DK171850B1 - Fremgangsmåde til fremstilling af 17alfa-ethynyl-17beta-hydroxy-18-methyl-4,15-østradien-3-on og mellemprodukter til anvendelse ved fremgangsmåden - Google Patents
Fremgangsmåde til fremstilling af 17alfa-ethynyl-17beta-hydroxy-18-methyl-4,15-østradien-3-on og mellemprodukter til anvendelse ved fremgangsmåden Download PDFInfo
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- DK171850B1 DK171850B1 DK168288A DK168288A DK171850B1 DK 171850 B1 DK171850 B1 DK 171850B1 DK 168288 A DK168288 A DK 168288A DK 168288 A DK168288 A DK 168288A DK 171850 B1 DK171850 B1 DK 171850B1
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- Prior art keywords
- methyl
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- carbon atoms
- methoxy
- hydroxy
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- 238000000034 method Methods 0.000 title abstract description 14
- SIGSPDASOTUPFS-XUDSTZEESA-N gestodene Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](C=C4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 SIGSPDASOTUPFS-XUDSTZEESA-N 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 title description 5
- 239000000543 intermediate Substances 0.000 title description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004665 trialkylsilyl group Chemical group 0.000 claims abstract description 5
- 238000006027 Birch reduction reaction Methods 0.000 claims abstract description 4
- 125000002252 acyl group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- YLCXGBZIZBEVPZ-UHFFFAOYSA-N Medazepam Chemical compound C12=CC(Cl)=CC=C2N(C)CCN=C1C1=CC=CC=C1 YLCXGBZIZBEVPZ-UHFFFAOYSA-N 0.000 claims 1
- 238000004020 luminiscence type Methods 0.000 claims 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006555 catalytic reaction Methods 0.000 abstract description 4
- 229910052763 palladium Inorganic materials 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract 1
- MECHNRXZTMCUDQ-RKHKHRCZSA-N vitamin D2 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)/C=C/[C@H](C)C(C)C)=C\C=C1\C[C@@H](O)CCC1=C MECHNRXZTMCUDQ-RKHKHRCZSA-N 0.000 abstract 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 238000006356 dehydrogenation reaction Methods 0.000 description 4
- -1 enol acetates Chemical class 0.000 description 4
- 239000000052 vinegar Substances 0.000 description 4
- 235000021419 vinegar Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- AMWRITDGCCNYAT-UHFFFAOYSA-L hydroxy(oxo)manganese;manganese Chemical compound [Mn].O[Mn]=O.O[Mn]=O AMWRITDGCCNYAT-UHFFFAOYSA-L 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 239000000583 progesterone congener Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- FHJVQLWFUQMADH-XSYGEPLQSA-N (8r,9s,13s,14s)-13-ethyl-3-methoxy-7,8,9,11,12,14,15,16-octahydro-6h-cyclopenta[a]phenanthren-17-one Chemical compound COC1=CC=C2[C@H]3CC[C@](CC)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 FHJVQLWFUQMADH-XSYGEPLQSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JKJWYKGYGWOAHT-UHFFFAOYSA-N bis(prop-2-enyl) carbonate Chemical compound C=CCOC(=O)OCC=C JKJWYKGYGWOAHT-UHFFFAOYSA-N 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229940124558 contraceptive agent Drugs 0.000 description 1
- 239000003433 contraceptive agent Substances 0.000 description 1
- 238000005661 deetherification reaction Methods 0.000 description 1
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 1
- 150000002084 enol ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 150000004688 heptahydrates Chemical class 0.000 description 1
- 125000000268 heptanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- KJGLZJQPMKQFIK-UHFFFAOYSA-N methanolate;tributylstannanylium Chemical compound CCCC[Sn](CCCC)(CCCC)OC KJGLZJQPMKQFIK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- YHLVIDQQTOMBGN-UHFFFAOYSA-N methyl prop-2-enyl carbonate Chemical compound COC(=O)OCC=C YHLVIDQQTOMBGN-UHFFFAOYSA-N 0.000 description 1
- 238000013048 microbiological method Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DNYWZCXLKNTFFI-UHFFFAOYSA-N uranium Chemical compound [U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U][U] DNYWZCXLKNTFFI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J13/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17
- C07J13/005—Normal steroids containing carbon, hydrogen, halogen or oxygen having a carbon-to-carbon double bond from or to position 17 with double bond in position 16 (17)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0059—Estrane derivatives substituted in position 17 by a keto group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
- C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0051—Estrane derivatives
- C07J1/0081—Substituted in position 17 alfa and 17 beta
- C07J1/0088—Substituted in position 17 alfa and 17 beta the substituent in position 17 alfa being an unsaturated hydrocarbon group
- C07J1/0096—Alkynyl derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
DK 171850 B1
Opfindelsen angår en særlig fremgangsmåde til fremstilling af 17a-ethynyl-17/3-hydroxy-18-methyl-4,15-østradien-3-on (I) (gestoden) og hidtil ukendte mellemprodukter til anvendelse ved fremgangsmåden. Gestoden er et meget virksomt gestagen, 5 som f.eks. kan anvendes som gestagenbestanddel i svangerskabsforebyggende midler (DE-PS nr. 25 46 062).
