DK160048B - PROCEDURE FOR DEALKYLING OF 14-HYDROXY MORPHINANALKALOIDS - Google Patents
PROCEDURE FOR DEALKYLING OF 14-HYDROXY MORPHINANALKALOIDS Download PDFInfo
- Publication number
- DK160048B DK160048B DK227685A DK227685A DK160048B DK 160048 B DK160048 B DK 160048B DK 227685 A DK227685 A DK 227685A DK 227685 A DK227685 A DK 227685A DK 160048 B DK160048 B DK 160048B
- Authority
- DK
- Denmark
- Prior art keywords
- formula
- chloroformate
- hydrolysis
- derivative
- ethyl chloroformate
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
- C07D489/06—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with a hetero atom directly attached in position 14
- C07D489/08—Oxygen atom
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Steroid Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
Abstract
Description
iin
DK 160048 BDK 160048 B
Thebain, som er et fra valmuer eller opium ekstraheret alkaloid, har som følge af sin ekstremt høje toksicitet ikke egenskaber, der kan gøres brug af terapeutisk.Thebain, which is an alkaloid extracted from poppies or opium, does not, due to its extremely high toxicity, have therapeutic properties.
På den anden side er det via en række kemiske reaktioner mu-5 ligt at omdanne thebain til forskellige stoffer, der har interessante terapeutiske egenskaber, først og frerrmest analgeti-ske egenskaber og/eller antagonistiske egenskaber over for opiumholdige lægemidler.On the other hand, through a variety of chemical reactions, it is possible to convert thebain to various substances having interesting therapeutic properties, first and foremost analgesic and / or antagonistic properties to opium-containing drugs.
Blandt disse stoffer kan nævnes forbindelserne med formlenAmong these substances are the compounds of the formula
HOHAY
X>LX> L
O ---s 1O --- s 1
^ J__ϊ1 ~R^ J__ϊ1 ~ R
10 d.v.s.10 i.e.
naloxon R1 = -CH0CH = CH„ R2 = O, i * ^ 2 naltrexon R = -CH2 R =0, nalbuphin R1 = -CH2 φ R2 ---OH, nalmefen R^ = -CH2 <3 R2 = CH2, 15 som alle er derivater af 14-hydroxymorphinan.naloxone R1 = -CHOCH = CH2 R2 = O, i * ^ 2 naltrexone R = -CH2 R = 0, nalbuphin R1 = -CH2 φ R2 --- OH, nalmefene R ^ = -CH2 <3 R2 = CH2, 15 all of which are derivatives of 14-hydroxymorphinane.
**
Disse forbindelser bærer på nitrogenatomet en substituent, der er forskellig fra den, som thebain bærer (methylgruppen), ogThese compounds carry on the nitrogen atom a substituent different from that carried by thebain (the methyl group), and
DK 160048 BDK 160048 B
2 det forekommer derfor, at demethylering af thebains tertiære amin udgør et obligatorisk trin i alle disse synteser.2 Therefore, it appears that demethylation of thebain's tertiary amine constitutes a mandatory step in all these syntheses.
Demethyleringen af thebain, før nogen anden omdannelse, kan kun udføres med lave udbytter som følge af udgangsforbindelsens 5 ustabilitet, og især som følge af det opnåede demethylerede produkts ustabilitet. Desuden er denne fremgangsmåde uanvendelig industrielt.The demethylation of thebain, before any other conversion, can only be carried out with low yields due to the instability of the starting compound 5, and in particular due to the instability of the obtained demethylated product. In addition, this approach is unusually industrial.
Thebain kan derimod ved hjælp af kendte fremgangsmåder omdannes til 14-hydroxyderivater, /^Y'o % / n-ch3Thebain, on the other hand, can be converted into 14-hydroxy derivatives by means of known methods,
\oH\ oH
10 som betegnes 14-hydroxydihydrocodeinon eller oxycodon, når R = CHog 14-hydroxydihydromorphinon eller oxymorphon, når R = H.10 which is designated 14-hydroxydihydrocodeinone or oxycodone when R = CH and 14-hydroxydihydromorphinone or oxymorphone when R = H.
