CS200458B2 - Method of producing novel starting compounds for prostaglandis analogues - Google Patents
Method of producing novel starting compounds for prostaglandis analogues Download PDFInfo
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- CS200458B2 CS200458B2 CS774126A CS412677A CS200458B2 CS 200458 B2 CS200458 B2 CS 200458B2 CS 774126 A CS774126 A CS 774126A CS 412677 A CS412677 A CS 412677A CS 200458 B2 CS200458 B2 CS 200458B2
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- yloxy
- tetrahydropyran
- solution
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- hydroxy
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- 239000007858 starting material Substances 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 3
- -1 2-tetrahydropyranyl Chemical group 0.000 claims description 37
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 claims 1
- 150000003180 prostaglandins Chemical class 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- 239000000243 solution Substances 0.000 description 35
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 28
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 8
- 239000011734 sodium Substances 0.000 description 7
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 239000007789 gas Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012299 nitrogen atmosphere Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 4
- 239000003929 acidic solution Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 4
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 4
- CMSYDJVRTHCWFP-UHFFFAOYSA-N triphenylphosphane;hydrobromide Chemical compound Br.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 CMSYDJVRTHCWFP-UHFFFAOYSA-N 0.000 description 4
- QNXPDYJGFDMQSY-SIYKVTCMSA-N 7-[(1S,2S)-2-(6-methoxyhexyl)cyclopentyl]-2-(oxan-2-yloxy)heptanoic acid Chemical compound O1C(CCCC1)OC(C(=O)O)CCCCC[C@H]1CCC[C@@H]1CCCCCCOC QNXPDYJGFDMQSY-SIYKVTCMSA-N 0.000 description 3
- 150000001241 acetals Chemical group 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 229940074439 potassium sodium tartrate Drugs 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000000457 gamma-lactone group Chemical group 0.000 description 2
- QIVUCLWGARAQIO-OLIXTKCUSA-N (3s)-n-[(3s,5s,6r)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,6-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1h-pyrrolo[2,3-b]pyridine-3,6'-5,7-dihydrocyclopenta[b]pyridine]-3'-carboxamide Chemical compound C1([C@H]2[C@H](N(C(=O)[C@@H](NC(=O)C=3C=C4C[C@]5(CC4=NC=3)C3=CC=CN=C3NC5=O)C2)CC(F)(F)F)C)=C(F)C=CC(F)=C1F QIVUCLWGARAQIO-OLIXTKCUSA-N 0.000 description 1
- YVHAIVPPUIZFBA-UHFFFAOYSA-N Cyclopentylacetic acid Chemical compound OC(=O)CC1CCCC1 YVHAIVPPUIZFBA-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 150000001336 alkenes Chemical group 0.000 description 1
- 229940006138 antiglaucoma drug and miotics prostaglandin analogues Drugs 0.000 description 1
- 150000002373 hemiacetals Chemical class 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 1
- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- AVTYONGGKAJVTE-OLXYHTOASA-L potassium L-tartrate Chemical compound [K+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O AVTYONGGKAJVTE-OLXYHTOASA-L 0.000 description 1
- 239000001472 potassium tartrate Substances 0.000 description 1
- 229940111695 potassium tartrate Drugs 0.000 description 1
- 235000011005 potassium tartrates Nutrition 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- RIOQSEWOXXDEQQ-UHFFFAOYSA-O triphenylphosphanium Chemical compound C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-O 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
R znamená vodík nebo alkyl s 1 až 3 atomy uhlíku,R is hydrogen or alkyl of 1 to 3 carbon atoms,
W značí jednoduchou vazbu nebo cis-dvojnou vazbu,W denotes a single bond or a cis-double bond,
Z značí jednoduchou vazbu nebo trans-dvojnou vazbu, n představuje celé číslo od 0 do 2, m představuje celé číslo od 0 do 4 aZ is a single bond or a trans-double bond, n is an integer from 0 to 2, m is an integer from 0 to 4, and
THP znamená 2-tetrahydropyranyl.THP stands for 2-tetrahydropyranyl.
Vynálea se týká způsobu výroby výchozích látek pro analoga prostaglandinů obecného vzorce IIThe present invention relates to a process for the preparation of starting materials for the prostaglandin analogues of the general formula II
kdewhere
W, THP, Z, R, n a m mají shora uvedený význam a vyznačuje se tím, že se neché reagovat sloučenina obecného vzorce IIIW, THP, Z, R, n and m are as defined above and are characterized by reacting a compound of formula III
kdewhere
THP, Z, R, n a m mají shora uvedený význam, s ylidem vzorce (CgH5)3P = CH - CH2CH2CH2 - COOH a popřípadě se postupně redukuje takto vzniklý produkt, aby se získala sloučenina obecného vzorce II, kde n, m, R a Z mají výše uvedený význam a W značí jednoduchou vazbu.THP, Z, R, Nam are as defined above, with an ylide of formula (CGH 5) 3 P = CH - CH 2 CH 2 CH 2 - COOH and, optionally, gradually reducing the thus formed product to obtain a compound of formula II wherein n, m, R and Z are as defined above and W denotes a single bond.
