NO132533B - - Google Patents
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- NO132533B NO132533B NO504/71A NO50471A NO132533B NO 132533 B NO132533 B NO 132533B NO 504/71 A NO504/71 A NO 504/71A NO 50471 A NO50471 A NO 50471A NO 132533 B NO132533 B NO 132533B
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- 150000001875 compounds Chemical class 0.000 claims description 35
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 31
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 150000004820 halides Chemical class 0.000 claims description 6
- 150000003333 secondary alcohols Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000005481 1,2-diphenylethanes Chemical class 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 150000002366 halogen compounds Chemical class 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 235000013312 flour Nutrition 0.000 claims 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000011541 reaction mixture Substances 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 8
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000000284 extract Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- -1 benzyl halide Chemical class 0.000 description 4
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical class C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- JIXDOBAQOWOUPA-UHFFFAOYSA-N 1-fluoro-2-methoxybenzene Chemical compound COC1=CC=CC=C1F JIXDOBAQOWOUPA-UHFFFAOYSA-N 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 230000001076 estrogenic effect Effects 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- NJIPZANRACFKHD-UHFFFAOYSA-N 1-(2-fluoro-4-methoxyphenyl)pentan-2-ol Chemical compound FC1=C(CC(CCC)O)C=CC(=C1)OC NJIPZANRACFKHD-UHFFFAOYSA-N 0.000 description 2
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- VKGBOMPRHQCSRL-UHFFFAOYSA-N 1-(2-fluorophenyl)-2-[(4-methoxyphenyl)methyl]butan-1-one Chemical compound FC1=C(C=CC=C1)C(C(CC)CC1=CC=C(C=C1)OC)=O VKGBOMPRHQCSRL-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- CKSIBFLEDRJUTN-UHFFFAOYSA-N 3-chloropentan-2-one Chemical compound CCC(Cl)C(C)=O CKSIBFLEDRJUTN-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000020335 dealkylation Effects 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005283 haloketone group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VCRYGHPVKURQMM-UHFFFAOYSA-N methane;platinum Chemical compound C.[Pt] VCRYGHPVKURQMM-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/24—Halogenated derivatives
- C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
- C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Foreliggende oppfinnelse angår en analbgifremgangsmåte ved fremstilling åv nye og verdifulle derivater av 1,2-difenylethan, som har meget sterke ostrogene egenskaper. The present invention relates to an analytical method for the production of new and valuable derivatives of 1,2-diphenylethane, which have very strong estrogenic properties.
De nye derivater av 1,2-difenylethan som fremstilles ifdl-ge foreliggende fremgangsmåte er forbindelser med den generelle formel " The new derivatives of 1,2-diphenylethane which are produced according to the present process are compounds with the general formula "
hvor R^ og R^ som kan være like eller forskjellige, er alkylradikal-er inneholdende opp til 6 carbonatomer, med det forbehold at R^ og R2 ikke begge er methyl eller ethylradikaler. where R^ and R^, which may be the same or different, are alkyl radicals containing up to 6 carbon atoms, with the proviso that R^ and R2 are not both methyl or ethyl radicals.
Når R^ og R^ er alkylradikåler inneholdende 3-6 carbonatomer, kan de være f.eks. n-propyl-, isopropyl-, n-butyl-, n-pent-yl- eller•n-hexylradikaler. When R^ and R^ are alkyl radicals containing 3-6 carbon atoms, they can be e.g. n-propyl, isopropyl, n-butyl, n-pentyl or•n-hexyl radicals.
Analogifremgangsmåten ifolge oppfinnelsen er kjennetegnet ved at The analogy method according to the invention is characterized by the fact that
a) en ether av generel formel II a) an ether of general formula II
hvor R" er et alkylradikal inneholdende opp til 6 carbonatomer, omsettes med en halogenforbindelse av generell formel III hvor R^ og R2 har de ovenfor angitte betydninger, Z betegner en hydroxylgruppe og Y betegner H, eller Y og Z sammen betegner et ... oxygenatom, og Hal betegner et halogenatom, hvorved der erholdes en forbindelse av generell formel: where R" is an alkyl radical containing up to 6 carbon atoms, is reacted with a halogen compound of general formula III where R^ and R2 have the above meanings, Z denotes a hydroxyl group and Y denotes H, or Y and Z together denote a ... oxygen atom, and Hal denotes a halogen atom, whereby a compound of the general formula is obtained:
hvor Rp R2 og R" har de ovenfor angitte betydninger', hvorefter;en forbindelse av formel (IVb) hydrogeneres til en forbindelse av formel (IVa) som dealkyleres under dannelse av den tilsvarende dihydr-oxyf or bind else, where Rp R2 and R" have the meanings given above, after which a compound of formula (IVb) is hydrogenated to a compound of formula (IVa) which is dealkylated to form the corresponding dihydroxyfur bond,
eller or
b) for fremstilling av forbindelser av generell formel (I) i hvi lken R^ og R? .... er alkylradi-kaler inneholdende 3 - 6 carbonatomer, at et syrehalogenid av generell formel X b) for the preparation of compounds of general formula (I) in which R1 and R? .... are alkyl radicals containing 3 - 6 carbon atoms, that an acid halide of general formula X
hvor Hal har den ovenfor angitte betydning og R3 er et alkylradika1 inneholdende 3-6 carbonatomer, omsettes med en ether- av generell formel (II) under dannelse av et keton av generell formel XI: hvor R^ og R" har de ovenfor angitte betydninger, hvilket keton derefter reduseres til den tilsvarende sekundære alkohol av generell formel: hvor R" og R^ har de ovenfor angitte betydninger, hvorefter denne alkohol halogeneres til det tilsvarende halogenid av generell for-mell. hvor R", og Hal har de ovenfor angitte betydninger, som omsettes med magnesium og jad på kjent måte for å gi den tilsvarende Grignard-f or-bindelse av generell formel: hvor R", R^ og Hal har dé ovenfor angitte betydninger, hvilken forbindelse omsettes med halogenid av formel XIII under dannelse av en forbindelse av formelen: where Hal has the meaning given above and R3 is an alkyl radical containing 3-6 carbon atoms, is reacted with an ether of general formula (II) to form a ketone of general formula XI: where R^ and R" have the meanings given above , which ketone is then reduced to the corresponding secondary alcohol of the general formula: where R" and R" have the meanings given above, after which this alcohol is halogenated to the corresponding halide of the general formula. where R", and Hal have the meanings given above, which are reacted with magnesium and jade in a known manner to give the corresponding Grignard-for bond of general formula: where R", R^ and Hal have the meanings given above, which compound is reacted with halide of formula XIII to form a compound of formula:
hvor R" og R^ har de ovenfor angitte betydninger, som darefter dealkyleres til den tilsvarende dihydroxyforbindelse av formel I. where R" and R^ have the meanings given above, which are then dealkylated to the corresponding dihydroxy compound of formula I.
Kondensasjonen av forbindelse (II) og halogenketon (III) utfores fordelaktig i nærvær av konsentrert svovelsyre eller vann-fritt aluminiumklorid ved redusert temperatur, f.eks. ved en temperatur på -25°C til 0°C, mens kondensasjonen av forbindelse (II) og den sekundære alkohol (III) fordelaktig utfores i nærvær av vann-fritt aluminiumklorid ved omgivelsestemperatur eller ved svakt for-hoyede temperaturer, f.eks. opp til 40°C. The condensation of compound (II) and haloketone (III) is advantageously carried out in the presence of concentrated sulfuric acid or anhydrous aluminum chloride at a reduced temperature, e.g. at a temperature of -25°C to 0°C, while the condensation of compound (II) and the secondary alcohol (III) is advantageously carried out in the presence of anhydrous aluminum chloride at ambient temperature or at slightly elevated temperatures, e.g. up to 40°C.
Hydrogeneringen av de umettede diethere (IVb) utfores fordelaktig katalytisk i iseddik i nærvær av en palladium- eller plati-nakatalysator. The hydrogenation of the unsaturated diethers (IVb) is advantageously carried out catalytically in glacial acetic acid in the presence of a palladium or platinum catalyst.
Dealkyleringen av de erholdte forbindelser av formel (IVa) kan utfores f.eks. ved hjelp av hydrobromsyre i eddiksyre. The dealkylation of the obtained compounds of formula (IVa) can be carried out, e.g. by means of hydrobromic acid in acetic acid.
Det er funnet at enkelte av 4,4'-dihydroxyforbindelsene ifolge foreliggende oppfinnelse er vanskelige å rense ved omkrysta 1-lisasjon. Dette problem kan lett overvinnes ved etherif iser.ing av 4,4'-dihydroxyforbindelsen .med et egnet benzylhalogenid, f.eks.^ benzylklorid, i nærvær av et alkalimetallhydroxyd, med fordel natriumhydroxyd. Denne forethring utfores hensiktsmessig i et inert opp-losningsmiddel. De således erholdte dibenzylethere kan lett omkrysta lliseres. Videre kan de rensede dibenzylethere derefter lett gjen-omdannes til de tilsvarende dihydroxyforbindelser ved hydrogen-olyse, f.eks. ved å opplo se dibenzyletheren i iseddik og riste opp-løsningen med hydrogen i nærvær av en hensiktsmessig katalysator, slik som palladium-kull eller platinakull. It has been found that some of the 4,4'-dihydroxy compounds according to the present invention are difficult to purify by recrystallisation. This problem can be easily overcome by etherification of the 4,4'-dihydroxy compound with a suitable benzyl halide, for example benzyl chloride, in the presence of an alkali metal hydroxide, preferably sodium hydroxide. This etherification is conveniently carried out in an inert solvent. The dibenzyl ethers thus obtained can be easily recrystallized. Furthermore, the purified dibenzyl ethers can then be easily converted back into the corresponding dihydroxy compounds by hydrogenolysis, e.g. by dissolving the dibenzyl ether in glacial acetic acid and shaking the solution with hydrogen in the presence of a suitable catalyst, such as palladium charcoal or platinum charcoal.
De nye forbindelser som fremstilles ifolge foreliggende-fremgangsmåte utviser en sterk ostrogen aktivitet. The new compounds produced according to the present method exhibit a strong estrogenic activity.
Denne aktivitet gjor den særlig egnet til behandling av hypertrophia prostatae. This activity makes it particularly suitable for the treatment of prostate hypertrophy.
En av de metoder som vanligvis anvendes for bestemmelse av en forbindelses ostrogene aktivitet er den såkaldte "vaginale for-horningstest" som er beskrevet av Emmett i "Hormone Assay" publisert av The Academic Press, New York 1950. Denne test er blitt utfort ved en representativ forbindelse ifolge oppfinnelsen sammenlignet med nær beslektede forbindelser ifolge DAS 1.902.331. Resultatene av denne test er som folger: One of the methods commonly used for determining the estrogenic activity of a compound is the so-called "vaginal horn test" described by Emmett in "Hormone Assay" published by The Academic Press, New York 1950. This test has been carried out by a representative compound according to the invention compared to closely related compounds according to DAS 1,902,331. The results of this test are as follows:
Forbindelser av folgende generelle formel ble sammenlignet: Compounds of the following general formula were compared:
Som det fremgår av tabellen er forbindelsen ifolge oppfinnelsen betydelig mer aktiv enn de tilsvarende andre forbindelser som ikke inneholder et fluoratom. Dessuten viser testen at de td ikke-halogenerte forbindelser er fullstendig inaktive ved denne test. As can be seen from the table, the compound according to the invention is significantly more active than the corresponding other compounds which do not contain a fluorine atom. Furthermore, the test shows that the eg non-halogenated compounds are completely inactive in this test.
Folgende Eksempler er gitt for å illustrere foreliggende oppfinnelse: The following examples are given to illustrate the present invention:
" Eksempel 1 "Example 1
En blanding av lOO g nydestillert 2-fluoranisol og 50 g 3-klorpentan-2-on, k.p. 134 137°C, ble kjdlet "til -20°C, hvorefter 125 ml konsentrert svovelsyre ble tilsatt dråpevis under omrdring-over en periode på 2 timer.' Efter ytterligere omroring 6 timer ble reaksjonsblandingen heldt over i isvann. Blandingen ble derefter ekstrahert med diethylether, etherekstrakten torket og etheren destillert fra, hvorefter det oljeaktige residuum.ble oppvarmet i 2 timer til 235 - 240°C ved en 15 mm Hg, og det erholdte destillat ble fraskilt. Residuet ble derefter destillert ved 160 - 170°C C/0,03 mm Hg og ga en hovedfraksjon på 20 g av. en olje som ikke kunne kry-stalliseres. Denne olje ble derefter opplost i 150 ml iseddik og ristet i en hydrogenatmosfære i nærvær' av 1,2 g palladium-kull (10 %) inntil hydrogenopptaket opphorte. Reaksjonsblandingen ble derefter filtrert og fordampet hvorved der ble erholdt ca. 20 g av en blanding av threo- og erythro-3,3 *-difluor-4,4'-dimethoxy-a-eth-yl-a'-methyl-dibenzyl. Efter krystallisasjon av denne blanding fra methanol fikk man isolert erythro-forbindelsen som hadde smeltepunkt på 106 - 107°C. ;En opplosning av 7,5 g erythro-3,3'-difluor-4,4'-dimethoxy-a-ethyl-a'-methyldibenzy1 i 70 ml iseddik og 40 ml hydrobromsyre ble oppvarmet under tilbakeldp i en nitrogenatmosfære i 6 1/2 time. Efter kjoling ble reaksjonsblandingen heldt over is og ekstrahert med ether. De ethriske ekstrakter ble vasket med vann cg ekstrahert med 2N natriumhydroxydopplbsning. Det alkaliske ekstrakt ble surgjort og ekstrahert med ether. Fordampning av det ethriske ekstrakt ga 6 g av et gulaktig fast stoff som ble opplost i benzen og fort gjen- , nom en kolonne inneholdende 50 g silicagel. Konsentrering av elua-tet resulterte i spaltning av ery thro-3, 3 ' -dif luor-4,4' -d-ihydroxy-a-ethyl-a'-methyl-dibenzyl som hadde et smeltepunkt på 152 - 153°C. ;Eksempel 2 ;26 g aluminiumklorid ble tilsatt i ldpet av 1 time til en omrbrt blanding av 26 g o-fluoranisol og 12>5 g 3-klorpentanol-2 ;i nitrogenatmosfære. Reaksjonsblandingen ble oppvarmet til 35°C i 60 timer og derefter overfort i isvann. Reaksjonsblandingen ble ekstrahert med ether og derefter opprystet med en vandig oppldsning av natriumcarbonat for å fjerne uonsket surt fenolisk materiale. Den gjenværende ethriske fase ble torket og fordampet' og ga et nbytralt materiale som ble fraksjonsdestillert. Den fraksjon som kokte ved 165 - 175°C/0,2 mm Hg (10 g). ble omkrystallisert fra methanol og ga 1,3 g erythro-3,3'-difluor-4,4T<->dimethoxy-a-ethyl-a'-methyl-diben-zyl som hadde et smeltepunkt på 106 - 107°C og var identisk med det produkt som ble erholdt i eksempel 1. ;Denne dimethoxyforbindelse.ble demethylert ved oppvarmning ;i en blanding av 25 ml iseddik og 10 ml hydrobromsyre under nitrogenatmosfære ved 140°C i 5 timer. Derefter ble oppldsningen kjolt og fortynnet med vann. Der ble således erholdt 1,05 g erythro-3,3r<->difluor-4,4'-dihydroxy-a-ethyl-a'-methyl-dibenzyl som, efter omkrystallisasjon fra benzen hadde et smeltepunkt på 152 - 153°C, og var identisk med det produkt som ble erholdt i eksempel 1. ;Den ikke-krystallinske modervæske ble demethylert på tilsvarende måte. Et produkt på 7,5 g ble erholdt og kombinert med den fenoliske fraksjon (6 g, k.p. 180 - 190°C/0,2 mm Hg) og blandet med 13 g benzylklorid i en opplosning av 4 g natriumhydroxyd i 100 ml alkohol. Reaksjonsblandingen ble kokt under tilbakelop 2 timer og derefter kjolt og fortynnet med vann. Der ble erholdt 1,9 g av et bunnfall av erythro-3,3'-difluor-4,4r<->dibenzyloxy-a-ethyl-a'-methyl-dibenzyl som efter omkrystallisasjon fra benzen/petroleumether hadde et smeltepunkt på' 131 - 132,5°C. Denne forbindelse kan debenzyleres ved opplosning i 50 ml eddiksyre, tilsetning av 0,5 g palladium-kull og omrystning med hydrogen 1 time. Efter frafiltrering av katalysa-toren og opparbeidelse av filtratet ble der erholdt 1,1 g erythro-3,3r<->difluor-4,4'-dihydroxy-a-ethyl-a'-methyl-dibenzyl. ;Eksempel 3 ;Ca. 70 g butyrylklorid ble tilsatt over eri periode på 30 minutter under omroring til en blanding av 81 g o-fluoranisol, lOOg aluminiumklorid og lOO ml carbondisulfid: Efter ytterligere omroring i 4 timer ble reaksjonsblandingen overfort i isvann og derefter ekstrahert ned ether. Det ethriske ekstrakt ble tofket over vann-, fritt natriumsulf.at og fordampet,. og residuet omkrystalliserte fra methanol, hvorved der ble erholdt o-fluoranisy.lbutyrofenon. ;En opplosning av 4 g nåtriumborhydrid i 20 ml vann ble tilsatt under omroring til en opplosning av ca. 40 g b-fluoranisyl-bu-tyrofenon i 200 ml methanol kjolt til 0°C. Reaksjonsblandingen ble omrdrt i 3 timer, fortynnet med vann og ekstrahert med benzen. Ben-zenekstraktet ga 1-o-fluoranisyl-n-butanol. ;Eri 0,2 M opplosning av 1-o-fluoranisyl-n-butanol i torr benzen ble tilsatt en kjolt suspensjon av 86 g fosforpentabromid i 50 ml torr. ether. Efter omroring 1 1/2 time ble reaksjonsblandingen overfort i isvann. Det derved fremstillede 1-o-fluoranisy1-n-butylbromidprodukt ble ekstrahert med benzen, og benzehoppldsningen ble efter fullstendig torkning overfort under omroring til en blanding av 4 g magnesium, 0,01-g jod og 20 ml torr ether. Reaksjonsblandingen ble kokt undéf tilbakelop* 15 timer og derefter overfort i en blanding av is og fortynnet saltsyre. Blandingen ble ekstrahert med ether, det etheriske ekstrakt torket og fordampet og residuet omkrystallisert fra kloroform/ether (k.p. 40 - 6Q°C). Der ble således erholdt 5,5 g meso-3,3'rdifluor-4,4'-dimethoxy-a,a'-dipro-pyl-dibenzyl"som hadde et smeltepunkt på 168 -. 169°C. A mixture of 100 g freshly distilled 2-fluoroanisole and 50 g 3-chloropentan-2-one, b.p. 134 137°C, was cooled to -20°C, after which 125 ml of concentrated sulfuric acid was added dropwise with stirring over a period of 2 hours. After further stirring for 6 hours, the reaction mixture was poured into ice water. The mixture was then extracted with diethyl ether, the ether extract dried and the ether distilled off, after which the oily residue was heated for 2 hours at 235-240°C at 15 mm Hg, and the obtained distillate was separated. The residue was then distilled at 160-170°C/0.03 mm Hg and gave a major fraction of 20 g of an oil which could not be crystallized. This oil was then dissolved in 150 ml of glacial acetic acid and shaken in a hydrogen atmosphere in the presence of 1.2 g of palladium charcoal (10%) until hydrogen uptake ceased. The reaction mixture was then filtered and evaporated to give about 20 g of a mixture of threo- and erythro-3,3 *- difluoro-4,4'-dimethoxy-α-eth-yl-α'-methyl-dibenzyl. After crystallization of this mixture from methanol, the erythro compound was isolated, which had a melting point of 106 - 107°C. ;A solution of 7 .5 g erythro-3,3'-difluoro-4,4'-dimethoxy-α-ethyl-α'-methyldibe nzy1 in 70 ml of glacial acetic acid and 40 ml of hydrobromic acid was heated under reflux in a nitrogen atmosphere for 6 1/2 hours. After cooling, the reaction mixture was poured over ice and extracted with ether. The ethereal extracts were washed with water and extracted with 2N sodium hydroxide solution. The alkaline extract was acidified and extracted with ether. Evaporation of the ethereal extract gave 6 g of a yellowish solid which was dissolved in benzene and passed through a column containing 50 g of silica gel. Concentration of the eluate resulted in cleavage of erythro-3,3'-difluoro-4,4'-d-ihydroxy-α-ethyl-α'-methyl-dibenzyl which had a melting point of 152-153°C. Example 2 26 g of aluminum chloride was added over the course of 1 hour to a stirred mixture of 26 g of o-fluoroanisole and 12>5 g of 3-chloropentanol-2 in a nitrogen atmosphere. The reaction mixture was heated to 35°C for 60 hours and then transferred to ice water. The reaction mixture was extracted with ether and then shaken with an aqueous solution of sodium carbonate to remove unwanted acidic phenolic material. The remaining ethereal phase was dried and evaporated to give a neutral material which was fractionally distilled. The fraction boiling at 165 - 175°C/0.2 mm Hg (10 g). was recrystallized from methanol and gave 1.3 g of erythro-3,3'-difluoro-4,4T<->dimethoxy-a-ethyl-a'-methyl-diben-zyl which had a melting point of 106 - 107°C and was identical to the product obtained in example 1. This dimethoxy compound was demethylated by heating in a mixture of 25 ml of glacial acetic acid and 10 ml of hydrobromic acid under a nitrogen atmosphere at 140°C for 5 hours. The solution was then cooled and diluted with water. 1.05 g of erythro-3,3r<->difluoro-4,4'-dihydroxy-α-ethyl-α'-methyl-dibenzyl were thus obtained which, after recrystallization from benzene, had a melting point of 152 - 153°C , and was identical to the product obtained in example 1. The non-crystalline mother liquor was demethylated in a similar manner. A product of 7.5 g was obtained and combined with the phenolic fraction (6 g, b.p. 180-190°C/0.2 mm Hg) and mixed with 13 g of benzyl chloride in a solution of 4 g of sodium hydroxide in 100 ml of alcohol. The reaction mixture was refluxed for 2 hours and then cooled and diluted with water. 1.9 g of a precipitate of erythro-3,3'-difluoro-4,4r<->dibenzyloxy-a-ethyl-a'-methyl-dibenzyl were obtained which, after recrystallization from benzene/petroleum ether, had a melting point of 131 - 132.5°C. This compound can be debenzylated by dissolving in 50 ml of acetic acid, adding 0.5 g of palladium charcoal and shaking with hydrogen for 1 hour. After filtering off the catalyst and working up the filtrate, 1.1 g of erythro-3,3-difluoro-4,4'-dihydroxy-α-ethyl-α'-methyl-dibenzyl were obtained. ;Example 3 ;Approx. 70 g of butyryl chloride was added over a period of 30 minutes with stirring to a mixture of 81 g o-fluoroanisole, lOOg aluminum chloride and lOO ml carbon disulphide: After further stirring for 4 hours, the reaction mixture was transferred into ice water and then extracted into ether. The ethereal extract was concentrated over aqueous, free sodium sulfate and evaporated. and the residue recrystallized from methanol, whereby o-fluoroanisylbutyrophenone was obtained. A solution of 4 g of sodium borohydride in 20 ml of water was added with stirring to a solution of approx. 40 g of b-fluoroanisyl-butyrophenone in 200 ml of methanol cooled to 0°C. The reaction mixture was stirred for 3 hours, diluted with water and extracted with benzene. The benzene extract gave 1-o-fluoroanisyl-n-butanol. A 0.2 M solution of 1-o-fluoroanisyl-n-butanol in dry benzene was added to a cooled suspension of 86 g phosphorus pentabromide in 50 ml dry. ether. After stirring for 1 1/2 hours, the reaction mixture was transferred to ice water. The 1-o-fluoranisyl-n-butyl bromide product thus prepared was extracted with benzene, and the benzene solution, after complete drying, was transferred with stirring to a mixture of 4 g of magnesium, 0.01 g of iodine and 20 ml of dry ether. The reaction mixture was refluxed for 15 hours and then transferred to a mixture of ice and dilute hydrochloric acid. The mixture was extracted with ether, the ethereal extract dried and evaporated and the residue recrystallized from chloroform/ether (b.p. 40 - 60°C). 5.5 g of meso-3,3'rdifluoro-4,4'-dimethoxy-α,α'-dipropyl-dibenzyl" were thus obtained, which had a melting point of 168 - 169°C.
Efter demethylering'av denne forbindelse med hydrobromsyre i iseddik på tilsvarende måte som beskrevet i eksempel 2, ble den ti 1 sva rende meso-3, 3r -dif luor-4,4 ' -dihydro.xy-a, a' -dipropy1-dibenzyl-forbindelse erholdt, som hadde et smeltepunkt på 139 - 140°C. After demethylation of this compound with hydrobromic acid in glacial acetic acid in a similar manner as described in example 2, the corresponding meso-3,3r-difluoro-4,4'-dihydro.xy-a,a'-dipropy1- dibenzyl compound obtained, which had a melting point of 139 - 140°C.
Foreliggende oppfinnelse innbefatter også innen sin ramme farmasoytiske materialer inneholdende én eller flere av de nye forbindelser. Disse farmasoytiske materialer kan administreres oralt eller parenteralt i blanding med en fast eller .flytende farmasdytisk bærer. The present invention also includes within its framework pharmaceutical materials containing one or more of the new compounds. These pharmaceutical materials can be administered orally or parenterally in admixture with a solid or liquid pharmaceutical carrier.
Faste materialer for oral administrering innbefatter sam-menpressede tabletter, piller, dispergerbare pulvere og granuler. I slike faste materialer blandes i det minste én aktiv forbindelse ifolge foreliggende oppfinnelse med minst én inert fortynner, slik som tribasisk kalsiumfosfat (Ca3(P04)2), stivelse, lactose, gelatin, acacia, sucrose, stearinsyre, talkum, alginsyre eller natriumalgi- Solid materials for oral administration include compressed tablets, pills, dispersible powders and granules. In such solid materials, at least one active compound according to the present invention is mixed with at least one inert diluent, such as tribasic calcium phosphate (Ca3(P04)2), starch, lactose, gelatin, acacia, sucrose, stearic acid, talc, alginic acid or sodium alginate.
nat. Materialene kan o_gså inneholde, som i vanlig praksis, ytterli- night The materials can also contain, as in normal practice, additional
gere forbindelser andre enn de inerte fortynnere, f.eks. smdremid- ' ger compounds other than the inert diluents, e.g. smdremid-'
ler, som magnesiumstearat, såvel som sdtnings- eller aromastoffer. clay, such as magnesium stearate, as well as sweetening or flavoring substances.
Den prosentvise mengde av den aktive ingrediens i materia- The percentage amount of the active ingredient in the materia-
let ifolge foreliggende oppfinnelse kan varieres, da det er nodven- easily according to the present invention can be varied, as it is necessary
dig å ha et slikt forhold at en egnet dose skal gi den dnskede tera-peutiske effekt. Vanligvis skal preparatene ifolge foreliggende oppfinnelse administreres med en effektiv dose fra ca. 0,OOOOl mg til 1 mg aktiv substans pr. kg kroppsvekt pr. dag. you to have such a relationship that a suitable dose should produce the desired therapeutic effect. Generally, the preparations according to the present invention are to be administered with an effective dose from approx. 0.0001 mg to 1 mg of active substance per kg body weight per day.
Claims (1)
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GB02554/70A GB1280767A (en) | 1970-03-16 | 1970-03-16 | Derivatives of 1,2-diphenyl-ethane |
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NO132533C NO132533C (en) | 1975-11-26 |
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AT (1) | AT303711B (en) |
BE (1) | BE764081A (en) |
CA (1) | CA948215A (en) |
CH (1) | CH558315A (en) |
DK (1) | DK146015C (en) |
ES (1) | ES389282A1 (en) |
FI (1) | FI55170C (en) |
FR (1) | FR2085710B1 (en) |
GB (1) | GB1280767A (en) |
IE (1) | IE35009B1 (en) |
IL (1) | IL36225A0 (en) |
NL (1) | NL146140B (en) |
NO (1) | NO132533C (en) |
PH (1) | PH10518A (en) |
SE (1) | SE393369B (en) |
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- 1971-02-15 IE IE175/71A patent/IE35009B1/en unknown
- 1971-02-16 CA CA105,562A patent/CA948215A/en not_active Expired
- 1971-02-16 SE SE7101951A patent/SE393369B/en unknown
- 1971-02-18 IL IL36225A patent/IL36225A0/en unknown
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- 1971-03-05 FI FI657/71A patent/FI55170C/en active
- 1971-03-08 CH CH332071A patent/CH558315A/en not_active IP Right Cessation
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FI55170C (en) | 1979-06-11 |
NL146140B (en) | 1975-06-16 |
CH558315A (en) | 1975-01-31 |
DK146015B (en) | 1983-05-24 |
ZA71927B (en) | 1971-10-27 |
AT303711B (en) | 1972-12-11 |
NO132533C (en) | 1975-11-26 |
DK146015C (en) | 1983-10-24 |
PH10518A (en) | 1977-05-26 |
FR2085710A1 (en) | 1971-12-31 |
ES389282A1 (en) | 1973-06-16 |
FI55170B (en) | 1979-02-28 |
IL36225A0 (en) | 1971-04-28 |
NL7103249A (en) | 1971-09-20 |
SE393369B (en) | 1977-05-09 |
CA948215A (en) | 1974-05-28 |
DE2110428A1 (en) | 1971-10-07 |
YU35331B (en) | 1980-12-31 |
BE764081A (en) | 1971-08-02 |
GB1280767A (en) | 1972-07-05 |
IE35009L (en) | 1971-09-16 |
JPS515378B1 (en) | 1976-02-19 |
YU53171A (en) | 1980-06-30 |
FR2085710B1 (en) | 1975-08-01 |
IE35009B1 (en) | 1975-10-15 |
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