CH363037A - Process for the preparation of a tertiary base of the tetrahydrofuran series - Google Patents
Process for the preparation of a tertiary base of the tetrahydrofuran seriesInfo
- Publication number
- CH363037A CH363037A CH5320657A CH5320657A CH363037A CH 363037 A CH363037 A CH 363037A CH 5320657 A CH5320657 A CH 5320657A CH 5320657 A CH5320657 A CH 5320657A CH 363037 A CH363037 A CH 363037A
- Authority
- CH
- Switzerland
- Prior art keywords
- sep
- methyl
- preparation
- tetrahydrofuran
- tertiary base
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 title claims description 4
- 238000002360 preparation method Methods 0.000 title description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000007868 Raney catalyst Substances 0.000 claims description 3
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 3
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- RRJMVBOQGJYNPF-UHFFFAOYSA-N 5-[(dimethylamino)methyl]-2-methyloxolan-3-ol Chemical compound CC1OC(CN(C)C)CC1O RRJMVBOQGJYNPF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- -1 methyl halides Chemical class 0.000 description 2
- 150000003839 salts Chemical group 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DHZVKDSJDZHVKS-UHFFFAOYSA-N 5-[(dimethylamino)methyl]-2-methylfuran-3-one Chemical compound CC1OC(CN(C)C)=CC1=O DHZVKDSJDZHVKS-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- IHCCAYCGZOLTEU-UHFFFAOYSA-N Furane-3-carboxylic acid Natural products OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 0.000 description 1
- 241000257229 Musca <genus> Species 0.000 description 1
- 229910021607 Silver chloride Inorganic materials 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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 238000005956 quaternization reaction Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008027 tertiary esters Chemical class 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Verfahren zur Herstellung einer tertiären Base der Tetrahydrofuranreihe Die vorliegende Erfindung betrifft ein neues Ver fahren zur Herstellung -eines nacemischen 2-Me- thyl- 3 -.hydroxy- 5 -dimethylaminomethyl-tetrahydro- furans,
welches ein wertrvolles Zwischenprodukt zur Herstellung von Arzneimitteln darstellt.
Es wurde gefunden, dass man das racemische 2 - Methyl- 3 -hydroxy- 5 -dimethylaminomethyl-tetra- hydrofuran der sterischen Formel
EMI0001.0026
in guter Ausbeute herstellen ,kann, .indem man 2 Me- thyl- 3 -oxo-5-dimethylaminomethyl-2,
3-dhydrofuran in schwachalkalischem Medium .in Gegenwart von Raney-Nickel bis zur Aufnahme von zwei Mol Was serstoff hydriert. Beispielsweise kann die Hydrierung in stark verdünnter, z. B. 0,2-1 alaiger wässriger Na tronlauge bei Raumtemperatur und Normaldruck durchgeführt werden.
Unter diesen :Bedingungen kommt die Wasserstoffaufnahme nach Verbrauch von ungefähr zwei Mol zum Stillstand. Dabei ist es über- raschend und war nicht voraussehbar,
d ass bei dieser Hydrierung von den vier theoretisch möglichen race- mischen Stereoisomeren ein einziges, nämlich das jenige mit eis-Stellung aller drei Ringsubstituenten, der Methylgruppe, Hydroxylgruppe und Dimethyl- aminomethylgruppe,
in einer weitaus überwiegenden Menge entsteht.
Das als Ausgangsstoff benötigte ungesättigte basi sche Keton kann in einer gut durchführbaren Reak tionsfolge erhalten werden, welche darin besteht, dass man 2-Methyl-5-formyl-furan-3-carbonsäure-alkyl- ester mit Dimethylformamid in Ameisensäure, nach Leuckart, umsetzt,
den- erhaltenen 2.-Methyl-5-dime- thylaminomethyl furan-3-carbonsäure-alkylester in das Azid der zugrundeliegenden Säure überübrt und das letztere oder viaen daraus durch Umsetzung mit einem Alkohol .bereiteten -Carbaminsäureester mittels Salzsäure
zersetzt.
Der erfindungsgemäss herstellbare basische Alko- hol kann beispielsweise durch Quaternierung müt Me- thylhalogeniden in pharmakologisch wert-volle . Halo genide einer zur Musca:riubase stereoisomeren qua- ternären Base übergeführt werden.
Weitere pharma- kologisch wertvolle quaternäre Salze erhält man z. B. durch Quaternierung mit anderen Alkylhalogeniden, mit Dialkylsulfaten oder Aralkylhalogeniden. Biolo gisch wirksame Stoffe sind auch die Ester, z.
