US2168929A - Isoquinoline compounds and derivatives thereof - Google Patents
Isoquinoline compounds and derivatives thereof Download PDFInfo
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- US2168929A US2168929A US178883A US17888337A US2168929A US 2168929 A US2168929 A US 2168929A US 178883 A US178883 A US 178883A US 17888337 A US17888337 A US 17888337A US 2168929 A US2168929 A US 2168929A
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- 125000002183 isoquinolinyl group Chemical class C1(=NC=CC2=CC=CC=C12)* 0.000 title 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 36
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 20
- 150000001875 compounds Chemical class 0.000 description 18
- 238000002844 melting Methods 0.000 description 18
- 230000008018 melting Effects 0.000 description 18
- 239000003208 petroleum Substances 0.000 description 11
- 239000002253 acid Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 150000002537 isoquinolines Chemical class 0.000 description 8
- 239000000155 melt Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 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 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 150000001408 amides Chemical class 0.000 description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 150000002431 hydrogen Chemical class 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- -1 isoquinoline compound Chemical class 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- 239000007859 condensation product Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229960001789 papaverine Drugs 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- ASUDFOJKTJLAIK-UHFFFAOYSA-N 2-methoxyethanamine Chemical compound COCCN ASUDFOJKTJLAIK-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- LJOODBDWMQKMFB-UHFFFAOYSA-N cyclohexylacetic acid Chemical compound OC(=O)CC1CCCCC1 LJOODBDWMQKMFB-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- WCRZVVKTTYYJPR-UHFFFAOYSA-N 1,3-dimethoxyisoquinoline Chemical compound C1=CC=C2C(OC)=NC(OC)=CC2=C1 WCRZVVKTTYYJPR-UHFFFAOYSA-N 0.000 description 1
- VPKAHUMPZYVNIV-UHFFFAOYSA-N 1,4-dihydroisoquinoline Chemical class C1=CC=C2CC=NCC2=C1 VPKAHUMPZYVNIV-UHFFFAOYSA-N 0.000 description 1
- SVPUBXQKOYGJNM-UHFFFAOYSA-N 1-cyclohexylisoquinoline Chemical class C1CCCCC1C1=NC=CC2=CC=CC=C12 SVPUBXQKOYGJNM-UHFFFAOYSA-N 0.000 description 1
- VABYVFZVTIDNOA-UHFFFAOYSA-N 2-cyclohexylacetyl chloride Chemical compound ClC(=O)CC1CCCCC1 VABYVFZVTIDNOA-UHFFFAOYSA-N 0.000 description 1
- BEGAUDNDNJFMIL-UHFFFAOYSA-N 4-(ethylamino)-2-methoxyphenol Chemical compound CCNC1=CC=C(O)C(OC)=C1 BEGAUDNDNJFMIL-UHFFFAOYSA-N 0.000 description 1
- JQJPBYFTQAANLE-UHFFFAOYSA-N Butyl nitrite Chemical compound CCCCON=O JQJPBYFTQAANLE-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- 101100112677 Mus musculus Ccnd3 gene Proteins 0.000 description 1
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical class NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- RVOJTCZRIKWHDX-UHFFFAOYSA-N cyclohexanecarbonyl chloride Chemical compound ClC(=O)C1CCCCC1 RVOJTCZRIKWHDX-UHFFFAOYSA-N 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical class OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 description 1
- 125000005805 dimethoxy phenyl group Chemical group 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 210000000232 gallbladder Anatomy 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 150000004800 hydroisoquinoline derivatives Chemical class 0.000 description 1
- CDZDPHPSWKHONZ-UHFFFAOYSA-N hypochlorous acid;phosphane Chemical compound P.ClO CDZDPHPSWKHONZ-UHFFFAOYSA-N 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- ZQWPRMPSCMSAJU-UHFFFAOYSA-N methyl cyclohexanecarboxylate Chemical compound COC(=O)C1CCCCC1 ZQWPRMPSCMSAJU-UHFFFAOYSA-N 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000005245 sintering Methods 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Definitions
- the present invention relates to isoquinoline compounds containing a hydroaromatic radical in l-position and to the derivatives thereof hydrogenated in the pyridine nucleus.
- isoquinolin-e compounds having an organic radical in l-position and the derivatives thereof hydrogenated in the pyridine ring are valuable physiologically active substances which in part are used in medicine.
- Isoquinoline compounds containing a hydroaromatic radical in l-position have hitherto been unknown.
- isoquinoline compounds of the latter kind are obtained by condensing, according to methods known for 'making isoquinoline compounds substituted in 1- position, an aromatic-aliphatic 1-aryl-2-aminoethane compound with a hydroaromatic acid, acid derivative or aldehyde, subjecting the condensation product so obtained to ring closure, advantageously after hydrogenation, and, if necessary, hydrogenating or dehydrogenating the isoquinoline compound so obtained.
- the corresponding 3:4-dihydro-isoquinoline compounds are obtained which may be hydrogenated to the corresponding tetrahydro-compounds or dehydrogenated to the isoquinoline compounds.
- the new isoquinoline derivatives may also be produced according to one of the processes known for obtaining isoquinolines, for instance, by condensing the aforesaid amines with hydroaromatic aldehydes and subjecting the condensation products thus obtained to ring closure to form the corresponding tetrahydro-isoquinoline which, if necessary, may be dehydrogenated in the pyridine nucleus.
- the process of the present invention may be carried out with acids which are only partially hydrogenated in the nucleus.
- acids which are only partially hydrogenated in the nucleus.
- the process of the present invention may also be carried out with hydroaromatic acids in which an aliphatic residue is contained between the nucleus and the carboxyl group.
- hydroaromatic acids in which an aliphatic residue is contained between the nucleus and the carboxyl group.
- the new compounds have the following general formula:
- R stands for cyclohexyl, cyclohexenyl or he'xahydrobenzyl
- Y stands for hydrogen, alkyl or cyclohexyl
- Z1 and Z2 each stand for hydrogen, hydroxy, alkoxy, or Z1 and Z2 together stand for alkylenedioxy.
- the compounds aresolid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.
- the 1-cyclohexyl-6 :7-dimethoxyisoquinoline is twice as effective spasmolitically as papaverine.
- the l-cyclohexenyl-Al-G:Z-dimethoxyisoquinoline has in the gall-bladder twice the activity and in the intestines four times the activity of papaverine.
- the l-cyclohexyl-Gz'I-dimethoxydihydro(3:4)-isoquinoline has a strong central-stimulating effect.
- the hydrogenated acids used as' parent materials are in part very readilyaccessible, and cheap parent materials for the production of isoquinoline compounds of the type named, hereas thealkoxyphenylacetic acids required for the production of papaverine and its homologues can only be made in a complicated manner.
- the compounds obtainable according to the present invention are intended for use in part as pharmaceutical prodnets and in part for the manufacture of other remedies.
- the acid solution is extracted with ether in order to remove smeary constituents, then rendered alkaline by means of alkali solution and again extracted with ether.
- the ethereal extract has been dried with potassium carbonate and the ether has been evaporated the 1-cyclohexyl-6z7- dimethoxyisoquinoline of the formula crystallises. It may be purified by repeated recrystallisation from petroleum ether or ether, or better by distillation under a highly reduced pressure. It boils under a pressure of 0.04 millimeter at a temperature of 176 C. to 180 C. The melting point is 106.5 C. to 107 C.
- the acid amide used as parent material can be obtained by causing 2 molecular proportions of 3:4-dimethoxyphenyl-methoxyethylamine to react with 1 molecular proportion of hexahydrobenzoyl chloride in dry benzene.
- A1 -cyclohe:cenyl- 6 :7 -dimethoxyisoquinoline (a) 31.9 grams mol.) of N-tetrahydrobenzoyl-p- (3 :4-dimethoxyphenyl) 43- m-ethoxyethylamine (melting point C. to 81 C.) in 300 cc. of dry chloroform are boiled for 2 hours with 50 cc. of phosphorus oxychloride and the product is worked up as described in Example 1.
- the base of the formula CHKO ⁇ N CHaO distils at 165 C. to 170 C. under a pressure of 0.02 millimeter; its melting point is 107 C. to 109 C.
- the 3:4-ethylenedioxyphenylethylarnine may be obtained from the corresponding styrene by catalytic reduction according to Kindler, Annalen, vol. 511, page 209 (1935). It boils at 167 C. to 169 C. under a pressure of 14 millimeters.
- the substance yields a dirty green color with ferric chloride solution.
- the distilled product is taken up in ether and from this solution the hydrochloride of the base is precipitated by means of ethereal hydrochloric acid. After triturating several times with dry acetone the salt of the base of the formula is obtained in a solid form. It melts at 207 C. to 208 C. after recrystallisation from. a mixture of isopropyl alcohol and acetone.
- the 3:4 dimethoxyphenylhydroxycyclohexylethylamine used as parent material may be prepared in the following manner:
- both Xs jointly stand for one of the groupings selected from the group consisting of R being a member of the group consisting of cyclohexyl, cyclohexenyl and hexahydrobenzyl, and Y being a member of the group consisting of hydrogen, alkyl and cyclohexyl, Z1 and Z2 each stand for a member of the group consisting of hydrogen, hydroxy and alkoxy, and compounds of the above general formula wherein both Xs have the same meaning as given above and Z1 and Z2 jointly stand for alkylenedioxy, said compounds being solid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.
- said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.
- said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Patented Aug. 8, 1939 UNITED STATES PATENT OFFICE TISOQUIINOLINE COMPOUNDS AND DERIVA TIVES THEREOF No Drawing. Application December 9, 1937, Se-
rial No. 178,883. In Germany December 12,
4 Claims. (01. 260289) The present invention relates to isoquinoline compounds containing a hydroaromatic radical in l-position and to the derivatives thereof hydrogenated in the pyridine nucleus.
It is known that isoquinolin-e compounds having an organic radical in l-position and the derivatives thereof hydrogenated in the pyridine ring are valuable physiologically active substances which in part are used in medicine. Isoquinoline compounds containing a hydroaromatic radical in l-position have hitherto been unknown.
Now we have found that isoquinoline compounds of the latter kind are obtained by condensing, according to methods known for 'making isoquinoline compounds substituted in 1- position, an aromatic-aliphatic 1-aryl-2-aminoethane compound with a hydroaromatic acid, acid derivative or aldehyde, subjecting the condensation product so obtained to ring closure, advantageously after hydrogenation, and, if necessary, hydrogenating or dehydrogenating the isoquinoline compound so obtained. When starting, for instance, from aromatic-aliphatic aminoalcohols of the formula RCI-IOHCH2NI-I2 (wherein R stands for aryl) or the ethers or homologues or analogues thereof, the corresponding amides are obtained by condensation with hexahydrobenzoic acids (chlorides, esters, etc.), which amides are converted into the 1- cyclohexyl-isoquinoline derivatives by means of acid condensing agents such as phosphorus oxychloride or the like. When starting from the corresponding amino-ketones the ketone-group is hydrogenated, preferably after the formation of the amide. When starting from aromaticaliphatic amines of the formula (wherein R stands for aryl) in carrying out the invention, the corresponding 3:4-dihydro-isoquinoline compounds are obtained which may be hydrogenated to the corresponding tetrahydro-compounds or dehydrogenated to the isoquinoline compounds. With the same good result the new isoquinoline derivatives may also be produced according to one of the processes known for obtaining isoquinolines, for instance, by condensing the aforesaid amines with hydroaromatic aldehydes and subjecting the condensation products thus obtained to ring closure to form the corresponding tetrahydro-isoquinoline which, if necessary, may be dehydrogenated in the pyridine nucleus. Instead of using saturated hydroaromatic. acids the process of the present invention may be carried out with acids which are only partially hydrogenated in the nucleus. In this case it may be advantageous to produce the nuclear double linkage subsequently by starting, for instance, from hexahydro-hydroXy-acids and splitting off water from the condensation products.
With the same or similar result the process of the present invention may also be carried out with hydroaromatic acids in which an aliphatic residue is contained between the nucleus and the carboxyl group. Thus, for instance, from cyclohexylacetic acid the corresponding hexahydrobenzyl-isoquinoline compounds are obtained.
The new compounds have the following general formula:
wherein both X's jointly stand for one of the following groupings:
wherein R stands for cyclohexyl, cyclohexenyl or he'xahydrobenzyl, Y stands for hydrogen, alkyl or cyclohexyl, Z1 and Z2 each stand for hydrogen, hydroxy, alkoxy, or Z1 and Z2 together stand for alkylenedioxy. l v
' The compounds aresolid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.
The new products have valuable characteristics from various aspects:
Thus the 1-cyclohexyl-6 :7-dimethoxyisoquinoline is twice as effective spasmolitically as papaverine. The l-cyclohexenyl-Al-G:Z-dimethoxyisoquinoline has in the gall-bladder twice the activity and in the intestines four times the activity of papaverine. The l-cyclohexyl-Gz'I-dimethoxydihydro(3:4)-isoquinoline has a strong central-stimulating effect.
It may furthermore be noted that the hydrogenated acids used as' parent materials are in part very readilyaccessible, and cheap parent materials for the production of isoquinoline compounds of the type named, hereas thealkoxyphenylacetic acids required for the production of papaverine and its homologues can only be made in a complicated manner. The compounds obtainable according to the present invention are intended for use in part as pharmaceutical prodnets and in part for the manufacture of other remedies.
The following examples serve to illustrate the invention, but they are not intended to limit it thereto:
1 1 -cycZohex' l-6 :7 -dimethoxyisoquznoline 32.1 grams mol.) of N-h'exahydrobenzoyl- B- (3 i4-dimethoxyphenyl) -B methoxyethylamine (melting point 105 C. to 106 C.) are heated for 2 hours in a reflux apparatus in 300 cc. of dry chloroform with 50 cc. of phosphorus oxychloride. The solvent is then distilled under reduced pressure and the residue is repeatedly extracted with hot water containing hydrochloric acid. The acid solution is extracted with ether in order to remove smeary constituents, then rendered alkaline by means of alkali solution and again extracted with ether. After the ethereal extract has been dried with potassium carbonate and the ether has been evaporated the 1-cyclohexyl-6z7- dimethoxyisoquinoline of the formula crystallises. It may be purified by repeated recrystallisation from petroleum ether or ether, or better by distillation under a highly reduced pressure. It boils under a pressure of 0.04 millimeter at a temperature of 176 C. to 180 C. The melting point is 106.5 C. to 107 C.
The acid amide used as parent material can be obtained by causing 2 molecular proportions of 3:4-dimethoxyphenyl-methoxyethylamine to react with 1 molecular proportion of hexahydrobenzoyl chloride in dry benzene.
2. 1 A1 -cyclohe:cenyl- 6 :7 -dimethoxyisoquinoline (a) 31.9 grams mol.) of N-tetrahydrobenzoyl-p- (3 :4-dimethoxyphenyl) 43- m-ethoxyethylamine (melting point C. to 81 C.) in 300 cc. of dry chloroform are boiled for 2 hours with 50 cc. of phosphorus oxychloride and the product is worked up as described in Example 1. The base of the formula CHKO\ N CHaO distils at 165 C. to 170 C. under a pressure of 0.02 millimeter; its melting point is 107 C. to 109 C.
(b) 33.7 grams 6 mol.) of N-hexahydro-Z- hydroxybenzoyl- 13 -(3:4 dimethoxyphenyl) [i methoxyethylamine (melting point 123 C. to
3. 1 -hexahydrobenzyZ-6 :7 -dimethozcyisoquinoline 33.5 grams (:9 mol.) of N-hexahydrophenylacetyl- 5 -(3:4 dimethoicyphenyl) p -methoxyethylamine (melting point 99 C. to 100 C.) in 250 cc. of xylene are boiled for half an hour with 70 cc. of phosphorus oxylchloride. After working up in the usual manner and recrystallisation from petroleum ether there is obtained the compound of the following formula:
CHaO
cnao
Hr- H:
Hz- H1 The melting point of the product is 104 C. to 105 C.
4. I-cyCZOhexyZ-G:7-diethoxyisoquinoline 36.3 grams mol.) of N-hexahydrobenzoyl-fi- (3 :4-diethoxyphenyl) -fi-ethoxyethylamine (melting point 109 C. to 110.5 C.) in 250 cc. of benzene are boiled for 3 hours with 50 cc. of phosphorus oxychloride. After recrystallisation three times from petroleum ether and once from ether the compound of the formula has a melting point of 83 C. to 84 C.
5. 1-cyclohea:yZ-6:7-ethylenediomyisoquinoline 10.3 grams of N-hexahydrobenzoyl-B-(3:4- ethylenedioxyphenyl)-{3-methoxyethylamine in 100 cc. of dry benzene are heated for 3 hours in a reflux apparatus with 15 cc. of phosphorus oxychloride. The base of the following formula onro melts at 97 C. to 98 C.
6. 1 -cyclohe.'cyl-3 :4 -dihydro- 6 :7 -dimethomyisoquinoline 11.5 grams of N-hexahydrobenzoyl-B:4-dimethoxyphenylethylamine (melting point 111 C. to 111.5 C.) in 55 cc. of dry choroform are boiled for 5 hours with 16 cc. of phosphorus oxychloride and the product is worked up as described in Example 1. The product of the formula so obtained melts at 79.5 C. to C. after recrystallization three times from petroleum ether.
7. 1-cyclohexyl-3 :4-dihg1dro-6:7-ethylenediowyisoquinoline 9 grams of N-hexahydrobenzoylethylenedioxyphenylethylamine (melting point 129.5 C.) in 50 cc. of dry chloroform are boiled for 5 hours in a reflux apparatus with 12 cc. of phosphorus oxychloride. There is obtained the product of the formula which melts at 106.5 C. to 107 0. when twice recrystallized from ether.
The 3:4-ethylenedioxyphenylethylarnine may be obtained from the corresponding styrene by catalytic reduction according to Kindler, Annalen, vol. 511, page 209 (1935). It boils at 167 C. to 169 C. under a pressure of 14 millimeters.
8. 1-cycZohexyl-3:4-dihydro-6-meth0wy-7-hydrozryisoquinolme 6.4 grams of N-hexahydrobenzoyl-B (3-methoxy 4 hydroxyphenyl) ethylamine (melting point 123.5 C. to 124.5 C.) in 33 cc. of chloroform are heated for2 hours in a reflux apparatus with 8 cc. of phosphorus oxychloride. The solvent is evaporated under reduced pressure and the residue is taken up withhotwater,
C. and under pressure.
filtered from undissolved resin and the solution is then extracted with benzene in order to remove non-basic constituents. The aqueous solution is then rendered alkaline while cooling by means of concentrated potassium carbonate solution and extracted with ether. After drying for a short time with potassium carbonate the hydrochloride of the desired base is precipitated by means of alcoholic hydrochloric acid. This salt which is first obtained in a smeary state is obtained in a powdered state by repeated trituration' alternately with ether and petroleum ether; it may be recrystallized from a mixture of isopropyl alcohol and acetone. The compound has the formula 2 OHaO &/
and a melting point of 148 C. to 149 C. The substance yields a dirty green color with ferric chloride solution.
9; 1 cycZohexyZ-6 :7 -dimethoxyisoquinoline (a) 13.1 grams of 1-cyclohexyl-3:4-dihydro- 6:7-dimethoxyisoquinoline (of. Example 6), in a. pure state, are hydrogenated with palladium at 50 C. in 50 cc. of N-hydrochloric acid and 300 cc. of water. After about 4 hours the absorption of hydrogen is complete. The whole is then filtered from the catalyst and concentrated under reduced pressure, whereby the hydrochloride of the new compound of the formula CHaO 2 NH cmo Hr H3 crystallizes. It may be purified by recrystallization from alcohol and then melts at 228 C. to 230 C. after previously sintering at C. to C.
(b) 13.6 grams of l-cyclohexyl-G:7-dimethoxyisoquinoline are hydrogenated with nickel in 50 cc. of N-hydrochloric acid and 300 cc. of water at After having been worked up as described under (a) there is likewise obtained the compound of the formula given above, which melts at 228 C. to 230 C.
11. 1-A1-cyclohexenyl-3-methyl-6.7 dimethoatyisoquinoline 6.1 grams of N-Al-tetrahydrobenzoyl-(3:4-dimethoxyphenyl) -2-aminopropanol (melting point 134 C. to C.) in 60 cc. of chloroform are boiled for 4 hours in a reflux apparatus with 12 cc. of phosphorus oxychloride. After working up in the usual manner the base is distilled under a highly reduced pressure. It boils at 172 C. to C. under 0.01 millimeter pressure. The distilled product is taken up in ether and from this solution the hydrochloride of the base is precipitated by means of ethereal hydrochloric acid. After triturating several times with dry acetone the salt of the base of the formula is obtained in a solid form. It melts at 207 C. to 208 C. after recrystallisation from. a mixture of isopropyl alcohol and acetone.
12. 1 A 1-cyZ0hexenyl-3-cycloheazyl-fi:T-dimethoxyisoquinoline 2.4 grams of N-tetrahydrobenzoyl-p-(3:4-dimethoxyphenyl) -[i hydroxy-u-cyclohexylethylamine (melting point 158 C. to 159 C.) in 20 cc. of dry benzene are boiled for 4 hours with 5 cc. of phosphorus oxychloride. After working up in the usual manner the crude base is dissolved in absolute ether and the hydrochloride of the base of the formula is precipitated therefrom by means of ethereal hydrochloric acid.
The 3:4 dimethoxyphenylhydroxycyclohexylethylamine used as parent material may be prepared in the following manner:
From veratrol and hexahydrophenylacetyl chloride there is obtained according to the F'riedel- Crafts reaction the 3:4-dimethoxyphenylhexahydrobenzyl ketone of melting point 52 C. to 53 C. This yields with butyl nitrite an isonitrosocompound of melting point of 145 C. to 147 C., from which the desired amine may be prepared with palladium and hydrogen in an alcoholic hydrochloric acid solution; the hydrochloride of the amine melts at 208 C. to 210 C.
1 3. 1 -cyclohemyZ-6 :7 -dz'methoxyis0quinoline 15 grams of 1-cyclohexyl-6z7 -climethoxytetrahydroquinoline are heated for 15 hours in a reflux apparatus with 70 'cc. of xylene and 2 grams of palladium. After the reaction product has been worked up and redissolved from ether there is obtained the 1 cyclohexyl 6:7 dimethoxyisoquinoline described in Example 1 which melts at 106.5 C. to 107 C.
1 4. 1 -cycZohea:yl-3 :4 -dz'hydroisoquinoline 28.4 grams of hexahydrobenzoic acid methylester and 31.4 grams of phenylethylamine are kept for 8 hours at a temperature of C. to C. The reaction product is dissolved in benzene and shaken out with dilute hydrochloric acid. After partially distilling the benzene and adding petroleum ether crystals are precipitated which melt at 93 C. to 94 C. when recrystallized from hexahydrobenzene.
10 grams of the amide so obtained are boiled for '7 hours in a reflux apparatus with 50 cc. of xylene and 15 cc. of phosphorus oxychloride. After distilling the solvent the residue is treated with ether and the ethereal solution is shaken with hydrochloric acid. The isoquinoline product is separated from the hydrochloric acid solution by means of alkali. The base of the formula distils at 145 C. to 150 C. under 4.5 millimeters pressure. The hydrochloride has a melting point of 146 C. to 147 C.
We claim:
1. As new compositions of matter the compounds of the following formula:
wherein both Xs jointly stand for one of the groupings selected from the group consisting of R being a member of the group consisting of cyclohexyl, cyclohexenyl and hexahydrobenzyl, and Y being a member of the group consisting of hydrogen, alkyl and cyclohexyl, Z1 and Z2 each stand for a member of the group consisting of hydrogen, hydroxy and alkoxy, and compounds of the above general formula wherein both Xs have the same meaning as given above and Z1 and Z2 jointly stand for alkylenedioxy, said compounds being solid colorless substances which are readily soluble in benzene, chloroform, ether and petroleum ether.
2. As a new composition of matter the compound of the following formula:
said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.
4. As a new composition of matter the compound of the following formula: 5
E: 01130 )w m said compound being a solid colorless substance H which is readily soluble in benzene, chloroform, ether and petroleum ether. H H,
3. As a new composition of matter the compound of the following formula: H,
CHaO
said compound being a solid colorless substance which is readily soluble in benzene, chloroform, ether and petroleum ether.
MAX BOCKMI jI-IL. HANS HERMANN.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2168929X | 1936-12-12 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US2168929A true US2168929A (en) | 1939-08-08 |
Family
ID=7988312
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US178883A Expired - Lifetime US2168929A (en) | 1936-12-12 | 1937-12-09 | Isoquinoline compounds and derivatives thereof |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US2168929A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504663A (en) * | 1980-12-22 | 1985-03-12 | Delalande S.A. | 3-Hydroxyalkyl-3,4-dihydro-1-substituted isoquinolines |
| US4745115A (en) * | 1984-10-19 | 1988-05-17 | Beecham Group P.L.C. | Isoquinolines or benzisoquinoliner having antiinflammatory activity |
-
1937
- 1937-12-09 US US178883A patent/US2168929A/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4504663A (en) * | 1980-12-22 | 1985-03-12 | Delalande S.A. | 3-Hydroxyalkyl-3,4-dihydro-1-substituted isoquinolines |
| US4745115A (en) * | 1984-10-19 | 1988-05-17 | Beecham Group P.L.C. | Isoquinolines or benzisoquinoliner having antiinflammatory activity |
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