DK156642B - ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES Download PDFInfo
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Description
DK 156642 BDK 156642 B
Den foreliggende opfindelse angàr en analogifremgangsmâde til frem-stilling af hidtil ukendte naphthalenderivater af den i krav l's indledning angivne art.The present invention relates to an analogous process for the preparation of novel naphthalene derivatives of the kind set forth in claim 1.
Visse naphthalenderivater vides at hâve værdifuld antiinflammatorisk 5 virkning og at være egnede til anvendelse i behandlingen af forskel-lige rheumatiske og arthritiske tilstande. Et særlig effektivt naph-thalenderivat, som har fundet klinisk anvendelse, er naproxen (Napro-syn®), som har formlen ICertain naphthalene derivatives are known to have valuable anti-inflammatory action and to be suitable for use in the treatment of various rheumatic and arthritic conditions. A particularly effective naphthalene derivative which has found clinical use is naproxen (Napro-syn®), which has the formula I
C02H ICOH 2 I
ch3o 10 Denne forbindelse og visse beslægtede forbindelser er beskrevet i de britiske patentskrifter nr. 1,271,132, 1,274,271, 1,274,272, 1,274,273, 1,291,386, 1,211,134, 1,297,306, 1,276,261, 1,216,882, 1,289,041, 1,321,347 og 1,296,493. Denne farmakologiske virkning af sâdanne forbindelser er ogsâ beskrevet i J. Med. Chem., 13, 203 15 (1970) og J. Pharm. Exp. Thera., 179, 114 (1971).This compound and certain related compounds are disclosed in British Patent Nos. 1,271,132, 1,274,271, 1,274,272, 1,274,273, 1,291,386, 1,211,134, 1,297,306, 1,276,261, 1,216,882, 1,289,041, 1,321,347 and 1,291,347. This pharmacological effect of such compounds is also described in J. Med. Chem., 13, 203 (1970) and J. Pharm. Exp. Thera., 179, 114 (1971).
Beslægtede forbindelser med antiinflammatorisk virkning er de i norsk fremlæggelsesskrift nr. 125.971 beskrevne forbindelserRelated compounds with anti-inflammatory effect are the compounds described in Norwegian publication no. 125,971
CH .JCH .J
l 3 i Z1 2l 3 in Z1 2
ZZ
(hvor ί)- er hydroxy eller acetoxy, og er CH3O, CH3 eller CH3S) og de i beskrivelsen til dansk patentansagning nr. 1861/70 beskrevne 20 forbindelser ch3(where ί) - is hydroxy or acetoxy, and is CH 3 O, CH 3 or CH 3 S) and the compounds described in Danish Patent Application No. 1861/70 described in the description
DK 156642BDK 156642B
2 (hvor Z betegner methyl, ethyl, isopropyl, cyclopropyl, trifluormeth-yl, vinyl, ethynyl, fluor, chlor, methoxy, methoxymethyloxy, difluor-methoxy, methylthio, methoxymethylthio eller difluormethylthio).2 (where Z represents methyl, ethyl, isopropyl, cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoro-methoxy, methylthio, methoxymethylthio or difluoromethylthio).
Uheldigvis kan forblndelsen med formlen I fremkalde alvorlig irrita-5 tion i fordejelseskanalen hos nogle patienter ved doser, som ikke i særlig grad overskrider den terapeutiske dosis.Unfortunately, the blending of the formula I can cause severe irritation in the alimentary canal in some patients at doses that do not greatly exceed the therapeutic dose.
Det har nu vist sig, at andre naphthalenderivater har god antiinflam-matorisk virkning, samtidig med at de har forbedrede terapeutiske forhold med hensyn til gastro-intestinal irritation. Det er sàdanne 10 forbindelser, som har den almene formel IIIt has now been found that other naphthalene derivatives have good anti-inflammatory effect, while also providing improved therapeutic conditions for gastrointestinal irritation. There are 10 such compounds having the general formula II
) rrrrr: CH-CO-CH3 | il hvor X betegner chlor, brom, methoxy eller alkyl med 1-4 carbonato-mer, R^· betegner hydrogen eller methyl, og den stiplede Unie betegner en yderligere binding eller hydrogen pâ hver af de forbundne 15 carbonatomer.) rrrrr: CH-CO-CH3 | wherein X represents chloro, bromo, methoxy or alkyl of 1-4 carbon atoms, R 2 represents hydrogen or methyl, and the dotted union represents an additional bond or hydrogen on each of the 15 carbon atoms connected.
I sàdanne forbindelser er X især en methoxygruppe.In such compounds, X is especially a methoxy group.
I sàdanne forbindelser er R·^ hensigtsmæssigt hydrogen.In such compounds, R 6 is suitably hydrogen.
Sâledes er særlig velegnede forbindelser med formlen II sàdanne, som har den almene formel IIIThus, particularly suitable compounds of formula II are those having the general formula III
(R1)-.-.----CH- CO-CH,(R1) -.-.---- CH- CO-CH,
20 1^.1 Λ III20 1 ^ .1 Λ III
CH3(5 hvor R^ og den stiplede Unie har den i forbindelse med formlen II anferte betydning.CH 3 (5 where R 1 and the dotted union have the meaning given in the formula II).
33
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Af det foregâende kan udledes, at foretrukne grupper af forbindelser, som ligger inden for den almene formel III, er sâdanne, soin har de almene formlen IV og VFrom the foregoing it can be deduced that preferred groups of compounds which are within the general formula III are such that the general formulas IV and V have
.CH (R1) -CH^-CO-CH, ΟΓΤ ch3o ) =CH-CO-CH3.CH (R1) -CH2 -CO-CH, ΟΓΤ ch3o) = CH-CO-CH3
5 V5 V
ch3o hvor R·*· betegner hydrogen eller methyl.wherein Ro is hydrogen or methyl.
Forbindelser med formlen II, hvor R·*· ikke er hydrogen, har tendens til at hâve estrogene virkninger ved store doser, hvorimod sâdanne, hvor R·*· er hydrogen, er mindre tilbojelige til at vise sâdanne virk-10 ninger. Foretrukne forbindelser er 4-(6'-methoxy-2'-naphthyl)butan-2-on og 4-(6'-methoxy-2'-naphthyl)but-3-en-2-on.Compounds of formula II, where R · * · is not hydrogen, tend to have estrogenic effects at high doses, whereas those where R · * · is hydrogen are less likely to exhibit such effects. Preferred compounds are 4- (6'-methoxy-2'-naphthyl) butan-2-one and 4- (6'-methoxy-2'-naphthyl) but-3-en-2-one.
De to anforte forbindelser og analoge dertil, i hvilke a-carbonatomet bærer en methylsubstituent, har udpræget antiinflammatorisk virkning, 15 nâr de afproves i en dosis pâ 100 mg/kg/dag ved den rotte-caragee-nin-antiinflammatoriske test, men irritérer ikke maven ved en tre gange sâ stor dosis.The two compounds and analogs thereto, in which the α-carbon atom carries a methyl substituent, exhibit anti-inflammatory action when tested at a dose of 100 mg / kg / day by the rat carrageenan anti-inflammatory test, but do not irritate the stomach at a dose three times the size.
4-(6'-methoxy-2'-naphthyl)butan-2-on (A) og 4-(6'-methoxy-2'-naph-thyl)but-3-en-2-on (B) har et gunstigere terapeutisk forhold (antiin-20 flammatorisk virkning i forhold til gastrisk irritation) end napro-xen. Den antiinflammatoriske virkning (Π^) blev ved grafisk af-læsning bestemt som en dosis, der fremkaldte 25% inhibering, medens gastrisk irritation (GTD,.^) blev bestemt ved den af Hitchens, J. T. et al., Pharmacologists, 9, 1969, s. 242, angivne metode. Resultater-25 ne er udtrykt som terapeutisk forhold.4- (6'-methoxy-2'-naphthyl) butan-2-one (A) and 4- (6'-methoxy-2'-naphthyl) but-3-en-2-one (B) have a more favorable therapeutic ratio (antiinflammatory action against gastric irritation) than naproxen. The anti-inflammatory effect (ΠΠ) was determined by graphical reading as a dose that caused 25% inhibition, while gastric irritation (GTD, ^ ^) was determined by that of Hitchens, JT et al., Pharmacologists, 9, 1969 , page 242, method indicated. The results are expressed as therapeutic relationship.
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... ___ 4_______... ___ 4_______
Naproxen A BNaproxen A B
GTD50 _ 1,95 >18,18 >23,4 5 ID25GTD50 _ 1.95> 18.18> 23.4 ID25
Ved afpravning af 4-(6'-methoxy-2'-naphthyl)butan-2-on (A) og 4-(6'-chlor-2'-naphthyl)butan-2-on (C) i et forsag med carageenin- indu-ceret adem (antiinflaimiiatorisk virkning) og med gastrisk irritation 10 pà rotter, der havde fastet natten over, blev der opnàet nedenstâende resultater udtrykt som heriholdsvis (mg/kg, pérorait) og GTD^q (mg/kg, pérorait), hvorhos GTD^Q-værdien blev beregnet ved Litchfield og Wilcoxans metode. Resultaterne er sammenlignet med de med naproxen opnâede resultater.By testing 4- (6'-methoxy-2'-naphthyl) butan-2-one (A) and 4- (6'-chloro-2'-naphthyl) butan-2-one (C) in a test with carrageenin-induced breath (anti-inflammatory effect) and with gastric irritation 10 in rats who had fasted overnight, the following results expressed as respectively (mg / kg, perorhea) and GTD ^ q (mg / kg, perorhea) were obtained. , where the GTD ^ Q value was calculated by Litchfield and Wilcoxan's method. The results are compared with the results obtained with naproxen.
