DD250930A1 - PROCESS FOR PREPARING NEW TETRAHYDROISOCHINOLINE DERIVATIVES - Google Patents
PROCESS FOR PREPARING NEW TETRAHYDROISOCHINOLINE DERIVATIVES Download PDFInfo
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- DD250930A1 DD250930A1 DD29224386A DD29224386A DD250930A1 DD 250930 A1 DD250930 A1 DD 250930A1 DD 29224386 A DD29224386 A DD 29224386A DD 29224386 A DD29224386 A DD 29224386A DD 250930 A1 DD250930 A1 DD 250930A1
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- hydrochlorides
- aliphatic alcohols
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- 150000003526 tetrahydroisoquinolines Chemical class 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 10
- 238000002360 preparation method Methods 0.000 claims abstract description 4
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 claims abstract 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 17
- -1 aliphatic alcohols Chemical class 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 150000003840 hydrochlorides Chemical class 0.000 claims description 6
- AYPKYQSHFKQVDL-UHFFFAOYSA-N 3-(chloromethyl)-2,3-dihydro-1,4-benzodioxine Chemical compound C1=CC=C2OC(CCl)COC2=C1 AYPKYQSHFKQVDL-UHFFFAOYSA-N 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 239000006227 byproduct Substances 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 230000002452 interceptive effect Effects 0.000 claims description 2
- 239000011541 reaction mixture Substances 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 238000001556 precipitation Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
- UCTWMZQNUQWSLP-UHFFFAOYSA-N adrenaline Chemical compound CNCC(O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-UHFFFAOYSA-N 0.000 abstract description 6
- 230000002776 aggregation Effects 0.000 abstract description 5
- 238000004220 aggregation Methods 0.000 abstract description 5
- 230000000144 pharmacologic effect Effects 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 2
- 210000001772 blood platelet Anatomy 0.000 abstract 1
- 239000007795 chemical reaction product Substances 0.000 description 4
- 108060003345 Adrenergic Receptor Proteins 0.000 description 3
- 102000017910 Adrenergic receptor Human genes 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- BLGXFZZNTVWLAY-UHFFFAOYSA-N beta-Yohimbin Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-UHFFFAOYSA-N 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 2
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical class C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- UCTWMZQNUQWSLP-VIFPVBQESA-N (R)-adrenaline Chemical compound CNC[C@H](O)C1=CC=C(O)C(O)=C1 UCTWMZQNUQWSLP-VIFPVBQESA-N 0.000 description 1
- 229930182837 (R)-adrenaline Natural products 0.000 description 1
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- BLGXFZZNTVWLAY-DKJBZYCGSA-N Corynanthine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-DKJBZYCGSA-N 0.000 description 1
- DDRUVFKWNXGBTK-UHFFFAOYSA-N Corynanthine Natural products C1=CC=C2C(CCN3CC4CCC(O)C(C4CC33)OC(=O)C)=C3NC2=C1 DDRUVFKWNXGBTK-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- BLGXFZZNTVWLAY-CCZXDCJGSA-N Yohimbine Natural products C1=CC=C2C(CCN3C[C@@H]4CC[C@@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-CCZXDCJGSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 description 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229960005139 epinephrine Drugs 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- HPMRFMKYPGXPEP-UHFFFAOYSA-N idazoxan Chemical compound N1CCN=C1C1OC2=CC=CC=C2OC1 HPMRFMKYPGXPEP-UHFFFAOYSA-N 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- LYKMMUBOEFYJQG-UHFFFAOYSA-N piperoxan Chemical group C1OC2=CC=CC=C2OC1CN1CCCCC1 LYKMMUBOEFYJQG-UHFFFAOYSA-N 0.000 description 1
- 229950007976 piperoxan Drugs 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- BLGXFZZNTVWLAY-DIRVCLHFSA-N rauwolscine Chemical compound C1=CC=C2C(CCN3C[C@H]4CC[C@H](O)[C@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-DIRVCLHFSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000002227 vasoactive effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229960000317 yohimbine Drugs 0.000 description 1
- BLGXFZZNTVWLAY-SCYLSFHTSA-N yohimbine Chemical compound C1=CC=C2C(CCN3C[C@@H]4CC[C@H](O)[C@@H]([C@H]4C[C@H]33)C(=O)OC)=C3NC2=C1 BLGXFZZNTVWLAY-SCYLSFHTSA-N 0.000 description 1
- AADVZSXPNRLYLV-UHFFFAOYSA-N yohimbine carboxylic acid Natural products C1=CC=C2C(CCN3CC4CCC(C(C4CC33)C(O)=O)O)=C3NC2=C1 AADVZSXPNRLYLV-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Tetrahydroisochinolinderivate, die aufgrund ihrer wertvollen pharmakologischen Eigenschaften als pharmazeutische Wirkstoffe zur Hemmung der insbesondere durch Adrenalin ausgeloesten Aggregation der Blutplaettchen eingesetzt werden koennen.The invention relates to a process for the preparation of novel tetrahydroisoquinoline derivatives which, owing to their valuable pharmacological properties, can be used as pharmaceutical active ingredients for inhibiting the aggregation of blood platelets, in particular caused by adrenaline.
Description
Hierzu 1 Seite FormelnFor this 1 page formulas
Die Erfindung betrifft ein Verfahren zur Herstellung neuer Tetrahydroisochinolinderivate. Diese Verbindungen können aufgrund ihrer wertvollen pharmakologischen Eigenschaften als pharmazeutische Wirkstoffe zur Hemmung der insbesondere durch Adrenalin ausgelösten Aggregation der Blutplättchen eingesetzt werden.The invention relates to a process for the preparation of novel tetrahydroisoquinoline derivatives. Because of their valuable pharmacological properties, these compounds can be used as pharmaceutical active ingredients for inhibiting the aggregation of platelets, in particular caused by epinephrine.
Dieses Ziel wird durch ein Verfahren zur Herstellung neuer Tetrahydroisochinolinderivate der allgemeinen Formel I erreicht, indem erfindungsgemäß Tetrahydroisochinolinderivate der allgemeinen Formel Il mit 2-Chlormethyl-1,4-benzdioxan der Formel Ml im Verhältnis 2:1 bei höheren Temperaturen unter Inertbedingungen umgesetzt werden, wobei die störenden Reaktionsnebenprodukte durch Extraktion im pH-Bereich von 1 bis 7 mit aromatischen Kohlenwasserstoffen und/oder Ether erfolgt und die Hydrochloride von I mit Salzsäure, gelöst in aliphatischen Alkoholen, dargestellt und anschließend aus Alkohol umkristallisiert werden.This object is achieved by a process for the preparation of novel tetrahydroisoquinoline derivatives of the general formula I by reacting tetrahydroisoquinoline derivatives of the general formula II according to the invention with 2-chloromethyl-1,4-benzodioxane of the formula III in a ratio of 2: 1 at elevated temperatures under inert conditions the interfering reaction by-products by extraction in the pH range of 1 to 7 with aromatic hydrocarbons and / or ether and the hydrochlorides of I with hydrochloric acid, dissolved in aliphatic alcohols, represented and then recrystallized from alcohol.
Dies erfolgt derart, daß die Reaktionspartner auf 180 bis 2000C erhitzt werden über mehrere Stunden und das entstehende Reaktionsprodukt durch eine pH-wertabhängige Extraktion von den Reaktionsnebenprodukten isoliert wird. Als Extraktionsmittel werden bevorzugt Benzen und/oder Diethylether verwendet. Die Reaktionsprodukte werden in Alkoholen, vorzugsweise Isopropanol, gelöst und aus der Lösung werden durch Zugabe von Isopropanol/Salzsäure die entsprechenden Hydrochloride ausgefällt.This is done so that the reactants are heated to 180 to 200 0 C for several hours and the resulting reaction product is isolated by a pH-value-dependent extraction of the reaction by-products. The extractants used are preferably benzene and / or diethyl ether. The reaction products are dissolved in alcohols, preferably isopropanol, and the corresponding hydrochlorides are precipitated from the solution by addition of isopropanol / hydrochloric acid.
Durch Umkristallisation aus Isopropanol bei pH-Wert 1 wird eine Reinigung der Umsetzungsprodukte erreicht.By recrystallization from isopropanol at pH 1, a purification of the reaction products is achieved.
Die neuen Tetrahydroisochinoline besitzen wertvolle pharmakologische Eigenschaften, insbesondere hemmen sie die durch Adrenalin ausgelöste Aggregation der Blutplättchen.The new tetrahydroisoquinolines possess valuable pharmacological properties, in particular they inhibit adrenaline-induced aggregation of the platelets.
