NO115028B - - Google Patents
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- Publication number
- NO115028B NO115028B NO161543A NO16154366A NO115028B NO 115028 B NO115028 B NO 115028B NO 161543 A NO161543 A NO 161543A NO 16154366 A NO16154366 A NO 16154366A NO 115028 B NO115028 B NO 115028B
- Authority
- NO
- Norway
- Prior art keywords
- parts
- formula
- mixture
- naphthoxy
- hydrogen
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 claims description 23
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 150000002790 naphthalenes Chemical class 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 6
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000003776 cleavage reaction Methods 0.000 claims description 3
- 230000020335 dealkylation Effects 0.000 claims description 3
- 238000006900 dealkylation reaction Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid group Chemical group C(C=1C(C(=O)O)=CC=CC1)(=O)O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims description 3
- 230000007017 scission Effects 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 101100516568 Caenorhabditis elegans nhr-7 gene Proteins 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- -1 hydroxyalkyl radical Chemical class 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 22
- KFZMGEQAYNKOFK-UHFFFAOYSA-N 2-propanol Substances CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 239000007787 solid Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 229960004592 isopropanol Drugs 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- AVLUBEJQNBBJCK-UHFFFAOYSA-N 2-[(4-methoxynaphthalen-1-yl)oxymethyl]oxirane Chemical compound C12=CC=CC=C2C(OC)=CC=C1OCC1CO1 AVLUBEJQNBBJCK-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 7
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 6
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 239000012259 ether extract Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- ZWXAXMRPUBPQCS-UHFFFAOYSA-N 2-[(4-propan-2-yloxynaphthalen-1-yl)oxymethyl]oxirane Chemical compound O1CC1COC1=CC=C(C2=CC=CC=C12)OC(C)C ZWXAXMRPUBPQCS-UHFFFAOYSA-N 0.000 description 3
- BOTGCZBEERTTDQ-UHFFFAOYSA-N 4-Methoxy-1-naphthol Chemical compound C1=CC=C2C(OC)=CC=C(O)C2=C1 BOTGCZBEERTTDQ-UHFFFAOYSA-N 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 2
- JYJCMNGOURBDDH-UHFFFAOYSA-N 1-chloro-3-(6,7-dimethoxynaphthalen-1-yl)oxypropan-2-ol Chemical compound ClCC(COC1=CC=CC2=CC(=C(C=C12)OC)OC)O JYJCMNGOURBDDH-UHFFFAOYSA-N 0.000 description 2
- FZYKRWFIXYQSGR-UHFFFAOYSA-N 1-chloro-3-(6-methoxynaphthalen-1-yl)oxypropan-2-ol Chemical compound ClCC(COC1=CC=CC2=CC(=CC=C12)OC)O FZYKRWFIXYQSGR-UHFFFAOYSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- MLFOCCNTZVTFBH-UHFFFAOYSA-N 2-[(5-methoxynaphthalen-1-yl)oxymethyl]oxirane Chemical compound C1=CC=C2C(OC)=CC=CC2=C1OCC1CO1 MLFOCCNTZVTFBH-UHFFFAOYSA-N 0.000 description 2
- LMAJNTFMXMHOBQ-UHFFFAOYSA-N 5-[2-hydroxy-3-(propan-2-ylamino)propoxy]naphthalen-2-ol Chemical compound OC1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 LMAJNTFMXMHOBQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000001871 Tachycardia Diseases 0.000 description 2
- ROUJENUXWIFONU-UHFFFAOYSA-N [2-hydroxy-3-(4-hydroxynaphthalen-1-yl)oxypropyl]-propan-2-ylazanium;chloride Chemical compound Cl.C1=CC=C2C(OCC(O)CNC(C)C)=CC=C(O)C2=C1 ROUJENUXWIFONU-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000003929 acidic solution Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000002026 chloroform extract Substances 0.000 description 2
- 239000012380 dealkylating agent Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002024 ethyl acetate extract Substances 0.000 description 2
- 208000019622 heart disease Diseases 0.000 description 2
- 150000003840 hydrochlorides Chemical class 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 229960001317 isoprenaline Drugs 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 208000010125 myocardial infarction Diseases 0.000 description 2
- 150000004780 naphthols Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 208000028591 pheochromocytoma Diseases 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical compound CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 230000006794 tachycardia Effects 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- AGKBPYHCMLFXDS-UHFFFAOYSA-N 1-(4-methoxynaphthalen-1-yl)oxy-3-(propan-2-ylamino)propan-2-ol;hydrochloride Chemical compound Cl.C1=CC=C2C(OC)=CC=C(OCC(O)CNC(C)C)C2=C1 AGKBPYHCMLFXDS-UHFFFAOYSA-N 0.000 description 1
- ISNZGJPEKXRSSQ-UHFFFAOYSA-N 1-(5-methoxynaphthalen-1-yl)oxy-3-(propan-2-ylamino)propan-2-ol Chemical compound C1=CC=C2C(OC)=CC=CC2=C1OCC(O)CNC(C)C ISNZGJPEKXRSSQ-UHFFFAOYSA-N 0.000 description 1
- FEWDJEPNDLNVLJ-UHFFFAOYSA-N 1-(5-methoxynaphthalen-1-yl)oxy-3-(propan-2-ylamino)propan-2-ol;hydrochloride Chemical compound Cl.C1=CC=C2C(OC)=CC=CC2=C1OCC(O)CNC(C)C FEWDJEPNDLNVLJ-UHFFFAOYSA-N 0.000 description 1
- NYMXVBIZRYJLOY-UHFFFAOYSA-N 1-(6-methoxynaphthalen-1-yl)oxy-3-(propan-2-ylamino)propan-2-ol Chemical compound CC(C)NCC(O)COC1=CC=CC2=CC(OC)=CC=C21 NYMXVBIZRYJLOY-UHFFFAOYSA-N 0.000 description 1
- ZWFAPQYDHNZNAF-UHFFFAOYSA-N 1-(6-methoxynaphthalen-1-yl)oxy-3-(propan-2-ylamino)propan-2-ol;hydrochloride Chemical compound Cl.CC(C)NCC(O)COC1=CC=CC2=CC(OC)=CC=C21 ZWFAPQYDHNZNAF-UHFFFAOYSA-N 0.000 description 1
- QWXUJPJVNKCDKJ-UHFFFAOYSA-N 1-(tert-butylamino)-3-chloropropan-2-ol;hydrochloride Chemical compound Cl.CC(C)(C)NCC(O)CCl QWXUJPJVNKCDKJ-UHFFFAOYSA-N 0.000 description 1
- KJZACUHZZJVVRG-UHFFFAOYSA-N 1-[benzyl(propan-2-yl)amino]-3-(4-methoxynaphthalen-1-yl)oxypropan-2-ol hydrochloride Chemical compound Cl.C(C1=CC=CC=C1)N(C(C)C)CC(COC1=CC=C(C2=CC=CC=C12)OC)O KJZACUHZZJVVRG-UHFFFAOYSA-N 0.000 description 1
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical class C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- CWEPACWBWIOYID-UHFFFAOYSA-N 4'-hydroxypropanolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=C(O)C2=C1 CWEPACWBWIOYID-UHFFFAOYSA-N 0.000 description 1
- WMVPFEQOLJSBDR-UHFFFAOYSA-N 4-propan-2-yloxynaphthalen-1-ol Chemical compound C1=CC=C2C(OC(C)C)=CC=C(O)C2=C1 WMVPFEQOLJSBDR-UHFFFAOYSA-N 0.000 description 1
- WLZPYTDCBHITRF-UHFFFAOYSA-N 5-methoxynaphthalen-1-ol Chemical compound C1=CC=C2C(OC)=CC=CC2=C1O WLZPYTDCBHITRF-UHFFFAOYSA-N 0.000 description 1
- MFTKJOKWLZMWFM-UHFFFAOYSA-N 6,7-dimethoxynaphthalen-1-ol Chemical compound C1=CC(O)=C2C=C(OC)C(OC)=CC2=C1 MFTKJOKWLZMWFM-UHFFFAOYSA-N 0.000 description 1
- LPPSENSUXVOOII-UHFFFAOYSA-N 6-methoxynaphthalen-1-ol Chemical compound OC1=CC=CC2=CC(OC)=CC=C21 LPPSENSUXVOOII-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical class CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- HNUALPPJLMYHDK-UHFFFAOYSA-N C[CH]C Chemical compound C[CH]C HNUALPPJLMYHDK-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical class Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- BQOWUDKEXDCGQS-UHFFFAOYSA-N [CH]1CCCC1 Chemical compound [CH]1CCCC1 BQOWUDKEXDCGQS-UHFFFAOYSA-N 0.000 description 1
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001264 acyl cyanides Chemical class 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical class OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- MMCPOSDMTGQNKG-UJZMCJRSSA-N aniline;hydrochloride Chemical compound Cl.N[14C]1=[14CH][14CH]=[14CH][14CH]=[14CH]1 MMCPOSDMTGQNKG-UJZMCJRSSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- UGUUDTWORXNLAK-UHFFFAOYSA-N azidoalcohol Chemical compound ON=[N+]=[N-] UGUUDTWORXNLAK-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001860 citric acid derivatives Chemical class 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- AKPUJVVHYUHGKY-UHFFFAOYSA-N hydron;propan-2-ol;chloride Chemical compound Cl.CC(C)O AKPUJVVHYUHGKY-UHFFFAOYSA-N 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- LYBKPDDZTNUNNM-UHFFFAOYSA-N isopropylbenzylamine Chemical compound CC(C)NCC1=CC=CC=C1 LYBKPDDZTNUNNM-UHFFFAOYSA-N 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 125000002960 margaryl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 229920001467 poly(styrenesulfonates) Polymers 0.000 description 1
- 150000003109 potassium Chemical class 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229920003002 synthetic resin Polymers 0.000 description 1
- 239000000057 synthetic resin Substances 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 231100000048 toxicity data Toxicity 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
Description
Fremgangsmåte for fremstilling av terapeutisk virksomme naftalenderivater. Process for the production of therapeutically effective naphthalene derivatives.
Foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av nye naftalenderivater, som er i besittelse av (3-adrenergisk blokkerende aktivitet og som er nyttige ved be-handlingen eller profylakse av hjertesykdommer, f. eks. angina pectoris og caridac arrhyt-mias, og ved behandling av hypertensjon, hjerteinfarkt (infarctum cordis) og phaeochro-mocytoma. The present invention relates to a method for the production of new naphthalene derivatives, which possess (3-adrenergic blocking activity and which are useful in the treatment or prophylaxis of heart diseases, e.g. angina pectoris and caridac arrhythmias, and in the treatment of hypertension, heart attack (infarctum cordis) and phaeochro-mocytoma.
I henhold til oppfinnelsen fremstilles terapeutisk virksomme naftalenderivater av formelen: According to the invention, therapeutically effective naphthalene derivatives of the formula are produced:
hvor R<1>står for hydrogen eller et lavere alkyl-eller hydroksyalkylradikal, eller et cykloalkylradikal med ikke mer enn 5 karbonatomer, R<2>står for hydrogen eller et alkylradikal med ikke mer enn 6 karbonatomer, og n er 1 eller 2, og estere og salter herav,karakterisert vedat where R<1>represents hydrogen or a lower alkyl or hydroxyalkyl radical, or a cycloalkyl radical with no more than 5 carbon atoms, R<2>represents hydrogen or an alkyl radical with no more than 6 carbon atoms, and n is 1 or 2, and esters and salts thereof, characterized thereby
a) en forbindelse av formelen:a) a compound of the formula:
hvor A står for gruppen where A stands for the group
eller or
—CH.OH.CH2X, hvor X står for et halogenatom, R<c>står for et alkylradikal med ikke mer —CH.OH.CH2X, where X stands for a halogen atom, R<c>stands for an alkyl radical with no more
enn 6 karbonatomer, og n har den ovenfor angitte betydning, omsettes med et amin av formelen R<1>. NHR<7>, hvor R<1>har den ovenfor angitte betydning, og R<7>er hydrogen eller en hydrogenolysbar beskyttelsesgruppe, eller med ftalimid, fulgt av avspaltning av ftalsyreresten, eller b) en forbindelse av formelen: than 6 carbon atoms, and n has the above meaning, is reacted with an amine of the formula R<1>. NHR<7>, where R<1> has the meaning given above, and R<7> is hydrogen or a hydrogenolisable protecting group, or with phthalimide, followed by cleavage of the phthalic acid residue, or b) a compound of the formula:
hvor R<6>og n har den ovenfor angitte betydning, omsettes med en forbindelse av formelen: X . CH2 . CHOH . CH2. NR<!>R7eller where R<6> and n have the above meaning, are reacted with a compound of the formula: X . CH2. CHOH. CH2. NR<!>R7or
CHgNRiR7 hvor X, R<1>og R<7>har den ovenfor angitte betydning, hvoretter erholdte forbindelser av formelen: CHgNRiR7 where X, R<1> and R<7> have the meaning given above, after which compounds of the formula are obtained:
hvor R<1>, R<8>og n har den ovenfor angitte betydning, og R<7>er en hydrogenolyserbar beskyttelsesgruppe, hydrogeneres katalytisk, om ønsket etter dealkylering av gruppen(e) OR°, where R<1>, R<8> and n have the above meaning, and R<7> is a hydrogenolysable protecting group, hydrogenated catalytically, if desired after dealkylation of the group(s) OR°,
og/eller erholdte forbindelser av formel II hvor R<6>og n har den ovenfor angitte betydning, og R1ogR<7>er hydrogen, om ønsket omsettes med en karbonylforbindelse av formelen R<3>COR<4>, hvor radikalet -CHR<3>R<4>har den for R<1>angitte betydning (unntatt hydrogen), under reduserende betingelser, and/or obtained compounds of formula II where R<6> and n have the above meaning, and R1 and R<7> are hydrogen, if desired are reacted with a carbonyl compound of the formula R<3>COR<4>, where the radical -CHR <3>R<4> has the meaning given for R<1> (excluding hydrogen), under reducing conditions,
og/eller gruppen(e) OR<6>i erholdte forbindelser av formel II hvor R<1>, R° og n har den ovenfor angitte betydning, og R<7>er hydrogen, om ønsket dealkyleres, and/or the group(s) OR<6> in obtained compounds of formula II where R<1>, R° and n have the above meaning, and R<7> is hydrogen, if desired dealkylated,
og om ønsket omdannes de erholdte forbindelser til estere eller salter. and if desired, the compounds obtained are converted into esters or salts.
Som en hensiktsmessig verdi for R<1>skal f. eks. nevnes metyl, etyl, n-propyl, isopropyl, s-butyl, t-butyl, 2-hydroksy-l, 1-dimetyletyl eller cyklopentylradikal og som en hensiktsmessig verdi for R<2>skal nevnes f. eks. hydrogen eller metyl eller isopropylradikal. Som en hensiktsmessig verdi for R<7>skal f. eks. nevnes benzylra-dikalet, og som en hensiktsmessig verdi for X skal f. eks, nevnes klor- eller bromatomet. As an appropriate value for R<1>, e.g. mention is made of methyl, ethyl, n-propyl, isopropyl, s-butyl, t-butyl, 2-hydroxy-1, 1-dimethylethyl or cyclopentyl radical and as an appropriate value for R<2> should be mentioned e.g. hydrogen or methyl or isopropyl radical. As an appropriate value for R<7>, e.g. the benzyl radical is mentioned, and as an appropriate value for X the chlorine or bromine atom should, for example, be mentioned.
Det vil forståes at ved fremgangsmåtetrinn (a) ovenfor, når R<1>står for hydrogen, så kan aminet i formelen R<l>NH2erstattes av ftalimid, etterfulgt av avspaltning av ftalsyreesteren, f. eks. ved anvendelse av hydrazin. It will be understood that in method step (a) above, when R<1> stands for hydrogen, then the amine in the formula R<1>NH2 can be replaced by phthalimide, followed by cleavage of the phthalic acid ester, e.g. using hydrazine.
Reaksjonen (b) hvor et naftolderivat er in-volvert, kan hensiktsmessig utføres i nærvær av et syrebindende middel, alternativt kan et alka-limetallderivat av naftolderivatet, f. eks. natri-um- eller kaliumderivatet, anvendes som utgangsmateriale. The reaction (b), where a naphthol derivative is involved, can conveniently be carried out in the presence of an acid-binding agent, alternatively an alkali metal derivative of the naphthol derivative, e.g. the sodium or potassium derivative is used as starting material.
Passende reduserende betingelser er slike som tilveiebringes ved tilstedeværelsen av hydrogen og en hydrogeneringskatalysator, f. eks. platina, i et inert fortynningsmiddel eller opp-løsningsmiddel, f. eks. etanol, og/eller i tilfelle av at nevnte karbonylforbindelse anvendes som utgangsmateriale, R<3>står for et alkylradikal, eller R<3>og R<4>er forenet med hverandre med det tilgrensende karbonatom så at det dannes et cykloalkylradikal, i et overskudd av karbonylfor-bindelsen som anvendes som utgangsmateriale, eller ved tilstedeværelse av et alkalimetallbor-hydrid, f. eks. natriumborhydrid, i et inert fortynningsmiddel eller oppløsningsmiddel, f. eks. vandig metanol, og/eller i et overskudd av kar-bonylforbindelsen som anvendes som utgangsmateriale. Det vil videre forståes at aminoderi-vatene som anvendes som utgangsmaterialer, kan dannes in situ, f. eks. ved reduksjon av det ailsvarende a-diazoketon, a-azido-keton og -al-kohol, cyanhydrin eller acylcyanid. Suitable reducing conditions are those provided by the presence of hydrogen and a hydrogenation catalyst, e.g. platinum, in an inert diluent or solvent, e.g. ethanol, and/or in the case that said carbonyl compound is used as starting material, R<3> stands for an alkyl radical, or R<3> and R<4> are united with each other with the adjacent carbon atom so that a cycloalkyl radical is formed, in an excess of the carbonyl compound used as starting material, or in the presence of an alkali metal borohydride, e.g. sodium borohydride, in an inert diluent or solvent, e.g. aqueous methanol, and/or in an excess of the carbonyl compound used as starting material. It will further be understood that the amino derivatives used as starting materials can be formed in situ, e.g. by reduction of the corresponding a-diazoketone, a-azido-ketone and -alcohol, cyanohydrin or acyl cyanide.
Som et passende dealkylerende middel skal f. eks. nevnes et salt av en organisk base, f. eks. et salt av en heterocyklisk base,, f. eks. pyridinhydroklorid eller pyridinhydrobromid, eller salt av en aromatisk base, f. eks. anilinhydroklorid, eller et salt av en alifatisk base, f. eks. hydro-kloridene av metylamin, dimetylamin, trimetyl-amin eller etanolamin. Alternativt kan det dealkylerende middel være et salt av en svak an-organisk base, f. eks. ammoniumklorid. Dealkyl-eringen kan utføres ved forhøyet temperatur, f. eks. en temperatur høyere enn 150°C, f. eks. en temperatur av mellom 150° C og 200° C. As a suitable dealkylating agent, e.g. mention is made of a salt of an organic base, e.g. a salt of a heterocyclic base, e.g. pyridine hydrochloride or pyridine hydrobromide, or salt of an aromatic base, e.g. aniline hydrochloride, or a salt of an aliphatic base, e.g. the hydrochlorides of methylamine, dimethylamine, trimethylamine or ethanolamine. Alternatively, the dealkylating agent may be a salt of a weak an-organic base, e.g. ammonium chloride. The dealkylation can be carried out at an elevated temperature, e.g. a temperature higher than 150°C, e.g. a temperature of between 150° C and 200° C.
Spesielle naftalenderivater som fremstilles i henhold til oppfinnelsen er f. eks. 1-isopropyl-amino-3- (4-metoksy-l-naf toksy) -2-propanol, 1- (4-hydroksy-l-naftoksy)-3-isopropylamino-2- propanol, l-(6,7-dimetoksy-l-naftoksy)-3-isopropylamino-2-propanol, l-amino-3- (4-metoksy-l-naftoksy)-2-propanol, l-(4-metoksy-l-naftoksy) -3-n-propylamino-2-propanol, 1- (4-metoksy-l-naftoksy)-3-t-butylamino-2- propanol, l-(2-hydroksyl,-l-dimetyletylamino)-3-(4-metoksy-l-naftoksy)-2-propanol, 1-cyklopen-tylamino-3- (4-metoksy-l-naftoksy) -2-propanol, l-isopropylamino-3-(5-metoksy-l-naftoksy)-2-propanol, l-isopropylamino-3-(6-metoksy-1-naftoksy)-2-propanol, l-(6-hydroksy-l-naftoksy)-3-isopropylamino-2-propanol og 1-isopro-pylamino-3-(4-isopropoksy-l-naftoksy)-2-propanol og salter herav. Special naphthalene derivatives produced according to the invention are e.g. 1-isopropyl-amino-3-(4-methoxy-1-naphthoxy)-2-propanol, 1-(4-hydroxy-1-naphthoxy)-3-isopropylamino-2-propanol, 1-(6,7- dimethoxy-l-naphthoxy)-3-isopropylamino-2-propanol, l-amino-3-(4-methoxy-l-naphthoxy)-2-propanol, l-(4-methoxy-l-naphthoxy)-3-n -propylamino-2-propanol, 1-(4-methoxy-1-naphthoxy)-3-t-butylamino-2-propanol, 1-(2-hydroxyl,-1-dimethylethylamino)-3-(4-methoxy-1 -naphthoxy)-2-propanol, 1-cyclopentylamino-3-(4-methoxy-1-naphthoxy)-2-propanol, 1-isopropylamino-3-(5-methoxy-1-naphthoxy)-2-propanol, 1-isopropylamino-3-(6-methoxy-1-naphthoxy)-2-propanol, 1-(6-hydroxy-1-naphthoxy)-3-isopropylamino-2-propanol and 1-isopropylamino-3-(4 -isopropoxy-1-naphthoxy)-2-propanol and salts thereof.
Som passende estere for nevnte naftalenderivater skal f. eks. nevnes O-estere erholdt fra syrer av formelen R. COOH, hvor R står for et alkyl-, alkenyl- eller arylradikal, eventuelt substituert, f. eks. et alkyl- eller alkenylradikal med ikke mer enn 20 karbonatomer eller et arylradikal med ikke mer enn 10 karbonatomer, f. eks. metyl-, pentadecyl-, heptadecyl-, heptadeca-|3-enyl-eller fenylradikalet. As suitable esters for said naphthalene derivatives, e.g. mention is made of O-esters obtained from acids of the formula R. COOH, where R stands for an alkyl, alkenyl or aryl radical, optionally substituted, e.g. an alkyl or alkenyl radical of not more than 20 carbon atoms or an aryl radical of not more than 10 carbon atoms, e.g. the methyl, pentadecyl, heptadecyl, heptadeca-|3-enyl or phenyl radical.
Som passende salter for det nevnte naftalenderivater skal nevnes syre-addisjonssalter, f. eks. salter utledet fra anorganiske syrer, f. eks. hydroklorider, hydrobromider, fosfater eller sul-fater, eller salter stammende fra organiske syrer, f. eks. oksalater, laktater, tartrater, acetater, sa-licylater, citrater, benzoater, naftoater, o-acet-oksybenzoater, adipater, maleater, eller l,l'-me- tylen-bis-(2-hydroksy-3-naftoater) eller salter med sure syntetiske harpikser, f. eks. sulfonerte polystyrenharpikser, f. eks. «Zeo-Karb» 225. Re-lativt uoppløselige salter f. eks. l,l'-metylen-bis-(2-hydroksy-3-naftoater), er nyttige ved at de tilveiebringer en forlenget blodkonsentrasjon av medikamentet. Suitable salts for the aforementioned naphthalene derivatives include acid addition salts, e.g. salts derived from inorganic acids, e.g. hydrochlorides, hydrobromides, phosphates or sulphates, or salts derived from organic acids, e.g. oxalates, lactates, tartrates, acetates, salicylates, citrates, benzoates, naphthoates, o-acetoxybenzoates, adipates, maleates, or 1,1'-methylene-bis-(2-hydroxy-3-naphthoates) or salts with acidic synthetic resins, e.g. sulfonated polystyrene resins, e.g. "Zeo-Karb" 225. Relatively insoluble salts, e.g. 1,1'-methylene bis-(2-hydroxy-3-naphthoates), are useful in that they provide a prolonged blood concentration of the drug.
Som angitt ovenfor, er naftalenderivatene som fremstilles i henhold til oppfinnelsen, i besittelse av en |3-adrenergisk blokkerende aktivitet og derfor nyttige ved behandling eller profylakse av hjertesykdommer, og ved behandling av hypertensjon, hjerteinfarkt og phaeochromo-cytoma. As indicated above, the naphthalene derivatives prepared according to the invention possess a β-adrenergic blocking activity and are therefore useful in the treatment or prophylaxis of heart diseases, and in the treatment of hypertension, myocardial infarction and phaeochromocytoma.
Oppfinnelsen skal klargjøres nærmere ved de. følgende eksempler, hvor deler betyr vektde-ler. The invention must be clarified in more detail by de. the following examples, where parts mean parts by weight.
Eksempel 1.Example 1.
En blanding av 10 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan og 20 deler isopropylamin opphetes under tilbakeløp i 2 timer. Blandingen inndampes derpå til tørrhet under redusert trykk og residuet rystes sammen med 50 deler 2N-saltsyre og 50 deler eter. Blandingen adskilles, den vandige fase gjøres alkalisk med 3N-natriumhydroksydoppløsning, og blandingen ekstraheres med 50 deler eter. Eterekstrakten tørkes med vannfritt magnesiumsulfat og filtreres. Filtratet ansyres med eterisk saltsyre. Blandingen filtreres derpå og det faste residuum vaskes med eter og omkrystalliseres fra en blanding av etylacetat og etanol. Det fåes på denne måte 1- isopropylamino-3-(4-metoksy-l-naftoksy) - A mixture of 10 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane and 20 parts of isopropylamine is heated under reflux for 2 hours. The mixture is then evaporated to dryness under reduced pressure and the residue is shaken together with 50 parts of 2N hydrochloric acid and 50 parts of ether. The mixture is separated, the aqueous phase is made alkaline with 3N sodium hydroxide solution, and the mixture is extracted with 50 parts of ether. The ether extract is dried with anhydrous magnesium sulfate and filtered. The filtrate is acidified with ethereal hydrochloric acid. The mixture is then filtered and the solid residue is washed with ether and recrystallized from a mixture of ethyl acetate and ethanol. In this way, 1-isopropylamino-3-(4-methoxy-1-naphthoxy)-
2- propanolhydroklorid, smp. 168—170° C. 2- propanol hydrochloride, m.p. 168-170°C.
l,2-epoksy-3-(4-metoksy-l-naftoksy)propa-net som anvendes som utgangsmateriale kan fåes på følgende måte: En blanding av 22,8 deler 4-metoksy-l-naftol, 6,6 deler natriumhydroksyd, 200 deler vann, 50 deler etanol og 15,6 deler epiklorhydrin om-røres ved romtemperatur under en strøm av nitrogen i 18 timer. Blandingen ekstraheres to ganger, hver gang med 150 deler kloroform. De forenede kloroformekstrakter tørkes over vannfritt magnesiumsulfat og filtreres. Filtratet inndampes til tørrhet under redusert trykk og residuet omkrystalliseres fra metanol. Det fåes på denne måte l,2-epoksy-3-(4-metoksy-l-naftoksy) -propan, smp. 80—81° C. The 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane used as starting material can be obtained in the following way: A mixture of 22.8 parts 4-methoxy-1-naphthol, 6.6 parts sodium hydroxide , 200 parts of water, 50 parts of ethanol and 15.6 parts of epichlorohydrin are stirred at room temperature under a stream of nitrogen for 18 hours. The mixture is extracted twice, each time with 150 parts of chloroform. The combined chloroform extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized from methanol. 1,2-epoxy-3-(4-methoxy-1-naphthoxy)-propane is obtained in this way, m.p. 80-81° C.
Eksempel 2.Example 2.
En blanding av 1,5- deler 1-isopropylamino-3- (4-metoksy-l-naftoksy) -2-propylhydroklorid og 3 deler pyridinhydroklorid opphetes ved 160— A mixture of 1.5 parts of 1-isopropylamino-3-(4-methoxy-1-naphthoxy)-2-propyl hydrochloride and 3 parts of pyridine hydrochloride is heated at 160—
170° C i 9 timer under nitrogen. Produktet av-kjøles og oppløses derpå i 15 deler vann. Den resulterende oppløsning nøytraliseres med natriumbikarbonat, og omrøres derpå i 30 minutter med 15 deler etylacetat. 170° C for 9 hours under nitrogen. The product is cooled and then dissolved in 15 parts water. The resulting solution is neutralized with sodium bicarbonate, and then stirred for 30 minutes with 15 parts of ethyl acetate.
Blandingen filtreres og det faste residuum oppløses i en blanding av etylacetat og etanol. Den resulterende oppløsning ansyres med eterisk saltsyre og filtreres derpå. Det faste residuum omkrystalliseres fra isopropanol, og det fåes på denne måte l-(4-hydroksy-l-naftoksy)-3-iso-propylamino-2-propanolhydroklorid, smp. 176— 178° C. The mixture is filtered and the solid residue is dissolved in a mixture of ethyl acetate and ethanol. The resulting solution is acidified with ethereal hydrochloric acid and then filtered. The solid residue is recrystallized from isopropanol, and 1-(4-hydroxy-1-naphthoxy)-3-iso-propylamino-2-propanol hydrochloride is obtained in this way, m.p. 176— 178° C.
Eksempel 3.Example 3.
En blanding av 1,2 deler l-klor-3-(6,7-dimetoksy-l-naftoksy)-2-propanol, 10 deler etanol og 12 deler isopropylamin opphetes i et forseglet kar ved 100° C i løpet av 10 timer. Etanolen og overskudd av isopropylamin fjernes ved inn-dampning under redusert trykk, og den gjenværende olje oppløses i 50 deler 2N-saltsyreoppløs-ning. Den sure oppløsning ekstraheres tre ganger, hver gang med 20 deler eter, og eterekstraktene kastes. Den vandige fase gjøres alkalisk med 2N-natriumhydroksydoppløsning og blandingen ekstraheres tre ganger, hver gang med 30 deler eter. Eterekstraktene forenes, vaskes med vann, tørkes med vannfritt magnesiumsulfat og eteren fjernes ved destillasjon. Det gjenværende faste stoff omkrystalliseres fra cykloheksan. Det fåes på denne måte l-(6,7-dimetoksy-l-naftoksy)-3-isopropylamino-2-propanol, smp. 108—110° C. 1 - klor- 3 - (6,7 -dimetoksy-1 -naf toksy) - 2 -pr o-panolen som anvendes som utgangsmateriale, kan fåes på følgende måte: En blanding av 1,05 deler 6,7-dimetoksy-l-naftol, 6,5 deler epiklorhydrin og 0,01 del piperidin opphetes ved 95° C i en tidsperiode av 6 timer. Overskuddet av epiklorhydrin fjernes ved destillasjon under redusert trykk og residuet oppløses i 30 deler kloroform. Kloroformoppløs-ningen vaskes én gang med 20 deler konsentrert saltsyre, to ganger med 20 deler vann, tørkes med vannfritt magnesiumsulfat og kloroformen fjernes ved destillasjon under redusert trykk. Det fåes på denne måte l-klor-3-(6,7-dimetoksy-naftoksy)-2-propanol som en blekgul olje. A mixture of 1.2 parts of 1-chloro-3-(6,7-dimethoxy-1-naphthoxy)-2-propanol, 10 parts of ethanol and 12 parts of isopropylamine is heated in a sealed vessel at 100° C. during 10 hours . The ethanol and excess isopropylamine are removed by evaporation under reduced pressure, and the remaining oil is dissolved in 50 parts of 2N hydrochloric acid solution. The acidic solution is extracted three times, each time with 20 parts of ether, and the ether extracts are discarded. The aqueous phase is made alkaline with 2N sodium hydroxide solution and the mixture is extracted three times, each time with 30 parts of ether. The ether extracts are combined, washed with water, dried with anhydrous magnesium sulphate and the ether is removed by distillation. The remaining solid is recrystallized from cyclohexane. In this way, 1-(6,7-dimethoxy-1-naphthoxy)-3-isopropylamino-2-propanol, m.p. 108—110° C. The 1-chloro-3-(6,7-dimethoxy-1-naphthoxy)-2-pro-panol, which is used as starting material, can be obtained in the following way: A mixture of 1.05 parts 6 ,7-dimethoxy-1-naphthol, 6.5 parts of epichlorohydrin and 0.01 part of piperidine are heated at 95° C. for a period of 6 hours. The excess of epichlorohydrin is removed by distillation under reduced pressure and the residue is dissolved in 30 parts of chloroform. The chloroform solution is washed once with 20 parts of concentrated hydrochloric acid, twice with 20 parts of water, dried with anhydrous magnesium sulfate and the chloroform is removed by distillation under reduced pressure. In this way, 1-chloro-3-(6,7-dimethoxy-naphthoxy)-2-propanol is obtained as a pale yellow oil.
Eksempel 4.Example 4.
En blanding av 1,15 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan og 0,75 deler N-ben-zyl-N-isopropylamin opphetes ved 100° C i 10 timer. Blandingen oppløses derpå i en blanding av 10 deler etylacetat og 10 deler eter, og opp-løsningen som fåes på denne måte, ansyres med eterisk saltsyre. Blandingen filtreres derpå, og det faste residuum vaskes med eter og omkrystalliseres fra isopropanol. Det fåes på denne må-te l-(N-benzyl-N-isopropylamino)-3-(4-metoksy)-2-propanolhydroklorid. Smp. 158—159° C. A mixture of 1.15 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane and 0.75 parts of N-benzyl-N-isopropylamine is heated at 100° C. for 10 hours. The mixture is then dissolved in a mixture of 10 parts ethyl acetate and 10 parts ether, and the solution obtained in this way is acidified with ethereal hydrochloric acid. The mixture is then filtered, and the solid residue is washed with ether and recrystallized from isopropanol. 1-(N-benzyl-N-isopropylamino)-3-(4-methoxy)-2-propanol hydrochloride is obtained in this way. Temp. 158-159° C.
En blanding av 0,4 deler l-(N-benzyl-N-iso-propylamino)-3-(4-metoksy-l-naftoksy)-2-propanolhydroklorid, 50 deler etanol og 0,1 del av 5 pst. palladium-på-benkullkatalysator rystes med hydrogen ved atmosfæretrykk og romtemperatur inntil opptagelse av hydrogen opphører. Blandingen filtreres, og filtratet inndampes til tørrhet under redusert trykk. Residuet omkrystalliseres fra en blanding av etylacetat og etanol. Det fåes på denne måte l-isopropylamino-3-(4-metoksy-l-naftoksy)-2-propanolhydroklorid, smp. 168—170° C. A mixture of 0.4 parts of 1-(N-benzyl-N-iso-propylamino)-3-(4-methoxy-1-naphthoxy)-2-propanol hydrochloride, 50 parts of ethanol and 0.1 part of 5% palladium -on-bone charcoal catalyst is shaken with hydrogen at atmospheric pressure and room temperature until absorption of hydrogen ceases. The mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is recrystallized from a mixture of ethyl acetate and ethanol. 1-isopropylamino-3-(4-methoxy-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 168-170°C.
Eksempel 5.Example 5.
En blanding av 0,087 deler l-amino-3-(4-metoksy-1-naftoksy)-2-propanol, 10 deler aceton og 0,05 deler platinaoksyd rystes med hydrogen ved atmosfæretrykk og romtemperatur inntil opptagelse av hydrogen opphører. Blandingen filtreres, og filtratet inndampes til tørrhet under redusert trykk. Residuet oppløses i 10 deler etylacetat, og oppløsningen som fåes på denne måte ansyres med eterisk saltsyre. Blandingen filtreres derpå, og det faste residuum vaskes med eter og omkrystalliseres fra en blanding av etanol og etylacetat. Det fåes på denne måte l-isopropyl-amino-3- (4-metoksy-l-naftoksy) -2-propanolhydroklorid ,smp. 168—170° C. A mixture of 0.087 parts of 1-amino-3-(4-methoxy-1-naphthoxy)-2-propanol, 10 parts of acetone and 0.05 parts of platinum oxide is shaken with hydrogen at atmospheric pressure and room temperature until absorption of hydrogen ceases. The mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure. The residue is dissolved in 10 parts of ethyl acetate, and the solution obtained in this way is acidified with ethereal hydrochloric acid. The mixture is then filtered, and the solid residue is washed with ether and recrystallized from a mixture of ethanol and ethyl acetate. 1-isopropyl-amino-3-(4-methoxy-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 168-170°C.
Eksempel 6.Example 6.
En blanding av 2,3 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan, 1,5 deler ftalimid og 5 deler etanol opphetes til 180° C, og man lar etanolen destillere av. Blandingen opphetes ved 180° C i 2 timer, avkjøles og residuet omkrystalliseres fra etanol. Det fåes på denne måte 1-ftal-imido-3-(4-metoksy-l-naftoksy)-2-propanol, smp. 152—154° C. En blanding av 0,75 deler av sistnevnte forbindelse, 1,0 del 100 pst.s hydrazin-hydrat og 10 deler etanol opphetes under tilba-keløp i 3 timer. Blandingen inndampes derpå til tørrhet under redusert trykk, og det faste residuum omrøres med 50 deler N natriumhydroksyd-oppløsning. Blandingen filtreres og det faste residuum omrøres med 50 deler 2N-eddiksyre og filtreres. Filtratet gjøres alkalisk med HN-na-triumhydroksydoppløsning, og blandingen ekstraheres med 50 deler varmt etylacetat. Etylacetatekstrakten tørkes over vannfritt magnesiumsulfat og blandingen filtreres. Filtratet ansyres med eterisk saltsyre og filtreres. Det faste residuum vaskes med eter og krystalliseres fra etanol. Det fåes på denne måte l-amino-3-(4-metoksy-l-naftoksy)-2-propanolhydroklorid, smp. 272° C efter mykning ved 258—260° C. A mixture of 2.3 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane, 1.5 parts of phthalimide and 5 parts of ethanol is heated to 180° C, and the ethanol is allowed to distill off. The mixture is heated at 180° C. for 2 hours, cooled and the residue recrystallized from ethanol. 1-Phthal-imido-3-(4-methoxy-1-naphthoxy)-2-propanol is obtained in this way, m.p. 152-154° C. A mixture of 0.75 parts of the latter compound, 1.0 part of 100% hydrazine hydrate and 10 parts of ethanol is heated under reflux for 3 hours. The mixture is then evaporated to dryness under reduced pressure, and the solid residue is stirred with 50 parts of N sodium hydroxide solution. The mixture is filtered and the solid residue is stirred with 50 parts of 2N-acetic acid and filtered. The filtrate is made alkaline with HN sodium hydroxide solution, and the mixture is extracted with 50 parts of hot ethyl acetate. The ethyl acetate extract is dried over anhydrous magnesium sulfate and the mixture is filtered. The filtrate is acidified with ethereal hydrochloric acid and filtered. The solid residue is washed with ether and crystallized from ethanol. 1-Amino-3-(4-methoxy-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 272° C after softening at 258-260° C.
Eksempel 7.Example 7.
En blanding av 1,5 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan og 10 deler n-pro-pylamin opphetes under tilbakeløp i 2 timer. Blandingen inndampes derpå til tørrhet under redusert trykk, og residuet omkrystalliseres fra 25 deler N-saltsyre. Det fåes på denne måte 1-(4-metoksy-l-naf toksy)-3-n-propylamino-2-propanolhydroklorid, smp. 151—153° C. A mixture of 1.5 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane and 10 parts of n-propylamine is heated under reflux for 2 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is recrystallized from 25 parts of N-hydrochloric acid. 1-(4-methoxy-1-naphthoxy)-3-n-propylamino-2-propanol hydrochloride is obtained in this way, m.p. 151-153°C.
Eksempel 8.Example 8.
En blanding av 1,15 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)-propan og 10 deler t-bu-tylamin opphetes under tilbakeløp i 2 timer. Blandingen inndampes derpå til tørrhet under redusert trykk og residuet oppløses i 5 deler etylacetat og ansyres med eterisk oksalsyre. Blandingen filtreres, og det faste residuum vaskes med eter og omkrystalliseres fra etanol. Det fåes på denne måte 1-(4-metoksy-l-naftoksy)-3-t-butylamino-2-propanolhydrogenoksalat, smp. 193—194° C. A mixture of 1.15 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)-propane and 10 parts of t-butylamine is heated under reflux for 2 hours. The mixture is then evaporated to dryness under reduced pressure and the residue is dissolved in 5 parts ethyl acetate and acidified with ethereal oxalic acid. The mixture is filtered, and the solid residue is washed with ether and recrystallized from ethanol. 1-(4-methoxy-1-naphthoxy)-3-t-butylamino-2-propanol hydrogen oxalate is obtained in this way, m.p. 193-194° C.
Eksempel 9.Example 9.
En blanding av 0,9 deler 4-metoksy-l-naftol, 1,0 deler 3-klor-l-t-butylamino-2-propanolhydroklorid, 0,6 deler natriumhydroksyd og 20 deler etanol opphetes i et lukket kar ved 100° C i 10 timer. Blandingen inndampes derpå til tørr-het under redusert trykk, og residuet rystes sammen med 25 deler vann og 25 deler eter. Eterekstrakten tørkes over vannfritt magnesiumsulfat og filtreres. Filtratet ansyres med eterisk oksalsyre og flitreres. Det faste residuum vaskes med eter og omkrystalliseres fra etanol. Det fåes på denne måte 1-(4-metoksy-l-naftoksy)-3-t-butylamino-2-propanolhydrogenoksalat, smp. 193—194° C. A mixture of 0.9 parts of 4-methoxy-1-naphthol, 1.0 parts of 3-chloro-1-t-butylamino-2-propanol hydrochloride, 0.6 parts of sodium hydroxide and 20 parts of ethanol is heated in a closed vessel at 100° C. in 10 hours. The mixture is then evaporated to dryness under reduced pressure, and the residue is shaken together with 25 parts of water and 25 parts of ether. The ether extract is dried over anhydrous magnesium sulfate and filtered. The filtrate is acidified with ethereal oxalic acid and filtered. The solid residue is washed with ether and recrystallized from ethanol. 1-(4-methoxy-1-naphthoxy)-3-t-butylamino-2-propanol hydrogen oxalate is obtained in this way, m.p. 193-194° C.
Eksempel 10.Example 10.
En blanding av 1,15 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan og 0,45 deler 2-amino-2-metylpropanol opphetes ved 100° C i 2 A mixture of 1.15 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane and 0.45 parts of 2-amino-2-methylpropanol is heated at 100° C. in 2
timer. Blandingen inndampes derpå til tørrhet hours. The mixture is then evaporated to dryness
under redusert trykk og residuet rystes sammen med 25 deler 2N-saltsyre og 25 deler eter. Blandingen adskilles, den vandige fase gjøres alkalisk under reduced pressure and the residue is shaken together with 25 parts of 2N hydrochloric acid and 25 parts of ether. The mixture is separated, the aqueous phase is made alkaline
med 11N natriumhydroksydoppløsning og blandingen ekstraheres med 50 deler etylacetat. Etylacetatekstrakten tørkes over vannfritt magnesiumsulfat og filtreres. Filtratet inndampes til tørrhet under redusert trykk og residuet omkrystalliseres fra cykloheksan. Det fåes på denne with 11N sodium hydroxide solution and the mixture is extracted with 50 parts of ethyl acetate. The ethyl acetate extract is dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized from cyclohexane. It is available on this one
måte l-(2-hydroksy-l,l-dimetyletylamino)-3-(4-metoksy-l-naftoksy)-2-propanol, smp. 96— 98° C. method 1-(2-hydroxy-1,1-dimethylethylamino)-3-(4-methoxy-1-naphthoxy)-2-propanol, m.p. 96— 98° C.
Eksempel 11.Example 11.
En blanding av 1,15 deler l,2-epoksy-3-(4-metoksy-l-naftoksy)propan, 10 deler n-propanol og 0,425 deler cyklopentylamin opphetes ved A mixture of 1.15 parts of 1,2-epoxy-3-(4-methoxy-1-naphthoxy)propane, 10 parts of n-propanol and 0.425 parts of cyclopentylamine is heated at
100° C i 2 timer. Blandingen inndampes til tørr-het under redusert trykk, og residuet omkrystalliseres fra en blanding av etylacetat og petroleter (kp. 60/80° C). Det fåes på denne måte 1-cyklopentylamino-3-(4-metoksy-l-naftoksy) - 2-propanol, smp. 94—96° C. 100° C for 2 hours. The mixture is evaporated to dryness under reduced pressure, and the residue is recrystallized from a mixture of ethyl acetate and petroleum ether (b.p. 60/80° C). 1-Cyclopentylamino-3-(4-methoxy-1-naphthoxy)-2-propanol is obtained in this way, m.p. 94-96° C.
Eksempel 12.Example 12.
Den fremgangsmåte som er beskrevet i eksempel 1, gjentas med unntagelse av at 2 deler l,2-epoksy-3-(5-metoksy-l-naftoksy)propan anvendes som utgangsmateriale istedenfor de 10 delene av l,2-epoksy-3-(4-metoksy-l-naftoksy)-propan. Det fåes på denne måte l-isopropylami-no-3- (5-metoksy-l-naftoksy) -2-propanolhydroklorid, smp. 184—196° C. The procedure described in example 1 is repeated with the exception that 2 parts of 1,2-epoxy-3-(5-methoxy-1-naphthoxy)propane are used as starting material instead of the 10 parts of 1,2-epoxy-3- (4-methoxy-1-naphthoxy)-propane. 1-isopropylamino-3-(5-methoxy-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 184—196° C.
1,2- epoksy- 3 - (5-me toksy-1 -naf toksy) pro-panet som anvendes som utgangsmateriale, kan 1,2-epoxy-3-(5-me toxy-1-naphthoxy)propane, which is used as starting material, can
fåes som beskrevet i annen del av eksempel 1 is obtained as described in the second part of example 1
under anvendelse av 5-metoksy-l-naftol istedenfor 4-metoksy-l-naftolen. Produktet som fåes på denne måte består av l,2-epoksy-3-(5-metoksy-l-naftoksy) -propan. using 5-methoxy-1-naphthol instead of 4-methoxy-1-naphthol. The product obtained in this way consists of 1,2-epoxy-3-(5-methoxy-1-naphthoxy)-propane.
Eksempel 13.Example 13.
2,8 deler l-klor-3-(6-metoksy-l-naftoksy)-2-propanol oppløses i 8 deler isopropylamin, og 2.8 parts of 1-chloro-3-(6-methoxy-1-naphthoxy)-2-propanol are dissolved in 8 parts of isopropylamine, and
blandingen opphetes i et forseglet kar ved 110° Cthe mixture is heated in a sealed vessel at 110°C
i løpet av 10 timer. Overskuddet av isopropylamin within 10 hours. The excess of isopropylamine
inndampes under redusert trykk, og residuet oppløses i 50 deler 2N-saltsyreoppløsning. Den sure oppløsning vaskes to ganger, hver gang med is evaporated under reduced pressure, and the residue is dissolved in 50 parts of 2N hydrochloric acid solution. The acidic solution is washed twice, each time with
20 deler eter, og etervaskevæskene kastes. Den 20 parts of ether, and the ether washings are discarded. It
sure vandige oppløsning gjøres alkalisk med 5N natriumhydroksydoppløsning, og ekstraheres tre ganger, hver gang med 30 deler kloroform. De forenede kloroformekstrakter vaskes med 30 deler vann, tørkes og inndampes. Residuet oppløses i 20 deler tørr eter, og oppløsningen ansyres med eterisk hydrogenklorid. Overskuddet av eter de-kanteres fra det faste produkt, som utgnis med aceton og omkrystalliseres fra isopropanol. Det fåes på denne måte l-isopropylamino-3-(6-metoksy) -1-naftoksy) -2-propanolhydroklorid, smp. 168—169° C. acid aqueous solution is made alkaline with 5N sodium hydroxide solution, and extracted three times, each time with 30 parts of chloroform. The combined chloroform extracts are washed with 30 parts of water, dried and evaporated. The residue is dissolved in 20 parts of dry ether, and the solution is acidified with ethereal hydrogen chloride. The excess of ether is decanted from the solid product, which is triturated with acetone and recrystallized from isopropanol. 1-isopropylamino-3-(6-methoxy)-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 168-169° C.
l-klor-3-(6-metoksy-l-naf toksy)-2-propa nol som anvendes som utgangsmateriele, kan få-es på følgende måte: En blanding av 2,5 deler 6-metoksy-l-naftol, 9,6 deler epiklorhydrin og 0,01 del piperidin opphetes i løpet av 18 timer ved 95—100° C. Overskuddet av epiklorhydrin inndampes under redusert trykk og residuet oppløses i 50 deler kloroform. Kloroformoppløsningen vaskes i rekke-følge med 20 deler av hver av 2N natriumhyd-roksydoppløsning, vann, konsentrert saltsyre, vann, natriumbikarbonatoppløsning og vann, og tørkes deretter over vannfritt magnesiumsulfat. Den tørre oppløsning inndampes derpå så det blir tilbake l-klor-3-(6-metoksy-l-naftoksy)-2-propanol som en olje. 1-chloro-3-(6-methoxy-1-naphthoxy)-2-propa nol, which is used as the starting material, can be obtained in the following way: A mixture of 2.5 parts of 6-methoxy-l-naphthol, 9.6 parts of epichlorohydrin and 0.01 part of piperidine is heated during 18 hours at 95-100 ° C. The excess of epichlorohydrin is evaporated under reduced pressure and the residue is dissolved in 50 parts of chloroform. The chloroform solution is washed successively with 20 parts each of 2N sodium hydroxide solution, water, concentrated hydrochloric acid, water, sodium bicarbonate solution and water, and then dried over anhydrous magnesium sulfate. The dry solution is then evaporated to leave 1-chloro-3-(6-methoxy-1-naphthoxy)-2-propanol as an oil.
Eksempel 14.Example 14.
En blanding av 0,3 deler l-isopropylamino-3-(6-metoksy-l-naf toksy)-2-propanolhydroklorid og 0,9 deler pyridinhydroklorid opphetes i en strøm av nitrogen ved 160—170° C i en tidsperiode av 6 timer. Blandingen avkjøles og opplø-ses i 10 deler vann. pH-verdien av oppløsningen reguleres til 7 med natriumbikarbonat og opp-løsningen vaskes derpå tre ganger hver gang med 16 deler petroleter (kp. 40—60° C). Den vandige oppløsning inndampes derpå og residuet utgnis med n-butanol og filtreres. Filtratet inndampes og residuet omkrystalliseres fra metanol. Det få-es på denne måte l-(6-hydroksy-l-naftoksy)-3-isopropylamino-2-propanol, smp. 178—180° C. A mixture of 0.3 parts of 1-isopropylamino-3-(6-methoxy-1-naphthoxy)-2-propanol hydrochloride and 0.9 parts of pyridine hydrochloride is heated in a stream of nitrogen at 160-170° C for a period of 6 hours. The mixture is cooled and dissolved in 10 parts water. The pH value of the solution is adjusted to 7 with sodium bicarbonate and the solution is then washed three times each time with 16 parts of petroleum ether (bp. 40-60° C). The aqueous solution is then evaporated and the residue is triturated with n-butanol and filtered. The filtrate is evaporated and the residue is recrystallized from methanol. 1-(6-hydroxy-1-naphthoxy)-3-isopropylamino-2-propanol is obtained in this way, m.p. 178-180°C.
Eksempel 15.Example 15.
En blanding av 0,2 deler l-(4-hydroksy-l-naf toksy)-3-isopropylamino-2-propanolhydroklorid, 4 deler acetylklorid og 5 deler eddiksyre opphetes under tilbakeløp i 2 timer. Blandingen inndampes derpå til tørrhet under redusert trykk. Residuet oppløses i 5 deler etylacetat og 15 deler eter tilsettes til oppløsningen. Blandingen filtreres, og det faste residuum vaskes med eter og omkrystalliseres fra en blanding av etylacetat og isopropanol. Det fåes på denne måte 2-(4-acetoksy-l-naftoksy)-l-(isopropylaminometyl) etylacetathydroklorid, smp. 172—174° C. A mixture of 0.2 parts of 1-(4-hydroxy-1-naphthoxy)-3-isopropylamino-2-propanol hydrochloride, 4 parts of acetyl chloride and 5 parts of acetic acid is heated under reflux for 2 hours. The mixture is then evaporated to dryness under reduced pressure. The residue is dissolved in 5 parts of ethyl acetate and 15 parts of ether are added to the solution. The mixture is filtered, and the solid residue is washed with ether and recrystallized from a mixture of ethyl acetate and isopropanol. 2-(4-acetoxy-1-naphthoxy)-1-(isopropylaminomethyl)ethyl acetate hydrochloride is obtained in this way, m.p. 172-174° C.
Eksempel 16.Example 16.
En blanding av 1,2 deler l,2-epoksy-3-(4-isopropoksy-l-naftoksy)propan og 10 deler isopropylamin opphetes under tilbakeløp i 2 timer. Blandingen inndampes til tørrhet under redusert trykk, og residuet omrøres sammen med en blanding av 25 deler N-saltsyre og 25 deler eter. Den sure fase adskilles og omrøres sammen med en blanding av 25 deler 2N natriumhydroksyd-oppløsning og 50 deler etylacetat. Fasene adskilles og etylacetatfasen tørkes over vannfritt magnesiumsulfat og blandingen filtreres. Filtratet ansyres med eterisk saltsyre, og filtreres og det faste residuum vaskes med eter og omkrystalliseres fra etylacetat. Det fåes på denne måte 1-isopropylamino-3-(4-isopropoksy-l-naftoksy) - 2-propanolhydroklorid, smp. 164—165° C. A mixture of 1.2 parts of 1,2-epoxy-3-(4-isopropoxy-1-naphthoxy)propane and 10 parts of isopropylamine is heated under reflux for 2 hours. The mixture is evaporated to dryness under reduced pressure, and the residue is stirred together with a mixture of 25 parts of N-hydrochloric acid and 25 parts of ether. The acidic phase is separated and stirred together with a mixture of 25 parts of 2N sodium hydroxide solution and 50 parts of ethyl acetate. The phases are separated and the ethyl acetate phase is dried over anhydrous magnesium sulphate and the mixture is filtered. The filtrate is acidified with ethereal hydrochloric acid, and filtered and the solid residue is washed with ether and recrystallized from ethyl acetate. 1-isopropylamino-3-(4-isopropoxy-1-naphthoxy)-2-propanol hydrochloride is obtained in this way, m.p. 164-165° C.
l,2-epoksy-3- (4-isopropoksy-l-naftoksy) - propan som anvendes som utgangsmateriale, kan fåes på følgende måte: En blanding av 0,9 deler 4-isopropoksy-l-naftol, 0,2 deler natriumhydroksyd, 2 deler vann, 10 deler metanol og 0,5 deler epiklorhydrin opphetes under tilbakeløp i en nitrogenstrøm i 2 timer. Produktet som fåes på denne måte, består av l,2-epoksy-3-(4-isopropoksy-l-naftoksy) - propan. 1,2-epoxy-3-(4-isopropoxy-1-naphthoxy)-propane, which is used as starting material, can be obtained in the following way: A mixture of 0.9 parts of 4-isopropoxy-1-naphthol, 0.2 parts of sodium hydroxide , 2 parts of water, 10 parts of methanol and 0.5 parts of epichlorohydrin are heated under reflux in a stream of nitrogen for 2 hours. The product obtained in this way consists of 1,2-epoxy-3-(4-isopropoxy-1-naphthoxy)-propane.
I de belgiske patentskrifter nr. 640 312 og 640 313-er vist at visse naftalenderivater er i besittelse av |3-adrenergisk blokkerende aktivitet. Denne aktivitet kan påvises ved virkningen av forbindelsen på isoprenalin-indusert tachycar-dia hos en anestisert katt. Potensen av den spesielle forbindelse måles ved den prosentuelle in-hibering av den isoprenalin-induserte tachycar-dia frembragt av en bestemt dose av forbindelsen. Som det fremgår av de eksperimentelle resultater som er oppført i tabell I, er potensen av naftalenderivatet, som bærer en substituent i kjernen av den type som er angitt i de ovenfor nevnte belgiske patentskrifter, generelt mindre enn for de usubstituerte derivater. In Belgian Patents Nos. 640,312 and 640,313, certain naphthalene derivatives are shown to possess β-adrenergic blocking activity. This activity can be demonstrated by the effect of the compound on isoprenaline-induced tachycardia in an anesthetized cat. The potency of the particular compound is measured by the percentage inhibition of the isoprenaline-induced tachycardia produced by a specific dose of the compound. As can be seen from the experimental results listed in Table I, the potency of the naphthalene derivative bearing a substituent in the nucleus of the type indicated in the above-mentioned Belgian patents is generally less than that of the unsubstituted derivatives.
Det har nu vist seg at de spesielle naftalenderivater hvor kjernen er substituert med i det minste ett hydroksy- eller alkoksyradikal er like så potent som utgangsforbindelsene som er usubstituert. Denne erkjennelse er uventet fordi de tidligere resultater førte til den slutning at sub-stituering på naftalenkjernen gir mindre potente forbindelser. It has now been shown that the special naphthalene derivatives where the nucleus is substituted with at least one hydroxy or alkoxy radical are just as potent as the starting compounds which are unsubstituted. This realization is unexpected because the previous results led to the conclusion that substitution on the naphthalene nucleus gives less potent compounds.
En sammenligning av de eksperimentelle resultater som er anført i tabell II, med resultate-ne som er anført i tabell I, viser at for en bestemt verdi av R er forbindelsene hvor naftalenkjernen bærer et hydroksy- eller alkoksyradikal A comparison of the experimental results listed in table II with the results listed in table I shows that for a certain value of R the compounds where the naphthalene nucleus carries a hydroxy or alkoxy radical
like så potente som forbindelsene hvor kjernene as potent as the compounds where the cores
er usubstituert, og mer potente enn de forbindelser hvor kjernen bærer andre substituenter. is unsubstituted, and more potent than the compounds where the nucleus carries other substituents.
Toksisitet-dataene for den første forbindelse i tabell I er som følger: The toxicity data for the first compound in Table I are as follows:
L.D. 50 i mus: L. D. 50 in mouse:
Claims (1)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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GB9092/65A GB1066613A (en) | 1965-03-03 | 1965-03-03 | Naphthalene derivatives |
Publications (1)
Publication Number | Publication Date |
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NO115028B true NO115028B (en) | 1968-07-08 |
Family
ID=9865202
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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NO161543A NO115028B (en) | 1965-03-03 | 1966-02-02 |
Country Status (14)
Country | Link |
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AT (6) | AT264510B (en) |
BE (1) | BE676821A (en) |
BR (1) | BR6677439D0 (en) |
CH (1) | CH486420A (en) |
DE (1) | DE1543685A1 (en) |
DK (1) | DK122274B (en) |
ES (1) | ES323083A1 (en) |
FI (1) | FI44622C (en) |
FR (1) | FR5516M (en) |
GB (1) | GB1066613A (en) |
IL (1) | IL25132A (en) |
NL (1) | NL6601686A (en) |
NO (1) | NO115028B (en) |
SE (1) | SE316191B (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE2644833A1 (en) * | 1976-10-05 | 1978-04-20 | Boehringer Sohn Ingelheim | NEW 1-ARYLOXY-2-HYDROXY-3-ALKYLENE AMINOPROPANES AND METHOD FOR THE PRODUCTION THEREOF |
US4376125A (en) * | 1980-11-05 | 1983-03-08 | University Of Virginia Alumni Patents Foundation | Aminobenzlpropranolol and pharmaceutical preparation thereof |
US8542005B2 (en) | 2010-04-28 | 2013-09-24 | Teradyne, Inc. | Connecting digital storage oscilloscopes |
US8502522B2 (en) | 2010-04-28 | 2013-08-06 | Teradyne, Inc. | Multi-level triggering circuit |
US8098181B2 (en) | 2010-04-28 | 2012-01-17 | Teradyne, Inc. | Attenuator circuit |
US8531176B2 (en) | 2010-04-28 | 2013-09-10 | Teradyne, Inc. | Driving an electronic instrument |
CN114224875B (en) * | 2021-11-04 | 2023-08-11 | 中南大学湘雅医院 | New use of alcohol compound and antitumor drug |
-
1965
- 1965-03-03 GB GB9092/65A patent/GB1066613A/en not_active Expired
-
1966
- 1966-02-02 NO NO161543A patent/NO115028B/no unknown
- 1966-02-04 DE DE19661543685 patent/DE1543685A1/en active Pending
- 1966-02-07 IL IL25132A patent/IL25132A/en unknown
- 1966-02-10 NL NL6601686A patent/NL6601686A/xx unknown
- 1966-02-14 SE SE1873/66A patent/SE316191B/xx unknown
- 1966-02-15 ES ES0323083A patent/ES323083A1/en not_active Expired
- 1966-02-15 FI FI660373A patent/FI44622C/en active
- 1966-02-21 BE BE676821D patent/BE676821A/xx unknown
- 1966-02-22 AT AT437967A patent/AT264510B/en active
- 1966-02-22 AT AT438167A patent/AT264512B/en active
- 1966-02-22 AT AT438267A patent/AT264513B/en active
- 1966-02-22 AT AT438367A patent/AT264504B/en active
- 1966-02-22 AT AT438067A patent/AT264511B/en active
- 1966-02-22 AT AT164866A patent/AT264509B/en active
- 1966-02-25 CH CH276766A patent/CH486420A/en not_active IP Right Cessation
- 1966-03-01 BR BR177439/66A patent/BR6677439D0/en unknown
- 1966-03-03 DK DK111866AA patent/DK122274B/en unknown
- 1966-06-02 FR FR63857A patent/FR5516M/fr not_active Expired
Also Published As
Publication number | Publication date |
---|---|
FI44622B (en) | 1971-08-31 |
IL25132A (en) | 1969-11-30 |
AT264509B (en) | 1968-09-10 |
DE1543685A1 (en) | 1969-12-18 |
BR6677439D0 (en) | 1973-09-18 |
AT264510B (en) | 1968-09-10 |
NL6601686A (en) | 1966-09-05 |
SE316191B (en) | 1969-10-20 |
DK122274B (en) | 1972-02-14 |
CH486420A (en) | 1970-02-28 |
AT264512B (en) | 1968-09-10 |
GB1066613A (en) | 1967-04-26 |
ES323083A1 (en) | 1967-01-01 |
BE676821A (en) | 1966-08-22 |
AT264513B (en) | 1968-09-10 |
FI44622C (en) | 1971-12-10 |
AT264504B (en) | 1968-09-10 |
FR5516M (en) | 1967-11-06 |
AT264511B (en) | 1968-09-10 |
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