15 Antiinflammato- Gastrisk irrita- GTD,.q risk virkning, tation, GID^ _15 Anti-inflammatory Gastric irritation GTD, risk effect, tation, GID
Forbindelse ED^q ED^q A 12,0 255 21,25 20 C 35,0 172 4,9Compound ED ^ q ED₂ q A 12.0 255 21.25 20 C 35.0 172 4.9
Naproxen 2,5 7,0 2,8Naproxen 2.5 7.0 2.8
Den ovènfor nævnte forbindelse (A) (Nabumetone) og det nærmest lig-gende aldehyd, 2-(6'-methoxy-2'-naphthyl)propanai, er blevet sammen-25 lignet direkte, dels for antiinflammatorisk virkning mod carrageenin-induceret adem pâ rottepoter og dels for gastrisk irritation.The above-mentioned compound (A) (Nabumetone) and the closely related aldehyde, 2- (6'-methoxy-2'-naphthyl) propanai, have been compared directly, partly for anti-inflammatory action against carrageenin-induced breath. on rat paws and partly for gastric irritation.
Ved carrageenin-forsaget fik rotterne 0,5% carrageenin i saltvand injiceret i hajre bagpote, og det derved fremkaldte adem blev mâlt 3 timer senere. Bortset fra kontroldyrene fik rotterne pérorait admini-30 streret testforbindelserne i forskellige doser i 0,7% methylcellulo-se, som det fremgâr af nedenstâende tabel, hvor det fremkaldte adem og den af testforbindelserne bevirkede irihibering er angivet.At the carrageenin test, the rats were injected with 0.5% carrageenin in saline in the hind paw, and the resulting breath was measured 3 hours later. Except for the control animals, the rats were administered the test compounds at various doses in 0.7% methylcellulose, as shown in the table below, indicating the induced breath and the irradiation induced by the test compounds.
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5 0dem fremkaldt af carrageenin 0dem ± s.e. % Inhibering A) Methylcellulose 58,6 ± 2,7 5 B) Nabumetone 45 mg/kg 35,6 ± 1,4 39 C) " 15 mg/kg 42,8 ± 3,8 27 D) " 5 mg/kg 55,8 ± 2,2 5 *** 10 E) Aldehyd 18 mg/kg 32,7+2,7 44 *** F) " 6 mg/kg 40,6 ± 2,9 31 G) " 2 mg/kg 51,4 ± 2,9 12 (n=8) **) p < 0,01 15 ***) p < 0,0015 0em induced by carrageenin 0dem ± s.e. % Inhibition A) Methyl cellulose 58.6 ± 2.7 B) Nabumetone 45 mg / kg 35.6 ± 1.4 39 C) "15 mg / kg 42.8 ± 3.8 27 D)" 5 mg / kg 55.8 ± 2.2 5 *** 10 E) Aldehyde 18 mg / kg 32.7 + 2.7 44 *** F) "6 mg / kg 40.6 ± 2.9 31 G)" 2 mg / kg 51.4 ± 2.9 12 (n = 8) **) p <0.01 15 ***) p <0.001
Nabumetone = 16,0 mg/kgNabumetone = 16.0 mg / kg
Aldehyd = 4,5 mg/kgAldehyde = 4.5 mg / kg
Styrkeforhold = 3,7Strength ratio = 3.7
Til bedommelse af den gastriske irritation blev rotterne sultet i 18 20 timer for testen. Forbindelserne blev indgivet oralt. 4 timer senere blev dyrene dræbt, og mavesækken blev vasket med 0,9% saltvand og spændt ud. Blodende erosioner i slimhinden blev bedomt ved en skala, hvis værdier var proportionale med dét eroderede areal. De admini-strerede mængder og de mâlte værdier fremgàr af nedenstâende tabel.To assess the gastric irritation, the rats were starved for 18 hours for the test. The compounds were administered orally. Four hours later, the animals were killed and the stomach was washed with 0.9% saline and stretched out. Bleeding erosions in the mucosa were assessed on a scale proportional to the eroded area. The quantities administered and the values measured are shown in the table below.
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Gastrisk irritationGastric irritation
Andel af rotteme Gennemsnits- med gastriske points for érosion 5 erosionerPercentage of rats Average with gastric points for erosion 5 erosions
Nabumetone 320 mg/kg 2/8 0,4 " 160 " 1/8 0,1 " 80 " 0/8 0Nabumetone 320 mg / kg 2/8 0.4 "160" 1/8 0.1 "80" 0/8 0
Aldehyd 80 " 5/8 2,3 10 " 40 " 4/8 1,8 " 20 » 3/8 1,3Aldehyde 80 "5/8 2.3 10" 40 "4/8 1.8" 20 »3/8 1.3
Methylcellulose - 0/6 0Methyl cellulose - 0/6 0
Det fremgâr af ovenstâende resultater, at aldehydet i en mængde pâ 20 mg/kg virker kraftigere irriterende end Nabumetone i en mængde pâ 320 15 mg/kg (styrkeforhold > 16).It is clear from the above results that the aldehyde in an amount of 20 mg / kg seems more irritating than Nabumetone in an amount of 320 15 mg / kg (potency ratio> 16).
Det kan af de to ovenfor beskrevne sammenligningsforsog konkluderes, at Nabumetone har et klart bedre terapeutisk forhold end den nærmest-liggende, kendte forbindelse.It can be concluded from the two comparative experiments described above that Nabumetone has a clearly better therapeutic relationship than the nearest known compound.
Forbindelseme med formleme II-V kan formuleres til antiinflammato-20 riske og/eller analgetiske præparater, som er egnede til oral administration til mennesker. Sâdanne præparater kan foreligge i en hvilken som helst sædvanlig form, fx som tabletter eller kapsler.The compounds of Formulas II-V may be formulated for anti-inflammatory and / or analgesic preparations suitable for oral administration to humans. Such preparations may be in any conventional form, for example as tablets or capsules.
Forbindelseme med formlen II er hidtil ukendte, og fremgangsmâden til fremstilling deraf er ejendommelig ved, atThe compounds of formula II are novel and the process for their preparation is characterized in that:
25 a) forbindelser med den almene formel VI(A) compounds of general formula VI
AVOUCH
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77
Unie har den ovenfor angivne betydning, omsættes med et methylme-talderivat med den almene formel VIIUnion has the meaning given above, is reacted with a methyl metal derivative of the general formula VII
CH3-Y2 VIICH3-Y2 VII
hvor Y2 er et métal, eller med LiCu( (^3)2, ellerwhere Y2 is a metal, or with LiCu ((^ 3) 2, or
5 b) til fremstilling af forbindelser med formlen II, hvor dobbelt-bindingen ikke forekommer, og hvor R-*- er hydrogen, forbindelser med den almene formel IXB) for the preparation of compounds of formula II where the double bond is absent and where R - * - is hydrogen, compounds of general formula IX
/CH=CH-CO-CH3 /OC· X ^/ CH = CH-CO-CH3 / OC · X ^
hvor X har den ovenfor angivne betydning, reduceres, eller 10 c) forbindelser med den almene formel Xwhere X has the meaning given above, or c) compounds of the general formula X are reduced
/CR I 3/ CR I 3
Γ Π CO„HΠ Π CO „H
AJUAJU
hvor X, R^- og den stiplede Unie har den ovenfor anforte betydning, eller et sait deraf decarboxyleres, ellerwherein X, R 2 and the dotted union have the meaning given above, or a site thereof is decarboxylated, or
d) til fremstilling af forbindelser med formlen II, hvor dobbelt-15 bindingen ikke forekommer, forbindelser med den almene formel XIIId) for the preparation of compounds of formula II where the double bond is absent, compounds of general formula XIII
1 31 3
^CHR-Y^ CHR-Y
!</ Νγ XIII! </ Νγ XIII
XX
hvor Y3 betegner en udskiftelig enhed, især chlor, brom eller iod, og X og r! har den ovenfor anforte betydning, omsættes med en anion, der er afledt af acetylacetone, ellerwhere Y3 represents a replaceable unit, especially chlorine, bromine or iodine, and X and r! has the above meaning, reacted with an anion derived from acetylacetone, or
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88
e) forbindelser med den almene formel XVe) compounds of general formula XV
hvor X, R^· og den stiplede linje har den ovenfor anfarte betydning, oxideres, ellerwherein X, R 2 and the dotted line have the meaning set forth above, oxidized, or
5 f) til fremstilling af forbindelser med formlen II, hvor X betegner OCH3, forbindelser med den almene formel XVIF) for the preparation of compounds of formula II wherein X represents OCH3, compounds of general formula XVI
/ CR] -"^rrr:CH-CO-CH., 3 xvi hvor R·*- og den stiplede linie har den ovenfor anfarte betydning, methyleres, eller 10 g) til fremstilling af forbindelser med formlen II, hvor dobbelt-/ CR] -Rrr: CH-CO-CH., 3 xvi where R R and the dotted line have the meaning given above, are methylated, or 10 g) to prepare compounds of formula II wherein
bindingen forekommer, og R^· er hydrogen, forbindelser med den almene formel XVIIthe bond occurs and R 1 is hydrogen, compounds of general formula XVII
hvor X har den ovenfor anfarte betydning, omsættes med et Wittig-15 reagens med formlen Q=CH-C0-CH3 hvor Q betegner et trisubstitueret phosphoratom, ellerwherein X is as defined above, is reacted with a Wittig reagent of the formula Q = CH-CO-CH 3 wherein Q represents a trisubstituted phosphorus atom, or
h) til fremstilling af forbindelser med formlen II, hvor dobbelt-bindingen forekommer, og R·*· er hydrogen, forbindelser med den almene 20 formel XVIIIh) for the preparation of compounds of formula II wherein the double bond occurs and R R is hydrogen, compounds of general formula XVIII
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9 CH (OH) -CH2-CO-CH3 XVI11 hvor X har den ovenfor anforte betydning, dehydratiseres.9 CH (OH) -CH2-CO-CH3 XVI11 where X has the meaning given above is dehydrated.