Ved at gå ud fra disse molekyler foretages demethylering af nitrogenatomet. For at undgå uønskede reaktioner er det imid-15 lertid nødvendigt, at den eller de hydroxylgrupper, der er til stede i molekylet, er beskyttet. Som oftest danner man den tilsvarende ester ved omsætning med eddikesyreanhydrid.Starting from these molecules, demethylation of the nitrogen atom is done. However, to avoid undesired reactions, it is necessary that the hydroxyl group (s) present in the molecule is protected. Most often, the corresponding ester is formed by reaction with acetic anhydride.
14-acetoxygruppen fremkalder således en vigtig sterisk hindring, der i betydelig grad begrænser mulighederne for demethylering.Thus, the 14-acetoxy group produces an important steric barrier that significantly limits the possibilities of demethylation.
33
DK '16 O O 4 a BDK '16 O O 4 and B
Dette er årsagen til, at forskellige reagenser, der er foreslået til demethylering af alkaloider, især inden for morphin-rækken, kun frembringer ringe udbytter med 14-hydroxymorphinaner, hvilket nødvendiggør vanskelige separationer til isolation 5 af den demethylerede forbindelse.This is why various reagents proposed for demethylation of alkaloids, especially within the morphine range, produce only poor yields of 14-hydroxymorphinans, necessitating difficult separations for isolation 5 of the demethylated compound.
Dette er især tilfældet for phenylchlorformiat, trichlorethyl-chlorformiat og α-chlorethylchlorformiat.This is particularly the case for phenyl chloroformate, trichloroethyl chloroformate and α-chloroethyl chloroformate.
I tilfælde af 14-hydroxymorphinaner er der hidtil kun blevet benyttet to reagenser. Der er for det første tale om cyanogen-10 bromid, omtalt af J.von Braun i Berichte 47, 2312 (1914), til morphinrækken, og det blev af M.Lewenstein, USA-patentskrift nr. 3.254.088, benyttet til 14-hydroxymorphinrækken.In the case of 14-hydroxymorphinans, only two reagents have so far been used. First, there is cyanogen-10 bromide, referred to by J.von Braun in Berichte 47, 2312 (1914), for the morphine series, and it was used by M.Lewenstein, U.S. Patent No. 3,254,088 to 14 -hydroxymorphinrækken.
Dette reagens fører til udbytter af størrelsesordenen 70% af demethyleret produkt. Det er ekstremt toksisk, og dets in-15 dustrielle anvendelse kræver meget betydelige forsigtighedsregler ved anvendelse.This reagent leads to yields on the order of 70% of demethylated product. It is extremely toxic and its industrial use requires very considerable precautions when used.
Der er desuden tale om vinylchlorformiat foreslået af R.Olof-son (USA-patentskrift nr. 3.905.981 og nr. 4.141.897). Med dette reagens varierer udbyttet af demethyleret produkt fra 20 70 til 85%. Dette reagens frembyder i industriel henseende to vigtige ulemper. For det første fører dets ustabilitet til varierende udbytter, og dets vanskelige fremstilling medfører for det andet en høj pris.In addition, it is vinyl chloroformate proposed by R. Olof-son (U.S. Patent Nos. 3,905,981 and 4,141,897). With this reagent, the yield of demethylated product ranges from 70 to 85%. This reagent presents, in industrial terms, two major disadvantages. Firstly, its instability leads to varying yields and, secondly, its difficult production entails a high price.
Ifølge den foreliggende opfindelse har det overraskende vist 25 sig, at man kan foretage demethyleringen af 14-hydroxymorphi- naners nitrogenatom ved som reagens at anvende ethylchlor-« formiat.Surprisingly, according to the present invention, it has been found that demethylation of the nitrogen atom of 14-hydroxymorphins can be carried out by using ethyl chloroformate as a reagent.
