DK146015B - ANALOGY PROCEDURE FOR THE PREPARATION OF ERYTHRO OR MESO FORMS OF 3,3'-DIFLUOR-4,4'-DIHYDROXYDIBENZYL DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF ERYTHRO OR MESO FORMS OF 3,3'-DIFLUOR-4,4'-DIHYDROXYDIBENZYL DERIVATIVES Download PDFInfo
- Publication number
- DK146015B DK146015B DK126571AA DK126571A DK146015B DK 146015 B DK146015 B DK 146015B DK 126571A A DK126571A A DK 126571AA DK 126571 A DK126571 A DK 126571A DK 146015 B DK146015 B DK 146015B
- Authority
- DK
- Denmark
- Prior art keywords
- general formula
- difluoro
- compound
- erythro
- dibenzyl
- Prior art date
Links
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
{ HI{HI
(19) DANMARK ^(19) DENMARK ^
§(.2) FREMLÆGGELSESSKRIFT (n, 146015 B§ (.2) SUBMISSION WRITING (n, 146015 B
DIREKTORATET FOR PATENT- OG VAREMÆRKEVÆSENETDIRECTORATE OF THE PATENT AND TRADEMARKET SYSTEM
(21) Patentansøgning nr.: 1265/71 (51) Intel.3: C 07 C 39/367 (22) Indleveringsdag: 16 mar 1971 (41) Aim. tilgængelig: 17 sep 1971 (44) Fremlagt: 24 maj 1983 (86) International ansøgning nr.:- (30) Prioritet: 16 mar 1970 GB12554/70 (71) Ansøger: ‘BIOREX LABORATORIES LIMITED; London N. 1, GB.(21) Patent Application No. 1265/71 (51) Intel.3: C 07 C 39/367 (22) Filing Date: 16 Mar 1971 (41) Aim. available: 17 Sep 1971 (44) Submitted: 24 May 1983 (86) International Application No :- (30) Priority: 16 Mar 1970 GB12554 / 70 (71) Applicant: 'BIOREX LABORATORIES LIMITED; London N. 1, GB.
(72) Opfinder: John Cameron *Turner; GB, Rosalind Po-Kuen 'Chan; GB.(72) Inventor: John Cameron * Turner; GB, Rosalind Po-Kuen 'Chan; GB.
(74) Fuldmægtig: Plougmann & Vingtoft Patentbureau (54) Analogifremgangsmåde til fremstilling af erythro- eller mesoformerne af 3,3’-<Iifluor-4,4’-dihydroxy-dibenzylderivater(74) Plenipotentiary: Plougmann & Vingtoft Patent Bureau (54) Analogous Process for Preparing the Erythro or Mesoforms of 3,3 '- <Iifluoro-4,4'-Dihydroxy-Dibenzyl Derivatives
Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte, værdifulde 3,3,-difluor-4,4'--dihydroxydibenzyIderivater i erythro- eller mesoform, som har yderst kraftige østrogene egenskaber.The present invention relates to an analogous process for the preparation of novel valuable 3,3, -difluoro-4,4 '- dihydroxydibenzyl derivatives in erythro- or mesoform, which have extremely potent estrogenic properties.
CDCD
φ De omhandlede 3,3,-difluor-4,4,-dihydroxydibenzylderivater er så-The 3,3, -difluoro-4,4, -dihydroxydibenzyl derivatives are thus
^ danne med den almene formel Iform with the general formula I
OISLAND
JO F FJO F F
g '®~O~0h 1g '® ~ O ~ 0h 1
Rx 2 148015 1 2 hvor R og R , som kan være ens eller forskellige, betegner alkyl- grupper indeholdende højst 6 carbonatomer, med det forbehold, at R"*" 2 og R ikke begge er methyl eller ethyl.Rx 2 148015 1 2 wherein R and R, which may be the same or different, represent alkyl groups containing not more than 6 carbon atoms, with the proviso that R 2 and R 2 are not both methyl or ethyl.
1 2 Når R og R er alkylgrupper indeholdende 3-6 carbonatomer, kan de f.eks. være n-propyl, isopropyl, n-butyl, n-pentyl og n-hexyl.When R and R are alkyl groups containing from 3 to 6 carbon atoms, they may e.g. be n-propyl, isopropyl, n-butyl, n-pentyl and n-hexyl.
Den foretrukne blandt de omhandlede forbindelser har formlen laThe preferred one of the compounds of the invention has the formula Ia
F FF F
ηο~\3~γ~ °h ia CH3 c2h5 —ηο ~ \ 3 ~ γ ~ ° h ia CH3 c2h5 -
Fremgangsmåden ifølge opfindelsen er ejendommelig ved, at a) en umættet diether med den almene formel IVThe process according to the invention is characterized in that: a) an unsaturated dieter of the general formula IV
F FF F
B.' _ o-hQ-C = C—^3-° ~ R IVB. ' _ o-hQ-C = C— ^ 3- ° ~ R IV
R1 R2 hvor R betegner en alkylgruppe indeholdende højst 6 carbonatomer, 1 2R1 represents where R represents an alkyl group containing not more than 6 carbon atoms, 1 2
og R og R har de ovenfor anførte betydninger, hydrogeneres til dannelse af den tilsvarende 3,3,-difluor-4,4,-dialkoxydiphenyl-forbindelse med den almene formel Vand R and R have the above meanings, hydrogenated to give the corresponding 3,3, -difluoro-4,4, -dialkoxydiphenyl compound of the general formula V
F FF F
E - °—. E VE - ° -. E V
R1 R2 3 14601 δ 1 2 hvor R, R og R har de ovenfor anførte betydninger, hvorefter meso- eller erythroformen af denne forbindelse isoleres og deal-kyleres til dannelse af den ønskede tilsvarende dihydroxyforbin-uelse I, ellerR1 R2 3 14601 δ 1 2 wherein R, R and R have the above meanings, after which the meso or erythroform of this compound is isolated and dealkylated to form the desired corresponding dihydroxy compound I, or
b) en ether med den almene formel IIb) an ether of the general formula II
FF
11 hvor· R har den ovenfor anførte betydning, omsættes med en11 where · R has the meaning given above is reacted with a
1,2-dialkyl-2-halogenethanol med den almene formel VI1,2-dialkyl-2-haloethanol of the general formula VI
\\
Hal - CH - CHOH VIHal - CH - CHOH VI
I, tI, t
ΊΓ RΊΓ R
1 2 hvor Hal betegner et halogenatom, og R og R har de ovenfor anførte betydninger, til dannelse af en 3,3'-difluor-4,4'-dialkoxy-diphenylforbindelse med den almene formel V, hvorefter meso- eller erythroformen af denne forbindelse dealkyleres til dannelse af den ønskede tilsvarende dihydroxyforbindelse, eller c) til fremstilling af forbindelser med den almene formel I, 1 2Wherein Hal represents a halogen atom and R and R have the meanings set forth above to form a 3,3'-difluoro-4,4'-dialkoxy-diphenyl compound of the general formula V, whereafter the meso or erythroform thereof compound is dealkylated to give the desired corresponding dihydroxy compound, or c) to prepare compounds of general formula I, 1 2
hvor R og R er ens alkylgrupper indeholdende 3-6 carbonatomer, et halogenid med den almene formel XIIIwherein R and R are identical alkyl groups containing 3 to 6 carbon atoms, a halide of general formula XIII
R - ° —/ \-- R1 XIIIR - ° - / \ - R1 XIII
HalHall
hvor R og Hal har de ovenfor anførte betydninger, og R betegner en alkylgruppe indeholdende 3-6 carbonatomer, omsættes med magnesium på kendt måde til dannelse af den tilsvarende Grignard-fforbindelse med den almene formel XIVwherein R and Hal have the above meanings and R represents an alkyl group containing 3-6 carbon atoms, reacted with magnesium in known manner to form the corresponding Grignard compound of general formula XIV
4 U60154 U6015
FF
V-TV Mg. Hal // \_ CH^V-TV Mg. Hal // \ _ CH ^
R - O -\_/- < , XIVR - O - \ _ / - <, XIV
'-' ' \ rj 3 hvor R, R og Hal har de ovenfor anførte betydninger, som in statu nascendi omsættes med ikke-omsat halogenid med formlen XIII, hvorefter reaktionsblandingen oparbejdes på kendt måde til dannelse af en forbindelse med den almene formel V, hvor R og R betegner ens alkylgrupper indeholdende 3-6 carbonatomer, hvorefter den vundne forbindelse dealkyleres til dannelse af den ønskede tilsvarende dihydroxyforbindelse I.wherein R, R and Hal have the above meanings which are reacted in statu nascendi with unreacted halide of formula XIII, after which the reaction mixture is worked up in a known manner to form a compound of general formula V, wherein R and R are identical alkyl groups containing 3 to 6 carbon atoms and then the compound obtained is dealkylated to form the desired corresponding dihydroxy compound I.
Den umættede diether med den almene formel IV kan fremstilles ved, at man omsætter en ether med den almene formel IIThe unsaturated diether of the general formula IV can be prepared by reacting an ether of the general formula II
FF
R - 0-1") IIR - 0-1 ") II
hvor R har den ovenfor anførte betydning, med en a-halogendialkylketon med den almene formel IIIwherein R is as defined above with an α-halo dialkyl ketone of the general formula III
Hal - CH - C = 0 IIIHal - CH - C = 0 III
*1 i* Έ3- Br* 1 i * Έ3- Br
Ί OΊ Oh
hvor R og R har de ovenfor anførte betydninger, og Hal betegner et halogenatom, fortrinsvis et chloratom.wherein R and R have the above meanings and Hal represents a halogen atom, preferably a chlorine atom.
Halogenidet med den almene formel XIII kan fremstilles ved, at en ether med den ovenfor viste almene formel II omsættes med et syre-halogenid med den almene formel XThe halide of general formula XIII can be prepared by reacting an ether of the above general formula II with an acid halide of general formula X
R3 - CO - Hal XR3 - CO - Hall X
33
hvor Hal og R har de ovenfor anførte betydninger, til dannelse af en 3-fluor-4-alkoxyphenylalkylketon med den almene formel XIwherein Hal and R have the meanings set forth above to form a 3-fluoro-4-alkoxyphenylalkyl ketone of the general formula XI
5 1460155 146015
hvor R og har de ovenfor anførte betydninger, som reduceres til den tilsvarende a-alkyl-3-fluor-4-alkoxybenzylalkohol med den almene formel XIIwherein R and have the above meanings which are reduced to the corresponding α-alkyl-3-fluoro-4-alkoxybenzyl alcohol of the general formula XII
FF
R - 0 —^ — OH - R3 XIIR - 0 - ^ - OH - R3 XII
OHOH
3 hvor R og R har de ovenfor anførte betydninger, hvorefter denne alkohol halogeneres til dannelse af halogenidet med den almene formel XIII.3 wherein R and R have the above meanings, after which this alcohol is halogenated to form the halide of general formula XIII.
Kondensationen af forbindelserne med formlerne II og III udføres fortrinsvis i nærværelse af koncentreret svovlsyre eller vandfrit aluminiumchlorid ved nedsat temperatur, f.eks. ved en temperatur på fra -25 til 0°C, medens kondensationen af forbindelserne II og VI fortrinsvis udføres i nærværelse af vandfrit aluminiumchlorid ved stuetemperatur eller ved let forhøjet temperatur, f.eks. en tempe= ratur på op til ca. 40°0.The condensation of the compounds of formulas II and III is preferably carried out in the presence of concentrated sulfuric acid or anhydrous aluminum chloride at reduced temperature, e.g. at a temperature of from -25 to 0 ° C, while the condensation of compounds II and VI is preferably carried out in the presence of anhydrous aluminum chloride at room temperature or at slightly elevated temperature, e.g. a temperature = up to approx. 40 ° 0th
Hydrogeneringen af den umættede diether med formlen IV udføres for= trinsvis katalytisk i iseddike i nærværelse af en palladium- eller platinkatalysator.The hydrogenation of the unsaturated dieter of formula IV is preferably catalytically carried out in glacial acetic acid in the presence of a palladium or platinum catalyst.
Som eksempler på opløsningsmidler, der kan anvendes ved chlorerin= gen eller bromeringen af forbindelserne med den almene formel IX, kan nævnes iseddike og vandige halogenerede carbonhydrider, f.eks. methylenchlorid eller chloroform.Examples of solvents which may be used in the chlorination or bromination of the compounds of general formula IX include glacial acetic acid and aqueous halogenated hydrocarbons, e.g. methylene chloride or chloroform.
Den ovenfor angivne dealkylering kan f.eks. udføres ved indvirkning af brombrintesyre i iseddike.The above dealkylation may e.g. is carried out by the action of hydrobromic acid in glacial acetic acid.