Med hensyn til fremgangsniâdevariant a) :With regard to progress variant (a):
Den sædvanlige og foretrukne forbindelse med formlen VII er methyl-5 lithium, LiCHg.The usual and preferred compound of formula VII is methyl-lithium, LiCHg.
Som det er almindeligt ved kædeforlængelsesreaktioner, hvor der anvendes alkylmetalderivater, udfores omsætningen fortrinsvis i et inert, aprot oplosningsmiddel ved lav temperatur og fortrinsvis under en inert atmosfære. Fx kan omsætningen udfores ved en temperatur pâ 10 under- 40°C i ter diethylether.As is common in chain extension reactions using alkyl metal derivatives, the reaction is preferably carried out in an inert, aprotic solvent at low temperature and preferably under an inert atmosphere. For example, the reaction may be carried out at a temperature of 10 below 40 ° C in diethyl ether.
Normalt sættes cuproiodid til reaktionsblandingen, sâledes at det pâgældende alkyleringsmiddel er LiCu(CH3)2·Normally, cuprous iodide is added to the reaction mixture so that the alkylating agent in question is LiCu (CH3) 2 ·
Med hensyn til fremgangsmâdevariant b):With regard to method variant (b):
Reduktionen kan udfores ved hydrogenering i nærværelse af en over-15 gangsmetalkatalysator sâsom palladium/kul. Omsætningen kan udfores ved en hvilken som helst passende ikke-ekstrem temperatur, men der foretrækkes stuetemperatur. Omsætningen udfores normalt i et inert organisk oplosningsmiddel sâsom ethylacetat eller éthanol under anvendelse af atmosfæretryk eller et let overtryk af hydrogen.The reduction can be carried out by hydrogenation in the presence of a transition metal catalyst such as palladium / coal. The reaction may be carried out at any suitable non-extreme temperature, but room temperature is preferred. The reaction is usually carried out in an inert organic solvent such as ethyl acetate or ethanol using atmospheric pressure or a slight overpressure of hydrogen.
20 Reduktion med et complext metalhydrid sâsom LiAlH^ under sædvanlige reaktionsbetingelser for olefinisk reduktion af en α-β-umættet keton kan ogsâ anvendes, men er undertiden mindre foretrukken, da reduktion af carbonylgruppen kan fore til uonskede produkter.Reduction with a complex metal hydride such as LiAlH ^ under usual reaction conditions for olefinic reduction of an α-β-unsaturated ketone can also be used, but is sometimes less preferred since reduction of the carbonyl group can lead to undesired products.
Med hensyn til fremgangsmâdevariant c): 25 Decarboxylering kan udfores pâ sædvanlig mâde for /3-ketosyrer, fx ved opvarmning, eventuelt i et surt miljo.With respect to process variant c): Decarboxylation can be carried out in the usual way for β-keto acids, for example by heating, optionally in an acidic environment.
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Syrer med formlen X er hidtil ukendte og kan freins tilles ved hydrolyse af deres ethylestere, som pâ deres side kan fremstilles ved omsætning af forbindelsen med formlen XIXAcids of formula X are novel and can be freely added by hydrolysis of their ethyl esters, which in turn can be prepared by reacting the compound of formula XIX
CH3.C0.CHNa.C02Et XIXCH3.C0.CHNa.C02Et XIX
5 med forbindelser med den almene formel XIII5 having compounds of general formula XIII
1 31 3
.. .CHR-Y.. .CHR-Y
J XIIIJ XIII
hvor Y3 betegner en udskiftelig erihed, og X og bA har den ovenfor anfarte betydning eller med forbindelser med den almene formel XXwherein Y3 represents a replaceable purity and X and bA are as defined above or with compounds of general formula XX
R1R1
XXXX
XX
10 hvor X og R^· har den ovenfor anfarte betydning, efterfulgt af dehy-dratisering. Sâdanne omsætninger foregâr under sædvanlige betingel-ser.10 where X and R 2 are as defined above, followed by dehydration. Such turnover takes place under usual conditions.
Med hensyn til fremgangsmâdevariant d):With regard to method variant d):
Dannelsen af en anion, der er afledt af acetylacetone, kan finde sted 15 far indfaringen af forbindelser med formlen XIII eller in situ.The formation of an anion derived from acetylacetone can take place prior to the introduction of compounds of formula XIII or in situ.
Omsætningen udfares normalt i et aprot oplasningsmiddel sâsom ethyla-cetat. Aile ikke-ekstreme temperaturer kan anvendes, men generelt foretrækkes stuetemperatur eller fofhajet temperatur, fx temperaturer pâ mellem 20 og 120eC. Omsætningen kan kræve lang tid til at fuld-20 endes. Hvis anionen darmes in situ, skal der være mindst ét ækviva-lent af en ifcke-nucleofil base til stede, fx natriumhydrid, natrium-carbonat eller kaliumcarbonat.The reaction is usually carried out in an aprotic solvent such as ethyl acetate. All non-extreme temperatures can be used, but generally room temperature or preheated temperature is preferred, for example temperatures between 20 and 120 ° C. Turnover can take a long time to complete 20. If the anion is depleted in situ, at least one equivalent of a non-nucleophilic base must be present, e.g., sodium hydride, sodium carbonate or potassium carbonate.
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1111
Med hensyn til fremgangsmâdevariant e):With regard to method variant (e):
Generelt kan der anvendes en hvilken son helst sædvanlig mild oxida-tiv metode, som vides at oxidere sekundære alkoholer til dannelse af ketoner. Sâdanne reaktioner foretages under sædvanlige betingelser.In general, any usual mild oxidative method known to oxidize secondary alcohols to form ketones can be used. Such reactions are carried out under usual conditions.
5 Med hensyn til fremgangsmâdevariant f):5 With respect to method variant f):
Omsætning af forbindelser med formlen XVI med methyleringsmidler foregàr fortrinsvis under sædvanlige betingelser. Egnede methyleringsmidler er fx methylbromid, methyliodid, dimethylsulfat, methyl-methansulfonat, methyl-p-toluensulfonat og diazomethan. Undtagen til 10 omsætning med diazomethan foreligger forbindelsen med formlen XVI fortrinsvis i form af anionen, eller der er mindst ét ækvivalent af en ikke-nucleofil base til stede. Sâdanne omsætninger kan generelt finde sted under betingelser, hvorved phénol omdannes til anisol.Reaction of compounds of formula XVI with methylating agents is preferably carried out under usual conditions. Suitable methylating agents are, for example, methyl bromide, methyl iodide, dimethyl sulfate, methyl methanesulfonate, methyl p-toluenesulfonate and diazomethane. Except for reaction with diazomethane, the compound of formula XVI is preferably in the form of the anion or at least one equivalent of a non-nucleophilic base is present. Such reactions can generally take place under conditions whereby phenol is converted to anisole.
Med hensyn til fremgangsmâdevariant g): 15 Sâdanne omsætninger finder normalt sted i et inert organisk oples-ningsmiddel. Egnede grupper Q, som almindeligvis giver acceptable udbytter, er (Cgl^^P, (0113)3? og (02115)3?. Disse omsætninger kan være utilfredsstillende.With respect to process variant (g): 15 Such reactions usually take place in an inert organic solvent. Suitable groups Q, which generally provide acceptable yields, are (Cgl 3 P, (0113) 3? And (02115) 3 ?. These reactions may be unsatisfactory.
Med hensyn til fremgangsmâdevariant h): 20 Udgangsforbindelsen med formlen XVIII kan fremstilles ved omsætning af en forbindelse med formlen XVII med acetone i alkalisk milje, og dehydratiseringen af den dannede forbindelse finder sted spontant, fx under indflydelse af varme eller en dehydratiseringskatalysator sâsom en syre. Sâdanne omsætninger gâr meget let.With respect to process variant h): The starting compound of formula XVIII can be prepared by reacting a compound of formula XVII with acetone in alkaline environment and the dehydration of the compound formed occurs spontaneously, for example under the influence of heat or a dehydration catalyst such as an acid. Such turnovers are very easy.
25 Fremgangsmâden ifolge opfindelsen belyses nærmere ved nedenstâende eksempler, idet fremstillingen af nogle udgangsmaterialer er beskre-vet i eksempel 1-4.The process of the invention is illustrated in more detail by the following examples, the preparation of some starting materials being described in Examples 1-4.