Der kendes allerede flere fremgangsmåder til fremstilling af gestoden. Problemet med indførelsen af Δ 15-dobbeltbindingen er imidlertid endnu ikke tilfredsstillende løst. Kemiske de-10 hydrogeneringsmetoder forløber med ringe udbytte, da 18-methylgruppen hæmmer reaktionen (DE offentliggørelsesskrift nr. 24 3 9 082). Dehydrogenering ved hjælp af mikrobiologi ske metoder viser sig at give store synteseomkostninger (DE offentliggørelsesskrift nr. 24 56 068). Fra DK 171.578 Bl 15 (ans. nr. 1975/86) kendes en fremgangsmåde til fremstilling af gestoden. Det ved denne fremgangsmåde anvendte udgangsprodukt fremstilles ved en mikrobiologisk metode, der indebærer førnævnte ulemper.
I Tetrahedron 42 (1986) 2971-2977 beskrives en fremgangsmåde 20 til dehydrogenering af ketoner ved palladiumkatalyseret omsætning af enolacetater med allylcarbonater.
Det har nu vist sig, at den palladiumkatalyserede dehydrogenering lader sig anvende ved indførselen af Δΐδ-dobbeltbindingen i gestoden. Fremgangsmåden har den fordel, at dehydrogenerin-25 gen forløber under relativt milde betingelser og i højere udbytte end med de kendte fremgangsmåder.
Opfindelsen angår således en særlig fremgangsmåde til fremstilling af gestoden, som er ejendommelig ved, at man omsætter en forbindelse med den almene formel II
Γ2 iTTi— 111 v DK 171850 B1 2 hvor
Ri betegner en alkylgruppe med 1-3 carbonatomer, og R2 betegner en acyl- eller en trialkylsilylgruppe med op til 10 carbonatomer,
5 under palladiumkatalyse til en forbindelse med den almene formel III
O
- 111 · hvor
Ri betegner en alkylgruppe med 1-3 carbonatomer, og på kendt måde reducerer 17-ketogruppen, omsætter den 10 aromatiske A-ring med flydende ammoniak ved Birch-reaktion til den tilsvarende 3-alkoxy-2,5 (10) , 15-østratrien-17jS-ol, reoxiderer 17-hydroxygruppen til en 17-ketogruppe, ethyny-liserer 17-ketogruppen og spalter 3-enoletheren til dannelse af forbindelsen med formlen I.
15 i formel II og III betegner Ri en alkylgruppe med 1-3 carbonatomer, hvor methyl- og ethylgruppen foretrækkes. Acylgruppen R2 i formlen II kan være afledt af organiske carboxylsyrer med op til 10 carbonatomer, f.eks. acetyl-, trif1uoracety1 -, tri-methylacetyl-, propionyl-, butyryl-, heptanoyl- og benzoyl-20 grupper, hvor acetyl gruppen er den foretrukne. Som trialkylsi-lylgruppe foretrækkes trimethylsilylgruppen.
Den palladiumkatalyserede omsætning af det tilsvarende enola-cetat med trialkylsi1y1 — eller trialkyltinalkoxid og allylcar- DK 171850 B1 3 bonat lykkes med godt udbytte. Som opløsningsmiddel anvendes nitriler, fortrinsvis acetonitril.
Ifølge en foretrukket udførelsesform behandles eno1 der ivatet, opløst i acetonitril, under kogning under tilbagesvaling med 5 en katalytisk mængde palladiumacetat og en katalytisk mængde tributyltinmethoxid under tilstedeværelse af allylmethylcarbo-nat i overskud. Efter en reaktionstid på 1-3 timer kan det de-hydrogenerede produkt fraskilles og renses kromatografisk.
Den videre behandling af forbindelsen med den almene formel 10 III til gestoden med formlen I forklares nærmere ved hjælp af følgende formelskema.
O OH OH
jCtf?3— jo5^— jofr^ RO RO K.O'
1 III 1 IV 1 V
O OH
* > II > 1"C,CH
o
RjO VI i 17-ketonen reduceres, f.eks. med natriumborhydrid under tilstedeværelse af Cer(111)-ionen. Efter Birch-reduktion af den aromatiske A-ring, oxidation af 17/3-alkoholen, f.eks. med 15 brunsten, ethynylisering af 17-ketonen og afsluttende sur enoletherspaltning, fås gestoden med formlen I.
DK 171850 B1 4 EKSEMPEL 1 17- acetoxy-3-methoxv-18-methv1-1,3,5(10),16-østratetraen 30 g 3-methoxy-18-methy1-1,3,5(10)-østratrien-17-on [J. Org. Chem. 40 (1975) 681] om røres i 200 ml isopropenylacetat med 5 1,5 g p-toluensulfonsyre i 22 timer i et bad på 120eC. Deref ter fortyndes der med eddikeester, vaskes med natriumcarbonat og kogsaltopløsning, tørres over natriumsulfat og koncentre res. Efter kromatografi opnår man 27,6 g 17-acetoxy-3-methoxy- 18- methyl-1,3,5(10),16-østratetraen med smp. 105-106eC.
10 EKSEMPEL 2 3-methoxy-18-methyl -1,3,5(10),15-østratetraen-17-on 3,4 g 17-acetoxy-3-methoxy-18-methy1-1,3,5(10),16-østratetraen koges i 50 ml acetonitril med 2,3 ml al lyImethylcarbonat, 220 mg palladiumacetat og 580 μΐ tr i buty 11 i nmethoxi d i 1,5 timer 15 under tilbagesvaling. Derefter fortyndes der med vand, ekstra-heres med dich1 ormethan og koncentreres i vakuum. Efter kromatografisk rensning opnåede man 2,1 g 3-methoxy-18-methyl-1,3,5(10),15-østratetraen-17-on med smp. 158-160eC.
EKSEMPEL 3 20 3-methoxy-18-methvl-1,3,5(10),15-østratetraen-17fl-ol
Til 4,7 g 3-methoxy-18-methy1-1,3,5(10),15-østratetraen-17-on i 30 ml tetrahydrofuran og 45 ml methanol sættes 6,8 g Cer- (III)-chlorid-heptahydrat. Ved 0eC tilsætter man portionsvis 1,0 g natriumborhydrid. Efter en time sættes reaktionsblandin-25 gen i isvand. Væsken over det udfældede produkt frasuges, produktet opløses i eddikeester, vaskes med vand og tørres. Der opnås 4,5 g 3-methoxy-18-methy 1 -1,3,5 (10) , 15-østratetraen-17/3-ol som skum.
DK 171850 B1 5 EKSEMPEL 4 3-methoxv-18-methvl-2.5(101.15-østratrien-178-ol 5,0 g 3-methoxy-18-methyl-l,3,5(10) , 15-østratetraen-17/3-ol i 250 ml tetrahydrofuran sattes ved -78eC til 250 ml flydende 5 ammoniak. Man tilsætter med 30 ml ethanol og tilfører 1,5 g lithium i små portioner. Efter fuldstændig omsætning lader man ammoniakken fordampe, tildrypper forsigtigt vand under afkøling, fortynder med eddikeester, vasker den organiske fase neutral med vand og tørrer. Man opnår 4,7 g 3-methoxy-18-meth-10 yl-2,5(10),15-østratri en-170-01 som skum.
EKSEMPEL 5 3-methoxy-18-methv1-2.5(101.15-østratri en-17-on 4,7 g 3-methoxy-18-methyl-2,5(10),15-østratrien-17ø-ol i 250 ml chloroform og 35 ml t-butanol koges med 10 g mangandi oxid i 15 18 timer under tilbagesvaling. Derefter frasuges væsken over celite, produktet eftervaskes med chloroform og koncentreres under nedsat tryk. Efter kromatografisk rensning på kiselgel med hexan/eddikeester opnår man 4,1 g rent 3-methoxy-18-meth-yl-2,5(10),15-østratrien-17-on med smp. 89-91eC.
20 EKSEMPEL 6 17a-ethynyl-17fl-hvdroxv-18-methy1-4,15-østradien-3-on (aestoden1
Til en opløsning af 40 ml n-buty 11 ithium (15% i hexan) i 100 ml tetrahydrofuran leder man ved 0eC acetylen i 30 minutter og 25 tildrypper derefter 4,0 g 3-methoxy-2,5(10), 15-østratrien-17-on i 40 ml tetrahydrof uran. Efter 45 minutter sættes 16 ml halvkoncentreret saltsyre til reaktionsblandingen, og der røres i 45 minutter ved stuetemperatur. Der fortyndes med eddikeester, vaskes neutralt med vand og tørres. Efter omkrystal-
Claims (4)
10 Rj betegner en alkylgruppe med 1-3 carbonatomer, og R2 betegner en acyl- eller en trialkylsilylgruppe med op til 10 carbonatomer, DK 171850 B1 7 under pa 11 ad iumkata1yse til en forbindelse med den almene formel III o y ni. hvor betegner en alkylgruppe med 1-3 carbonatomer, 5 og på kendt måde reducerer 17-ketogruppen, omsætter den aromatiske λ-ring med flydende ammoniak ved Birch-reaktion til den tilsvarende 3-alkoxy-2,5 (10) , 15-østratrien-17/S-ol, reoxiderer 17-hydroxygruppen til en 17-ketogruppe, ethynyli-serer 17-ketogruppen og spalter 3-enoletheren til dannelse af 10 forbindelsen med formlen I.
2. Forbindelse, kendetegnet ved, at den er 3- methoxy-18-methyl-1,3,5 (10) , 15-østratetraen-17/3-ol.
3. Forbindelse, kendetegnet ved, at den er 3- methoxy-18-methyl-2,5(10), 15 - østratrien-17/S-ol.
4. Forbindelse, kendetegnet ved, at den er 3- methoxy-18-methyl-2,5(10),15-østratrien-17-on.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19873710728 DE3710728A1 (de) | 1987-03-31 | 1987-03-31 | Verfahren zur herstellung von 17(alpha)-ethinyl-17ss-hydroxy-18-methyl-4,15-estradien-3-on und die neuen zwischenprodukte fuer dieses verfahren |
| DE3710728 | 1987-03-31 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK168288D0 DK168288D0 (da) | 1988-03-25 |
| DK168288A DK168288A (da) | 1988-10-01 |
| DK171850B1 true DK171850B1 (da) | 1997-07-07 |
Family
ID=6324491
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK168288A DK171850B1 (da) | 1987-03-31 | 1988-03-25 | Fremgangsmåde til fremstilling af 17alfa-ethynyl-17beta-hydroxy-18-methyl-4,15-østradien-3-on og mellemprodukter til anvendelse ved fremgangsmåden |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US4923640A (da) |
| EP (1) | EP0285548B1 (da) |
| JP (1) | JP2752366B2 (da) |
| AT (1) | ATE56214T1 (da) |
| AU (1) | AU611426B2 (da) |
| CA (1) | CA1306993C (da) |
| DD (1) | DD281191A5 (da) |
| DE (2) | DE3710728A1 (da) |
| DK (1) | DK171850B1 (da) |
| ES (1) | ES2032051T3 (da) |
| GR (1) | GR3000953T3 (da) |
| HU (2) | HU200472B (da) |
| IE (1) | IE62481B1 (da) |
| PT (1) | PT87117B (da) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4232521A1 (de) * | 1992-09-22 | 1994-03-24 | Schering Ag | Gestagen wirksame 4,5;11,12-Estradiene, Verfahren zu ihrer Herstellung, diese Estradiene enthaltende Arzneimittel sowie deren Verwendung zur Herstellung von Arzneimitteln |
| IT1271004B (it) * | 1994-09-09 | 1997-05-26 | Ind Chimica Srl | Processo per la preparazione del gestodene |
| JPH099304A (ja) * | 1995-06-24 | 1997-01-10 | Matsushita Electric Ind Co Ltd | ビーム位置シミュレーション調整装置 |
| JP2014505721A (ja) * | 2011-02-17 | 2014-03-06 | ルピン・リミテッド | レボノルゲストレルを調製するための改良された方法 |
| HUE029252T2 (en) * | 2011-06-01 | 2017-02-28 | Estetra Sprl | Process for the preparation of intermediates of estetrol |
| SG195121A1 (en) | 2011-06-01 | 2013-12-30 | Estetra S A | Process for the production of estetrol intermediates |
| EP2383279A1 (en) | 2011-07-19 | 2011-11-02 | Pantarhei Bioscience B.V. | Process for the preparation of estetrol |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR1476573A (fr) * | 1965-09-13 | 1967-04-14 | Dérivés du gonatriène et leur procédé de préparation | |
| DK133051C (da) * | 1973-07-13 | 1976-08-16 | Schering Ag | Analogifremgangsmade til fremstilling af 1,3-oxygenerede 8alfa-ostratriener |
| DE2439082A1 (de) * | 1974-08-12 | 1976-02-26 | Schering Ag | 17 alpha-hydroxy-1,3,5(10),15-oestratetraene und verfahren zu ihrer herstellung |
| DE2456068A1 (de) * | 1974-11-23 | 1976-08-12 | Schering Ag | Verfahren zur herstellung von oestren3,17-dion-derivaten |
| US4081537A (en) * | 1975-10-10 | 1978-03-28 | Schering Aktiengesellschaft | Δ15 -Steroids and pharmaceutical compositions thereof |
| DE2546062A1 (de) * | 1975-10-10 | 1977-04-21 | Schering Ag | Delta hoch 15 -steroide |
| CN1008820B (zh) * | 1985-05-10 | 1990-07-18 | 施林工业产权保护股份公司 | 17α-乙炔基-17β-羟基-18-甲基-4，15-雌甾二烯-3-酮的制备方法 |
-
1987
- 1987-03-31 DE DE19873710728 patent/DE3710728A1/de not_active Withdrawn
-
1988
- 1988-03-25 DE DE8888730075T patent/DE3860541D1/de not_active Expired - Lifetime
- 1988-03-25 AT AT88730075T patent/ATE56214T1/de not_active IP Right Cessation
- 1988-03-25 EP EP88730075A patent/EP0285548B1/de not_active Expired - Lifetime
- 1988-03-25 ES ES198888730075T patent/ES2032051T3/es not_active Expired - Lifetime
- 1988-03-25 DK DK168288A patent/DK171850B1/da not_active IP Right Cessation
- 1988-03-29 AU AU14030/88A patent/AU611426B2/en not_active Expired
- 1988-03-29 DD DD88314162A patent/DD281191A5/de not_active IP Right Cessation
- 1988-03-29 JP JP63073503A patent/JP2752366B2/ja not_active Expired - Lifetime
- 1988-03-30 CA CA000562962A patent/CA1306993C/en not_active Expired - Lifetime
- 1988-03-30 IE IE95588A patent/IE62481B1/en not_active IP Right Cessation
- 1988-03-30 PT PT87117A patent/PT87117B/pt not_active IP Right Cessation
- 1988-03-30 HU HU881582A patent/HU200472B/hu unknown
- 1988-03-31 US US07/176,111 patent/US4923640A/en not_active Expired - Lifetime
- 1988-10-04 HU HU895125A patent/HU200471B/hu unknown
-
1990
- 1990-10-19 GR GR90400304T patent/GR3000953T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DD281191A5 (de) | 1990-08-01 |
| ES2032051T3 (es) | 1993-01-01 |
| EP0285548B1 (de) | 1990-09-05 |
| GR3000953T3 (en) | 1991-12-10 |
| DK168288A (da) | 1988-10-01 |
| IE880955L (en) | 1988-09-30 |
| JP2752366B2 (ja) | 1998-05-18 |
| HUT46925A (en) | 1988-12-28 |
| DE3860541D1 (de) | 1990-10-11 |
| EP0285548A1 (de) | 1988-10-05 |
| IE62481B1 (en) | 1995-02-08 |
| AU1403088A (en) | 1988-09-29 |
| DK168288D0 (da) | 1988-03-25 |
| PT87117B (pt) | 1992-07-31 |
| CA1306993C (en) | 1992-09-01 |
| PT87117A (pt) | 1988-04-01 |
| HU200472B (en) | 1990-06-28 |
| DE3710728A1 (de) | 1988-10-13 |
| JPS63258487A (ja) | 1988-10-25 |
| AU611426B2 (en) | 1991-06-13 |
| US4923640A (en) | 1990-05-08 |
| ATE56214T1 (de) | 1990-09-15 |
| HU200471B (en) | 1990-06-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |