI-m- tocopherol is equal to 100, the vitamin E activity of d-, 8-tocopherol is 15, of dy- Tocopherol 3 and of d-8 tocopherol 2.
For this reason there has been no shortage of attempts to convert the less active tocopherols into m-tocopherol. The conversion methods described in the literature, in which the hydroquinone derivatives obtained from the tocopherols in question by ring opening are methylated and then cyclized, always provide a mixture of two epimers consisting of: approx. 41% [2R, 4'R, 8'R] - α-tocopherol and about 59% [2S, 4'R, 8'R] -α-tocopherol.
The vitamin E activity is for [2RS, 4'R, 8'R] -x-tocopheryl acetate = 73 [2R, 4'R, 8'R] -> α-tocopheryl acetate = 100 [2S, 4'R, 8'R] -α-tocopheryl acetate = 42
The preparative separation of the epimer mixture and isolation of the [2R, 4'R, 8'R] -a-tocopherol with the highest vitamin E activity is difficult to carry out and involves high losses.
The method characterized by the present invention now makes it possible to convert the tocopherylquinone present in the configuration of the natural x-tocopherol with a retention of over 90% to chroman derivatives with [2R, 4'R, 8'R] - To cyclize configuration, which can be converted into [2R, 4'R, 8'R] -a.-tocopherol.
The process according to the invention is characterized in that 2- ([3R, 7R, IIR] -3 ', 7', 11 ', 15'-tetra-methyl-3'-hydroxy-hexadecyl) -trimethyl-p-benzoquinone is used Formula II
EMI2.1
cyclized in the presence of an alkanoyl halide.
Of the alkanoyl halides, lower alkanoyl halides are preferred, e.g. B. propionyl chloride and in particular acetyl chloride. The alkanoyl halides can be used without adding a solvent.
The cyclization is preferably carried out at a moderate temperature, e.g. B. carried out at 0-40 C, especially at room temperature. It is generally sufficient to let the alkanoyl halide act on the quinone for a long time.
The chroman derivatives obtained in this way, in particular the [2R, 4'R, 8'R] -x-tocopheryl acetate which is chlorine-substituted in the 5-methyl group, and the [2R, 4'R, 8'R] -x-tocopherol obtainable therefrom, are distinguished by high vitamin E activity.
Example 11 g of α-tocophenylquinone are dissolved in 55 ml of acetyl chloride and stored at room temperature for 16 hours. The reaction mixture is then poured onto ice, extracted with ether, the lipophilic phase washed six times with water, dried with sodium sulfate and evaporated. 5-Chloromethyl-Y-tocopheryl acetate is obtained in the form of an oil which can be crystallized from methanol. U.V. absorption spectrum (in fine spirit): = 294mtL; E = 53.
Claims (1)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH787069A CH491103A (en) | 1965-10-12 | 1965-10-12 | Process for the production of chroman derivatives |
| NL6614239A NL6614239A (en) | 1965-10-12 | 1966-10-10 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH787069A CH491103A (en) | 1965-10-12 | 1965-10-12 | Process for the production of chroman derivatives |
| CH1404965A CH475977A (en) | 1965-10-12 | 1965-10-12 | Process for the production of a chroman derivative |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH491103A true CH491103A (en) | 1970-05-31 |
Family
ID=25702376
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH787069A CH491103A (en) | 1965-10-12 | 1965-10-12 | Process for the production of chroman derivatives |
Country Status (2)
| Country | Link |
|---|---|
| CH (1) | CH491103A (en) |
| NL (1) | NL6614239A (en) |
-
1965
- 1965-10-12 CH CH787069A patent/CH491103A/en not_active IP Right Cessation
-
1966
- 1966-10-10 NL NL6614239A patent/NL6614239A/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NL6614239A (en) | 1967-04-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PL | Patent ceased |