Ethyl-3-(6'-methoxy-2'-naphthyl)-2 -butenoat 12 EKSEMPEL 1Ethyl 3- (6'-methoxy-2'-naphthyl) -2-bututenate EXAMPLE 1
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10,8 g natriumhydrid (60%'s dispersion i mineralolie) vaskes tre gange med cyclohexan og blæses tort med en nitrogenstrom. 150 ml tort 5 1,2-dimethoxyethan tilsættes, og opslæmningen omrores ved stuetem-peratur. 54 g triethylphosphonoacetat tilsættes drâbevis, og blandin-gen omreres ved stuetemperatur i 1 time under nitrogenatmosfære. En oplosning af 30 g 2-acetyl-6-methoxynaphthalen i 300 ml 1,2-dimeth-oxyetban lades lobe til, og oplosningen koges under tilbagesvaling 10 natten over under nitrogenatmosfære.10.8 g of sodium hydride (60% dispersion in mineral oil) is washed three times with cyclohexane and inflated with a nitrogen stream. 150 ml of tort 5 1,2-dimethoxyethane are added and the slurry is stirred at room temperature. 54 g of triethylphosphonoacetate are added dropwise and the mixture is stirred at room temperature for 1 hour under a nitrogen atmosphere. A solution of 30 g of 2-acetyl-6-methoxynaphthalene in 300 ml of 1,2-dimethoxyethane is added to the lobe and the solution is refluxed overnight under a nitrogen atmosphere.
Reaktionsblandingen fortyndes med vand, syrnes og ekstraheres med ether. Etherfasen vaskes med natriumcarbonatoplesning og med vand, terres over vandfrit magnesiumsulfat og inddampes, hvorved der fâs ethyl-3-(6'-methoxy-2'-naphthyl)-2-butenoat i form af et gult fast 15 stof i kvantitativt udbytte. Produktet vises ved NMR-spektrometri at være overvejende trans-isomeren.The reaction mixture is diluted with water, acidified and extracted with ether. The ether phase is washed with sodium carbonate solution and with water, triturated over anhydrous magnesium sulfate and evaporated to give ethyl 3- (6'-methoxy-2'-naphthyl) -2-butenoate in the form of a yellow solid in quantitative yield. The product is shown by NMR spectrometry to be predominantly the trans isomer.
NMR-Spektrum: Trans-vinylisk proton 3,69r, cis-vinylisk proton 4,0r.NMR Spectrum: Trans-vinylic proton 3.69r, cis-vinylic proton 4.0r.
-CO2CH2GH3: Triplet (3 protoner) ved 8,62r, 20 J = 11,5 cps.-CO2CH2GH3: Triplet (3 protons) at 8.62r, 20 J = 11.5 cps.
kvart (2 protoner) ved 5,71τ, J = 11,5 cps.quart (2 protons) at 5.71τ, J = 11.5 cps.
-CH3: To toppe meget tæt ved hinanden ved -7,28r, svarende til i ait 3 protoner.-CH3: Two peaks very close to each other at -7.28r, corresponding to ait 3 protons.
25 IR-Spektrum: Garbonylabsorption ved 1708 cm-^-.IR Spectrum: Garbonyl absorption at 1708 cm -1.
EKSEMPEL 2EXAMPLE 2
Ethyl-3-(6'-methoxy-2'-naphthyl )butyrat 24 g ethyl-3-(6'.-methoxy-2'-naphthyl)-2-butenoat optages i 100 ml __ ethylacetat, og der tilsættes 2,4 g 10%'s palladium/kul. Blandingen 30 hydrogeneres ved stuetemperatur og et tryk pâ 3,5 kg/cm^ i to timer.Ethyl 3- (6'-methoxy-2'-naphthyl) butyrate 24 g of ethyl 3- (6'-methoxy-2'-naphthyl) -2-butenoate is taken up in 100 ml of ethyl acetate and 2 is added. 4 g of 10% palladium / coal. The mixture is hydrogenated at room temperature and a pressure of 3.5 kg / cm 2 for two hours.
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Katalysatoren fjernes ved filtrering, og filtratet inddampes, hvorved der fâs ethyl-3-(6'-methoxy-2'-naphthyl)butyrat i form af et farve-lest fast stof i kvantitativt udbytte.The catalyst is removed by filtration and the filtrate is evaporated to give ethyl 3- (6'-methoxy-2'-naphthyl) butyrate in the form of a colorless solid in quantitative yield.
IR-Spektrum: Mættet estercarbonylabsorption ved 1730 cm"^·.IR Spectrum: Saturated ester carbonyl absorption at 1730 cm "·.
5 NMR-Spektrum: CH3-CH: 3 proton dublet ved 8,68r, J = 11 cps.5 NMR Spectrum: CH3-CH: 3 proton doubled at 8.68r, J = 11 cps.
Fravær af vinyliske protoner.Absence of vinylic protons.
EKSEMPEL 3 3 - (6 '-Methoxy-2'-naphthyl)smorsyre 10 14,4 g ethyl-3-(6'-methoxy-2'-naphthyl)butyrat optages i 300 ml methanol og 150 ml 10%'s natriumhydroxidopl0sning, og blandingen koges under tilbagesvaling i 2 timer. Reaktionsblandingen fortyndes med vand og ekstraheres med ethylacetat. Den vandige fase syrnes og ekstraheres med ethylacetat. Den sure ekstrakt vaskes med vand, 15 terres over vandfrit magnesiumsulfat og Inddampes, hvorved der fâs 11,9 g (92% af det teoretiske) 3-(6'-methoxy-2'-naphthyl)smorsyre i form af et hvidt fast stof med smeltepunkt 126-129“C.EXAMPLE 3 3- (6'-Methoxy-2'-naphthyl) butyrate 14.4 g of ethyl 3- (6'-methoxy-2'-naphthyl) butyrate is taken up in 300 ml of methanol and 150 ml of 10% sodium hydroxide solution. , and the mixture is refluxed for 2 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The aqueous phase is acidified and extracted with ethyl acetate. The acidic extract is washed with water, quenched over anhydrous magnesium sulfate and evaporated to give 11.9 g (92% of theory) of 3- (6'-methoxy-2'-naphthyl) formic acid as a white solid mp 126-129 ° C.
IR-Spektrum: Carbonylabsorption ved 1700 cnT^-.IR Spectrum: Carbonyl absorption at 1700 cnT
EKSEMPEL 4 20 Trans-3-(6'-methoxy-2'-naphthyl)crotonsyre 27,4 g ethyl-trans-3-(6'-methoxy-2'-naphthyl)-2-butenoat optages i 600 ml methanol og 300 ml 10%'s natriumhydroxidoplesning, og blandingen koges under tilbagesvaling i 2 timer. Natriumsaltet af det enskede syreprodukt udkrystalliserer og frafiltreres. Filtratet 25 ekstraheres med ethylacetat, og den vandige fase fraskilles.EXAMPLE 4 Trans-3- (6'-methoxy-2'-naphthyl) crotonic acid 27.4 g of ethyl trans-3- (6'-methoxy-2'-naphthyl) -2-butenoate are taken up in 600 ml of methanol and 300 ml of 10% sodium hydroxide solution and the mixture is refluxed for 2 hours. The sodium salt of the single acid product crystallizes and is filtered off. The filtrate 25 is extracted with ethyl acetate and the aqueous phase is separated.
- - - 14- - - 14
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Natriumsaltet af syren suspenderes i den vandige fase, og blandingen symes. Der tilsættes ethylacetat, og blandingen opvarmes, indtil ait det faste stof er oplest. Ethylacetatfasen fraskilles, vaskes med vand, terres over vandfrit magnesiumsulfat og inddampes, hvorved der 5 fâs 20,7 g af et lysegult fast stof. Produktet omkrystalliseres af ethylacetat, hvorved der fâs 15,9 g (67,8% af det teoretiske) trans- 3- (6'- methoxy-2'-naphthyl)crotonsyre i form af et farvelest fast stof med smeltepunkt 195-204°C.The sodium salt of the acid is suspended in the aqueous phase and the mixture is simmered. Ethyl acetate is added and the mixture is heated until the solid is dissolved. The ethyl acetate phase is separated, washed with water, triturated over anhydrous magnesium sulfate and evaporated to give 5 g of 20.7 g of a pale yellow solid. The product is recrystallized from ethyl acetate to give 15.9 g (67.8% of theory) of trans 3- (6'-methoxy-2'-naphthyl) crotonic acid in the form of a colorless solid, m.p. 195-204 °. C.
IR-Spektrum (Nujol): Carbonylabsorption ved 1680 cm"·*-.IR Spectrum (Nujol): Carbonyl absorption at 1680 cm
10 EKSEMPEL 5 4- (6'-Hethoxy-2'-naphthyl)pentan-2-on 8,15 ml thionylchlorid sættes drâbevis til en oplesning af 19,0 g 3-(6'-methoxy-2'-naphthyl)sm0rsyre i 200 ml tort benzen, og blandingen koges forsigtigt under tilbagesvaling natten over. Oplesningsmid-15 let afdampes, hvorved der fâs det râ syrechlorid i form af en brun olie.EXAMPLE 5 4- (6'-Hethoxy-2'-naphthyl) pentan-2-one 8.15 ml of thionyl chloride is added dropwise to a solution of 19.0 g of 3- (6'-methoxy-2'-naphthyl) butyric acid in 200 ml of tort benzene and boil gently under reflux overnight. The solvent is evaporated to give the crude acid chloride in the form of a brown oil.
253 ml methyllithium (2,18M i ether) fortyndes til 2 liter med ter ether, afkeles til 0°G og omreres under nitrogenatmosfære. 48,6 g cuproiodid tilsættes, og omreringen fortsættes i 10 minutter. Blan-- 20 dingen afkeles til -70°C, og en oplesning af det râ syrechlorid i 250 ml ether lades lebe til. Blandingen omreres under nitrogenatmosfære ved- 70°C i 15 minutter. 350 ml methanol tilsættes for at stand-se omsætningen, og blandingen fortyndes med vand og symes. Der tilsættes kiselgur som filtreringshjælp, og reaktionsblandingen 25 filtreres gennem en pude af kiselgur. Etherfasen vaskes med natrium-carbonatoplesning og vand, terres over vandfrit magnesiumsulfat og inddampes, hvorved der fâs en brun olie. Produktet renses ved kort kolonnechromatografi, hvorved der fâs 4-(6'-methoxy-2'-naphthyl)-pentan-2-on i form af en bleggul olie, som ved henstand sterkner 30 langsomt. Udbytte 10,7 g, hvilket svarer til 57% af det teoretiske.Dilute 253 ml of methyl lithium (2.18M in ether) to 2 liters with ether, cool to 0 ° G and stir under a nitrogen atmosphere. 48.6 g of cuprous iodide are added and stirring is continued for 10 minutes. The mixture is cooled to -70 ° C and a solution of the crude acid chloride in 250 ml of ether is added. The mixture is stirred under nitrogen atmosphere at -70 ° C for 15 minutes. 350 ml of methanol are added to stop the reaction and the mixture is diluted with water and simmered. Diatomaceous earth is added as a filtration aid and the reaction mixture is filtered through a pad of diatomaceous earth. The ether phase is washed with sodium carbonate solution and water, triturated over anhydrous magnesium sulfate and evaporated to give a brown oil. The product is purified by short column chromatography to give 4- (6'-methoxy-2'-naphthyl) -pentan-2-one in the form of a pale yellow oil which slowly solidifies on standing. Yield 10.7 g, which corresponds to 57% of theory.
IR-Spektrum: Carbonylabsorption ved 1705 cm"·*-.IR Spectrum: Carbonyl Absorption at 1705 cm -1
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NMR-Spektrum: CH3CO-: 3 proton singlet ved 8,01τ· CH3-CH-: 3 proton dublet ved 8,12r, J = il cps.NMR Spectrum: CH3 CO-: 3 proton singlet at 8.01τ · CH3-CH-: 3 proton doubled at 8.12r, J = 1 cps.
EKSEMPEL 6 5 Trans-4-(6'-methoxy-2'-naphthyl)pent-3-en-2-on 8,15 ml thionylchlorid sættes drâbevis til en oplosning af 14,0 g trans-3-(6'-methoxy-2'-naphthyl)crotonsyre i 140 ml tort benzen, og blandingen koges forsigtigt under tilbagesvaling i 4 timer. Oplos-ningsmidlet afdampes, hvorved der fâs det râ syrechlorid i form af en 10 brun olie.EXAMPLE 6 Trans-4- (6'-methoxy-2'-naphthyl) pent-3-en-2-one 8.15 ml of thionyl chloride is added dropwise to a solution of 14.0 g of trans-3- (6'- methoxy-2'-naphthyl) crotonic acid in 140 ml of tort benzene and the mixture is gently refluxed for 4 hours. The solvent is evaporated to give the crude acid chloride as a brown oil.
173,3 ml methyllithium (2,1 M i ether) fortyndes til 1200 ml med ter ether, afkoles til 0°C og omreres under nitrogenatmosfære. 34,75 g cuproiodid tilsættes, og omroringen fortsættes i 10 minutter. Blandingen afkoles til -70°C, og en oplosning af det râ syrechlorid i 15 150 ml ether lades lobe til. Blandingen omrores under nitrogenatmos fære ved- 70°C i 15 minutter. 150 ml methanol tilsættes for at stand-se reaktionen, og blandingen fortyndes med vand og syrnes. Der tilsættes kiselgur for at hjælpe filtreringen, og reaktionsblandingen filtreres gennem en pude af kiselgur. Etherfasen vaskes med natrium-20 carbonatoplosning og med vand, terres over vandfrit magnesiumsulfat og inddampes, hvorved der fâs et gult fast stof. Produktet renses ved chromatografi pâ en kort sojle, og ved omkrystallisation af petrole-umsether med et kogeinterval pà 60-80eC fâs 11,5 g (82,¾¾ af det teo-retiske) trans-4-(6'-methoxy-2'-naphthyl)pent-3-en-2-on i form af et 25 lysegult fast stof med smeltepunkt 98-101°C.Dilute 173.3 ml of methyl lithium (2.1 M in ether) to 1200 ml with ter ether, cool to 0 ° C and stir under a nitrogen atmosphere. 34.75 g of cuprous iodide are added and stirring is continued for 10 minutes. The mixture is cooled to -70 ° C and a solution of the crude acid chloride in 150 ml of ether is allowed to pass. The mixture is stirred under nitrogen atmosphere at 70 ° C for 15 minutes. 150 ml of methanol are added to stop the reaction and the mixture is diluted with water and acidified. Diatomaceous earth is added to aid filtration and the reaction mixture is filtered through a pad of diatomaceous earth. The ether phase is washed with sodium carbonate solution and with water, triturated over anhydrous magnesium sulfate and evaporated to give a yellow solid. The product is purified by chromatography on a short column and by recrystallization of petroleum ether with a boiling range of 60-80 ° C, 11.5 g (82, ¾¾ of the theoretic) trans-4- (6'-methoxy-2 ') is obtained. -naphthyl) pent-3-ene-2-one in the form of a pale yellow solid, mp 98-101 ° C.
IR-Spektrum (Nujol): Carbonylabsorption ved 1680 cm .IR Spectrum (Nujol): Carbonyl absorption at 1680 cm.
NMR-Spektrum: Vinylisk proton singlet ved 3,30 CH3CO-: 3 proton singlet ved 7,30.NMR Spectrum: Vinyl proton singlet at 3.30 CH 3 CO-: 3 proton singlet at 7.30.
4- (6 '-Methoxy-2'-naphthyl)-3-buüen-2-on EKSEMPEL 7 164- (6'-Methoxy-2'-naphthyl) -3-buen-2-one EXAMPLE 7 16
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Ved denne fremgangsmâdevariant indtræder en spontan dehydratisering, som kan illustreres ved felgende reaktionsskema oh" .. JL ^In this process variant, spontaneous dehydration occurs, which can be illustrated by the following reaction scheme.
MeO MeOMeO MeO
\ςΗ2° o 5 30 g 6-methoxy-2-naphthaldehyd omrores i 500 ml acetone med 10 ml 10%'s vandig natriumhydroxidoplosning i 3 timer. Oplesningen syrnes og ekstraheres med ether. Etheroplosningen terres over magnesium-sulfat og inddampes under reduceret tryk, hvorved der fàs 30 g af et fast stof. Dette urene materiale renses pâ en silicagelsejle under 10 anvendelse af benzen som elueringsmiddel, hvorved der fâs 15 g 4-(6'-methoxy-2'-naphthyl)-3-buten-2-on med et smeltepunkt pâ 120°C.30 g of 6-methoxy-2-naphthaldehyde are stirred in 500 ml of acetone with 10 ml of 10% aqueous sodium hydroxide solution for 3 hours. The solution is acidified and extracted with ether. The ether solution is triturated over magnesium sulfate and evaporated under reduced pressure to give 30 g of a solid. This crude material is purified on a silica gel gel using benzene as the eluent to give 15 g of 4- (6'-methoxy-2'-naphthyl) -3-buten-2-one having a melting point of 120 ° C.
EKSEMPEL 8 4-(6'-Methoxy-2'-naphthyl)butan-2-on 32 g 4-(6'-methoxy-2'-naphthyl)-3-buten-2-on i 500 ml ethylacetat 15 rystes ved stuetemperatur over 3 g 10%'s palladium/kul under hydrogen ved atmo s fare tryk, indtil der ikke optages yderligere hydrogen, hvorved der fâs 22,5 g 4-(6'-methoxy-2'-naphthyl)butan-2-on med smeltepunkt 78,5°C.Example 8 4- (6'-Methoxy-2'-naphthyl) butan-2-one 32 g of 4- (6'-methoxy-2'-naphthyl) -3-buten-2-one in 500 ml of ethyl acetate is shaken room temperature over 3 g of 10% palladium / carbon under hydrogen at atmospheric pressure until no additional hydrogen is obtained to give 22.5 g of 4- (6'-methoxy-2'-naphthyl) butane-2 on melting point 78.5 ° C.
EKSEMPEL 9 4-(6'-Methoxy-2'-naphthyl)butan-2-on 17EXAMPLE 9 4- (6'-Methoxy-2'-naphthyl) butan-2-one 17
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En blanding af 0,1 mol 6-methoxy-2-brommethyl-naphthalen, 0,1 mol acetylacetone og 0,1 mol kaliumcarbonat i 125 ml éthanol koges under 5 tilbagesvaling i 16 timer. Ethanolet afdampes under reduceret tryk, og remanensen rystes med 400 ml vand/ether-blanding i forholdet 1:1. Etherfasen terres over magnesiumsulfat og inddampes i vakuum, hvorved der fâs en klar olie, som efter rensning giver 4-(6'-methoxy-2'-naphthy1)butan-2-on.A mixture of 0.1 mole of 6-methoxy-2-bromomethyl-naphthalene, 0.1 mole of acetylacetone and 0.1 mole of potassium carbonate in 125 ml of ethanol is boiled under reflux for 16 hours. The ethanol is evaporated under reduced pressure and the residue is shaken with 400 ml of water / ether mixture in a 1: 1 ratio. The ether phase is triturated over magnesium sulfate and evaporated in vacuo to give a clear oil which after purification gives 4- (6'-methoxy-2'-naphthyl) butan-2-one.