Charakteristik der bekannten technischen LösungenCharacteristic of the known technical solutions
Es ist bekannt, daß zu den Plättchenfunktionshemmstoffen neben den nichtsteroidalen Antiphlogistika vasoaktive Pharmaka gehören, die den CAMP-Gehalt in den Blutplättchen über eine Aktivierung der Adenylatzyklase oder Hemmung der Phosphordiesterase erhöhen (Packham, M. A. Thromb. Haemoestas. 50, 610-619 [1983]). Hemmstoffe der Phosphodiesterase, wie Papaverin, hemmen die Adhäsion, die durch verschiedene Stimuli ausgelöst Aggregation und Freisetzungsreaktion sowie die Retraktion (Markwardt, F. et al.: Naunyn-Schmiedebergs Arch. exp. Path. Pharmak. 257, 420-431 [1967]).Platelet function inhibitors, in addition to non-steroidal anti-inflammatory drugs, are known to include vasoactive drugs that increase platelet CAMP levels via activation of adenylate cyclase or inhibition of phosphodiesterase (Packham, MA Thromb, Haemoestas, 50, 610-619 [1983] ). Inhibitors of phosphodiesterase, such as papaverine, inhibit adhesion induced by various stimuli Aggregation and release reaction as well as retraction (Markwardt, F. et al .: Naunyn-Schmiedebergs Arch. Exp. Path. Pharmac. 257, 420-431 [1967] ).
Des weiteren ist bekannt, daß Antagonisten mit hoher Affinität zu den a2-Rezeptoren an den Plättchen besonders wirksame Hemmstoffe der adrenalinbedingten Aggregation sind, da die a^-adrenergen-Rezeptoren der Blutplättchen diesem Typ zuzuordnen sind (Glusa, E. und Markwardt, F.: Haemostasis 13,96-101 [1983]). Neuere pharmakologische Befunde zeigen, daß Benzdioxanderivate je nach Art der Substitution eine hohe Affinität zu a-,- oder a2-adrenergen Rezeptoren besitzen (Dabire, H., P.Mouille, M.Andrejak, B.Fournierand H.Schmitt Pre-and postsynaptica-adrenoceptor blockade by (imidazolinyl-2)-2-benzodioxane 1-4(170 150): Antagonistic action on the central effects of clonidine Arch. Int. Pharmacodyn. 254,252-270(1981), Doxey, J. C, A. C. Lane, A. G. Roach an N. K. Virdee Comparison of the a-adrenoceptor antagonist profiles of idazoxan (RX'781094), yohimbine, rauwolscine and corynanthine. Naunyn-Schmiedebergs Arch. Pharmacol. 325,136-144(1984).Furthermore, it is known that antagonists with high affinity for the a 2 receptors on the platelets are particularly effective inhibitors of adrenaline-induced aggregation, since the platelet adrenergic receptors are associated with this type (Glusa, E. and Markwardt, F .: Haemostasis 13, 96-101 [1983]). More recent pharmacological findings show that Benzdioxanderivate depending on the type of substitution a high affinity for a -, - or a 2 -adrenergic receptors (Dabire, H., P.Mouille, M.Andrejak, B.Fournierand H.Schmitt have pre-and postsynaptica-adrenoceptor blockade by (imidazolinyl-2) -2-benzodioxanes 1-4 (170-150): antagonistic action on the central effects of clonidine Arch. Int. Pharmacodyn., 254, 252-270 (1981), Doxey, J. C, AC Lane, AG Roach to NK Virdee Comparison of the a-adrenoceptor antagonist profiles of idazoxane (RX'781094), yohimbine, rauwolscine and corynanthine, Naunyn-Schmiedebergs Arch. Pharmacol., 325, 136-144 (1984).
Kapur, H. and D. R. MottramKapur, H. and D.R. Mottram
A comparative study on the pre- arid postsynaptic alpha blocking activity of a series of benzodioxanes Biochem. Pharmacol. 27,1879-1880 (1978).A comparative study on the pre-arid postsynaptic alpha blocking activity of a series of benzodioxanes biochem. Pharmacol. 27, 1879-1880 (1978).
Timmermans, P.B.M.W. M., J.E.van Kemenade, H. D. Batinkand P.A. vanZwieten Selectivity of benzodioxane α-adrenoceptor antagonists for ar and a2-adrenoceptors determined by binding affinity Pharmacology 26, 258-269 (1983).Timmermans, PBMWM, jevan Kemenade, HD Batinkand PA vanZwieten Selectivity of benzodioxanes α-adrenoceptor antagonists for a r and a 2 -adrenoceptors deterministic mined by binding affinity Pharmacology 26, 258-269 (1983).