6 1460156 146015
De vundne 4,4’-dihydroxyforbindelser kan om ønsket renses ved først at omdannes til dibenzyletherne, som undertiden kan være lettere at rense ved omkrystallisation end 4,4'-dihydroxyfor-bindelserne. Dibenzyletherne kan fremstilles ved etherificering under anvendelse af et benzyleringsmiddel, f.eks. et benzylhalo-genid såsom benzylchlorid, i nærværelse af en stærk base. De på denne måde vundne dibenzylethere kan let omkrystalliseres, hvorefter de på denne måde rensede dibenzylethere let kan føres tilbage i de tilsvarende dihydroxyforbindelser ved hydrogenolyse, f.eks. ved at opløse dibenzyletheren i iseddike og ryste opløsningen med hydrogen i nærværelse af en egnet katalysator, f.eks. palladium/kul eller platin/kul.The 4,4'-dihydroxy compounds obtained can be purified, if desired, by first being converted to the dibenzyl ethers, which can sometimes be easier to purify by recrystallization than the 4,4'-dihydroxy compounds. The dibenzyl ethers can be prepared by etherification using a benzylating agent, e.g. a benzyl halide such as benzyl chloride, in the presence of a strong base. The dibenzyl ethers thus obtained can be readily recrystallized, after which the dibenzyl ethers thus purified can be readily returned to 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, e.g. palladium / coal or platinum / coal.
I tysk offentliggørelsesskrift nr. 1.902.331 beskrives forbindelser, der er meget nært beslægtede med de her omhandlede forbindelser, men som dog ikke udviser den for de her omhandlede forbindelser essentielle fluorsubstitution i begge benzenkerner. Det anføres i offentliggørelsesskriftet, at de pågældende forbindelser har østrogene og anti-østrogene egenskaber og kan anvendes til regulering af ovulationen og spermatogenesen, medens der intet er antydet om, at forbindelserne har de samme meget interessante terapeutiske egenskaber som de her omhandlede 3,3'-difluor-substituerede forbindelser, der kan anvende til reduktion af størrelsen af prostata og udmærker sig ved ikke at udvise de samme ulemper som det normalt til reduktion af prostatastørrel-sen anvendte middel stilboestrol, som det fremgår af nedenstående forsøgsrapport, hvor resultaterne af et sammenligningsforsøg mellem stilboestrol og forbindelsen erythro-3,3'-difluor-4,4' -dihydroxy-a-ethyl-a' - methyl-dibenzyl er anført. 1 nedenstående tabel er anført virkningen på vægten for forskellige organer ved behandling med henholdsvis 50^ug/dag stilboestrol og 50yUg/dag, erythro-3,3'-difluor-4,4'-dihydroxy-a-ethyl-a ' -methyl-dibenzyl . Det fremgår, at der i de første 3 uger sker en betragtelig væksthæmning i de behandlede dyr ved 50^ug stilboestrol, medens dette kun er tilfældet i den første uge med 50^ug af den her omhandlede forbindelse.German Patent Specification No. 1,902,331 discloses compounds which are very closely related to the compounds of the present invention, but which do not, however, exhibit the fluorine substitution essential for the compounds of the present invention in both benzene cores. It is stated in the disclosure that the compounds in question have estrogenic and anti-estrogenic properties and can be used to regulate ovulation and spermatogenesis, while there is no indication that the compounds have the same very interesting therapeutic properties as the 3.3 disclosed herein. -difluoro-substituted compounds which can be used to reduce the size of the prostate and are distinguished by not exhibiting the same disadvantages as the normal prostate size reducing agent used for the use of stilboestrol, as shown in the test report below, the results of a comparative experiment. between stilboestrol and the compound erythro-3,3'-difluoro-4,4'-dihydroxy-α-ethyl-α '- methyl-dibenzyl are listed. The table below lists the effect on the weight of various organs of treatment with 50 µg / day stilboestrol and 50 µg / day, erythro-3,3'-difluoro-4,4'-dihydroxy-α-ethyl-α '-methyl, respectively. -dibenzyl. It is evident that during the first 3 weeks there is considerable growth inhibition in the treated animals with 50 µg stilboestrol, whereas this is only the case in the first week with 50 µg of the compound concerned.
Under behandlingen og restitutionsperioden synes væksthastig heden at følge det normale mønster, hvor dyrene opnår lignende legemsvægte efter 14 til 15 ugers forsøg.During the treatment and recovery period, the growth rate seems to follow the normal pattern where the animals achieve similar body weights after 14 to 15 weeks of testing.
7 1460157 146015
Det fremgår af tabellen, at testes kun modificeres moderat af de her omhandlede forbindelser, vokser støt under behandlingen og efter 2 ugers restitution har samme vægt som kontrollerne, medens der med stilboestrol ses en markant reduktion af testesvægten, som igen stiger meget langsomt.The table shows that tests are only moderately modified by the compounds of this invention, grow steadily during treatment and after 2 weeks of restoration have the same weight as the controls, while with stilboestrol a marked reduction in test weight is observed which again increases very slowly.
Der konstateres testesfunktion ved behandling med de her omhandlede forbindelser og hos kontrollerne, men ikke hos de med stilboestrol behandlede rotter; testesfuriktionen vender under restitueringen gradvis tilbage hos de rotter, der er behandlet med stilboestrol.Testing function is found in treatment with the compounds of this invention and in the controls, but not in the stilboestrol treated rats; during recovery, testesurfiction gradually returns in the rats treated with stilboestrol.
Ved behandling med stilboestrol ses en udtynding af hårvæksten samt en reduktion af leucocyttallet, medens dette ikke er tilfældet med de her omhandlede forbindelser.When treated with stilboestrol, thinning of the hair growth as well as a reduction of the leucocyte count is seen, while this is not the case with the compounds of the present invention.
Den væksthæmning, der forekommer, synes at være afhængig af medikamentet, idet fødeindtagelsen kun reduceres moderat under behandlingen, formodentlig på grund af en medikamentinduceret anorexia. Det er kendt, at potente østrogener reducerer serumvæksten og hormonniveauet og påvirker væksthastigheden, og de har derfor været anvendt til behandling af nogle hyperhypofyse-tilstande, herunder acromegali.The growth inhibition that occurs appears to be drug dependent, with food intake only moderately reduced during treatment, presumably due to a drug-induced anorexia. Potential estrogens are known to reduce serum growth and hormone levels and affect growth rate, and have therefore been used to treat some hyperhypophyseal conditions, including acromegaly.
Den således iagttagede virkning for erythro-3,3'-difluor-4,4'--dihydroxy-a-ethyl-a'-methyl-dibenzyl indicerer anvendelse ved prostataforstørrelse og prostatasygdomme, herunder cancer.The effect thus observed for erythro-3,3'-difluoro-4,4 '- dihydroxy-α-ethyl-α'-methyl-dibenzyl indicates use in prostate enlargement and prostate diseases, including cancer.
På grund af de særlig fordelagtige terapeutiske egenskaber for erythro-3,3'-difluor-4,41-dihydroxy-a-ethyl-a'-methy1-dibenzy1 går et foretrukket aspekt af den foreliggende opfindelse ud på, at denne forbindelse fremstilles.Because of the particularly advantageous therapeutic properties of erythro-3,3'-difluoro-4,41-dihydroxy-α-ethyl-α'-methyl-dibenzyl, a preferred aspect of the present invention is the preparation of this compound.
8 146015 vovd «3> i— -tf m in vd r—i m r- oo H oo o ooin ooo m -a* ^ v, ^ ^ tk k ·> V K S V *- U m o o m oi h oooooohoooo +i co +| r- +1 H +1 o +i +l H +l8 146015 vovd «3> i— -tf m in vd r — i m r- oo H oo o ooin ooo m -a * ^ v, ^^ tk k ·> V K S V * - U m o o m oi h oooooohoooo + i co + | r- +1 H +1 o + i + l H + l
H HH H
M 0) ¢1 (Ti 00 P- oo 5 cm m o co r- ry oo in H r- m o «.«fc Ik «k Ik *, W *. N *» o ffi η o in o hid mo h m ho mo + | m H ID +1 H +1 0+1 +1 H +1M 0) ¢ 1 (Ti 00 P- oo 5 cm mo co r- ry oo in H r- mo «.« Fc Ik «k Ik *, W *. N *» o ffi η o in o hid mo hm ho mo + | m H ID +1 H +1 0 + 1 +1 H +1
+1 H+1 H
h m m h oo M< Η Ο σι *3* H OO OH 00 H O' 'f W W ^ %. k· V ^ V s *· ^ ^h m m h oo M <Η Ο σι * 3 * H OO OH 00 H O '' f W W ^%. k · V ^ V s * · ^^
it <HO HID OlO HOOO'S’mOinOit <HO HID OlO HOOO'S'MOinO
a) +1 Η 00 rn 00 Η +1 VD +1 +1 H +1 +) in +i m +i + 0 ------------a) +1 Η 00 rn 00 Η +1 VD +1 +1 H +1 +) in + i m + i + 0 ------------
Pi p* oo id oo m r- to in m oo O' r~ m m mo or- C< «* «k v *,%,-* ^ ^ ^ ** U m o oo oo oo o ho oo m ho ho UJ +| 00 H 00 Η H +1 ID +1 +1 H +1 Ο H +1 +1 ΛPi p * oo id oo m r- to in m oo O 'r ~ mm mo or- C <«*« kv *,%, - * ^ ^ ^ ** U mo oo oo oo o ho oo m ho ho UJ + | 00 H 00 Η H +1 ID +1 +1 H +1 Ο H +1 +1 Λ
η M Q) in co m oo id Η Hη M Q) in co m oo id Η H
Q) Cji OH moo 00 O' OO’S'HmOHHOQ) Cji OH moo 00 O 'OO'S'HmOHHO
H G U» G - -- -- - - - - ' ' -- dj td G cqho com r~~ oo ho om ho ho Λ tr> H ro +l t" +i ο +ι h +l m +i +1 H +1HGU »G - - - - - - - '' - dj td G cqho com r ~~ oo ho om ho ho Λ tr> H ro + lt" + i ο + ι h + lm + i +1 H +1
r3 Μ Hr3 Μ H
IH O ^IH O ^
GG
Pi id m co -a· m-+oor- mo m *3* oooo id n mo m ·μ* H-i Φ - - - - - - - - - ' -- pq (¾ i*i o m h oo oh ho ooo +) +| m 00 *3* -¾1 H +1 ID +1 +1 H +1 tn oo +i oo _______ > m oo r- vo m m vom mm ·*3< o m ·<3* <U ^ h vo oo - -------- rrj ». *, - ». ro co mo m *3* ho r-o xs v m ο h m r- H +i id +i +i +l •H +1 CO H +1 a +! Φ U> G H m oo m *0 γ-h •'tfoo mo mm r-o oh 'im offlmo mm oo com ho mo h +i m h m η h +i r- +i +i +i H +1 H +1 co m m oo m mo ro»* r- h oo mm kk k. k.Pi id m co -a · m- + over- mo m * 3 * oooo id n mo m · µ * Hi Φ - - - - - - - - - '- pq (¾ i * iomh oo oh ho ooo + ) + | m 00 * 3 * -¾1 H +1 ID +1 +1 H +1 tn oo + i oo _______> m oo r- vo mm vom mm · * 3 <om · <3 * <U ^ h vo oo - - ------- rrj ». *, - ». ro co mo m * 3 * ho r-o xs v m ο h m r- H + i id + i + i + l • H +1 CO H +1 a +! Φ U> GH m oo m * 0 γ-h • 'tfoo mo mm ro oh' im offlmo mm oo com ho mo h + imhm η h + i r- + i + i + i H +1 H +1 co mm oo m mo ro »* r- h oo mm kk kk
*<mo oh ho oo ο ·*3< ho mo +i mm o m H +l m +i +l H +l m +i oo+i* <mo oh ho oo ο · * 3 <ho mo + i mm o m H + l m + i + l H + l m + i oo + i
Cn MCn M
— «3 Φ Φ- «3 Φ Φ
+ M 01 M+ M 01 M
Φ 01 (C SB >ι ΦΦ 01 (C SB> ι Φ
D,(U + H+IMM MD, (U + H + IMM M
o, 4J m Λ — O'-* >1 Φ Φ *dG 01 OG» 'dU'iftU» G U» U'-* > --· HG Φ US SB g ’ >t 6 rig >itP Φ U» B Ο Eh ft-" 01-" 1 35- (¾ — S3 — J — 9 146015 r- tn m VD pH O 00 N PI CM Γ~· LO r—1 Γ" *, «. k. * ^ V V *» *» *» ^ U co o ho m in roo om mo ro o +l in ί1 Γ'· m H +i in +i +1 η +1 +1 n +i ro oo ro m · μ r~m σ\ r~ ooo oo ω in η lo •o’ σ' (J) k. k.o, 4J m Λ - O '- *> 1 Φ Φ * dG 01 AND »' dU'iftU» GU »U '- *> - · HG Φ US SB g'> t 6 rig> itP Φ U» B Ο Eh ft- "01-" 1 35- (¾ - S3 - J - 9 146015 r- tn m VD pH O 00 N PI CM Γ ~ · LO r — 1 Γ "*,«. K. * ^ VV * »*» * »^ U co o ho m in roo om mo ro o + l in ί1 Γ '· m H + i in + i +1 η +1 +1 n + i ro oo ro m · μ r ~ m σ \ r ~ ooo oo ω in η lo • o 'σ' (J) kk
hi ill n o <ri*a< om ro o m η» mo ·μ*ο σ +1 H ro Η* Η Η +1 r--1-1 +1 Η +1 o r- +i m +i ^hi ill n o <ri * a <om ro o m η »mo · μ * ο σ +1 H ro Η * Η Η +1 r - 1-1 +1 Η +1 o r- + i m + i ^
HH
co σ> n· m h [-.,-1 oo o co m m tn h vo inco σ> n · m h [-., - 1 oo o co m m tn h vo in
*, Si ^ ». * » ^ k k N*, Si ^ ». * »^ K k N
rtj co o •cf m ro m h h -m· mo roo Crtj co o • cf m ro m h h -m · mo roo C
+ | oo ro Μ1 ri +| VD +1 +1 pH +1 fl) vo +1 yp +i____ -g +) φ *β ni jj co m ^ m i oi4j ^ o in H mm o HHt^co h+ | oo ro Μ1 ri + | VD +1 +1 pH +1 fl) vo +1 yp + i ____ -g +) φ * β ni jj co m ^ m i oi4j ^ o in H mm o HHt ^ co h
Jj Q »s k. ·» ** *· *> * * - - £1 jju rj cjcoo oro in in hh r~m mo h* o ÆJj Q »s k. ·» ** * · *> * * - - £ 1 jju rj cjcoo oro in in hh r ~ m mo h * o Æ
n c o +l H m ·ο< m h +i in +i +ι H +i -JJn c o + l H m · ο <m h + i in + i + ι H + i -JJ
IH Id H +1 ro +1 % Λ +> f H co 3 o o> in en - Η o ‘Η Γ0Η LOr-O <£> ΟΓΟΗ oIH Id H +1 ro +1% Λ +> f H co 3 o o> in and - Η o 'Η Γ0Η LOr-O <£> ΟΓΟΗ o
rtj H ij Μ K k. * * kt * ·* ^ ** Irtj H ij Μ K k. * * kt * · * ^ ** I
n todJfflroo o in in co oh mr~ mo in H T* (rt H <U tn +1 CO Η1 I" CO H +i vo +i +l H +1 gin todJfflroo o in a co oh mr ~ mo in H T * (rt H <U tn +1 CO Η1 I "CO H + i vo + i + l H +1 gi
HU Pi ^ Γ0+ΙΓ0+Ι HHU Pi ^ Γ0 + ΙΓ0 + Ι H
σ' Η in σι h co ^ ·ςρ r—I Lf) CO C'** ^ ^ H CO O oσ 'Η in σι h co ^ · ςρ r — I Lf) CO C' ** ^^ H CO O o
0 s. * ·. ^ * ^ - v v v v I0 s. * ·. ^ * ^ - v v v v I
<coo r·» o o mo toro mo tno<coo r · »o o mo toro mo tno
ji +1 tn in ro ro H +1 to +1 +1 H +1 Xji +1 tn in ro ro H +1 to +1 +1 H +1 X
n tn -H _________ Pn tn -H _________ P
ti , -----— "^i— ro co in Hti, -----— "^ i— ro co in H
00h H oior~ ro o cn Μ1 Ό μ H *. «. .»«.·. ·> ^ " s ί*ι ni 'OO'OH’oroHiocomo'S’O ,c00h H oior ~ ro o cn Μ1 Ό µ H *. '. . ''. ·. ·> ^ "S ί * ι ni 'OO'OH'oroHiocomo'S'O, c
(H U ro +| Η H ro Η +1 I- +1 +1 Η +1 H(H U ro + | Η H ro Η +1 I- +1 +1 Η +1 H
> θ' +1 ro +1 rp> θ '+1 ro +1 rp
H JH J
Η Η Η Μ* H "f g h ro m h1 m o o o r-H co o lΗ Η Η Μ * H ”f g h ro m h1 m o o o r-H co o l
fflrno oro r- oo mo o ro HO ro O O' Offlrno oro r- oo mo o ro HO ro O O 'O
+ | om OH H +1 O+l +1 H +1 3 3 H m +1 m +i+ | about OH H +1 O + l +1 H +1 3 3 H m +1 m + i
Q) O IHQ) O IH
Dl 1/1 d d ΦDl 1/1 d d Φ
ro ro t" co in v Iro ro t «co in v I
oo ro Η Γ'- OHi ooo roo οι 'ϊ H - ^ ^ s k n ^ s 0 Γ0 < co o m oo Η'Η* ho rom mo ^ o H * + 1 r~ m ro tn H +1 o +| +1 H +1 +) ro in +i tn +i “ · H 0) 0 O O hoo ro Η Γ'- OHi ooo roo οι 'ϊ H - ^^ s k n ^ s 0 Γ0 <co o m oo Η'Η * ho rom mo ^ o H * + 1 r ~ m ro tn H +1 o + | +1 H +1 +) ro in + i tn + i “· H 0) 0 O O h
Yy\ Li M >Q fUYy \ Li M> Q fU
— dj Q) OJ +* H +> +) Η cfl M G H >i- dj Q) OJ + * H +> +) Η cfl M G H> i
0) CO (C g >1® , 0 -P H0) CO (C g> 1®, 0 -P H
q.<D+> H +1 Η Η Η Αίωο) Q, +> CO λ Λ'"' O--' >1 —» Φ 0) hg co οσ> rdtji &Di ΰσ> ii il il HH <0 Hg gg >ig -jg >t0? »2 . m r.q. <D +> H + 1 Η Η Αίωο) Q, +> CO λ Λ '"' O-- '> 1 -» Φ 0) hg co οσ> rdtji & Di ΰσ> ii il il HH <0 Hg gg > ig -jg> t0? »2. m r.
ti c- ^ cn—' K'-' fflw is iJ'-' nijwu 10 146016ti c- ^ cn— 'K'-' fflw is iJ'- 'newlyw 10 146016
Opfindelsen belyses nærmere ved følgende eksempler:The invention is further illustrated by the following examples:
Eksempel 1.Example 1.
a) 3,3'-Difluor-4,4'-dimethoxy-a-ethyl-a'-methyl-stilbena) 3,3'-Difluoro-4,4'-dimethoxy-α-ethyl-α'-methyl-stilben
En blanding af 100 g gendestilleret 2-fluoranisol og 50 g 3-chlor= pentan-2-on (kogepunkt 134 - 137°0) afkøles til -20°C, og der til= sættes dråbevis under omrøring i løbet af 2 timer 125 ml koneentre= ret svovlsyre. Efter omrøring af reaktionsblandingen i yderligere • 6 timer hældes den ud i isvand. Een resulterende blanding ekstrahe= res med diethylether, etherekstrakterne tørres, og etheren afdestil= leres, hvorefter den olieagtige remanens opvarmes i 2 timer ved 235 - 240°C og et tryk på 15 mm Hg, og et eventuelt fremkommet de= stillat kasseres. Remanensen destilleres derefter ved 160 - 170°C/0,03 mm Hg, hvorved der fås en hovedfraktion på 20 g af en olie, som ikke kan krystalliseres.A mixture of 100 g of restored 2-fluoroanisole and 50 g of 3-chloro = pentan-2-one (boiling point 134 - 137 ° 0) is cooled to -20 ° C and added dropwise with stirring over 2 hours 125 ml wife trees = quite sulfuric acid. After stirring the reaction mixture for an additional • 6 hours, it is poured into ice water. A resulting mixture is extracted with diethyl ether, the ether extracts are dried and the ether is distilled off, then the oily residue is heated for 2 hours at 235 - 240 ° C and a pressure of 15 mm Hg, and any resulting scaffold is discarded. The residue is then distilled at 160 - 170 ° C / 0.03 mm Hg to give a major fraction of 20 g of an oil which cannot be crystallized.
b> erythro-3,3'-Difluor-4,41-dimethoxy-a-ethyl-a'-methyl-dibenzylb> erythro-3,3'-Difluoro-4,41-dimethoxy-α-ethyl-α'-methyl-dibenzyl
Den under a) dannede olie opløses derefter i 150 ml iseddike, og opløsningen rystes i hydrogenatmosfære i nærværelse af 1,2 g 101's palladium/kul, indtil hydrogenoptagelsen ophører. Reaktionsblandingen filtreres og inddampes, hvorved der fås ca. 20 g af en blanding af threo- og erythro-3,3'-difluor-4,4'-dimethoxy-a-ethyl-α'-methyl-dibenzyl. Efter krystallisation af denne blanding af methanol fås erythroforbindelsen, som har et smeltepunkt på 106 - 107°C.The oil formed under (a) is then dissolved in 150 ml of glacial acetic acid and the solution is shaken in hydrogen atmosphere in the presence of 1.2 g of palladium / coal of 1.2 g until hydrogen uptake ceases. The reaction mixture is filtered and evaporated to give ca. 20 g of a mixture of threo- and erythro-3,3'-difluoro-4,4'-dimethoxy-α-ethyl-α'-methyl-dibenzyl. After crystallization of this mixture of methanol, the erythro compound having a melting point of 106 - 107 ° C is obtained.
c) erythro-3,3'-Difluor-4,4'-dihydroxy-a-ethyl-a'-methyl-dibenzylc) erythro-3,3'-Difluoro-4,4'-dihydroxy-α-ethyl-α'-methyl-dibenzyl
En opløsning af 7,5 g erythro-3,3'-difluor-4,4'-dimethoxy-a-ethyl-a ' -methyl-dibenzyl i 70 ml iseddike og 40 ml brombrinte-syre opvarmes ved tilbagesvaling i nitrogenatmosfære i 6 1/2 time. Efter afkøling hældes reaktionsblandingen ud på is, og der ekstraheres med ether. Etherekstrakterne vaskes med vand og ekstraheres med 2N natriumhydroxidopløsning. Den alkaliske ekstrakt syrnes og ekstraheres med ether. Ved inddampning 11 146015 af etherekstrakten fås 6 g af et gulligt fast stof, som opløses i benzen og føres gennem en søjle indeholdende 50 g silicagel. Med en koncentrering af eluatet udskilles erythro-3,3,-difluor-4J4,-dihy= dr oxy-oc-ethyl-ct1-methyl-dibenzyl, som har smeltepunkt 152 - 153°C.A solution of 7.5 g of erythro-3,3'-difluoro-4,4'-dimethoxy-a-ethyl-a'-methyl-dibenzyl in 70 ml of glacial acetic acid and 40 ml of hydrochloric acid is heated at reflux in nitrogen atmosphere for 6 hours. 1/2 hour. After cooling, the reaction mixture is poured onto ice and extracted with ether. The ether extracts are washed with water and extracted with 2N sodium hydroxide solution. The alkaline extract is acidified and extracted with ether. Evaporation 11 146015 of the ether extract yields 6 g of a yellowish solid which is dissolved in benzene and passed through a column containing 50 g of silica gel. With a concentration of the eluate, erythro-3,3, -difluoro-4J4, -dihydroxy-oc-ethyl-ct1-methyl-dibenzyl, which has a melting point of 152 - 153 ° C, is excreted.
Eksempel 2.Example 2.
meso-3,3'-Difluor-4,4'-dihydroxy-a,a'-dipropyl-dibenzyl a) 1-o-fluoranisyl-n-butylbromidmeso-3,3'-Difluoro-4,4'-dihydroxy-α, α'-dipropyl-dibenzyl a) 1-o-fluoroanisyl-n-butyl bromide
Oa. 70 g butyrylchlorid sættes· i løbet af 30 minutter under omrøring til en blanding af 81 g o-fluoranisol, 100 g aluminiumchlorid og 100 ml carbondisulfid. Efter yderligere omrøring i 4 timer hældes reaktionsblandingen ud i isvand, hvorpå den ekstraheres med ether. Etherekstrakten tørres over vandfrit natriumsulfat og inddampes, og remanensen omkrystalliseres af methanol, hvorved der fås o-fluor= anisylbutyrophenon.Oa. 70 g of butyryl chloride are added over 30 minutes with stirring to a mixture of 81 g of o-fluoroanisole, 100 g of aluminum chloride and 100 ml of carbon disulfide. After further stirring for 4 hours, the reaction mixture is poured into ice water and then extracted with ether. The ether extract is dried over anhydrous sodium sulfate and evaporated and the residue is recrystallized from methanol to give o-fluoro-anisylbutrophenone.
En opløsning af 4 g natriumborhydrid i 20 ml vand sættes under omrø= ring til en opløsning af ca. 40 g o-fluoranisyl-butyrophenon i 200 ml methanol, som er afkølet til 0°C. Reaktionsblandingen omrøres i 3 timer, fortyndes med vand og ekstraheres med benzen. Af benzen= ekstrakten fås 1-o-fluoranisyl-n-butanol.A solution of 4 g of sodium borohydride in 20 ml of water is added with stirring to a solution of approx. 40 g of o-fluoroanisyl-butyrophenone in 200 ml of methanol cooled to 0 ° C. The reaction mixture is stirred for 3 hours, diluted with water and extracted with benzene. From the benzene = extract is obtained 1-o-fluoroanisyl-n-butanol.
En 0,2M opløsning af 1-o-fluoranisyl-n-butanol i tørt benzen sættes til en afkølet suspension af 86 g phosphorpentabromid i 50 ml tørt ether. Efter omrøring i 1 1/2 time hældes- reaktionsblandingen ud i isvand. Det på denne måde vundne 1-o-fluoranisyl-n-butylbromid ek= straheres med benzen, og benzenopløsningen tørres grundigt .A 0.2M solution of 1-o-fluoroanisyl-n-butanol in dry benzene is added to a cooled suspension of 86 g of phosphorus pentabromide in 50 ml of dry ether. After stirring for 1 1/2 hours, the reaction mixture is poured into ice water. The 1-o-fluoroanisyl-n-butyl bromide thus obtained is extracted with benzene and the benzene solution is thoroughly dried.
b) meso-3,3'-Difluor-4,4'-dihydroxy-α,a’-dipropyl-dibenzyl.b) meso-3,3'-Difluoro-4,4'-dihydroxy-α, α'-dipropyl-dibenzyl.
Den under a) fremstillede tørrede benzenopløsning af 1-o-fluor-anisyl-n-butylbromid hældes under omrøring til en blanding af 4 g magnesium, 0,01 g iod og 20 ml tørt ether. Reaktionsblandingen koges under tilbagesvaling i 15 timer, hvorpå der hældes ud i en blanding af is og fortyndet saltsyre.The dried benzene solution of 1-o-fluoro-anisyl-n-butyl bromide prepared under a) is poured into a mixture of 4 g of magnesium, 0.01 g of iodine and 20 ml of dry ether. The reaction mixture is refluxed for 15 hours, then poured into a mixture of ice and dilute hydrochloric acid.
12 14601512 146015
Blandingen eks trail er es med ether, og etherekstrakten tørres og ind= dampes, hvorefter remanensen omkrystalliseres af chloroform/ether (kogeinterval 40 - 60°C). På denne måde fås 5,5 g meso-3,3*-di= fluor-4,4'-dime thoxy-cc, oc '-dipr opyl-dibenzyl, som har et smeltepunkt på 168 - 169°0.The mixture is extracted with ether and the ether extract is dried and evaporated and the residue is recrystallized from chloroform / ether (boiling range 40 - 60 ° C). This gives 5.5 g of meso-3,3 * -di = fluoro-4,4'-dime thoxy-cc, oc '-dipr opyl-dibenzyl, which has a melting point of 168 - 169 ° 0.
Efter demethylering af denne forbindelse med brombrintesyre i ised= dike på analog måde som beskrevet i eksempel lc fås det tilsvarende meso-3,3’-difluor-4,4’-dihydroxy-α,a’-dipropyl-dibenzyl, hvis smelte= punkt er 139 - 140°C.After demethylation of this compound with hydrochloric acid in glacial acetic acid in an analogous manner as described in Example 1c, the corresponding meso-3,3'-difluoro-4,4'-dihydroxy-α, α'-dipropyl-dibenzyl, whose melt = point is 139 - 140 ° C.
Eksempel 3.Example 3
26 g alumimiumchlorid sættes i løbet af 1 time til en omrørt blan= ding af 26 g o-fluoranisol og 12,5 g 3-chlorpentanol under nitro= genatmosfære. Reaktionsblandingen opvarmes ved 35°C i 60 timer og hældes derefter ud i isvand. Blandingen ekstraheres med ether og rystes derefter med en vandig opløsning af natriumcarbonat til fjer= nelse af uønsket surt phenolisk materiale. Ben tilbageværende ether= fase tørres og inddampes, hvorved der fås et neutralt materiale, som destilleres fraktioneret. Ben fraktion, som koger ved 165 - 175°C/0,2 mm Hg (10 g) omkrystalliseres af methanol, hvorved der fås 1,3 g ery thr o- 3,3' -difluor-4,41 -dimethoxy-cc-ethyl-a * -methyl-dibenzyl, som har smeltepunkt 106 - 107°C, og som er identisk med det ifølge eksempel Ib fremstillede produkt.26 g of aluminum chloride are added over a period of 1 hour to a stirred mixture of 26 g of o-fluoroanisole and 12.5 g of 3-chloro pentanol under a nitrogen atmosphere. The reaction mixture is heated at 35 ° C for 60 hours and then poured into ice water. The mixture is extracted with ether and then shaken with an aqueous solution of sodium carbonate to remove unwanted acidic phenolic material. Bone residual ether = phase is dried and evaporated to give a neutral material which is fractionally distilled. Bone fraction boiling at 165 - 175 ° C / 0.2 mm Hg (10 g) is recrystallized from methanol to give 1.3 g of ery thr o-3,3 '-difluoro-4,41-dimethoxy-cc -ethyl-α * -methyl-dibenzyl, having a melting point of 106 - 107 ° C, which is identical to the product of Example 1b.
Benne dimethoxyforbindelse demethyleres ved opvarmning i en blanding af 25 ml iseddike og 10 ml brombrintesyre under nitrogenatmosfære ved 140°C i 5 timer. Berefter afkøles opløsningen, og den fortyndes med vand. På denne måde fås 1,05 g erythro-3,3’-difluor-4,4,-di= hydroxy-a-ethyl-α’-methyl-dibenzyl, som efter omkrystallisation af benzen har smeltepunkt 152 - 153°0, og som er identisk med det ifølge eksempel lc fremstillede produkt.Benne dimethoxy compound is demethylated by heating in a mixture of 25 ml glacial acetic acid and 10 ml hydrochloric acid under nitrogen atmosphere at 140 ° C for 5 hours. The solution is cooled and the solution is diluted with water. This gives 1.05 g of erythro-3,3'-difluoro-4,4, -di = hydroxy-α-ethyl-α'-methyl-dibenzyl, which after recrystallization of benzene has a melting point of 152 DEG-153 DEG. and which is identical to the product of Example 1c.