10 EKSEMPEL 10 4-(6'-Methoxy-2'-naphthyl)butan-2-on 0,45 mol 3-ethoxycarbonyl-4-(6'-methoxy-2'-naphthyl)butan-2-on i éthanol (totalrumfang 1200 ml) og 470 ml 5N HCl koges under tilbagesvaling i 7 timer, hvorefter tyndtlagschromatografi viser fuldstændig 15 omsætning. Ethanolet afdampes under reduceret tryk, hvorved der udskilles et hudfarvet fast stof. Dette opleses i 1,0 liter ethylace-tat, og den vandige syrefase fraskilles og vaskes med yderligere 100 ml ethylacetat. De sammerihældte organiske oplesninger vaskes med mættet natriumhydrogencarbonatoplesning til pH-værdi 8 (800 ml i 20 flere portioner) og vand og terres over natriumsulfat.EXAMPLE 10 4- (6'-Methoxy-2'-naphthyl) butan-2-one 0.45 mole of 3-ethoxycarbonyl-4- (6'-methoxy-2'-naphthyl) butan-2-one in ethanol ( total volume (1200 ml) and 470 ml of 5N HCl are refluxed for 7 hours, after which thin layer chromatography shows complete reaction. The ethanol is evaporated under reduced pressure to give off a skin-colored solid. This is read in 1.0 liter of ethyl acetate and the aqueous acid phase is separated and washed with an additional 100 ml of ethyl acetate. The co-poured organic solutions are washed with saturated sodium hydrogen carbonate solution to pH 8 (800 ml in 20 several portions) and water and triturated over sodium sulfate.
Ved afdampning af oplesningsmidlet under reduceret tryk fâs 103,6 g (101% af det teoretiske) lysebrunt farvet fedt, fast stof, som ifelge glc indeholder 70% af titelforbindelsen.Evaporation of the solvent under reduced pressure gives 103.6 g (101% of theoretical) light brown colored fat, solid which according to glc contains 70% of the title compound.
Ved krystallisation af 588 ml 80% ethanol/^O med pâfelgende afkeling 25 fâs 56,0 g (54,6% af det teoretiske) cremefarvede mikrokrystaller af titelforbindelsen, smeltepunkt 78,5-79,5°C med 96%'s renhed ifelge glc.Crystallization of 588 ml of 80% ethanol / O with subsequent cooling 25 afforded 56.0 g (54.6% of theory) of cream-colored microcrystals of the title compound, mp 78.5-79.5 ° C with 96% purity according to glc.
Ved afdampning af oplesningsmidlet og krystallisation af den merke remanens (46,6 g) af 70 ml éthanol under afkeling fâs yderligere 18Evaporation of the solvent and crystallization of the mark residue (46.6 g) of 70 ml of ethanol on cooling gives an additional 18
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9,2 g (9,0% af det teoretiske) krystaller af titelforbindelsen, smeltepunkt 78-79,50C, som ifolge glc har 94%'s rerihed.9.2 g (9.0% of theory) crystals of the title compound, m.p. 78-79.50 ° C which, according to glc, have 94% ripeness.
Stoffet krystalliseres igen af 275 ml éthanol under afkeling, hvorved der fâs 55,9 g (54,5% af det teoretiske) af titelforbindelsen, smel-5 tepunkt 80,5-81°C, i form af blege cremefarvede mikronàle, som ifolge glc har en renhed pâ 97,7%. NMR-Spektrum stemmer overens med struk-turen.The substance is crystallized again by 275 ml of ethanol upon cooling to give 55.9 g (54.5% of theory) of the title compound, m.p. 80.5-81 ° C, in the form of pale cream-colored microns, as a result glc has a purity of 97.7%. The NMR spectrum is consistent with the structure.
EKSEMPEL 11EXAMPLE 11
Fremstillîng af 4-(6'-methoxy-2'-naphthyl)butan-2-on ved oxidation af 10 en alkohol 500 mg 4-(6'-methoxy-2'-naphthyl)butan-2-ol i 100 ml acetone oxideres under anvendelse af CrÛ3 i vand/svovlsyre (Fieser and Fieser, Reagents for Organic Synthesis, bind 1, s. 142). Oxidationsmidlet til-sættes drâbevis, indtil den orange farve ikke forsvinder mere. Ved 15 tyndtlagschromatografi (silicagelplader/toluen) vises, at reaktionen er fuldstsndig. Ved filtrering af oplesningen, afdampning af oplas-ningsmidlet og krystallisation af remanensen af ethanol/vand fâs 330 mg 4-(6'-methoxy-2'-naphthyl)butan-2-on, smeltepunkt 79°C.Preparation of 4- (6'-methoxy-2'-naphthyl) butan-2-one by oxidation of an alcohol 500 mg of 4- (6'-methoxy-2'-naphthyl) butan-2-ol in 100 ml of acetone oxidized using CrÛ3 in water / sulfuric acid (Fieser and Fieser, Reagents for Organic Synthesis, Vol. 1, p. 142). The oxidizing agent is added dropwise until the orange color disappears. At 15 thin layer chromatography (silica gel plates / toluene), the reaction is shown to be complete. By filtration of the solution, evaporation of the solvent and crystallization of the residue of ethanol / water, 330 mg of 4- (6'-methoxy-2'-naphthyl) butan-2-one were obtained, m.p. 79 ° C.
EKSEMPEL 12 20 Fremstillîng af 4-(6'-methoxy-2'-naphthyl)butan-2-on ved methylering af en naphthol 4,35 g 4-(6'-hydroxy-2'-naphthyl)butan-2-on koges under tilbagesva-ling i 100 ml methanol og 30 ml koncentreret svovlsyre i 3 timer.Example 12 Preparation of 4- (6'-methoxy-2'-naphthyl) butan-2-one by methylation of a naphthol 4.35 g of 4- (6'-hydroxy-2'-naphthyl) butan-2-one Boil under reflux in 100 ml of methanol and 30 ml of concentrated sulfuric acid for 3 hours.
Blandingen haldes ud i 500 ml vand og filtreres, hvorved der fâs 25 3,7 g af et lysebrunt fast stof, smeltepunkt 65°C. Dette omkrystalli- seres af ethanol/vand, hvorved der fâs 2,15 g 4-(6'-methoxy-2'-naph-thyl)butan-2-on, smeltepunkt 75,5°C.The mixture is poured into 500 ml of water and filtered to give 3.7 g of a light brown solid, mp 65 ° C. This is recrystallized from ethanol / water to give 2.15 g of 4- (6'-methoxy-2'-naphthyl) butan-2-one, m.p. 75.5 ° C.
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19 EKSEMPEL 13 1,5 g 6-methoxy-2-naphthaldehyd, 4 g triphenylacetonylphosphin og 200 ml tetrahydrofuran koges under tilbagesvaling i 120 timer. 100 ml 5N HCl sættes til blandingen efterfulgt af 200 ml ethylacetat. Den 5 organiske fase fraskilles, den vandige fase ekstraheres to gange med hver gang 200 ml ethylacetat, og de samlede organiske faser vaskes med vand, terres over vandfrit natriumsulfat og inddampes, hvorved der fâs et lysebrunt fast stof.EXAMPLE 13 1.5 g of 6-methoxy-2-naphthaldehyde, 4 g of triphenylacetonylphosphine and 200 ml of tetrahydrofuran are refluxed for 120 hours. 100 ml of 5N HCl is added to the mixture followed by 200 ml of ethyl acetate. The organic phase is separated, the aqueous phase is extracted twice with 200 ml of ethyl acetate each time, and the combined organic phases are washed with water, triturated over anhydrous sodium sulfate and evaporated to give a light brown solid.
Det faste stof chromatograferes pâ en silicagelkolonne .under anven-10 delse af benzen som elueringsmiddel, hvorved der fâs 400 mg af alde-hydet og 1,15 g 4-(6'-methoxy-2'-naphthyl)but-3-en-2-on, som efter krystallisa*tion af petroleumsether (kogeinterval 8O-1O0°C) smelter ved 120°C.The solid is chromatographed on a silica gel column using benzene as the eluent to give 400 mg of the aldehyde and 1.15 g of 4- (6'-methoxy-2'-naphthyl) but-3-ene -2-one which after crystallization of petroleum ether (boiling range 8O-10O ° C) melts at 120 ° C.
EKSEMPEL 14 15 4-(6'-Chlor-2'-naphthyl)pentan-2-on 8,0 g 3-(6'-chlor-2'-naphthyl)butansyre koges under tilbagesvaling natten over i 250 ml tort toluen indeholdende 4,0 ml thionylchlorid.EXAMPLE 14 4- (6'-Chloro-2'-naphthyl) pentan-2-one 8.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid is boiled under reflux overnight in 250 ml of tort toluene containing 4.0 ml of thionyl chloride.
Toluenet afdampes, hvorved der fâs 7,7 g rât syrechlorid i form af en brun olie.The toluene is evaporated to give 7.7 g of crude acid chloride in the form of a brown oil.
20 Omsætning af syrechloridet med methyllithium/cuproiodid: under i de eksempel 5 beskrevne betingelser efterfulgt af omkrystàllisation af ether/pentan giver 2,0 g rent 4-(6'-chlor-2' -naphthyl)ptentan-2-on, smeltepunkt 52-54°C.Reaction of the acid chloride with methyl lithium / cup iodide: under the conditions described in Example 5 followed by recrystallization of ether / pentane gives 2.0 g of pure 4- (6'-chloro-2 '-naphthyl) pententan-2-one, m.p. -54 ° C.
%-NMR-spektrum (CDC13): δ = 7,9-7,15 (m, 6H); 3,36 (m,ΊΗ); 2,66 (d, 25 - J=6Hz, 1H), 2,64 (d,J=8Hz, 1H); 1,95 (s, 3H) og 2,29 (id, J=7Hz, 3H).% NMR spectrum (CDCl3): δ = 7.9-7.15 (m, 6H); 3.36 (m, ΊΗ); 2.66 (d, 25 - J = 6Hz, 1H), 2.64 (d, J = 8Hz, 1H); 1.95 (s, 3H) and 2.29 (id, J = 7Hz, 3H).
Udgangsmaterialet fremstilles pâ felgende màde: 43,2 g triethylphosphonoacetat sættes ved stuetemperaüor i lebet af 1The starting material is prepared as follows: 43.2 g of triethyl phosphonoacetate are added at room temperature over 1
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20 time til en suspension af 6,48 g natriumhydrid i tort dimethoxyethan under nitrogenatmosfære og omreres i yderligere 1 time.20 hours to a suspension of 6.48 g of sodium hydride in tort dimethoxyethane under nitrogen atmosphere and stir for an additional 1 hour.
24,1 g 2-acetyl-6-chlor-naphthalen i 200 ml tort dimethoxyethan lades lebe til, og reaktionsblandingen koges under tilbagesvaling natten 5 over. Blandingen fortyndes med 500 ml vand, symes med 5N saltsyre og ekstraheres med ether. De etheriske ekstrakter vaskes med IN natrium-carbonatoplesning, terres over natriumsulfat og inddampes. Den râ ester chromatograferes pâ siliciumdioxid under anvendelse af chloro-form som eluant, hvorved der fâs 16,54 g 3-(6'-chlor-2'-naphthyl)but-10 2-ensyre-ethylester.24.1 g of 2-acetyl-6-chloro-naphthalene in 200 ml of tort dimethoxyethane are added and the reaction mixture is refluxed overnight. The mixture is diluted with 500 ml of water, sieved with 5N hydrochloric acid and extracted with ether. The ethereal extracts are washed with 1 N sodium carbonate solution, triturated with sodium sulfate and evaporated. The crude ester is chromatographed on silica using chloroform as eluant to give 16.54 g of 3- (6'-chloro-2'-naphthyl) but-2-enoic acid ethyl ester.
16,54 g af denne ester hydrogeneres i ethylacetat under anvendelse af 3,00 g 10%’s palladium/kul som katalysator, hvorved der fâs 16,0 g 3- (6'-chlor-2'-naphthyl)butansyre-ethylester.16.54 g of this ester is hydrogenated in ethyl acetate using 3.00 g of 10% palladium / carbon as catalyst to give 16.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid ethyl ester .
16,0 g af denne mættede ester hydrolyseres ved kogning under tilba-15 gesvaling natten over i 300 ml methanol indeholdende 4,00 g natrium-hydroxid og 10 ml vand. Reaktionsblandingen fortyndes med vand og ekstraheres med ethylacetat. Den vandige fase syrnes med koncentreret saltsyre, ekstraheres med ethylacetat, og den organiske ekstrakt terres over natriumsulfat og koncentreres. Omkrystallisation af 20 râproduktet af éthanol giver 10,0 g 3-(6'-chlor-2'-naphthyl)butan-syre, smeltepunlct 109-110°C.16.0 g of this saturated ester is hydrolyzed by boiling under reflux overnight in 300 ml of methanol containing 4.00 g of sodium hydroxide and 10 ml of water. The reaction mixture is diluted with water and extracted with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid, extracted with ethyl acetate, and the organic extract is triturated over sodium sulfate and concentrated. Recrystallization of the crude product from ethanol gives 10.0 g of 3- (6'-chloro-2'-naphthyl) butanoic acid, mp 109-110 ° C.
EKSEMPEL 15 4- (6'-methyi-2'-naphthyl)butan-2-onExample 15 4- (6'-Methyl-2'-naphthyl) butan-2-one
En blanding af 78 g 2-brommethyl-6-methylnaphthalen, 15 g acetyl-25 acetone og 21 g kaliumcarbonat i 500 ml éthanol koges under tilbagesvaling i 48 timer. Blandingen lades afkele og filtreres, og oples-ningsmidlet fjernes ved inddampning pâ rotationsfordamper. Til det vundne materiale sættes 500 ml ether og 200 ml vand. Efter rystning fraskilles og terres etherfasen, og oplesningsmidlet fjernes pâ 30 rotationsfordamper. Den resulterende râ olie chromatograferes pâ aluminiumoxid under anvendelse af petroleumsether (kogeinterval 40-A mixture of 78 g of 2-bromomethyl-6-methylnaphthalene, 15 g of acetyl-25 acetone and 21 g of potassium carbonate in 500 ml of ethanol is refluxed for 48 hours. The mixture is allowed to cool and filtered, and the solvent is removed by evaporation on a rotary evaporator. To the material obtained is added 500 ml of ether and 200 ml of water. After shaking, the ether phase is separated and the solvent removed on 30 rotary evaporators. The resulting crude oil is chromatographed on alumina using petroleum ether (boiling range 40-
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21 60°C), hvorved der fâs 10 g rent 4-(6'-methyl-2'-naphthyl)butan-2-on, smeltepunkt 55-57°C.21 to 60 ° C) to give 10 g of pure 4- (6'-methyl-2'-naphthyl) butan-2-one, m.p. 55-57 ° C.
Mellemproduktet fremstilles ved omsætning af 38 g brom og 82 g 2,6-dimethylnaphthalen i l0bet af 3 timer i en under tilbagesvaling 5 kogende oplesning i 200 ml carbontetrachlorid indeholdende nogle iodkrystaller.The intermediate is prepared by reacting 38 g of bromine and 82 g of 2,6-dimethyl naphthalene over a period of 3 hours in a refluxing 5 boiling solution in 200 ml of carbon tetrachloride containing some iodine crystals.
EKSEMPEL 16 4-(6'-Metbyl-2'-naphthyl)but-3-en-2-onExample 16 4- (6'-Methyl-2'-naphthyl) but-3-en-2-one
En blanding af 11 g 6-methyl-2-naphthaldehyd, 160 ml acetone og 5 ml 10 10¾'s vandigt natriumhydroxid omreres natten over ved stuetemperatur.A mixture of 11 g of 6-methyl-2-naphthaldehyde, 160 ml of acetone and 5 ml of 10 10¾ aqueous sodium hydroxide is stirred overnight at room temperature.
Den resulterende oplosning inddampes og ekstraheres derefter med ether. Etheroplosningen terres over natriumsulfat og Inddampes under reduceret tryk, hvorved der fâs et lysegult fast stof. Dette urene materiale renses pâ en aluminiumoxidsojle under anvendelse af benzen 15 som eluant, hvorved der fâs 3,5 g 4-(6'-methyl-2'-naphthyl)but-3-en- 2-on, smeltepunkt 128-129eC.The resulting solution is evaporated and then extracted with ether. The ether solution is triturated over sodium sulfate and evaporated under reduced pressure to give a pale yellow solid. This crude material is purified on an alumina column using benzene 15 as eluant to give 3.5 g of 4- (6'-methyl-2'-naphthyl) but-3-en-2-one, m.p. 128-129 ° C.
Farmakologiske dataPharmacological data
Under anvendelse af en sædvanlig Allen-Doisy-test vises'den estrogene aktivitet hos visse forbindelser, som er fremstillet ved fremgangs-20 mâden ifelge opfindelsen. Resultaterne er anfert i tabël I. Den antiinflammatoriske virkning af visse forbindelser pâvises ved anvendelse af standardrottepote-carrageenin-testen. Disse resultater er ligeledes anfort i tabel I.Using a conventional Allen-Doisy test, the estrogenic activity of certain compounds prepared by the method of the invention is shown. The results are given in Table I. The anti-inflammatory effect of certain compounds is demonstrated using the standard rat paw carrageenin test. These results are also listed in Table I.
Resultaterne viser, at forbindelserne, som fremstilles iifelge opfin-25 delsen, har et godt aktivitetsniveau ved en dosis, hvor overdreven estrogenicitet ikke skulle ventes. Det antages endvidexe, at manglen-de forgrening ved α-carbonatomet i vid udstrækning reducerer eventuel estrogenicitet, medens det ikke i nogen saerlig grad har.indflydelse pâ forbindelsernes antiinflammatoriske virkning.The results show that the compounds prepared according to the invention have a good level of activity at a dose where excessive estrogenicity should not be expected. It is further believed that the lack of branching at the α-carbon atom greatly reduces any possible estrogenicity, while not having any significant effect on the anti-inflammatory action of the compounds.
22 DK 156642 B22 DK 156642 B
Det har endvidere vîst sig, at 6'-methoxyforbindelser med formlen II ikke i særlig grad irriterer rottemaven ved en dosis pâ 300 mg/kg/dag indtaget oralt efter 3 dages forleb, medens der efter 1 1/2 dags oral behandling med den kendte forbindelse naproxen kan iagttages svær 5 gastrisk Irritation ved det samme dosisniveau.Furthermore, it has been found that 6'-methoxy compounds of formula II do not particularly irritate the rat stomach at a dose of 300 mg / kg / day taken orally after 3 days while after 1 1/2 days oral treatment with the known compound naproxen can be observed severe gastric irritation at the same dose level.
Ved den af Meier, R.K. et al., Experimentia. 6, 1950, s. 469 beskrevne vatpellet-granulomtest for antiinflammatorisk virkning viste den ifolge eksempel 15 fremstillede forbindelse sig at være virksom ved en dosis pâ 50 mg/kg pérorait/dag indgivet fra dag 0 til dag 5 og ved 10 samme dosis hverken at være gastrisk irriterende eller estrogent virksom.By that of Meier, R.K. et al., Experimentia. 6, 1950, p. 469, described in Example 15 the cotton pellet granuloma test for anti-inflammatory action was found to be effective at a dose of 50 mg / kg per day / day administered from day 0 to day 5 and at the same dose neither be gastric irritant or estrogenic.
Ved vatpellet-granulomtesten viste den ifelge eksempel 14 fremstillede forbindelse sig at være antiinflammatorisk virksom ved en dosis pâ 10 mg/kg pérorait, og i samme test var den ifolge eksempel 8 frem-15 stillede forbindelse virksom ved en dosis pâ 20 mg/kg pérorait.In the cotton pellet granuloma test, the compound prepared according to Example 14 was found to be anti-inflammatory at a dose of 10 mg / kg of perorheate, and in the same test, the compound prepared according to Example 8 was effective at a dose of 20 mg / kg of perorhea .
Claims (6)
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK236080A DK236080A (en) | 1973-09-11 | 1980-05-30 | ANALOGY PROCEDURE FOR PREPARING 4- (6-METHOXY-2-NAPHTHYL) BUTAN-2-ON. |
| DK119384A DK156562C (en) | 1973-09-11 | 1984-02-28 | NAPHTHALENDER DERIVATIVES FOR USING INTERMEDIATES IN THE PREPARATION OF PHARMACEUTICAL ACTIVE NAPHTHALENDER DERIVATIVES |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4255073 | 1973-09-11 | ||
| GB4255073A GB1474377A (en) | 1973-09-11 | 1973-09-11 | Naphthalene derivatives |
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| Publication Number | Publication Date |
|---|---|
| DK477674A DK477674A (en) | 1975-05-12 |
| DK156642B true DK156642B (en) | 1989-09-18 |
| DK156642C DK156642C (en) | 1990-01-29 |
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| DK477674A DK156642C (en) | 1973-09-11 | 1974-09-10 | ANALOGY PROCEDURE FOR THE PREPARATION OF NAPTHALEND DERIVATIVES |
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| Country | Link |
|---|---|
| JP (4) | JPS5920655B2 (en) |
| BE (1) | BE819794A (en) |
| CH (8) | CH603524A5 (en) |
| CY (2) | CY1083A (en) |
| DE (2) | DE2463219C2 (en) |
| DK (1) | DK156642C (en) |
| FR (1) | FR2242972B1 (en) |
| GB (1) | GB1474377A (en) |
| HK (2) | HK56180A (en) |
| IE (1) | IE40001B1 (en) |
| KE (2) | KE3081A (en) |
| MY (2) | MY8100198A (en) |
| NL (1) | NL175812C (en) |
| SE (2) | SE420598B (en) |
| ZA (1) | ZA745441B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| IL52006A0 (en) * | 1976-05-13 | 1977-07-31 | Beecham Group Ltd | Novel nephthalene derivatives their preparation and pharmaceutical compositions containing them |
| GB2014993B (en) * | 1977-11-03 | 1982-05-12 | Beecham Group Ltd | Chemical compounds |
| EP0003074B1 (en) * | 1978-01-07 | 1981-04-15 | Beecham Group Plc | Process for the preparation of 4-(6-methoxy-2-naphthyl)butan-2-one and 2-acetyl-3-(6-methoxy-2-naphthyl) propenoic acid esters |
| CA1142965A (en) * | 1979-06-08 | 1983-03-15 | Alexander C. Goudie | Substituted decalins, their preparation and use |
| GB8416638D0 (en) * | 1984-06-29 | 1984-08-01 | Beecham Group Plc | Topical treatment and composition |
| GB8607119D0 (en) * | 1986-03-21 | 1986-04-30 | Beecham Group Plc | Process |
| DE69120491T2 (en) * | 1990-09-18 | 1996-11-14 | Fujitsu Ltd | Cursor shift control device for a computer display |
| GB9108128D0 (en) * | 1991-04-15 | 1991-06-05 | Zambeletti Spa L | Novel formulation |
| GB9201857D0 (en) | 1992-01-29 | 1992-03-18 | Smithkline Beecham Plc | Novel compound |
| GB9222849D0 (en) * | 1992-10-31 | 1992-12-16 | Smithkline Beecham Plc | Novel use of pharmaceutical compositions |
| WO1997032837A1 (en) * | 1996-03-06 | 1997-09-12 | Sumitomo Pharmaceuticals Co., Ltd. | Nonsteroidal estrogen derivatives |
| US5861538A (en) * | 1997-08-04 | 1999-01-19 | Albemarle Corporation | Production of alkoxynaphthyl-substituted ketones from naphthaldehydes |
| CN1675154A (en) * | 2002-06-07 | 2005-09-28 | 科蒂科股份有限公司 | Napththalene derivatives which inhibit the cytokine or biological activity of macrophage migration inhibitory factor (MIF) |
| EP2123621A1 (en) | 2008-05-20 | 2009-11-25 | Bayer Schering Pharma Aktiengesellschaft | New [F-18]-marked L-glutamic acids and L-glutamic acid derivatives (1), application thereof and method for their manufacture |
| EP2123619A1 (en) | 2008-05-20 | 2009-11-25 | Bayer Schering Pharma AG | New [F-18]-marked L-glutamic acids and L-glutamic acid derivatives (II), application thereof and method for their manufacture |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO125971B (en) * | 1969-05-22 | 1972-12-04 | Syntex Corp | |
| DK145820B (en) * | 1969-10-09 | 1983-03-14 | Syntex Corp | ANALOGY PROCEDURE FOR PREPARING D-2- (6-METHOXY-2-NAPHTHYL) PROPANAL |
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1973
- 1973-09-11 GB GB4255073A patent/GB1474377A/en not_active Expired
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1974
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- 1974-08-20 CY CY1082A patent/CY1082A/en unknown
- 1974-08-21 IE IE1740/74A patent/IE40001B1/en unknown
- 1974-08-26 ZA ZA00745441A patent/ZA745441B/en unknown
- 1974-09-04 DE DE2463219A patent/DE2463219C2/de not_active Expired
- 1974-09-04 DE DE2442305A patent/DE2442305C2/en not_active Expired
- 1974-09-05 SE SE7411261A patent/SE420598B/en not_active IP Right Cessation
- 1974-09-05 FR FR7430151A patent/FR2242972B1/fr not_active Expired
- 1974-09-09 JP JP49103764A patent/JPS5920655B2/en not_active Expired
- 1974-09-10 DK DK477674A patent/DK156642C/en not_active IP Right Cessation
- 1974-09-11 CH CH999677A patent/CH603524A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999377A patent/CH603523A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999977A patent/CH603527A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999877A patent/CH603526A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999777A patent/CH603525A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999477A patent/CH613932A5/xx not_active IP Right Cessation
- 1974-09-11 CH CH999577A patent/CH603543A5/xx not_active IP Right Cessation
- 1974-09-11 BE BE148417A patent/BE819794A/en active Protection Beyond IP Right Term
- 1974-09-11 CH CH1236974A patent/CH599090A5/xx not_active IP Right Cessation
- 1974-09-11 NL NLAANVRAGE7412060,A patent/NL175812C/en not_active IP Right Cessation
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1979
- 1979-08-23 SE SE7907064A patent/SE7907064L/en unknown
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1980
- 1980-09-06 KE KE3081A patent/KE3081A/en unknown
- 1980-09-06 KE KE3082A patent/KE3082A/en unknown
- 1980-10-02 HK HK561/80A patent/HK56180A/en unknown
- 1980-10-02 HK HK562/80A patent/HK56280A/en unknown
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1981
- 1981-12-30 MY MY198/81A patent/MY8100198A/en unknown
- 1981-12-30 MY MY197/81A patent/MY8100197A/en unknown
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1982
- 1982-10-29 JP JP57190680A patent/JPS5921850B2/en not_active Expired
- 1982-10-29 JP JP57190679A patent/JPS6033818B2/en not_active Expired
- 1982-10-29 JP JP57190681A patent/JPS605580B2/en not_active Expired
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NO125971B (en) * | 1969-05-22 | 1972-12-04 | Syntex Corp | |
| DK145820B (en) * | 1969-10-09 | 1983-03-14 | Syntex Corp | ANALOGY PROCEDURE FOR PREPARING D-2- (6-METHOXY-2-NAPHTHYL) PROPANAL |
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