B. das Acetat und das Benzoat des erfindungsgemäss her- stellbaren Alkohols, sowie deren Salze und die von den tertiären Estern sich ableitenden quaternären Ammoniumverbindungen. <I>Beispiel</I> 3,36 g 2-Methyl-3-oxo-5-dimethylaminomethyl- 2,3-dihydrofuran werden- in 100 cm3 dest. Wasser,
welches 0,5g Natriumhydroxyd enthält, in Gegen wart von 5 g Raney Nickel bei Raumtemperatur und Normaldruck bis zur Aufnahme von etwa 1000 cm3 Wasserstoff hydriert. Dann wird vom Katalysator ab- filtriert,
das Filtrat mit 50 cm3 eiskalter konz. Natron lauge versetzt und dreimal mit Methylenchlorid extra hiert.
Die vereinigten Extrakte werden mit gesättigter Natnumchloridlösung gewaschen, mit Natriumsulfat getrocknet und eingedampft. .Der Rückstand wird im Hochvakuum destilliert, wobei das 2-'Vlethyl-3-hy- ,droxy-5-dimethyl-aminomethyl-tetrahydrofuran unter 0,
005 mm Druck bei 36-37 übergeht-
EMI0002.0001
Diese <SEP> tertiäre <SEP> Base <SEP> kann <SEP> man <SEP> in <SEP> .ihr <SEP> .Methojodid
<tb> überführen, <SEP> .indem <SEP> man <SEP> z. <SEP> B. <SEP> 1 <SEP> :
g <SEP> derselben <SEP> in <SEP> 15 <SEP> cm3
<tb> Aceton <SEP> mit <SEP> 1 <SEP> cms <SEP> Methyljodid <SEP> umsetzt. <SEP> Nach <SEP> Ab klingen <SEP> der <SEP> exothermen <SEP> Reaktion <SEP> fügt <SEP> man <SEP> Äther
<tb> zu, <SEP> wobei <SEP> das <SEP> Methojodid <SEP> ausfällt <SEP> und <SEP> sofort <SEP> zu
<tb> kristallisieren <SEP> beginnt. <SEP> .Die <SEP> Kristalle <SEP> werden <SEP> abfil triert <SEP> und <SEP> die <SEP> Substanz <SEP> einmal <SEP> aus <SEP> Aceton <SEP> und <SEP> an schliessend <SEP> aus <SEP> Isopropanol <SEP> umkristallisiert, <SEP> worauf
<tb> sie <SEP> ,bei <SEP> 136=140 <SEP> schmilzt. <SEP> Zur <SEP> Umwandlung <SEP> in <SEP> das
<tb> Methochlorid <SEP> kann <SEP> man <SEP> das <SEP> Methojodid <SEP> in <SEP> Wasser
<tb> m.
<SEP> --rschüssic."em <SEP> Silberchlorid <SEP> schütteln, <SEP> bis <SEP> die
<tb> r <SEP> *t <SEP> <B>üb</B>
<tb> wässrige <SEP> Lösung <SEP> jodfrei <SEP> ist <SEP> .(etwa <SEP> 5 <SEP> Stunden). <SEP> Nach
<tb> zweimaliger <SEP> Umkristallisation <SEP> aus <SEP> Äthanol/Athylacetat
<tb> schmilzt <SEP> das <SEP> sehr <SEP> bygroskopische <SEP> Methochlorid <SEP> bei.
<tb> 137-140 .
Process for the preparation of a tertiary base of the tetrahydrofuran series The present invention relates to a new process for the preparation of a nacemic 2-methyl-3-hydroxy-5-dimethylaminomethyl-tetrahydrofuran,
which is a valuable intermediate product for the manufacture of pharmaceuticals.
It has been found that the racemic 2-methyl-3-hydroxy-5-dimethylaminomethyl-tetrahydrofuran of the steric formula
EMI0001.0026
can be produced in good yield by adding 2 methyl-3-oxo-5-dimethylaminomethyl-2,
3-dhydrofuran in a weakly alkaline medium. In the presence of Raney nickel hydrogenated until the absorption of two moles of hydrogen. For example, the hydrogenation can be carried out in very dilute, e.g. B. 0.2-1 alaiger aqueous sodium hydroxide solution can be carried out at room temperature and normal pressure.
Under these: conditions the hydrogen uptake comes to a standstill after consumption of about two moles. It is surprising and could not be foreseen
that in this hydrogenation of the four theoretically possible racemic stereoisomers only one, namely the one with all three ring substituents, the methyl group, hydroxyl group and dimethylaminomethyl group,
arises in a vast majority.
The unsaturated basic ketone required as a starting material can be obtained in a readily feasible reaction sequence, which consists in converting 2-methyl-5-formyl-furan-3-carboxylic acid alkyl ester with dimethylformamide in formic acid, according to Leuckart ,
the resulting 2.-methyl-5-dimethylaminomethyl furan-3-carboxylic acid alkyl ester is transferred into the azide of the underlying acid and the latter or viaen from it by reaction with an alcohol .prepared carbamic acid ester using hydrochloric acid
decomposed.
The basic alcohol which can be prepared according to the invention can be converted into pharmacologically valuable ones, for example, by quaternizing with methyl halides. Halo genides of a quaternary base stereoisomeric to the Musca: riubase can be converted.
Further pharmacologically valuable quaternary salts are obtained z. B. by quaternization with other alkyl halides, with dialkyl sulfates or aralkyl halides. Biologically active substances are also the esters, z.
B. the acetate and the benzoate of the alcohol which can be prepared according to the invention, as well as their salts and the quaternary ammonium compounds derived from the tertiary esters. <I> Example </I> 3.36 g of 2-methyl-3-oxo-5-dimethylaminomethyl-2,3-dihydrofuran are in 100 cm3 of distilled water. Water,
which contains 0.5 g of sodium hydroxide, hydrogenated in the presence of 5 g of Raney nickel at room temperature and normal pressure up to the absorption of about 1000 cm3 of hydrogen. Then the catalyst is filtered off,
the filtrate with 50 cm3 ice-cold conc. Sodium hydroxide solution is added and the mixture is extracted three times with methylene chloride.
The combined extracts are washed with saturated sodium chloride solution, dried with sodium sulfate and evaporated. .The residue is distilled in a high vacuum, the 2-'Vlethyl-3-hydroxy, hydroxy-5-dimethyl-aminomethyl-tetrahydrofuran below 0,
005 mm print at 36-37 passes -
EMI0002.0001
This <SEP> tertiary <SEP> base <SEP> can <SEP> man <SEP> in <SEP> .your <SEP> .Methoiodide
<tb> transfer, <SEP> .by <SEP> you <SEP> z. <SEP> B. <SEP> 1 <SEP>:
g <SEP> of the same <SEP> in <SEP> 15 <SEP> cm3
<tb> Acetone <SEP> with <SEP> 1 <SEP> cms <SEP> converts methyl iodide <SEP>. <SEP> After <SEP> subsides <SEP> of the <SEP> exothermic <SEP> reaction <SEP> adds <SEP> to <SEP> ether
<tb> to, <SEP> where <SEP> the <SEP> methoiodide <SEP> fails <SEP> and <SEP> immediately <SEP> to
<tb> crystallize <SEP> begins. <SEP>. The <SEP> crystals <SEP> are <SEP> filtered off <SEP> and <SEP> the <SEP> substance <SEP> once <SEP> from <SEP> acetone <SEP> and <SEP> finally <SEP> recrystallized from <SEP> isopropanol <SEP>, <SEP> whereupon
<tb> she <SEP>, at <SEP> 136 = 140 <SEP> melts. <SEP> For <SEP> conversion <SEP> into <SEP> das
<tb> Methochloride <SEP> can <SEP> and <SEP> the <SEP> methoiodide <SEP> in <SEP> water
<tb> m.
<SEP> --rschüssic. "Em <SEP> silver chloride <SEP> shake <SEP> to <SEP> the
<tb> r <SEP> * t <SEP> <B> over </B>
<tb> aqueous <SEP> solution <SEP> iodine-free <SEP> is <SEP>. (about <SEP> 5 <SEP> hours). <SEP> After
<tb> Twice <SEP> recrystallization <SEP> from <SEP> ethanol / ethyl acetate
<tb> melts <SEP> the <SEP> very <SEP> bygroscopic <SEP> methochloride <SEP> at.
<tb> 137-140.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5320657A CH363037A (en) | 1957-11-29 | 1957-11-29 | Process for the preparation of a tertiary base of the tetrahydrofuran series |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH5320657A CH363037A (en) | 1957-11-29 | 1957-11-29 | Process for the preparation of a tertiary base of the tetrahydrofuran series |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH363037A true CH363037A (en) | 1962-07-15 |
Family
ID=4518508
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH5320657A CH363037A (en) | 1957-11-29 | 1957-11-29 | Process for the preparation of a tertiary base of the tetrahydrofuran series |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH363037A (en) |
-
1957
- 1957-11-29 CH CH5320657A patent/CH363037A/en unknown
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