Timmermans, P. B. M. W. M., J. Q. Qian, R. R. Ruffolo and P. A. van ZwietenTimmermans, P.B.M.W.M., J.Q. Qian, R.R. Ruffolo and P.A. van Zwieten
A study of the seletivity and potency of raouwolscine, RX 781094 and RS 21361 as antagonists of alpha-1 and alpha-2 adrenoceptors J. Pharmacol, exp. Ther. 228,739-748 (1984).A study of the seletivity and potency of raouwolscine, RX 781094 and RS 21361 as antagonists of alpha-1 and alpha-2 adrenoceptors J. Pharmacol, exp. Ther. 228, 739-748 (1984).
Ein bekannter Vertreter ist PiperoxanA known representative is piperoxan
das vorrangig a2-adrenerge Rezeptoren blockiert (Starke, K. Rev. Physiol. Biochem. Pharmacol. 88,199-236 [1981]).which primarily blocks a 2 adrenergic receptors (Starke, K. Rev. Physiol, Biochem Pharmacol 88, 189-236 [1981]).
96,5g e^-Dimethoxy-i^^^-tetrahydroisochinolin werden mit 46,13g 2-Chlormethylbenzdioxan vereinigt acht Stunden auf 1900C erhitzt.96.5 g e ^ -Dimethoxy-i ^^^ - tetrahydroisoquinoline are combined with 46.13g 2-Chloromethylbenzdioxan eight hours at 190 0 C heated.
Danach werden zur abgekühlten Reaktionsmischung 600ml verdünnte Salzsäure gegeben und diese mit 100ml Benzen ausgeschüttelt. Die salzsaure wäßrige Phase wird nochmals mit weiteren 100ml Benzen und 100ml Diethylether extrahiert.Thereafter, 600 ml of dilute hydrochloric acid are added to the cooled reaction mixture and shaken with 100 ml of benzene. The hydrochloric acid aqueous phase is extracted again with another 100 ml of benzene and 100 ml of diethyl ether.
Danach wird in der wäßrigen Phase mit konzentrierter Ammoniaklösung ein pH-Wert von 7 bis 8 eingestellt und mit 300ml Diethylether extrahiert.Thereafter, a pH of 7 to 8 is adjusted in the aqueous phase with concentrated ammonia solution and extracted with 300 ml of diethyl ether.
Nach dem Trocknen deretherischen Phase über Natriumsulfat wird isopropanolische Salzsäure zugegeben, wobei das 2(1,4-Benzdioxan-^-yl-methyD-e^-dimethoxy-i^^^-tetrahydroisochinoiinhydrochlorid auskristallisiert und nach Umkristal!isation aus Isopropanol unter Zusatz von Isopropanol/Salzsäure in 20%iger Ausbeute erhalten wird.After drying the ethereal phase over sodium sulfate, isopropanolic hydrochloric acid is added, whereby the 2 (1,4-benzodioxan-1-yl-methyl-e-dimethoxy-1,2,3-tetrahydroisoquinoiin hydrochloride crystallizes out and after recrystallization from isopropanol with the addition of Isopropanol / hydrochloric acid is obtained in 20% yield.
Analog Beispiel 1 werden 103,5g i-Methyl-e^-dimethoxy-I^S^-tetrahydroisochinolin mit46,13g 2-Chlormethylbenzdioxan umgesetzt. Nach Extraktion der wäßrig-salzsauren Lösung des Reaktionsproduktes mit Benzen und Diethylether analog Bsp. 1 wird die wäßrige Phase mit 300 ml Benzen überschichtet und mit konzentrierter Ammoniaklösung ein pH-Wert von 7 bis 8 eingestellt. Die benzenische Phase wird abgetrennt, über Natriumsulfat getrocknet und eingeengt. Der Rückstand wird in Isopropanol gelöst und mit Isopropanol/Salzsäure unter Rühren sauergestellt. Die auskristallisierte Substanz wird abgesaugt und aus Isopropanol umkristallisiert.Analogously to Example 1, 103.5 g of i-methyl-e, -dimethoxy-1H-tetrahydroisoquinoline are reacted with 46.13 g of 2-chloromethylbenzdioxane. After extraction of the aqueous hydrochloric acid solution of the reaction product with benzene and diethyl ether analogously to Example 1, the aqueous phase is covered with 300 ml of benzene and adjusted with concentrated ammonia solution, a pH of 7 to 8. The benzenic phase is separated, dried over sodium sulfate and concentrated. The residue is dissolved in isopropanol and acidified with isopropanol / hydrochloric acid with stirring. The crystallized substance is filtered off and recrystallized from isopropanol.
