DE2436332A1 - SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTION - Google Patents
SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTIONInfo
- Publication number
- DE2436332A1 DE2436332A1 DE19742436332 DE2436332A DE2436332A1 DE 2436332 A1 DE2436332 A1 DE 2436332A1 DE 19742436332 DE19742436332 DE 19742436332 DE 2436332 A DE2436332 A DE 2436332A DE 2436332 A1 DE2436332 A1 DE 2436332A1
- Authority
- DE
- Germany
- Prior art keywords
- hydrogen
- chemical factory
- tetrahydrofuran
- substituted tetrahydrofurans
- production
- 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 6
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 239000000126 substance Substances 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 12
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- NFHRNKANAAGQOH-UHFFFAOYSA-N triphenylstannane Chemical compound C1=CC=CC=C1[SnH](C=1C=CC=CC=1)C1=CC=CC=C1 NFHRNKANAAGQOH-UHFFFAOYSA-N 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- LEVJVKGPFAQPOI-UHFFFAOYSA-N phenylmethanone Chemical compound O=[C]C1=CC=CC=C1 LEVJVKGPFAQPOI-UHFFFAOYSA-N 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 239000012362 glacial acetic acid Substances 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 150000003180 prostaglandins Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical class O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- DERLEQYHZCMIPL-UHFFFAOYSA-N 1-(triphenyl-$l^{5}-phosphanylidene)heptan-2-one Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)CCCCC)C1=CC=CC=C1 DERLEQYHZCMIPL-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- YEJRWHAVMIAJKC-UHFFFAOYSA-N 4-Butyrolactone Chemical group O=C1CCCO1 YEJRWHAVMIAJKC-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- -1 Oct-1-en-3-onyl Chemical group 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910000039 hydrogen halide Inorganic materials 0.000 description 1
- 239000012433 hydrogen halide Substances 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002997 prostaglandinlike Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
Description
CHEMISCHE FABRIKEN
Patent-u.Lizenz-Abteilung . Ludwigshafen/Rh. , 23.7.I974CHEMICAL FACTORY
Patent & License Department. Ludwigshafen / Rh. , July 23, 1974
Substituierte Tetrahydrofurane und Verfahren zu deren HerstellungSubstituted tetrahydrofurans and processes for their preparation
Die Erfindung betrifft neue, substituierte Tetrahydrofurane, die zur Herstellung von"Oxaprostaglandxnen geeignet sind.The invention relates to new, substituted tetrahydrofurans which are suitable for the production of "oxaprostaglandxnen" are.
Prostaglandine sind relativ schwer zugängliche Verbindungen. Da sie ein recht breites Wirkungsspektrum besitzen, ist eine gezielte therapeutische Anwendung sehr schwierig. Es ist daher von Interesse, Prostaglandin-ähnliche Substanzen darzustellen, die sich besser anwenden lassen. Prostaglandinderivate, die anstelle des Cyclopentanrings einen Butyrolactonring besitzen, sind bereits bekannt, nicht jedoch solche, die sich von einem Tetrahydrofurangerüst ableiten. Prostaglandins are compounds that are relatively difficult to access. Since they have a fairly broad spectrum of activity, a targeted therapeutic application is very difficult. It is therefore of interest to use prostaglandin-like substances that can be used better. Prostaglandin derivatives, which instead of the cyclopentane ring a Have butyrolactone ring are already known, but not those which are derived from a tetrahydrofuran structure.
Es wurde nun ein Zwischenprodukt gefunden, aus dem sich leicht 11-Oxaprostaglandine herstellen lassen.An intermediate product has now been found from which 11-oxaprostaglandins can easily be prepared.
Gegenstand der Erfindung sind Verbindungen der allgemeinen Formel IThe invention relates to compounds of the general formula I
509887/1013509887/1013
ORIGINAL INSPECTEDORIGINAL INSPECTED
CHEMISCHE FABRIKENCHEMICAL FACTORY
4 3 6 3 34 3 6 3 3
worin A die Gruppewhere A is the group
C=OC = O
OHOH
oderor
OHOH
mit R in der Bedeutung eines Alkylrestes mit 1-4 Kohlenstoffatomen ist undwith R meaning an alkyl radical with 1-4 carbon atoms is and
B einen verzweigten oder unverzweigten Alkylrest mit 1-10 Kohlenstoffatomen bedeutet.B denotes a branched or unbranched alkyl radical having 1-10 carbon atoms.
