DE912812C - Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline - Google Patents

Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline

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Publication number
DE912812C
DE912812C DEL730A DEL0000730A DE912812C DE 912812 C DE912812 C DE 912812C DE L730 A DEL730 A DE L730A DE L0000730 A DEL0000730 A DE L0000730A DE 912812 C DE912812 C DE 912812C
Authority
DE
Germany
Prior art keywords
benzyl
tetrahydro
vol
isoquinoline
isoquinolone
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.)
Expired
Application number
DEL730A
Other languages
German (de)
Inventor
Dr Hans Henecka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer AG
Original Assignee
Bayer AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Bayer AG filed Critical Bayer AG
Priority to DEL730A priority Critical patent/DE912812C/en
Application granted granted Critical
Publication of DE912812C publication Critical patent/DE912812C/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

Verfahren zur Herstellung von 1-Benzyl-bz-tetrahydro-isochinolin Das zur Synthese von Substanzen der Morphinreihe wichtige i-Benzyl-bz-tetrahydro-isochinolin und seine im Benzylrest methoxylierten Derivate waren bisher nur durch komplizierte metallorganische Synthesen zugänglich. So erhält man nach Grewe und Mondon, Berichte der deutschen chemischen Gesellschaft, Bd. 81, S. 279ff. (i948), durch Einwirkung von Benzylmagnesiumchlorid auf N-Methyl-bz-tetrahydroisochinoliniumjodid das N-Methyl-i, 2-dihydroderivaf des i-Benzyl-bz-tetrahydro-isochinolins, während die Verbindung selbst erhalten wurde durch Einwirkung von Benzaldehyd auf i-Lithium-bz-tetrahydro-isochinolin und Reduktion des zunächst entstandenen Carbinols (Grewe, Mondon und Nolte, Liebigs Annalen der Chemie, Bd. 564, S. 16i ff. (i949) Es wurde nun gefunden, daB man in wesentlich einfacherer und auch technisch durchführbarer Weise dadurch zum i-Benzyl-bz-tetrahydro-isochinolin gelangen kann, daB man das aus Cyclohexanon und Phenylessigester durch Esterkondensation herstellbare i-Phenacetyl-cyclohexanon-(2) mit Cyanacetamid kondensiert zu i-Benzyl-bz-tetrahydro-4-cyan-isochinolon-(3), hieraus z. B. durch Kochen mit Bromwasserstoffsäure die Cyangruppe abspaltet, das so erhaltene i-Benzyl-bz-tetrahydro-isochinolon-(3) chloriert und die 3-Chlorverbindung enthalogeniert.Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline Das i-Benzyl-bz-tetrahydro-isoquinoline, which is important for the synthesis of substances of the morphine series and its derivatives methoxylated in the benzyl radical were previously only complicated organometallic syntheses accessible. According to Grewe and Mondon, reports are thus obtained of the German Chemical Society, Vol. 81, pp. 279ff. (1948), by action from benzyl magnesium chloride to N-methyl-bz-tetrahydroisoquinolinium iodide the N-methyl-i, 2-dihydroderivaf of i-benzyl-bz-tetrahydro-isoquinoline, while the compound itself was obtained by the action of benzaldehyde on i-lithium-bz-tetrahydro-isoquinoline and reduction of the carbinol initially formed (Grewe, Mondon and Nolte, Liebigs Annalen der Chemie, Vol. 564, pp. 16ff. (1949) It has now been found that in a much simpler and also technically feasible way to i-benzyl-bz-tetrahydro-isoquinoline it can be achieved that this can be obtained from cyclohexanone and phenyl acetic ester by ester condensation producible i-phenacetyl-cyclohexanone- (2) with cyanoacetamide condensed to i-benzyl-bz-tetrahydro-4-cyano-isoquinolone- (3), from this z. B. splits off the cyano group by boiling with hydrobromic acid, the The i-benzyl-bz-tetrahydro-isoquinolone- (3) obtained in this way is chlorinated and the 3-chloro compound dehalogenated.

Beispiel 33,7 g i-Phenacetyl-cyclohexanon-(2) (KP", = i45°; Cu-Salz: F. 153 bis i54°; erhalten durch Kondensation von Cyclohexanon mit Phenylessigsäuremethylester unter dem Einfluß von Natriummethylat) werden mit 14,2 g Cyanacetamid, 400 ccm Aceton, 25 g Kaliumcarbonat 15 Stunden zum Sieden erhitzt. Der nach dem Abdampfen des Acet ns erhaltene Rückstand ergibt beim Behandeln mit verdünnter Säure 40 g i-Benzyl-bz-tetrahydro-4-cyan-isochinolon-(3), das nach dem Umkristallisieren aus Eisessig bei 245 bis z48° schmilzt; feine farblose Nadeln.Example 33.7 g of i-phenacetyl-cyclohexanone- (2) (KP ", = i45 °; Cu salt: mp 153 to i54 °; obtained by condensation of cyclohexanone with methyl phenylacetate under the influence of sodium methylate) are mixed with 14, 2 g of cyanoacetamide, 400 cc of acetone, 25 g of potassium carbonate, heated to boiling for 15 hours. The residue obtained after evaporation of the acetone gives, on treatment with dilute acid, 40 g of i-benzyl-bz-tetrahydro-4-cyano-isoquinolone- (3 ), which after recrystallization from glacial acetic acid melts at 245 to z48 °; fine, colorless needles.

40g dieses Kondensationsproduktes werden mit 400 ccm Bromwasserstoffsäure (D. = 1,49) 15 Stunden zum Sieden erhitzt. Nach dem Verdampfen der Säure im Vakuum (4o bis 5o°) erhält man einen kristallinen Rückstand, aus dem man durch Behandeln mit Natriumacetatlösung 34,5 g i-Benzyl-bz-tetrahydroisochinolon-(3) erhält, das nach dem Umkristallisieren aus Methanol oder 5o°%iger Essigsäure feine, bei 245° schmelzende Nadeln darstellt. Ausbeute: 33,5 g. 40 g of this condensation product are heated to boiling with 400 cc of hydrobromic acid (D. = 1.49) for 15 hours. After evaporation of the acid in vacuo (4o to 5o °), a crystalline residue is obtained from which 34.5 g of i-benzyl-bz-tetrahydroisoquinolone- (3) are obtained by treatment with sodium acetate solution, which after recrystallization from methanol or 50% acetic acid represents fine needles that melt at 245 °. Yield: 33.5 g.

50 g dieses Isochinolonderivates werden im Rohr mit 25o ccm Phosphoroxychlorid 5 Stunden auf i55° erhitzt. Nach dem Verdampfen des überschüssigen Phosphoroxychlorides im Vakuum bei 6o° erhält man einen Rückstand, aus dem beim Behandeln mit Eiswasser das i-Benzyl-bz-tetrahydro-3-chlor-isochinolin sich abscheidet. Ausbeute: 45.5 g. Man reinigt entweder durch Destillation (Kp"", = Z62°) oder durch Umkristallisieren aus verdünntem Methanol oder Äther/Petroläther. F.87 bis 88°; glänzende Kriställchen. 50 g of this isoquinolone derivative are heated in a tube with 250 cc of phosphorus oxychloride for 5 hours at i55 °. After evaporation of the excess phosphorus oxychloride in vacuo at 60 °, a residue is obtained from which the i-benzyl-bz-tetrahydro-3-chloro-isoquinoline separates out on treatment with ice water. Yield: 45.5 g. It is purified either by distillation (bp "", = Z62 °) or by recrystallization from dilute methanol or ether / petroleum ether. F. 87 to 88 °; shiny crystals.