Jak je ukázáno na reakčním schématu A,přeměna VIII—»IX je způsobena reakcí s (4-karbohydroxy-n-butyl)trifenylsulfoxidem při teplotě místnosti nejméně za 2 hodiny. Směs se potom okyselí například vodnou kyselinou chlorovodíkovou a potom se extrahuje ethylacetátem, odpaří a zahustí.As shown in Reaction Scheme A, the conversion of VIII → IX is caused by reaction with (4-carbohydroxy-n-butyl) triphenylsulfoxide at room temperature for at least 2 hours. The mixture is then acidified with, for example, aqueous hydrochloric acid and then extracted with ethyl acetate, evaporated and concentrated.
V souvislosti s reakčním schématem B přeměna XIII—»XIV je analogická jako VIII—»IX v reakčním schématu A.In connection with Reaction Scheme B, the conversion of XIII → XIV is analogous to VIII → IX in Reaction Scheme A.
Reakční schéma A ,Reaction Scheme A,
IXIX
Reakční schéma BReaction Scheme B
Příklad 1 (Výchozí látka)Example 1 (Starting substance)
Roztok 310 mg (0,71 mmolu) y~laktonu 2-f5o(-hydroxy-3«(-(tetrahydropyran-2-yloxy)-2/J-(3ít-/tetrahydropyran-2-yloxy/-7-oxa-trans-1 -okten-1 -yl)cyklopent-1«t-yi] octové kyseliny v 5 ml suchého toluenu se ochladí na -78 °C v atmosféře suchého dusíku. K tomuto chladnému roztoku.se přikape 1,5 ml 20% diisobutylaluminumhydridu v n-hexanu takovou rychlostí, že vnitřní teplota nikdy nepřestoupí asi -65 °C (15 minut). Po dalších 45 minutách míchání při -78 °C se přidává bezvodý methanol, dokud není vývoj plynu ukončen a reakční smšs se nechá ohřát na teplotu místnosti. Reakční směs se spojí se 100 ml etheru, promyje 50% roztokem vínanu sodnodraselného (4x20 ml), vysuší (MgSQ^ a odpaří. Získá se 290 mg (93 %) y-hemiacetalu 2-[5<<-hydroxy-3(<-(tetrahydropyran-2-yloxy)-2(J-(3<4-/tetrahydropyran-2-yloxy/-7~oxa-trans-1 -okten-1 -yl)cyklopent-1 -yl] acetaldehydu.A solution of 310 mg (0.71 mmol) of γ-lactone 2-fo (-hydroxy-3 '- (- (tetrahydropyran-2-yloxy) -2 H- (3 H-) tetrahydropyran-2-yloxy) -7-oxa- trans-1-octen-1-yl) cyclopent-1'-yl] acetic acid in 5 mL dry toluene was cooled to -78 ° C under an atmosphere of dry nitrogen, to which 1.5 mL of 20% was added dropwise. of diisobutylaluminum hydride in n-hexane at such a rate that the internal temperature never exceeds about -65 ° C (15 minutes) After stirring for an additional 45 minutes at -78 ° C, anhydrous methanol is added until gas evolution is complete and the reaction mixture is allowed to warm. The reaction mixture was combined with 100 mL ether, washed with 50% sodium potassium tartrate solution (4 x 20 mL), dried (MgSO 4) and evaporated to give 290 mg (93%) of 2- [5'-hydroxy-] - hemiacetal. 3 (<- (tetrahydropyran-2-yloxy) -2 (N - (3- (tetrahydropyran-2-yloxy) -7-oxa-trans-1-octen-1-yl) cyclopent-1-yl) acetaldehyde .
Příklad 2Example 2
K roztoku 870 mg (2,0 mmolů) (4-karbohydroxy-n-butyl)trifenylfosfoniumbromidu v atmosféře suchého dusíku, v 5,0 ml suchého dimetylsulfoxidu se přidají 2,0 ml (4,4 mmolů) 2,2 M roztoku methylsulfinylmethidu sodného v dimethylsulfoxidu. K tomuto červenému roztoku ylidu se přikape 290 mg (0,66 mmolu)jMiemiacetátu 2-[5<í-hydroxy-3<X.“(tetrahydropyran-2-yloxy)“ -2/3-( 3á.-/tetr ahydropyran-2-yloxy/-7-oxa-trans-1 -okten-1 ~yl )-cyklopent.~ Icí-ylJ acetaldehydu ve 3,0 ml suchého dimethylsulfoxidu během 20 minut. Po dalších 2 hodinách míchání při teplotě místnosti se reakční směs vylije do ledové vody. Bazický vodný roztok se dvakrát promyje ethylacetátem (20 ml) a okyselí přibližně na pH 3 10% vodným roztokem kyseliny chlorovodíkové. Kyselý roztok se extrahuje ethylacetátem (3x20 ml) a spojené organické extrakty se jednou promyjí vodou (10 ml), vysuší (MgSO^) a odpaří na pevný zbytek o hmotnosti 784 mg. Tento pevný zbytek se trituruje s ethylacetátem a filtruje. Filtrát se čistí sloupcovou chromatografii na silikagelu za použití ethylacetátu jako eluentu. Po odstranění nečistot s velkým Rf se získá 225 mg (66 %) 9ýí-hydroxy-11d.,15«6-bis(tetrahydropyran-2-yloxy)-19-oxa-ciS5-trans-13-prostadienové kyseliny.To a solution of 870 mg (2.0 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide under a dry nitrogen atmosphere in 5.0 mL of dry dimethylsulfoxide was added 2.0 mL (4.4 mmol) of a 2.2 M methylsulfinylmethide solution. sodium in dimethylsulfoxide. To this red ylide solution was added dropwise 290 mg (0.66 mmol) of 2- [5 ' -hydroxy-3 " (tetrahydropyran-2-yloxy) < -2 > 2-yloxy / -7-oxa-trans-1-octen-1-yl) -cyclopent-3-yl-acetaldehyde in 3.0 mL of dry dimethylsulfoxide over 20 minutes. After stirring for another 2 hours at room temperature, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (20 mL) and acidified to approximately pH 3 with a 10% aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate (3 x 20 mL) and the combined organic extracts were washed once with water (10 mL), dried (MgSO 4) and evaporated to a solid residue of 784 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by silica gel column chromatography using ethyl acetate as eluent. Removal of the impurities with large Rf gave 225 mg (66%) of 9H-hydroxy-11d, 15,6-bis (tetrahydropyran-2-yloxy) -19-oxa-15S-trans-13-prostadienoic acid.
NMR spektrum (CDCl^) vykazuje multiplet (variabilní) při 5,84 až 6,38§”(2H) pro -OH protony, multiplet při 5,27 až 5,68<J(4H) pro olefinické protony, multiplet při 4,52 až 4,84 <?(2H) pro acetalové protony, singlet při 3,34 Sí.3H) pro methyletherové protony a multiplety při 3,25 až 4,35 Š (9H) a 1 ,20 až 2,72J(28H) pro zbývající protony.The NMR spectrum (CDCl3) shows a multiplet (variable) at 5.84 to 6.38 (2H) for -OH protons, a multiplet at 5.27 to 5.68 (J) for olefinic protons, a multiplet at 4 52 to 4.84? (2H) for acetal protons, singlet at 3.34 Si (3H) for methyl ether protons and multiplets at 3.25 to 4.35S (9H) and 1.2, 20 to 2.72J ( 28H) for the remaining protons.
Příklad 3 (Výchozí látka)Example 3 (Starting substance)
Roztok 575 mg (1,28 mmolu) surového y-laktonu 2-[54-hydroxy-34-tetrahydropyran-2-yloxy)-2p-(34-/tetrahydropyran-2~yloxy/-7-oxa-trans-1-nonen-1-yl)cyklQpent~1<<-yl]octové kyseliny v 5,75 ml suchého toluenu se ochladí na -78 °C v atmosféře suchého dusíku. K tomuto ochlazenému roztoku se přikape 1,8 ml 20% diisobutylaluminumhydridu v n-hexanu takovou rychlostí, že vnitřní teplota nikdy nepřestoupí -65 °C (15 minut). Po další 1 hodině míchání při -78 °C se přidává bezvodý methanol, dokud se nepřestane vyvíjet plyn a reakční směs se nechá ohřát na teplotu místnosti. Reakční směs se spojí s 50 ml etheru, promyje 50% roztokem vinanu sodno-draselného (4x10 ml), vysuší (MgSO^) a odpaří. Získá se 458 mg (80 %) y-hemiaoetálu 2-[54-hydroxy-3í(-(tetrahydropyran-2~yloxy)-2p-(34-/tetrahydropyran-2-yloxy/-7-oxa-trans-1-nonen-1-yl)cyklopent-1-yl} ao e taldehydu.A solution of 575 mg (1.28 mmol) of crude 2- [54-hydroxy-34-tetrahydropyran-2-yloxy) -2β- (34- (tetrahydropyran-2-yloxy) -7-oxa-trans-1-) Nonen-1-yl) cyclopent-1-yl] acetic acid in 5.75 mL of dry toluene was cooled to -78 ° C under a dry nitrogen atmosphere. To this cooled solution was added dropwise 1.8 mL of 20% diisobutylaluminum hydride in n-hexane at such a rate that the internal temperature never exceeded -65 ° C (15 minutes). After stirring for an additional 1 hour at -78 ° C, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 50 mL of ether, washed with 50% potassium sodium tartrate solution (4 x 10 mL), dried (MgSO 4) and evaporated. 458 mg (80%) of 2- [54-hydroxy-3 - (- (tetrahydropyran-2-yloxy) -2β- (34- (tetrahydropyran-2-yloxy) -7-oxa-trans-1-) -) - was obtained. nonen-1-yl) cyclopent-1-yl} o taldehyde.
Přiklad4Example4
K roztoku 1 330 mg (3,0 mmolů) (4-karbohydroxy-n-butyl)trifenylfosfoniumboramidu v atmosféře suchého dusíku v 6 ml suchého dimethylsulfoxidu se přidá 3,4 ml (6,8 mmolů) 2,0 11 roztoku methylsulfinylmethidu sodného v dimethylsulfoxidu. K tomuto červenému roztoku ylidu se přikape roztok 454 mg (1,0 mmolu) surového y--hemiacetalu 2- [5«í-hydroxy-34-( tetrahydro pyran-2-yloxy )-2p-( 34-/tetrahydropyran-2-yloxy/-7-oxa-trans-1-nonen-1 -yl) cyklopent-W-yl] acetaldehydu ve 3,0 ml suchého sulfoxidu během doby 20 minut. Po 2hodinovém mícháni při teplotě místnosti se reakční směs vylije do ledové vody. Bazický vodný roztok se promyje dvakrát ethylacetátem (30 ml) a okyselí na asi pH 3 pomocí 10% vodného roztoku kyseliny chlorovodíkové. Kyselý roztok se extrahuje ethylacetátem (4x25 ml) a spojené organické extrakty se jednou promyjí vodou (25 ml), vysuší (MgSO^) a odpaří na pevný zbytek o hmotnos ti 900 mg. Tento pevný zbytek se trituruje s ethylacetátem a filtruje. Filtrát se čistí sloupcovou chromatografii na silikagelu za použití ethylacetátu jako eluentu. Po odstranění nečistot o velkém Rf se shromážgdí 290 mg (54 %) 9/-hydroxy-114,15«(-bis(tetrahydropyran-2-yloxy)-19-oxa-cis-5-trans-13-<J“homo-prostadiendvé kyseliny.To a solution of 1330 mg (3.0 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium boramide under a dry nitrogen atmosphere in 6 mL of dry dimethylsulfoxide was added 3.4 mL (6.8 mmol) of 2.0 L sodium methylsulfinylmethide solution in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 454 mg (1.0 mmol) of crude γ-hemiacetal 2- [5'-hydroxy-34- (tetrahydro-pyran-2-yloxy) -2β- (34- / tetrahydropyran-2)]. -yloxy / -7-oxa-trans-1-nonen-1-yl) cyclopent-N-yl] acetaldehyde in 3.0 mL dry sulfoxide over 20 minutes. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water. The basic aqueous solution was washed twice with ethyl acetate (30 mL) and acidified to about pH 3 with 10% aqueous hydrochloric acid. The acidic solution was extracted with ethyl acetate (4 x 25 mL) and the combined organic extracts were washed once with water (25 mL), dried (MgSO 4) and evaporated to a solid residue of 900 mg. This solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by silica gel column chromatography using ethyl acetate as eluent. After removal of large Rf impurities, 290 mg (54%) of 9 H -hydroxy-114,15 '(- (bis (tetrahydropyran-2-yloxy) -19-oxa-cis-5-trans-13-) homo) was collected. -prostadiene acids.
NMR spektrum (CDCl^) vykazuje multiplet (variabilní) při 6,2 až 6,6 J(2H) pro -OH protony, multiplet při 5,3 až 5,7δ(4Η) pro olefinické protony, multiplet při 4,6 až 4,9 $ (2H) pro acetalové protony, kvartet při 3,5^ (2H) pro ethyletherické protony a multiplety při 3,3 až 4,4 JOH) a 1 ,0 až 2,6 δ(31Η) pro zbývající protony.NMR spectrum (CDCl3) shows a multiplet (variable) at 6.2 to 6.6 J (2H) for -OH protons, a multiplet at 5.3 to 5.7δ (4Η) for olefinic protons, a multiplet at 4.6 to 6.6 $ 4.9 (2H) for acetal protons, quartet at 3.5 ^ (2H) for ethyl ether protons and multiplets at 3.3 to 4.4 JOH) and 1.0 to 2.6 δ (31Η) for remaining protons .
Příklad .5 (Výchozí látka)Example .5 (Starting substance)
Roztok 880 mg (2,01 mmolů) surového y-laktonu 2-£54-hydroxy-3X-(tetrahydropyran-2-yloxy)-2P-(3řt-/tetrahydropyran-2-yloxy/-6-oxa-trans-1-okten-1-yl) cyklopent-1nt-yl]oetové kyseliny v 8,8 ml suchého toluenu se ochladí na -78 °C v atmosféře suchého dusíku. K tomuto ochlazenému roztoku se přikapou 3 ml 20% diisobutylaluminumhydridu v n-hexanu takovou rychlostí, že vnitřní teploty nikdy nevystoupí asi na -65 °C (15 minut.). Po dalších 20 minutách míchání při -78 se přidává bezvodý methanol, dokud neustane vývoj plynu a reakční směs se nechá ohřát na teplotu místnosti. Reakční směs se spojí se 100 ml etheru, promyje 50% roztokem vinanu sodno-draselného (4x10 ml), suší (MgSO^) a odpařením se získá 654 mg y-hemiaoetalu 2-[5/-hydroxy-34-(tetrahydropyr'an-2-yloxy)-2p-(34-/tetrahydropyran-2-yloxy/-6-oxa-trans-1-okten-1-yl)cyklopent-1-yl] acetaldehydu.A solution of 880 mg (2.01 mmol) of crude γ-lactone 2- £ 54 -hydroxy-3X- (tetrahydropyran-2-yloxy) -2β- (3 H- / tetrahydropyran-2-yloxy) -6-oxa-trans-1 -octen-1-yl) cyclopent-1-yl-acetic acid in 8.8 mL of dry toluene was cooled to -78 ° C under a dry nitrogen atmosphere. To this cooled solution was added dropwise 3 ml of 20% diisobutylaluminum hydride in n-hexane at such a rate that the internal temperatures never rose to about -65 ° C (15 minutes). After an additional 20 minutes of stirring at -78, anhydrous methanol was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 mL of ether, washed with 50% potassium sodium tartrate solution (4 x 10 mL), dried (MgSO 4) and evaporated to give 654 mg of 2- [5 H -hydroxy-34- (tetrahydropyrane) γ-hemioetal. -2-yloxy) -2β- (3 H- tetrahydropyran-2-yloxy) -6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetaldehyde.
Příklad 6Example 6
K roztoku 2 600 mg (6,0 mmolů) (4-karbohydroxy-n-butyl)trifenylfosfoniumbromidu v atmosféře suchého dusíku v 6 ml suchého dimethylsulfoxidu se přidá 6,0 ml (12,0 mmolů) 2,0 M roztoku methylsulfinylmethidu sodného v dimethylsulfoxidu. K tomuto červenému roztoku ylidu se přikape roztok 660 mg (1,5 mmolu) surového ^-hemiacetalu 2-[54-hydroxy-3nt-(tetrahydropyran-2-yloxy)-2p-(34-/tetrahydropyran-2-yloxy/-6-oxa-trans-1-okten-1 -yl) cyklopent-lei -yl] acet aldehydu v 5,0 ml suchého dimethylsulfoxidu během 20 minut. Po dalších 2 hodinách míchání při teplotě místnosti se reakční směs vylije na led a vodu. Bazický vodný roztok se promyje dvakrát ethylacetátem (100 ml) a okyselí asi na pH 3 pomocí 1096 vodného roztoku kyseliny chlorovodíkové. Kyselý roztok se extrahuje ethylacetátem (3x100 ml) a spojené organické extrakty se jednou promyjí vodou (25 ml),.suší (MgSO^) a odpaří na pevný zbytek. Pevný zbytek se trituruje s ethylacetátem a filtruje. Filtrát se čistí sloupcovou chromatografií na silikagelu za použití ethylacetátu jako eluentu. Po odstranění nečistot s vysokým Rf se shromáždí 550 mg (70%) 9X-hydroxy-l Ig, 15<4-bis( tetrahydropyran-2-yloxy)-18-oxa-cis-5-trans-13-prostadienové kyseliny.To a solution of 2600 mg (6.0 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide under a dry nitrogen atmosphere in 6 mL of dry dimethyl sulfoxide was added 6.0 mL (12.0 mmol) of a 2.0 M solution of sodium methylsulfinylmethide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 660 mg (1.5 mmol) of crude 2- [54-hydroxy-3nt- (tetrahydropyran-2-yloxy) -2β- (34- (tetrahydropyran-2-yloxy)] -. 6-oxa-trans-1-octen-1-yl) cyclopent-1-yl] acetaldehyde in 5.0 mL dry dimethylsulfoxide over 20 minutes. After stirring at room temperature for a further 2 hours, the reaction mixture was poured onto ice and water. The basic aqueous solution was washed twice with ethyl acetate (100 mL) and acidified to about pH 3 with 1096 aqueous hydrochloric acid solution. The acidic solution was extracted with ethyl acetate (3 x 100 mL) and the combined organic extracts were washed once with water (25 mL), dried (MgSO 4) and evaporated to a solid residue. The solid residue was triturated with ethyl acetate and filtered. The filtrate was purified by silica gel column chromatography using ethyl acetate as eluent. After removal of high Rf impurities, 550 mg (70%) of 9X-hydroxy-1 Ig, 15β-bis (tetrahydropyran-2-yloxy) -18-oxa-cis-5-trans-13-prostadienoic acid was collected.
NMR spektrum (CDCl^) ukazuje multiplet (variabilní) při 6,2 až 6,6 5(2H) pro -OH protony, multiplet při 5,3 až 5,75·(4Η) olefinových protonů, multiplet při 4,6 až 4,9ž>(2H) pro acetalové protony, kvartet při 3,5^ (2H) ethyletherických protonů a multiplety při 3,3 až 4,4Ů(9H) a 1,0 až 2,6 £(31H) pro zbývající protony.NMR spectrum (CDCl3) shows multiplet (variable) at 6.2-6.6 δ (2H) for -OH protons, multiplet at 5.3-5.75 · (4Η) olefin protons, multiplet at 4.6-6 4.9> (2H) for acetal protons, quartet at 3.5 ((2H) ethyl ether protons and multiplets at 3.3 to 4.4 ((9H) and 1.0 to 2.6 ((31H) for the remaining protons .
Příklad 7 (Výchozí látka) y-hemiacetal 2-[5o(-hydroxy-3<í-(tetrahydropyran-2-yl-oxy )-20-( 3|>-/tetrahydropyran-2-yloxy/8-oxa-trans-1-nonen-1-yl)cyklopent-1g-yl]acetylaldehydu (8a)EXAMPLE 7 (Starting Material) γ-Hemiacetal 2- [5o (-hydroxy-3R- (tetrahydropyran-2-yloxy) -20- (3R) -tetrahydro-pyran-2-yloxy) -8-oxa-trans 1-Nonen-1-yl) cyclopent-1g-yl] acetylaldehyde (8a)
Roztok 900 mg (2,0 mmolů) j*-laktonu 2-[54~hydroxy-3«(-(tetrahydropyran-2-yloxy)-2|>-(3p-/tetrahydropyran-2-yloxy/-8-oxa-trans- 1-nonen-1-yl)-eyklopent-1«(-yl]octové kyseliny (7a) v 15 ml suchého toluenu se ochladí na -78 °C v atmosféře suchého dusíku. K tomuto studenému roztoku se přikape 2,7 ml 20% diisobutylaluminumhydridu v n-hexanu takovou rychlostí, že vnitřní teplota nikdy nevystoupí nad -65 °C (15 minut). Po dalších 45 minutách míchání při -78 °C se přidává bezvodá kyselina octová,dokud neustane vývoj plynu a reakční směs se nechá ohřát na teplotu místnosti. Reakční směs se spojí se 60 ml toluenu, promyje 50% roztokem vinanu sodno-draselného (1x25 ml), vysuší (Na2S0^) a odpaří. Po chromatografování se získá 564 mg y-hemiacetalu 2[5<í-hydroxy~3<i(-(tetrahydropyran-2-yloxy)-2|5-(3pr/'tetrahydropyran-2-yloxy/-8-oxa-trans-1-nonen-1-yl)cyklopent-1-yl] acetaldehydu (8a).A solution of 900 mg (2.0 mmol) of 2- [54-hydroxy-3 '- (- (tetrahydropyran-2-yloxy) -2H- (3β- / tetrahydropyran-2-yloxy) -8-oxa) -α-lactone. -trans-1-nonen-1-yl) -clopent-1 '(- yl) acetic acid (7a) in 15 mL dry toluene was cooled to -78 ° C under an atmosphere of dry nitrogen. 7 ml of 20% diisobutylaluminum hydride in n-hexane at a rate such that the internal temperature never rises above -65 ° C (15 minutes) .After stirring for 45 minutes at -78 ° C, anhydrous acetic acid is added until gas evolution and reaction mixture cease. The reaction mixture was combined with 60 mL of toluene, washed with 50% potassium tartrate solution (1 x 25 mL), dried (Na 2 SO 4) and evaporated to give 564 mg of γ-hemiacetal 2 after chromatography. 5? -Hydroxy-3? - (- (tetrahydropyran-2-yloxy) -2,5- (3β-tetrahydropyran-2-yloxy) -8-oxa-trans-1-nonen-1-yl) cyclopent- 1-yl] acetaldehyde (8a).
Příklad 8 (Výchozí látka) y-hemiacetal 2-[5«C-hydroxy-3«(-(tetrahydropyran-2~yl-oxy)-2(9-(3(5-/tetrahydropyran-2-yloxy/-8-oxa-trans-1-nonen-1-yl)cyklopent-1o(-yl]acetaldehydu (8)Example 8 (Starting material) γ-hemiacetal 2- [5'-C-hydroxy-3'- (- (tetrahydropyran-2-yloxy) -2- (9- (3 (5- (tetrahydropyran-2-yloxy)) - -8)) -oxa-trans-1-nonen-1-yl) cyclopent-10o-yl acetaldehyde (8)
Roztok 3,5 g (7,75 mmolů) f-laktonu 2-[5g~hydroxy-3<t~(tetrahydropyran-2-yloxy)-2íi~(3c(-/tetrahydropyran-2-yloxy/-8-oxa-trans-1-nonen-I-yl)cyklopent-1«(-yl] octové kyseliny (7) v 25 ml suchého toluenu se ochladí na -78 °C v atmosféře suchého dusíku. K ochlazenému roztoku se přikape 10,5 ml 20% diisobutylaluminumhydridu v n-hexanu takovou rychlostí,A solution of 3.5 g (7.75 mmol) of 2- [5 g-hydroxy-3 - [(tetrahydropyran-2-yloxy) -2 H- (3 C (-) - tetrahydropyran-2-yloxy) -8-oxa] -p-lactone -trans-1-nonen-1-yl) cyclopent-1 '(- yl) acetic acid (7) in 25 mL dry toluene was cooled to -78 ° C under an atmosphere of dry nitrogen, and 10.5 mL was added dropwise to the cooled solution. 20% diisobutylaluminum hydride in n-hexane at such a rate,
2e vnitřní teplota nikdy nevystoupí nad -65 °C (15 minut). Po dalších 45 minutách míchání při -78 °C se přidává bezvodá kyselina octová v toluenu,dokud neustane vývoj plynu a reakční směs se nechá ohřát na teplotu místnosti. Reakční směs se spojí se 100 ml etheru, promyje 50% roztokem vinanu sodno-draselného (1x50 ml), suší (NaSO^) a odpaří. Po chromatografování se získá 2,6 g p-hemiacetalu 2-(5á -hydroxy-3<(-( tetrahydropyr an-2-yloxy)-2(3-( 3«4-/tetrahydropyran-2-yloxy/-8-oxa-trans-1-nonen-1-yl)cyklopent-1-yl]acetaldehydu (8).2e the internal temperature never rises above -65 ° C (15 minutes). After an additional 45 minutes of stirring at -78 ° C, anhydrous acetic acid in toluene was added until gas evolution ceased and the reaction mixture was allowed to warm to room temperature. The reaction mixture was combined with 100 mL of ether, washed with 50% potassium sodium tartrate solution (1 x 50 mL), dried (Na 2 SO 4) and evaporated. After chromatography, 2.6 g of 2- (5α-hydroxy-3 - (- (tetrahydropyran-2-yloxy) -2- (3- (3,4-tetrahydropyran-2-yloxy) -8-) tetrahydropyran-2-yloxy) p-hemiacetal is obtained. oxa-trans-1-nonen-1-yl) cyclopent-1-yl] acetaldehyde (8).
Příklad 9Example 9
9«<-hydroxy-1 \tís 15/-bis(tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans-13-<^-homo-prostadienová kyselina (9)9 «<- hydroxy-1 \ three 15 / bis (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13 - <^ - homo-prostadienoic acid (9)
K roztoku 7,65 g (17,25 mmolů) (4-karbohydroxy-n-butyl)trifenylfosfoniumbromidu v atmosféře suchého dusíku ve 20 ml suchého dimethylsulfoxidu se přidá 15,3 ml (32,2 mmolů) 2,1 M roztoku methylsulfinylmethidu sodného v dimethylsulfoxidu. K tomuto červenému roztoku ylidu \To a solution of 7.65 g (17.25 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide under an atmosphere of dry nitrogen in 20 mL of dry dimethyl sulfoxide was added 15.3 mL (32.2 mmol) of a 2.1 M solution of sodium methylsulfinylmethide. in dimethylsulfoxide. To this red ylide solution \
se přikape roztok 2,6 g (5,76 mmolů) y-hemiacetalu 2-[5X-hydroxy-3«(-(tetrahydropyran-2-yloxy)-2|)-( 3Á-/tetrahydropyran-2-yloxy/-8-oxa-trans-1 -nbnen-1-yl)cyklopent-lR-yl] acetaldehydu (8) v 15,0 ml suchého dimethylsulfoxidu během 20 minut. Fo dalěích 2 hodinách mícháni při teplotě místnosti se reakční směs vylije na ledovou vodu (60 ml), 250 ml ethylacetátu a 35 ml IN roztoku kyseliny solné. Kyselý roztok se dále extrahuje ethylacetátem (2x120 ml) a spojené organické extrakty se jednou promyjí vodou (60 ml), suší (MgSO^) a odpaří na zbytek. Zbytek se čistí sloupcovou chromatografií na silikagelu za použití ethylacetátu jako eluentu. Po odstranění nečistot s vysokým Rf se dostane 3,1 g,9eí-hydroxy-11«í,* 15á-bis(tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans-13-«-homo-prostadienové kyseliny.a solution of 2.6 g (5.76 mmol) of 2- [5X-hydroxy-3 '- (- (tetrahydropyran-2-yloxy) -2') - (3α- (tetrahydropyran-2-yloxy) -) - 8-oxa-trans-1-benzen-1-yl) cyclopent-1R-yl] acetaldehyde (8) in 15.0 mL of dry dimethyl sulfoxide over 20 minutes. After stirring at room temperature for a further 2 hours, the reaction mixture was poured into ice water (60 ml), 250 ml of ethyl acetate and 35 ml of 1N hydrochloric acid. The acidic solution was further extracted with ethyl acetate (2 x 120 mL) and the combined organic extracts were washed once with water (60 mL), dried (MgSO 4) and evaporated to a residue. The residue was purified by silica gel column chromatography using ethyl acetate as eluent. After removal of the high Rf impurities, 3.1 g of 9? -Hydroxy-11?, 15? -Bis (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13 -? - homo-prostadiene are obtained acid.
PřikladloHe did
94-hydroxy-11e(,15p-bis(tetrahydropyran-2-yloxy)-20-oxa-cis-5-trans-13-«-homo-prostadienová kyselina (9a)94-hydroxy-11e (, 15β-bis (tetrahydropyran-2-yloxy) -20-oxa-cis-5-trans-13-N-homo-prostadienoic acid (9a)
K roztoku 2 120 mg (5,0 mmolů) (4-karbohydroxy-n-butyl)trifenylfosfoniumbromidu v atmosféře suchého dusíku v 8,0 ml suchého dimethylsulfoxidu se přidá 5,02 ml (9,3 mmolů)To a solution of 2120 mg (5.0 mmol) of (4-carbohydroxy-n-butyl) triphenylphosphonium bromide under an atmosphere of dry nitrogen in 8.0 mL of dry dimethyl sulfoxide was added 5.02 mL (9.3 mmol).
1,85 M roztoku methylsulfinylmethidu sodného v dimethylsulfoxidu. K tomuto červenému roztoku ylidu se přikape roztok 564 mg (1,22 mmolu) j—hemiacetalu 2-[5X-hydroxy-3<i(-(tetrahydropyran-2-yloxy)-2/}-(3p-/tetrahydropyran-2-yloxy/~8-oxa-trans-1 -nonen-1-yl)cyklopent-1^-yl] acetaldehydu (8a) v 5,0 ml suchého dimethylsulfoxidu během 20 minut. Po dalěích 2 hodinách míchání při teplotě místnosti se reakční směs vylije na ledovou vodu. Bazický vodný roztok se extrahuje ethylacetátem (2x100 ml) a spojené organické extrakty se jednou promyjí vodou (40 ml), vysuší (MgSO^) a odpaří na zbytek. Tento zbytek se čistí sloupcovou chromatografií na silikagelu za použití chloroformu a ethylacetátu, jako eluentů. Po odstranění nečistot s vysokým Rf se získé 642 mg 9é-hydroxy-11«C,15£-bis(tetrahydropyran-2-yloxy)-20-oxacis-5-trans-13-w-homo-prostadienové kyseliny.A 1.85 M solution of sodium methylsulfinyl methide in dimethylsulfoxide. To this red ylide solution was added dropwise a solution of 564 mg (1.22 mmol) of 2- [5X-hydroxy-3 - [(tetrahydropyran-2-yloxy) -2 H] - (3β-) tetrahydropyran-2] hemiacetal. -yloxy- (8-oxa-trans-1-nonen-1-yl) cyclopent-1H-yl] acetaldehyde (8a) in 5.0 mL dry dimethylsulfoxide over 20 minutes After stirring at room temperature for a further 2 hours The basic aqueous solution was extracted with ethyl acetate (2 x 100 mL) and the combined organic extracts were washed once with water (40 mL), dried (MgSO 4) and evaporated to a residue which was purified by silica gel column chromatography using chloroform. and ethyl acetate as eluents After removal of high Rf impurities, 642 mg of 9? -hydroxy-11? C, 15? -bis (tetrahydropyran-2-yloxy) -20-oxacis-5-trans-13-w-homo- is obtained. prostadienic acids.
Přikladli ’They attached '
9tf-hydroxy-11í,15«(-bls(tetrahydropyran-2-yloxy)-19-oxa-prostanová kyselina (2)9H-hydroxy-11,15 '(- bls (tetrahydropyran-2-yloxy) -19-oxa-prostanoic acid (2)
Heterogenní roztok 9et-hydroxy-11 eí, 15í-bis(tetrahydropyran-2-yloxy)-cis-5-trans-13-19-oxe-prostadienové kyseliny a 5 % paládia na uhlí v methanolu se hydrogenuje při 0 °C 2 hodiny za tlaku 0,1 MPa. Reakční směs se filtruje a odpaří, čímž se dostane požadovaný produkt.A heterogeneous solution of 9? -Hydroxy-11?, 15? -Bis (tetrahydropyran-2-yloxy) -cis-5-trans-13-19-oxe-prostadienoic acid and 5% palladium on carbon in methanol was hydrogenated at 0 ° C for 2 hours at a pressure of 0.1 MPa. The reaction mixture was filtered and evaporated to give the desired product.
Přiklad 12Example 12
9«ť-hydroxy-11 «ί, 15«(-bis( tetrahydropyran-2-yloxy )-13-trans-19-oxaprostenová kyselina9'-hydroxy-11'''15'-bis (tetrahydropyran-2-yloxy) -13-trans-19-oxaprostenoic acid
Homogenní roztok 9«(-hydroxy-11ot,15«(-bis(tetrahydropyran-2-yIoxy)-13-trans-19-oxaprostadienové kyseliny a 5 % paládia na uhlí v methanolu se hydrogenuje při -22 °C 4 hodiny za tlaku 0,1 MPa. Reakční směs se filtruje a chromatografuje, čímž se získá požadovaný produkt.A homogeneous solution of 9? (- hydroxy-11?, 15? (- bis (tetrahydropyran-2-yloxy) -13-trans-19-oxaprostadienoic acid) and 5% palladium on carbon in methanol is hydrogenated at -22 ° C for 4 hours under pressure The reaction mixture was filtered and chromatographed to give the desired product.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CS774126A CS200458B2 (en) | 1972-06-02 | 1977-06-22 | Method of producing novel starting compounds for prostaglandis analogues |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US25921572A | 1972-06-02 | 1972-06-02 | |
| CS734017A CS200457B2 (en) | 1972-06-02 | 1973-06-04 | Method of producing novel analogues of prostaglandis |
| CS774126A CS200458B2 (en) | 1972-06-02 | 1977-06-22 | Method of producing novel starting compounds for prostaglandis analogues |
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| Publication Number | Publication Date |
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| CS200458B2 true CS200458B2 (en) | 1980-09-15 |
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| CS774126A CS200458B2 (en) | 1972-06-02 | 1977-06-22 | Method of producing novel starting compounds for prostaglandis analogues |
| CS774127A CS200459B2 (en) | 1972-06-02 | 1977-06-22 | Method of producing novel starting compounds for prostaglandins analogues |
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| CS774127A CS200459B2 (en) | 1972-06-02 | 1977-06-22 | Method of producing novel starting compounds for prostaglandins analogues |
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| CS (2) | CS200458B2 (en) |
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