Gegenstand der Erfindung ist weiter ein Verfahren zur Herstellung von Verbindungen der allgemeinen Formel I, welches darin besteht, dass man eine Verbindung der allgemeinen Formel IIThe invention also relates to a method of production of compounds of the general formula I, which consists in the fact that one is a compound of the general formula II
CH3-CO-OCH 3 -CO-O
CH3CO-CH 3 CO-
••■■\•• ■■ \
00C2Hr 00C 2 H r
CHOR-CH2ORCHORUS-CH 2 OR
worin R ein Acetyl- oder Benzoylrest darstellt, mit Chloroder Bromwasserstoff reagieren lässt, einengt, in dem Rückstand mit Triphenylzinnhydrid das Halogen gegen Wasserstoff austauscht, das so erhaltene 2ß-(l',2'-Diacyloxyäthyl)-3acarbäthoxymethyl-4a-acetoxy-tetrahydrofuran mit Säure behandelt, einer Glykolspaltung unterwirft und anschliessend nach Wittig umsetzt.wherein R represents an acetyl or benzoyl radical, with chlorine or Lets hydrogen bromide react, constricts, in the residue with triphenyltin hydride the halogen against hydrogen exchanges the 2ß- (l ', 2'-diacyloxyethyl) -3acarbäthoxymethyl-4a-acetoxy-tetrahydrofuran thus obtained treated with acid, subjected to glycol cleavage and then according to Wittig.
ORIGINAL INSPECTEDORIGINAL INSPECTED
509887/1013509887/1013
CHEMISCHE FABRIKENCHEMICAL FACTORY
Die erfindungsgemässe Reaktion verläuft über folgende Stufen: The reaction according to the invention takes place in the following stages:
CH3COOCH 3 COO
CH3COOCH 3 COO
COOC0HCOOC 0 H
Halogen-Wasserstoff Halogen-hydrogen
CHOR-CH2OR CH3CO-OCHORUS-CH 2 OR CH 3 CO-O
Hal·Hal
COOC2II CHOR-CH2ORCOOC 2 II CHORUS-CH 2 OR
(C6H5J3SnH(C 6 H 5 J 3 SnH
CH3CO-OCH 3 CO-O
COOC0HCOOC 0 H
CHOR-CH2ORCHORUS-CH 2 OR
JO. 4JO. 4th
HOH-CH2OHHOH-CH 2 OH
WittigWittig
A-BAWAY
Π 9 B B 7 Π η 1 ORIGINAL INSPECTEDΠ 9 B B 7 Π η 1 ORIGINAL INSPECTED
2 4 3 B 3 32 4 3 B 3 3
CHEMISCHE FABRIKENCHEMICAL FACTORY
Der Umsatz des Ausgangsmaterials mit Chlor- oder Bromwasserstoff erfolgt vorzugsweise so, dass man die Substanz in einem Lösungsmittel wie Methylenchlorid, Chloroform oder Äther löst und den Halogenwasserstoff bis zur Sättigung einleitet. Dieser Reaktionsschritt kann auch mit Bromwasserstoff in Eisessig bei Gegenwart von Acetanhydrid durchgeführt werden. Der Austausch des Halogenatoms gegen ein Wasserstoffatom erfolgt durch Umsetzung mit Triphenylzinnhydrid vorzugsweise bei Raumtemperatur.The conversion of the starting material with hydrogen chloride or hydrogen bromide is preferably carried out so that the substance in a solvent such as methylene chloride, chloroform or Ether dissolves and the hydrogen halide to saturation initiates. This reaction step can also be carried out with hydrogen bromide in glacial acetic acid in the presence of acetic anhydride will. The halogen atom is exchanged for a hydrogen atom by reaction with triphenyltin hydride preferably at room temperature.
Die Ausbeuten bei der Lactonisierung von 2ß-(l',2'-Diacyloxyäthyl)-3a-carbäthoxymethyl-4a-acetoxy-tetrahydrofuran zu 2ß-(1', 2'-Dihydroxyäthyl)-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lacton mit den üblichen Säuren und Lösungsmitteln sind in der Regel nicht sehr gut. Führt man diesen Reaktionsschritt jedoch mit p-Toluolsulfonsäure in Methanol durch, so erhält man Ausbeuten von über 70 %. The yields in the lactonization of 2ß- (l ', 2'-diacyloxyethyl) -3a-carbäthoxymethyl-4a-acetoxy-tetrahydrofuran to 2ß- (1', 2'-dihydroxyethyl) -3a-carboxymethyl-4a-hydroxy-tetrahydrofuran 4-lactone with the usual acids and solvents are usually not very good. However, if this reaction step is carried out with p-toluenesulfonic acid in methanol, yields of over 70 % are obtained.
Die Glykolspaltung kann in bekannter Weise durchgeführt werden. Im vorliegenden Fall hat sich Natriumperjodat als besonders geeignet erwiesen. Auch der Umsatz mit dem Wittig-Reagenz erfolgt in üblicher Weise.The glycol cleavage can be carried out in a known manner will. In the present case, sodium periodate has proven to be particularly suitable. Also sales with the Wittig reagent takes place in the usual way.
Das vorliegende Verfahren besitzt den Vorteil, dass als Ausgangematerial eine Substanz verwendet wird, die leicht aus Glukose erhältlich ist, und dass ein sterisch einheit-The present method has the advantage that, as a starting material, a substance is used which is easily is obtainable from glucose, and that a sterically uniform
-S--S-
7/10137/1013
CHEMISCHE FABRIKENCHEMICAL FACTORY
liches, optisch aktives Produkt erhalten wird. Die nach dem erfindungsgemässen Verfahren hergestellten Verbindungen entsprechen in ihrer sterischen Anordnung den natürlichen Prostaglandinen. Bislang musste man bei der Herstellung von hochsubstituierten Tetrahydrofuranen von Furan- oder Tetrahydrofuran-Verbindungen ausgehen. Diese Synthesen gestalten sich jedoch ausserordentlich schwierig und aufwendig, da die Furan-Verbindungen sehr empfind lich gegen Säure und Alkali sind und Gemische von Stereoisomeren anfallen. Liches, optically active product is obtained. The compounds prepared by the process according to the invention correspond in their steric arrangement to the natural prostaglandins. So far you had to make it of highly substituted tetrahydrofurans start from furan or tetrahydrofuran compounds. These However, syntheses are extremely difficult and expensive because the furan compounds are very sensitive Lich are against acid and alkali and mixtures of stereoisomers are produced.
5 0 9 B % 1 i 1 Π 1 35 0 9 B % 1 i 1 Π 1 3
3 6 3 33 6 3 3
CHECHE
Herstellung des Ausgangsmaterials.Production of the starting material.
a) Zu einer Lösung von 27 g S-Desoxy-S-carbäthoxymethyl-1,2-5,6-di-O-isopropyliden-oc-D-allofuranose (l) in 250 ml Methanol fügt man 250 ml 0,8%±ge wässrige Schwefelsäure. Nach 16 Stunden Stehenlassen bei Raumtemperatur wird mit BaCO,, neutralisiert, zwecks besserer FiI-trierbarkeit des Niederschlags kurz zum Sieden erhitzt, abfiltriert und das Methanol im Vakuum entfernt. Die verbleibende wässrige Lösung füllt man auf 250 ml auf, entfernt die organischen Verunreinigungen durch Ausschütteln mit η-Hexan und engt ein. Ausbeute: 18,9 g bzw. 83 % S-Desoxy-S-carbäthoxymethyl-l,2-0-isopropyliden-5i 6-dihydroxy-oc-D-allofuranose. a) 250 ml of 0.8% are added to a solution of 27 g of S-deoxy-S-carbäthoxymethyl-1,2-5,6-di-O-isopropylidene-oc-D-allofuranose (l) in 250 ml of methanol ± ge aqueous sulfuric acid. After 16 hours of standing at room temperature, it is neutralized with BaCO 2, heated briefly to boiling for the purpose of better filterability of the precipitate, filtered off and the methanol is removed in vacuo. The remaining aqueous solution is made up to 250 ml, the organic impurities are removed by shaking with η-hexane and concentrated. Yield: 18.9 g or 83 % of S-deoxy-S-carbethoxymethyl-1,2-0-isopropylidene-5i 6-dihydroxy-oc-D-allofuranose.
b) 5 g S-Desoxy-S-carbäthoxymethyl-l^-O-isopropyliden-5,6-dihydroxy-a-D-allofuranose löst man in 10 ml Pyridin und fügt 4 ml Acetanhydrid hinzu. Nach dreistündigem Stehenlassen bei Raumtemperatur wird in 100 ml Chloroform oder Methylenchlorid aufgenommen, mit 5%±gev Salz säure, 5%±ger Natronlauge und anschliessend mit Wasser gewaschen und nach Trocknung mit Na3SO. eingeengt. Ausbeute: 5,4 g S-Desoxy-S-carbäthoxymethyl-l^-isopropyliden-5$6-diacetoxy-a-D-allofuranose. b) 5 g of S-deoxy-S-carbäthoxymethyl-l ^ -O-isopropylidene-5,6-dihydroxy-aD-allofuranose are dissolved in 10 ml of pyridine and 4 ml of acetic anhydride are added. After standing for three hours at room temperature, it is taken up in 100 ml of chloroform or methylene chloride, washed with 5% ± gev hydrochloric acid, 5% ± ger sodium hydroxide solution and then with water and, after drying, with Na 3 SO. constricted. Yield: 5.4 g of S-deoxy-S-carbethoxymethyl-l ^ -isopropylidene- 5 $ 6-diacetoxy-aD-allofuranose.
509887/1013509887/1013
CHEMISCHE PABRIKENCHEMICAL PLANTS
243633?243633?
c) 5 g S-Desoxy-G-carbäthoxymethyl-l, 2-0-isopropyliden-5, o-diacetoxy-oc-D-allofuranose werden in 40 ml Eisessig gelöst und mit 4 ml Acetanhydrid und 0,6 ml konzentrierter H„S0, versetzt. Nach zweitägigem Stehenlassen schüttet man das Gemisch auf 500 ml Eis/Wasser und extrahiert erschöpfend mit Chloroform, trocknet die vereinigten organischen Phasen und engt ein. Ausbeute: 4,8 g (86 %) S-Desoxy-S-carbäthoxymethyl-l,2-5,6-tetraacetyl-a-D-allofuranose, c) 5 g of S-deoxy-G-carbäthoxymethyl-1,2-0-isopropylidene-5, o-diacetoxy-oc-D-allofuranose are dissolved in 40 ml of glacial acetic acid and mixed with 4 ml of acetic anhydride and 0.6 ml of concentrated water S0, offset. After standing for two days, the mixture is poured onto 500 ml of ice / water and extracted exhaustively with chloroform, the combined organic phases are dried and concentrated. Yield: 4.8 g (86 %) of S-deoxy-S-carbethoxymethyl-l, 2-5,6-tetraacetyl-aD-allofuranose,
509887/1013509887/1013
CHEMISCHE FABRIKENCHEMICAL FACTORY
A) 6 g S-Desoxy-S-carbäthoxymethyl-l,2-5,6-tetraacetyla-D-allofuranose werden in 30 ml trockenem Methylenchlorid gelöst. Durch die Lösung leitet man 30 Minuten bei Raumtemperatur einen trockenen HBr-Strom und dampft anschliessend im Wasserstrahl-Vakuum unter Zwischenschaltung eines P_0--Trockenrohres zunächst bei Raumtemperatur ein. Zur Entfernung der noch anhaftenden Bromwasserstoffsäure steigert man die Temperatur nach Entfernung des Lösungsmittels für 30 Minuten auf 60°C.A) 6 g of S-deoxy-S-carbethoxymethyl-1,25,6-tetraacetyla-D-allofuranose are dissolved in 30 ml of dry methylene chloride. The solution is passed for 30 minutes a dry HBr stream at room temperature and then evaporated in a water jet vacuum with interposition of a P_0 drying tube initially at room temperature. To remove the still adhering Hydrobromic acid is raised to the temperature for 30 minutes after removal of the solvent 60 ° C.
B) Den Eindampfrückstand löst man unter Feuchtigkeitsausschluss in 30 ml trockenem Methylenchlorid und fügt 20 ml einer ätherischen Triphenylzinnhydrid-Lösung hinzu, welche aus 11 g Trxphenylzinnchlorid und 0,55 g LiAlH. bereitet wurde. Nach 30 Minuten dampft man ein und chromatographiert den Rückstand an desaktiviertem Kieselgel, Wassergehalt 30 %. Durch Elution mit η-Hexan trennt man zunächst die Verunreinigung ab, nach deren Entfernung mit Chloroform/Methanol 10;1 eluiert wird. Die Ausbeute an 2ß-(l»,2'-diacetoxyäthyl)· 3a-carbäthoxymethyl-4a-acetoxy-tetrahydrofuran beträgt 4,9 g oder 94 %. B) The evaporation residue is dissolved in 30 ml of dry methylene chloride with exclusion of moisture and 20 ml of an ethereal triphenyltin hydride solution, which is made up of 11 g of trxphenyltin chloride and 0.55 g of LiAlH, is added. was prepared. After 30 minutes, it is evaporated and the residue is chromatographed on deactivated silica gel, water content 30 %. The impurity is first separated off by elution with η-hexane, after which it is eluted with chloroform / methanol 10; 1. The yield of 2ß- (1 », 2'-diacetoxyethyl ).3a-carbethoxymethyl-4a-acetoxy-tetrahydrofuran is 4.9 g or 94 %.
~ 9 5Q9887/ in 1 3 ~ 9 5Q9887 / in 1 3
2 A 3 R 3 32 A 3 R 3 3
CHEMISCHE FABRIKENCHEMICAL FACTORY
C) 3,5 g 2ß-(l»,2'-Diacetoxyäthyl)-3oc-carbäthoxymethyl-4oc-acetoxy-tetrahydrofuran werden in 5 ml Methanol, welche 0,25 g p-Toluolsulfonsäure enthalten, gelöst und 16 Stunden unter Rückfluss am Sieden gehalten. Anschliessend wird eingeengt und an desaktiviertem Kieselgel, welches 30 % Wasser enthält, mit Chloroform/Methanol 10:1 chromatographiert. Die Ausbeute an 2ß~(l',2'-Dihydroxyäthyl)-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-1acton beträgt 1,3 g oder 72 %. C) 3.5 g 2ß- (l ', 2'-Diacetoxyäthyl) -3oc-carbäthoxymethyl-4oC-acetoxy-tetrahydrofuran contained p-toluenesulfonic acid in 5 m l of methanol, which 0.25 g, and treated for 16 hours under reflux kept simmering. It is then concentrated and chromatographed on deactivated silica gel which contains 30 % water with chloroform / methanol 10: 1. The yield of 2β ~ (l ', 2'-dihydroxyethyl) -3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone is 1.3 g or 72 %.
D) 5,4 g 2ß-(l',2'-Dihydroxyäthyl)-3a-carboxymethyl-4ahydroxy-tetrahydrofuran-4-1acton werden in 25 ml Wasser gelöst und portionsweise mit 5 g NaJO . versetzt, wobei man durch Zufügen von 5#iger wässriger NaOII ρ 7 einhält. Danach wird mit Chloroform/lsopropanol erschöpfend extrahiert, die vereinigten organischen Phasen mit Na0SO- getrocknet und eingeengt. Die Ausbeute an 2ß-Formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lacton beträgt 4,3 g oder 96 %. D) 5.4 g of 2β- (l ', 2'-dihydroxyethyl) -3a-carboxymethyl-4ahydroxy-tetrahydrofuran-4-lactone are dissolved in 25 ml of water and mixed in portions with 5 g of NaJO. added, while maintaining ρ 7 by adding 5 # aqueous NaOII. Thereafter, isopropanol exhaustively extracted with chloroform /, the combined organic phases with Na 0 SO- dried and concentrated. The yield of 2β-formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone is 4.3 g or 96 %.
E) 12,6 g 2ß-Formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-1acton werden in 500 ml Tetrahydrofuran gelöst und mit 60 g Hexanoylmethylen-triphenylphosphoran eine Stunde unter Rückfluss am Sieden gehalten. Man dampft ein und löst den Rückstand in Essigsäureäthylester, wobei die Hauptmenge an Triphenylphosphin-E) 12.6 g of 2β-formyl-3a-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-1actone are dissolved in 500 ml of tetrahydrofuran and 60 g of hexanoylmethylene triphenylphosphorane kept at the boil for one hour under reflux. It is evaporated and the residue is dissolved in ethyl acetate, where the main amount of triphenylphosphine
- 10 -- 10 -
509887/1013509887/1013
243R332243R332
CHEMISCHE FABRIKENCHEMICAL FACTORY
oxid auskristallisisrt. Man saugt von der Verunreinigung ab, engt die Mutterlauge ein und löst den Eindampfrückstand in wenig Äther. Beim Versetzen der ätherischen Lösung mit η-Hexan fällt das 2ß-(Oct-l-en-3-onyl)~3oc-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lacton kristallinoxide crystallized out. One sucks off the contamination from, concentrates the mother liquor and dissolves the evaporation residue in a little ether. When moving the essential solution 2ß- (Oct-1-en-3-onyl) ~ 3oc-carboxymethyl-4a-hydroxy-tetrahydrofuran-4-lactone precipitates with η-hexane crystalline
Fp 66°C, Ausbeute 13,1 g oder 64$.Mp 66 ° C, yield 13.1 g or $ 64.
5 g S-Desoxy-S-carbäthoxymethyl-l^-Sjo-tetraacetyl-a-D-allofuranose werden in einer Mischung von 20 ml Eisessig und 4 ml Acetanhydrid gelöst. Nach Zufügen von 15 ml HBr/Eisessig 40 % Iä3st man 90 Minuten bei Raumtemperatur stehen und engt anschliessend im Hochvakuum ein, wobei die Temperatur allmählich auf 70°C gesteigert wird. Der Eindampfrückstand wird wie in Beispiel IB-E beschrieben weiterbehandelt. Die Ausbeute entspricht der des Beispiels 1.5 g of S-deoxy-S-carbäthoxymethyl-l ^ -Sjo-tetraacetyl-aD-allofuranose are dissolved in a mixture of 20 ml of glacial acetic acid and 4 ml of acetic anhydride. After adding 15 ml of HBr / glacial acetic acid 40 %, the mixture is left to stand at room temperature for 90 minutes and then concentrated in a high vacuum, the temperature gradually increasing to 70.degree. The evaporation residue is treated further as described in Example IB-E. The yield corresponds to that of Example 1.
Beispiel 3Example 3
In eine Lösung von 6 g S-Desoxy-S-carbäthoxymethyl-l,2-5,6-tetraacetyl-a-D-allofuranose in 30 ml Methylenchlorid lei-In a solution of 6 g of S-deoxy-S-carbäthoxymethyl-1,25,6-tetraacetyl-a-D-allofuranose in 30 ml of methylene chloride
- Il -- Il -
509837/1013509837/1013
2 k 3 R 3 3 ? 2 k 3 R 3 3 ?
CHEMISCHE FABRIKENCHEMICAL FACTORY
tet man bei O C etwa zwei Stunden einen Strom von trockenem HCl-Gas ein und lässt anschliessend etwa eine Woche bei Raumtemperatur stehen. Anschliessend behandelt man das Gemisch wie in Beispiel IB-E beschrieben, die Ausbeute an dem Endprodukt ist etwas geringer als die des Beispiels 1.a stream of dry water is used at OC for about two hours HCl gas and then leave to stand for about a week at room temperature. Then you treat the mixture as described in Example IB-E, the yield on the end product is slightly lower than that of Example 1.
Dr.WK/bu/2Dr.WK / bu / 2
- 12 -- 12 -
9 8 *Π Π fH 39 8 * Π Π fH 3
Claims (2)
Priority Applications (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742436332 DE2436332A1 (en) | 1974-07-27 | 1974-07-27 | SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTION |
| NL7507149A NL7507149A (en) | 1974-07-27 | 1975-06-16 | SUBSTITUTED TETRAHYDROFURANS AND METHOD OF PREPARATION. |
| BE157491A BE830423A (en) | 1974-07-27 | 1975-06-19 | SUBSTITUTE TETRAHYDROFORANES AND PREPARATION PROCESS |
| GB2669275A GB1458164A (en) | 1974-07-27 | 1975-06-24 | Substituted tetrahydrofurans |
| FR7522891A FR2279751A1 (en) | 1974-07-27 | 1975-07-22 | SUBSTITUTE TETRAHYDROFURANS AND PROCESS FOR THEIR MANUFACTURE |
| AT572575A AT342582B (en) | 1974-07-27 | 1975-07-24 | METHOD FOR PRODUCING NEW SUBSTITUTED TETRAHYDROFURANS |
| JP9101475A JPS5136492A (en) | 1974-07-27 | 1975-07-25 | CHIKANTETORAHIDOROFURANNO SEIHO |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742436332 DE2436332A1 (en) | 1974-07-27 | 1974-07-27 | SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2436332A1 true DE2436332A1 (en) | 1976-02-12 |
Family
ID=5921758
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19742436332 Pending DE2436332A1 (en) | 1974-07-27 | 1974-07-27 | SUBSTITUTED TETRAHYDROFURANS AND PROCESS FOR THEIR PRODUCTION |
Country Status (7)
| Country | Link |
|---|---|
| JP (1) | JPS5136492A (en) |
| AT (1) | AT342582B (en) |
| BE (1) | BE830423A (en) |
| DE (1) | DE2436332A1 (en) |
| FR (1) | FR2279751A1 (en) |
| GB (1) | GB1458164A (en) |
| NL (1) | NL7507149A (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1532551A (en) * | 1975-01-16 | 1978-11-15 | Chembro Holdings Pty Ltd | Furo(3,4-6)furone derivatives and their preparation |
| US6025044A (en) | 1993-08-18 | 2000-02-15 | W. L. Gore & Associates, Inc. | Thin-wall polytetrafluoroethylene tube |
| US5814660A (en) * | 1995-12-22 | 1998-09-29 | Alcon Laboratories, Inc. | 9-oxa prostaglandin analogs as ocular hypotensives |
| US5866602A (en) * | 1995-12-22 | 1999-02-02 | Alcon Laboratories, Inc. | Keto-substituted tetrahydrofuran analogs of prostaglandins as ocular hypotensives |
| DE69633136T2 (en) | 1995-12-22 | 2005-09-01 | Alcon Laboratories, Inc., Fort Worth | SUBSTITUTED TETRAHYDROFURAN ANALOGS OF PROSTAGLANDINES AS EYE PRESENTING MEDICAMENTS |
-
1974
- 1974-07-27 DE DE19742436332 patent/DE2436332A1/en active Pending
-
1975
- 1975-06-16 NL NL7507149A patent/NL7507149A/en not_active Application Discontinuation
- 1975-06-19 BE BE157491A patent/BE830423A/en unknown
- 1975-06-24 GB GB2669275A patent/GB1458164A/en not_active Expired
- 1975-07-22 FR FR7522891A patent/FR2279751A1/en not_active Withdrawn
- 1975-07-24 AT AT572575A patent/AT342582B/en active
- 1975-07-25 JP JP9101475A patent/JPS5136492A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| BE830423A (en) | 1975-12-19 |
| FR2279751A1 (en) | 1976-02-20 |
| GB1458164A (en) | 1976-12-08 |
| NL7507149A (en) | 1976-01-29 |
| ATA572575A (en) | 1977-08-15 |
| AT342582B (en) | 1978-04-10 |
| JPS5136492A (en) | 1976-03-27 |
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