50 g dieses Chlor-isochinolinderivates werden in Zoo ccm Methanol nach Zusatz von Palladium-Tierkohle (aus 5 ccm io°/oiger PdC12 Lösung) mit Wasserstoff geschüttelt. Nach Beendigung der Wasserstoffaufnahme wird vom Kontakt abgetrennt, das Methanol im Vakuum verdampft, der kristalline Rückstand in schwach angesäuertem. Wasser aufgenommen und aus der klaren Lösung die Base mit Lauge abgeschieden. KPo,a = Z43°. Helles, etwas dickflüssiges Öl. Pikrat: F. Z32°, saures Sulfat: F. 214°, Ausbeute: 36 g. C H2-/ CHz_: \ @ CHz-\. @\. I C G C NH H Br NH #'H `E O NH2 H -# ! H@' + CO C O ,@ C C H ,'0 H%C I i CN CN POC13 C Ha -./_--/ CHI- C E H 1I I PATENTANSPRUCH: CH Cl 50 g of this chloroisoquinoline derivative are shaken with hydrogen in zoo cc of methanol after adding palladium animal charcoal (from 5 cc of 10% PdC12 solution). After the uptake of hydrogen has ended, the contact is separated off, the methanol is evaporated off in vacuo, and the crystalline residue in weakly acidic. Absorbed water and deposited the base with lye from the clear solution. KPo, a = Z43 °. Light, somewhat thick oil. Picrate: F. Z32 °, acid sulfate: M. 214 °, Yield: 36 g. C H2- / C Hz_: \ @ CHz- \. @ \. I. CGC NH H Br NH # 'H `EO NH2 H - # ! H@' + CO C O, @ CCH , '0 H% CI i CN CN POC13 C Ha -. / _-- / CHI- C. EH 1I I. PATENT CLAIM: CH Cl

Claims (1)

Verfahren zur Herstellung von i-Benzyl-bztetrahydro-isochinolin, dadurch gekennzeichnet, daB man i-Phenacetyl-cyclohexanon-(2) mit Cyanacetamid kondensiert, das entstandene x-Benzylbz-tetrahydro-4-cyan-isochinolon-(3) verseift und decarboxyliert zu i-Benzyl-bz-tetrahydro-isochinolon-(3), dieses halogeniert zu x-Benzyl-bz-tetrahydro-3-halogen-isochinoIin und das Halogen reduktiv abspaltet. Angezogene Druckschriften: Journal of Indian Chem. Soc. 8, S.321 bis 327 (1931); Annalen der Chemie, Bd. 516, S. 243 bis 248 (1935); Helvetica Chimica Acta, Bd. 30, S.1339/1340 (1947); Annalen der Chemie, Bd. 564, S. 16z bis 183 (1949) ; Chemisches Zentralblatt 1927, 11, S.435/436; Journal of Chem. Soc. (London), 1929, S. 2224; Berichte der deutschen Chemischen Gesellschaft, Bd. 82, 38 (1949) ; Henecka, Chemie der Beta-dicarbonylverbindungen, Berlin 1950, S. 292ff.; Berichte der deutschen Chemischen Gesellschaft, 8d. 81, S. 27o bis 286 (1948); schweizerische Patentschrift Nr. 253 71o.Process for the preparation of i-benzyl-bztetrahydro-isoquinoline, thereby characterized that i-phenacetyl-cyclohexanone- (2) is condensed with cyanoacetamide, the resulting x-benzylbz-tetrahydro-4-cyano-isoquinolone- (3) saponified and decarboxylated to i-benzyl-bz-tetrahydro-isoquinolone- (3), this halogenates to x-benzyl-bz-tetrahydro-3-halogen-isoquinolone and the halogen is split off reductively. Referred to: Journal of Indian Chem. Soc. 8, pp. 321 to 327 (1931); Annalen der Chemie, Vol. 516, pp. 243 to 248 (1935); Helvetica Chimica Acta, Vol. 30, pp. 1339/1340 (1947); Annals of chemistry, Vol. 564, pp. 16z to 183 (1949); Chemisches Zentralblatt 1927, 11, pp 435/436; journal of Chem. Soc. (London), 1929, p. 2224; Reports of the German Chemical Society, Vol. 82, 38 (1949); Henecka, Chemistry of Beta-Dicarbonyl Compounds, Berlin 1950, P. 292ff .; Reports of the German Chemical Society, 8d. 81, pp. 27o to 286 (1948); Swiss patent specification No. 253 71o.
DEL730A 1950-01-03 1950-01-03 Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline Expired DE912812C (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
DEL730A DE912812C (en) 1950-01-03 1950-01-03 Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
DEL730A DE912812C (en) 1950-01-03 1950-01-03 Process for the preparation of 1-benzyl-bz-tetrahydro-isoquinoline

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DE912812C true DE912812C (en) 1954-06-03

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH253710A (en) * 1947-02-12 1948-03-31 Hoffmann La Roche Process for the preparation of 5,6,7,8-tetrahydroisoquinoline.

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH253710A (en) * 1947-02-12 1948-03-31 Hoffmann La Roche Process for the preparation of 5,6,7,8-tetrahydroisoquinoline.

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