Ben ikke-krys tallinske moderlud demethyleres på lignende måde. Bet vundne produkt (7,5 g) kombineres med den phenoliske fraktion (6 g, kogepunkt 180 - 190°C/0,2 mm Hg) og blandes med 13 g benzylchloridBones non-cross talline mother liquor are demethylated in a similar manner. Bet obtained product (7.5 g) is combined with the phenolic fraction (6 g, boiling point 180 - 190 ° C / 0.2 mm Hg) and mixed with 13 g benzyl chloride
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB02554/70A GB1280767A (en) | 1970-03-16 | 1970-03-16 | Derivatives of 1,2-diphenyl-ethane |
GB1255470 | 1970-03-16 |
Publications (2)
Publication Number | Publication Date |
---|---|
DK146015B true DK146015B (en) | 1983-05-24 |
DK146015C DK146015C (en) | 1983-10-24 |
Family
ID=10006781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
DK126571A DK146015C (en) | 1970-03-16 | 1971-03-16 | ANALOGY PROCEDURE FOR THE PREPARATION OF ERYTHRO OR MESO FORMS OF 3,3'-DIFLUOR-4,4'-DIHYDROXYDIBENZYL DERIVATIVES |
Country Status (18)
Country | Link |
---|---|
JP (1) | JPS515378B1 (en) |
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) |
YU (1) | YU35331B (en) |
ZA (1) | ZA71927B (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5597271U (en) * | 1978-12-28 | 1980-07-05 |
-
1970
- 1970-03-16 GB GB02554/70A patent/GB1280767A/en not_active Expired
-
1971
- 1971-02-11 NO NO504/71A patent/NO132533C/no unknown
- 1971-02-15 ZA ZA710927A patent/ZA71927B/en unknown
- 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
- 1971-03-03 YU YU531/71A patent/YU35331B/en unknown
- 1971-03-05 FI FI657/71A patent/FI55170C/en active
- 1971-03-08 CH CH332071A patent/CH558315A/en not_active IP Right Cessation
- 1971-03-09 FR FR7108077A patent/FR2085710B1/fr not_active Expired
- 1971-03-10 BE BE764081A patent/BE764081A/en not_active IP Right Cessation
- 1971-03-11 NL NL717103249A patent/NL146140B/en not_active IP Right Cessation
- 1971-03-11 AT AT209771A patent/AT303711B/en not_active IP Right Cessation
- 1971-03-15 PH PH12292A patent/PH10518A/en unknown
- 1971-03-16 DK DK126571A patent/DK146015C/en not_active IP Right Cessation
- 1971-03-16 JP JP46014646A patent/JPS515378B1/ja active Pending
- 1971-03-16 ES ES389282A patent/ES389282A1/en not_active Expired
Also Published As
Publication number | Publication date |
---|---|
DE2110428B2 (en) | 1976-08-26 |
FI55170C (en) | 1979-06-11 |
NL146140B (en) | 1975-06-16 |
CH558315A (en) | 1975-01-31 |
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 |
NO132533B (en) | 1975-08-18 |
JPS515378B1 (en) | 1976-02-19 |
YU53171A (en) | 1980-06-30 |
FR2085710B1 (en) | 1975-08-01 |
IE35009B1 (en) | 1975-10-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CH445512A (en) | Process for the production of new indole derivatives | |
FI57113B (en) | FRAMEWORK FOR THE FRAMEWORK OF THE GONA-4,9 (10) -DIENER WITH NETWORK PROTECTION | |
Fieser et al. | 20-Methyl-4-azacholanthrene | |
US1880566A (en) | Condensation product from alpha non-hydroxylated benzyl alcohol | |
DE69736945T2 (en) | BIPHENYL COMPOUNDS AND ITS APPLICATION AS ESTROGENIC AGENTS | |
Lutz et al. | Reduction studies in the morphine series. IX. Hydroxycodeinone | |
DE2607305C2 (en) | 6-Oxo-6H-indeno[5,4-b]furan-2-carboxylic acids, processes for their preparation and medicaments containing these compounds | |
DK146015B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF ERYTHRO OR MESO FORMS OF 3,3'-DIFLUOR-4,4'-DIHYDROXYDIBENZYL DERIVATIVES | |
DE1493426A1 (en) | 4'-tert-Aminoalkoxy-biphenyls substituted in the 4-position | |
PL85198B1 (en) | ||
PL101181B1 (en) | METHOD OF MAKING NEW DERIVATIVES OF TRIAMINOANDROSTANE | |
PL131227B1 (en) | Process for preparing novel derivatives of 1,1,2-triphenyl-propene | |
Kalinowski et al. | Cyclization of phenoxyacetic acid and some chlorophenoxyacetic acids | |
Dauben et al. | The preparation of 14β, 18-cyclosteroids from n-desmethyl-n (20)-conene derivatives and 18-aminosteroids | |
JPS6045191B2 (en) | new anti-fertilization agent | |
GB1561153A (en) | Process for the preparation of thiochroman derivatives | |
Haller | Rotenone. XXV. The Synthesis of Tetrahydrotubanol and Tetrahydrotubaic Acid | |
Clemo et al. | 40. Experiments on the synthesis of aza-steroids. Part I | |
Barnes et al. | 547. The synthesis of thyroxine and related substances. Part VII. The preparation of diphenyl ethers from 2: 6-di-iodophenols | |
DE581331C (en) | Process for the preparation of 1-phenyl-2-alkylaminopropan-1-ols hydroxylated in the phenyl nucleus | |
CZ355498A3 (en) | Derivatives of polyhydroxyphenol and medicaments containing thereof for prevention and therapy of bone and cartilage diseases | |
Fisher et al. | THE HALOFORM REACTION. VI. ALPHA-HALOGEN DERIVATIVES OF HINDERED KETONES | |
Hinegardner et al. | NEW PHENOLIC COMBINATIONS OBTAINED BY COUPLING CHAULMOOGRIC ACID WITH RESORCINOL1 | |
US2528000A (en) | Process of preparing 2-cyano-1-keto-7-r-1,2,3,4-tetrahydrophe-nanthrenes, and products of such process | |
Fujimoto et al. | An Intermediate in the Grignard Reaction |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PBP | Patent lapsed |