Die Ausbeute beträgt 10g 1-Methyl-2-(1,4-benzdioxan-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisochinolinhydrochlorid. Fp 165 bis 1760C.The yield is 10 g of 1-methyl-2- (1,4-benzdioxan-2-ylmethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. Mp 165 to 176 0C .
42,45g i-Benzyl-e^-dimethoxy-i^^^-tetrahydroisochinolin werden mit 13,84g 2-Chlormethylbenzdioxan vereinigt und acht Stunden unter Argon auf 1900C erhitzt.42.45 g of i-benzyl-e ^ -dimethoxy-i ^^^ - tetrahydroisoquinoline are combined with 13.84 g of 2-chloromethylbenzdioxane and heated to 190 0 C under argon for eight hours.
Nach Beendigung der Reaktion werden 1,51 Wasser und 300 ml Benzen zugegeben, durch Zusatz von verdünnter Salzsäure wird ein pH-Wert von 1 eingestellt und anschließend kräftig geschüttelt.After completion of the reaction, 1.51 of water and 300 ml of benzene are added, by addition of dilute hydrochloric acid is adjusted to a pH of 1 and then shaken vigorously.
Die benzenische Phase wird abgetrennt und über Natriumsulfat getrocknet. Aus der Benzenlösung kristallisieren 27,8g 1-Benzyl-2(1,4-benzdioxan-2-ylmethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisochinolin aus, welches durch Lösen in Isopropanol und Sauerstellen mit Isopropanol/Salzsäure in das entsprechende Hydrochlorid überführt wird.The benzenic phase is separated and dried over sodium sulfate. From the benzene solution, 27.8 g of 1-benzyl-2 (1,4-benzdioxan-2-ylmethyl) -6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline crystallize out, which is obtained by dissolving in isopropanol and acidifying with isopropanol / Hydrochloric acid is converted into the corresponding hydrochloride.
Die Reinigung erfolgt analog Beispiel 1 und 2. · - . The cleaning is carried out analogously to Example 1 and 2. · -.
Fp 172 bis 1860C.Mp 172 to 186 0C .
250250
CH3 CH3OCH 3 CH 3 O
^CH2-^ CH 2 -
Formel IFormula I
CH3 CH 3 CH3 CH 3
Formel JTFormula JT
LCH2-CiLCH 2 -Ci Formel JHFormula JH
-9.3.87- 41358-9.3.87- 41358
Claims (7)
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DD29224386A DD250930A1 (en) | 1986-06-08 | 1986-06-08 | PROCESS FOR PREPARING NEW TETRAHYDROISOCHINOLINE DERIVATIVES |
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| DD29224386A DD250930A1 (en) | 1986-06-08 | 1986-06-08 | PROCESS FOR PREPARING NEW TETRAHYDROISOCHINOLINE DERIVATIVES |
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| DD250930A1 true DD250930A1 (en) | 1987-10-28 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009013390A1 (en) | 2007-07-20 | 2009-01-29 | Orion Corporation | 2, 3-dihydrobenzo[1, 4] dioxin-2-ylmethyl derivatives as alpha2c antagonists for use in the treatment of peripheric and central nervous systeme diseases |
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1986
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009013390A1 (en) | 2007-07-20 | 2009-01-29 | Orion Corporation | 2, 3-dihydrobenzo[1, 4] dioxin-2-ylmethyl derivatives as alpha2c antagonists for use in the treatment of peripheric and central nervous systeme diseases |
| US8492549B2 (en) | 2007-07-20 | 2013-07-23 | Orion Corporation | 2,3-dihydrobenzo(1,4) dioxin-2-ylmethyl derivatives as alpha2C antagonists for use in the treatment of peripheric and central nervous systeme diseases |
| US8697723B2 (en) | 2007-07-20 | 2014-04-15 | Orion Corporation | 2,3-dihydrobenzo(1,4) dioxin-2-ylmethyl derivatives as alpha2C antagonists for use in the treatment of peripheric and central nervous system diseases |
| US8809536B2 (en) | 2007-07-20 | 2014-08-19 | Orion Corporation | 2,3-dihydrobenzo[1,4] dioxin-2-ylmethyl derivatives as alpha2C antagonists for use in the treatment of peripheric and central nervous system diseases |
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