Dette reagens har allerede været benyttet som N-demethyleringsmiddel for alkaloider. Siden 1921 har J.Gadamer & F.Knoch,This reagent has already been used as an N-demethylating agent for alkaloids. Since 1921, J.Gadamer & F.Knoch,
DK 160048 BDK 160048 B
44
Arch.Phar. 259, 135-158 (1921), undersøgt ethylchlorformiats virkning på N-methylerede alkaloider, og de har konkluderet, at morphin, codein og heroin ikke spaltes.Arch.Phar. 259, 135-158 (1921), investigated the effect of ethyl chloroformate on N-methylated alkaloids and concluded that morphine, codeine and heroin are not cleaved.
Senere har E.Jucker & A.Lindenmann (svejtsisk patentskrift 5 nr. 442.318) og G.Kraiss & K.Nador (Tetrahedron Letters 1, 57-58, 1971) omtalt anvendelsen af ethylchorformiat som deme-thyleringsmiddel for nitrogenatomet i derivater tilhørende tropanfamilien. De opnåede udbytter er temmelig lave.More recently, E. Jucker & A. Lindenmann (Swiss Patent 5,442,318) and G.Kraiss & K.Nador (Tetrahedron Letters 1, 57-58, 1971) have discussed the use of ethyl chevre formate as the demethylation agent for the nitrogen atom in derivatives belonging to the tropane family. . The yields obtained are rather low.
M.Abdel-Monen & P.Portoghese, J.Med.Chem. 15 (2), 208-210 (1972), 10 har demethyleret morphin og codein ved omsætning med ethylchlor-formiat med udbytter af størrelsesordenen 40%.M.Abdel-Monen & P. Portoghese, J.Med.Chem. 15 (2), 208-210 (1972), 10 have demethylated morphine and codeine by reaction with ethyl chloroformate with yields of the order of 40%.
På lignende måde kommer K.Rice & E.May, J.Heterocyclic Chem. 14, 665 (1977) til samme konklusion.Similarly, K.Rice & E.May, J.Heterocyclic Chem. 14, 665 (1977) to the same conclusion.
Endelig har M.Schwartz & R.Wallace, J.Med.Chem. 24, 1525-1528 15 (1981) bragt ethylchlorformiat til omsætning med codein til dannelse af N-ethoxycarbonylcodein, som blev underkastet en hel række reaktioner med henblik på omdannelse deraf til 14-hydroxymorphinanderivatet, som derefter blev hydrolyseret til det tilsvarende N-nor-derivat.Finally, M.Schwartz & R.Wallace, J.Med.Chem. 24, 1525-1528 (1981) introduced ethyl chloroformate into codeine to form N-ethoxycarbonylcodeine, which was subjected to a variety of reactions to convert it to the 14-hydroxymorphinane derivative, which was then hydrolyzed to the corresponding N-nor. derivative.
20 I betragtning af de kendte vanskeligheder ved demethylering af 14-hydroxymorphinaner, som er omtalt ovenfor, kunne intet af disse trykskrifter efterlade håb om gunstige resultater ved anvendelse af ethylchlorformiat til demethylering af oxycodon eller oxymorphon.20 Given the known difficulties in demethylation of 14-hydroxymorphinans discussed above, none of these prints could leave hope for favorable results using ethyl chloroformate for demethylation of oxycodone or oxymorphone.
25 Ikke desto mindre viser de med ethylchlorformiat opnåede resultater på helt uventet måde dette reagens* overlegenhed i forhold til de hidtil benyttede.Nonetheless, the results obtained with ethyl chloroformate show, in an unexpected way, this reagent * superior to that previously used.
55
DK 16C043BDK 16C043B
Ved fremgangsmåden ifølge opfindelsen dannes N-ethoxy-carbonylderivatet ved omsætning af ethylchlorformiat i overskud med det til demethylering bestemte derivat i nærværelse af kaliumcarbonat og i et opløsningsmiddel/ fortrinsvis di-5 chlormethan eller chloroform, under tilbagesvaling. N-ethoxy-carbonylderivaterne af 14-acetoxydihydronorcodeinon og 14-acetoxydihydronormorphinon er hidtil ukendte og udgør nøglemellemprodukter ved den foreliggende fremgangsmåde. Fremgangsmåden ifølge opfindelsen illustreres ved hiælp af det 10 efterfølgende reaktionsskema: R'Ov ^ 3 ClCO-OCH2CH3 ^-0 - c - CH- II ^ 0^ (1) *'V) \J^^3-c-o=2h5 —s!- o—C-CH-*1 .1 3 (2) (R' = CH3 eller C0CH3)In the process of the invention, the N-ethoxy-carbonyl derivative is formed by reaction of ethyl chloroformate in excess with the derivative for demethylation in the presence of potassium carbonate and in a solvent / preferably dichloromethane or chloroform, under reflux. The N-ethoxy-carbonyl derivatives of 14-acetoxydihydronorcodeinone and 14-acetoxydihydronorphinone are novel and constitute key intermediates in the present process. The process of the invention is illustrated by means of the following reaction scheme: R'Ov ^ 3 ClCO-OCH2CH3 ^ -0 - c - CH-II ^ O ^ (1) * 'V) \ J ^^ 3-co = 2h5 - s 1 - o-C-CH- * 1,1 3 (2) (R '= CH 3 or COCH 3)
DK 160048BDK 160048B
6 R0'SnY^VsSvi6 R0'SnY ^ VsSvi
Vsk'vsk '
OHOH
(R = CH3 eller H)(R = CH 3 or H)
Hydrolysen af carbamatet gennemføres i stærkt surt miljø, især ved hjælp af svovlsyre med en koncentration mellem 5 og 10 N. Fortrinsvis anvendes en blanding af eddikesyre og svovlsyre under tilbagesvaling, hvilken blanding fører til 5 mindre nedbrydning end svovlsyren alene. Hydrolysen af carbamatet ledsages af forsæbning af den eller de tilstedeværende acetatestere i molekylet.The hydrolysis of the carbamate is carried out in a highly acidic environment, in particular by means of sulfuric acid having a concentration between 5 and 10 N. Preferably, a mixture of acetic acid and sulfuric acid is used at reflux, which mixture leads to less decomposition than the sulfuric acid alone. The hydrolysis of the carbamate is accompanied by saponification of the acetate ester (s) present in the molecule.
Det følgende eksempel vil bibringe en klarere forståelse af opfindelsen.The following example will provide a clearer understanding of the invention.
10 A) N-ethoxycarbonyl-14-acetoxydihydronorcodeinon (2) (R' = CH3).A) N-ethoxycarbonyl-14-acetoxydihydronorcodeinone (2) (R '= CH 3).
En blanding af 28 g 14-acetyloxycodon [(1) R1 = CH3], 12,5 g kaliumcarbonat og 45 ml ethylchlorformiat opvarmes under tilbagesvaling i 21 timer i 30 ml chloroform.A mixture of 28 g of 14-acetyloxycodone [(1) R1 = CH3], 12.5 g of potassium carbonate and 45 ml of ethyl chloroformate is heated at reflux for 21 hours in 30 ml of chloroform.
15 Efter køling vaskes reaktionsblandingen med 150 ml vand. Man fraskiller den vandige fase, som ekstraheres 2 gange med 50 ml chloroform.After cooling, the reaction mixture is washed with 150 ml of water. The aqueous phase is separated, which is extracted twice with 50 ml of chloroform.
Chloroformekstrakterne forenes, og der inddampes til tørhed.The chloroform extracts are combined and evaporated to dryness.
Man opnår en brunlig olie, der anvendes som sådan til den ef terfølgende operation.A brownish oil is obtained which is used as such for the subsequent operation.
DK 160048BDK 160048B
77
Man kan eventuelt fremstille en analytisk prøve af produktet 5 ved at opløse olien i methanol under tilbagesvaling. Ved køling udskilles krystaller, som man filtrerer fra og vasker med isopropylether.Optionally, an analytical sample of product 5 can be prepared by dissolving the oil in methanol under reflux. Upon cooling, crystals are separated from which one is filtered and washed with isopropyl ether.
Efter tørring: smeltepunkt 146 - 147°C.After drying: mp 146 - 147 ° C.
Tyndtlagskromatografi: 1 enkelt plet (benzen-acetone, 70/30 10 vol/vol).Thin layer chromatography: 1 single spot (benzene-acetone, 70/30 10 vol / vol).
Grundstofanalyse:EA:
Beregnet: C 63,60, H 6,07, N 3,37.Calculated: C 63.60, H 6.07, N 3.37.
Fundet: C 63,61, H 6,04, N 3,28.Found: C 63.61, H 6.04, N 3.28.
B) Noroxycodon (3) (R = CH^)· 15 Den som ovenfor anført opnåede olie optages i 30 ml eddikesyre, hvorpå man tilsætter en blanding af 20 ml 36 N svovlsyre og 140 ml vand. Der opvarmes under tilbagesvaling i 21 timer. Efter køling bringes reaktionsblandingens pH-værdi op på 11 ved tilsætning af en 30% opløsning af natriumhydroxid under 20 køling til opretholdelse af en temperatur i blandingen på ca.B) Noroxycodone (3) (R = CH 2) · The oil obtained as above is taken up in 30 ml of acetic acid, to which is added a mixture of 20 ml of 36 N sulfuric acid and 140 ml of water. Reflux for 21 hours. After cooling, the pH of the reaction mixture is raised to 11 by adding a 30% solution of sodium hydroxide under 20 cooling to maintain a temperature in the mixture of approx.
25°C. 100 ml chloroform tilsættes, der køles til 0°C, og der filtreres i nærværelse af et filtreringshjælpemiddel. Filterkagen vaskes 2 gange med 100 ml chloroform. Chloroformen dekanteres fra, og den vandige fase ekstraheres 3 gange med 25 100 ml chloroform. Chloroformekstrakterne forenes og inddam pes til tørhed under vakuum.25 ° C. Add 100 ml of chloroform, cool to 0 ° C and filter in the presence of a filtration aid. The filter cake is washed twice with 100 ml of chloroform. The chloroform is decanted off and the aqueous phase is extracted 3 times with 100 ml of chloroform. The chloroform extracts are combined and evaporated to dryness under vacuum.
Den faste rest optages i en blanding af 15 ml eddikesyre og 150 ml vand. Det faste stof opløses ved opvarmning til 35 -The solid residue is taken up in a mixture of 15 ml of acetic acid and 150 ml of water. The solid dissolves by heating to 35 -
DK 160048 BDK 160048 B
8 40°C/ hvorefter man gør opløsningen basisk ved tilsætning af ammoniak under køling til 20°C. Det faste stof filtreres fra, vaskes med vand indtil neutralitet og tørres i en ovn ved 80°C.8 40 ° C / and the solution is then made basic by adding ammonia under cooling to 20 ° C. The solid is filtered off, washed with water until neutrality and dried in an oven at 80 ° C.
Man opnår 21,6 g noroxycodon.21.6 g of noroxycodone are obtained.
5 Smeltepunkt 160°C (under dekomponering).Melting point 160 ° C (during decomposition).
Udbytte 92% for de 2 trin tilsammen.Yield 92% for the 2 steps combined.
Forbindelsen er på ethvert punkt identisk med en autentisk prøve af noroxycodon.The compound is identical at any point to an authentic sample of noroxycodone.
Fremgangsmåden ifølge opfindelsen fører derfor til særlig 10 fordelagtige resultater.The process of the invention therefore leads to particularly advantageous results.
For at vise fremgangsmådens overlegenhed har man gentaget operationen beskrevet i eksemplets afsnit A), d.v.s. dannelsen af carbamatet ved at variere arten af det benyttede chlorformi-at.In order to show the superiority of the method, the operation described in section A) of the example, i.e. the formation of the carbamate by varying the nature of the chloroformate used.
15 i hvert tilfælde har man ved ekstraktion med fortyndet saltsyre bestemt mængden af udgangsforbindelse, der ikke blev omdannet til carbamat.In each case, by dilution with dilute hydrochloric acid, the amount of starting compound which was not converted to carbamate was determined.
De opnåede resultater fremgår af den efterfølgende tabel 1:The results obtained are shown in the following Table 1:
DK 160048 BDK 160048 B
9 TABEL 1.9 TABLE 1.
Benyttet chlorformiat Ikke til carbaitiat om dannet oxycodon (%)Chloroformate used Not for carbohydrate formed oxycodone (%)
Ethylchlorformiat cicooc2h5 4 5 Trichlorethylchlorformiat cicooch2cci3 α-chlorethylchlorformiat 2gEthyl chloroformate cicooc2h5 4 5 Trichloroethyl chloroformate cicooch2cci3 α-chloroethyl chloroformate 2g
ClCOOCH-CH-, i 3ClCOOCH-CH-, i 3
ClCl
10 Allylchlorformiat 3QAllyl Chloroformate 3Q
ClCOOCH2CH=CH2ClCOOCH2CH = CH 2
Vinylchlorformiat ^ cicooch=ch2Vinyl chloroformate ^ cicooch = ch2
Methylchlorformiat 13 15 ClCOOCH3Methyl chloroformate 13 ClCOOCH3
Disse resultater viser tydeligt/ at ved omsætning af en 14-hydroxymorphinan med et chlorformiat til dannelse af det tilsvarende carbamat er det ethylchlorformiatet/ der fører til den bedste omdannelsesgrad.These results clearly show that by reacting a 14-hydroxymorphinan with a chloroformate to form the corresponding carbamate, it is the ethyl chloroformate / which leads to the best degree of conversion.
20 Denne omdannelsesgrad er tilstrækkelig høj til ikke at nødvendiggøre rensning af carbamatet før syrehydrolyse. Sidstnævnte fører direkte og med et højt udbytte til en ren forbindelse efter en enkelt krystallisation.This degree of conversion is sufficiently high to not necessitate purification of the carbamate before acid hydrolysis. The latter leads directly and with a high yield to a pure compound after a single crystallization.
1010
DK 1600*8BDK 1600 * 8B
Endvidere frembyder fremgangsmåden ifølge opfindelsen følgende fordele: - Anvendelse af et reagens, ethylchlorformiat, der er fuldstændig stabilt, og som bl.a. muliggør opnåelse af reproducerbare ud- 5 bytter, - anvendelse af et reagens, der er mindre toksisk end de hidtil benyttede, d.v.s. cyanogenbromid og vinylchlorformiat, - anvendelse af et billigt reagens som følge af dets lette fremstilling.Furthermore, the process according to the invention offers the following advantages: - The use of a reagent, ethyl chloroformate which is completely stable and which, inter alia, enabling reproducible yields to be obtained, - the use of a reagent which is less toxic than the hitherto used, i.e. cyanogen bromide and vinyl chloroformate, - use of a cheap reagent as a result of its light preparation.
Claims (4)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8408273 | 1984-05-25 | ||
| FR8408273A FR2564838B1 (en) | 1984-05-25 | 1984-05-25 | PROCESS FOR DEALKYLATION OF ALKALOIDS AND INTERMEDIATES |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| DK227685D0 DK227685D0 (en) | 1985-05-22 |
| DK227685A DK227685A (en) | 1985-11-26 |
| DK160048B true DK160048B (en) | 1991-01-21 |
| DK160048C DK160048C (en) | 1991-06-17 |
Family
ID=9304425
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK227685A DK160048C (en) | 1984-05-25 | 1985-05-22 | PROCEDURE FOR DEALKYLING OF 14-HYDROXY MORPHINANALKALOIDS |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0164290B1 (en) |
| JP (1) | JPS60258183A (en) |
| AT (1) | ATE46163T1 (en) |
| AU (1) | AU577379B2 (en) |
| CA (1) | CA1244825A (en) |
| DE (1) | DE3572819D1 (en) |
| DK (1) | DK160048C (en) |
| ES (1) | ES543338A0 (en) |
| FR (1) | FR2564838B1 (en) |
| NO (1) | NO164981C (en) |
| NZ (1) | NZ212193A (en) |
| PT (1) | PT80519B (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4795813A (en) * | 1981-08-17 | 1989-01-03 | The Florida Board Of Regents On Behalf Of The Florida State University | Synthesis of derivatives of codeine and other 3-O-alkylmorphines |
| US6067749A (en) | 1996-07-11 | 2000-05-30 | Tasmanian Alkaloids Pty. Ltd. | Papaver somniferum strain with high concentration of thebaine and oripavine |
| GB2438401A (en) * | 2006-05-25 | 2007-11-28 | Alpharma Aps | Preparation of morphinan derivatives comprising N-demethylation, reductive amination and O-demethylation steps |
| GB2471802B (en) * | 2006-05-25 | 2011-02-16 | Alpharma | Chemical process |
| GB2444052A (en) * | 2006-05-25 | 2008-05-28 | Alpharma Aps | Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps |
| US8962841B2 (en) | 2007-06-29 | 2015-02-24 | Brock University | Methods for one-pot N-demethylation/N-functionalization of morphine and tropane alkaloids |
| US7999104B2 (en) * | 2007-06-29 | 2011-08-16 | Brock University | Methods for one-pot N-demethylation/N-acylation of morphine and tropane alkaloids |
| CA2709872C (en) * | 2007-12-17 | 2016-06-14 | Peter X. Wang | Processes for the preparation of normorphinan salts |
| US9131649B2 (en) | 2008-03-07 | 2015-09-15 | Tasmanian Alkaloids Pty. Ltd | Papaver somniferum strain with high concentration of thebaine |
| CA2720034A1 (en) * | 2008-03-31 | 2009-10-08 | Sun Pharmaceutical Industries Ltd. | An improved process for the preparation of morphinane analogues |
| WO2011154827A2 (en) | 2010-06-11 | 2011-12-15 | Rhodes Technologies | Transition metal-catalyzed processes for the preparation of n-allyl compounds and use thereof |
| AU2011263416B2 (en) | 2010-06-11 | 2014-04-10 | Rhodes Technologies | Process for N-dealkylation of tertiary amines |
| WO2012151669A1 (en) * | 2011-05-06 | 2012-11-15 | Brock University | Process for the preparation of morphine analogs via metal catalyzed n-demethylation/functionalization and intramolecular group transfer |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4141807A (en) * | 1977-03-01 | 1979-02-27 | Stauffer Chemical Company | Photopolymerizable composition stabilized with nitrogen-containing aromatic compounds |
| DE2727805A1 (en) * | 1977-06-21 | 1979-01-04 | Goedecke Ag | METHOD FOR PRODUCING OXYNORMORPHONE |
| US4390699A (en) * | 1981-07-16 | 1983-06-28 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | 6-Keto-morphinans belonging to the 14-hydroxy-series |
| US4472253A (en) * | 1981-08-17 | 1984-09-18 | The Florida Board Of Regents On Behalf Of The Florida State University | Process for the preparation of an N-substituted 3-O-alkyl-14-hydroxynormorphinone derivative |
| DE3381560D1 (en) * | 1982-09-24 | 1990-06-21 | Poudres & Explosifs Ste Nale | VINYLCARMABATE AND PRODUCTION METHOD. |
-
1984
- 1984-05-25 FR FR8408273A patent/FR2564838B1/en not_active Expired
-
1985
- 1985-05-21 AT AT85400996T patent/ATE46163T1/en not_active IP Right Cessation
- 1985-05-21 ES ES543338A patent/ES543338A0/en active Granted
- 1985-05-21 EP EP85400996A patent/EP0164290B1/en not_active Expired
- 1985-05-21 DE DE8585400996T patent/DE3572819D1/en not_active Expired
- 1985-05-22 CA CA000482102A patent/CA1244825A/en not_active Expired
- 1985-05-22 DK DK227685A patent/DK160048C/en not_active IP Right Cessation
- 1985-05-23 PT PT80519A patent/PT80519B/en not_active IP Right Cessation
- 1985-05-24 NO NO852091A patent/NO164981C/en unknown
- 1985-05-24 NZ NZ212193A patent/NZ212193A/en unknown
- 1985-05-24 JP JP60113016A patent/JPS60258183A/en active Pending
- 1985-05-24 AU AU42843/85A patent/AU577379B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| ES8603893A1 (en) | 1986-01-01 |
| FR2564838A1 (en) | 1985-11-29 |
| CA1244825A (en) | 1988-11-15 |
| NO852091L (en) | 1985-11-26 |
| JPS60258183A (en) | 1985-12-20 |
| AU577379B2 (en) | 1988-09-22 |
| NO164981C (en) | 1990-12-05 |
| PT80519B (en) | 1988-01-22 |
| AU4284385A (en) | 1985-11-28 |
| EP0164290A1 (en) | 1985-12-11 |
| FR2564838B1 (en) | 1986-11-07 |
| DE3572819D1 (en) | 1989-10-12 |
| PT80519A (en) | 1985-06-01 |
| ES543338A0 (en) | 1986-01-01 |
| DK160048C (en) | 1991-06-17 |
| DK227685A (en) | 1985-11-26 |
| ATE46163T1 (en) | 1989-09-15 |
| NO164981B (en) | 1990-08-27 |
| NZ212193A (en) | 1988-10-28 |
| EP0164290B1 (en) | 1989-09-06 |
| DK227685D0 (en) | 1985-05-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR100363486B1 (en) | Preparation of oxymorphone, oxycodone and derivatives | |
| EP2222642B1 (en) | Process and compounds for the production of (+) opiates | |
| EP2222678B1 (en) | Processes for the production of (+)-'nal' morphinan compounds | |
| DK160048B (en) | PROCEDURE FOR DEALKYLING OF 14-HYDROXY MORPHINANALKALOIDS | |
| JP2012524726A (en) | Preparation of morphinan and morphinone compounds | |
| EP0496830A4 (en) | Total synthesis of northebaine, normorphine, noroxymorphone enantiomers and derivatives via n-nor intermediates | |
| EP2480555A2 (en) | Methods for producing hydrocodone, hydromorphone or a derivative thereof | |
| CA2761287A1 (en) | Synthesis of morphine and related derivatives | |
| US4087426A (en) | Oxybisberberine and a process for its production | |
| Marton et al. | Synthesis of N-substituted 7β-diprenorphine derivatives | |
| EP0168686B1 (en) | Process for n-demethylating morphinane alkaloids | |
| Hosztafi et al. | Synthesis of N-Demethyl-N-Substituted-14-Hydroxycodeine and Morphine Derivatives+ | |
| Leland et al. | Analgesic narcotic antagonists. 4. 7-Methyl-N-(cycloalkylmethyl)-3-hydroxy morphinan-6-one and-isomorphinan-6-one | |
| MAEDA | Synthesis and Reactivities of 1-Methyl-2-trichloromethyl-1, 2-dihydroquinolines | |
| Kikuchi et al. | Pachysandra Alkaloids. V. Structure of Epipachysamine-A,-B,-C,-D,-E, and-F | |
| HU188065B (en) | New process for the dealkylation of tertiary amines | |
| IIDA et al. | Studies on the Syntheses of 7, 8-Disubstituted 1-Benzylisoquinoline and Related Compounds.(4). Synthesis of dl-Cularidine | |
| Kotick | Analgesic narcotic antagonists. Part 14. 6, 7. alpha.: 14, 7. beta.-Bis (oxymethylene) dihydromorphines | |
| Berényi et al. | Synthesis of a new azatetracyclodecane ring system via intramolecular addition of azide on double bond | |
| Lee | Department of Biochemistry, College of Natural Science, Dongguk University, Gyeongju, Gyeongbuk 780-714, Korea Received August 6, 2002 | |
| GB2471803A (en) | Processes of preparing morphinan derivatives such as naltrexone and naloxone comprising O- and N-demethylation and reductive alkylation steps | |
| ITMI20000835A1 (en) | PROCESS FOR THE PREPARATION OF DECAIDRO-2A, 4A, 6A, 8A-TETRAAZACICLO-PENT (FG) ACENAFTILENE AND FUNCTIONALIZED DERIVATIVES. |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |